Pocket Nephrology

Edited by Wooin AHN JAI RADHAKRISHNAN COLUMBIA UNIVERSITY IRVING MEDICAL CENTER l8LWolters Kluwer Philadelphia Baltimore New York London Buenos Aires Hong Kong Sydney Tokyo Editor: Robin Naiar S.Wimer Coordinator: Cody l?Adams Senior Production Project Manager:Alicia jackson Team Lead, Design: Steve Druding Senior Manufacturing Coordinator: Beth Welsh Prepress Vendor: Apmra. Inc. Acquisitions Devel opment Edi tor : Ar i el Editorial C o p yrig h t ©2020 Wo lt ers K lu w er. All rights reserved.This book Is protected by copyright. No par! of this book may be reproduced or transmitted in any form or by any means. including as photocopies or scanhedin or other electronic copies. or utilized by any information storage and retrieval system without written permission from the copyright owner. except for brief quotations embodied in critical articles and reviews. 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This work is no substitute for individual patient assessment based upon healthcare professionals examination of each patient and consideration of.among other things. age. weight, gender current or prior medical conditions. medication history. laboratory data and other factors unique to the patient.The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals. and not the publisher: are solely responsible for the use of this work including all medial iudg ments and for any resulting diagnosis and treatments. Given continuous. rapid advances in medical science and health information. inde pendent professional verification of medical diagnoses. indications. appropriate pharma ceutical selections and dosages. and treatment options should be made and healthcare professionals should consult a variety of sources.When prescribing medication. health care professionals are advised to consult the product information sheet (the manufac turers package insert) accompanying each drug to verify.among other things, conditions of use.warnings and side effects and identify any changes in dosage schedule or contra indications. particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range.To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property.as a matter of products liability. negligence law or otherwise. or from any refer ence to or use by any person of this work shop.lww.com CONTRIBUTING AUTHORS Wooin Ahn, MD, PhD Assistant Professor of Medicine. Columbia University Vagelos College of Physicians and Surgeons Gerald B.Appel, MD Professor of Medicine. Columbia University Vagelos College of Physicians and Surgeons Director, Glomerular Kidney Center New YorkPresbyterian Hospital/Columbia University Irving Medical Center Rachel Arakawa, MD Clinical Fellow. New YorkPresbyterian Hospital/Columbia University Irving Medical Center Rupali S.Avasare, MD Assistant Professor of Medicine. Oregon Health & Science University Yorg Azzi, M D Assistant Professor of Medicine, Department of Medicine.Alberc Einstein Medical Schcoi Vasanthi Balaraman, MD Assistant Professor. Department of Surgery. University of Tennessee Health Science Center Transplant Nephrologist/Physician. Department of Surgery. Methodist University Hospital Andrew Beer ken, MD, PhD Postdoctoral Clinical Fellow. Columbia University Vagelos College of Physicians and Surgeons David Bennett, MD Attending Nephrologist. Department of Medicine. Bridgeport Hospital Andrew S. Bomback, MD, MPH Associate Professor of Medicine. Columbia University Vagelos College of Physicians andSurgeons Pietro Canetta, MD, MSc Assistant Professor of Medicine. Columbia University Vagelos College of Physicians andSurgeons jae Hyung Chang, MD Assistant Professor of Medicine. Columbia University Vagelos College of Physicians andSurgeons Efren A. Chavez Morales, MD Clinical Fellow. New YorkPresbyterian Hospital/Columbia University Irving Medical Center JenTse Cheng, MD Assistant Professor of Clinical Medicine (retired), Columbia University Vagelos College of Physicians and Surgeons Chief (retired). Division of Nephrology and Hypertension. Harlem Hospital Center Russell J. Crew, MD Assistant Professor of Medicine. Columbia University Vagelos College of Physicians andSurgeons Yelena Drexler MD Assistant Professor University of Miami Geoffrey K. Dube, MD Assistant Professor of Medicine. Columbia UniversityVagelos College of Physicians and Surgeons E Hilda Elena Fernandez, MD, MSCE a Assisrann Professor of Medicine. Columbia University Vagelos College of Physicians 2 and Surgeons 5 Abdallah S. Gears, MD 3, Assistant Professor of Clinical Medicine, University of Pennsylvania jonathan Hogan, MD Assistant Professor. University of Pennsylvania S.Ali Husain, MD, M P H Assistant Professor of Medicine. Columbia University Vagelos College of Physicians and Surgeons Sean D. Kalloo, MD, M B A Assistant Professor of Medicine (in Radiology). Columbia University Vagelos College of Physicians and Surgeons jeanne Kamal, MD lnscructor in Medicine. Columbia University Vagelos College of Physicians and Surgeons Pascale Khairallah, MD Clinical Fellow, New YorkPresbyterian Hospital/Columbia University Irving Medical Center M i nesh K hat ri , M D Clinical Assistant Professor State University of New York at Stony Brook K nyszt of K i ryl uk, M D, M S Associate Professor of Medicine. Columbia University College of Physicians & Surgeons MarkV lL K ozicky, MD Adjunct Assistant Clinical Professor Department of Medical Education/Medicine, Lake Erie College of Osteopathic Medicine Assistant Program Directory, Department of Internal Medicine/Nephrology. SL Johns Riverside Hospital Wai Lang Lau, M D Assistant Professor. University of Florida Hila Milo Rasouly, P hD Associate Research Scientist. Columbia University Vagelos College of Physicians and Surgeons S umit Mohan, MD, MP H Associate Professor of Medicine and Epidemiology, Columbia University Vagelos College of Physicians and Surgeons and Mailman School of Public Health Heat her M orri s, M D Assistant Professor of Medicine. Columbia University Vagelos College of Physicians and Surgeons M ari a B ereni ce Novo, M D Nephrologist, Department of Medicine. Kaiser Permanente (San Diego. California) Jordan Gabri el a Nest or, M D Postdoctoral Clinical Fellow, Columbia UniversityVagelos College of Physicians and Surgeons Thomas Nickolas, MD, MS Associate Professor of Medicine. Columbia University Vageios College of Physicians and Surgeons Akshta Pai, MD, MPH Assistant Professor. Division of Immunology and Organ Transplantation. Division of | Renal Disease and Hypertension, McGovern Medical SchooIThe University of Texas Health Sciences Center at Houston Yonatan Peleg, MD Clinical Fellow. New YorkPresbyterian Hospital/Columbia University Irving Medical Center jail Radhakrishnan, MD, MS Professor of Medicine, Columbia University Vagelos College of Physicians and Surgeons Maya K. Rao, MD Assistant Professor of Medicine, Columbia UniyersityVagelos College of Physicians and Surgeons Renu Regunat hanS henk, M D Assistant Professor. George Washington University Dom i ni ck S ant ori el l o, M D Assistant Professor of Pathology and Cell Biology. Columbia UniversityVagelos College of Physicians and Surgeons Shayan Shirazian, MD Assistant Professor of Medicine. Columbia UniversltyVagelos College of Physicians and Surgeons E ric S iddall, MD Assistant Professor of Medicine. Columbia University Vagelos College of Physicians and Surgeons Meghan E. Sise, MD, MS Assistant Professor of Medicine. Department of Medicine. Harvard Medical School jacob Sam Stevens, MD Instructor in Medicine, Columbia University Vagelos College of Physicians and Surgeons Zachary H.Taxin, MD Internal Medicine Resident. New YorkPresbyterian Hospital/Columbia University Medical Center DemetraTsapepas, PharmD, BCPS Assistant Professor of Clinical Surgical Sciences. Columbia University Vagelos College of Physicians and Surgeons Director of Quality and Research in Transplantation. Department of Transplantation. New YorkPresbyterian Hospital/Columbia University Irving Medical Center Anthony M.Valeri, MD Professor of Medicine. Columbia UniversityVagelos College of Physicians and Surgeons Hector Alvarado Verduzco, MD Clinical Fellow. NewYorkPresbyterian Hospital/Columbia University Irving Medical Center Romina Wahab, MD Assistant Professor of Medicine. Columbia University Vagelos College of Physicians and Surgeons PREFACE Pocket Nephrology joins the Pocket Notebook series as a complete resource for topics related no renal kidney physiology and pathophysiol ogy designed as a first bedside reference for the busy clinicians.This book is intended for medical students, internal medicine and nephrology trainees as well as seasoned clinicians involved in the care of patients with kidney disease.The book is divided into two sections.The first part discusses the general approach to disorders of the kidney.The second part of book will address individual topics under each of the following categories: Electrolytes and Acid-Base Balance.Tubular, Interstitial and Cystic Diseases, Extrarenal Diseases, Glomerular and Vascular Diseases, Hypertension, Renal Replacement Therapy, and Transplantation. Individual topics are written to make pertinent information readily available to clinicians in order to facilitate evidencebased patient care. Wooin AHN AND JAI RADHAKRISHNAN CONTENTS Contributing Authors Preface CLINICAL MANIFESTATIONS Wooin Ahn,jai Radhakrishnan,Abdallah S. Geara,Yonoton Peleg, Romina Wahab, Eric Siddoll,jonathan Hogan, Minesh Khotri, Shayon Shirazian, Hilda Elena Fernandez Proteinuria Hematuria Polyuria Urinary Symptoms Fluid imbalance Hypotension Edema Nephrotic Syndrome (NS) Glomerulonephritis (GN) Thrombotic Microangiopathy Acute Kidney Injury (AKI) Chronic Kidney Disease (CKD) Transition of Care for Young Adults DIAGNOSIS S.Afi Husain,Anthony M. Vaferi,Wooin Ahn,jenTse Cheng, David Bennett, Dominick Santoriello, Hila Milo Rasoufy R e n a l Fu n cti o n U ri n e Stu d y Imaging Renal Biopsy Renal Pathology Ge n e ti cs 21 22 28 210 2 12 217 TREATMENT ANDTOXIN Minesh Khatri, Hector Alvarado Verduzco, Wooten Ahn, Demetra Tsopepas, jai Radhakrishnan,jacob Sam Stevens, Geoffrey K Dube,Yorg Azzi, Anthony M. Valeri Nutrition Fluid Therapy Pharmacology RAAS inhibitors Nonsteroidal AntiInflammatory Drugs Diuretics Immunosuppressive Therapy Prophylaxis Illicit. Herbal. and Environmental Toxins Plasma Exchange (PLEX) intoxication and Poisoning 31 32 36 39 311 312 316 327 330 333 334 V ELECTROLYTES AND ACID BASE BALANCE | Abdallah S. Geara, Zachary H.Taxin,Wooin Ahn Renal Tubules Evaluation of Acid-Base Balance Metabolic Acidosis Metabolic Alkalosis Respiratory Alkalosis Respiratory Acidosis Potassium Sodium and Water Calcium Phosphate Magnesium 41 43 44 412 414 415 415 4-21 428 431 433 TUBULAR, INTERSTITIAL,AND CYSTIC DISEASES Minesh Khatri,jocob Sam Stevens,}ai Radhakrishnan, Wooin Ahn, Krzysztof Kiryluk Acute Tubular Necrosis (ATN) Pigment Nephropathy Cryst al Nephropat hy Urinary St one Disease Interstitial Diseases I mmunoglobulin G4Relat ed Disease Sporadic Cystic Diseases Heredit ary Cyst ic Diseases Renal Cell Carcinoma (RCC) 51 52 53 56 58 510 s11 512 515 EXTRARENAL DISEASES Hilda Elena Fernandez Urinary Tract Obstruction (UTO) Reflux Nephropat hy Urinary Tract I nf ect ion (UTI ) 61 62 63 GLOMERULAR AND VASCULAR DISEASES Renu Regunathan-Shenk, Pietro Canetta, Rupali S.Avosare,Wailang Lau, Gerald B.AppeI,jordan Gabriela Nestor Minimal Change Disease (MCD) Focal Segmental Glomerulosclerosis M em branous Nephropat hy (M N) P auciI mmune Glomerulonephrit is A nt i GB M Di sease I mmunoglobulin A Nephropat hy Lupus Nephrit is InfectionRelated Glomerulonephritis I m m une Com pl ex-m edi at ed M P GN C3 Glom erulopat hy (C3G) Cryoglobulinemia Amyloidosis Nonamyloid Deposit ion Diseases Heredit ary Glomerular Diseases 71 72 74 77 7 10 711 713 7 15 717 7 18 720 721 724 725 Antiphospholipid Syndrome (APS) HUS and TTP Complementmediated HUS HYPERTENSION Yelena Drexler; Andrew S. Bomback General Hypertension Hypertension in ESRD Resistant Hypertension Hypertensive Emergencies Antihypertensives Obstructive Sleep Apnea (OSA) Renal Artery Stenosis (RAS) Hyperaldosteronism Pheochromocytoma 81 2 84 85 86 87 89 8 10 812 8 15 SPECIF IC T OPICS Russell j. Crew, Geoffrey K. Dube, Shayan Shirazian, Maria Berenice Nava, Meghan E Sise,jordan Gabriela Nestor Wooten Ahn,Andrew Beer ken, Maya K. Rao, jai Radhakrishnan,Abdallah S. Geara, S.Ali Husain, Rachel Arakawa, Thomas Nickofas, Minesh Khatri,Vasanthi Balaramon, jae Hyung Chang, Mark W Kozicky Cardiology Pulmonology Extracorporeal Membrane Oxygenation Gastroenterology Hepatology Hepatitis BVirus (HBV) Hepatitis CVirus (HCV) Hematology Anticoagulation Monoclonal Gammopathy (MG) Hematopoietic Stem Cell Transplantation Oncology Infectious Diseases Human Immunodeficiency Virus (HIV) Diabetes Mellitus Hyperlipidemia Obesity CKDMineral and Bone Disorder Osteoporosis Primary Hyperparathyroidism Uric Acid (UA) Rheumatology Pain Medicine Psychiatry, Sleep Medicine, and Neurology Obstetrics Radiology Dermatology Ophthalmology 91 96 99 910 913 916 9 17 919 924 925 928 929 934 937 939 942 9-43 944 945 948 949 951 954 956 961 966 968 970 Geriatrics Palliative Care 971 973 RENAL REPLACEMENTTHERAPY 1 Anthony M. Voleri,Wooin Ahn, Efren A, Chavez Morales, Sean D. Kalloo, Sumit Mohan, Pascale Khairallah General Concepts of RRT RRT Initiation RRT Modality Decision Continuous Renal Replacement Therapy HD Initiation and Prescription HD Adequacy HD Water Treatment HD Complication HD Vascular Access PD Concepts PD Prescription PD Adequacy PD Complication PD Catheter 101 103 10-4 105 108 1011 1013 1014 1019 1026 1027 1030 1031 1033 TRANSPLANTATION Vosanthi Balaraman,jae Hyung Changjeanne Kamal, Sumit Mahon, Heather Morris,Akshta Pai, Russell j. Crew, Dominick Santoriello,Yorg Azzi, Geoffrey K Dube,Yelena Drexler; Andrew S. Bomback, Hilda Elena Fernandez Recipient Evaluation Living Donor Evaluation Immunologic Testing and Monitoring Kidney Allocation Allograft Dysfunction Acute Cellular Rejection (ACR) Antibodymediated Rejection (AMR) Infection after KT Metabolic Complication after KT Hypertension after KT Malignancy after KT Renal Complication in Other Organ Transplantation PHOTO INSETS JenTse Cheng, Dominick Santoriello Urine Sediment Images Renal Pathology Images p11 P21 APPENDIX Units and Molecular Weights 121 ABBREVIATIONS 13-1 INDEX 11 PROTEINURIA Pro:einuria: protein in urine >150 mg/d t ESRD risk w/ UACR 20-200 mglg in men and 30-300 mglg in women x13.0: UACR >200 ms/s in men and >300 mg/g in women x471 UASN 20\>9.20:1069) Albuminuria t ESRD. al l cause and car di ovascul ar mor tal i ty I mmune 2010hJ75;1073) Urinary Proteins Protein NlVadueISize Tamm-Horsfall protein (THP: uromodulin) 9-35 mg/d as kD Albumin <20 mg/d 69 kD <163 kg/d 21 kD <19 rngld 27 kD <300 kg/L (24hr level not established) 12 kD Retinolbinding protein (RBP) u1 microglobulin Remarks Synthesized and secreted in TAL Defense against UTI: inhibit Ca crystallization The matrix of various casts, including LC cast Gene mutation causes ADTKD Predominant serum protein Very small propanion is Filtered and reabsorbed Urine level is T in early stage of graft failure (AIr 2013:13:676) Hemebinding protein with antioxidant activity Synthesized in all nuclear cells Component of class I MHC Serum level is elevated in MM, lymphoma. and has prognostic value: renal dysfunction t Precursor of ABZM (dialysis related) amyloid Odler minor proteins (kD): myoglobulin (18). hemoglobin (64). Cystatin C (13), K (22.5) and 2. (45) light chain.vitamin D-binding protein (58). polypeptides B2 microglobulin gzip Low-Mole c ula r We ight (LMW) Pr ote ins Proteins of a size smaller than albumin: RBR n1, B2 microglobulin and lg light chain Freely filtered in the glomerulus Megalin-cubilin-amnionless complex in PT reabsorbs albumin and LMW proteins 1 urinary LMW protein (tubular proteinuria) suggests proximal tubule dysfunction Workup Evaluation of Prvoteinuria Test Dipsticlc reaction wl tetrabromophenol blue Random protein to creatinine ratio (UPCR) Random albumin to creatinine ratio (UACR) 24hr urine protein Cons insensitive to LMW proteins Semiquantitauve: affected by urine concentration False (+): pH >9 wl urea splitting organisms. iodinated contrast Diurnal variation Pros Sensitive to albumin Rapid.cheap Possible home monitoring Convenient Correlates wl 24hr (NUM 1983:)0&1$43) Sensitive in detecting glomerular lesion Gold standard Can /CrCl together Not elected by diurnal variation Diumal variation More expensive than UPCR Miss nonalbumin proteintina Cumbersome Over or undercollection: / w/ creatinine for adequacy Initial proteinuria workup: J both UPCR and UACR Spot urine albumin/protein ratio: < 0.4: tubulointerstidal [nor z01z 27:1s34): <0.2S: light chain cast nephropathy in monoclonal gammopathy (qAsn 2012:7:1964) Sulfosalicyiic acid (SSA): semiquantitatively detects all proteins including LC;add 3% SSA to urine and ./ turbidity;false (+) w/ iodinated contrast. PCN,and ceph. Assay Sensitivity o¢Various Proteins and Substances Assay Dipstick SSA Total protein Albumin Iodinated Contrast Albumin LMW Proteins Light Chain Lysozyrne + +I - +I - + + + + + + + _ 4 + - + 4 _ + 4 Transient proteinuria caused by fever. extreme cold. seizure, and exercise Orthostatic proleinuriazcommon in child and adolescents;benign condition GLOMERULAR PROTEINURIA Loss of glomerular filtration barrier;albuminuria: hallmark of glomerular damage Infection. exercise can cause transient glomerular proteinuria Moderately increased (A2.formerly mica) dbuminuria: 30-300 mglg or 3-30 mglmmol Severely increased (A3.formerly macro) albuminuria:>300 mglg or 30 mg/mmol Tool to monitor glomerular diseases: J proteinuria wl stable renal function = remission General Management Low sodium died more effective than dual RAASi iam;201\=J4J¢a4zes) ACEr or ARB: nonDHP CCB (xi 2004¢e 5.1~m) BP goal: 125/75 vs 140/90 in 24hr UPCR >0.22 aM i CKD progression (HR 0.73) (AASK ne//.1 201036391 $1; in 21 g/d proteinuria a/w L ESRD after 14 yr (HR 0.59) (up 1017,zeevu TUBULAR PRO TEINURIA Proximal tubular damage -> inability of absorption of Nkered LMW protein Can be missed wl dipstick (discordance between UPCR and dipstick) Acquired Causes ATN. uibulointerstitial diseases Light chain proximal tubulopathy: mlc cause of acquired Fanconi syndrome Heavy metals (I d. cadmium, mercury. copper). ifosfamide. tenofovir Cystinosis AR mutations of CTNS gene encoding lysosomal protein cystinosin: cystine accumu. lotion in proximal tubular cells; mlc cause of inherited Fanconi syndrome Dent Disease Type 1:xlinked defect in CLCNS gene encoding Cl'/H exchanger. CLC5,exprased in the FT aM CD intercalated cells - . cubilin and megalith expression -» LMW proteinuria Type 2: xlinked defect in OCRL gene encoding 4.5bisphophace 5phosphatase PT damage (unclear mechanism): aminoaciduria.glycosuria. phosphaturia,and hyper calciuria: CaO>dCaP nephrolithiasis/nephrocalcinosis; FQGS (qAsn 201J;821979) Biopsy: FQGS (83%), mild segmental FPE (57%), focal interstitial fibrosis (60%), interstitial lymphocytic infiltrate (53%), tubular damage (70%) (QASN z01s:11:116a) Rare Genetic Causes ofTubular Proteinuria DonnaiBarrow/faciooculoacousticorenal syndromes:AR mutation of LDL receptor protein 2 (megalith). Hypertelorism. myopia. hearing loss. and proteinuria Grasbeck-lmerslund disease:AR defect in eider cubilin or amnionless. Megaloblastic anemia: Biz absorption is mediated by cubilin amnionless complex O VERFLO W PRO TEINURIA The amount of filtered protein exceeding reabsorption capacity Causes: light dlain ast nephropadry. rhabdomyolysis (myoglobulin.l3 on UPEP).helndysis (hemoglobulin), lysozymeinduced nephropathy L yso zyme In d u ce d N e p h ro p a th y (AJKD 2009:54;1$9) Lysozyme (muramidase): small (15 kD) cationic protein produced by monocytes and macrophages; filtered by glomeruli and reabsorbed in the Fly causing injury Chronic myelomonocytic leukemia (CMML): neoplasm producing mature monocytes: chronic monocytic leukemia. multiple myeloma,sarcoidosis who 2011:59::cmiii) " r region in SPEP w/ (-) SIEE (+) urine dipstick protein: t serum. urine lysozyme AKI. hypokalemia LM: eosinophilic protein granules In PT: EM: large prominent lysosomes in PT Tx treatment of primary disease PRO T EINUMA AF T ER KIDNEY T NANSrL ANT AT iO N Albuminuria (>proteinuria) predicts renal outcome after :xp (AJKD 2011;57:73J) Proteinuria is alw cardiovascular morbidity and mortality (fiumplanmuinn z001.73:134$1 Proteinuria from native kidney rapidly declines after txp (A/T zoom.1660> Causes: transplant glomerulopathya de fl0lD or recurrent glomemlar disease.acute rejection Biopsy unexplained proteinuria 23 old Ii(DIGo;Ayr 200949 so: 3:S1) HEMATURIA Hematuria: 23 RBCIHPF on a properly collected specimen (avoid during menstruation) Dipstick , ,sediment for RBC: not hemauiria: consider myo or hemoglobinuria, semen Hemoglobinuria: mused by any inuavascular hemolysis (et. HAHA transfusion vacdan. and PNH) with hemoslderinuria (Prussian blue ; tubular cdls).l hapcoglobin, T LDH May cause Prussian blue hemosiderin deposit in PT aim 101 0.$6:7S0) Prevalence of hemacuria: 2.5-1 B% in healthy individuals Persistent asympzomadc microscopic hemaruria x18.5 risk of ESRD UAMA 2011;zo¢mi Causes of Hematur ia Origin Selected Causes Glomerular lgAnllgAv. thin basement membrane disease.AIpon syndrome Warfarinrelated nephropathy. Loin pain hematuria syndrome.TMA Any other glomerular diseases including DN (41%) inwmun Chi Mia zueaiownisl and MCD (29%) lqAs~ z00u;44s1 Imerstidal nephritis, papillary necrosis, pyelonephritis. BKV infection Cystic diseases (PKD. acquired cystic kidney disease). Benign mass Malignancy (RCC. lymphoma. metastatic cancer) Hypercalciuria. hyperuricosuria Nonglomerular renal Nonrenal urinary mc: Nephro/uroIid1iasis. trauma (catheterization. instrumentation) Prostadtis, BPH. endometriosis. malignancy (TCC. SCC. prostate) Cystitis (infection. chemical. et. CYCassociated). urethritis Vascular Renal artery thromboembolism. renal vein thrombosis. renal AVM History Relevant History for Hematuria Evaluation Histor y Potential Causes AKI CKD RPGN. inr.ratubular RBC casts (eg. Igor) Blood clot Acquired cystic kidney disease Nonglomerular origin Recent upper respiratory infection Posunlectious GN. IgA nephropathy Sensorineural hearing loss. retinopathy. Ienticonus Alport syndrome Heavy exercise Exerciseinduced hematurialhemolysis Recent renal procedure or injury Unilateral flank pain Renal aneriovenous malformation (AVM) Stone. renal infarction. pyelonephritis Irritative voiding symptoms (frequency. urgency. dysuria). suprapubic pain Increased sexual activity,perineal pain. dysuria, terminal hematuria Cyclic hematuria aw menstruation Bladder cancer. cystins Prosutitis Blunt trauma a/w lower rib fractures Traumatic renal injunes Excessive anticoagulation Anticoagulantrelated nephropathy Travel/residence in Africa. the Middle East Schistosoma hematobium <ystit.is Endometriosis of urinary tract Sickle cell disease Renal infarction. papillary necrosis Sickle cell trait Renal medulla carcinoma Ancirhromborics e hemacuriarelared complications. bladder ca dx UAMA 2017;31e11160); should continue hemaruria wlu for underlying causes lAM IM 1994:I54:649) Gross Hematurla Timing Pattern and Potential Sites Timing Potential Site of Bleeding As the beginning Urethra Ac the end Prosraze gland or the :rigor al area of the bladder Throughout Bladder. ureter or kidn Workup Urine dipstick detects peroxidase activity of Hb; myoglobin has pseudoperoxidase activity; ascorbic acid can induce false e Urine sediment: 23 RBC/HPF; RBC casts.dysmorphic RBC glomerular: supernatant is clear in hematuria; extreme pH (<5 or >8) can cause RBC lysine Proteinuria >0,5 g/d glomerular. hematuria doesnt cause significant proteinuria If >10 RBCIHPF + 2 old proteinuria. 93% glomerular. 83% GN (NDT 1018;33<1197) Urine albumin/protein >0.59. wl urine protein 25 -» glomerular origin lqxn 2008;$22351 Urocrit (hematocrit test of urine) >1% urologic Urine culture: if . reevaluate 6 wk after treatment Renal UIS: blood clot can cause hydronephrosis: Doppler study detects AVM Stone protocol (low radiation) CT wlo contrast only if stone is likely cause CT orography and cystoscopy if risk factor of urinary malignancy w/o obvious other causes 4/ Ural Z012;108:24731. Reevaluate after resolution of other causes Risk Factors of Urinary Tract Malignancy u u»uz012;1eez47J; Ann IM 2o1s;\u1.ea, Male. >50 lo. past or current smoking, analgesic abuse Exposure to benzenes or aromatic amines. alkylazing agent, arisrolochic add Gross hemawria (even if selfIimized). urologic disorder or disease Irritative voiding symptoms (dysuria. urgency. and frequency) Pelvic ir dar i n oh . nic UTI. chronic indwelling Foreign body Cyswscopy: identify bleeding source and ureter laterality: eg. unilateral ureter bleeding excludes glomerular origin CT orography CT wlo contrast (stone. calcification. unenhanced baseline): contrast renal parenchymal phase (enhancing renal mass):excretory phase (collecting system evaluation) Cytology very low sensitivity: not recommended for initial workup iA» AM 2016:164:458) 24hour urine study. detect hypercalciuria. hyperuricosuria Possible Causes of AKI in Hematuria Gross and glomerular: intratubular RBC cast and ATN, common in IgAN Microscopic and glomerular: crescentic GN.vascular lesion (vasculitis.TMA) Gross and nonglomerular: blood clot causing urinary tract obstruction T r eatment Glomerular hematuria: consider ACEi or ARB. kidney biopsy Can serve as marker of activity predicting future relapse (c;As~2018;13:251) Nonglomerular Origin gross hematuria: generous fluid intake to prevent blood clot obstruction of the ureter or bladder; bladder irrigation if refractory If urologic workup is negative, /annual urinalysis.After 2 negative annual urinalyses. no further urinalyses are necessary U ml 2012;1881247:i1 EXERCISEINDUCED HEMAT URIA Direct uuuma to :he kidneys +I- bladder in contact sports: renal ischemia dl: T blood flow to muscles and nutcracker syndrome in noncontact sports Gross or microscopic hemaruria after strenuous exercise: resolves wu 1 wk w/ rest Tx: observation, if persists after 1 wk of rest rlo other causes a Exerciseinduced hemolysis, aka march hemoglobinuria or runners hemolysis: presents wl intravascular hemolysis. hemoglobinuria (dipstick sediment Hemosiderinuria (Prussian blue 8 tubular cells), urine iron loss IDA NUTCRACKER SYNDROME Left renal vein (LRV) entrapment between SMA and aorta -» LRV HTN rupture of thin vein into collecting system -» hemaruriaz can be complicated by left RVT Gross or microscopic hematuria +I- left flank pain in children and Asians Dx: Doppler UIS, MRA of LRV Tx: stent: transposition of the SMA or LRV. autotransplantation of left kidney LOIN PAIN HEHATURIA SYNDROHE Glomerular hypertension or GBM instability causing capillary rupture into renal wbules and tubular obstruction IA/xo zuos;414wl Recurrent uni or bilateral flank pain. microscopic or gross. w/ nl renal function Urine sediment dysmorphic RBCs. Kidney bx: RBCs or RBC casts in the tubules Tax:ACEi/ARB:analgesics, celiac plexus block. kidney autotransplantation. renal dener Y 3IiOh (n/xo 2017:69:15$). Unilateral nephrectomy not recommended dl: frequent relapses I in the contralateral kidney RENAL ARTeRlovEnous MAU=ORt4ATION (AVM) A communication between :he intrarenal artery and vein Usually congenital.Acquired forms.calIed AVE caused by trauma or kidney bx (4_18%) Hematuria. renal colic. hypertension (T renin secretion from hypo perfusion distil to the AVM)..' renal function decline. CHF Dx: doppler study, CT angiography. MR angiography.and digital subtraction angiography Tx: observation. symbolization. total or partial nephrectomy POLYURIA UOP >3 Ud; commonly w/ nocturia (inability (O concentrate the urine overnight) A patient with normal cognition and normal Mint reflex will try to compensate for polyuria and usually keep serum Na and osmolality within the normal range Osmotic diuresis Etlologles of Polyuria Glycosuria. sodium diuresis Urea diuresis: improving AKI, high pmt diet. tissue catabolism, parenteral nutrition 1° polydipsia High free water intake do psychiatric illness. hypodialamk lesions CDI: defect in ADH secretion NDI: renal resistance to ADH idiopathic. trauma. pituitary surgery, ischemk. familial (thirst center) Hereditary: mutations d AVPR2 (Xlinked). aquaporin2 (AD or AR) Hypeiicalcemia. hypokalemia Lithium (chronic). cidofovir. loscarnet, vasopressin antagonists. ifosfamide. demeclocydine Gestational DI Others Release of vasopressinase from the placenta during pregnancy Sickle cell diseaseltnit. Sj6grens. bilateral obstructive unopathy. Bart¢ers. cystinosis Workup Na >145 + low umm (<P°,,,,) diabetes insipidus (DI) Water restriction yes: (WRT) is not necessary and desmopressin challenge an be done to differentiate between central DI (CDI) and nephrogenic DI (NDI). WRT differentiates between the different ecologies: Step 1: restrict water intake and measure UOP and Um Q1h; [Na] and Pm Q2h Step 2: stop WRT and proceetl to step 3 when U.,,... >600; Um sable for 3 hr: Na >145 or Pm >300 Step 3: desmopressin challenge: measure Um and UOP every 30 min following des mopressin 10 mcg IN or 4 mcg SC or IV J Plasma and urine ADH levels if the response to the WRT is noncondusive Polyuria >3 Ud UM <250 up, >300 Water diuresis Osmotic diuresis/ solute diuresis 'U polydipsia Up, < Pow Desmopressln challenge 10 mcg INo r4 m cg SC o rlV r No TU,,,.., Complete NDI Tum by >100% Complete CDI TU¢,,\ by 15- 50%, >300 Partial CDI TUm by up to 45%, <300 panlal NDI Copepdn (Coerminal segment of vasopressin pmhermone) level after 3% MCI 250 mL may differentiate 1 polydipsia from CDI IN£/M z01a4379=41s;. CopeptinIPn, 20.02 pro/L: 1 polydipsia: <0.02 pmol/L: partial CDI Basal copeptin <2.6 mol/L complete CDI 1 polydipsia can induce partial NDI (decrease urea accumulation in the medullary interstilium - defect of the corticomedullary gradient) CENTRAL DIAae1£s Ir4slru>us (CDI) Pathogenesis release of antidiuretic hormone (ADH) (or AVP) from the hypothalamus idiopathic or autoimmune (30-50%) Hypothalarnic lesions: tumor. inUltradve disease (eg. Langerhans cell histiocytosis. sarcoidosis. GPA. and autoimmune lymphocytic hypophysitis). trauma. surgery Autoimmune disease: IgG4related disease. GPA Familla\l:AR or AD mutations In ADH gene Wblfram syndrome (DlDMOAD):AR muiadcn of WFS 1 encoding wolframln. endaplasmk reticulum piwatdn. Planillesadons: QI. . gpiic atrophy and deafness: hydronephiosis Congenital liypopituiurism. septaoptic dysplasia PostSVT:uansient (Tuft atrhl and systemic pressure -» 1 secretion ofADH) Clinical Manifestations Polyuria. polydipsia. nocturia. predilection for iced water: abrupt onset Na high normal (>142). no to mild increase of Um with WRT. no change to mild response to desmopressin (U.,... <300) Low bone mineral density (is not corrected by desmopressin therapy) During pregnancy. asymptomatic patients with partial CDI start m have symptoms due to vasopressinases released from the placenta Surgical or traumatic damage of the hypothalamus has triphasic response: initial poly uric phase (1-5 d 1 ADH release). antidiuretic phase (6-11 d: release ofADH by degenerating posterior pituitary) followed by permanent CDI or resolution (most cases are not permanent) Treatment Desmopressin: 0.1 or 0.2mg tablet or 5-10 mcg of the nasal spray preferably at bedtime (to decrease the nocturia), cilrane up depending on the noczuria. Na should be measured within 24-48 hours to check for hyponarremia (patient should be edu cared no decrease free water nuke) The response to the IN desmopressin is more predictable than the PO Thiazide diuretics and NMIDs (used mainly in NDI) Other drugs (less effective, more toxic): chlorpropamide and carbamazepine (enhances renal response toADH) and dofibrate (T ADH release) A lowsolute (mosdy lowsodium, lowprotein) diet: for pacienzs with partial and mild DI NEPHROaNNIC DIAaeTss lnslplous (NDI) Pathogenesis Hereditary NDI:V2 receptor (AVPR2) (Xlinked) and aquaporin2 gene (AD.AR) Chronic lidiium toxicity: dysfunction of the aquaporin2 in the principal cells Hypercalcemia and hypokalemiaz interference with the countercurrent mechanism: iaquaporin2 expression Mild NDI (elderly.AKI, CKD): interference with die countercurrent mechanism Pos obstructive AKI,sickle cell disease or trait. PCKD. renal amyloidosis, Siogrens Drugs: vasopressin antagonists, cidofovir, foscarnet. amphoterkin B. demedocycline. ifosfamide, olloxacin, orlistan and didanosine Hereditary tubular syndrome Basters. cystinosis. familial hypomagnesemia with hypercalciuria and nephrocalcinosis Clinical Manifestations Polyuria. polydipsia. nocturia; gradual onset Na >142. no or mild Um with WR12 no or mild response to desmopressin (Um <300) Tre a tme n t A lowsolute (mostly lowsodium <1.3 old. lowprotein 51 glug/d) die: is sufficient in mos: patients with intact thirst response: medical therapy is only for patient intolew ant to polyuria/polydipsia Thiazides diuretics: (1) volume depletion » proximal sodium reabsorption -» 1 UOFW (2) Inhibition of the urine concentration in the DCT Amiloride: added thiazide (corrects thiazideinduced potassium wasting) or in lithium induced NDI (blocks lithium entry through ENaC in the collecting tubule cells unSAIDs: inhibition of renal PG synthesis. mainly for Bartterlike syndromes Desmopressin can help in some cases of partial NDI GESTATIONAL DIAISTES INSIPIDUS U cyan '5w\°!<°l Coll 1010;32:215) Folyuria can be due to release of vasopressinase from :he placenta Same lab pattern as central DI Polyuria response to desmopressin (DDAVP) since in is not inactivated by the vaso presslnase (arginine vasopressin is degraded by vasopressinase) Transient condition; treatment is by Increasing access to free water +I- desmopuessin URINARY SYMPTOMS Causes and Assoclamed Conditions of Urine Change Glomerular hematuria If no RBC on sediment.: myoglobinuria. hemoglobinuria Nonglomerular hemaruria Beers. blackberries. rhubarb.food colorir\g.fava beans Phenazopyridine (iridium). phenytoin. phenolphthalein. rilampin. doxorubicin. deferoxamine, chloroquine, ibuprofen. methyldopa Levodopa. merronidazole, nitrofunnwin. iron sorbitol, chloroquine. rnedwyldopa Alkapconurix :urns dark brown if left standing/alkalinizacion Bilirubin from hepatocellular or obstructive jaundice Methylene blue. amitriptyline, indomelhacin, zriamxerene Red. smoky brown. colacolor Bright red. pink Brown Orange Green or blue Pink or reddish orange Bright yellow Purple Propolol (Lama 2u09;m:146zI; UTI of pseudomonas Uric acid crystal lawn Cur m¢4201139981 al 201zs 1:11s1) Riboflavin (vit BE) Porplryria (t porphohilinageu. poiphynn5). UTI with E ii. Kklzdela larvruw/¢qz0ollu=n9) Black Disseminated melanoma l~=lm z0193siz11ul. alkapronuria (homagendsic acid) Turbid, milky WBCs. bmeria, fungi; chyluria up 2006:1u 1s1a; Crystals: uric acid. Ca pin phosphates and indinavir Hea alburninuria in NS;yellow foam from bilirubin Foa R e o u c s n U R I N E O U T PU T Determinants of Urine Output (UOP) Renal function (glomerular filtration): UOP can be preserved in advanced kidney injury as in nonoliguric AKI or stagey CKD Tubular reabsorption: directed by ADHmediated water reabsorpdon . UW.; 60-1.200 mOsmoI/kg: correlate with ADH activity Urine solute (mOsmol/d)allected by diet and protein ataholisnm600-900 wide usual did I( Um is fixed at 150 (et. nephrogenic DI), solute intake should be decreased Solute load 600: UOP 600/150 : 4 L Solule load 900: UOP 900/1 SO = 6 l.: may lose more water. increasing [Na] If Ueun is Fixed at 300 (eg.SlADH). solute intake should be increased Solute load 600: UOP 600/300 = 2 L: may retain water. decreasing [Na] Solute load 900: UOP 900/300 = 3 L O l i guri a Used to define and stage AKI along with creatinine elevation Definitions of Oliguria and UOP Criteria i n A K l Conventional <400 or 500 cold If solute load Is 600 mOsmolId and kidney can maximally concentrate urine (1,200 mOsmoIIkg). UOP will be 500 mL RIFLE (OlU:ulCanlD04£rR204) Risk: <0.5 mUkglhr for 6 hr Injury <0.5 nUke/hr for 212 hr Failure: <0.3 nUke/hr for 224 hr or anuria for 212 hr AKIN (on Care 7.007:11:R]1. armco AKI 20121 Sa ge 1 <0 .5 mUk glhr for 6 -1 2 hr Sage 2 <0.5 mUkyhr for 212 hr Stage 3: <0.3 mUkgfhr for 224 hr or anuria for 212 hr • Consecutive oliguria for a shorter (3-5 hr) period may predkt AKI risk (Cl*9* 2014%1199 Oliguria is alw T mortality (Kr 1011:80:760). T dialysis requirement., >90 d dialysis and hospital mortality dt nonoliguric AKI lN=p'\~°~ an Flue 101(x11s:¢s9) Diuretic use for conversion from oliguria to nonoliguric AKI is alw worse outcome (}AMA ioazzss.1 s4n: consider only in volume overload not requiring RRT odlerwise In KRT requiring AKI. urine output as initial cessation for CRRT without diuretics is the best predictor of renal recovery (Cm Car: med 2009;37;1576) Can J CrCl when UOP >30 mUhr (77.0 mud) (NEjM 1008335%7) Anuria UOP <100 mud; severe AKI. eg. shock RPGN. renal infarct. bilateral urfnary obstruction URINARY RETENTIO N Definition: inability to voluntarily pass urine Normal postvoid residual volume is <50 mL in <65 y0.<100 mL in 265 yo 24% of hospitalized 270 yo patients have urinary netendon >150 mL ww//m4201s;12s¢17l Acute: predominantly in elderly men alw prostatic enlargement Chronic: postvoid residual > 300 mL chat persisted for >6 mo and documented on 2 or more separate occasions <AUA1 Ural 2017;I98:153) Causes Bladder outlet obstruction BPH (mlc in *), constipation. malignancy (prostate, blad der), urethral stricture. urolithiasis. phimosis. paraphimosis. blood dots (nonglomeru lar hematuria, eg. kidney biopsy). urethral diverticulum 9 ; organ prolapse (eg. cystocele or rectocele).Gbroids obstructing the urethra Underactive bladder:autonomic dysfunction (DM. Parkinson disease). spinal cord injury: stroke. medications with antimuscarinic property Diagnosis and Workup Bladder scan: postyoid >300 cc diagnostic: 150-300 cc possible retention Bladder and renal U/S to rlo hydronephrosis: EMR urinalysis. urine culture CKD and hydnonephrosis regarded as high risk -\ furdier work. eg. umdynamic sandy :Aw Uui 1017;198:1S3) T reat m en t an d Mo n it o rin g Urinary catheterization: sometimes also diagnostic; indwelling or intermittent Bladder decompression may cause transient hypotension Monitor postobstructive diuresis and hypernatremia Treat UTI: common complication NOCTURIA Nocturia: the need to wake at night 21 for voiding; 2x2/night a/w impaired quality of life law um:101ms7:4ea) Nocturnal polyuria: nocturnal UOP >33% of daily UOP in >65 yo (>20% in younger adults) of daily UOP wlo global polyuria (>3 Ud) Causes and Pathogenesis Global polyuria (>3 Ud): osmotic (DM. salt) or water (DI) diuresis. primary polydipsia Nocturnal polyuria: Volume overload (CKD. NS. liver cirrhosis.CHF): supine position -» mobilization of fluid from the LE to trunk _» fluid shift into vascular space T namurel.ic peptide Aging: blunted diurnal variation of vasopressin: high at night in normal Pelvic floor dysfunction: position change may l pelvic floor musculature support Autonomic dysfunction (et. Parkinson disease): L sympathetic activity Evening dose diuretics: excessive drinking in the evening Low bladder capacity: postvoid residual (BPH).bladder irritation (cystitis).bladder wall fibrosis/surgerylcancer/stone/detrusor overactivity Sleep apnea (Mom M1242016;s5901): wake up dlt sleep disorder x T natriuretic peptide Clinical Manifestations law QoLlal.fra»:u.ue,dea:h u LH¥)\(k1B44I413:lUd1011;1$:S71),dq>l8dON ¢uul=g 2n07:s%91) Wo rk u p Frequency volume chart: rlo polyuria STOPBANG for sleep apnea (sup m¢4 an 2017:36:57) T reat m en t Avoid fluid intake (esp. caffeine and alcohol). diuretics in the evening Furosemide 6 hr before bedtime up url 1m;a1:z1s> Desmopressin: l hocturia (Coduane umm Syn Rn 1017710CD0120§9) CPAP in sleep apnea: 1 nocturia. nocturnal UOP (u»=lwzois;as;zaJl Lower UMNARY Tum SYMPTOMS (LUTS) U uwazonmsmsssl Symptoms Causes Symptomatic treatments lopes of LUTS (nays 1012:u1:24an Storage Symptoms Obstructive Symptoms Frequency. nocturia, bladder pain Incomplete emptying. weak Overactive bladder: urgency 3 urge stream. hesitancy delay in incontinence initiation. intermiuency. involuntary interruption. straining, terminal dribbling BPH. prostatius, epididymitis (6) All causes of bladder outlet Bladder: cystirJs. cancer obstruction including: BPH, prostate cancer (6 ) Low bladder capacity, ureterovesical reflux. urethral and meatal stricture Urethral stricture Spinal cord injury Antimuscarinic: oxybutynin, a1 antagonist (osier) tolterodine. darilenacin. solifenacin. doxaz. \:eraz. alfuz*. fesoterodine. uospium tzmsul*. siled sle: (orthosutic) hypoten sign; sle: urinarylgastric retention. T HR. dry (*) mouth, blurred vision, dementia and a1a selective drugs brain atrophy UAMA nwiul m1473nil have less I, BP Dysuria 9 >> d;common causes include cyszitis.ured1rids,vaginicis,and prostatids Common organisms causing urethritis (9): N. gonorrhoeoe. Chlamydia, Mycoplasma geni tol i um, Tr i char nonos vagi nal i s, HSV Irrizative symptoms (urgency. urge incontinence,frequency. dysuria. nocturia) + hema rurix risk factors of bladder cancer; /cystoscopy (ACP Am IM 2016116414488 lnxerscizial cystitis/bladder pain syndrome: bladder pain. pressure. discomfort alw LUTS of >6 wk. wlo infection or other idemiNable causes (n¢unvna ulv4y»» 1009;zs¢z741 Urinary Incontinence vcr wan Ami :m 2014;1i1:429) Stress Incontinence Symptom Small amount urine loss wl exertion, sneezing, coughing or laughing Daytimelstanding position only Causes Weakened support structures of the uredlra Age. obesity. pregnancy. repetitive pelvic floor stress Vaginal delivery up 7.01B;l},0;243gl Radical prosxatecto > TURP Urge Incontinence Large amount urine loss wlo prediction Day and night urgency and frequency Bladder irritation: infection. inflammation, stone. cancer Stroke. spinal cord injury Workup Tneatrnent Pelvic floor muscle training Weight losslbariarric surgery if overweight up IM Z0l5:\7S:1]78) Midurerhral sling were2013;36%1124) Urine culture Cystoscopy. urodynamlc swdy Bladder training Anrimuscarlnk Mirabegron: B3 agonist sle: HTN Overflow incontinence: incompiere emptying dl: underactive bladder 1 outlet obstruction FLUID IMBALANCE Fluid Intake Water and food Intake 25-35 mUkgld -» :k climate. habits, level of physical activity CHO oxidation 200300 mud Body Fluid Compartment: Estimation by Percentage of Ideal Body Weight (law) Body Fluid Compartment Total body water (1BW) Intracellular fluid (ICF): 2/3 ofT BW Extracellular fluid (ECF):1l3 ofT BW Interstitial fluid: 3/4 of ECF Intravascular fluid: 1/4 of ECF Young Male Elderly Male, Young Female Elderly Female 60 40 20 15 5 S0 33 16.7 12.5 4,2 45 30 15 11.3 3.8 Transcellular (1-2 L): synovial. peritoneal. pericardial, inrraoculan and CSF Volume TBW Extracellular Intracellular Plasma Blood volume Imersririal fluid Measurement of Body Fluid Volumes Indicators Deuterium, tritium, antipyrine "Na, 115liodwalamaze. nhiosulfare. insulin Calculate = TBW - extracellular volume "Slalbumin. Evans blue dye "Crlabeled RBCs: calculate = plasma volumel(1lkt) Cokulme = extracellular - Plasma volume Fluid Loss Insensible: respiratory tract. skin 500-700 mud -o T extensive burns. cold weather: fever. tachypnea. open wounds. T metabolism (>10fold) Sweat hypotonic. highly variable -100 mud _.1 exercise. ho: climate (1-2 Uhr) Feces/GI: ~1S0 mud; T diarrhea. NGT drainage fistula Urine: main regulator. multiple mechanisms (0.5-20 Ud): also regulates Na, CI. K 0.5 L to excrete 600 mOsm with maximal ADH activity (1,200 mOsmIL) Sodium and Water Imbalance Manifestation of Sal! .nd Water Imbalance Dehcir Excess Salt Volume depletion Volume overload Water Dehydration/Hypernalremia He natremia DEHYDRATION Effective osmoles cannot cross cell membranes wlo transporter activity eg, Na. K. glcuose. and mannitol Ineffective osmoles: freely cross cell membranes. do not affect transmembrane water flow, eg. urea and alcohol Osmolality: :he mllllosmoles of solutes per 1 kg of water In is the same through ICF and ECF since water (via aquaporlns) can freely traverse plasma membrane Calculated P..,, = 2 x [Na] + [glucose (mg/dL)]/18 + [BUN (mgldL)]I2.B Tonicity: :he ratio of plasma effective osmoles (solutes that do not cross membrane barriers) to plasma water. It dictates :he movement of water across a membrane. Approximately 2 x [Na] + [glucose (mg/dL)]l1B Dehydration: a loss ofT BW resulting in hypertonicityn s volume depletion Hypernatremia: [Na] >145, mainly from water deficit. rarely (rom mul body Na or K increase with relative TBW deficit High urea is hyperosmolar but not hypenonit; hypernatremia is hyperosmolar and hypertonic Pa t h o p h ysio lo g y Changes in plasma tonicity >280-289 mOsmlkg are sensed in hypothalamus -» :him sensation/water intake and ADH go up in a linear manner -o ADH acts on the V2 receptor on the outer and inner medullary collecting duct resulting in luminal AQP channel placement in a cAMPdependent manner -+ water absorption -r tonicity -» hypothalamic stimulus is turned off Water deficit results from decreased thirst/water intake +I- decreased renal concen trating capacity (Dl).although the former is the more common mechanism Increased plasma osmolality-» water shift from the intracellular to the extracellular space -» cellular shrinkage In hypematremia/hypenonicity brain cells generate osmolytes to increase Intracellular osmolality and counter the increase in extracellular osmolality. II hypernatremia correction Is rapid, iatrogenic cerebral edema can occur due to the delayed decrease in intracellular osmolality in brain cells. C lin ica l M a n if e st a t io n s Thirst. oliguria. anorexia. NN generalized weakness, fatigue, lethargy irritability, confusion Severity of neurologic symptoms related to rate of rise of [Na] than absolute value Signs: dry mucous membranemlongiuidinal tongue furrows,seizures. coma.lCH (in infants) Hypernatremia. T Um. T Urine specific gravity, relative polycythemia Workup Determine Me parlen:s overall sodium balance (volume status) Salt and Water Balance and Mechanisms in Hypematnemia Volume Status Hypovolemic Euvolemic Hyperwolemic Salt + T Water l l - Mechanism Loss of hypotonic fluids Loss of elecrroiyte free water Excessive salt intake Hypovolemic hypematremia (negative sodium balance): loss of hypotonic fluids Un, >2(k renal loss: diuretics. postATN. postobstructive, osmotic Un. <2& extrarenal loss: vomiting, diarrhea, enterocutaneous fistula. swearing. burns Euvolemic hypematremia (normal sodium balance): loss of electrolyte free water UM <300: renal loss. complete DI Um 300600: renal loss, partial Dl.ccmpensated diuresis Um >700800: extrarenal (cutaneous. respiratory) losses. primary hypodipsia. limited H20 access. post seizures. severe exercise Causes of Diabetes lnsipidus (DI) ADHindependent DI Exogenous vasopressin does not t Um Hereditary NDI: Xlinked recessive, CDI: congenital. trauma, neurosurgery. CNS rumor. inflILrau\re. hypoxia encephalopathy. complete or partial Acquired NDI: Ca.l K.lithium. hemorrhage, CNS infection. aneurysm demeclocydine. amphotericin B. fosamet. Gestational DI: vasopressinase mediar.ed ADHdependent DI Exogenous vasopressin T Uw mezhoxyfiurane. vaprans. chronic imerszizial kidney disease dlt medullary cystic disease. sickle cell disuse. amyldd. Sjé s.malnuzriUon Hypernatremia Not Caused by Total Body Water Deficit Hypervolemic (positive sodium balance): least common;often iatrogenic after receiv ing hypertonic fluids. salt poisoning, rarely due co mineralocorticoid excess Intracellular water shift: electroshockinduced seizures and severe exercise, transient Treatment Identify and :rear underlying cause and replete water defick CDI: desmopressin NDI: Thiazide: (1) mild volume depletion -» * reabsorption <9 l tubular fluid and urine volume: (2) NCCindependent aquaporin 2 expression (Air Rend 2014;306;F$251 Low Na and protein diets: decreased urine output and water loss NSAID: PGE; L AQP2 expression: desmopressin if partial Positive sodium balance: diureticsldialysisa loop diuretics T electrolyte free water loss as well as natriuresis and thus requires ongoing free water replacement VOLUME DEPLETION Definitions Volume depletion: a deficit in ECF volume, caused by loss or sequestration of sodium containing fluids Effective arterial blood volume: required to maintain effective tissue perfusion In nonedematous states. it is proportion to ECF volume In edematous states, ECF and effective arterial blood volume are not proportionate Pathophysiology Control Mechanisms of Extracellular Fluid Component Regulation Elle n Response to ECF volume Deficit R ¢ninAngiotensin Aldoster one System ( RAAS) T renin release as JG apparatus granular cells by: 1. perfusion pressure at affer ent arteriole by baroreceptor 2.. NaCl delivery to macula denser in the TALH 3. Badrenefgc receptor acdvradon Sodium reabsorpUon Vasoconstriction SNS Activated by 1 perfusion pressure/stretch at carotid sinus and aorta Nonosmotic release of ADH All T release of ADH . HR. BP RAAS activation AD H Natr iur etic Peptides Response to ECF volume Excess Released by stretch at atria and LV Water retention Vasopressor effect Sodium excretion l renin release Etiologies Glzvomiting. diarrhea.bleeding. external drainage (while on avg only 150 cold. 3-6 Ud are generated by GI tract. normally all resorbed. if GI pathology lose ability to resorb and become volume depleted) Renal: diuretics, osmotic diuresis. salt wasting nephropathies. hypoaldosteronism In healthy kidney. 120-180 Uday Filtered across glomemlus with >98% resorbed. if there is even a mild tubulopathy with even a slight L in resorptive capacity, dis will result in volume depletion (seen in chronic interstitial diseases) Skin: 1-2 Uhr can octur in hot/dry climate; bum Hemorrhage: sequestration into a third space: GI catastrophes (pancreatitis, obstruction. peritonitis), crush 'niuries C lin ica l M a n if e st a t io n s Weight loss. orthostatic dininess.oliguria. muscle cramps.agitation. thirst.confusion Ordiosiztic hypotension. T HR: progress to supine hypotension THR Diminished skin turgor (less reliable in the elderly), delayed capillary refill Organ ischemia: nonocclusive mesenteric ischemia . Hypovolemic shock: cold. clammy extremities, cyanosis. pulsus paradoxus (. SBP 210 during inspiration: DDx: cardiac tamponade. constrictive pericarditis) Laboratory Flndlngs ofVolume Depletion LN: T Hb. albumin False (-): low muscle mass and liver cirrhosis T urea reabsorption in proximal tubule False (+): steroid. GIB, tetracycline l ADH activity: masked by accompanied dehydration False (): SlADH. HE cirrhosis. NS. CKD. 1 polydipsia Hemoconcentration, masked by accompanied anemia. hypoalbuminemia Na reabsorption in renal tubules False (-): Salt wasting from diuretics or underlying renal disease High rare of water reabsorpcion Metabolic alkalosis from vomiting HCO; is excreted and pulls Na with it. /urinary chloride False (»): HE cirrhosis. NS Um T ADH: False (): dehydration Diagnosis Fluid responsiveness: improvement of stroke volume and cardiac index by fluid is diagnostic of volume depletion: prediction prior to fluid administration is challenging History taking Including weight change Physical examination: insensitive UAMA 1999:181:1011: I an Care z01J11a1s37,¢1 l St a t ic Asse ssm e n t s CVP: did not predict fluid responsiveness (Guest 1oca;n4:1 n: cm Care m¢4 2013;41¢17741 PACIPCWPguided therapy in CHF (sscApz;A~u\ z00s;194=1 szs),ARDS :MMA zoo1:2vo.z71al. and acute lung injury (n£/M 10D6;3$4:22131 didnt improve outcome Dynamic Assessments: may be more indicative of volume responsiveness and potentially improve clinical outcome (on Can M¢42017:4s:1$3a> Pulse pressure variation (PPV) Incan }00&161:134: Cm Cafe med 2009:37:1642) Stroke volume variation (SW) (~!A»v==s<1- 2008;101:7612 A»»¢=uiA»»:¢. 1009;10B;$13) Flassivelegraisinglsetnileornbentposidonwidi4$elevalionofupperpartdhody-»lows upper body and elevate legat45 xi mirtbrings 300-500cctod\ehar!:TCOand SVV and PPV predicts fluid responsiveness (Armin-ia*ca»¢z011;1;1; Oucnnenua zolz 101zs1a4au¢ IVC respiratory variation (lntenwe Can Med 2004;30:I8341 Intensive Can Med 2004;l0:I740) Management Rapid 1-2 L of isotonic fluid to restore tissue perfusion if there is evidence of shock Nor possible to precisely predict :he total fluid deficit for a given patient. clinical signs such as BR MAR UOR MS. peripheral perfusion can guide adequacy of resuscitation VOLUME OVERLOAD Background and Clinical implication Volume overload: sodium excess and expanded ECF volume a/w longer ICU stay and mortality (on: Care z013:17:msl In septic shock. alw mortality (vAssT Go Core Med 101 iznssl In decompensated HE hemoconcentradon (absence of volume overload. measured by T protein, albumin. Hot by diuresis) is alw 1 eGFR, T survival (aimlamn zoimmz6s) In acute lung injury, conservative management targeting CVP <4, PCWP <8 was a/w improved oxygenation index increasing ventilatorfree and ICU free days c/t liberal management targeting CVP 1o-14 or PCWP 14-18 iFAcn Ne/M z00s;3s4:zss4i. In AKI a/w T mortality x2,07 lx/ zc0s76:422). 1 renal recovery up 200976¢417s nor z01z.z7.9stn In CKD a/w rapid progression who 2014263¢681 Volume overload at the RRT initiation is aw morality ion Cae 2012,16=n1971 Hemodilution may lead to underestimation of the severity ofAKl it c0~201m14na2) Pathophysiology Appropriate response: stretch at cardiac receptors (atria and ventricle) -» atria release ANR ventricles release BNP -» natriuriesis. Heart failure: cardiac output -» i perfusion pressure 4 low effective arterial blood volume SNS and RAAS activation Cirrhosis: vasodilatation -» 1 perfusion pressure - low effective arterial blood volume -» T SNS and RAAS activation Nephrotlc syndrome: . oncotic pressure - . tissue perfusion .. low effective ans rial blood volume SNS and RAAS activation (underfill); 1: Na retention (overfill) Chronic kidney disease: blunted response to rapid sodium intake Clinical Manifestations weight. t BRJVD, orthopnea. paroxysmal nocturnal dyspnea. nocturia Peripheral edema: pretibial and ankle in ambulatoryc sacral in bedridden patients: periorbital edema in nephrotic syndrome Ma ni fe s ta ti ons of Fl ui d O v e rl oa d i n O rga ns CVS Pulmonary edema (mies). pleural effusion filling pressure. 1 cardiac output. conduction disturbances. vasodilation Lungs GI Ascixes. gut edema. malabsorption Liver Congesti ve hepatopathy Skin, soft tissue Wound i nfecti on. poor wound heal i ng, pr essur e ulcer CNS Cer ebr al edema. del i r i um Ki dn I nter sti ti al edema, T r enal venous congesti on -» . r enal functi on Hy pona ue mla z 1 tis s ue pe rfus ion in HE c irrhos is -» tADH Hypcalbuminemix T ulivary loss i\ the NS. L synthesis in cirrhosis. ciludaual;diludonal anemia T BNR NTproBNP: cleared by kidney; less reliable in CKD TP CWP >2 2 m m Hg Thoracic ultrasound: B lines (aka comerrail images) (am: 1005;1z7: 1s90) Management Monitor volume status: /daily fluid balance and weight Address underlying cause and treat appropriately HF: neurhormonal blockade Cirrhosis: antivirals/immunosuppression depending of etiology NS: immunosuppression/RAAS inhibition Low Sal: diet: restrict dietary Na intake Lo <2 g (87 mEq) per day Avoid drugs that foster sodium retention as able such as unSAIDs. nonspecific vasodi Iators. highdose l¥blockers or central uagonists Diuretics based on underlying conditions Adjust dose to achieve threshold dose: if weight loss is not achieved, can I24hr urine urinary Na excretion OR 1-2 hr pos: loop diuretic FEn, If U's >100 mEqld or FEm >2%ceflective diuledcs:if not losing weighuesuict sak htake If Un. <100 mEqld or FEn, <2%: ineffective diuretics; t diuretic dose In severe hypoalbuminemia (eg.cirrhosis with ascites or nephrotic syndrome). albumin assisted diuresis may be used uAs~ 2001;11:1010: swf/ xfanqoarlumpi 2012:23;J71) In decompensated HE it is essential to have enough BP to ensure tubular delivery of furosemide (Nt/M 1011:364:7971. lnotropeassisted diuresis can be considered in low ouqnut and congestive status in severe LV systolic dysfunction Dialysis initiation F L u i l :> I r 4 S A L A N C S i n E S R D Ba c k gr ound Volume depletion: alw loss of vascular access and residual renal function (cIA5n 2010;$:1255)C hypotensi on. death UAS~ 2015361720 Volume overload: a/w LVH and death lcmmI4u¢n 2009:11n71: ;ASN 2017:2571491) Postdialysis weigh: >2 kg above and below are alw monalicy lqAs~ 201s=1 aaae) Dr y We i ght (DW) Weight do the patient needs to achieve at the end of dialysis with minimal symptoms or signs of hypovolemia or hypervolemia Normal blood pressure s/p HD can be used to assess euvolemia.but d is requires t he pa t i e nt t o no: be on any other antihypertensive which is rare in HD patients Needs to be reevaluated periodically (O follow flesh weight change Overestimated DW: may cause pulmonary edema and HTN Underestimated DW: weakness,cramps, and hypotension DW Assessment Clinical evaluation: edema (peripheral. pulmonary); absence does not r/o overload Bioimpedance applying electrodes to :he skin and esdmacing volume status by measur ing resistance encountered by an electrical current passed dmmugh :he bodys tissues. no: FDA approved in the u.s. war zoesauoe. or 1014.B6.489) Relative Blood (or Plasma) Volume Monitoring Blood volume estimation with continuous hematocrit (Htt) measurement Volume overload: continuous transfer of fluid from interstitial to intravascular com partment during UF -» stable Hot. flat curve Volume depletion: refill rate from the interstitium to intervascular space lags behind the UF rate -» 1 Hct,blood volume" drop More hospiizlization and mortality than conventional care (JASN 2005:16:2162i No l intradialytic hypotension (qAs~ 1017:11:1831) Management WM 1014:64:6B5) The normalization of the ECF volume is a primary goal of dialysis (volume first") In HD, fluid removal should be gradual: l interdialytic weight gain. treatment duration 24 hr. UF rate <10-13 mUkg/hr; excessive UF during routine HD associated with morbidity and mortality (Dons K1 100616942221 HEMO Vu 20119912512 Aixo 201e4se:911> Avoiding intradialytic sodium loading: sodium profiling T morality (qAsn 1019;14:3asi Dietary counseling: low sodium diet; fluid restriction Highdose loop diuretics: if urine output >-200 ccld: Linterdialytic weigh: gain, UF amount. and intradialytic hypotension (ClASN 201%14:95) HYPOTENSION Absolute (SBP <90. MAP <65) or relative (drop in SBP >40 from baseline) Nor synonymous with shock H YPO T EN SI O N I N D U C ED AKI Autoregulacion: hypowision, 1 perfusion pressure - PG.mediated afferent arteriole dila tion.and angiotensin II (All)-mediated efferent arteriole constriction 4 maintain GPR unSAIDs and RASi impair autoregulatory mechanisms If perfusion pressure drops below the autoregulatory range. endogenous vasocon strictors and endothelial cell injury T afferent arteriolar resistance -» 1 glomerular capillary pressure -» 1 GFR If autoregulation is impaired.renal perfusion is dependent on MAP (KI 1994;4623181 Systemic arterial vasodilation from distributive shock (eg. sepsis) and liver cirrhosis 1 renal perfusion and GFR +I- systemic hypotension Persistent renal hypoperfusion leads to tubular cell injury/ATN SHOCK Space of :issue hypoxia due to inadequate oxygen delivery or impaired oxygen udliudon Most commonly occurs when dvere is reduced tissue perfusion in seeing of hypotension Multiple zypes of shock often coexist Types of Shock and Physiologic Charuterisdcs (Parameter) Preload Pump Afterload Tissue (PCWP) Function (CO) (SVR) Perfusion (5.01) Types: Causes 4 NL or l i NL or 4 Hypovolemic: fluid loss, hemorrhage Distr ibutiveNasodilator y: septic. anaphylactic. neuwcgenk. adrenal insuflicienqq thyroid dysfunction. bums. trauma. pancneaiitis. postoperative ¢=S°PI¢Si= Cardiogenlc: MI, CHE anrhythmimvaive rupture.VSD. critical valvular stenosis. dissection. myncarditis O bstructive: tension pneumothorax. pulmonary embolism, pulmonary hypertension crisis. cardiac umpgnadg NLorl NL or T 1 t T 1 1 1 fLora NLorl T variable Clinical Manifestations Hypotension. tachycardia. altered mental status. rachypnea. oliguria, cool clammy. or warmlvasodilated depending on etiology of shock Exam: mucous membrane, rashes.JVD. murmurs/rubs. lungs crackles/breath sounds/ hyperinflation. tense or soft abdomen. LE edema. cap refill Workup Lactate. cardiac enzymes. renal/liver function. CBC and differential. coagulation parameters.ABG. natriuretic peptides ECG. CXR.TTE.infectious cultures. bedside ultrasound.additional imaging as needed No benefit to the routine use of pulmonary artery catheter monitoring for shock or ARDS QAMA z003;29m271:i; new z00e;zs4=zz 1zi. highrisk surgical patients requiring ICU stay (NSW 2003;34e:S): no large studies examining use in tardiogenic shock G ener al T r eatment Treat underlying etiology of shock while providing resuscitation: fluid. vasopressors. inotropes based on hemodynamic assessment Fluid Resuscitation in Septic Shock 30 mUkg IV crystalloid in the first 3 hr (Intensive Care Med 2017;43:304; JAMA z017;3I7;s47) Balanced crystalloid is particularly beneficial in sepsis (NEJM 1018;378829) Early goaldirected therapy (EGDT): fluids. vasopnessors. blood transfusions, and inorro pes with target MAP 265. CVP B-12. central venous Oz sat 270% within the Nm 6 hr 1 hospital mortality from 46,5-30.5% dt usual care jam pmiuai it/m z001:a4s:13w) However 3 large multicenter RCTs (process nor/l 2014370168J: Amss new 2014:l71:14%; promise ~flm 101537213011 and :he prospective patientIe~eI metaanalysis of the RCTs (PRISM new 2017:37eu23> failed to show lower mortality with EGDT (Likely reflects early recognition of sepsis and early antibiotics/fluids in most patients since EGDT trial) Can rend lactate clearance (21084/2 hr) instead of central venous Oz UAMA z01 czz0a139) No morality difference in targeting MAP 65-70 vs 7085 in septic shock: in pre specified subgroup of patients with chronic HTN. higher MAP group had less renal dysfunction and less need for RRT than lower MAP group SE PSISMAM NEJM 2014;3702158J1 Transfuse PRBC only when Hgb <7 in adults,unless active Ml or acute hemorrhage (TRICC num 1999.34<r409: Truss NE]M 20141371:1381) Albumin: conside if substantial amounts of aysdloids required (inane Care MM 201791309 Avoid fluid overload a/w T mortality (vAssr GU cm Ms. 1011399591 St e r o id s in Se p t ic Sh o ck Initially showed benefit UAMA Z002;2SS:a611 but not replicated in subsequent trials (CORTICUS n9/m 100e:Jsa:111: ADRENAL nz/14l 2018:378909) Hydrocortisone + fludroconisone 1 90 day mortality (APROCGISS NE]M 2018;378:797) Small benefits in mortality. length of ICU and hospital stay (cmcmmea2018¢4e14111 Avoid routine use: hydrocortisone 200 mg IV per day if hemodynamic stability not achieved with fluid resuscitation and vasopressors alone (fntenave Can m¢4 2017;43:304) Steroids are indicated in patients on chronic steroid therapy or adrenal dysfunction s/e: neuromuscular weakness. hypernatremia VASOPRESSORS AND INOTROPES Vasopressors generally improve GFR u "wif 19s1;321112 qAs~ zoas¢a:s4e> Norepinephrine: preferred over dopamine as firstline: no overall mortality difference bu: more arrhythmias with dopamine (seA»= II new 201(x362=7791 Vasopressin or epinephrine: can be added to norepinephrine to meet MAP target Epinephrine = norepinephrine for achieving MAP goal (Intensive Care Mm 100e;34;122s) Phenylephrine vs other vasopressors on clinical outcomes in shock not well studied Angiotensin II (Giapieza°): in vasodilatory shock. 1 MAR 1 SOFA score <~=1m 20\7;377419); in AKI requiring RR111 28d mortality and T RRT liberation Lou Cum Med 201&46949) Lowdose dopamine: does not prevent AKI: may worsen renal perfusion (KI zocwmwal Vasopressors in Septic Shock Mortality was lowes: when begun 1-6 hr after onset with IV fluid (cut cm 1¢I¢4101442.21589 Every hour of delayed norepinephrine was ailw t 5.3% mortality (cut Can 201411;532) Norepinephrine: 1st choice (Intensive can m:4 1017;43:304: /AMA 2017:317:847) Vasopressin at 0.03 U/min added to lowdose norepinephrine: no difference in mor tality do highdose norepinephrine; mortality benefit seen in a prespecihed subgroup of less severe septic shock on 5-14 mcg/min norepinephrine (vAssT no//n 2cas;3s8.e771 Vasopressin (up to 0.06 Ulm in) vs Norepinephrine: no difference in kidney failurefree days or death. but vasopressin group had less use of RRT ¢VANISH1AMA 20\6;]16;509) Norepinephrine + dobuamine vs epinephrine: no difference in mortality lime 20071370679 lnotropes May be added to vasopressors for shock when the etiology is primarily cardiogenic or significant cardiac contribution in mixed shock states (et, septic/cardiogenic shock, obstructive/cardiogenic shock in a large acute pulmonary embolus) Use often prompted by low central venous Oz sat despite vasopressor support Milrinone dose should be adjusted for reduced kidney function RENAL REPLACEMENTTHERAPY IN SHOCK CRRT: more likely to 1 fluid accumulation than HD (xv 2009;7 s:4z1) Timing of RRT In multicenter trial on AKI (KDIGO 3) requiring mechanical ventilation early vs delayed RRT showed no mortality benefit at 60 d iAKIKI NE/M 2016;375;I 22). Posthoc analysis in ARDS or septic shock, no benefit of early RRT (A/RCCM 201&198:581 In singlecenter vial on AKI (KDIGO 2-3) and NGAL >150 WmL early RRT was a/w i 90 day mortality (£LAIN;AMA 201ea1s:21s0), L 1yr mortality and T renal recovery (up 201Bz1%1011) In multicenter trial on AKI (RIFLE failure stage) with septic shock. early RRT not alw mortality reduction. 62% of delayed group dad not require RRT (fig/u 201mz79=14311 ORTHOSTATIC Hyrorsuslon (OH) Physiologic response to standing: :he pooling of 500-1.000 mL of blood in the lower extremities and splanchnic circulation -» L venous return to :he heart and cardiac output and BP -» T sympathetic outflow (baroreceptor reflex) -» t peripheral vascular resistance. venous return. cardiac output, and BP OH: postural reduction in SBP 220 or DBP 210 wu 3 min of standing BP fall w/i 1 mln was alw dizziness. fracture. syncope,and death UAMA IM 101117711319 Delayed OH: OH after 3 min of standing; alw Parkinson disease i--vw z01s:as:136z) Postural tachycardia syndrome (POTS): T HR 230 beatslmin wu 10 min of standing or headup tilt in the absence of OH Postprandial hypotension: BP reduction within 1-2 hr aker a meal Causes Volume depletion: fluid loss. overdiuresis. overdialysis: adrenal insufficiency. anemia Autonomic dysfunction: amyloidosis. DM. Parkinson disease. multiple system atrophy Drugs:all antihypertensives,111blockers (for BPH or HTN). trazodone. SSRI, MAOi, TCA. vasodilators (including PDE5 inhibitors) Clinical Manifestations Dizziness. weakness. palpicarions. blured vision. fall, syncope. fall Sometimes asymptomatic due to auroregulacion of the cerebral blood How Treatment Volume repletion. dlc of causing drugs; avoid rapid postunl change Compression stockings. abdominal binder Fludrocordsonez mineralocorticoid, s/e: supine HTN. hypokalemia.sodlum retention Midodrine:u1agonist s/e: supine HTN. urinary brendon. piloerection, scalp prurirus and paresthesia. bn dycardia. bowel ischemia (On Care mm 1018;46:e628] Droxidopa: norepinephrine precursor: less supine HTN than midodrine wuinmaimiwnuw 201B:521182) Familial Dysautonomia Ashkenazi }ewish.AR. mutation of IKBKAR ormhosradc hypotension. supine HTN,T CKD 19% cl alive pus as age 25 required dialysis l4ll(ozuoe4e7so); KT is an option Ieyasu 201l>.&1s76l EDEMA Edema occurs when :here is sodium retention by the kidney with resultant expansion of the interstitial space The sodium retention by the kidney can be 1° (renin and aldosterone are suppressed) or 2 (renin and aldosterone are increased d/t a hemodynamic stimulus) In 2° renal sodium retention. the stimulus can be an absolute decrease in the intra vascular volume (as with disorders of capillary leakage) or due to arterial underfilling. Disorders of arterial underfilling are characterized by an increase in total blood volume. but an inadequate arterial perusing volume Mechanical causes of edema tend to cause edema diet is localized (ie.to an extremity) in contradistinction to other conditions in which it is more generalized Causes ('causes that do not respond to diuretics) Pri ma ry re n a l so d i u m re te n ti o n . CKDIESRD. nephrotic syndrome (NS, rnaiority) (KI 2012;S2:63S1. thiazolidinediones Slecondary mud sodium retention Arterial underfilling (}ASN 2007;1ez0zs) HF of various etiologies (including constricuve pericarditis). cirrhosis. pregnancy Severe hypoalbuminemia, usually <2.0. of diverse causes (generally alw relative or absolute hypotension) NS (minority) In 2012:82:635) Protein losing enteropadiy. kwashiorkor, severe chronic illness (particularly infection) Decreased arteriolar tone causing increased capillary pressure *Vasodilator antihypertensive medications: minoxidil. hydralazine. dihydropvyridine Calcium channel blockers (co Cmulal up 2002:4:479) Increased capillary penneabilicy *Sepsis. preeclampsia. pancreatitis *Capillary leak syndromes (xv 1017;9131) idiopathic systemic capillary leak syndrome (SCLS) aka Clarkson disease Druginduced (lL2. lL11,IL12.gemcitabine. OKT3, alemtuzumab and rimximab in hematologic malignancies) Engraftment syndrome. graftvshost disease following allogeneic BMT Differentiation syndrome,ovarian hyperstimulacion syndrome Hemophagocytic lymphohisrjocytosis. viral hemorrhagic fever Unknown: hypodryroidlmyxedemaexact mechanism is unclean: but it is characterized by Tplasma volume. l cardiac output. and 1 GFR Mechanical causes: 'lymphedema."venous obstruction. or insufficiency Clinical Manifestations Edema will be unilateral/localized in mechanical causes and symmetric in other causes In nonmechanical causes. extremity edema may coexist with serous cavity effusions (pleural. pericardial. peritoneal) or pulmonary edema Workup History and physical: relevant new medications: evidence of hear: failure, cirrhosis. NS NS and CKD: serum creatinine. urine protein: creatinine ratio. serum albumin Liver disease: coagulation studies and albumin, abdominal ultrasound Heart failure: Btype natriuretic peptide, cardiac ultrasound Myxedema:TSH.free T4 Venous insufhciencyz venous LE U/S to evaluate competence of venous valves Further evaluation for uncommon causes as dictated by the clinical presentation Treatment of Edema Cause Treatment 1° renal Na retention.arcerial underfilling Severe hypoalbuminemia (<2) with poor response to diuredcslvolume depletion Mechanicalcauses Others Loop diuretics +I- zhiazide diuretics IV albumin (to achieve serum albumin >2,0) + loop diuretics +I- thiazides Addras mechanical cause Treat underlying disease NEPHROTIC SYNDROME (NS) D e f in it io n a n d Pa t h o g e n e sis , Pnoteinuria: >3.$ old or >3 g/g by urine protein to Cr ratio (UPCR) due to podocyte injury i Hypoalbuminemia (<3.5 g/dL): urinary losses + tubular metabolism > hepatic synthesis Edema: 1° Na retention (overfilling) 1 L oncotic pressre (underfilling)lRAAS activation Hyperlipidemia (cholesterol and/or TG): not required to fulfill the criteria for NS; low plasma oncotic pressure leads no T LDL T angiopoietinllke 4 - T TG (Not Med 1.1411&371 NS is a phenotype (not a disease): microscopic hematuria.AKI possible (overlapping f e a t u re s wit h n e p h rit ic syn d ro me ) E t io lo g ie s Primary podocyte/GBM injury: MCD. FSGS, MN. Some cases of IgAN. MPGN Glomerular injury dlt systemic diseases: DM (nephrotic range proteinuria > NS). amyloidosis, lupus nephritis (esp. class V) gzip E p id e mio lo g y 518 yo: MCD > MPGN > FSGS ctr 197911159) 1860 yo: FSGS = MN > MCD > LN > DN > IgAN 260 yo: MN > amyloid > MCD > FSGS > DM > loAn (AGID 7.0111961) 2% yo: MCD > MN > amyloid > FSGS > leAn > DM (Acre 1011:19:611 ExtraRenal Clinical Manifestations Hypercoagulability: unclear mechanism: adults > children:venous > arterial thrombo ses; MN > other diseases: risk factors:Alb <2.B. heavy proteinuria (qAsn 1012:7:513) Pleural effusion transdates pattern as in cirrhosis. CHE constrictive pericarditis Ascites: serum ascites albumin gradient <1.1 as in peritonitis. peritoneal carcinomatosis Gut edema: NN abdominal discomfort; pericardial effusion t TSH: thyvoxinebinding globulins loss from proteinuria Vitamin D deficiency: vitamin D-binding protein loss in urine In fe ctio n , h yp o g a mma g lo b u lin e mia za n tib o d y lo ss in u rin e Nephritic SyndromeAssociated Conditions unSAIDs. penicillamine MCD. MN Lithium. IFN. pamidronate. HIV MCD. Collapsing FSGS Riiampin. ampicillin. EBV. syphilis. ehrlichiosis. mycoplasma Hodgkin lymphoma. dvymoma. ampy/eczema MCD Slmngyfoides sterroralis (xi re 20183141 MCD.Tip FSGS Heroin, anabolic steroids. sirolimus. HCV DAA (H4¢ul=¢, 1017:666$8) CMV. SV40. parvovirus B19. leishmaniasis. filariasis HLHlMacrophage acdvauon syndrome. cerebd arredds. aukonset Still disease. MClD. multiple myeloma. SCD. acute monoblzsdc leukemia. FSGS polycythemia Vera. essential durombocydiania. primary rrrydcibrosis Gold. mercury. capropril: HBV. syphilis. Malaria. SLE. RA Malignancy (lung. colon. breast. pros re. UKEFUS. gastric) MN Chronic osreomyeliris. tuberculosis. RCC. RA. IBD Familial Mediterranean fever. hidradenitis suppuraliva M amyloidosis Workup and Diagnosis Kidney bx required in most cases Lab: hepatics B and C serologies. HIV.ANA.C3. C4.SPEP with IFE. kappallambda free light chain assay. UPEP with IFE, Hb Alc. antiPLA2R Ab In diabetics.consider kidney biopsy if rapidly progressive kidney disease.exu'arenal symptoms dw systemic disease. (+) serologies.and in patients with short duration of DM Management of Complications Volume overload: loop. dmiazdes. MRBs diuretics PO (absorption may be reduced from gut edema) or IV; IV diuretics + IV albumin if severe/relractory Hypertension: goal <130/80. use RAAS blockade If persistent protelnurla Hypercoagulability: prophylactic anticoagulation if bleeding risk is low and serum alb <2.8 for MN (al 2013;8521412). Role of prophylactic anticoagulation for other NS etiolo gies uncertain, but could be considered if serum alb <2.0 Hyperlipidemia: statins if persistent due to tHMGCoA reductase activity and risk of coronary heart disease in NS (Ki 199144638) Hypothyroidism: treat unless resolves with management of NS GLOMERULONEPHRITIS (GN) Definition and Renal Manifestations Microscopic or gross hemaouriz dysmorphic RBCslaand1ocytes. RBC asks on sediment Azoremia, HTN common: proteinuria. usually subnephrotic (<3,5 old). can also have nephrozic range proteinuria (overlapping presentation with NS) GN is a phenotype of infiammamory glomerular disease. not a specific disease Diagnosis Based on kidney bx and clinical history/labs Proliferation (mesangial, endocapillary.extracapillarylcrescents) common on bx Glomerular injury secondary to systemic diseases: et. infections such as endocarditis. SLE.ANCAassociated vasculitis, Henoch-SchOnlein purpura. Goodpasture syndrome Lab workup depending on clinical presentation: C3. C4.ANA. hepatitis B and C serolo gies.ANCA (including anuMPO and ami-PR3 Ab titers). antiGBM Ab. HIV. SPEP/IFE. serum kappa/lambda free light chain assay, cryoglobulins. RE and blood culture Common Serum Complement Changes in GN Low Complement Normal Complement Immune complex-mediated MPGN. lupus nephritis In1ecdonrela¢ed GN, cryoglobulinemic GN, C3G PGNMID, MIDD (esp, hea chain). immunoracxoid GN Pauciimmune GN AntiGBM dz I nephrivJs.libriIIa GN ExtraRenal Manifestations of Systemic Diseases That Cause GN Disease Extr aR enal Pr esentation lA Vasculitis (gAv. aka HSP) Skin: uniaria, ecchymoses, maculae. palpable purpura Gl:Abd pain, GIB. nausea. vomiting MSK: arthralgias, arthritis Systemic lupus erythematosus (SLE) Constitutional: fever. malaise. weight loss Skin: molar rash. discoid lupus Lung pleuritis; cardiac: pericardids Gl:abdominaI pain. GIB MSK: ardiralgias. arthritis; neuron: confusion, seizure. stroke ANCAassociated vasculitis Constitutional: fewer. malaise. weight loss Skin: palpable purpura Lung cavities. nodules. pulmonary hemoorrhage. cough Gl: abdominal pain, GIB MSK: ardiralgias. arthritis: neuro: mononeuritis multiplex ENT: riiinosinusitis. hearing loss. cartilage destruction Pulmonary hemorrhage AntiGBM dz Npon syndrome ENT: sensorineural hearing loss Eyes lens. retinal and corneal defects Cryoglobulinemic GN Skin: palpable purpura. ulcers Neuro: neuropathy MSK: arthralgias. arthritis. myalgias RAPIOLY Pnocnessuvs GLOMERULONEPHRMS (RPGN) Clinical presenlzdon of inflammatory glomerular disease with rapidly worsening kidney function over days. weeks.or months -» associated with poor prognosis if unrreaced Causes:ANCAassociated vasculids. antiGBM dz. lupus nephritis. IgAN/IgAV. infectionrelated GN (especially endocardiris) Crescents (extracapillary proliferation) often seen on kidney bx in RPGN cases Requires rapid diagnosis (kidney bx) and creacmen: If awaiting biopsy, empiric treatment with pulse IV glucocorticoids (methyiprednisolone 500-1.000 mild X 3 days): will not change biopsy results PLEX: consider in DAH and severe AKI THROMBOTIC MICROANGIOPATHY Endothelial damage -» microangiopathic hemolytic anemia (MAHA). platelet aggregation and consumption in small vessel -» organ damage Causes (new 2014:371:654) infection: enterohemonrhagic E coli (Shiva toxin), Shigella dysenteriae, S. pneumonia. Influenza AIH 1 N 1. HN EBV. CMV. M. pneumoniae, Bordetella pertussis. Parvovirus B19 TTP: hereditary or autoimmune ADAMTS13 deficiency Atypical HUS: hereditary or autoimmune disorders of complement regulation Pregnancy or postpartum: (pre)eclampsia. HELLP syndrome Transplantation: solid organ. bone marrow or stemcell transplantation Metabolic: cobalamin C (vitamin Be) def (Lanai 1015;386:1011: am" n¢w--=l z015.10=1z0z> Autoimmune: SLE.APS.scleroderma renal crisis (SRC, in systemic sclerosis type) Malignancies: metastatic adenocarcinoma. monoclonal gammopathy (KI Z017;91:691) Malignant hypertension Drugs: CNI. gemcicabine. quinine. ticlopidine.antiVEGF therapy (NEW zouauasanml Genetic: ocxe (Na Gale 2013:45:531; qAs~ N1510.1011). lNF2 we zo\6:4:10s41 Clinical Manifestation and Diagnosis Hematologic TMA: MAHA (t netic count. T LDH. haptoglobin, t indirect bilirubin. from schistocytes on peripheral blood smear) + thrombocytopenia (<150 or >25% baseline) » organ dysfunction Renal TMA:AKL proteinuria. glomerular hematuria. hematologic TMA. hypertension Not all renalTMA has all feawres of hematologic TMA Biopsy: fibrin thrombi (when acute). endotheliosis, mesangiolysis. intimal edema. "onion skinning" (myocyte proliferation) of vessel wallsaglomeruloid body (organized thrombus. specific for APLA). capillary loop duplication. subendothelial electrolucent material on EM (in chronic) SRC and malignant hypertension: vascular damage predominantly ExtraRenal Manifestations (Nam nail 2014;1197: x12017;91539) Neurologic: irritability. mental status change. stroke. focal deficits. seizure. coma GI: NN bloody diarrhea. pancreatitis. liver injury Skin: purpura. small vessel vasculopathy. gangrene Cardiac: cardiomyopathy. Ml. myocarditis. CHE occlusive CAD Others: pulmonary hemorrhage. rhabdomyolysis T M A Wo r ku p Cause, Clues Wo r ku p All TMA Culture studies. HIV. homocysteine. methylmalonic acid: cobalamin C deiciency Paraprotein studies: SPER slFE. serum FLC HUS: diarrhea (D)+ Stool studies for STEC EHEC aHUS: no other history or family lo TMA Complement studies: C3. C4. CH50. gene mutations/ autoantibodies: J if KT being considered TTP ADAMTS13: activity, inhibitor and antigen SLE ANA. aCL Ab. ll2Gp1 Ab. lupus anticoagulant Scleroderma Malignant HTN RNA polymerase III ab. skin exam Retinal exam.TTE. and ECG (for LVH) Preeclampsia/ HELLP LFls. fetal monitoring. placental ultrasound T reat m en t Empiric: PLEX if no obvious etiology identified. CS if low suspicion of scleroderma or infection; stop potential offending agents TMA Treatment When Etiology Known Cause Tr e a tm e nt HUS: D+ Supportive care: fluid/electrolyte management. dialysis if needed aHUS PLEX. eculizumab INE;M 2013.za 2169); CS. rizuximab if auloAb+ TTP CS. plasma infusionlPLEX. Cyclosporine. or rizuximab if refractory. Spleneczomy rarely needed _ Auloi immune Immunosuppression for SLE,ACEi for SRC. andcoaguladon for APS Malignant HTN Aggressive blood pressure control (Pre)eclampsia Deliver baby -» consider alcemative dx ilTMA does not improve ACUTE KIDNEY IN]URY (AKI) Ba c k gr ound a nd E pi de m i ol ogy Overall global incidence 22% in hospitalized patients (qASN 2018:8:1482) Up to 67% of ICU patients (cm cm z0os:1ixn7:) Up to 50% in septic shock,associated mortality -707G (KDIGOAlfJ 2012) Risk factors: volume depletion, age. hypoalbuminemia. female. CKD. DM. 1 EE car diac surgery. chronic liver disease. malignancy (»(oicoAxl 2011> De fi n i ti o n Sudden loss of kidney function. clinically manifested as l creazinine +I- 1 UOP AKI Staging fKDlGOAKI 1011) Stage Cre a ti ni ne Ur i ne O utput (UO P ) t 0,3 in 48 hr or t to 1.5-1.99x baseline wu 7 d <0.5 cdkg/hr for >6-12 hr 2 T to 2.0-2.99x baseline wu 7 d <05 cdkg/hr for 212 hr 3 t to 23x baseline wu 7 d: OR increase in Cr to 24.0; OR need for RRT <03 cdkghr for 224 hr or anuria for 212 hr 1 More advanced stages associated with worse outcomes an moruliry CAus E s or AKI Causes of anuric renal failure: usually due co severe shock. RPGN. bilateral (or single if one kidney) renal artery or urinary obszruction Prerenal: L effective arterial volume Hypovolemia. cirrhosis, early shock of any etiology before progressing to ATN, car diorenal (CHEAS. RV dysfunction). abdominal comparunem: syndrome. hepatorenal syndrome. hypercalcemia. capillary leak syndrome I n tr a r e na l Glomeruli: GN. look out for RPGN AnuGBM disease Immune complex: infectionrelated GN. SLE. cryo. loAn, IgAV/HSR endoardicis Pauciimmune:ANCAassociated (GPA, MPA) Thrombotic:TMA (TTP/HUS, DIC. complemenrldrugmediated TMA. anriphospholipid antibody syndrome. preeclampsia/HELLE malignancy) Vasculature:TMA (malignant HTN, scleroderma renal crisis). emboli (eg. cholesterol). renal artery occlusion. renal vein thrombosis. polyaneritis nodosa Tubules:ATN (sepsis, ischemia, toxins). light chain cast nephropathy. Crystal induced: urane from tumor lysine. PO. from oral and possibly enema (KI 201680u1 lntersrjtium (AIN): Drugs (70%) especially antibiotics, unSAIDs, Ppls Infections (many bacterial incl sizph. suep. syphilis. Legionella; viruses: mycobacteria) Autoimmune diseases (SLE,SjOgrens, lgG4 vasculitis. sarcoidosis) Miscellaneous (TINU syndrome. lymphoma) P os tre na l Stones. BPH/prosme cancer. retroperkoneal Fibrosis. bladder/pelvic malignancies. transitional cell carcinomajungus balls. blood clots. papillary necrosis with sloughed issue causing obstruction Wom c ur of A K I History and Physical Examination Hypotension: absolute or relative vs baseline Drugs: unSAIDs. diuredcs.ACEilARB, Pal,andbiotics, herbal remedies/ illicit drug Volume depletion: diarrhea.poor PO intake Injection/sepsis, IV contrast Recent surgery/arterial catheterization: cholesterol emboli Markers of volume status: BP. skin turgon mucous membranes.JVD, edema. rates Changes in urine output (oliguria). hematuria Rashes/joint pain: vasculitis. endocarditis.AlN Respiratory symptoms: pulmonary renal syndrome. eg.ANCA. andGBM. SLE, cryo In i ti a l L a b o ra to ry Wo rku p J on most patients: BME LFTs. Ca, PO4.aIbumin. CPK. UA with microscopy and sedi ment. spot urine protein/sodium/urea/creadnine.CBC with differential BUNlCreatinine ratio:normaI roughly 10:1 >20:1 suggests prerenal because hypovolemia causes t reabsorption of sodium and water in proximal tubule.and urea follows passively <20:1 suggests intrinsic renal disease False T BUN: steroids, GI bleeding from increased urea production: creatinine lilith low muscle mass (eg. elderly. cirrhotics) False LBUN: low protein intake: T creatinine release from rhabdomryolysis or impaired tubular creatinine secretion (eg. trimethoprim. cimetidine) FEm.: used to distinguish prerenal from other causes <1X. (prerenal): 1-2% (prerenal or intrarenal); >2% (intrarenal or obstruction) <1% cutoff for prereial only applies for marked L GFR, prerenal physiology with normal kidney function can have FE~ <0.1% Caveats: nonprerenal <1% can occur with contrast nephropathy. rhabdomyolysis, GN. ATN in background of severe prerenal state (eg. cirrhosis. CHF): prerenal with >1% can occur with background CKD or diuretic therapy FF~ accounts for water handling. better than urine sodium alone FEw,..: likely better than FEm on diuretits (NephiunGnPh:a 201¢z114:¢145) Laboratory Findings of Prerenal AKI and ATN Measurement Prerenal ATN BUN/Cr ratio Urine sediment >20:1 Bland or hyaline casts Urine specific gravity Urine osmolaliry Urine sodium >1.020 >500 <10-20 <1% Renal tubular epithelial cells.muddy brown casts," granular casts 1.010 <350 >20-40 >2% <35% >35% FEn. FM.. <20:1 Urine sediment: uciliry conuoversialc considerable inneroperator variability: polar ized light to see crystals, lipid droplets in NS (makese crosses) Urine Sediment Findings and Significance Finding RB C Significance Nonglomerularz stones. tumor. exercise. menses. infection. imersrizial cysuris. transient. AVM. papillary necrosis. PKD. medullary sponge. Dysmorphic RBC RBC casts WBC WBC casts hypercakiuria Glomerular: GN.thin basement membrane nephropa¢hylAlports GN, loinpain hemawna syndromeaacanrhocyzes are subtype with 98% specificity for GN 1xl 1991:4al1sI GN usually. less commonly AlN who zoirsancl AlN.TB. schiswsomiasis. fungal. stone. rumor. infection. interstitial cysdsis MM zmsaniw) AIN, GN. pyelonephriris Only 3% of AIr with WBC casts (A 2014: 54558) Medications: acyclovir, indinavin sulfamethoxazole. sulfadiazine. methotrexate. amoxicillin. Ciprofloxacin CaOx: ethylene glycol. hypercalciuria.enteric or primary hyperoxaluria. orlistaf. vitamin C CaP. phosphate nephropaihycalkaline pH Unk acid: hyperuricemia. orate nephropathy, tumor lysine: acidic pH Renal tubular epithelial cell casts Granular casts Hyaline casts Waxy casts Cystinuria. Struvite: Mgammoniumphosphate."triple phosphate". with unease splitting bacteria. alkaline pH ATN Any RTEC or granular casts may predict ATN with sensidvlzy 83% and specificity 77% (qASN 2008:8:16151 Derived from degenerated epithelial cell casts;"muddy brown casts" are pigmented version (ATN, hyperbilirubinemia) Nonspecihcz seen in h Ithy and disease states Degenerated granular casts: nonspecific. seen in both chronic and acute disease Urinalysis Specific gravity an approx urine osmolality;- 1.010 - 300 mOsms/kg (intrinsic disease, >1.020 with prerenal disease): discordance with large. heavy molecules (contrast. glucose) which T sp gravity more than osmolality (-) blood wlo RBC: myoglobin (rhabdomyolysis, /CK). Hb (/blood smear hemolysis) () proteinuria only detects albumin (and usually only >300 mg/g crest. previously known as macroalbuminuria"): if discordante between dipstick proteinuria and quantified proteinuria. then likely LMW proteins or paraproteins present; sulfosali tylic acid can be added to detect nonalbumin proteinuria (~) glucose with serum glucose <180 suggests proximal tubular defect (aminoglyco sides. paraprotein disease. heavy metals. cisplatin. tenolovir) or SGLT2 inhibitor Quantilled proteinuria Spot UPCR or UACR; approximates 24hour urine protein or albumin excretion if daily creatinine excretion is 1 old (can significantly underestimate or overestimate daily proteinuria in large/muscular or low muscle masslelderly. respectively) Spot ratio can also be inaccurate when serum creatinine is fluctuating Nevertheless 24hour urine collection not usually needed in AKI Quantify proteinuria even if dipstick protein negative to evaluate for nonalbumin proteinuria (eg, paraproteins in multiple myeloma) % urine albumin excretion <25% may predict cast nephropathy in dysproteinemic kidney disease (c/As~ 2012;71964) AKI on CKD-proteinuria may be due to the chronic process,and not acute (eg. ATN in patient with preexisting diabetic nephropathy) CBC with differential Eosinophilia may suggest AlN.atheroembolic disease Significant anemia can suggest CKD.TMA (especially if thrombocytopenia). multiple myeloma. hemolysis (and pigmentrelated injury) Thrombocytopenia can suggest TMA (eg.TTR HUS, DIC). SLE. antiphospholipid anti body syndrome, cirrhosis. / smear for schistocytes if anemic. coags Leukocytosis can suggest sepsis. myeloproliferative disorder Calcium T: can cause AKI (prerenal.ATN); or clue for multiple myeloma. sarcoldosis. malignancy i CKD. hyperphospharemia: pancreatids, tumor lysine, rhabdomyolysis Serum albumin If low. in nephroric range proteinuria, suggests primary NS Very low levels (<2.8) in NS can increase risk of thrombosis. including renal vein thrombosis (especially with primary membranous nephropathy) Large gap between total protein and albumin level suggests paraprotein disease Radiographic Testing Renal ultrasound (preferred) or noncontrast CT in mos: patients to rlo obstruction Small kidneys (<9 cm) suggests chronicity (except with diabetes) Large kidneys (>11-12 cm) suggests AIN. diabetes. amyloid. PKD. lymphoma. HIVAN. renal vein thrombosis Echogenicity not a reliable indicator of CKD IQASN 20142923731 Asymmetric kidneys suggest unilateral renovascular or congenial disease Additional Tesclng: Dictated by Other Clinlcal Flndlngs Paraprotein workup - / SPEP/IFE. serum free light chains. UPEP Ge: if > age 50 wl unexplained AKI; or manifestations of MM.amyloidosis. etc Serum uric acid: " in any renal disease due to decreased renal clearance: especially t in tumor lysine. rhabdomyolysis. myeloproliferative disorders. acute orate nephropathy If t out of proportion to renal failure (je. >15) then could be cause rather than effect of kidney disease: urine uric acid:creatinine ratio >1 suggestive of this If acute orate nephropathy suspected. treatment is IV saline. rasburitase. XOI If suspecting glomerular disease: serologic workup can include hepatitis B/C. ANCA.ANA. dsDNA. C3. C4, cryo, andGBm, SPEP/IFE. serum free light chains. UPER HIV. blood culwres: ultimately need kidney biopsy to confirm Novel biomarkers for ATN (not yet clinically available) Urine neutrophil gelatinaseassociated lipocalin (NGAL) (An IM z0ae.14a;s101 Urine kidney injury mdeculel (KIM1) us zcuetnlcus) Indications for Kidney Biopsy in AKI Unresolving AKI; suspected GN;AIN for which steroid treatment is being tonsldered Common Pattems Associated with Acute or Subacute Kidney Diseases Findings Possible Diagnosis Acellular unne, minimal protelnuria (<1 g) Prerenal and ATN most likely.Aln also possible (even without pyuria or proteinuria). obstruction. crystal disease (oxalate. orate. phosphate nephropathy). cast nephropathy. atheroemboli Nephrotic range proteinuria, +Imicrohematuria Pyuria with minimal proteinuria (<1 g) Subnephrotic proteinuna and cellular urine Pulmonary-renal syndromes NS wl ATN (usually minimal change). FSGS (especially Dermatology-renal syndromes Low complements collapsing). amyloid and other paraproteinrelated glomerulopadwya renal vein thrombosis (especially MN) Infection,AIN, alheroemboli Inflammatory glomerulonephritis (immunecomplex such as SLE/infection relatedllgA. antiGBM.ANCA),TMA. malignant HTN. PAN ATN from sepsis (pneumonia).ANCA.andGBM. SLE. cryo. AIN from pulmonary infection (Legionella.TB, Streptococcus) or the antibiotics used for treatment. infectionrelated GN.AKl with volume overload and pulmonary edema. scleroderma. sarcoidosis. drugs (PTU. cocaine). lgAv (rare pulmonary hemorrhage). loAn (hematuria following URI), CJG following URI Vasculius (ANCA. SLE. cryo. PAN. HSP).AIN. endocarditis. infectionrelated (cellulitis). scleroderma. atheroemboli. hep C (porphyry). amyloidosis (purpura). HIV (Kaposi sarcoma. eosinophilic lollkulitis) SLE. infectionnelazed, cryo. C3G. other MPGN, lgG4related disease. endocarditis, atheroembolism PREVENTION oF AKI General preventive measures: minimize nephrotoxins (et. contrast. NSAIDs).volume depletion, hypotension: renally dose medications No single medication consistently shown to prevent septic or ischemic ATN Lowdose dopamine ineffective and potentially even harmful (KA 200s;sm659) Fenoldopam 1 AKI but not RRT/mortality: needs more data Lon Cane 101s=1*r449) Auial natriuretic peptide (ANP) with mixed results 1qASN 1009141261) Remote ischemic preconditioning safe but uncertain efficacy: metaanalysis negative. do not recommend currently for ischemic ATN icumum Onwiiw So Rev 2017:CDOl0777) Off pump cardiac surgery did not rates of AKI requiring dialysis (NEW 201I:368:1179) Withholding ACEi/ARB prior to surgery of uncertain benefit. may prevent periop hypotension, but need RCT to determine effect on hard outcomes Aminoglycosides: oncedaily dosing reduces AKI without affecting efficacy (Am/l4¢alui Syn Mann 1996: 53;1141): gentamicin > tobramycin > amikacin. in decreasing toxicity Fluld Resuscitatlon Use crysralloids over colloids;balanced crystalloids reduced kidney evenr,s vs NS in ICU (new 1018;378:819) and nonICU settings (NEW z01a. annals) Contrast Nephropathy Use low/isoosmolar agents. minimal contrast dose. periprocedure normal saline if pulmonary status ok Conflicting data on NAC, likely not beneficial we 101&3781603-14), isotonic sodium bicarbonate not beneficial over NS (new 201s. J7&w3) MANAGEMENT oF AKI Mainly supportive; control of underlying process (et. sepsis, volume depletion. RPGN) No single medication shown IO improve outcomes after septic/ischemic ATN Loop diuretics can be used no manage volume while awaiting recovery. bu: does nor hasten renal recovery and should not be used co delay dialysis if indiaced R e n a l R e p la ce r n e n t T h e r a p y Indications: acidosislhyperkalemialvolume overload refractory to medications. uremia (pericardial effusion, AMS). certain ingestions M o d a lit ie s: Continuous renal replacement therapy (CRRT). intermittent HD (HD). slow low efficiency dialysis (SLED); no modality proven to be superior UA/W\ zaoeaswvsl Hemofiluation may improve clearance of middle molecules but no improvement in outcomes over hemodialysis (cm Core 1012:16:R145) CRRT or SLED preferred over HD if patient is hemodynamically unstable. or with increased intracranial pressure (less dramatic osmotic shifts than HD) Dose: 3xlwk noninferior to 6xlwk for HD. effluent rate of 20 cc/kglhr noninferior to 35 cc/kglhr for CRRT (nE/A1 z00s¢3 se1>; aim for modestly higher effluent rate for CRRT as interruptions will limit actual delivered dose compared to prescribed dose: weekly Kt/V 23.9 for intermittent or extended daily dialysis (Kolco Ax: 10121 Timing of RRT most evidence does not suggest mortality benefit for early vs delayed initiation of RRT lAKll(l num 2o16=37s1122. naya 201B;37&143\)i n o sp e cif ic B I JN o r Cr threshold when to start Pnocnosls oF AKI Depends on severity and duration of injury, baseline function. comorbidities Furosemide stress test; 1-1.5 mglkg of furosemide: increased urine output predicts more favorable outcome. but does no: alter outcome UAS~ 201§:162023) Nonoliguric ATN generally w/ better prognosis. possibly dl: less severe injury and better volume saws; positive fluid balance wlAKI alw worse outcomes (Cn cm mfazoiwri7sai Full extent of recovery with ATN occurs usually by 6-12 wk Up to 1/3 of all AKI istransient" (recovery w/i 3 days). but still alw t hospital mor tality vs no AKl (NDT 201m251833> T morality in survivors of AKI (rate ratio 2.59) who 1009:s3:961i Cardiac surgeryAKl T longterm monality.even w/ complete AKI recovery (aodauan 2009;1\91444) Longterm mortality in survivors of AKI worse if renal function doesnt normalize (46% vs 83%) cm (one z01z 16n13) AKI increases risk for CKD (HR 8.8). ESRD (HR 3.1). mortality (HR 2.0) (to zoizei 4421 ICU: hospital mortality t with T severity ofAKl; 8,8-26.3% range (Cm cm 1006;10a73i 35% hospital mortality, 49% 6month mortality in AKl requiring RRT in Finland ICUs ion co 2012:\6:iuJ1;47% hospital morality. 65% 1 yr mortality in another study in AKI requiring RRT in ICU CHRONIC KIDNEY DISEASE (CKD) Definition CKD:prsencedkidneydamageorllddneyfuncdon(eGFR<60)for23mo(4p(Dl9n&3951) Kidney damage: UACR >30 mg/g. active urine sediment. kidney transplant. or abnor malities on biopsy or imaging (Lama 2012:37%165) Staging risk stratifies pts and aids in management we 2002;39:51) CKD Staging (G: GFR category;A: albuminuria ca gregory) G G1 G2 G3a G3b GFR (mUminI1.73 m1) 290 - kidney damage A A1 AER (M8/4) 60-89 45-59 A2 AA 30-300 >]00 30-44 + kidney damage G4 G5 15-29 <15 <30 Stages are classified into risk categories (based on rnorxzlicy CV morl:ali:y.and ESRD risk) All G3b. G4. G5.ar\dA3 prs are consider at high or very high risk (xoico can 2012) Epidemiology (zoia may annul day wvfll Prevalence of predialysis CKD (1-5) was -14.8% of the U.S. population in 2013-2016 Stage 3 (6.4%) the most prevalent Females > males (16.7% vs 12,9%): CKD T w/ age (32.2% of adults >60). <10% of CKD pts aware of disease 1.4/n z01zas:191).5M awareness in stage 4 CKD Etiologies of CKD Category Possible Causes Urinalysis Renal UIS Prerenal Chronic CHF Chronic cirrhosis HTN (APOLLO) Renal vascular disease TMA Chronic glomerular disease DM (ml cause of CKD) inherited disease: cystic kidney disease eg. PKD, CAKUT Infiltrative disease Cl\ronicTlN ObsrrucUve uropazhy RP fibrosis Minimal protein, bland sediment Minimal protein. bland sediment Small kidneys excluding DM (+) protein. +I- RBCs HIV. DM: large kidneys (+) protein <2 old, PKD: large cystic kidneys DM. infiluative disease: large kidneys () hydronephrosls RP fibrosis: +/- hydro Vascular Glomerular Tubulointerstitial Postrenal +I- WBCs Minimal protein . 36% w/ CKD have DM.31% HTN.and 40% cv disease (1018 USRDSanmIldau ftP°f¢l C V a n d Al l C a u se Mo rta l i ty o f C KD CKD a/w traditional CAD risk factors such as HTN. DM.smoking. HLD.older age. and :he metabolic syndrome UASN 2®S:16§19) 4 eGFR, T UACR = independent risk factors for CV and allcause mortality (Ann IM 1007;167:2490: [ASN 1002.\1745) CKD is CAD risk equivalent -» risk factor reduction is needed lcnmiiuin z00J;1oa;z1s4l Nontraditional CAD risk factors: anemia (Ain I cnuiii 20(8:l02:166). inflammation l}ASN Z004;15:530). <<alciurn balance for 100s;z1=z464). CKDMBD (nor z0os;z1:z4¢4) Proportion of CV deaths. infections. DM complications T w/ . eGFR UASN 2015:16:1504) Progression to ESRD Injury -» Adaptive hyperiiltration initially LCr _> eventually CKD progression Rate of transition 3 4 CKD - ESRD: 1,5%lyr (AmIM z004:141:9s) Pts with uncontrolled HTN. DM, and CKD lose -12 mUm in GFRlyr.When treated 4 mUm in GFRlyr In z001:s9:7021 2 and syr kidney failure risk can be predicted with 4 or 8 variables it zoi 1=:0s1ssJ1 WE* 2016;315:164.a~:ilahlu at o»(mD'> GENERAL CKD TREATMENT Evaluate Etiology and Treat Reversible Causes dlc potential nephrotoxins;prerenaI: hold diuretics. unSAIDs. RASi Renal UlS to J for obstruction If Not Reverslble Goals Should Be Slow progression: adjust medications by eGFR; management of complications Refer to nephrology when GFR <30. UACR 2300 mglg. glomerular hemawria. or CKD of unknown eciologyaprepare for RRT CKD TREATMENT To SLow PROGRESSION Blood Pressure and Protelnuria Control in Nondiabetic CKD In nonproteinuric CKD pts. SBP >130 a/w ? CKD progression (A IM 1015:l61:1SB) L BP in nonproteinuric CKD pus has not slowed CKD progression but l morality (;ASNz011;28za12> In proteinuric CKD pos. L BP (SBP 110-129) 1 CKD progression (A/mlm 1003;13911441 In nondiabetic CKD pl.s w/ proteinuria 2500 mglday.ACEi i CKD progression vs other antihypertensive: (;Asr4 2007;18:19S9). RASi LCKD progression in proteinuric pts Independent of BP (lnnm I 998:352:1252). RASi i CKD progression in advanced. proleinuric CKD (N£lM 2006354 131) Combo ACEi +ARB did not L CKD progression or i mortality T serious adverse events (ONTARGET Inna( 200&371:547) Blood Pressure and Protelnuria Control in Dlahetlc CKD 10 mmHg J. SBP J. 12% renal failure. and 1. 5 mmHg 1 cv events we z0003z124121 RASi > other antiHTNsve meds iCKD progression INE;/VI 1001:14s:as11 RASI 1 CKD progression independent of BP effect (~5/m 1991;329114s6; new 20019459611 Combo ACEi and ARB did not LCKD progression or i mortality serious adverse events (VANEPHI\OND NEW 2G13;369:\091) Glycemic Control In Diabetic CKD InT1DM, intensive glucose treatment to nearnormal levels may 4 CKD progression (DCCTIEDIC NEjM 201156512368 In T2DM. HbA1 c of 7.0% vs 7.9% 1 CKD progression luxros Lancer iweasmsm SGLT2 inhibitors 1 CKD progression in TZDM (enpA.Rsc ourcoms ~4m 2016:37s8m> 1 kidney failure and CV events (caeosncs NUM 2019138011298 Treat to goal HbA1 c - 7.0% to icxo progression We mizmasol Other Treatments Low protein intake -0.8 glkgld may x related deaths lam-nie Canoe" so a¢y 1n09.cnao1a9zl Smoking cessation: L CKD progression UASN 1004;15:S58) NaHCO; PO mgT ID (if [HCOa] 16-20) T to target [HCO)] 223 1 CKD progression and improves nutritional status UASN z009;m107s> Multifactorial therapy (diet. exercise, smoking cessation.ACEi, and statins) 1 CKD progression (NE/M 2uoJ;z4e:3a3) TREATMENT OF CKD COMPLICATIONS Hyperkalemia Emergency if K >6.5, symptoms or ECG changes: stabilize ardlac myocytes (IV Ca) then shift K (insulin 4 glucose. IV bicarbonate. D2 adrenergic agonists) den eliminate from the body (diuretics +I- saline. sodium polystyrene sulfonate) Lower K in nonoliguric or planning surgery: low K diet, stop offending agents (eg,ACEllARB. unSAIDs), NaHCO;. diuretics. cation exchangers Gl cation exchangers Paliromer. s/e: l Mg. binds other meds (NE/M 101$;)72:111) Sodium zirconium cydosilicate: exchanges Na and H for K sie: edema (HARNONIZE We 2014::i 1};121]) Avoid Kayexalate +I- sorbitol unless lifethreatening hyperkalemia given risk of colonic necrosis Plneler dysfunction T BT dlt uremic toxins. anemia. T platelet NO synthesis Correct it active bleeding or invasive procedure (eg. kidney biopsy) To DDAVP 0.3 mcg kg IV 1 hr prior to invasive procedure.hepanin4iee HD or PD. tx anemia to Hb > 10 widi resistant bleeding add cryoprecipitate Caused by uremiarelated anorexia, decreased intestinal absorption and digestion. and metabolic acidosis Maintain die: w/ 30-35 kcal/kgld and 0.8-1.0 glkgld protein Check dry weights and serum albumin if decreasing -» star: dialysis Malnutrition Anemia Background 1 EPO production by the kidneys normocytic normocliromic [Hb] <13.0 in males and <12.0 in females. T prevalence wl CKD progression: 1% eGFR 60, 9% eGFR 30. 33-67% eGFR 15 (new it 2002;16z1401l /RBC indices, relic count. iron.TIBC. ferritin.WBC w/ diff, platelets.and Biz and folate if MCV >100 If anemia + off ESA, monitor every 3 mo Anemia - Iron Iron deficiency 4 ifTSat 520% or lenritin $100 fig/mL Iron may * Hb ifTSa: 530% and ferritin $500 nglmL Oral iron: 65mg elemental iron QD or QOD (1-3 mo trial) IV iron (iron dexinn.ferric carboxymaltose. sodium ferric gluconate complex, ferumoxyiol. iron sucrose. ferric pyrophosphate citrate) it severe deficiency or no T Hb w/ oral iron Anemia - ESA Address correctable causes of anemia prior to ESA Treating anemia no nornormal Hb in predialysis CKD wid\ darbe T smoke F1NSAT new zuntaaifnm Consider ESAs if Hb <10 to prevent blood transfusion Goal Hb 10-11.5 Dont use if malignancy. severe HTN, recent stroke POW retention, i Ca. 1 calcitriol, T FGF23 and 1 klotho 1st step: PO 4 retention -> 1 PTH who mummy t PTH. l. calciuiol when eGFR <60 tqasn zuo9,4;\a4. Kl z007:71=3\1 T P04 when eGFR <30 (POW controlled as higher eGFR due to T FGF23 and PTH uAs~ Z09$;16:120S) /serial POW. Ca, and PTH levels. Imaging, bx not yet used for o< Tx Phos to normal w/ diet and phos binders Non-Cabased phos binders > Cobased u4(\12013;:arma1 If PTH Ting -9 correct T POW. 1 Ca.l vitamin D Cakiuiol or vitamin D analogs if severe and worsening T PTH No vitamin D (nutritional or active) if Ca 29.5 or t P04 CKDMBD Background CKDMBD Treatment ENDSTAGE RENAL DlSEASE (ESRD) Definition (2018 USRDSAnnud Dao Raven) Defined by CMS as a condition in which regular longterm dialysis or KT is neces sary to maintain life. ESRD includes chronic HD. PD. or slp kidney transplant Results from :he progression of CKD or if AKI persists for 23 mo Epidemiology (20152018 usaos AwmI Do Report) The USRDS database contains UTD info on epidemiology 726.331 prevalent ESRD cases; 124.675 incident cases in 2016 ESRD prevalence is 9.5x > in American Indians/Alaska Natives. 3.7x > in Blacks. 1.5x > Native Hawaiians/Pa¢:iGc lslanders.and 1,3x >Asians than Whites Prevalent ESRD with DM 40%:T cognitive impairment in HD (nwwqy 2006:67:1I 6) Prevalence of depression in ESRD pts is 3040% (Kl101J>s4=I7v) 35.4% with little or no preESRD nephrology are; mean eGFR at dialysis initiation 9. Renal Replacement Therapy (1018 urns Aiuunl Dan Know) 87.3% incident ESRD pts iecewe HD,9.7% PD.and 2.8% a preempthie kidney transplant • 63.1% prevalent ESKD pts receive HD. 7.0% PD. and 29.6% have a kidney transplant In 2015.home dialysis (HHD or PD) accounted for 8.6% of prevalent dialysis pts 80% use a catheter at HD initiation 62.8% HD pts use an AVE 80% were using an AVF or AVG at 1 yr after initiation 39% ofAvFs fail to mature: median time to first use ofAVF is 108 days Prognosis of ESRD 4 z017z01s usaosA~»\»l Day m9-=f=1 Survival: transplantation w/o dialysis > transplantation after dialysis Mortality 265 yr T 7x than general population ESRD pts are hospitalized . Zxlyr 48% of deaths in dialysis 7J2 CV causes (arrhyd\mias.cardiac arrest. C H E A M L A S H D ) I mortality on Monday orTuesday aker a long weekend <~€Jm 1011:3651099) Stalins do not J. CV risk 4si4Aru= lame: 1011:377:11B1) 1 K HD bath a/w arrhythmias (Vu 19002171a11l Medicare spending on ESRD in 2016 was $35.4 billion (72% of overall budget). $28 billion on HD and $90,971lpt/yn PD costs < HD per pt Treatment of ESRD Diet. exercise we zouo.as:s17l Sodium, potassium. phosphorus, and liquid restriction Protein intake for HD and PD = 1.2-1.3 g/kgld Energy invoke for HD and PD = 35 k<1II*s if <60 yo and 30-35 kcal/ Adequate dialysis Target a deiivened KW of 1.2 per HD session. No T beneNzs kg if 2 60 we louaas$n Exercise is a/w improved health outcomes (Ago 2014;s43BJI (moon Aero z01 s=seas4= W)2M1l&$"] Volume Overload from 1 KrlV... memo NeIM 200z147¢z010I Minimum of 3 hr HD with a biocompatible membrane For PD. target a minimum KtlVurea of 1.7/Wk (residual kidney function + PD clearance) No f from T KdVurea lAnv£x M94 z0oru1s0n Optimize dry weigh! Chronic fluid overload T mortality (C[A$N 1015.moa1 T ultrafiltration rates (>10 mUhr/kg) T CV mortality (KJ 7.0\1:79:1S0) HTN SBP <120 and SBP 2150 T mortality uAsr4 zoos;w;sn» L BP with antihypertensive: 1 CV events wwuie.=»=~ zno9.s:¢as0l No RCTs of BP targets in ESRD Tx: 1st step is L dry weight to achieve euvoleni;Target 0.5 kg ,T per session.Then consider medicadon [iB. RASi. DHP CCB Bblocker 1 CV event.. hospitalizations in HD prs w/ LVH war 2014;2%672) In PD. RASi preserves residual renal function WM u104.4J210s0l Hyperkalemia Emergency if K >6.5.symptoms or ECG changes: stabilize cardiac my<oytes. shift K, then emergency dialysis Urgency if K 5.5-6.5:stabilize.shifL then urgent dialysis win 6-12 hr For dialysis pts with chronic t K, use GI cation exchangers Avoid low K HD bath:T arrhythmias in \9sixinin Anemia txt:>l<;oA»~nn MII) CKDMBD It(DiGO man zom Evaluate monthly: IV iron ifTSAT <30X and ferrite <500 WmL and no active systemic infections E845 when Hb 9.0-10.0: stop ESAs when Hb >11,5 Evaluate POI. Ca, and PTH levels serially Treat T POl wl diet and binders: restrict dose of Cabased binders Non-Cacontaining POl binders: sevdamen landlanum.fenic citrate. sucroferric oxyhydroxide Dialysate [alciuml 2.5-3.0 mErelL Maintain PTH at 2-9 x ULN of assay wl caldmimedcs or vitamin D analogs; severe T PTH: parathyroidectomy 90% of adolescents and young adults (AYA) w/ special health care needs survive into adulthood.Adult services have increasing numbers ofAYA who have either transi zioned from pediatric care or presented directly to adult services. Medication adherence worsens posttransfer (Miami nqinmi 1009;24:1055) 17-24 yo :up recipients have higher graft failure rate than older irimqiimuan zoiiazmn Some childhood onset renal diseases have new clinical manifestations in adulthood. eg. cystinosis: DM, myopathy. pulmonary, and CNS dysfunction (Non hdau 10I 7i3I191) Childhood kidney disease even w/ nl renal function is a/w adult ESRD (Ng/4 zomm428) AYA w/ CKD has impaired sense of selfworth. perceive a precarious future. and feel limited in their physical and psychosocial capacities We 2013 61975) Health Care Transition (HCT) Purposeful. planned efforts to address the biopsychological needs of early adolescents (11-15 yo). late adolescents (16-18 yo). and emerging adults (18-25 yo) Goal is co ensure AYA obtain selfmanagement knowledge and skills necessary to manage their daily treatment needs as independently as possible and become a liter are health consumer u Alan" NW, Z017:35:160) Transfer of Care Dual process of locating & arranging 1°. specialty.& interdisciplinary providers who provide care to AYA as their eligibility provided by pediatric providers ends Actual shift from pediatric to adult care Consensus Statement From lSN and IPNA (KI z011=aw04) Only transfer AYA following assessment of transition process and AYA preparedness Health Care Transition Process should: . Include key supporc parents, family, or significant others Offer opportunity of informal visit to adult service prior to transfer Tools to aid in acquisition of disease selfmanagement skills Transfer from Pediatric to Adult Nephrology Individualized transition plan, agreed upon jointly by AYA and medical team Should take place during a period without crisis Take into account treatment plans by other subspecialties . Take place with due consideration of financial factors,with adequate preparation TRANSITION STEPS Extended HCT Preparation (12-18 yo) Plan of care with measureable outcome.with derailed timeline HCT coordinator tocl1ampion"Ilead uansidon,coordinate reie11als.hald1 are coverage Age of majority (18 yo or on graduation from high school in AK. NV. OH.TN. UT. VA,WI) needs to be considered.discussion of guardianship. HIPAA Discuss changing role of parent from 1 caregiver to :hat of coach/consultant.AYA as CEO of own health Transfer of Care Period (18-21 yo) Pediatric providers can provide resources for adult providers Direct handoff between pediatric and adult providers. with a Transfer Summary Transfer Summary: comprehensive written and verbal summary of all multidisciplinary aspects of young persons care: medical. Nursing. Dietary. Social and Educational Post HCTlTransfer of Care Period (>18 yo) Documentation that transfer has taken place and AYA connected with adult providers Assessment ofAYA knowledge & skills; identify and adult 1° care provider and dentist Review an emergency plan,whom to contact if ill or needs re6lls Assess ongoing insurance coverage-referral to Financial Coordinators Discuss future goals with AYA alone and with support system lnuoducdon ofAYA to key clinic staff: consultation letter to referring pediatric provider Knowledge and Skllls Assessment Tools Got Transition/Center for Health Care Transition Improvement U. North Carolina STARx Program ht:p:/IwwvLgo:tr:nsizion.org/ https:llpediazrics.med.un¢.edu/transition etsu.cdu/com/pediatricsltraq Transition Readiness Assessment Questionnaire httpsul/ RENAL FUNCTION PURPOSES OF RENAL FUNCTION ASSESSMENT CKD staging: allows adherence to stagespecific management guidelines Reduced renal function is one marker of kidney damage along with: albuminuria. abnormal urine sediment (eg, glomerular hematuria). renal tubular disorders. abnor mal pathology. abnormal imaging (et, polycystic or dysplastic kidneys or cortical scarring). and kidney transplantation (KDICO CKD 2011) Mediation dosing adjusunencs based on renal function Prognosis: eGFR associated MM renal outcomes (development of ESRD),cardiovascular outcomes. and allcause death 1~£1m 1013:369932) Transplantation donor evaluation MEASUREO GLol4snuLAn FILTNArlON RATE (mGFR) Administration of exogenous hluadon markers (insulin, iohexol. iothalamate. EDTA) followed by serial measurements of blood/urine concentrations over time Most accurate assessment d renal function; imp4acdal for routine use d/t cost, complexity Does not provide a quantification of tubular function CREATININE Organic cation, metabolic byproduct of creatine from muscle and dietary meat Not reabsorbed or metabolized by kidney Secreted by organic cation uansporters in PCT Increased secretion in late sages of CKD Conditions That Change Serum Cleadnlne Creatinine 1 GFR T GFR T Generation: T muscle mass/bodybuilder. upper extreme 1 Generation: 1 muscle mass (limb loss. cachexia, cirrhosis. of height T Intake: creatine. high mea: diet lower extremes of height) J Secretion: cimezidine. trimethoprim, pyrimethamine, T Secretion: hypoalbuminemia dolutegravir. rilpivirine. cobicistat, ritonavin in NS (nor 200$:20.707) amiodarone. dronedarone. ranolazine Peritoneal reabsorption: uroperitoneum from bladder 1 Creatinine rupture (NDI 20069111119). ureter leak Cross reactivity in alkaline picrate method: atetoaceme in DKA. celoxitin. ilucytosine RENAL FUNCTION IN CKD Creatininebased Estimated GFR (eGFR) In steady state.creatinine level can estimate GFR by MDRD or CKDEPI equations Use serum Cr, sex.age. and race to calculate eGFR Decreased precision at higher levels of GFR (CKDEPI better dun MDRD).and possibly in advanced age and race other than white/black Blood Urea Nitrogen (BUN) Filtered but passively reabsorbed in the proximal tubule Rises more than creatinine in volume depletion or renal hyperperfusion Not affected by above conditions affecting creatinine level. but overall a less reliable indicator of kidney function GFRindependent e BUN: GI bleed. corticosteroids. high protein intake. catabolic state (fever. burns) GFRindependent 1 BUN: low protein intake/malnutrition. liver disease Cystatin C-based eGFR Endogenous protease inhibitor produced by most nucleated cells at stable rate Cysratin C generation displays less interperson variability tl\an Cr Affected by smoking.thyroid disease,corr.icosteroid use Alternative CKDEPI equation using both cystadn C and creatinine performs best (NEW 2012:367:20) Other Crbased eGFR formulas (CAPA. BIS) not shown to outperform CKDEPI UAS~2015:19811 Limitation: cystatin C assays not as well standardized as for Cr Timed Cr Clearance (C,) and Urea Clearance (C.,,,.) Measurement of serum Cr and urea and umed urine Cn urea and volume Practical alternative to measure GFR In patients for whom eGFR is inadequate (e g . kid n e y d o n o rs. p rio r to ch e mo th e ra p y) C.,,.: underestimates GFR due to passive reabsorption of urea in the PCT C". overestimates GFR due to secretion of creatinine in the PCT Mean of C.,.., and Cu: partially adjusts for these limitations Limited by accuracy of urinary collection: over or undercollection can lead to e xtre me ly in a ccu ra te e stima te s Estimated CrCl (Cockcroft-Gault Equation) CrCI (mUm in ) = [ (1 4 0 age) x weight in kg x 0.85 (if female)]l(72 x SCr) Less accurate estimation of GFR than eGFR, should not be used in routine clinical p ra ctice fo r CK D id e n tifica tio n a n d sta g in g Many drug dosing recommendations are based on CrCI instead of eGFR N u c l e a r Re p ro g ra m Can b e u se d to e stima te th e re la rlve co n zrib u rio n of each kidney n o o ve ra ll re n a l f u n ct io n (e t , p rio r t o n e p h re cmmy) RENAL FuncTion ON RENAL REPLACEMENT THERAPY • Residual kidney function for padenzs on HD/PD assessed using timed urine collection of creatinine and urea May be able to use serum [Strace protein. [32microglobulin,cyszazin C rather :han using collection. bu: not common practice (m 1016:89.\099) R EN A L F u n cT io n IN A K I Cannot use eGFR in AKI blc Cr not at steady slate (ACr lags behind AGFR) Changes in UOP may be informative. but cannot be relied upon since UOP an be preserved even after large decrease in GFR Kinetic GFR estimate (KeGFR) uses rate of Cr change to estimate GFR when Cr Is not an steady state (1Asr4 2013:24:577;lvailahll as Q»<mD') URINE STUDY URI NE DI P S T I CK Should wa it for 3 0 s -1 min be fore re a ding Urine dipstick is semiquantitative assay Specific Gravity (SG): relative weight (mass) to water Osmolality is concentration of dissociated solute particle number Ead\ 0.001 rise from 1 - t 30-35 mOsm/kg when urine solutes are Na. K.NH* url only SG overestimates osmolality when urine contains hwy sdureszghicose. protein,conuast SG underestimates osmolality after saline diuresis (Amy mm so 200zm39) I nte r pr e ta ti on of S G 1.aca-1.012 Isosrhenurla Similar SG of plasma Possible concenxrarion defect In ATN. CKD <1.008 Low SG (hyposrhenuria) .L ADH: DI. 1 polydipsia; inner diluting capacity. impending Na rise w/ water reszricrion >1.012 High SG T ADH: dehydration, volume depletion p H (n o rma l: 5 . 5 -6 . 5 ) <5.5 in metabolic alkalosis: nonbicarbonate nonreabsorbable anions. et. cicarciilin, carbenicillin, piperacillin (CjASN 101*r 14:306) L: metabolic acidosis.1 protein diet volume depletion (T aldoinduced TH excretion) T: vegetarian diet. unease (urea -» CO1 + NH;)forming bacteria.ATN >8: urea splitting organism >6.5: bicarbonate in urine: high pH suggests NN in hypokalemia uimjme42017;1J0B46) >5.5 in NAGMA: dRTA, hypokalernia ( ammoniagenesis). toluene P ro t e in (n o rma l: n e g a t ive ) Trace. 5-20 mgldL; 1+. 30 mg/dL: 2+. 100 mg/dL; B+. 300 mg/dL: 4+, >2.000 mg/dL <1+ rules out urine albumin creatinine ratio (UACR) 2300 mg/g (Ajxb 201\;58219) Highly sensitive to albumin. but cannot detect microalbuminuria (<3 mzldL) Less sensitive to globulin or light chains. Suspect B]P when a dipstick test shows trace to 1+ protein yet a turbidity test for urine protein shows 3+ proteinuria (+) in renal impairment. suggestive of glomerular injury (-) in renal impairment. suggestive of tubulointerstitial injury False (+) buffered alkaline urine Blood (normal: negative) Detects pseudoperoxidase activity of hemoglobin and myogfobin Punctate staining: 1-4 RBCIHPF hematuria Homogeneous staining: free hemoglobin or myoglobin. False (): ascorbic acid Leukocyte Esterase (normal: negative) 5-15 WBC/HPF will give a positive granulocyte esterase reaction Lymphocytes in chyluria will not produce a positive test False (+): contamination with vaginal fluid Nitrite (normal: negative) Urine nitrate is converted by nitrate reductase of Enterobacteriaceae (~) with nonEmerobucterioceae bacteria; False (+): dipsticks exposed to humidity Glucose (normal: negative) Glucose oxidase reaction. allowing semiquantitatlon for glycosurla (+): hyperglycemia >180. proximal tubular dysfunction (Fancohi syndrome).SGLT2 inhibitor or mutation, familial renal glucosuria (qA$N 201&$:133) False (-): ascorbic acid Ketones (normal: negative) Detects acetoacetate and acetone. Does not react with Blvydroxybutyrate (dominant ketoacid in alcoholic ketoacidosis). Bilirubin (normal: negative) Detects conjugated bilirubin; small fraction that is not reabsorbed in die PT Unconjugated bilinubin binds to albumin and does not pass glomerulus (*): obstructive or hepatocellular jaundice False (+): chlorpromazine.phenazopyridine:delta bilirubin (albumin bound bilirubin) in prolonged cholestasis False ():ascorbic acid Urobilinogen (normaI:0.2-1 my dL) Conlugated bilirubin is metabolized to urobilinogen by bacteria in die colon Not reliable for detection of porphobilinogen in porphyry T: hepatocellular jaundice. hemolysis; (): obstructive jaundice URINE Ssomsm EXAMINATION av Mlcnoscors Procedure Spin 12 mL of clean catch urine in a centrifuge tube at 3.000 rpm for 5 min Completely invert the centrifuge tube. Resuspend the sediment in the urine that drains back down from :he side of the tube. Flick the bottom of the tube to mix the sedimemAspirate the sediment with a clean disposable pipette. plate a drop of sedi ment onto a microscope slide. and cover with a cover slip. Examine the sediment (wet mount) with subdued light by partially dosing the iris dia phragm and lowering the condenser of the microscope until optimum contrast is achieved.The fine adjustment of the microscope should be continuously adjusted up and down to see die depth of the oblect as well as other structures that maybe on a different plane. Scan the entire cover slip under lower magnMcation (x100) and then turn to the highpower magnification (x400) to identify specific cells and casts. Pay special atten tion to the edge of the coverslip where many casts tend to accumulate. Quantify and report casts as numberllowpower field (LPF) Quantity and report cells as number per highpower field (HPF) Stains are useful in specific instances. SedlStain: cellular elements: Gram stain: bacteria or fungi . Hansel stain (a modified Wright stain): eosinophils and other cellular elements Sudan Ill stain: oval fat bodies (OFB). fat globules. and fatty casts Urine Sediment Findings Comments and Possible Causes or Associated Conditions Findings Cells RBCs Dysmorphic: glomerulan eg, glomerulonephritis. vasculitis Isomorphic: extraglomerular. kg. interstitial nephritis. UTI. trauma. stone. or tumor UTI. interstitial nephritis. glomerulonephritis WBCs Epithelial cells Desquamated cells from renal tubules. urinary bladder. vaginal epithelium. urethra. or foreskin Oval fat bodies Sloughed renal tubular cells containing lipid droplets, typically seen Bubble cells Vacuolated renal tubular cells seen in acute tubular injury or tubular in nephrotic syndrome but may be seen in polycystic kidney disease and Fabry disease necrosis UASN 199 l:1:999) Casts: cylindrical structures in the tubule lumen;Tamm-Horsiall protein is matrix RBC or Hb asks WBC casts Fatty casts Tubular cell casts Granular casts Waxy casts Hyaline casts GN.vastulitis lntersuiial nephritis. pyelonephritis or GN Nephrotic syndrome Renal tubular injury/ATN Dark muddy brown granular cast is alw ATN Advanced renal disease Benign Crystals: solid particle with a geometric shape men 1016:J745:2465) Calcium oxalate Envelope or needle shaped dihydrate or Ethylene glycol poisoning (NEW 2017377314673 And /1444 l98GI4:l45), monolvydrate Caidum dwosphate dihydrate (bmshke) Uric acid Cystine Triple phosphate (struvite) Sulfa drug lndinavir Acyclovir Bacteria Yeasts or Fungi hyperoxaluria, hypercalciuria Asymmetrical rodshaped aggregates; in hypertalciuria, renal stone disease Rhombic plates or lOS¢ll£S. In many forms in acid unine.seen in healthy individuals: in patients with gout. hyperuricosuria. after recurrent seizure. after propolol anesthesia. renal stone disease. and heat stressrelated Mesoamerican nephropathy Hexagonal.Cysdnuria: . PT reabsorption x cystinosis Coffin lid shaped in infected urine or alkaline urine: infected renal stone disease Sheaves of needles on sulfadiazine in volume depletion Starburst form in HIV patients i/~» IM 1997;127:1191 Needleshaped crystals in sediment or inside WBCs;Valacyclovir or acyclovir toxicity UTI.contaminauon. or overgrowth after prolonged standing UTI,contaminations: prolonged indwelling Fol catheter URINE LABORATORY TesTs lqAsn 201214¢309 Random Spot Urine Collection Convenient: affected by diurnal variation; both random and timed always need Cr level Timed Urine Collection 24hr: gold standard for many IESIS. but susceptible to over or undercollection Creatinine should be checked together to monitor collection adequacy If nonrenal excretion is negligible and not produced or metabolized in body. reflects intake in steady state Can be used for concentration: et. UPEP Urine Creatinine, Spot (Random) Should be checked with other quantitative spot urine assays to correct the effect of urine volume or to consider the amount of glomerular filtration. eg. Fractional excretion (FE) and random protein/creatinine ratio Higher than in the serum. Used when suspected urine leak. eg.urinoma dlt post transplant fluid collection or kidney trauma. urinothorax (pleural effusion from urine) Urine Creatinine, 24hr Significant variation in 24hr values suggests over or undercollection Estimated 2 4 h r Urine Creatinine Level (mglkg) (n4luun 1976:16:31) = 2 8 - (0 .2 x a c ) 70 Age 20 30 40 50 60 Male 24 22 20 18 16 14 Female (10.85) 20.4 18.7 17 15.3 13.6 11.9 Can be used to calculate CrCl (¢ eGFR due to tubular cieatinine secretion) Urine Osmolality (Umm. mOsm/kg):ADH Actlvlty Number of solute particles per unit volume: mainly Na and K salts and urea Correlates with aquaporin2 activity controlled by ADH Ranges 60-1.200 to remain plasma osmolality widlin 275-290 and extracellular volume Aging is aM decreased concentration and diluting capacity: range decreased co 100800 U ri n e Osmo l e s, 2 4 h r 600-900 mOsmolld with normal die: and renal funcuon Low urine osmoles: low protein, low sodium diet (beer. tea and toast), malnutrition; CHO and alcohol 1 endogenous protein catabolism; l water excretion (}A$n zaosneiom High urine osmoles: osmotic diuresis (hypernatremla).sak wasting (hyponatremia) Urine Protein and Albumin Random: protein or albumin (rngldL)lCr (mgldL) - 2Mr protein or albumin (g) excretion 24hr: gold standard for prowinuria evaluation Fractional Excretion (FE) The percent of filtered solute that is excreted in the urine Used to evaluate renal handling of the solute excluding the effect of water reabsorption FE of solute X = Quantity of X excreted in the urine/Quantity of X filtered (u, )<V)l(S, x CrCl) = (U,JS,)I(U<,IS.) U . urine concentration of X.S,: serum concentration of X.V: urine volume Depending on solute.filtered fraction should be considered. eg.0.7 x serum Mg is filtered dlt protein binding U rl n e So d i u m (u m) Sodium avidity (low level): reflects RAAS activation and sodium ieabsorption 24hr: approximate measurement of dietary sodium intake; nonrenal excretion is unable >10 mEqld; B7 mmol = 2 g: 100 mmol = 2.3 g UN,/UI< <1 in minenlocorticoid excess (hypovolemia. hyperkalemia) Fractional Excretion of Sodium (FEm) In AKI <198 volume depletion. CHF. liver cirrhosislHRS.nephrotic syndrome, severe bum Vasoconstriction: iodine CIN, rhabdomyolysislhemolysis, sepsis (Cm Can 1013=17=R234). acute urinary obstruction. acute GN. acute allograft reiecdon T by diuretics: furosemide can achieve 8% of FEn. (lm um: ~q=»~~=1 z010,41:2731 If <B%.other sire inhibition would be necessary. eg.thlazide Urine Urea Nitrogen (UUN) FE.,.,,: 1 in volume depletion (d/t T reabsorption) and adrenal insufficiency: not affected by diuretic Urea clearance: used to estimate residual kidney function in dialysis patients Protein catabolic rate (PCR, protein equivalent of nitrogen appearance) can estimate protein intake if nitrogen balance is even and protein catabolism is not significant (steady BUN with steady renal function) Da i l y Ni troge n Ba l a nc e Input O u tp u t Protein invoke Urine urea nitrogen Endogenous protein catabolism Nonuiea nitrogen excretion (g. nonuio urinary nluugen + fecal urea excretion) 0.031 x weigh: (kg) in 19952758) Protein (nitrogen) intake - urine urea nitrogen + nor urea nitrogen excretion x 6 .2 5 to c onv e rt nitroge n (g) no prote in (g) et. 60 kg. Up 7 old: weight normalized PCR = [(7 + 0.031 x 60) x 615]/60 0.92 glkgld F ract io n al Excret io n o f Uric Acid ( F Eu d ) L in volume depletion dlt T reabsorpdomnot affected by diuretic use >12% in SIADH ucem 2o0a;9a¢1991l.rhiazideinduced hyponarremia UG 2017:127:nsn Urine Chloride (UCI) Low Ucl in metabolic alkalosis Cl responsive requiring NaCl Un, may T due to other anions: bicarbonate. ticarcillin. carbenicillin. piperacillin High Us in metabolic acidosis due to NHL In hypokalemia Un.IU¢, >1.6 suggests NN <0.7 suggests Iaxacive (Am m¢4 z017;1ma4e) Urine Anlon Gap (UAG) and Urine Osmolal Gap (UOG) Used to estimate NH( renal excretion in NAGMA: NH( <40 mmol/d is dw dRTA Urlne Anton Gap (mEaL or mmoIIL) = Un. + Un - Us Negative Positive Appropriate distal tubule nH.' excretion: Inappropriate nH.* excretion in NAGMA: GI HCO1 loss (diarrhea) dRTA and type 4 RTA Ingestion of NH4Cl Appropriate NHi excretion with pRTA due to T unmeasured action unmeasured anions in NAGMA: (NHL) wlo significant change of unmea Bicarbonate (alkali dierapy for pRTA) sured anion -» unmeasured cation Bhydroxybutyrate and acetoacelate (NHL. Calf r48*) >unmeasured anion Hippurate (toluene) (HCO; , $04 .PO4,other organic Dlactate (Dlactic acidosis) anions) INEW 198&J1es941 5cxoproline (acetaminophen) Typical Western diet (10-90 mEaL) wlo NAGMA lA»n;m¢asa 19412911981 Respiratory alkalosis: can be used to differentiate from NAGMA when ABG is unavailable u 1017;7Q440) Urine Osmolal Gap (mOsmollkg) = Measured Um - Calculated Uwn Calculated UW.. = (2 x [U* + Url) + [u.,,, (m8/dL)]/78 + [Uucp~»~ (mgldL)]/18 >Z00-400 Appropriate NHL excision in: GI HCO; loss (diarrhea), pRTA Unease-producing bacteria: formation of NH/ in :he bladder or container Osmotically act solutes: mannitol. methanol. ethylene col <150 Inappropriate NHi excretion w/ NAGMA: dRTA and type 4 RTA Healthy individual wlo metabolic acidosis: 10-100 In advanced CKD, UAG is a poor surrogate for nH. excretion ac;Asn z01s:13:z0s) Solutefree Water Clearance (Cl4,0) Urine f1 ow (V) = Osmolal clearance (C.,,...) + Free water clearance (Cl41O) C.; the volume needed to excrete all solul.es as the concentration of plasma csmolality Caw :V x U 0¢m'P°w C12o. a theoretical volume of solutefree water that is added to or reabsorbed from the soosmolal urine to create eidler a dilute (hypoosmolal) or concentrated (hyperosmolal) urine Cu,o =V _ Cm-V - (V x U,,,,JP.,,,.,) =V x (1 - U../Paw) U,,JP.,,,, determines the direction of solutefree water How: excretion vs ieabsorption U.,,JP.,,,.. <1.0. dilute. (+) C:l,Q.the addition of a soluteNree water to the soosmolal urine U°,,,JP..,.. >1.0, concentrated. (-) C»4,o reabsorption of solutefree water from the soosmolal urine Electrolytefree Water Clearance (C'u1°) Since the calculation of Cu,o has included ineffective osmoles such as urea. which plays no role in transmembrane water movement and body fluid tonicity. C»42o may not be accurate in reflecting renal excretion or reabsorption of electrolytefree water Instead. evaluation and calculation of C>420 will provide a more accurate assessment of renal response to change in water metabolism (Am) m¢4 1986;81:1033) C»i,o =V * [1 ... (Un * UI<)/PN.] In a patient on high protein feeding who develops polyuria and frypematremla from urea osmotic diuresis.d\e Cu,o value may remain ().as a result of high urea content musing Um > Pm., thus suggesting continued reabscrpdon of free water: However. due calculation d C'14,<0 will give a (_) value and accurately indicates continued renal loss d electrolyte flee water widi resultant development of hypematremia. requiring free water replacement (U- + UK)/Pn, for bed side evaluation of patients with hryponatremia or hypematremla (U* + U»()lPN. 21.0: zero or (-) C'»4,0 no loss of electrolytefree water (UN, + Ux)/Pro <0.5: (+) C,4,0. renal excretion of significant amount of electrolytefree water i; Med so 2009t 319:140) Urine Laboratory Tests in Appropriate and Inappropriate Renal Handling Causes of Inappr opr iate Renal in a p p r o p r ia t e H a n d lin g Urine Lab Appr opr iate Un. <20 UN,/(Un/Su) <1 FEn. (Ag) <1 Uo (mEn/L) <15-25 FEw (96) Uw../BUN <35 >20 FEud (Ag) Um... U"/S" Um"/Sm Specific gravity <12 >500 >40 >1 .4-2 >20 <3S0 <20 >1 .020 u... <100 <1 .012 H yponatr emia >100 UM >700800 Hyper natr emia <700800 DL diuresis (osmotic. loop) U: (mE~/L) 24hr Up (mEq/d) <1 S-25 <20-25 U 1(/Uv (miqlg) <13-20 <2-3 TTKG Un (mEq/L) 24hr Un( (mE/d) Un(/U (m£q18) TTKG >20-30 >40 >30-200 >7-11 Volume D epletion >40 Tubular injury. sak wasting. diuretics. >1 adrenal insuNiciency. metabolic >2 alralosisc Na coupled w/ HCO: excretion:AGMA: Na coupled wl orpnic anions >40 Tubular injury, Sal: wasting, diuretics. NAGMA: CI coupled w/ NH( excretion PT injury, acerazolamide. osmotic >50-65 diuresis (mannkol. glucose). sepsis. <10 elderly High protein diet and catabolism <1-1 .2 Hypokalemia >30-40 >30 >13 >4-7 Hyper kalemia <20 <30 <30 <3-6 PT injury Tubular injury. loop diuretic Inefficient water reabsorption from tubular injury SIADH. severe renal failure. rhiazides. volume depletion, Sal: wasting Hyperaldosv.¢ronism,Vomidng. NGT. Mg deficiency. dRTA, pRTA. DKA Hypoaldosreronism 1 Na delivery to CD Type4 RTA PHAGE,PHAGE Hyper calcemia 24hr FEW (78) 24hr Ca (mud) >2 >200 UcJUc I3/8) >0.01 rem. 24hr Po. (mg/al <5% <100 see. >1S% F5.4 (use 0.7 x serum Mg) 24hr Mg (mg/d) <2% <10 <1 <100 Familial hypocalciuric hypercakemia. (Thiazide. milkalkali syndrome) 4.01 Hypophosphatemia >5% Hyperparazhyroidism.Vi: D def, >100 Oncogenic osteomalacia: T FGF23 pRTA. Heredity hypophospharenic tickets Hyper phosphatemia <15% Hypoparanhyroidism Hypomagnesemia >2% Renal washing >10-30 RENAL ULTRASOUND (UIS) \€1A$~ z0 I4,9.;ez) Indications Used to evaluate AKI. CKD.and as a guide for percutaneous renal biopsy Can detect real cysts, nephrolithiasls. nephrocalcinosis. hydmnephrosis.ADPKD. postkidney transplantation perinephric liuid collection (urinoma. hematoma. lymphccele) Can detect nonrenal abnormalities: fluid collection, BPH. bladder retention Kidney Size Normal Kidney Length (mm, 10th-90th percentile) WR 1999;1SM3) Left Right All 101-123 9a-122 30s 104-12s 101-124 40s 103-123 100-123 50s 102-125 100-122 60s 100-122 95-120 70s 94-120 91-118 Small (bilateral): CKD. renal scarring Large (bilateral) hyperfikration (obesity. diabetic nephropathy). interstitial nephritis (AIN, lgG4related disease). interstitial infiltration (lymphoma, amyloidosis. sarcoidosis). HIVAN.ADPKD w/ multiple cysts Asymmetric (>1 cm discrepancy) hypertrophy from contralateral kidney dysfunction. pyelonephritis. RAS. renal infarction. renal vein thrombosis, congenital abnormality of the kidney and urologic tract Echogenicity: normally equal to or less than spleen and liver;sinus is echogenic Echogenic kidney with combined length <20 cm a/w severe disease (KI 2005;67:1$15) Increased conical echogenicity (>spleen.Iiver without fatty liver changes) Alteration/intrinsic histology damage: interstitial inflammation and tubular atrophy Increased medullary echogenicity with normal cortex: medullary nephrocalcinosis. Tamm-Horsfall protein In tubules, sickle cell disease. medullary sponge kidney Decreased cortical echogenicityc acute cortical necrosis, edema Other Possible Markers of CKD Kidney volume for 2aon4:1690); Conical tllickness We 1010:19$W146) Hydronephrosis Dilation of renal pelvis: high sensitivity for urinary tract obstruction False (+) diuresis with nephrogenic DI. pregnancy: renal cysts. congenial megacalyces. calyceal diverticula. parapelvic cyst. transplanted graft (when it is mild) False (-): volume depletion. early acute obstruction. RP fibrosis, staghom calculi. infil trative metastasis; can re J after l1 uid; consider retrograde pyelography If finding is different from clinical suspicion.can J radionuclide scan or CT Cystic and Solid Mass Simple cysts: sharply demarcated with thin smooth walls.anechoic content. and strong posterior wall echo: no further imaging is necessary Complex cysts: calcifications. septations. mural nodules. internal echoes. majority are not malignancy: still need contrast CT or MRI to try to exclude malignancy Solid mass: need contrast CT or MRI Duplex Doppler Ultrasound Check flow of renal artery and veins: assessment for RAS and RVT RAS: main renal artery to aortic peak systolic velocity ratio >3.5 RVT: reversed diastolic flow. absent venous flow, thrombus in venous lumen. t Rl Ureteral jets. urine flow into the bladder rules out complete ureteral obstruction Resisd¢e index (Rl) 0.56-0.66 normal >0.85: nonspezific sign of microvascular compromise. eg. graft reiection.ATN urereral obstruction. pyeloneph ritis IndIcatIons Noncontrast CT: for urinary stone (more sensitive than contrast CT in detecting small scones). hydronephrosis (attenuation: renal parenchyma > urine > sinus fat), localization of obstruction. chronicity of renal disease (cortical thinning) Contrast CT: for complex cyst (for Bosniak criteria). mass. cancer staging, renal/ perinephric abscess, retroperitoneal Fibrosis, RMS, RW papillary or cortical necrosis. infarction. adrenal masses CT orography (wlo and w/ contrast): for hematuria with highrisk urothelial cancer CT Findings Calcification: stones. nephrocalcinosis. cortex (cortical necrosis,chronic GN). medulla (tubular pathology. medullary sponge kidney. papillary necrosis) Perinephric/periureteral siranding nonspecific sign of urinary obstruction. inflammation Pseudotumor: various conditions can mimic malignancy (A}R 1007;18&13&) Developmental: prominent columns of Berlin. Dromedary hump, persistent fetal lob ulation Infectious: focal pyelonephritis (/DMSA scan). abscess. scarring Inflammatory: xaruhogranulomatous pyelonephritis, sarcoidosis. malakopkkia. lgG4RD Vascular: AVM. hematoma. extramedullary hematopoiesis MR I A N D MR A For complex cyst. mass (esp. small lesion). RAS. pregnancy widl any indication of CT scan slezgadoliniuminduced nephrogenic systemic Fibrosis (NSF) In pa with stage 4-5 CKD, macrocyclic or newer linear (gadobenate dimeglumlne and gadoxerate disodium) gadoliniumbased contrast agents (GBCA) can be adminis tered when GBCAenhanced MRI is considered necessary and no alternative test is available lcfin Assoc m4442018;69136) MRA without contrast. such as phase contrast MRA is available RADIONUCLIDE RENAL SCAN Radiotracers Used for Renal Scan Radiotracer ""TcDTPA ""TcMAG3 * Tc D MSA Function Glomerular filtration Clinical Use GFR measurement Urinary trac: obstruction Tubular secretion: by Split renal function: Urinary tract obstruction the PCT Evaluate effective renal plasma flow Used when renal function is reduced Tubular retention: binds Split renal junction to the SH groups of Conical scarring or infarction:WR PCT Focal lonephritis vs cancer ""TcDMSA. uchnecium 99mlabeled dimercaplosuccmaze "TcDTPA. technetium 99mIabckd dielhylenerruminepenuacelk acid Split radionuclide renal scan: predict posuiephrectomy dialysis requirement Furosemide renal scan: '*"T¢.oTpA¢"'"T<r1AGa if reduced renal functiomdelayed renal pelvis clearance in urinary tract obstruction Capropril renal scan: "'"TcDTPA; use ""TcMAG3 if reduced renal function: can show peak activity delay or l GFR in the kidney with RAS OTHER IMAGING TssTs Angiography Definitive Les: for and. for some diseases, treatment of vascular abnormalities. RAS. FMD. large and medium (eg. polyarteritls nodosa) vessel vasculitis Risk of CIN (in CKD) and cholesterol arheroemboli Pyelography For suspicious urereral obstruczion in :he absence of hydronephrosis on UIS or CT and proper renal contrast excretion is not expected due to AKI Retrograde: contrast into distal ureter or bladder priNce performed by urologist along with cystoscopy Anterograde contrast injection into collecting system: performed by interventional radiologist along wid\ therapeutic nephrostomy Complications: upper urinary tract infection V oi di ng Cy s tour e thr ogr a phy To diagnose and evaluate vesicoureteral reflux Radionuclide cyssogram an be used for followup evalwadon for less radiation exposure Posit ron Emission Tomography ( PET) cyst infection in ADPKD l~or 200s;2z:404) and renal graft PTLD (H¢m°l='°s1<v z0139e2m> P l a i n Abdom i na l Ra di ogr a phy Can detect radiopaque stone. nephrocalcinosis.and other calcification I n tr a v e n o u s P y e l o g r a m evaluation of upper urinary tract in hematuria. flank pain. and stone disease Replaced by noncontrast CT scan RENAL BIOPSY Indications of Renal Biopsy (bx) RPGN: proreinuria >1 old (with proteinuria >0.S): unexplained renal impairment Impact of Biopsy on Diagnosis and Management Diagnosis (AMC Nepiuul ZG09;10:11] Bx Affected Management (nor 199411159 Pr edi cted di agnosi s confi r med 29% Nephr oti c r ange pr otei nur i a 86% One of di ffer enti al di agnosi s 14% Acute ki dney i nj ur y 71% Unexpected di agnosi s 15% Chr oni c ki dney di sease 45% Bx done (0 assess ase sever i ty 29% Hematur i a and pr otei nur i a 32% Nondi agnosdc 11% Subnephr osi c pr otei nur i a 12% Technical failure 2% Hemacur i a al one 3% Over al l 42% Absolute Contraindications to Percutaneous Renal Biopsy Uncooperative patient or inability w follow instructions during bx. uncontrolled severe HTN (>180/120). unconectable bleeding diathesis Relative Contraindications to Renal Biopsy Inability to provide informed consent. recent antiplatelet or anticoagulant therapy. Hb <8.0. platelet <100. INR >1.5. T aPTT. liver cirrhosis Echogenic small kidneys (<10 cm) (Kl1005;s7:1515).solkary kidney. multiple bilateral cysts. hydronephrosis. horseshoe kidney, ESRD. UTI. pyelonephritis, or perirenal abscess/infection. pregnancy after 32 wk gestation Inability to stop anticoagulation (eg.w/i 3 mo after prosthetic heart valve) Preparation:Admit HighRisk Patients Emergent bx is a/w major complications (3.7 vs 0.5% w/ elective) (nor zcoatzsasal Hold ASA, dipyridamole. clopidogrel. unSAIDs, UFH. LMWH. GP lib/llla inhibitors. omega 3 fatty acids (nor Plus 2011:4:Z70) it clinically indicated Prebiopsy Labs: CBC. PI aP7T type and screen. factor X ifAL amyloid is suspected If Hb <8.0. blood transfusion or hospitalization: BP <140/90:anxiolytic pro II factor X def. FFR Prothrombin complex concentrate 3factor (II. IX. X. eg. Bebulin. Profilnine) WH 2014.a91 Isa) or 4factor (II,vll, IX. X. eg. Beriplex. Octaplex, Keenua) Antiplatelets and unSAIDs Antiplatelets and unSAIDs (vs d/c 5 d before) T 21.0 Hb drop.no difference in die need for blood transfusion. surgical or radiological intervention (NDT zuaenaasssl ASA within 10 d of bx did not increase risk of major bleeding (Ala 20 i0.i94¢7a4) unSAIDs (esp.one w/ long halflife) T bleeding; Renal impairment 1 clearance Hal fLi fe of unSAI Ds wav :m 1w1. 1 5121969) 0 - 3 hr fenopr ofen. i bupr ofen, 4 - 5 hr i ndomezhaci n. kewpr ofen >1 5 hr pi r oxi cam mecl ofenamaxe sodi um, tol medn 6 - 1 5 hr di ¢1uni sal . naproxen. sul i ndac unSAIDs should be stopped 5 hal(lives for complete elimination Hold anriplarelets for 7-10 d before in low CV event risk (Acer Chen 10 1z141=¢3us) In highrisk pos undergoing noncardiac surgery. perioperative ASA 7 d pre to 3 d posrprocedure 1 major adverse cardiac events wlo T bleeding 1S¢IAMMI 1010;104:305) Anticoagulation Conditions wkh HighRisk Perioperative Thromboembolism (ACCP Gun 2012;14mJus): stop vitamin K anugonists 5 d before die biwfr bridge mM N UFH (stop 4-6 hr before) or LMWH (stop 24 hr before) Mechanical HeartValve AFib VTE Any MV prosthesis Any cagedball or tilting disc AV prosdiesis S or TIA w/i 6 mo CHAD5z >5 Stroke or TIA wu 3 mo Rheumatic valvular heat disuse VTE li 3 mo Def of protein C, protein S. or anziLhrombin;APLA, multiple abnormalities Uremic Platelets Renal failure can cause bleeding dl: disturbances in platelet adhesion and aggregation Unclear if correction of the BT (bleeding time) L clinical bleeding.A low Hot is alw a t BT: may be corrected by ESA or transfusion (Ann Sur, 1998113311341 ESA wkh Hot t 230% improved platelet function in uremic patients (xi 199r41=ssa1 DDAVP 0.3 uglkg 1 hr prior to bx 1 hematoma BT (13. 8% vs 30.5%) (A/KO z0\1;578s0) can be shortened by HD ><2 lcs»App4Th»w»=b»4¢»n¢¢ 1012;1B:1B5), estrogen w9/»1 198e31517311. cryoprecipitate 10 bags over 30 min, 1-12 hr WM 19a0x30J=13181 Ultrasoundguided Percutaneous Renal Biopsy No difference in complications between U/Smarked blind vs realtime UIS guided procedure and performed by nephrologists vs radiologists (arc nepnui 10\441s9961 Realume U/S guided bx may have better tissue yield (CK:201sx:151;amc ~¢l=~-l z014;1 $961 Spring loaded devkes w/ 14G. 16G, or 18G needles.The larger needle provide more ds sue and glomeruli (m 2000=$&390). Complication t wl 14G needle WKD 201zw4s2).>5 passes CTguided Percutaneous Renal Biopsy When kidney position does no: support U/Sguided bx In does not allow direct realtime visualization who 200lk36:4\9). Tra n sju g u la r B io p sy Performed when bleeding disorders prevent conventional biopsy, for patients on mechanical ventilation.and if there is a need for bx of both the liver and kidney The access is via the right internal jugular and an introducer sheather.The right renal vein is more amenable to bx because of orientation and the shorer length to access. Contrast (required)induced nephropathy can happen ()\u< linen New 1008;191546) Slmilar yield (95.8 vs 95.5%) and major complications (1 vs 0.75%) dw percutaneous bx (naming 1000=21s;aa9l; other series also showed its safety (inncec 1990;33$:1512) Laparoscopic or Open Biopsy When percutaneous bx fails. for pos on chronic anticoagulation which unnot be stopped or w/ coagulopathy religious faith (eg.Jehovahs witness). solitary kidney. multiple bilateral renal cysts. or body habitus (eg, morbid obesity.cerebral paley) lx/ 199a.s425151 P o st b io p sy C o m p lica t io n s Automated Biopsy Device and Redtime UIS Guidance 1AprD 101u061i Postbiopsy Complications Factors on Erythrocyte Transfusion Rate Macroscopic hemaluria 3.5% Age 240 vs <40 1.0 vs 0.2% Need for PRBC transfusion Angiographic intervention 0.9% 0.6% Cr 22 vs <2 SBP 2130 vs <130 2.1 vs 0.4% 1.4 vs 0.1% Hb <12 vs 212 2.6 vs 0.5% Nephrectomy 0.01% Bladder obstruction 0.3% D 0.02% AVF (4-18%): rarely cause hypotension. highoutput HE and hemamria. Diagnosed w/ Doppler U/S or angio. Most spontaneously regress. but some require embolizacion or surgical ligation depending on size/symptoms UAS~ 1994.5:1J00} Hematoma (4%) (}ASN 2D04;15:142). pseudoaneurysm Page kidney: subcapsular hematoma can cause RAS activation. HTN Pain: dl: subcapsular hematoma, ureteral obstruction of blood clot Vasovagal pseudohemcrrhage: i BP & HR during procedure UAMA 1977;237:1159) AKI T complications: transfusion 8%. intervention 2%. hematoma 7% [qAsn 201&13:1sJJ) Monitoring and Postbiopsy Care 67% off complications occur wu 8 hn 11% an be seen >24 hr after biopsy UASN 200%1§:141) Can J U/S 1 hr after percutaneous be: the absence of hematoma has a high NPV for minor (95%) or major (98%) complications (nor z009:24n4J3) Bed rest for 4 hi:avoid heavy object lifting,iog.exercise for 1 wk Vital signs: BP q15rnin x 1 hr. q30min x 2 hr. q60min x 2 hr ./ for gross hematuria; /CBC 4 hr postprocedure: for inpatients, CBC in following AM Resume antiplatelet and/or anticoagulation in 2-7 d.The exact timing for resumption o f th e ra p y sh o u ld b e ta ilo re d to e a ch p a tie n t Management of Bleeding Complications Bed rest, PRBC. FFP transfusion as needed Most patients with perinephric hematoma or hematuria will resolve spontaneously N unremitting gross hemawria especially with clot. a 3way bladder irrigation adweuer sh o u ld b e in se rt e d a n d irrig a t io n co mme n ce d If hemodynamic compromise, transfusion requirements or persistent gross hematuria >72 hr, CT angiogram may show the bleeding vessel or AVF; followed by selective a n g io e mb o liza tio n o f th e b le e d in g a rte ry Transarterial symbolization is safe; Rare complications: dissection Postembolization syndrome: flank pain. fever, NN ileus. rare w/ partial symbolization RENAL PATHOLOGY PROCESSING OF TISSUE Light Microscopy (LM) Formalinfixed, paraffinembedded tissue; sections cut at 2-3 um Stain with hematoxylin & eosin (H&E). Periodic acid-Schiff (PAS),Jones methenamine silver (JMS). and Trichrome Typical Color after Shining PAS ]MS Magenta Black Glassypink Red Pale Red Matrix material* Immune material Fibrin Trichrome Blue Fuchsinophilic Bright red *Basement membrane (BM) and mesangial matrix » Special stain: Congo red (amyloid).von Koss: (calcium phosphate deposit) lmmunofluorescence (IF) Zeus or Michels transport medlum.frozen and cur on cryostat! Slain with antisera to IgG. IgM, IgA. C3. C1.albumin. Fibrinogen. kappa, lambda. and C4 d (tra n sp la n t o n ly) Special techniques protease IF from paraffin block (salvage. masked deposits. LCPT). loG subtypes (loG 1-lgG4; 1 subtype favors monoclonal), COL4A (112 and a5 chains) Ele ct r o n M ie r o se o p y ( EM ) 2.5% glutaraldehyde;1 pm toluidine bluestained survey section. Pb/Urstained section COMMON PATTERNS OF GLOMERULAR IN]URY De6nitions for Commonly Ulod Terms for Glomerular Injury Focal Involving minority (<50%) of glomeruli Diffuse Involving maioriry (>50%) of glomeruli Part of glomerulus (60%) involved Segmental Global Whole of glomerulus (>50%) involved Mesangial Proliferative Glomerulonephritis LM: diffuse increase mesangial cells (23 per mesangial area) IF and EM: granular mesangial immune deposits Ddx : ly \n, LN c la s s II. re s olv ing IRGN.C3 G Endocapillary Proliferative Glomerulonephritis LM: occlusion of capillary lumina by infiltrating leukocytes and/or swollen endodvelial cells IF and EM: subendozhelial 2 mesangial immune deposits Ddx: IRGN: endoapillary neuuophils.C3dominant IF w/starrysky" paper. subepi humps Autoimmune (eg. LN): fullhouse IE strong Clq staining, extraglomerular immune g 3 deposits. endothelial TRls Cryoglobulinemic: monocytes. immune thrombi O the rs : P G NMI D (monoc l ona l I F), I gAN. C3 G Membranoproliferative Glomerulonephritis (MPGN) LM: hyperlobulated glomeruli owing to increased mesangial cells and matrix. GBM double contours with cellular interposition. variable endocapillary llypercellularity Current MPGN Classl6cation Based on IF Type Immune complextype: classical pathway mediated C3 glomerulopa\hy: alternative pathway mediated Mimickers" IF lgzc3 Etiologies Autoimmune: LN. Siogren syndrome Infectious: HCM endovascular bacteria I Cryoglobulinemicz HCV. S}ogrens. LPD Dysproteinemic or idiopathk C3 z 2 x l g C3 G (C3 G N. DDD) Negauye (Znonspecific I and C3) TMA. type III collagen glomerubpa Historical MPGN Classification Based on EM Tow E M Fe a ture s 1 Mesangial and subendo 2 Mesangial ring forms and highly electron dense intramembranous a Mesangial and complex subendo. incramembranous.and su i Col umbi a Cl a s s i fi c a ti on of FS G S Va rla nt De fi ni ng Fe a ture s Clinic a l Fe a ture s Associations Collapsing Implosive retraction of capillaries with overlying VEC Primary or secondary: severe nephroric syndrome and AKI; Viral infections (esp HIV), Drugs (pamidronate. INF),APOL1. acute vasoocclusion hyperplasia, severe tubular injury. tubular microcysu. diffuse FPE black racial predominance. worst prognosis Tip Adhesion of ruff as tubular pole w/ foam celIs.di1¥use FPE Usually primary, abrupt onset nephrozic syndrome Ce llula r Expansile lesion with endocapillary Usually primary Usually steroid responsive. favorable prognosis hypercellularity (foam cells, leukocytes) Perihilar Hyalinosis and sclerosis centered as vascular pole. glomerulomegaly. focal FPE NO S Does not meet features of above variants Usually secondary: adaptation m glomerular hyperlilrrarion Obesity, HTN, low nephmn number sickle cell mlc variant. primary or secondary Nodular Mesangial Sclerosing Glomerulopathy Mos: commonly diabetic glomerulosclerosis (DGS):acellular PAS+ nodules i mlcro aneurysms. capsular drop lesions (BC hyalinosis). PAS+ GBM and TBM thickening, IFITA. arteriolar hyalinosis. arteriolosclerosis Idiopathic nodular glomerulosclerosis (ING. aka smokingrelated glomerulopathy): seen in nondiabetic cigarette smokers ~ endothelial lined channels in expanded mesangium and at hilus, chronic TMA features common (mesangiolysis wl microaneu rysms. narrow GBM duplications) Me mb ra n o u s N e p h ro p a th y (MN ) LM: normal GBM (stage 1) - thickened GBM wick spikes (stage 2) -> chainlike GBM thickening with intramembrancus Iucencies (stages 3-4) IF: granular glomerular capillary wall (subepi) staining for IgG. C3. in. A EM: small subepi immune deposits (stage 1) - intervening GBM spikes (stage 2) » incorporated into GBM by neomembrane (stage 3) -» undergo resorption and become more electron lucent (stage 4) (-80%;antiPl.A2R. 3-5% antiTHSD7A) vs 2 (autoimmune. infection [HBV. parasites. syphilis]. malignancy. drugs) Indirect lF staining for PLAZR; positive in 80lS of patients with 1 MN Th ro mb o ti c Mi cro a n g i o p a th y (TMA) Early changes Glomeruli: fibrin thrombi. entrapped schistocytes.endotheliosis. mesangiolysis, subendothelial fluff," ischemic Loft retraction . Vessels: endothelial swelling. intraluminal and subendozhelial fibrin. entrapped schistocytes. mucoid intimal edema. myointimal cellular proliferation Late changes . Glomeruli: GBM duplication. mesangial sclerosis. glomerulosclerosis Vessels: concentric (onionskin") intimal Nbrosis.organization and reanalization of intraluminal thrombi Etiologic considerations: dHUS. aHUS. scleroderma.APLS. malignant HTN. preeclampsia. druginduced (antiVEGE gemcitabine. proteasome inhibitors), HIV -» vascular changes of TMA predominate in malignant HTN and scleroderma Glomerular Diseases with Organized Deposits Glomerular Diseases with Organlzed De posit! Disease Pathology Cor r elation Cryoglobulinemic GN LM: MPGN or DPGN. abundant infiltrating monocytes. inuacapillary immune thrombi lF:monoclonaI In (type I). IgM » x > IgG + 1. (type ll).polyclonal IgG v IgM (type III) EM:annulartubular substructure (3050 nm). may be focal Immune deposits may be spare by IF and EM blc of aggressive phagocytosis by monocytes (prionase IF useful) Type I: LPD Type II: HCV. S16grens, LPD (esp.wm). endovascular bacterial infections Type Ill: autoimmune condkions IMMU"0BCEOid GN LM: MPGN or DPGN IF: usually monoclonal IgG 94: parallel stacks d microtubule (30-50 nm) Fihrillary GN LM: MPGN > MesGN > DPGN > MGN; PAS pale silver () deposits:Congo red ( ) IF: polyclonal IgG ("smudgy") 2 C3 & C1: lgGl a lgG4 subtypes EM: randomly oriented nonbranching fibrils that infiltrate mes and GBM (16-24 nm) IHC: DNAjB9 +Mspike, Me1l lymphoprolilerative disorders.l C Idiopathic: association with HCV DysproteinemiaRelated Renal Diseases Can Involve all 3 renal parenchymal cornpartmenu Useful special rechniqueszcongo red srain.pro\eomics (Alg); IgG subzypec (PGNMID): protease lF (LCPT. masked monoclonal deposits) Dysprotelnemiarelated Renal Diseases Associations Pathology MM LM: hard/fractured casts. PASpalelnegative. Disease LCCN cellular reaction IF: xi), restricted staining LM: intracellular crystals in PTC (PASpale, Trichromered) IE >90% molten requires protease IF EM: geometrically shaped or ropey crystals in PTC LCPT MIDD LM: nodular mesangial sclerosis IF: linear staining involving all renal BMS; 90% s: (LCDD): can have monoclonal lg component (HCDD, HLCDD) Fanconi syndrome; MM. smoldering MM. MGRS MM. smoldering MM or MGRS: -1/3 occur wl LCCN EM: finely granular puncute deposits in BMS AL amyloidosis LM: amorphous eosinophilic. PASpale. silver negative. Congo red+ material MM. smoldering MM or MGRS lF:smudgy" staining. 9. > x EM: randomly oriented nonbranching fibrils (8-10 nm) PGNMID LM: MPGN. endoapillary proliferative GN lF: 1 IgG subclass + 1 light chain; lgG3x mlc EM: granular electron dense de sits Paraprotein identified in 20-3094; Ddx: type 1 cryo, ITGN EndothelialTubuloreticular Inclusion (TRI):"IFN footprint" Causes: SLE. HIV. CMV log z0\4;7i 114). exogenous IFN01, p, and y (6m5~ zo1o5.son,Ar1R COMMON PATTERNS OF TUBULOINTERSTITIAL INJURY Acute Tubular Necrosis (ATN) Epithelial simplification. loss of PAS+ brush border, coarse clear intracytoplasmic vac uolization and enlarged nuclei with prominent nucleoli 2 degenerating cellular casts Ddx = ischemic vs toxic tubular insults Histology generally nonspecific except in rare instances (it,dysmcrphic mitochon dria = tenofovir toxicity) Interstitial Nephritis (Pathologic Clues) Interstitial inllammauon and edema 4 oubuliris 1 tubulointerstidal scarring ~70% allergic/druginduced (inrerscicial eosinophils) -20% autoimmunelsysremichnfectious: Siégren syndrome (plasma cellrich). sarcoidosis (nonaseauhg granulomas; perivascular). IgG4related (lgG4+ plasma cells, storiform fibrosis.TBM immune deposits by IF & EM). pyelonephrizis (neuuophilic i:ubuli:is. neutrophil casts) -10% idiopathic RENAL TNANSPLANr PATHOLOGY (Bon1yCmena A/r 2018;1B.293) A¢uteTcell Mediated Reiecdon Grade Histologic Criteria Borderline Foci of lubulitis (L > 0) 4 minor interstitial infiarnmnion (i0-1),or moderatrsevere interstitial inflamrnazion (il-3) + mild tubulitis (t1) IA Interstitial iniiammation involving >25% of nonscarred cortex (zi2) + moderate wbulicis (t2) Inrerscizial inflammation involving >25% of nonscarred cortex (QI2) + severe tubulkis (r3) Mild [0 moderate intimal arzerizis (vi) 2 any Vi IB IIA Severe intimal anerizis (v2) + any it: Transmural arzerinis and/or fibrinoid necrosis (v3) 1 any Vt IIB III Chmnlc Active Tic dl Mediated Rejection Histologist Cnteria lnrersdtial inflammation involving >25% of :oral cortex. mainly in scarred alias (ti2-3. ilFTA2-3) + moderate tubulitis (:2) Interstitial inflammation involving >25% of :oral cortex. mainly in scarred areas (:i2-3. iIFTA2-3) + severe tubulitis (8) Chronic alto ft arterio ( c03) Grade IA IB II Active Antibody Mediated Rejection' 1. Histologist evidence of acute tissue injury (21 ) Microvascukr inflammation: glomerulitis (g > 0) and/or peritubular capillaritis (ptc > 0) Arteritis (v > 0) Acute thrombotic microangiopathy without other apparent cause Acute tubular injury without other apparent cause 2. Evidence of antibody interaction with endothelium (21 ) Linear C4d staining in peritubular capillaries (Cid 2 2 by IE C4d 2 0 by IHC) » As least moderate microvascular inliammation (g + ptc 22:3 must be 21 ifTCMR) 3. Seroi c evidence of donorspecific antibodies . *All 3 criteria must be met for diagnosis. Chronic Active Antibody Mediated Re)ecdon° 1. Histologist evidence of chronic tissue injury (21) Transplant glomerulopadiy (cg > 0) Severe peritubular capillary BM muldlayering (EM) Arterial intimal fibrosis wlo other apparent cause 2. Evidence of antibody interaction with endothelium (21) Linear C4d staining in peritubular capillaries (Cid 2 2 by IE C4d 2 0 by IHC) At least moderate microvascular inflammation (g + ptc 22:3 must be 21 ifTCMR) 3. Seal , . ic evidence of donorspecific antibodies *All 3 cnceria must be met for diagnosis. GENETICS Background Jun an nepnfa Z018;14:8J: nsi/in 2019:380:142) Genetic testing has a high diagnostic yield: almost 10% for all cause CKD. >17% for patients with nephropathy of unknown origin,and >70% for pediatric cases Genetic diagnosis can: Confirm a suspected hereditary cause Discern specific subcategory of condition within broader clinical diagnosis Reclassify the diagnosis and Identify a molecular cause for patients with nephropathy of unknown origin Genetic diagnosis can affect patient management. prognosis.and have familial implications F eat ur es of G enet ic D iseases Earlyonset: eg, congenial kidney anomaly or malformation Extrarenal manifestations: eg. sensory delicit.s.developmental problems. birth defects. facial dimor phism; Positive family histor y Absence of clear environmental causes for kidney disease (je. DM. CVD) Cautionary Note: many patients widl a genetic condition do not have affected family members and do have other medical problems that can be thought to cause CKD. like diabetes. heart conditions, or hypertension Terms Used in Genetics and Genetic Testing Genetic Counseling: a clinical consultation for individuals and d1 eir families who have genetic disease or are at risk for a disease.facilitating informed decisionmaldng. Under current guidelines. the ordering clinician is expected no ensure informed consent. Informed Consent: required for all Genetic testing. Discussion of benefits, limita tions (je, sensitivity and specificity of the rest). and risks. so d1 e patient can decide if. when, and how he/she wants to do genetic testing Allele: one copy of a gene; each of us has two alleles for all genes on autosomes (and X chromosome in females).which can be identical or different Variant: a different allele than the reference allele. aka the allele found in the majority of the population Zygosity; how many variant alleles a patient has Heterozygote: the pauent has one variant allele and one reference allele Hemizygote: variant allele of a gene on the X chromosome in male; since males have only one X. they have a single copy of the allele . Biallelic: 2 variant alleles for the gene Homozygote = same variant: Compound Heterozygote n two different variants TYPES OF GENETIC TESTING Any :est that can identify changes in chromosomes.genes (DNA sequencing). or proteins (biochemical rests) Biochemical cesu are helpful for diagnosing metabolic renal diseases Genetic Testing Modalities (Na: Revnq=n~1 Zu1a;14¢sJI A K Gene SNVs and small indels panels Medium and small indels MLPA CMA Large indels Large genomic rearrangements Single gene Multiple gene Most exons Whole genome Proponlon of DNA tested In one single test Odds for Incidental tlndlngs SNVs: singlenucleotide variants Indels: insertions or deletions Genomic rearrangements: duplications. deletions. uanslocations, and inversions Karyotype: picture of :he chromosomes; count them and identify large genomic rear rangements Chromosomal microarray (CMA): identify genomic ieanangemems such as duplications and deletions of at least 200 kb Multiplex ligationdependent probe amplification (MLPA): identify relatively small deletion and duplications Sanger sequencing: identify variants (singlenucleotide variants [SNVs] and very small insertions or deletions) in small. targeted fragments of DNA Gene panels using targeted nextgeneration sequencing (NGS): identify variants in a predefined list of genes Wholeexome sequencing (WES): identify variants in the exons (proteincoding) of most genes: does not cover certain parts of the genome (eg, noncoding regions) Wholegenome sequencing (WGS): includes noncoding variants and better detects genomic rearrangements versus WES BENEFITS AND RISKS OF GENETIC TESTING Diagnosis of Renal Genetic Disease Potential Benefits .nd Risks of Diagnosis Potential Risks I Medical workup additional tests can be required to validate the genetic diagnosis Change care: et. initiate needed subspecialty Negative psychological impact genetic referral. targeted workup. and/or findings can be uncertain, which can lad surveillance: guide choice of therapy fdentificadon of extrarenal anomalies to T anxiety (nui New Nniosu z013114¢4es) Family counseling for relatives identified xo Incidental finding: relevant for noncargeted genetic testing be at risk of having or transmitting die disorder Participation in targeted clinical trials Incidental finding: relevant for nontargeted genetic testing Potential Benefits Diagnosis: 4 need for further testing Diagnosis of Incidental Findings Incidental finding any genetic finding unrelated no the primary zest indication (syn onym: secondary finding). Some genes associated with diseases for which inzerven tions preventing or lessening the disease complications exist. such that they are med ically actionable" and have been recommended for broad return (am m¢¢ 2017;1*r249) Only in the case of nonrargeced genetic resting Potential Benefits and Risks of Incidental Findings Potential Benefits Change care: eg. initiate needed sulrspecialty referral. targeted workup. and/or surveillanceaguide choice of dierzpy Family counseling: for relatives identified to be as risk of having or transmitting the disorder Participation in targeted clinical trials Potential Risks t Medical workup: the term genetic predisposition" by definition indicates that there might be no disease YET but it might develop in the future Incidental findings can require lifelong medical surveillance Discriminadomthe Genetic information NonDiscriminadon Act (GINA) protects against discrimination from employers and haldi insurers. but gives exemptions to certain employers. and does not include oder types of insurance. including life and disability coverage Predictive genetic information could be used to discriminate individuals in contexts such as housing U up Med tuna 1016:44:216) and child custody disputes (co GenetMedRepz01s=49a1 Selffulfilling prophecy: genetic diagnosis an worsen the clinical symptoms: as in ApoE and Alzheimer (Am 1 lsidvavy 1014;171;10\) and obesity (Hour mf aenuv 20l6;4J:))7] Negative psychological impact: in the presence of an incidental genetic Ending. die patient becomes a patient in waiting" U :mini so new zoiostsaal GENETICS RESULTS INTERPRETATION (Genet Med 2015:17405) Criteria for Pathogenic Variants De novo variant: variant that is absent in the parents of die index.t odds for pathogenicity Reported pathogenic variant variant previously reported in patients as causing a disease . t O dds for pathogenicity The main :we databases cataloguing chose variants are ClinVar and HGMD Caution: both have a lot of false positive variants. Minor allele frequency (MAF): frequency at which the allele occurs in a given popula tion. Current population database:gnomad.broadinstitute.org includes 123.136 exhume sequences and 15.496 wholegenome sequences used to calculate each alleles MAF. The rarer the variant the T odds for pathogenicity Novel variant: variant not previously reported: it odds for pathogenicity Deleteriousness prediction: there are many insilico scores trying to predict the impact of a variant on the protein function (lossoffunction.gainoffunction. dominant negative effect) II Benign Likely pathogenic Va r ia n t C la ssif ica t io n Variant classification is based on current knowledge Thus. all classifications can change with as new knowledge emerges The patient and his/her family medical histories weigh in the decision whether the variant should be considered pathogenic or not Pr o b a b ilist ic D e f in it io n s Pathogenic (P): the variant is thought to cause a genetic disease.AKA diseasecausing variants (formerly called "mutations") Likely Pathogenic (LP): the variant probably causes a genetic disease. but current knowledge is not suflitient to categorize it as a pathogenic variant Variant of unknown significance (VUS): current knowledge is NOT sufficient to cate gorize the variant as either benign or pathogenic Likely Benign (LB): the variant probably does not cause a genetic disease. but current knowledge is NOT sufficient to categorize it as a benign variant Benign (B): the variant is thought to not cause a genetic disease CLINICAL GENETIC TESTING AND OTHERTYPES OF GENETIC TESTING Genetic Research (Na: an napiwi 1018:14:83) • Aim: generate generalizable knowledge useful for future patients Timeline: while results from clinical resting an be returned relatively fast (res: and lab dependent). research is usually unpredictable Results type: most researchsetting are not returning VUS. and P and LP variants usu ally need to be validated in a clinically certified laboratory by the Clinical Laboratory Improvement Amendments (CLIA) DirecttoConsumer (DTC) Genetic Testing Aim: different DTC companies have different aims. including ancestry.as well as clini cally actionable diagnosis.They usually do not offer comprehensive genetic diagnosis. Scope: similarly. different DTC companies are using different genetic nesting modalities UseFuL WEsslrss RENAL GENETIC DISEASES Inheritance Modes and Associated Family Patterns Inheritance Dominant (AD and XLD) disorders Variant Zygosicy Examples Hererozygoze or ADPKD, BOR. Hemizygore MODY5, Renal variant coloboma syndrome Biallelic variants Autosomal recessM (AR) disorders Family Pattern One of the parent has the disorder or the patient is die it (O have the disorder in the family (de novo) Bardet-Biedl Parents are nor affected Syndrome (BBS).Jouber1 tanriers Siblings may be syndrome, Barrier affected (25% risk [or each) syndrome Family Counseling 50% risk for each of the par.ienzs kid to have the disorder Unafhczed siblings have a 66% risk to be armers Risk for the next generation depends on the spouses carrier slaws (higher risk in case of consanguinity) Sisters have a Xlinked H emizygore Xlinked Alporr Females ans not syndrome. af1gcggd Male 50% chance of recessive variants siblings may be being carriers Fabry disease. disorders affected (50% (XLR) Dem disease risk for mah). Additional male family members may be aRecced on the modlers side of :he family Maternal Mitochondrial Variants in \he MELAS.MERRF. Variable inheritance: if mitochondrial Pearson disorders depending on probated is a (Miro) genome or syndrome. (nuclear genes depletion of Keams-Sayre the proportion female. at risk d af|ected of zransmining encoding the syndrome. mitochondria :he disorder mitochondrial miwchondnial Leigh Siblings may be Sisters of proteins will genome syndrome aM*ecled.aswen aflecred be in the as additional individual at above risk of inheritance 'w i n members on transmitting modes) :he modlers the disorder side d the f=l"i!7 Extrarend Anomalies Assodetied with Genetic Renal Diseases (laura a01(kJ15:1N1) Disease G r oup Extr ar enal Anomalies Causal Genes lichen Polycystic kidney disease Liver cysts. brain PKD 1. PKD2, PKHD1 ADLAR (PKD) aneurysms Tubulointerstizial kidney disease (ADTKD) MODY5 diabetes (HNF 18). anemia (REN). Gout UMOD, REN. mus, HNF 1B AD Ciliopathies (nephronophthisis, BBS) Congenital anomalies (CAKUT) Retinitis pigmemosa. polydactyl. MR. hypogenitalism. obesity MODY5 diabetes (HNF 1B), deafness (EYA 1). eye anomalies (PAX2) Bone abnormalities. immunodeficiency. neurologic impairment. cardiomyopathy (C0Q2) Hearing loss. anterior Ienticonus Short stature. eye anomalies, skeletal anomalies NPHP 1NPHP9, BBS 1, BBS 12 AR PAX2. HNF 15. EYA 1. SALL1: FMS 1, FREMZ AD:AR WTLTRPC6: NPHS 12. COQ22 MTTL 1 AD:AR: Miro. COl.4A36 AD; AR: XLR XLR: AR Retinopathy. peripheral neu ropazhy, vascular anomalies $l.C9A3R 1: SLCJA 1, AGXT Nephrozic syndrome Alpon syndrome Tubulopathies Nephrolithiasis. nephrocalcinosis CLCN5, ocxu SLC12A 1, SLC 12A3 AD:AR NUTRITION Nutrition consultation for CKD 3-5: rigorous RCT data lacking Cohort studies associate poor diet with incident or worsening CKD (AJKD 10iJ;s2¢267) Western diet more acidifying than a fruit/vegetable diet; acidosis may contribute to CKD progression, which may improve with high fruidvegetable diet (qAsn 201:l:&371) Higher dietary acid load alw t prevalence of CKD u Fu.. no 2018:4:zs11 Western diet. high animal protein diet. and fructose consumption tunic add levels, linked to incident CKD i;A94 znoan9;1z04l; UASH diet a/w 1 incident CKD We zoismsasa) Sodium (Na) High Na diets antagonize antiproteinurlc effect ofACEllARB 1 Na in t a ke f ro m 1 5 0 100 mEqld .L BP by 2.1/1.3 in preHTNIstage 1 HTN: 1 to 50 mEqld further . BP by 4.6/1 .7 leAsH NUM 2001::44:3) No RCT has been done in CKD looking at hard endpoints Low Na diets lower proteinuria and BP Mien added to ARB and diiazide UASN 20ce 19s9s1 Low Na diets had larger proteinuria and SBP L than dual RASi (Bm/2011:34:l:a4zs6) Protein Low protein diets (0.8 g/kg/d) in CKD ND may 1 hyperfiltratlon and eGFR decline Animal protein may lead to more hyperfiltration than vegetable protein, also contains more phosphorus :han equivalent amount of vegetable protein Largest protein restriction RCT underpowered. inconclusive (mono new 1994;]30:877) Higher protein diets (1.2 glkgld) needed in dialysis to prevent proteinenergy wasting Limited data suggest protein restriction safe in nephrotics ac/ 1997;99:2479) Potassium (K) High K diets may 1 BP (3.5/2.0) and stroke (24%) (sm/2013=34e¢n37a) High K decreases activity of NaCl cotransporter (NCC) in DCT (!*IN 10 u»171981) Low K die: associated with saltsensitive HTN and worsened eGFR (qAs~ z01s310121 $2) Recommended Intake in CKDIESRD lktwso cm aim; xnooi W) lll00.3$:s1) Na <2 ad for CKD: insullitient evidence for <1.5 g/d (Hui of Mia R°v°¢ 20131 K Tailor based on Ca eGFR. K levels. and concomitant medications (eg.ACEllARB): usually no need for restriction for CKD 1-3 <2 old for HD; 3-4 Yd for PD (more efficient K removal) Nondialysis CKD 3-5: <0.8 glkgld: HD/PD: 1,2 g/kgld (NDT 200$;20:i3) <1.500 mud of elemental calcium (combined die: and medications) P04 800-1.000 mg/d: T bioavailability with animal and processed food sources vs Protein Fluids Fiber Calories Fats vegetables: boiling foods L phosphorus lo lowering protein content Nondialysis:no restriction unless hyponatremic: HD/PD: 1-1.5 Ud No CKD guidelines: 20-35 old for general (us Dietary Guidelines 101s10101 30-35 kal/kg: 20-30 kcal/kg in AKl up' #fns1n Mimi- 2005:15:63) <30% tool calories from favs.<10% from sawrar.ed fats ProteinEnergy Wasting up 200a:73:a91) Syndrome of muscle wasting, malnutrition. and inflammation in advanced CKD Associated with increased morality and hospitalizations No validated criteria bun some characteristics include BMI <23: unintentional wt loss (5% in 3 mo); body far <10% Albumin <3.8; prealbumin <30 mg/dL;tot chol <100:muscle:reduced 5% in 3 mo Protein intake <0.8 g/kg/d (assessed by interview or calculated nPNA) Treaunent: oral supplements, optimize dialysis prescription, treat comorbidities lntradialytic parenteral nutrition costly with limited data. consider if not responding to of supplements alter 2 no;Amino acid solutions in PD (unavailable in US) hGH improved nutrition. QOL; limited data. experimental l;Asn 2007;i&m1) Protein Catabolic Rate (PCR. protein equivalent of nitrogen appearance rate) Estimates protein intake in HD patients using interdialytic BUN change; less often used in PD: significant caveats limit utility Formula uses interdialytic BUN change,also urinary urea losses if residual renal func tion: normalized to weight (nPCR). goal >1.2 g/kg/d Requires steadystate nitrogen balance.oiten not the case Overestimates protein intake in catabolic states. underestimates if anabolic Usually increases with improved dialysis (KtN) due to increased protein intake No association with mortality in US wu:1004;44:39) FLUID THERAPY INTRAVENOUS FLUID (IVF) FOR VoLur4E DEPLETION Four Phases of Resusclndon (QA z014m.740) Rescue Lifethreatening shock; fluid bolus >500 mU1§ mln for a MAP 60-65 Optimization Campensated shock fluid challenge 100200 mU5-10 min with assessment of tissue perfusion (MAP >65, Cl >2.2 Uminlmz, UDP >0.5 ml./kglhr), Stabilization Steady state. maintenance of fluid losses Deescalauon Promote negative balance lactate {<2 mmol/L) Crystalloids: solutions capable of passing semipermeable membrane; may be isotonic. hypersonic. hypotonic; ideal in pt with 1 volume not from bleeding, 1 expensive but T intersdual edema; can be used for rescue and scabilizadon phase Colloids: highmolecular weight: draw fluid into intravascular compartment via T oncotic pressure with low volume of fluid Blood products: for active bleeding. coagulopathy: improve tissue oxygenation Composldon of Crystalloids Electrolytefree na/cl/K/c=n4g H;OlECF Osmoladt (mOsmIL) (mErelL) pH Fluid Distribution (%) 100/33 252 0/0/0/0/0 3.5-6.5 D5W 34l34lolol0 3.5-6.5 78/50 321 D516 saline 50/66.6 406 77I77/0lOl0 3.5-6.5 D595 saline 1541154/ 010/ 0 4.5-7 0/100 308 0.9% NS 342/ 347JOI 0/ 0 4. 5-7 2% saline 0/100 684 513151310i0i0 4.5-7 3% saline 01100 1.025 Balanzed crystalloids: buffered solution containing organic a ions. lactate, or acetate 13111111514 5-7 Hannon 12/ 100 278 13011091413 6-7.5 13/100 273 Lactated Ringers 130/ 112/ 515f 2 6-8 12I100 276 Acerxe Ringers 0/100 294 1401981510/3 PlasmaL b ilnzravascular dissribudonz ii of ECF distribution 'osmolalicy in intravascular space: 0.93 x osmolariry PlasmaLy:cA pH 7.4; PlasmaLyte 148 pH 5.5 Compos i ti on of Col l ol ds Onc otic P re s s ure ( m m H g )30 V ol ume E x pa ns i on (X of Adm i ni s te 100-130 r e d V ol um e ) Na CI 5% albumin 20-30 70-100 145 14s 25% albumin 70-100 300-500 145 145 154 154 Fluid Hydroxyezhyl starch (Heostarch) 6% Dextran40 (1098) Dexrran70 (6%) Gelatins 168-191 200 154 154 56-68 120 154 154 lofusine. luemaccel): can cause an is. not available in the US Monitoring: individual ossessmenL clinical (eg, oral dryness, delayed capillary refill. neurologic symptoms, UOP); technical findings (Passive kg raising, lactate clearance, dynamic [SW BPM PPV]. vdumeuic [IT BV. GEDV]. echo [IVC. CO]) Fluid Therapy Consideration forVarious Scenarios ICU. severe sepsis or septic shock Balanced crysralloidsz additional albumin . mortality in septic shock subgroup INJEM z01u101411i Hyperchlorefnic (eg 03% NS) fluid 1 NAGMA,AKlIRRI1 death W" IM 2014:161347: WM 2012:3001S66. N£}M 201B,378819) Eadygualdheaeddiaupylmoruilkylargeli1gCW8-12wid\ crysialbid o rco lo id ,MA P 2 6 5 wide vascacliveagenis.UOP205 rnUI¢glhr;ScvO2 70% widl transfusion we 2001345 u's) but, not reproducible in subsequent Main iv-new ~ew }!J14J7(!IS83.ARISE new 2.0\4;37l:l4%; PmMISe ~=/m 1015:)7Z:\J01; msn NEW z017:.7em3) Balanced cryszalloids J. major adverse kidney even's (num zoisaruIs) No n I CU Metabolic acidosis Balanced crysulloids In AKI wl T Cr > x2 or oliguria NaHCO; 4.2% (0.5 mEqlmL) to keep pH >7.3 I death. RRT uum¢i 20\s.3miI No dear evidence for adding NaHCO; to correct acidemia and Lactic acidosis volume deck. but might help to L arrhythmias. t response to catecholamines. T CO in ' LV conxracriliry Urine alkallnlzarion For removal of weak acids:aspirin, phenobarbital, high dose MTX TCA o ve rd o se NaHCO; 1-2 11188 x1-2: infusion once QRS normalited Meobolic alkalosis with hypovolemia 0.9% NS Hypercalcemia 0.9% NS: metabolic acidosis HRS vs volume depletion Albumin 1 glkgld up to 100 g x 2-3 d Avoid lacraze containing fluid in severe liver dysfunction Therapeutic Albumin 6-8 g/L of ascizic fluid removal (e t . vln s + 5 0 -1 0 0 mE q Na HCO ; ) renal Ca nezbsorption Hsu 2NOs;17¢171 paracenresis Poswbstruclive. p o s: A TN Hypotonic fluid (et, }'ANS) co replace Yz the UOP (D avoid Traumatic brain NS preferred to albumin (t mortality) were 2007:3s7:s741 Avoid hypotonic balanced crystalloids to avoid cerebral edema Hypertonic not beneficial UAMA 2010.J04: l4551 injury hypematremia Mannitol T AKI (mea10ne 201$I94:e10!11 Trauma. hemorrhagic shock S"fs=r1 Packed RBC + platelet + FFP or whole blood Permissive hypotension w/ SBP goal 80-90:avoid routine use of crystalloids (new zoimm7ssl Balanced crystalloids in; sw;201s.10zz41 Major abdominal surgery no difference in disabilityfree survival in restrictive (net zero fluid balance goal) vs liberal (10 mUkg during induction followed by 8 mUg/hr) fluid resuscitation in the first 24 hr but f AKI in restrictive (8.6 vs 596) (new zoie37ema1 IVF for Sodium and Water Imbalance IVF Considerations for Sodium and Water imbalance Hypovolemic hyponatremia Hypertonic if acute or symptomatic Eu or hypervolemic Hyponatremia Hypertonic if acute or symptomatic; d/c cause of NS otherwise with frequent lab J hyponatremia No lV fluid initially, otherwise J lab frequently Hypovolemic hypernainemia }§ saline or D;W + NS;after volume deficit connected Euvolemk hypematremia Enteral water (preferred) or D WWI dextrose can can rewm to oral repletion lead to osmotic diuresis worsening water loss Rate of Na correction goal: <0.5 mEqIUhr, can correct 1-2 mE/Uhr initially un¢il symptoms improve if pr with severe neurologic symptoms (confusion. seizures.AMS) but do not exceed 10- 12 mEq in 24 hr Correction can be estimated by following equations but they are dynamic processes and does not consider loss; needs frequent plasma Na monitoring 'P w Estimated Na Convection by 1 L of IVF (NE/M 1000.34z 15e1) APn. - (lniusatei Hyponatremia + Infusate Hypernatremia If acute or symptomatic. use hypertonic solution 3% NaCl 100 mL (51 mE) or 8.4% NaHCOx 50 mL (50 mEq) over 10 min x3 as needed eg. in 70 kg young male with Pn. 110. 3% NaCl 100 mL will change Pn. by: 0.1 x (513 - 110)1[(70 x 0.6) + 1] Pn ,)l(TBW + 1 ) Free water deficit (L) ¢TBW x (P~,l140) - 1] et. in 70 kg young male with Pn, 150. (nee water dehcix is 3 L Initial D§W 1 L will change Pm by: 0.9 mEqIL 1 x (0 150)1[(70 x 0,6) + 11 -3.5 mErelL Estlmated ongoing renal water losses: significant in DI (L UM). osmotic diuresis (T Um) Urine output Electrolyte clearance + Electrolyte free water clearance (€Hx°) Electrolyte clearance = Urine volume x [(UN, + U,<)IP~.] C°H,o = Urine volume x [1 - (UN, + UK)/PN.] Interpretation of Electrolytefree Water Clearance (C'n,o) C'i4,o (+): free water excretion Condition Interpretation Hyponatremia Hypematremia Will be corrected if free water intake <Cl4,0 May worsen wlo water input; C'»4,o should be added to estimated free water deficit (-): free water retention Hyponatnemia Fluid restriction only will not correct hyponauemia Consider furosemide to enhance water excretion Hypernauemia May improve if :here is no signifianz nonrenal loss C'n,o should be subtracted from free water deficit Nonrenal insensible losses GI, skin. respiratory uact; 10- 1S cclkgld (Q), 15-20 cclkgld (d); t during fever. tachypn , burns, open wounds. diarrhea. ecc. Ma in t e n a n ce I V F Th e ra p y When pr is NPO. to correct electrolyte imbalances. perioperai:ively.ven¢ilator. cannot provide basal requirements solely with PO intake Goal to preserve H;Olelectrolyte balance and nutrition; need monitoring for volume excess (eg. edema) or depletion (eg, 1 skin turgor. ¢ BP) The amount of water needed to maintain homeostasis = C'n,o + nonrenal insensible fre e wa te r lo sse s (ca n n o t b e a ccu ra te ly e stima te d ) 1 . 4 0 0 -1 . 6 0 0 co ld o r 6 0 -6 5 cc/ h r Water requirement is increased in fever. GI loss Water requirement is decreased in oliguria. humidified air.water excess (SIADH. liver cirrh o sis. CHE a n d h yp o t h yro id ism) Elecuolytes replacement: deficit + loss (renal + nonrenal) J electrolytes: sodium level reflects water balance: others reflect their balance Elecerolyn Deficit Repletion Potassium Magnesium 20 mEq IV or PO (equivalent wlo vomiting/diarrhea) T 0.1-0,2 mEaL 2 g IV MgSO4 over 3060 min T 0.4 mgldL Administer 50% calculated dose in impaired renal function Calcium 1 g IV Ca gluconate over 30-60 min T 0,15 mgldL Ca chloride if severe hypocalcemir monitor for tissue extravasation Phosphate 15 mmol sodium phosphate at rate 4-S mmol/hr t 0.4 mg/dL Administer 50% calculated dose in im ired renal function Dextrose 100 g (2L of 576) - 340 kcal suppress catabolism CO MPL ICAT IO NS o F IVF T HERAPY AKI AKI from high CI fluid: renal vasoconstriction and l renal blood ilow UCI 19a8;71;7261 AKI from hydroxyedlyl smirch: osmotic PT injury; T RRT requitement. T mortality (N£IM 2008:3S81251 20111J67:114: /AMA z01330916781 Rap id So d iu m Co rrect io n Osmotic demyelination syndrome: from rapid correction of hyponatremia Cerebral edema: from rapid correction of hypernatremia/hypertonicky O t h er Co m p licat io n s Volume overload: need careful monitoring in HF. CKD.cirrhosis. and NS Hyperchloremic NAGMA:from large volume high Cl fluid (eg. 0.9% NS) Metabolic alkalosis: large volume balanced crystalloids by metabolism of lactate or acetate co bicarbonate Hyperglycemia and hypokalemia: from dextrose conmining fluid Osmotic diuresis: from large volume saline (sodium diuresis) or dextrose Fluid Coagulopathyzdilution of clotting factors and platelets: use blood products in hemor rhage Anaphylaxis or anaphylactoid reaction: hydroxyethyl starch, gelatin colloids BLOOD PRODUCTS Bl ood P roduc ts Packed RBC 225-350 mL: should be used with platelet and FFP (1:1:1) in trauma Whole blood 300-400 mL: can be used in trauma FFP 200-250 mL: used in coagulopathy MM active bleeding. HUS.TTE and PLEX: needs to be ABOidentical or compatible as in blood 4factor prothrombin :omplex concentrate (PCC) ioinuiw 20ll:128:l234). 3factor PCC are akemadves if bleeding diadiesis. reduced risk of volume overload and transfusion reactions Hb <9 is alw death in AKI requiring dialysis flnleMiw Care ma 200$;31:1529). still threshold for blood tra ns fus ion in AKI a nd CKD is unc le a r RBC transfusion is nor alw momliry in severe AKI (cn: cm raw 2016:44:a9z1 Studles on Hb Threshold for Blood Transfusion in Nontnuma Conditions ICU Symptomatic CAD 7 vs 10 lmulciorgan dysfunction. Ml. and pulmonary edema: 1 momliry in less ill and <55 ylo Mme new 19993404091 10 vs 8: trend for fewer major cardiac events and deaths (Am Ikan I 201l;155:964) UGIB Septic shock Cardiac surgery 7vs 9: T survival me at 6 wk (NEIM 20\J;2ss11) 7 vs 9: no difference mortality and ischemic event (NE/M Z014;371;1JaI) 7.5 vs 9: more deaths. no difference in serious infection or an ischemic event lNEIM 10IS:372.997) 7.5 vs 9.5 in ICU and 8.5 in nonICU ward not inferior at 28 d (NEW 2017:]77:1I]3) and 6 mo [NUM zo1aamzzo Restrictive Hb target <7 in ICU or GIB is alw 1 mortality (inhospital x0.74. wal x0.80). rebleeding (x0.64).ACS (x0.44), pulmonary edema (x0.48), bacterial infections (x0.86) w~/m=~120141117:124) Complications of Blood Transfusion Infections: bacterial or viral Acute allergic +/ anaphylactic reactions; delayed hemolytic transfusion reaction Acute hemoiysis: heme pigment nephropathy Iron overload from chronic transfusion HLA alloimmunization in KT candidate (L by leukoreduced blood) Transfusionrelated acute lung injury (TRALI): acute (during transfusion 6 hr) hypoxemic respiratory distress with bilateral lung infiltrates on CXR wlo volume overload/HF/preexisting ARDS Transfusionassociated circulatory overload: T risk in CKD (x27). CHF (x6.6). and + fluid balance (x9.4) with T mortality (x3.2) rAm; Mai 2013;1z6..as1.¢19): prevention with slow infusion (1 mUkg/hr) +I- diuretic use Hyperkalemia: released from RBC from t storage time, T pRBCs. irradiated: especially in massive trauma. impaired renal function and infants/newboms Dialyzer circuit clotting with heparinfree HD Complications of Massive Blood Transfusion (>I0 units/24 hr) Metabolic alkalosis: 1 mmol citrate. c,H,o(coo):' -» 3 mmol HCO: in liver Hypokalemia: d/t metabolic alkalosis; uanscellular exchange of H and K Hypocalcemia: citrate toxicity in liver failure:1 iCe ORAL FLUID Requirement: vary by age. sex. pregnancy. and breast feeding status Water absorption in GI: NaIH exchanger (NHE). electrochemical gradient. Nacoupled cotransport with carrier solutes (eg. glucose via SGLT1) Low Na in oral fluid Turine ourpuc (s»¢/A»1n»,w¢1oae;1o3¢sas) Oral Rehydration Solution (ORS) Indications: watery diarrhea wlo severe volume depletion/shock ORS recommended by WHO: osmolality 245 mOsmIL.glucose 13.5 g/L (75 mmol/L). Na 75 mEq/L. K 20 mEq/L Cl 65 mErelL. citrate 10 mmolIL equimolar Nalglucose 2 phases: rehydration (correct in 3-4 hr by frequent. small amounts) & maintenance Advantages: lower cost. easier to administer. less invasive. ambulatory Commindications: AMS. aspiration. ileus.conditions that limit GI absorption (et. show bowel), resuscitation, severe volume depletion or vomiting Water Benefits: J. recurrence of stones U Url 199e;1 ss=839); l :AMR potential to slow cyst growdl In ADPKD (c,IAs~ 201D:5:693). 1 recurrent UTI in premenopausal women UAMA IM 2018:\78:1$09) No general benefit to support B glasses (2 L) of water UASN 200a:19:10411 Compliadons: hyponauwesnia ap. in competitive mnnes. psychotic poiydipsia,eaa5y use PHARMACOLOGY Knowledge of changes in drug disposition from pharmacokinetic and pharmacody namic alterations in the presence of reduced kidney function among patients with CKD is important to individualize pharmacotherapy and ensure optimal outcomes PHARHACOKiNETiCS (AssoapTion, DISTRIBUTION, MsTAaousm, ExcasTlon) Absorption Absorption of a medication and subsequently bioavailability (% of medication that reaches the systemic circulation), may be altered in patients with renal disease CKD complications that may impact drug absorption. include: changes in GI transit time from gastroparesis. vomiting and diarrhea. alterations in gastric pH from use of acid suppressing agents (et. proton pump inhibitors. histamine 2 antagonists) Phosphate binders form insoluble complexes with some mediations quinolowe amzibioda Distribution Distribution of medications into body comparunents: plasma,watei1 fat. red blood cells. intracellular/extracellular binding sites. and tissue Volume of distribution (Vd) is a proportionality constant for the amount of drug in the body to serum concentration and can be used in clinical practice to calculate medication doses (drug concentration. mg/L* Vd. Ukg) to achieve a desired drug level Patients with CKD display significant alterations in Vd due to qualitative changes in tissue binding sites. competitive binding inhibition by accumulation of endogenous or exogenous substances such as uremic waste. decreased concentrations and confor mational changes of albumin. and high concentrations of metabolites that accumulate and may interfere with binding of the parent compound Vd (Ukg) of Select Medications Normal ESRD Comments Drug Increased Furosemide Phenytoin Decreased Digoxin Ezhamburol 0.11 0.64 0.18 1.4 Decreased plasma protein binding increases free 7.3 3.7 4 1.6 Uremic toxins are thought to dnsplace drug flam cedar binding sites; Reduced tissue levels M Na/KATPase plasma fraction Metabolism The breakdown of medications through enzymatic pathways within the liver. gunlungs. and plasma: oxidation. reduction, acetylation. glucuronidadon. or hydrolysis CKD may affect hepatic drug metabolism due to accumulation of uremic toxins. increased oxidative stress from a chronic inflammatory state. and downreguladon of CYP3A4 and CYPZC9 enzyme expression in the liver and intestine Pharmacologically active metabolites or metabolites with toxic effects may be formed Many drugs can stimulate or inhibit the activity of metabolizing enzymes. common padways. inhlbitors.and inducers are summarized Excretion Excretion is the process of removal of a drug from the body Primary processes hepatobiliary excretion and renal clearance Hepatobiliary excretion: liver actively secretes drug and/or meraboli¢e(s) into the bile which then gets excreted in :he feces. Some agents may be reabsorbed through diffusion by the small intestine and undergo enterohepatic recirculation. Renal excretion: drug is filtered into the nephron - collecting ducts urine. Compounds excreted in the urine are water soluble; agents that are lipid soluble must first be metabolized to increase water solubility. Renal clearance (CLI\) is a composite of glomerular filtration rate (GPR). tubular secretion (C ow). and tubular reabsorption (Cl,.,,,,,,,,,,,,) and is dependent on the fraction of drug that is unbound (f,,); [CL* = (GFR*fu) + CLnAen - CL,,.,...,¢...] Proxlrnal Tubule Drug Transporters Transporters LuminaJ Membrane MATE OCTN Substrates Inhibitors Ritonavir Cobicisrar Cimetidine Pyrimethamine Dolutegravir Basolateral Membrane OAT Dolucegravir Rilpivirine Cimeridine Quinidine Rifampicin Prazosin OCT HATE. multidrug and :oouc compound extrusion: OCTN.organic carionfcarnirine transporter: MAR multidrug resistant proceen transporter; PEPI peptide transporters OAT. organic anion cransporrer: OCT. organic action transporter CKD may change drug disposition through akeranions in Elzralion, secretion. or reab sorpnion Secondary processes excretion through lungs, milk, sweat, nears. skin, hair, or saliva DRUG DOSING ADIUSTNENTS Eszimadon of creatinine clearance from clinical data (age. gender. height. weight. serum creatinine) remains the guiding factor for drugdosage regimen design Stepwise Approach to Dosimetry in Patients with Renal Insufllciency Step 2 Obtain history and relevant demographic and clinical information Quantitative estimate of renal function; Creatinine clearance by Cockroft-Gault Method: estimated glomerular filtration rate (eGFR).or calculated from timed Step 3 Review medications and identify if there is a need for individualized treatment Step 4 Determine treatment goals.talculate loading and maintenance dose by varying StepS Monitor parameters of drug response as well as drug levels (total drug vs free Step 6 drug and peak/trough levels) Assess clinical res use and adjust Step 1 urine collection dose or varying interval or combination method men based on tents outcome HEMODIALYSIS AND DRUG THERAPY Factors that affect dialyzability of medications include drug characterlsdcs. dialysis conditions.and patients clinical condition Hemodialysis units generally administer drugs after the patient has undergone dialysis to minimize the loss of drug Drugrelated factors which preclude dialyzabillty Include the molecular weigh: or size (>1,000 daltons). degree of protein binding (high),and distribution volume (large) Dialysis prescription: composition and surface area of the dialysis filter and blood and dialysate flow races. Highflux membranes have a large pore size (allow passage of drugs with molecular weights of up to 20.000 daltons) and mimic the filtration characteristics of the human kidney vs conventional hemodialysis. Drugs extensively cleared by HD: vancomycin, atenolol.and metoprolol. angiotensin converting enzyme inhibitors (except fosinopril) CONTINUOUS RENAL REPLACEMENT THERAPY AND DRUG THERAPY CRRT will remove medications by convection (unbound) and diffusion Litde is known about drugdosing requirements for patients receiving CRRT; however. dosing strategies can be between those used for outpatient intermittent hemodialysis using a GFR <10 up to those used in mild impairment classified as GFR $080 RAAS INHIBITORS Renin Angiotensin Aldosterone System (RAAS) Release Activator s Release Inhibitor s Act ion Inhibitor s C omments and Actions Renin 1 Afferent arteriole stretch 1 DCT Na SNS (un Natriuretic peptides unSAIDs 131 blockers CNI. DN DRI PGE2 mediates release Convert angiotensincgen to angiotensin I Angiotensin II (All) ACE Not T K ACEr ARB Vasoconstrktion (efferent > afferent arteriole): T Glom capillary pressure Component t BP (NUM 2017:377419) Aldosterone (Aldo) An: K Adrenal insufficiency. ketoconazole ACEr, AR B, heparin T Aldosterone.ADH T NHE3, NCC. ENaC activity Na reabsorption 1 ROMK; T K excretion an colon or seen 1998227459751 MRA. ENaC t ENaC. T ROMK: t Na inhibitors reabsorption in CD & CNI TK and H' secretion DN T Na leahsoqnion by colon T ROS. inilammationl fibrosis (nu: Rev nepnm1 201 !:%459) Angiotensinconverting enzyme (ACE): present at pulmonary and renal endothelium; Converts angiotensin I to angiotensin II; Kininasezdegrades bradykinin Natriuretic peptides (ANR BNR CNP): released from atria (ANP) or LV (BNP): " cGMR inhibition of NHE3. NKCC2. ENaC. vasodilation. L renin release. T GFR Neprilysin (CD10): neutral endopeptidase. abundant in kidney; degrades natriuretic peptides. adrenomedullin. bradykinin.VlR and angiotensin II Potential Changes of RAAS Components by Medicines Renin Renin Aldo Level/ Level Activity All Level Aldo Level Renin Activity Type 4 +4 6 + D1 blocker T DRI TT u L 1 ACEr T Tt 1 T TT T 1 ARB t MRA T TT T 1 T t Nepril in inhibitor 1 l l l T Clinical Use o¢ACEl and ARB Mild T Cr: could be sign of 1 glomerular hyperfiltration In CKD,ACEi use is alw 28% . mort. 39% J. kidney failure; 18% l major CV events; ARB 30% I, kidney failure: 24% L major CV events IA/xo z0161672M1 In T2DMlDN.ARB 16-20% ¢ doubling Cn ESRD and death (RENAAL NE/M 20011345184 lDNTNEW'2001:]45:8$1) ACEi or ARB is recommended for all diabetic patients with UACR >30 mild and nondiabetic patients with UACR >300 mg/d lkoioo coo 2012). Proteinuria that would quickly remit as In MCD can be monitored w/o ACEi or ARB (KDIGO Gn 2011). In renovascular disease. 1 death. Ml. or stroke and dialysis (A»4/200a:1sss49) Even in predialysis CKD5.ACEi and ARB aw i dialysis. death (WM IM 1014;174347) Supramaximal ARB 1 proteinuria wlo lowering BP (nu 200s;6e:1 we }Asr4 2009;z0.s9al Losartan has less maximal efficacy in BP lowering than other ARBs: losartan 100 mg <irbesartan 300 mg, valsartan 320 mg. telmisartan 80 mg. candesartan 32 mg Losartan T uric acid excretion by inhibition of the proximal orate transporter 1 (URAT1). uric acid reabsorption mechanism WH 2008;2111157) Use at night: improve BP (ASH 201194 can. L DM incidence l0i4wwf 2016:59:255) ARBs and fosinoprll are not removed by HD: odmer ACEi are removed by HD Angioedema from ACEi Incidence is 0.68% (Ap41004:171103)1 rare with ARB (Ann IM 2011971115823 Am] Caluiui 20124110 ssl): Usually happens wu 1" wk of ACEi. but can happen anytime bradykinin mediated by LACEmediated degradation Swelling of lips,tongue. face,and throat (laryngeal edema):abd painzdiarrhea Absence of urticaria or pruritus An¢¢gyA»uwna can nmmuiur 101117 Suppl 1:s91 Recurrence: 46% after dlc ofACEi 1" recurrence wu 3 mo except 1 case (Ii"59.445 201 1119n731: should not be attributed to alternative drug.such as ARB Tx: dlc ACEr. airway protection: icatibant (NS/M 2015;]72:41B). ecallantide. C1 inhibitor concentrate. FFP Approximate Equivalent ACEi and ARB Dose (mg, Daily Unless Specified) Drugs Low Moderate High Lisinopril. Fosinopril Enalapril (qdhid) Enalaprilar (q6h) Captopril (rid) Ramipril Benazepril. Quinapril Moexipril Perindopril Trandolapril Losarun Valsarun Candesartan Olmesanan Irbesarran Eprosarran Telmisarun 2,5-5 2.5-10 0.625-1.25 q6h 6.25-12.5 tid 1.25-2.5 5-10 7.5 2 1 25-50 40 4-8 S 75 400 20 10-20 20 2.5 q6h 25-50 did 5-10 2040 15 4-8 2-4 100 80-160 16 10-20 150 600800 40 3040 40 5 q6h 100-150 rid 20 80 30 16 8 320 32 40 300 80 Side Effects ofACEi and ARB TCr: in bilateral renal artery stenosis. HF and CKD; /BPIP wu 1 wk after start Even 1 Cr <30% alw ESRD, ml. HE and death (mu z017:3s6¢i791) Hyperkalemiaz possible in anuric HD patients (Am}m¢4 2002;1112110); Patiromer may be used in hyperkalemic pts on RAAS blockade IN£}M 201s::n:211) ACEi +ARB T AKI and r K in DN IN£;M 1013.J69.1a91) Teratogenic y: CNS and CVS malformation in 1" trimester (NEW 2006;J54:24431: uro genital and renal malformation in 2° trimestercavoid MRA and DRI Anemia: both ACEi and ARB (Q/m 2015;10a;a79).Angiotensin II type 1 receptor enhance EPOstimulated erythroid proliferation Wm 1ss9;1os; 1s8);ACEi 1 IGF1. erythropoiesis promoter (fiumplonmuun 1997:64:913). Used for posttxp erythrocytosis or zoonnasol. Dry cough in ACEr PLEX reaction in ACEi: Klnin mediated: dlc 24 hr prior to PLEX (rIuvmiman 1994:34;B91) No T cancer U Hlpenevs 2011;19;623; am;1018:361:k38$1) Mineralocorticold Receptor Antagonists (MRA) Addition to ACEr or ARB BR proteinuria ac/is~ Z009;4$41: ac nqmhml 20161111271 Effective addon drug for resistant hypertension (Lancet 2015:J86:2059) imoriality in NYHA II HF wl EF <35% (new z011:364:11> a postMI low EF(NEJM 1003.34B:1309) In HD patients. spironolactone 50 mg bid i BP WND 100$146941, S0 mg qd 1 hyperkalemia w/o changing LV mass (al 101935:973:Z019;9598]) sle: hyperkalemia esp in CKD UASH 201024295), t Cr Direct Renin Inhibitor (DRI) Aliskiren » Iosarran L proteinuria dw losartan only (AvolD nsjm Z008;358:2433) Addition of aliskiren to ACEr or ARB did not improve CV or renal outcome (ALWUDE NEW 2011;367:2204: 2016:3141S21) In HF aliskiren +ACEi t Cr;1 K.l BP wlo benefit (NEIM 2014974115211 sle: hyperkalemia. i Cr. angioedema Angiotensin Receptor Neprilysin Inhibitor (ARNI): Sacubitril Neprilysin inhibitor T natriuretic peptides, bradykinin. and angiotensin (reason ARB combination is always required); NTproBNP is not t by neprilysin inhibitor Indicated for symptomatic HE NYHA It-IV w/ LVEF $40% despite ACEi or ARB HF w/ NYHA II-III on ACEi or ARB should transition to ARNi (ACCIAHA /Acc 10w270177sl Do not combine wl ACEi for risk of angioedema icnulaw z002;I06¢920): 36 hr washout for conversion. conversion from ARB does not require washout 20% J, CV mortality and HF hospitalization (NEW 2014=37w931 and greater 1 NTproBNP in hospitalized pts dw ACEr (new 201913a95m sie: more hypotension. less Cr 22.5, K >6 than ACEi (Ne1M 20w371¢993). angioedema Avoid use prior to PLEX to prevent possible bradykininmediated reaction NON STEROIDAL ANTIINFLAMMATORY DRUGS Actions of Progstaglandins (PG) and Effects of unSAIDs Actions of PG Effects of unSAIDs Hypotension, 1 perfusion pressure - PGI; and PGE; L Renal blood flow and GFR mediated vasodilation: mainly afferent arteriole: maintain renal perfusion when RAAS is activated High Sal: intake natriuresis medullary PGE; inhibits NKCC2 0 Volume depletion cortical PGE; renin release from JG cells - RAAS -u K excretion and BP PGE; . AQP2 expression Maintenance of medullary interstitial cell blood perfusion TXA}S platelet a2,re son Sodium retentionlederna Hypertension T Concentration ability Hyperkalemia t Concentration ability SIADH; used in NDI Papillary necrosis T Bleeding Kidney express both cyclooxygenase (COX)1 and 2 Pharmacology of unSAIDs Short Yz life (<6 hr): ibuprofen, indomethadn, ketorolac. diclofenac Long Y: life (>6 hr): naproxen. piroxicam; phenylburazone (a veterinary NSAID) Mainly metabolized by liver:Tightly bound to protein Topical unSAIDs can induce systemic renal effects INDI 1999214 1 B7) Effects on Renal Function,AKl and CKD Current NSAID exposure is a/w AKI w/ OR 1.73 (mc nepnfd 101711a,156). ? 20% of AKI and CKD UAMA Nelw of z019.2:¢1s7s96I: t AKI s. hyperkalemia (nor z019.a4,1 i 451 AKI: from renal vasoconstriction. especially when combined use with diuretics and/or RAASI i AKI lx:201838396) Rapid progression of CKD (An»Im¢4 z007=t 2<na0,¢1; Other Renal Manifestations of unSAIDs Interstitial nephritis: acute or chronic T K: unSAIDs used In Bartter (T PG pathogenic) www 20a113431w1 yAsnz017;w1s40) and Gitelman l;As~2015126:468) dRTA and 1 K by carbonic anhydrase II inhibition (Cate Rep on Care z013.a7sasn Potentiate ADH action: can cause SIADH; used in nephrogenic DI (NDI) MCD, FSGS; MN lA;Kn 20n26z10111 Papillary necrosis: especially with vascular diseases, eg. sickle cell. DM Sloughed papillae may cause renal colic. urinary obstruction Contrast CT: irregular papillary tip. loss of papillae IV orography. ring shadow Increased risk of pyelonephritis when used in lower UTI (Bm)2017:3S914784) Longterm use may be alw RCC wdilm 2011:171:1487) Extrarenal Clinical Manifestations Analgesia, antiinf1ammatory effect T BP (Lancet zooaarwoI; l antihypertensive effectiveness r CV events man 1W5:351:1lJ91: BM; lll06:3]2:l30Z)I even in the 1 wk of use lciwiiuvn 2011;113:1126: WJ 2017;]S7:l1909) T MI: diclofenac. but not w/ naproxen: indication might matter: spondyloarthritis >OA (Ann Rheum on 201817721137): HF admission iw/ 2016; 3$4: i48$7) Dyspepsia. peptic ulcer and bleeding unSAIDs Intoxication and Overdose Common cause of drug intoxication Nausea.vomiting,drowsiness,anion gap acidosis (lactic acidosis 4; acidic metabolite). seizure.aplastic anemia. and granulocytosis (in phenylbutazone intoxication) AKl:usually reversible Tx: conservative: HD is ineffective dlt protein binding; may consider PLEX in severe intoxication (eg, anaphylaxis) unSAIDs Should be Avoided in the Following Conditions Any use in GFR <30. prolonged use in GFR <60 w/ lithium and RAASi lxoioo ci<o 1012): HTN (especially poorly controlled) and HF Poral hypertension and cirrhosis (AGA an Gaauuenmul Hepnuul 10ltl7:59$) DIURETICS DIURETICS ACTINC on THE Pnoxinai. CONVOLUTED TuauLe (PCT) Site of 60-70% of Na reabsorpdon Drugs: carbonic anhydrase inhibitors (CAI). acerazolamide L NaIH exchanger (NHE3) and T HCO: excretion by 25-30% and Na is brought further downstream as the counterion (NKJM 19S4;254759) Clinical Use: metabolic alkalemia induced by highdose loop diuretics in CHF. glaucoma. pseudotumor cenebri. highaltitude mountain sickness. posthypercapnea alkalemia (Run #Mai 1987;1011]6) W e a k natriuretic when used alone dlt T distal Na reabsorption (N£IM 19s4=2so¢s00) Effective as a natriuretic when used in combination with more distal inhibitors (1 CarMawsc Pharmacy 1997:29:367; UM) 1990112318831 PK: usual dose is 250-500 mg daily: Secreted by OAT in PCT (Semen news 2011:31:483) Electrolyte Effects: metabolic acidosis.profound hypokalemia from distal nephron Na/K exchange;ensure K replete in considering use (NEW 19$4:250IS9) DIURETICS ACTING ON THE LOOP OF HENLE Site of 25% Na reabsorption Drugs: furosemide. torsemide. bumeranide: ethacrynic acid (nor sulfabased) Inhibit apical NaK2Cl couansponer (NKCC1) in the TAL of LOH Clinical Use: greatest natriuretic eliiect among Me diuretics ("high ceiling" diuretic). Starting diuretic for volume management in advanced CKD.cirrhosis. CHE and nephrosis. FK: variable PO absorption with furosemide (see table). Highly protein bound, very little Gltered. Secreted by OATs in PCT (chi HlamThu 19ao:z77a4). Pharmacokinetics of Loop Dluretlcs (NEW 1 wmamal= Am]17»er zu09;1w1 Equivalent Dose Diuretic Furosemide Torsemide Bumetanide Ethacrynic acid Oral Bioavailability (76) 10-100 80-100 B0-100 100% PO (mg) 40 20 1 S0 IV (mg) 20 Tm (it) - 3-4 1 2-4 1.5-2 1 50 Tar: significantly increases i CKD. CHE and cirrhosis INE}M 199B;339387). Ceiling Doses of Furosemide (Amjm¢4sa 1u00.3\9¢JU):anlons neulned in renal failure compete with OAT Condition eGFR 20-50 eGFR <20 CHF IV (ms) a0 200 4080 PO (mg) 160 400 80-160 Electrolyte Effects: 1 K (A0.3 mEqIL) and 1 Mg common: 1 Na less common than in thiazides as NKCC2 inhibition L medullary interstitial osm (s¢mwI n¢w-=l10I1;a1:s42> Other sle: hypersensitivity (sulfabased. except ethacrynic acid),AIN (uncommon). ototoxicity (NKCC1 antagonism in inner earzavoid concomitant aminoglycoside administration. more common MM ethacrynic acid).Vascular smooth muscle relaxation with improvement in pulmonary congestion in some patients IN£;M t 973¢za&1oen. Can worsen LC cast nephropathy. DlunETlcs ACTINC on THE DISTAL CONVOLUTED TubuLe (DCT) Sire of -5% Na reabsorption Drugs: hydrochlorothiazide (HCTZ), chlorothiazide. chlorthalidone. metolazone Inhibit apical NaCI cotransporter (NCC) in the DCT Clinical Use: antihypertensive in pts with GFR >30; Edema:used in combination w/ loop diuretic for acute decompensated HF (ADHF) UACC 2010t56=1527);Ca nephrolithiasis. nephrogenic DI (along with low solute intake) PK: blunted effect when GFR <30 Diuretic H c Tz Chlorthalidone Metolazone Chlorothiazide Plnrmacoklnetks of Thiuides yAcc z0I0s&Is2n Equivalent Duration of Duration in CKD Dose (mg) Action (hr) T 25 (PO) 6-12 12.5 (PO) 24-72 t t 2.5 (PO) 12-24 T 250 (IV) 6-12 Electrolyte Effects: 1 K (A~0.5-0.9 mEqIL) and LM; common Other sle: hypersensitivity (sulfabased).AIN (uncommon), hyperlipidemia, pancreatitis. i insulin sensiziviry. T Li. T Uric acid. gout. Some thiazide class diuretics have carbonic anhydrase inhibition (chlorozhiazide. chlorthalidone. and indapamide are strongest). Thia zide Induc e d H y pona tr e m ia (TIH ) Risk Factors: old.female. low BW low BMI. highdose thialide, previous h/o TIH common in 1" 3 mo of thiazide. risk remained high ~10 yr (AmjM¢4 2011:124:1064) Mechanisms of ThiazJdeInduced Hyponatremi. lack of effects on medullar interstitial osmolality as in loop diuretic NCC independent upregulate aquaporin2 (Ayllemllowaosrszsl Increased water intake (And IM I909.I\a24, lHrw1~~ ZOl5;33:6171 | Water clearance dlt low solute intake: Urine urea <330 mmolld I/»#»v~==~ 201 sa3¢sm Polymorphisms of gene encoding PG trans . her. EP4 Taqu rin2 zo11:1z7:aas7I Low uric acid. FEm \4 >12% Tx: permanently dlc d\Ialide. t solute intake 2 fluid restriction DlunETlcs ACTING on THE COLLSCTINC DucT (CD) 1-2% Na reabsorption Mineralocordcoidreceptor blockers (MRB) and ENaC antagonists: Ksparing Drugs: spironolactone (MRB). eplerenone (MRB). amiloride (ENaC antagonist). trl amterene (ENaC antagonist);Trimethoprim component ofTMP/SMX inhibits ENaC MRBs antagonize effects of aldosterone (basolateral NaK ATPase. apical ENaC, apical ROMK),while ENaC antagonists directly antagonize apical ENaC in principal cells in the terminal DCI CCIZ CCD limn n°p"wl2011:314a3) Clinical Use: as mainstay in cirrhosis and nephrosis.and as adjunctive in CHE Can attenuate the need for K supplementation in combination diuretic regimens. PK: MRBs enter cytosol via basolateral membrane. ENaC antagonists are secreted by OCT in PCT Electrolyte Effects: T K, 4 HCO3 (Semis nepiw 20u;z154z) Oth e r sie: gynecomasUa (MRBs):Triamterene can result to crystalluria and stone formation in up to 50% of patients (co. Nephrnl 19B6;16:169) Sire of OTHSN AGENTS WITH DIURETIC EFFECT Vasopressin Antagonists Drugs: tolvaptan (PO). conivapran (IV) Vasopressin2 receptor antagonism blocks effect of ADH. leading to aquaresis Clinical Use: FDA approved for the treatment for hypervolemic 1 Na and SIADH PK: dose reductions required with ketoconazole. darithromycin. ritonavir. saquinavin erythromycin. fluconazole. verapamil Electrolyte Effects: T K. 1 HCOJ (sm mama 20119115411 Other sle: can cause significant t ALT >AST > bilirubin; Conivaptan also hasV1a receptor antagonism. can lead to variceal bleeding Sodium Glucose CotranspowtenZ (SGLT2) Inhibitors Used in TZDM; 1 mortality. CV events. T wt loss. BR and improved renal outcomes: we/H zo19;anu9s= JAMA 20188191\5801 GtuiaUun 2016:802277: q/iw 1017111:751: xi 2018;9]231) Osmotic Agents wa- :m 1981:141:493) Mannitol is altered by glomerulus. exerts osmotic action throughout nephron Generally no benefit; should only be used for nondiuresis indications B N P I A N P Potentiation (run Anna Sachem 1991;14=zoal Sacubitril: neprilysin inhibitor: T natriuretic peptides: sacubitrlllvalsartan (Entresto°) 4 CV mortality and HF hospitalization lnslm 2014;:719931; in HF with NYHA IIIII on ACEi or ARB should transition to ARNi (ACC/AHA;ACC 1017:70776) Nesiritide: recombinant human BNP: no effect on mortality and rehospitalizadon in ADHF INE;M 101\:36582); not currently recommended therapy DIURETIC RESISTANCE wxl;2017:69:136) First assess for dietary adherence (24 hr Un. <100 mmol - 2.3 g) and medication adherence.Then consider alternative mechanisms for resistance (below). Diuretic not reaching target: too low dose. poor absorption. organic acids of uremia competing with OATs in PCT in CKD Blunted diureuc response (concomitant use of NSAIDs.activadon of RAAS and Na retention after diuretics (Ki 1983;24:13J)). disizl nephron adaptation with Na avidity If 24 hr Un. <100 mmol.then increase PO :oral daily dose (dose or frequency). If no response.add distal diuretic (DCT or CD). If no response.then transition no IV. DISEASESPECIFIC MANAGEMENT Hypertension ISQNI1 Nephrol 2011,31495:Am 1 Hypenenx 2016;29:1110) Thiazides included in 1"line therapy recommendations by JNC8 kw zo14:a 11=s0n Furosemide BID vs wmemide QD » similar i BP in CKD2 and 3 (KI 2WJ;64:6321 A cu t e K id n e y I n ju ry Diuretic use in critically ill wtienu with AKI is a/w adverse ewnu in this group (con relation, no: clearly causal): may delay initiation of RRT locAno;w 2W2;1W:254" Diuretic use co achieve a negative fluid balance in paden w/ ARDS and AKI conferred a 60d mortality benefit (nm qAsn 1011;£9") Diuretic challenges" in AKI may be trialed to manage volume overload, but requires frequent reassessment for reWnoriness so as not to delay RRT No clear role in AKI other than volume management (Grade ZC) (KolGo Axi 20121 Chronic Kidney Disease may may 101ze:1w) Orpnic acids compete with lobular secretion by OAK rightward shift of doseresponse cu rve re su ltin g in higher required doses 9ASN 2W1:13n8) Addition of thiuide to loop diuretic in CKD 3b and 4 results in l weight. plasma vo lu me . a n d B P in mm 1 %1 ;U:9 2 9 l In ESRDHD. if still urinates continuing loop diuretic alw lower IDWG. less T K.and preservation of residual renal function at 1 yr (oomux02w7=4914261 and 1 hospital iza tio n & in tra d ia lytic h yp o te n sio n (Cl*5 ** z0 \m4 9 5 ) Co n g e stive He a rt Fa ilu re (Se m Ne p n mi z0 1 1 :3 1 =s0 1 ) Diuretic resistance from several mechanisms. but afferent vasoconstriction primarily responsible for 1 diuretic secretion (both -» and l shift of doswesponse curve) Torsemide results in fewer ADHF admissions than furosemide (AmI m¢4 z001:1\1;s1s) For hospitalized patients.similar results in bolus vs continuous IV dosing of loop diuretics (DOSE new 2011;3s4;n11; however, prior study in resistant patients noted increased urine output and less ototoxicity with gtt vs bolus dosing (}Acc 1996:7.8:37b) Combination loop diuretics and thiazide an double FE~, and wt loss, but T risk of 1 K, 1 Mg. L Na.. BP, and worsening renal function (WRF) (;Acc 2010s6¢1s171 Addition of metolazone vs thlorothiazide resulted in similar UOP and adverse events in d iu re tic re sista n ce in A DHF is-wa rm 1 0 1 s;3 J¢ 4 1 > In severe. refractory cases. some evidence to support the use of hyperwnic therapy + highdose loop diuretics (an 1 Heart FM zoaatzwsl (Semn nepml 201 1.311s031 Combination therapy with loop diuretic and spironolactone. usually in a 2:5 mg dose Cirrh o sis ratio u Can Gown 19s13a suppl1:73: l4=W4'°l°tY 2W3:38:1S8) 90% will have effective management with Narestriction and this combination If CKD or OLT. need less MRB and more loop (100;B0 or 100:120) given risk of t K Loop diuretic monotherapy is Mt recommended. except in cases of 4 K S p iro n o la cto n e mo n o th e ra p y if K <3 .4 Avoid L K given risk of worsening hyperammonemia (intracellular acid in PCT) Hold diuretics for worsening encephalopathy or severe LNa <120 No role for IV therapy. even in resistant cases (more WRF with IV) Amiloride and triamterene less effective than spironolactone (OCTs in PCT) Ascites: goals of therapy depend on sate of peripheral edema w/ p e rip h e ra l e d e ma » <2 kg / d wlo peripheral edema -» <0.3-0.5 kgld (consider paracentesis if symptomatic) N e p h ro ti c Syn d ro me (N S) Hypoalbuminemia may reduce diuretic delivery and intrduminal albuminuria may bind secreted diuretics (not confirmed in humans) l;Asn 1000;11:11W) Unclear role for coadministration of albumin and furosemide (KJ 1999;$5sz9) routinely. Consider albumin if signs of intravascular volume depletion (r:,lASN 1uc~x4:907) Combination with loop diuretics including thiazides, amiloride (filtered plasminogen _» plasmin activates ENaC) (IASN 1009342991 IMMUNOSUPPRESSIVE THERAPY PRINCIPLES OF IMMUNOSUPPRES5IVE THERAPY Glomerular Diseases Many glomerular diseases are mediated by immune mechanisms (KI 2014:a6:90$) and immunomoduladng therapy is a mainstay of treatment lmmunosuppression (IS) therapy is divided into 2 phases in some glomerular disease :her relapse frequently (et, lupus nephritis and ANCAassociated vasculitis) Induction therapy: intensive IS to induce remission in proliferative glomerulone phritis (eg. pulse methylprednisolone followed by cyclophosphamide) Maintenance therapy: after remission is induced. reduced IS is given co prevent relapse avoiding severe toxicity of IS (eg.AZA. moderate dose MMF) Renal dysfunction, hypogammaglobulinemia. and complement loss from proteinuria all susceptibility to infection (Aim 19941414271 Gut mucosal edema d/t NS can l PO absorption of medications Hypoalbuminemia and proteinuria affect drug metabolism and clearance Regimens are tailored to the clinical syndrome being treated. patient compliance (IV or qd instead of multiple dosing if nonadherent). and comorbidides Comorbldides and Selection of lmmunomodulators in Glomerular Diseases Comorbidity Avoid if Possible Hay Consider Advanced CKD DM Gou: Pregnant CNI CS.Tac AZA if on xanthippe oxidase inhibitor MME CYC (contraindicated) . CS.MMF CsA, HMF MMF CS.AZA. or CNI Choice of Induction Based on Immunolodc Risk Factors for Acute Rejection H ig h r isk Lowrisk Use lymphocytedepleting agen: (ATG more common than alemcuzumab) Use either lymphocytedeple¢ing aden: or IL2RA ATG more effective :han IL2RA as 1 and 5 yr II preventing acute rejection. though no difference In patient/graft survival Dm are mixed whedler ATG more effective as preventing rejection dw basiliximab. though adverse events with ATG (r.....¢ii»i¢u~\ iwxsvnan u~=¢ 2016;388:3006) (NEW 20083551967: 200e335921 vi Early rejection equal between ATG and alemzuzumab, T lame rejection with alemtuzumab [NgI4101 mummy Maintenance therapy: ongoing IS to prevent acute reiection.Typically 2 or o n . Most regimens consist of a CNI (in US -90% Tac and -10% CsA) and andmeabolite (in US >91>% MMF). +I- CS (in US. 67%) WT zola;1s $uppl1:1 B). If unable [D tolerate CNI d/¢ severe s/e. can convert to mTORi or belatzcept Nonadherence occurs in 20% of KTR and is a/w T late acute neiection and graft sur vinlal; more common in adolescent: (QASN 2010.sn10s: re,ww 1W5;18:l12I) In pts as T risk of ncnadherence, consider simplified dosing regimen of daily medkadons (TacER. prednisone, sirolimus. and/or AZA) and/or use of monthly IV belanacepv: Infection Screening Prior to IS ¢c}As~ 101a;131z641 J HBsAg. antiHB: Ab. HCV Ab, HIV Ab. strongyloides Ab • ./ PPD and/or IFNgamma release assay (IG RA) IS can cause false (-) in many Ahdetecting and cytokinebased methods. Nuclek acid testing and both o( PPD and [GRA should be considered [O T sensitivity gzip Kidney Transplantation IS can be achieved by depleting lymphocytes Cr blocking lymphocyte response Fcell activation postTx dependent on 3 responses: Signal 1: antigen-Tcell receptor interaction (via CD3 signal) Signal 2: costimulation with dendrite cells (via CD80l86:CD28 interaction) Signal 3: activation ofTeR pathway -» cellular proliferation (new 1004051:2719 Induction therapy: intense IS in 1H wk postTx; can be either lymphocyte depleting (thymoglobulin, alemtuzumab) or nondepleting (basiliximab); CS typically also given Risk factors for acute rejection: number of HLA mismatches: younger recipient age: older donor age;AfrlcanAmerican race: PRA >0%; presence of DM; blood group incompatibility; DGF; cold ischemia time >24 hr or zooms supplJ:S8) C o a T l c o s T ER o 1 o s ( C S) Mechanisms ofAction CS refers to a class of steroid hormone and the synthetic analogues that bind to glucocorticoid and mineralocorticoid receptors Glucocorticoids bind to the inuacellular glucocorticoid receptor -» binds to glucocorticoidresponsive element -i gene expression regulation -» t antiinflammatory protein, i proinflammatory protein Neutrophil migration to inflammation site: T neutrophil secretion of bone marrow Inhibition of the function ofAPC; inhibition of the vasodilation: 1 vascular permeability Inhibition of the swithesis of arachidonic acid -» L PG and LT F o r m u l a ti o n s Relative Activity and Action Duration of CSs (Alqynavna an lnmuwl 1MBMB) Drugs Gluc oc ortic oid Mi ne ra l oc orti c oi d Hydrocortisone 1 1 Cortisone 0.8 0.8 Prednisone 4 0.8 Prednisolone 4 0.8 Merhylpredraisolone 5 0 Dexamenhasone 30 0 Beramedwasone 30 0 Ac ti on Dur a ti on Short (8-12 hr) Incermediaze (12-36 hr) Long (36-72 hr) Prednisone/prednisolone 5 mg = methylprednisolone 4 mg - hydrocortisone 20 mg Physiologic cortisol: peak as 6 AM; equivalent. to prednisone 5-7.5 mild Clinical Use and Dose Dose early in AM; mult iple dose may T sle union Diabet es End¢1<llnaI 201B: 6: 173) Tapering: unnecessary if CS used <3 wk. Rapid tapering may T relapse and withdrawal. No consensus on tapering method I; Rheumalal 2013;40:1646). RPGN: methylpnednisolone 500-1.000 mg or 7-15 mglkg IV qd x3 d followed by highdose PO CS.eg. prednisone 1 mglkg qd Proliferative GN (eg. lupus nephritis. pauciimmune GN): highdose CS Glucocorticaid responsive MCD and FSGS. 1g/\N: prednisone 2 mg/kg god or 1 mg/kg qd Adult MCD may require high dose for 4 mo (qAsr4 2no7:2:44s1;Avoid use >6 mo A cu t e i n t e r st i t i a l n e p h r i t i s Induction and maintenance iS aker KT: CS withdrawal is center dependent: 71.8% on cs 1 yr after KT in 2016 (ovrwsurni/r201m1s :ii 118) No consensus on the optimal maintenance dose after KT 1K1:>IGo As 2009.9 suppl 3.si) Early steroid withdrawal alter transplant performed to avoid longterm sle of CS Early dlc alw T risk of recurrent GN but no T in graft failure (riuiapiiiniiaan 2011191113861 In lowrisk. early dl: a/w similar patiendgraft survival & rejection rates (qAsn 20 lZ:7:494) In highrisk, similar Gndings with early steroid withdrawal (fmiisplalimuan 2004;78=1397) Lace steroid withdrawal after transplant a/w T risk of acute rejection and graft failure In pts who have 1st acute rejection after steroid withdrawal, maintenance CS may l risk of 2nd acute rejection and graft failure or z007;7:194a) Acute cellular and antibodymediated rejection Pharmacology Metabolized by cytochrome P450 (CYP) 3A4 Infection Pneumonia x5.42. candidiasis x4.93. sepsis x3.96, zoster >(2.37 (runs mu 101Q1J¢¢i002024) Risk is a/w dose Inner of an re Am 1016:42:1$7) Adrenal Insufficiency 3 adrenal insufficiency from withdrawal of chronic CS use; rare with <3wk use Weakness. fatigue. anorexia. NM hyponatremia, hypotension TX: T dose to physiologic dose (prednisone 5-7.5 mg/d) and retry tapering stllss dose CS for surgery and shock Osteoporosis and Fracture INEJM zo1a:anzs47l .L eGFR and T albuminuria are alw fracture (Ach IM 2007;167:1!1l: A/xo 2016;67:21B) Vitamin D deficiency is common in proteinuria from vitamin D binding protein loss CS .. bone formation of osteoblasts. T bone resorption of osteoclasts. T RANKL Prevention for all raking prednisone 22.5 mg/d for 23 mo lAcitAiu»n» Nienmuiai z017;¢<z1s11l GlucocorticddInduced Fracture Risla (Act wins luununi 1011421511i Aduks 240 lo Adults <40 ylo Management Low FRAX <10%Is1% None below Ca.Vir D. lifestyle Moderate-High Prior oszeopororic Prior osteoporotic Ca.vit D. lifestyle fracture fracture PO bisphosphonate FRAX >10%l>1% Ol1 prednisone 7.5 mg Hip or spine BHDT for >6 mo AND score S-2.5 in cl hip or spine BMD 250 lo and Z score <-3 or postmenopausal 9 rapid bone loss >10%lyr . If 240 lo /FRAX (hnps:llwww.sheffield.ac.uk/FRAXI) for 10yr risk of major osteo porolic and hip fracture Risk If prednisone S-7.5 mg/d. / glucocorticoids use and use reported risks If prednisone >7.5 mg/d. J glucocorzicoids use and x1,15 for major osteoporotic. x1.2 for hip fracture risks If <40 lo and has h/o osleopororlc fracture or has risk factors (malnutrition, signifi an: weight loss or low body weight, hypogonadism, 2 HPI thyroid disease. FHx of hip fracture. ha of alcohol use [23 units/d] or smoking). /BMD wu 6 mo of the star! of CS All require optimal Ca (1,000-1.200 mold) and vitamin D (600-800 lUld) invoke All require lifestyle modifications: balanced diem. maintaining weigh: in the recommended range.smoking cessation. regular weightbearing or resistance training exercise. limiting alcohol intake to 1-2 alcoholic beveragesld PO bisphosphonates (aler. iban. risedronaze) are prelerned and safer than IV O t her Slde Ef f endi HBV reacdvarion: prophylaxis (et, enlecavir 0.5 mg qd) if andHBcAb (+) and predni sone dose 210 mg/d for 24 wk or andHBcAb (+). HBsAg (+).and any dose prednisone for 24 wk (AGA Guideline auuuneimulig z01s¢ 14ez1sl Hypertension. fluid retention, weight gain. DM, hyperlipidemia, avascular necrosis Psychosis, mood change, insomnia Atrophic striae.acne vulgaris. myoparhy. dermal thinning. cauracrs.glaucoma GI ulcerauon/bleeding unclear association when used wlo unSAIDs IAMAM 1991;114.73s) AnnEnocoRTlcoTnoplc Hon rous (ACTH) Mechanisms of Action cs release; melanocortin 1 receptor activation J proteinuria UASN 20II:21:1290) Formulat ions an d Do se ACTH=r° gel: porcine pituitary preparation: 80 IU/mL SC or IM x2-llwk Synacd1en°: synthetic tetracosactide: 1 mg IM x2/wk: available in Europe Clinical Use and Side E¢yects MN (Ajxb 1006:47:23J). other resistant NS (Amjuephm12011136;58; C/ASN zmamonl Cortisol level may remain low due no consolbinding globulin loss through proteinuria Similar side effects to CS C A L C IN £U N iN IN H iSiT O R S ( C N I) Mech an ism s o f Act io n Calcineurin dephosphorylates NFAT -» nuclear translocation of NFAT -Transcription of IL2 and other cytokines and T cell signaling Calcineurin dephosphorylates synaptopodin -» synaptopodin degradation -» module cytoskeleton of podocytes (nm m¢4 2coe;149J1l Cyclosporine A (CsA) binds to cyclophilinnzcrolimus (Tac) binds to FKBP12: these complexes inhibit phosphatase activity of calcineurin Clinical Use Maintenance immunosuppression after transplantation.Tac is superior to CsA: less acute rejection, better allograft survival (NEW 2007;357:1561> MCD. FSGS. MN. dassv LN (ASr zc09.z0=901) In naive kidney disease. consider avoiding use In advanced CKD. esp severe interstitial fibrosis and tubular atrophy Formulations and Dose CsA modified: neoralz capsule. solution; initial dose 9-12 mglkg/<1 in 2 divided doses CsA nonmodified: sandimmune°°: capsule. solution. IV Conversion from PO [O IV: 1/3 of the PO dose Tac immediate release (IR): prograf: Starr w/ 0.2 mglkg/d in 2 divided doses Conversion from PO IR to SI.: 1/2 of the PO dose in divided doses q12h ITnueplnm nu 1010.4243]1i Fl'¢'"'°<°0*'°P/1013:33:31) Conversion from PO IR to IV: 1/3 1/5 of die PO dose as a continuous infusion over 24 hr. Its correlation with AUC is less known; SL form is preferred. Tac extended release (ER):Astagraf XL°,Envarsus XI: no generic formulation Not interchangeable with IR and each other: time peak level and daily AUC differ among formulations. Starting conversion dose from PO IR to PO ER: total daily dose of IR = daily dose of Astagraf; dose of Envarsus XR = 7 0 8 0 % tota l da i l y dos e of IR or 201721714321 Tac ER has similar efficacy to TacIR and may have fewer side effects: Envarsus XR may be alw fewer neurologic sle than other formulations [Clin Tiuniylnnl zo1 s.293m1 No difference in allograft survival.acute rejection rates.or renal function among Tac formulations or z010:10z632; AjKD2016:67:648) Unclear whether ER formations improve adherence (Arr 2014:14:2796;1010.10L1632) Pharmacology and Drug Interaction Nanow therapeutic window needs therapeutic drug monitoring trough level is preened Target Trough Levels (fig/mL) in KT: should be individualized according to rejection risk. ieiul Iunczion, other immunosuppressive agents. and infection risks CsA 0 -3 m o 3 -6 m o >6 mo 250-350 150-250 50-150 8 -1 2 Tac 6 -1 0 5 -8 Unclear above level should be achieved in glomerular diseases Mainly metabolized by CYP 3A4 and S: CsA inhibits CYP. avoid or use with low dose of simvasratin. Iovastadn > acorvastaUn: rosuvastz:in.piravasmdn.and pravastacin are safer Due to CYPIPglycoprotein inhibition. CsA markedly increases colchicine exposure. Use reduced dose of colchicine for prophylaxis and uearmenc of acute gou: racks in patients on CsA innnua Rheum 2011;63:2226) CsA binds IO Iipoprozeinsnac binds to albumin.u1 acid glycoproteimand RBC: RBC exchange :ransfuse used for coxiciry (Fen ail mann:2011:26:2145) Fa c tors Affe c ti ng Drug Le v e l s of CNI Increasing Decreasing CYP inhibitors: grapefruit juice. pomegranate CYP inducers: rifampin. rifabutin. SL John iuite. diltiazem. verapamil. azoles. won. antiepilepdcs (phenytoin. darithromycin. erythromycin. protease barbiturates). nakillin. ciro. imipenem. inhibitors Diarrhea: intestinal CYP and pglycoprotein ticlopidine. ocrreotide Cinacalcet for 209&1311049 inhibition (Pedatr Tranwinnl zuosnisi Henadc im torment Rifampin. phenobarbiral. & phenytoin (Case Rep hunapbm 2013:2013:375163): used for toxicity S i de E ffe c ts S ide E ffe c ts of CNIS Com m on S i de E ffe c ts Nephropathyz afferent vasoconstriction, tubular isometric vacuolization. arteriolar vacuolization. arteriolar hyalinosis. FSG$.TI*1A, striped interstitial fibrosis Hypertension: . NCC acziviry (no #442011:17:130q. hyperkalemia Infections: CMV. PML.]C. BK. parvo B19. fungal Malignancy: skin. lymphoproliferarive Neuroloxicizy tremor. headache, PRES (headache. seilure. posterior MRI lesion). CNI pain syndrome: LEx pain (as 1 Plum z0ms1ss4»1 | More Common in CsA Hirsuzism. hyperuricemia. hyperlipidemia. hypenriglyceridemia Gingival hyperplasia: metronidazole (lunar 1994;J43sesl or azizhromycin (flwViwwfivvl 199B;6$:\611)mayhelp roTOR INHIBITORS (Smounus AND EveRoLlr4us) Mechanism ofAction Blnds to FKBP12.an intracellular protein -v inhibition of mammalian (or mechanistic) target of rapamycin (roTOR). serine/direonine kinase -» inhibition ofT cell response to cytokines G1 cell cycle arrest - Inhibition of lymphocyte proliferation roTOR signaling is important in pathogenesis of tuberous sclerosis. various cancers. and antiphospholipid Abmediated endothelial cell injury WM 20141371=a031 Clinical Use Maintenance IS following KT in combination with CNI 1 CS: less commonly CNI avoidance protocols. Used in <5% of recipients in the US Wt 201s;\s Sippi1¢1Bi Often avoided in early postoperative period due to delayed wound healing Conversion from CNI to mTORi used as CNIsparing strategy to preserve renal function alter KT and nonrenal solid organ transplantation (NRSOT) May be slight improvement in GFR over time but no difference on allograft survival lffiiwlillwififivfl 2017;1irI57). KT pts with l GFR or proteinuria at time of conversion less likely to benefit (Twnpbmadan 2009.8722331. Baseline proceinuria also reduces chance of renal benefit with roTOR conversion after hear: u »4¢¢n Um Transplant 2011;315651 and lung Txp (an Transplant 201421s1u6213 Renal function improves with conversion after liver Txp but there is an increased rate of acute rejection lTuuplalun zowiasziy. Switching from CNI to sirolimus Kaposis sarcoma (NE/M 200S;3521317) i new squa MolJ$ cell carcinoma 1~£/m 201z=w.3291 L 56% risk NMSC vs CNI in 2014:349¢:°579) after K[ Sirolimus but alw higher mortality (qASN 2016;11:1845). x angiomyolipoma size In tuberous sclerosis or sporadic lymphangioleiomyomatosis (l.¢nl 2018;381:l17)2 adjunctive therapy for breast cancer, RCC; 1 seizure in tuberous sclerosis (lima 1015389111531 Sirolimus L endothelial hyperplasia graft failure in APS (NUM 10142371;3031 Contraindicated in pregnancy Formulation and Dose Sirolimus (rapamycin): Rapamune°: sir: 1-5 mg qd: Loading dose can be given: trough level goal: 5-15 fig/mL Everolimus: Zortress°;0.75 mg q12h:trough level goal: 3-8 nglmL Side Effects Proteinuria, edema. hypertension.AKI: FSGS and TMA (KI Rep zola 2017;3;ZB1) Bone marrow suppression: rhrombocynopenia. anemia. Ieukopenia. neuuopenia Delayed wound healing/wound dehiscence Angioedema when used with ACEr (c;A5~ zo1ms:10:> DM. hyperlipidemia, hypertrigiyceridemia. Iymphoprcliferative disorder Mucositis/stomatids. ILD (T"=v~=a4¢wvr PM zumsam) MVCOrHENOLATe MOFETiL (MMF), MYCOPHENOLATE Soolum (MPA) Mechanisms ofAction MMF metabolized to MPA: inhibits racelimiting enzyme, cosine monophosphate dehydrogenase in the de novo pathway of purine synthesis; ' Iympho¢yl.e proliferation Clinical Use Maintenance IS following KT: superior co AZA for graft survival and prevention of acute rejection (Cndnune Daiaaae Syn Rev 2015;11:CD007746) Lupus nephritis (LN) III and IV induction & maintenance; ANCA vasculitis induction [Ann Rum. o; 2019;78399) & maintenance; Inierszitial nephritis IQASN 1IJ06;1;71B) Contraindicated in pregnancy Formulations and Dose MMF: CellCept°:; PO. IV; 1,000 mg q 12h for KT African American requires higher dose. 1.500 mg q12h (Tmiuplmmuan 1997;64:1277) Oral and IV are equivalent • Entericcoated (EC) MPA Myfortic°;720 mg MMF 1,000 mg Pharmacology and Drug Interaction Highly (97%) protein bound. Unbound form is active. Primarily liver clearance. Factors Affecting Drug Levels of MMFIMPA Increasing Tacrolimus HypoalbuminemialNS Uremia Decreasing 1 Absorption: sevelamer. Ca. Mg. iron. Hz anugonlst. PPI (1h¢wnq10l¢¢y N1Q49:2%1 : A;r 200949:1650) CsA: by inhlbidon of enrerohepazic circulation CSto200116z10eo) Therapeutic drug monitoring is no: routinely performed Side Effects Nausea.abdominal pain.diarrhea: splitting (low frequent dose) and delayed lower GI absorption of EC MPA may lower GI intolerance: can cause colitis with similar appearance to IBD. not related to dose (lisxapaunaligy 1013:63:649) Neutropenia.anemia. pure red cell aplasia.temtogenicity. pregnancy loss Lymphoma, hypertension, hyperglycemia. hypercholesterolemia Infection: esp.. herpes virus: no P.jiiuvecii infection from ? protective effect (an mm on zoozassal. Lower risk of serious infection Chan CYC or CS In LN (ac mm z01s8141m. AZATH»OPRINe (AZA) Mechanism ofAction Metabolized no 6mercaptopurine (6MP) -2 inhibi: de novo and salvage pathways for purine synthesis -» inhibit DNA replication -r inhibit lymphocyte proliferation Clinical Use Maintenance for ANCA vasculitis: superior co MMF wl more relapse (x1.69) (mAMA zoIma04=ns1); maintenance therapy for lupus nephritis Maintenance immunosuppression following KT Relaciveiy safer for pregnancy than MMF and cyclophosphamide Formulations and Dose Imuran° (50 mg).Azasan° (7S. 100 mg): 1-3 mglkg (usually 50-150 mg/d) qd: adjust forWBC Pharmacology and Drug Interactions Metabolized by xanthippe oxidase or thiopurine methyltransferase (TPMT) TPMT deNciencyr T toxicity; enzyme activity. and genotype are /ed when initiating AZA in IBD IAGA Gauiueuaulqy 2017.153:827). Not routinely /ed for KT or glomerular disease. Xanthine oxidase inhibitors (allopurinol, febuxosrat) T toxicity: avoid coadministration or iAZA dose by 75% and monitor CBC closely Side Effects Myelosuppression, hepatitis. chclesusis. pancreaxiris Infection: bacterial, fungal. prorozoal: lymphoma. PTLD LEFLUNOMIDE Mechanism ofAction Metabolized to teriflunomide -» noncompetitive inhibition of dihydroorome dehy drogenase - inhibit pyrimidine synthesis in lymphocytes Clinical Use Refractory BK nephropathy after KT (rmniplnmnlmn 2006:11904: qAs~201);7:1093) BK hemorrhagic cystitis after HSCT (Aan Haemaw zoIJ:I:o.s2): resistant CMV infection (co Rep mpnrd Dial 20!5:S:96) RA: contraindicated in pregnancy Formulations and Dose Arava° (10 mg, 20 mg): Dose 2040 mg daily: Can give loading dose 100 mg qd x 3 d Monitoring of drug levels not routinely performed Monitor CBC and LFTs: do not use if ALT >2x ULN Pharmacology and Drug Interactions Active metabolite (teriflunomide) has long terminal halflife as undergoes enterohe padc recirculation; detectable levels may persist in plasma for 2 yr after discontinua r.ion.To eliminate drug rapidly if toxicity develops.give cholestyramine B g :id x 11 d o r a ctiva te d ch a rco a l 5 0 g b id x 1 1 d . May 1 or L warfarin level through interaction with CYP metabolism; monitor INR Due to effect on CYPZC9 may alter levels of glipizide, Celecoxib, and fluvasratiri S i d e E f f e ct s Nausea and diarrhea (may be more severe if loading dose given). rash, alopecia Leukopenia.anemia, thrombocytopenia: cytopenias more common if concurrent use of other marrow toxic medications. May T INR in pts on warfarin. Hepatotoxicity (31 f in ASTIALT) in up to 13%. reversible with dlc. severe liver inlury and fatal liver failure are rare. More common in concunent use of unSAIDs. MTX, or EtOH. II ALT T to >2x ULN. dlc and sun cholestyramine wash out (FDA am sally Corrvnunltauan htqas1lwwvmldago»Dm1slDru¢Saietylu¢m2186791. Hypertension: more common with concurrent NSAID use 4Af¢i IM 19'i9.159:1542) .. ILD, avoid use it h/o ILD or MTX lung toxicity (Anhnus Rheum 2ooe;s4 1435) Peripheral neuropathy: develops after mean 6 mo on Rx. may be reversible if discon tinued early after symptoms develop (cu. Iliaymocolfher 2004;7sse01 CVCLOPHOSPHAr4IOE (CYC) Mechanism ofAction Alkylate DNA -» J. DNA replication, transcription -o cell death of proliferating cells Clinical Use and Dose Indications: induction therapy of lupus nephritis (LN) Ill. IV. and ANCA GN LN NIH IV dose is used for other aggressive forms of proliferative GN. eg.ANCA GN (1A$n 1996:7:33). crescentic loAn (nor 1003;18:1321) Contraindication: pregnancy. untreated infection/malignancy. urinary retention Cy c lo p h o s p h a mid e Do s e s Regimen I n i t i a l Do se Do se A d j u st me n t LN NI H (Una: 1~m534a7411 I v 0 . s- 1 u m* mo n zh i y X I St an an 0. 5 glmza adiusz f or L N E u r o L u p u s mvl ml s n m- i m I V 5 0 0 mg q 2 wk x6 No : r e q u i r e d WB C 10014411211 LN icuw 200s. 4. 11s4) PO 1-1. 5 m A NCA G N ( A we mild) for 2-4 mo iv 15 mg/kg (max 1.2 s) d (max Required 150 1c09.1 saalol Cr >3 . 4 : l b y 2 . 5 mg / kg q 2 - 3 wk u n t i l 3 mo a f t e r 60-70 lo: . by 2.5 mg/kg remission >70 ylo: L hry S mglkg WBC <3K: I 2076: <2K; 140% A NCA G N ( i n : m m0ms0; s70) unt il remission. 1. 5 mg/ 6 0 - 7 0 ylo: 1 by 25% >70 lo: l by 50% kg l d x3 mc WB C <4 K : h o l d a n d r e st a r t PO 2 mglkgld (max 200 mg/ d) wh e n >4 K wl L 2 5 mo l d A mi G B M d i se a se l A M i n P O 2 - 3 mg / kg l d >5 5 yl o P O 2 . 5 mg l kg l d i n mo 2 . 4 . 6 Required 2001.1!o1033I MNP ' l o d i f i e d P o n ci ce l l i regimen" IIASN 199u,4441 MN (nor 2004;19 1147; AMC N=F1"°l 2017:1Bz44) wit h CS in mo 1. 3. 5 PO 1. 5-2. 5 mg/ kg/ d f or Required 2 - 1 2 mo 1 p r e d n i so n e 2 K TX Dose adiusrmen: for renal funcuionc et. 30% for CrCl <40. 50% for CrCI <20 Do se adjustment of age: eg, 50% for > 60 loa HD removes CYC: dose alter HD Highdose regimens require dose adjusunent to keep WBC >3-4K Mesna (2mercap:oerhane sulfonate) 60-100% of CYC dose with IV CYC to rever: hemorrhagic cystitis. no evidence of bladder cancer prevention (Ardvmx Rheum 2010.s2:91 Pharmacology Prodrug: CYP metabolized to phosphoramide mustard (active mecaboliu) and acrolein All mecabolires are excreted by urine; adjust dose for low renal function Malignancy NHSC. nonmelanoma skin cancer No established safe cutoff dose Prevention: lowest possible dose, lifestyle modification (eg. smoking cessation) Screening: at least USPSTF recommended level, urinamis. CBC. skin exam Other Side Effects Lymphopenia, agranulocytosis:Tx with GCSF or GMCSF Hemorrhagic cystitis dl: acroleinz correlate w/ cumulative dose and duration: PO > IV plw hematuria (microscopic or gross). bladder irritation. blood clot prevention:AM PO dosing: Mesna Female infertility ovarian failure T w/ age and cumulative dose (0% in <30 ylo <10 g; 100% in >40 lo >30g) (Amino Rheum 199e44118311 Prevention: GnasH agonists (leuprolide depot 3.75 mg lM.goserelin) 14 d prior to monthly CYC; amenorrhea (xO. 12) in SLE (aim ewe us Tree: 2010.msoaI Ovarian tissue cryopreservation is an option Male infertility: azoospermic or severely oligospermicz 72% recover after cumulative dose <7.5 x/m1 and 11% recover after >7.5 g/m2 (caiar 1992;7027031 Sperm cryopreservation, testosterone can be used (Am IM \997;1z6;292. A;KD zaaeszaan SIADH: common with high dose of hypotonic fluid (NDT 2010;25:I520> ANTIBODY AGENTS Polyclonal Ab: MG. thymoglobulin Monoclonal Ab Agents Chimera (75% human. ximab) Humanized (95% human. zumab) Basiliximab Alemruzumab. Daclizumab, Belimumab Riruximab Eculizumab Ofarumumab Human (10056 human. una) All Ab agents can be removed by PLEX: If PLEX is required, info$eAb regimen after PLD( Infusion (Related) Reactions Common with rituximab, alemtuzumab.antithymo»:yte globulin (ATG). MG Mechanisms:Ag-Ab interaction cytokine release Fever, rigors, pruritus. flushing. dyspnea. chest discomfort NN/D Preventiomacetaminophen. diphenhydramine, and methylprednisolone pretreatment and slow infusion lower incidence Tx: hydrocortisone. diphenhydramine. aceunminophen: slow infusion rate Anaphylaxis Rare, but fanalz reported with riruximab,ATG (All¢llyAld$ma Um lmniuna 2011113131 IgEmediated type I hypersensitivity reaction Urticaria. cough, wheeze. angioedema. throat lightness (laryngeal edema). shock in addition to other symptoms of infusion related reactions Lab: T nrypcase.DIC T>c dlc infusion,ep6nephrine 0.2-0.5 mg (1:1.000.0.2-0.5 mL) IM.O2 2 inzubazion. IV fluid Do not rechallenge w/o proper desensitization AAA¢fgy an Nwnual 2a0a;12z:s7l INTRAVENOUS Immune GLoauun (MG) Mechanism of Action 1qAsn 1l)16:11:331) Prepared from plasma pooled from healthy donors Binding to natural Ab. cytokines. inhibition of complement fixation; inhibition of FcR mediated recycling of native IgG -v antiinflammatory effects, immunomodulation Clinical Use Desensitization for (») crossmatch living donor donation.ABO and HLA incompatible living donor KT with rituximab (NE/M 10085512421 AMR: 100 mgNq after PLEX. followed by rituximab WT 20awx1099> Less common: refractory KT rejection: 2 glkg (Tmnsplanmuan 1001;72:419): BK nephritis lrfumpmmn 2006:5:117) Parvovirus B19 prevention and tx WTz0\1;11.19s) rdiaetory CMV infection or 201113931 Premedications: diphenhydramine. acetaminophen Side Effects AKI from osmotic proximal tubular damage with sucrose containing MG lqAs~ 2006:1:844;Ajxn 2000lSl.49l), hemolytic anemia: pigment nephropathy (A}KfJ 201lkS§148) Hyponatremia dlt water retention (on be new# 1006:10124). pseudohyponatremia d/t protein load (NE/M 199s;aJ<rs32); / asm to differentiate Thrombosis. MI. aseptic meningitis ANTITHYMOCYTE GLoauun (ATG) Mechanism ofAction Polyclonal Ab against humanT cellsztargets multipleT cell markers; lymphocyte depletion Clinical Use, Formulation,and Dose 1st choice induction immunosuppiession in KT in high risk for acute rejection or DGF L Acute relection. similar DGF dt basiliximab (~fi~1 znae:ass:19s7) Thymoglobulin (rabbit origin) preferred in KT: 1.5 mg/kg for 4-10 d for induction (centerdependent): x7 d for acute cellular relection (IB, ZA. 2B, 3). Giving total dose as continuous infusion for induction alw similar outcomes dw divided daily dosing. Starting infusion intraoperatively a/w 1 DGF compared with starting postoperatively (nunspiantauan z00&es1u91;1003;76i798) Atgarn° (equine origin): 10-20 mg/kg x 8-14 d for aplastic anemia, Inferior to thymo giobulin when used for induction or treatment of acute rejection after KT lrlulqiiiiniauan 1999;67:1011: 1998:66:29) Premedications: methylprednisolone. diphenhydramine. acetaminophen Dose adiustmenrs to keep lymphocytes <5%. absolute count 5100; Can follow CD3. CD4 Keep WBC 23, plt >7$K; 150% for WBC 2-3. pit 50-75K: hold for WBC <2. pit <50K Serum Sickness (App: Z010:55:141) 7-27% in KTR, with prior rabbit exposure Immune complex-mediated type Ill hypersensitivity reaction Clinical manifestations: arthialgia (jaw. temporomandibular joint), even rash. malaise 7-14 d after ATG initiation: clinical diagnosis Tx Corticosteroids (CS) +I- PLEX Other Side Effects Leukopenia. thrombocytopenia. anemia Infusion reactions/cytokine release: fever/chills. L BR pulmonary edema: anaphylaxis PTLD: more than with other induction agents or 1001¢71z619) ALEMTUZUMAB Mechanism ofAction Recombinant DNAderived humanized monoclonal Ab against CD52 CD52 is expressed OnT cells. B cells. monocytes. macrophages, NK cells Lymphocyte depleting agent Clinical Use Induction IS in KT (offlabel): L early acute rejection in low risk for rejection or basiliximab or thymoglobulin. Similar efficacy in high risk KT m5;/A z0 n.3s419091 Lacute rejection (x0.42) dt basiliximab induction (Lin 1014.za41\s041 ACR (offlabel): may be alw Trisk of infectionrelated death lT1v~p'°mm"1009=87.1092i Multiple sclerosis. CLL. Sectary syndrome Formulation and Dose Campathsz 30 mg IV x 1-2 d for induction and acute cellular reiecdon Premedicadons: merhylprednlsolone. diphenhydramine. acetaminophen Side Effects BASILIXIMAB/DACLIZUHAB Mechanism ofAction Interleukin2 receptor antagonists (lL2RAs): Humanized monoclonaIAb against IL2 receptor G chain (CD25) on T cells -» inhibits IL2 mediated actions Nonlymphocyte depleting agent Clinical Use, Formulation, and Dose Basiliximab (Simulect°): 20 mg IV on d 0 and on d 3 or 4: daclizumab: withdrawn Induction IS in KT with low immunologic risk (eg. 2 haplotype match living donor): l acute rejection rate and graft loss dt placebo. No difference in graft loss or clinical acute rejection. biopsyproven acute rejection at 1 yr. l s/e and malignancy dt antithymocyte globulin (eww¢ Drhaee so Rev 201D:CD00389l) History or expected thymoglobulin intolerance (et, cardiopulmonary disease) Side Effects Infections. lymphoproliferarive disorders BELATACEPT Mechanism ofAction Humanized fusion protein monoclonal Ab. CTLA4Ig: Fc fragment of human lgGl + extracellular domain of CTLA4 (CD152): competitively Inhibit CD28 on T cell CD28 OnT cells binding to B71 (CD80) or B72 (CD86) on APCs -» T T cell activity CTLA4 OnT cells binding to B71 or B72 -» IT cell activity CTLA4 is constitutively expressed on regulatory T cells Clinical Use, Formulation, and Dose Nulo]ix® De novo IS after KT: used in combination with MMF and prednisone as CNIsparing regimen. Higher 1yr acute rejection rate than CsA. but higher eGFR and patient/ graft survival than CsA (NEW 2016:374=3331 10 mg/kg on d 1. 5.at the end ofwk 2.4.8. & 12. then 5 mgA<g quo wk beginning at wk 16 Conversion from CNIbased regimen following KT: T acute rejection in 1" yr. slight T eGFR at 3 yr. no difference in patiendallugraft survival (qASN 20\1:6:430. Ayxo 1017:69:557) 5 mg/kg on d 1. 15. 29, 43. 57.then S mg/kg every 4 wk. Reduce CNI dose by 50% on d 15, discontinue d 29. Slower taper of CNI may be a/w .L risk of rejection. CNI should be reduced slowly every 2 wk (no reduction on d 1. 50% reduction on d 15, 80% reduction on d 23, discontinue d 29) / EBV IgG: must be (+) due to risk of PTLD in IgG (-) pts Side Effects PTLD (predominant involving the CNS). anemia. and Ieukopenia Diarrhea. increased risk of infection: CMV. HSV. fungal, protozoa! BELIMUMAB Mechanism ofAction Human monoclonal Ab against the soluble form of a B cell survival factor. B cell activating factor (BAFE aka B lymphocyte stimulator. BLy$) Clinical Use and Side Effects Approved for active autoantibodypositive SLE (lance: 101 I;177;72\) iSerum BLyS level but did not reduce naive B cell number in KTR (Lana: 2018439196191 May lower proteinuria in lupus nephritis (Auzaunmun Rev 20I7;l6:187) Side Effects: infusion reactions R l1 ux lm A s ( R TX ) Me ch a n ism o f Act io n Chimeric murine monoclonal Ab against CD20 on B lymphocytes Prevent SMPDL3b downregulation in podocytopathy Isa r»u»¢Im¢42011¢Jxsr=4e) Inhibit of B cell derived IL4 mediated proteinuria u6H»=»1»~ z01ns1 s:el C lin ica l U se AN C A vasculitis: induction luv: nz/1»1 z01Qu3¢221: ruruxvAs new 1010.n3¢1111 and main tenance (NEW 2014;371:1771)2 refractory LN: cryoglobulinemia (Animas Rheum 2012:64:843), MCD. FSGS (NEMCHASN zo 1412s=aso>. MN (MENTOR new 101%]813¢:]ASN 2017L28:34B1 Induction IS for (+) crossmatch living donor donadon.ABO and HLA incompatible living donor KT with lymphocyte depleting agents. MG l~£1m 200a:3s9141) and PLEX Antibodymediated rejection (ABMR):with CS. IVIG.and PLEX F o r m u la t io n a n d D o se Rituxan 1.000 mg ><2, 2 wk apart: 375 mglmz x4, weekly; 375 mg/m7 xi eg, for ABMR Can redose if CD19(+) cell is not depleted (>5-10 cellslmm') or lymphocytes >1% J HBsAg. HBsAb. HBcAb prior to administration HBV Sefulogy Interpreatlon and Rituxlmab Administration (H¢¢nli!y N\u1:1M) HBsAg HBsAb + + HBcAb Management Administer rizuximab Vaccination prior no rinncimab or 6-12 mo after Administer riruximabz HBV immunized Administer rizuxirnab wish prophylaxis + /r/O window period (HBc IgM ~) 4 Administer rkuximab widl prophylaxis Vaccination if no: from and co inuermediaxe or higi endemicity + 0 Hold rixuximab: /ALT. HBeAg. HBV DNA Refer co h solo 3 Premeditations: acetaminophen. diphenhydramine. methylprednisolone 100 mg umm Rheum 1006;54:1390) Slow infusion (first dose83 mo since previous dose or poorly tolerated previous infusion): Start at 50 mg/hr;T by 50 mg/hr q30min; max 400 mg/hr Sundard infusion (previously well tolerated infusion <3 mc): Stan at 100 myhr: t by 100 mg/hr q30min; max 400 mglhr HBV Reactivation impairing 2018:67:1560: Caaraunemiqy 2017:1$2:1297) Reappearance or t of HBV DNA or reverse seroconversion of HBsAg p/w impaired synthetic junction (TBII >3, INR >1.5). ascites,encephalopatlry,and deadi RM factors: HBsAg (12.3% vs 1.7% w/o HBsAg). high baseline HBV DNA level. HBeAg. chronic hepB; HBsAb () (14% vs 5% w/ HBsAb) (»4=n<=¢d°¢v z017:66.379y Rituximab T risk of reactivation:24% w/o HBsAb. 5.6% wl HBsAb (H¢p¢i¢iqy zor 7:se.a79l Prophylaxis: see prophylaxis chapter:Tx: HBV treaunent Progressive Multifocal Leukoencephalopathy (PML) Subacute demyelinating CNS infection caused by JC virus reactivation Multiple cases reported in HIV. hematologic malignancy SLE and RA; Incidence 4/100.000 in rituximabuated RA vs 0.4/100.000 in untreated RA (in-naw so zonnzsrl Many cases in SLE were found w/ minimal IS wlo RTX or alkylating agent (Auraimmun Rev 20ce1s;144); Rarely in GPA treated with CYC and CS (JAMA rsszzselsool No report in MCD. FSG S.and MN Cognitive impairment, motor weakness (hemiparesls. ataxia).vislon or speech problems Median survival in PML wlo HIV is 3 mo (An new z006;so¢1 $2) MRI: unifocal or muluTocal white matter lesion:]C virus DNA in brain biopsy or CSF Tx: reduction of IS: allogenic BK virus specific T cells Ive;/m z01e¢a79:144:l O t h e r Sid e Ef f e ct s Infusion reactions: fever.chills. rash. itching, mild wheezlng:28% in MN (/ASN 2012;23114161; common with 1st dose; prevented by slow infusion and premedicazions Tx slow me or hold infusion and resume if symptoms resolve Anaphylaxis: urticaria. hypotension. angioedema. hypoxia. bronchospasm. strider Tx: dlc RTX. epinephrine 0.2-0.5 mg (1:1,000.0.2-0.5 mL) IM. O21 incubation. lV Huid Ofatumumab: human monoclonal CD20 Ab: successfully used after anaphylaxis asso dared with ricuxlmab (n5/m 2018:37B:92) Rarely pulmonary infil:rates.ARDS. MI.VF. cardiogenic shock. or death Ser um si ckness (s¢»wl Anhmn Rheum zo1 s;4s:n4): fever . r ash. ar r hr al gi az type I I I hyper sensl :ivicy reaction 7-21 d after infusion; low complemencTx: CS Blumed immune response no vaccination UACJ 2011;1z&129s) Hypogammaglobulinernia: esp low IgM; T with repeated cycle U Rnwmmal 20102375558) Leukopenia (even 3-6 mo after adminiszra¢ion).anemia Not al w T mal i gnancy (Ann Rheum Du 2017:76:1064) E CULI ZUMAB Mechanism ofAction Monoclonal Ab against CS: inhibition of C5 cleavage to C5a (neutrophil chemoatuac tant) and CSb (component of membrane attack complex) Clinical Use and Dose Monitoring (goal): CH50 (<10% of nl), alternative pathway hemolytic activity/AH50 (M 10% of nl). eculizumab trough level (50-100 mcg/mL); sC5b9 may remain detect able. not recommended for monitoring (KJ 2017;91:S39) aHUS: IV eculizumab 900 mg weekly x4, 1,200 mg 1 wk later,then every 2 wk: sup plemental 600 mg wu 60 min after each TPE PNH: IV eculizumab 600 mg weekly x4, 900 mg 1 wk later. then every 2 wk OHlabel use: C3G (qAs~ z01zm74a). ref ract ory APS I A/ unt s Rheum 2012: 64: 1719; Case nap Hmtol 20i4;704371); recurrence prevention ofAPS after KT <~£1m z01¢xss1=\744; Offlabel use: prevention and treatment of acute AMR (fmnsplnnintion zovxmlo; 30801549). chronic AMR or 2017:17:681) and desensitization or 2011;1 122405) Prophylaxis (co op" u»f¢¢i of 201923191 Meningococcal vaccination: both polysaccharide quadriwalent and serogroup B vaccines (can be oWn simultaneously at different sites) >2 wk prior to the 1st dose; if <2 wk.give penicillin VK 250-500 mg bid or ciproiloxacin $00 mg qd until 4 wk after last vaccine Meningococcal polysaccharide quadrivalent conjugate vaccine (MenACWY): MCV4D (Menactra°) or MCV4CRM (Menveo°l),2 doses, 8 wk apart: boost every 5 yr Meningococcal serogroup B vaccine (MenB): MenE4C (Bexserow. 2 doses 1 mo apart) or MenBFHbp (Trumenba°. 0, 2. and 6 mo) (MMWR 2015;64:600) Pneumococcal vaccine: PCV13 and PPSV23; Haemophilus inffuenzae vaccine Side Effects Infection: encapsulated bacteria esp. meningococcus (MMWR 20\6:6S:696) lgG2 and IgG4 x staining of eculizumab: not pathogenic (MSN 2011;2311229) PROPHYLAXIS VACCI NATI ONS CKD who 2012¢s<»\:s61. NS we 1994;z4447l.and immunosuppresslon (IS) • risk of InfeWon I S decr eases effi cacy of the vacci ne: eg. i t takes 1 y r no r e ga i n i m m une r e s pons e a f t e r riruximab ilAlknlv aw. Imnrnnol 2011;\188:1195)I in may take longer depending on disease: et. ANCA (Amni Rzsfher 1017;19:101) More vaccines are recommended than nonCKD population: vaccination should be s ta rre d prior to IS a nd progre s s ion to a dv a nc e d CKD Recommendation Based on Vaccine Type Ann an willem. Air zoner: no 45111 Vaccine Prior to ISIKT During IS After KT Household and close contacts inactivated Vaccines Live Vaccines FCV13. PPSV23.Tdap/Td Inactivated influenza, RN HW Ideally 22 wk prior to the mIuaum Recommended if indicated Recommended if indicated Usually 2-6 mo after KT If influenza outbreak. 1 mo after KT or 2011;\\:10201 Recommended if indicated MMR.Varicella. ZVL Ideally 24 wk prior to the imuauon Contraindicated Contraindicated Recommended if indicated If rash develops after ZVL or varicella. avoid contact and consider antiviral prophylaxis 1n Vaccination Indication (R: Recommended; X: Contraindicated) hupallwww.cdc.govlvaccines, (xntco CKD 1012; IDSA oo zo14;sa:Jot A11201393 sqapl 41311) Vaccine no ~. M CKD O n I S I KTR lnlluenza. inactive R: annually TdapfTd R:Tdap x1,Td q10y MMR R if born in 1957 or later X Varicella R if born in 1980 or late X RZV R i( 250 lo Insufficient data HPV R i f 9 Q UO l o 6 $ 2 1 l o Pneumococcal R H BV R For eGFR <30 Z o s te r V a c ¢ i n e Recombinant lester vaccine (RZY Shingrix°) is recommended for nonimmunosup pressed 250 y/o regardless of past foster infection or zoster vaccine live (ZVL) vaccination history RZV: contains adjuvant suspension r.ha\: boosts Tcell function.TheoreticaI graft rejection and glomerular disease flare up were not well studied. ZVI.: is contraindicated in pts on IS and KTR. Disseminated zoster on low level IS (MUM 2017;66:763) and a fatal case in Can re 2016:PMlD 271476291 reported. P ne um oc oc c a l V a c c i ne Recommended for all adult CKD including <65 lo. pts on IS and KTR PneumococcalVa¢¢ine in CKD (eGFR do) and Immunocompmmised States Prior Vaccine Indicated Vaccine None FCV13 - PPSV23 28 wk Iver then 2" FFSV23 25 yr Iazer 1 dose d PPSV23 PCV13 21 yr after :he PPSV23 :hen PPSV23 28 wk aker 2 doses of PPSV23 PCV13 21 yr after :he most recent dose of PPSV23 PCV13 PFSV23 28 wk after PCV13 den 2"' PFSV23 25 yr after dte 1 PPSV23 PCV13 and 1 dose of PPSV23 2' PPSV23 28 wk after PCV13 and 25 yr after :he 1" PCV13 and 25 yr after the 1st PPSV23 PPSV23 If the most recent dose of PPSV23 was at age <65 yr, as age 265 yr. administer a dose of PPSV23 28 wk after PCV13 and 25 yr after the las: dose o( PPSV23 PCV13 to PPSV23 interval should be 21 yr for chose indicated only by age 265 H e p a t it is B Va ccin e CKD patients have reduced immune response to vaccination 50-60% vs 90% in non CKD W/(0 1<19&31:10411; require higher dose J AntiHBsAb 1-2 mo after series in (pre)dialysis and immunocompromised patients If antiHBsAb <10 mlU/mL r epeat another ser ies If annual antiHBs Ab falls m <10 mIUImL Recombivax HE or EngerixB' 40 mcg xi Surveillance in HD: monthly HbsAg if antiHBs Ab <10 mIUlmL HBsAg could be (+) after vaccinatiomdo not / w/i 3-4 wk (ISSN 19964711228) (+) HBsAg: use dedicated machine at isolated room Unknown HBsAg: bleach disinfection of diamis machine Recommended HBV Vacdnadon Dose (mcg) and Schedule (mo) Condi ti ons Re c o m b i v a x HB' E nge ri x B' NonCKD 10: 0, 1,6 20: o. 1. 6 20: 0. 1 Immunocompromised 40: 0. 1. 6 40: 0. 1. 6 lnsufhcienz day (Pre)dia 41k 0. 1. 6 40: 0. 1.2. 6 Insufficient data is He pl i s a v B' ANTIMICROBIAL PROPHYLAXIS Antlmlcroblal Prophylaxis for Patients on Immunomodulators CMV or :mans Sufi 491) Alter KT,Valgancklovir (adjusted for CrCI) for as least 6 mo in high risk (D+/R) and 3 mo in intermediate risk (R+): Pneumocystis iraieai consider 3 mo in low risk (D-/R) Also prevent HSV1, HSV2, EBV.VZV. HHV6,7.8 Alter KT.TMP/SMZ SS (801400 mg) qd x 1 yr (prevent also UTI. Ilsteria. and nocardia infection) If sulfa allergy, dapsone 100 mg qd (/G6PD before; sie: melhemoglobinemia) (Cami 10II;117:3454] or atovaquone 1,500 ms qd Wr z01an a Swv! 41272) No consensus in IS use for nontransplanulion setting. One reeommendazion is TMP/SMZ DS (160/800 mg) x3Iwk in pi: receiving an equivalent of prednisone >16 mg qd x 28 wk 1NE/M 20041Jsaz4s71 Umm Ds avi NAM z01s:42: 1st Candida or zuuss so>pI 3:62) After KT. fluconazole or dozrlmazole (may T CNI and Lav.enl:TB (A/1 romans Suppl 1:66) mTORi level; monitor Ievel).or nysuzin 4-6 mL bid. Total prophylaxis for 1-3 mo. If positive PPD or IGRA (Quan:iFERON gold°) Isoniazid 300 mg qd x 9 mo widi pyridoxine 25-50 mg qd or Rifampin 10 mglkg (max 600) x 4 mo (no 1018;J79440): may i CNI level: monitor level of CNI HBV PROPHYLAXIS (ca==»»<~==m1»=v 2015:148:215: A)T 20\5;l5:1162l *If HBsAg (+). consider obWning hepaxology consuk: HBV DNA 22.000 UImL and ALT elevation: Chunk Mpuixis B requiring :naunenr 'Morison /HBsAg. ALT. HBV DNA q3mo Regimen: Entecavir 0.5 mg qd (if CrCI 30-50 q48h; if CrCl 10-30 q72h: if CrCI <10 qwk) Tenofovir alafenamide (TAF): 25 mg qd (avoid if CrCI <15); better renal function than TDF (lance: Gasziuenierd Hw.al 2016.1.185; 1 Hepalal 2018;68:672) Tenofovir disoproxil fumarate (TDF): avoid for proximal zubulopathy Lamivudine: avoid for resistance Sian: 2-4 wk before initiation of IS End: 212 mo of last dose of B celldepleting aden: (eg. rituximab) or 26 mo others: reactivation beyond 12 mo has been reported in malignancy (nun Re 201615046) Prophylaxis is alw 87% and 83% reducion of reactivation and hepatitis Rares. respecmrely ic.1==»==~»=~=lw zo1s;14&zzn: reactivation rarer with HBsAg (-) pa up 2013331127651 ILLICIT, HERBAL, AND ENVIRONMENTAL TOXINS The kidneys are vulnerable to injury from exogenous toxins dl: to their filtration, concentration.and metabolism. i clearance in CKD may cause T toxicity Older adults use OTC (42%).dietary supplements (49%) frequently QAMA tooasoozssn 1/12 US adults is raking Z1 harmful supplement with kidney disease (AlKD 2018;6117391 Herbal supplements are not regulated by FDA for content or purity; Side effects may rise from contaminants. such as heavy metals Purpose of the medicine may give clues: pain control (analgesic nephropadiya salicylate intoxication). diuretic (salt wasting. hypokalemia. volume depletion) Renal toxicity could be from other organ injury: hepatorenal syndrome from hepato toxic substance. rhabdomyolysis from seizure evoking component Lists of herbal supplements to avoid in CKD. hyperkalemia.and hyperphosphatemia: https:/lwww.kidney.org/atozlcontentlherbalsupp HERBAL AND DIETARY SUPPLEr4SNTARY AGENTS Aristolochic Acid Sourcezariswlochia plan: containing slimming Chinese herbs;flour in Balkan endemic nephropadly (BEN): endemic in Bosnia, Croatia, Bulgaria. and Romania pRTA. tubular proteinuria, concenrraning capacity impairment. expensive inzersririal fibrosislrubular atrophy. cellular atypia Renal insufficiency is a/w cumulative dose, may plugress after dlc TCC T lifelong risk: the renal pelvis. ureter > bladder: cysroscopy not sufficient (num zuaaJ4z1¢sal; 52.9% after °<p during 27 mo flu (un in zc09xz=z0ol Tx: GC may be tried in early nephropathy (AjKD 19*Js;27:2091 Cancer surveillance: yearly CT + urereroscopy Bilateral nephrourecerecromy prior so LDKT or DDKT Iisring um :m 2013:15s:469) Herbal, Supplementary, or Nonprescription Agents and Renal Toxicity Substance Bee pollen Cats claw Chromium picolinate Cranberry Creatine Dienkol Bean Ephedra [MaHuang) Flavonoid G¢11y\;l\iull\ Glucosamine Glycyrrhiza (Licorice) Used for Appetite. stamina Antiinflammatory Glc. lipid. we control UTI Muscle performance Meal in Southeast Asia Allergy, weight loss Vascular disease Immunity joint pain Antiinflammatory. sweet taste lanes tridentaia (Chaparral) Joint pain, weight loss Mg trisilkate Antacids Quinine Drink (Tonic water), tramp Rough Bark (guaiienesin) Chest congestion. cough Star fruit (carambola) Renal Toxicity AIN AIN ATN.AIN Oxalate nephnopadvylnephrolidiiasis AIN AKI. needlelike crystals HTN. urinary stone ATN ATN AIN AME (HTN. hypokalemia. metabolic alkalosis) RCC Silicate calculi TMA (~f:m 2017.375:74): 33% of drug induced TMA um 7012125 may Urinary stone Oxalate nephropathy who 20013741s1 Delirium. hiccups. vomiting. paresis Sugar sweetened beverages Triptolide (Thunder God Vine) Vitamin C Vitamin D Willow Bark (Salix daphnoides) Wormwood Yohimbine CKD(a»s~1019;14¢491 Hypotension.ATN in CKD; dialyzable (nor z003:1a=1 10) Antiinflammatory Pain Oxalate nephropathy/nephrolithiasis Milk alkali syndrome/hypercalcemia Papillary necrosis Digestion Erectile dysfunction AKI, rhabdomyolysis AKI. drug induced lupus Cold DRUGS OF ABUSE IVDU is alw inrersMial inllammazion and renal parenchymal alciiiacion WKD 101443545) Tobacco Current smoking 1 risk of CKD (34%) and ESRD (51%) INN z017;n:47s) alw nodular glomerulosclerosis (Hm tuna zoozzmezel. glomerular hypedikradon & prcceinuria (qAsn 2011:612462)l passive smoking 1 CKD lqAsn Z019:14:515) Heroin Heroinassociated nephropathy: FSGS.AA amyloidosis (95% used heroin in the Pacific Northwest) (qAsn 1018413110101 from recurrent infection and inflammation. Declined with highpur ity her oin. Possibly alw ApoL1 nephropathy. HIV. HCVmediated renal lesions _ Rhabdomyolysis: heroin crystal nephropathy (clq z01 s;eaz9l. CKD in ~29n~l 2016:44:447) E O xymor phone Injection of reformulated Opana ER°TMA lmmwn 101J:62:1: up 20ll;63:1022). HIV. HCV PLEX was tried. but unnecessary (AJH 1014824951 C o ca in e Rhabdomyolysis. malignant hypertension; hypertensive and ischemic damage (Aalto 1014;63:945). renal infarction Is" ~¢n~l 2009=722341,AlN (Ago 100B:S2:79Z) ANCA GN (very high MPO or MPO and PR3) wl skin ulcer: contaminated levamisole lqA$n z011:6:2799)I hyponauemia (Can Nepal 2011;7511) Methylenedioxymethamphetamine (Ecstasy) lqAs~100e:3¢1ssz: nor 2013:18:2277) Amphetamine derivative: release serotonin. dopamine, norepinephrine Hyponatremia: T ADH secretion polydipsia (thirst. hyperpyrexia, ready availability of fluids and iGl motility - water absorption); common in single.first use in young 9 AKI: nonuaumatic rhabdomyolysis. liver failure. and vasculitis Cerebral edema. pulmonary edema. hypertension, arrhythmia Anabolic Steroid [MSN 2010;21:163) Used by bodybuilder s with highpr otein die: Rl. proteinuria (1.3-26.3 old). NS (3/10); Can improve w/ dlc and recur with reuse Biopsy, FSGS. collapsing or perihilar, 15-95% too: process effacement C a n n a b is ( M a r iju a n a ) Cannabinoid hyperemesis syndrome is associated with heavy daily use of marijuana: AKI (mainly prerenal azozemia) has rarely been reported in such pts Synthetic ("designer") drugs that do not appear on urine toxicology screen have also been associated with AKI l.vlmwR 20 1316z9932 qasrv 2013:8:5131 BiopsyATN,AlN 1c/Asn zowmvsel; AKI resolved w/o RRT Brodifacoum associated T lnR.gross hemaruria and abdominal pain: renal imaging abnormalizies: perinephric stranding. dilacarion of collecting system (NEW zo 1a;379:121s) alw DKA in T1 DM (x1.98) up IM 2019:119415) Synthetic Cathinone (Bath Salts) Nor detected on toxicology screen AKI. rhabdomyolysis. hyperuricemia WM 2012:$<k2731 DIC. liver failure.muluorgan failure,coagulopathy (some contains vitamin K antagonism) METALS Alumlnum lKDOQI nun 2003; KolGo Mao 2009) Source:aluminumcontaining phosphate binder and antacid. dialysate contamination Dementia. osteomalacia. bone and muscle pain, ironresistant microcytic anemia. hypercalcemia. and neurologic abnormalities Rare dlt less use of aluminum hydroxide. improved water purification. high flux dialyzers Dx: /Serum level: if 20-200 ugIL, /deferoxamine stimulation test (+ if increase in serum aluminum of >50 kg/L 2 d after infusion) Prevention: avoid aluminumcontaining drug and citrate ( GI aluminum absorption) TX: daily HD w/ high flux dialyzer if baseline >200 kg/I; deferoxamine if stimulation tests C admium Source: battery. metal alloy plants. g1ass.ct>ntaminated rice. cigarette smoke Itaiitai disease:osteoporosis, osteomalacia.and kidney damage Tubular proteinuria (eg. 132micoglobulin). pRTAIFanconi syndrome. hypercalciuria. stone, chronic TIN.gfomerular ischemia. HTN Occupational exposure is alw ESRD (x2.3) (AjKD 200123&1001) A : Lead Source: foundry. paint (pre1978 building). gasoline (removed in 1980s), diet. drinking water. smoking, dust. soil Organic cation transport system at PCT reabsorbs lead: mitochondrial damage Stored in bones: halflife is decades Acute toxicity: pRTA (inclusion body in PT cells)lFanconi syndrome. hemolytic anemia. peripheral neuropathy, encephalopathy Chronic toxicityc triad of gout. HTN and CKD (chronic TIN); nephrdithiasis. CKD progression (n5/m 100];348:177), CVD (Lanai Mk »4:w1 201B:3:0177) High level is a/w lower kidney function (MMA IM 2010. 17a7s; Ayxo 1018;72:381) Chelation (WM z013a09:12411 controversial; Highdose EDTA is alw AKI Other Metals and Renal Toxicity Metal Source Chromium Contaminated food and water CKD esp with lead and cadmium (XJ 2017927201 Mercury Bakery. alloy. mirror plants Food, water. mining, pesticide, woodpreservaniyes Seafood concaining organic form is less :oxk Medical use (RA) Medical use (cancer) Arsenic Gold Platinum Manifestation Chronic TlN,ATN. pRTA. MN TIN.ATN; CKD. proteimria quo 20 17:7a7an CVD (Am IM 201195%6491 Kidney. bladder. lung izncer (/4402018;11m411 MN ATN ( pr.osis and necrosis) ENVIRONMENTAL SUBSTANCE Pardculare matter air pollution is alw T CKD and ESRD (;ASN 201sIz9:21e) and t MN: PLA2R was (-) in 83% uAsr4 201697137391 Pathogenesis: inflammation. oxidation stress. coagulabiliry (Na: Rev n9p»».ui 201&14313) Silica exposure i s a / w ANCA vasculit is (qAsn 2M7: 2: 290) and CKD (Run an 2011=345401 Renal Effects of Environmental Chemicals (nm an nqm m i z01s;1 1:6101 Phthalates BisphenolA TAlbuminuria, BFW used in IV tubing: level may Tx9 after HD Dioxins t Albuminurla. BP. uric acid.. eGFR T Albuminuria. BR uric acid.. eGFR Polychlorinated biphenyls Perfluorinated chemicals Melamine TAlbuminuria. BE used in IV tubing; levels high in HD. PD pts r BR uric acid, . eGFR lqAs~ 1019:13:14199 Radiolucent stone. l eGFR EXERCISE AND HEAT Swear is hypotonic t Na (28%) > i Na (5%) (Am Icinriuml 2oo 13z:3a6) Heat stroke:AKl, Mabdomyolysis Exerciseassociated Hyponatremia (EAH) (Clip j Span mm 201522533031 Occurs often in endurance events in 6% (PNAS 2005;\07;185$0) Risk factors: high fluid intake w/ weigh: gain. unSAIDs use. low BMI Pathogenesis: excessive water intake with hypotonic fluid >water loss;ADH secretion Manifestation: asymptomadc.weakness. headache. NN seizure. coma. cerebral edema TX: if mild. oral hypertonic saline; if severe 100 mL 3% (51 mEq) NaCl or 50 mL 8.4% (50 mEq) NaHCO; over 10 min;can repeat x2; avoid hypo or isotonic fluid Prevention:"drink to thirst" Mesoamerican Nephropathy (CKD of Unknown Etiology, CKDu) Endemic in Central America (El Salvador. Nicaragua. Costa Rica) (A1KO 20 1z1s9s31). Sri Lanka (qAsn 1019: 14: 224). Uddanam in I ndia (A/ xo 20161683z441 Potential pathogenesis: recurrent dehydration (hyperosmolarity)induced aldose reductase (polyp pathway) leading to glucose to sorbitol and fructose, hyperthermia, volume depletion -> " Heat suess nephropathy" (QASN 2016.11:14n) Risk factors of rapid GFR decline: outdoor work. agricultural work. lack of shade availability during work break UAW 10189942001 Manifestations 1 Na, K. Mg. T uric acid. lowgrade proteinuria Bx: glomerular ischemic injury. inr.ersutial fibrosis. and tubular atrophy who 10174916261 PLASMA EXCHANGE (PLEX) Apheresis Extracorporeal treatment that removes blood components Therapeutic plasma exdiange (FLEX) is a type of apheresis do removes plasma and replaces with allogenic plasma.colIoid.or crystalloid. PLEX can be performed using highly permeable fiber widl standard HD equipment or a centriibgation device. Membrane used for apheresis has pore size of 0.2 pm with MW cutoff 2.000 kDa Substances Removed by Apheresis PLEX: proteins (cryoglobulin, Ig including Ab form drugs). complement components. Immune complex. cytokines. drugs w/Vd <0.2 Ukg and protein binding >80% (Pllasma ltuelTn:vls1\ls fzdinal l 984:$:305) Rituximab can be given 24-36 hr before PLEX (Ami an :we 100a=1u1s9z1 Cyvapheresis (hemapheresis): leukocytes (hyperleukemlc leukosusis). platelets (severe thrombocyzosis). abnormal red cells (sickle cell disease),and parasites LDL apheresis: Ilpcproreins Indications in Renal Diseases (Amman Saauyfamuele; ah4nuz01s=J1=149) Should be Considered Can be Considered ANCA RPGN wl Cr >6. dialysis dependence or DAH AntiGBM disease w/ DAH or dialysis independence Atypical HUS with factor H amibodies.TTP Recurrent FSGS after o<p.AMR Desensizizazion in LDKT.ABO incompatible in LDKT Catastrophic APLS Symptomatic/severe cryoglobulinemia Myeloma cast nephropathy Severe SLE Co n sid erat io n s Prio r t o St art F L EX Ideally. diagnostic lab specimen should be drawn prior (D start PLEX:ANCA, andGBM Ab.ADAMTS 1 3 . CFH Ab. C3 ne phritic fa c tor Timing of antibodybased medicine: dose eculizumab, riruximab after PLEX session PLEX Regimen Volume: 1-1.5 plasma volume will maximize efficiency 1 plasma volume = 50 mUkg of weigh: or 70 mUkg of weight x [1Hct] Single 1 plasma volume . plasma macromolecule by 6094; 1.4 plasma vol l 75% Replacement fluid (RF): 5% albumin +I- NS +I- FFP FFP is given at the end of session to prevent coagulation factor removal FFP if (1) repletion of any plasma component is desiredTTR some forms of aHUS or (2) coagulation factor should be repleted: DAH, recent surgery. kidney bx. T PT Cryoprecipitates: for low fibrinogen Schedule: daily if life threatening (eg.active DAH) then god Number: not standardized;7 in ANCA vasculitis lMEFEX}ASN 1017.1e=21sol;can continue until disappearance of target (eg. antiGBM Ab) Access: dialysis catheter,AVF or AVG: anticoagulation: citrate. heparin Complications and Monitoring Albumin RF is alw less adverse reaction than FFP (1.4 vs 20%) WKD 1994933171 ACEiassociated reaction:flushing. hypotension. abdominal cramping; Kin in mediated: alw albumin RF lrlwnw 1994;34:s91);Witl\hoId ACEr for 24 hr prior Coagulation factor def: /PT. fibrinogen; replace w/ FFR cryoprecipitates, respectively Immunoglobulin depletion. injection (including catheter related) Metabolic alkalosis: from FFP containing citrate conversion to bicarbonate and reduced renal excretion:Tx: switch to albumin replacement: can be corrected by HD Metabolic acidosis: acidic profile of albumin replacement Tx: can be partially corrected by 40 mEq NaHCO; PO or IV (fulufuslun 1015;55:1653) Hypokalemia: common with nonplasma RE dilutional: Hypomagnesemia Hypocalcemiazl iCe by citrate chelation:Albumin RF also an fuse (I ample 199%14:114) Can be prevented by 10% calcium gluconate 10-20 mL (1-2 g) Potentially rebound antibody production; use as supplementary to antiproliferative Kau E- unihulu -adinn rnnliinn INTOXICATION AND POISONING General Management of Drug Intoxication . Airway. breading, circulation.volume repletion: prevent AKI. increase toxin elimination Dextrose: correct hypoglycemia in AMS. Hemoperfusion can cause hypoglycemia. In aspirin intoxication seizure can happen from low CNS glucose wl nl serum glucose Poison Control 8002221222; http://www.extripworkgroup,org Activated Charcoal Urine Alkalinization (Goal: Urine pH z7.5) Facilitate renal excretion of weak acids: aspirin. barbi:umtes.mechotrexace NaHCO; IV 1-2 mEqlkg bolus followed by 150 mErelL NaHCO; in 1 L of D5W Complication: hypokalemia. hypocalcemia, volume overload. CaP precipitation EXTRACORPOREAL THERAPY OF INTOXICATION Characteristics of Drug and Toxin Removed by Hemodialysis (HD) SmallVd (<1 Ukg):any noncontinuous extracorporeal methods Large Vd need for continuous therapy: rebound after therapy Small solute (MW <500 D) can be removed by HD with diffusive clearance 5-20 kD: high flux membrane with high Qb and Qdzconvective clearance helps 45-100 kD: only high cutoff membrane (unavailable in USA) can remove Lower (<80%) protein bound: high protein bound drug can be removed by PLEX Water soluble: less rebound (movement from storage cornpanments into circulation) Considerations for HD May need high flux (efficiency) dialyzer and long session for maximal clearance Dialysate designed for reduced renal function can cause 1 K, l PO 4. 1 Mg. and metabolic alkalosis in normal kidney function Maximal clearance may cause dialysis disequilibrium in CKD patients If significant rebound is expected (lithium, methotrexate,dabigatran. metformin) repeat HD early or initiate CRRT Hemoperfusion The passage of blood through a circuit containing an adsorbent (charcoal. carbon. or polystyrene resin) Remove theophylline. disopynmide. phenytoin. phenobarbital, procainamide. carbam azepine. valproic acid. dapsone. methotrexate,Amanita mushrooms Can remove large MW proteinbound.and lipophilic toxins and drugs Blood How (Qb) 250-400 mUm in: can cause hypotension Circuit similar (0 HD;wlo dialysate: no electrolyte/lluid overload correction Anticoagulation required sle: charcoal symbolization. 1 Ca, 1 gk, l BP: leucopenia. thrombocytopenia Other Extracorporeal Therapies CRRT: lower clearance than HD; consider for hefnodynamically unsuble pts: molecule with rebound;when dialysis disequilibrium risk exceeds benefit of rapid removal PD ineflectjve. not recommended Plasma exchange (PLEX): an remove lipid or proteinbound substances with smalIVd (<0.2 Ukg) regardless of size; rarely used for Amanita mushroom poisoning. snake envenomation. paraquat. dioxin (digoxinfab complex removal), cisplatin. amitriptyline. nanalizumab (Semin on: 2012;25:201) Drugs Removed by HD (MW,Vd, Protein Binding) Drugs Clin ic a l Fin d in g s I n d ic a t io n o f HD O t h e rTn e a t me n t s Aspirin AGMA, respiratory alkalosis Acid e mia t CNS toxicity >100 mgldL >8 0 mg /d L w/ CKD Meubolic acidosis w/ pH s7.2 Aczivared charcoal Keep blood pH 7.57.59: avoid acetazolamide Seizures dlt low brain glucose wl NL serum glucose level Pulmonary edema Seizures. coma, cerebral edema AKI Keep glucose >80: urine alkalinincicn Da b lg a t ra n (628, 50-70 L 35%) Bleeding lqAs~2013: Lifethreatening Idarucizumab: nemralizing Ab (Lacer 2015:JB6:6W) Me d o rmin (165. 1-5 Ukg, No) lactic acidosis (Lype B) NN abd pain Death 23-30% (lm £/vu!ma z009;s4a1& Cm Cue zuoa 1z¢a14sl Lactate >20 mmollL pH 57.0 Shock Failure of supportive measures Decreased level of consciousness L it h iu m L A G (L i is ca tio n ) NN/D. leukocytosis AMS. ataxia. seizure. irritability. tremor. myoclonus. fasciculations FlatT wave. T QT. bradycardia >$ mEq/L >4 mEq/L w/ AKI. CK D >2 .5 mE /L with symptoms IV fluid: T urinary Li excretion Bowel irrigation widl SR nab Sodium polystyrene sulfate Th e o p h y llin e (180.0.5 Ukz. 5 0 6 0 %) Ventricular arrhythmias. l BR tremor. seizure, abd pain, NN ¢ K. PO 4. Ca, gk. lactic acidosis 60 up/mL >50 kg/mL in infants Aczivared charcoal Hemoperfusion Me t h o t re x a t e (454.0.4-0.8 !Jl<8. 50%) Renal intruubular precipitation L ive r to xicity. NN No consensus Marked rebound (138. 0.2 Ukg, 8 0 -9 0 %. lo we r wl toxic level) (7.0.6-1.0 ukg, 0%) 8:1533) bleeding Activated charcoal (acute overdose) Na HCO ; : controversial < 6 mo o r > 6 0 lo Seizures, shock. arrhythmias IV fluid. urine alkalinization le u co vo rin Gluca dase TOXIC ALCOHOLS For an AGMA of uncertain cause or clinically suspected toxic ingestion. /osmolality alcohol (methanol. ethanol, ethylene glycol. isopropanol and acetone) level Isopropanol ingestion manifests w/o anion gap Causes of Osmolal Gap (OG) >10 mOsmlkg (+) Anion Gap Metabolic Acidosis (-) Metabolic Acldosls Merlunol. ethylene glycol, diechylene glycol. propylene glycol Formaldehyde, paraldehyde Advanced CKD wlo regular dialysis Keloacidosis (diabetic and alcoholic) Lactic acidosis Edlanol. isopropanol, diethyl ether Glycine. sorbkol.or mannirol solutions Pseudohyponatremia: severe hyperproceinemia or hyperlipidemia Early stage: typically OG >10 Late stage: metabolites are not active osmoles, but are anions with sodium as the accompanying cation; L OG, AG were 201887831701 qAsn 2008:3:208) Methanol AS... (mOsmlL) per 10 mgldL Serum Alcohol (qASN 2008.17.08) 3.09 Isopropyl alcohol 1.66 Propylene glycol Ethanol 2.12 Ethylene glycol 1.60 Diethylene glycol 1.31 0.9 Clinical Manifestations of Toxic Alcohol Ingestion Alcohol Methanol (/11) . Manliest dons of Toxic Alcohols (AGIOG) Manifestation Source Metabolism (391115) Windshield wiper fluid, industrial produns Ethylene glycol (l ) Antifreeze (fluorescence of urine under UV light). adhesives. pesticides, inks lsopropanol (n u 1 ) Rubbing alcohol. hand sanitizers Dietliylene glycol (tlt or NL) Automotive brake fluid, industrial products Propylene glycol (NL or WT) lV lorazepam . diazepam, phenobarbital. etomidate Hemonrhagidischemic injury to basal ganglia. Blurred vision. central scoromara. blindness. coma. death CaOx deposition in Glycolaldehyde kidney (AKI. -» Glycolic acid (tubular hematuria. oliguria, toxicity) blank pain). hear -» Qxalit acidloxaiue (myocardial (crysta can be seen dysfunction), lung on urine sediment) and brain (CN palsies) .l Ca (tuscany. low BP) CV collapse. coma in Acetone massive ingestion (levels >500 mg/dL and osmolal gap >100) AKI: could be 2hydroxyethoxy inwersible aceuldehyde 4 1hydroxvedmxyagetic Hepatitis. pancreadtis AMS. peripheral 194 facial diplegia, flaccid tetraparesis Minimal clinical Lactaldehyde abnormality -a D and l:liSiiie RareAKl Formaldehyde - formic acid/formate lnrrir =rill Kemnes General Management olToxic Alcohol Ingestion Acidemia " uncharged toxic metabolite.formic acid that can enter endorgan tissue IV NaHCO; to correct metabolic acidosis (1-2 mEq/kg for pH <7.3 followed by a continuous infusion no maintain systemic pH >7.35) No role for GI decontamination. eg.acdvated charcoal Fomepizole (4Methylpyrazole) Inhibit: alcohol dehydrogenase and aldehyde dehydrogenase:has . need for HD Initiate if alcohol level >20 mg/dL Preferred over ethanol that requires level moniwring (>100 mg/dL) and sedative effect To . more toxic metabolites: methanol. ethylene glycol. diethylene glycol Do not use when metabolites are less toxic: isopropanol (acetone less toxic) Dose: IV 15 mg/kg loading followed by 10 mg/kg q12h x4.then 15 mg/kg q12h (increased dose for alcohol dehydrogenase induction by fomepizole) Until alcohol level <20 mgldL (methanol <6.2 mmole/L or ethylene glycol <31 mmoleIL) Removed by HD: 1-1.5 mg/kg/hr during HD or redose immediately after HD HD in Toxic Alcohol Ingestion All of the alcohols are dialyzable: low MW little or absent protein binding. lowVd General indication:AKl,anion gap metabolic acidosis with pH <7.3 Treatment of Toxic Alcohol (MW,Vd) Ingestion Indication of H D O ther T r eatment >50 mgldL Blurred vision or blindness. seizures Fornepizole Folic acid SO mg N q6h or leucovorin 50 mg IV q6I\ to replete tetrahydrofolate: T Formate metabolism Ethylene glycol (62, 0.5-0.8 Ultg) >50 (300 K lcmepizole given) mg/aL Altered sensorium, coma, seizures Fomepizole Thiamine 100 mg IV qd and pyridoxine 100 mg IV qd: T Glyoxylate metabolism lsoproprandol (60. 0.6 UP >500 mgldL Hypotension. lactic acidosis Supportive Do not use fomepizole Alcohols Methanol (32,0.6-0.7 Ukg) Fomepizde Diethylene glycol ( 106.12,0.5 up Propylene glycol (75 11 lacto acidosis Stop infusion containing propylene glycol it able HD duration (h): V In (SIA)/0.06k we 100$:46:509) V: Watson estimate of :oral body water (L).A: the initial alcohol level (mmolIL) For mg/dL - mmolIL. x03121 (methanol), 0.1611(ezhylene glycol), 0.1644 (isopropanol) k: 80% of the dialyzer urea clearance (mUm in) at the observed Qb Avoid heparin if methanol ingestion suspected (risk of basal ganglia hemorrhage) RENAL TUBULES PROXN4ALTUBULE (PT) Physiology of the Pmxlmal Tubule NaCl. water: 60-70% of isownk reabsorpzion Glucose: lull reabsorpdon AA: full reabsorption HCOJI reabsorpcion P043 rvabsorprion Peritubular capillaries pressures . All and Norepinephrine Luminal SGLT1, SGLT2 Luminal NaM conranspon Luminal NHE3 Luminal NaPi Reabsorpnion of K. POI. Ca, Mg. urea. orate: ammonia production Complete neabsorprion and metabolism of LMW pnueins Secretion of orate. cationic drugs Transporters + paracellular transport allow 70% of ulua6I:rate reabsorpdon Cystinosis AR mutation of CTNS gene encoding cystinosin, protein that transports cysteine across the lysosomal membrane -» accumulation of cystine in lysosome - Cystine 1 glutathione -» T oxidative stress - apoptosis: cystine forms crystals in DT - stone 3 clinical presentations depending on the underlying genetic mutation: the infantile (nephropathic) form. the lateonset (juvenile) form, and the adult (benign) form Nephropathic cystinosis -> PT dysfunction: polyurialpoiydipsia, tubular proteinuria.gly cosuria. phosphaturia. hypounicemia.and aminoaciduria (symptoms of volume depletion and electrolytes imbalance starting at 3-6 mo). Usually progress to ESRD by mid.teens. Extrareml symptoms: rid<ets.growth retardation. corneal cysteine deposiWpliotophobia. hepatomegalyq portal hypertension. hypothyroidism.T1 DM. myopathy. hypogonadism. azoospermia,and excessive bone fracture. Patients have normal cognitive function. Dx: T cystine content of WBC. cystine corneal crystals. or genetic testing Tx (1) symptomatic treatment for the volume and die electrolyte imbalances: (2) nutrition supplement (some pt require Gtube feeding): (3) cysteamine Cysteamine (metabolizes cysteine): preserves kidney function and delays most extra renal manifestation except for the cornel deposits (treated w/ cysteamine eye drops). it does not reverse the preexisting organ dysfunction immediate release quo. enteric release form q12h. / WBC cystine level for efficacy. sle GI intolerance. unpleasant breath. sweat odor,and bruiselike skin lesions at the elbow and knee. Renal exp. successful w/ excellent longterm outcome wlo recurrence in the graft Continue cysteamine to avoid progression of the extrarenal manifestations. LOOP OF HENLE Urine dilution and sodium reabsorption (15-25%) via NKCC2 Countercurient multiplier creates the medullary osmotic gradienc responsible for concentrating the urine in collecting duct Basolateral NaKATPase 4 l intracellular Na - reabsorption of Na.K. Cl via luminal NKCC2 -» K secretion via luminal ROMK - electropositive lumen Paracellular reabsorption of Ca. Mg via claudin 16. 19, driven by luminal + charge CaSR inhibits ROMK and NKCC2 to decrease calcium uptake in hypercalcemia Tubuloglomerular feedbadc 1 NaCl delivery to macula denser of ascending limb of Henle - t PGE2 production -» t renin release from juxtaglomerular (]G) cells and ladenosine mediated afferent arteriole vasoconstriction; SGLl12 inhibitor may inhibit renin release Bartter Syndrome Heterogeneous presencarionzchildhood onset. MR.growth defects. polyurialpolydipsia Types of Bartter Syndrome Type Mutated Protein Clinical Manifestations I II III Luminal NKCC2 Luminal ROMK Basolazeral ClCKb Severe, nephrocalcinosis. ESRD. early onset IV v Bartin,l3 subunit of CICKb GOF mumion of basolateral CaSR Sensorineural deafness. less nephroalcinosis. CKD Classic, less severe. later onset: some mutations have hypocakiuria: CKD. nephrocakinosis AD. Milder, laser onset. 4 Ca. 1 Mg. No . PGE2 DISTALTUBULE Reabsorption of NaCl via NCC. las: diluting segment of the tubule Reabsorption of Ca (TRPV5) and Mg (TRPM6) Connecting tubule glomerular feedback: T NaCl transport in the connecting tubule (sensed by ENaC -o afferent arteriole vasodilatation) Gitelman Syndrome: Loss of Function of NCC AR. late childhood and adulthood presentation. more severe phenotype in Q Polyuria. nocturia, cramping. fatigue. chondrocalcinosis. CPPD disease x Tx: NaCl ad ibiwm. K/Mg supplements. Ksparing diuretics (an worsen sodium depletion). Q unSAIDs UAS~ zoisaessal, avoid QT prolonging meds Bartter Syndrome Gitelman Syndrome AR.. K. meubolic alkalosis, 2° t renin (hyperplasia of d 1e IG apparatus) and 1 Aldo Volume contraction. 1 BR loss of maximal diluting capacity Mimics/bunted response so loop diuretics Pluuvions in NKCC in the TAL Loss of concentrating capacity Hypercalciuria +I hypomagnesemia PGE2 - Vasodiladon Mimicslblunted response to rhiazide Mutations in NCC in the dismal tubule Preservation of the concentrating apaciry Hypocalciuria + hypomagnesemia Nomlal PG secretion EASTlSeSAME Syndrome Muradons of the basolateral K channel (KCNJ10; Kir4.1) -» i NaK ATPase activity - L Na gradient for NCC -v renal Sal: wasting, T renin. hypoK. met alk. and lownl BP Epilepsy. anoxia. sensorineural deafness, and tubulopathy/seizures. sensorineural deaf ness, aizxia. mental retardation. and electrolyte imbalance) Pseudohypoaldosteronism Type 2 (Gordon Syndrome) WNK1.4,Cullin3. or Kelch3 muxadon -» T NCC. mirror image of Gitelmanlzhiazides Familial hyperkalemic HTN. metabolic acidosis. L renin. l aldoscerone, low BMD. hypercalciuria dl: l Na and Ca absorption in PCT To: low sak diet. chiazides COLLECTING DucT K secretion via ROMK and BK: T by aldo (ROMK. BK).r.ubular How (BK). 1 Mg Sodium reabsorption via ENaC: T by aldo Urine concentration via aquaporin: . by ADH Urea absorption is both passive and UT1: by ADH Acid (H) secretion at typeA intercalated cell via H ATPase Base (HCO,) secretion at type B incercalated cell via pendrin. CIIHCO: exchanger Liddle Syndrome AD. GOF mutation of ENaC (inability to bind wl a ubiquity protein ligase. Nedd4) HTN at young age. L K. metabolic alkalosis. l PRA. PAC Tx: amiloride. triarnterene: spironolactone is NOT effective Pseudohypoaldosteronism Type 1 AR form: ENaC mutation. militia crystcallina popular rash dl: high Na in sweat, chest congestion d/t airway expression of EnaC man 199<ra41.1s61 AD form: mutation of MR milder salt wasting. improves with age Volume depletion. FTT,T PRA. T PAC (aldosterone resistance) . Tx: high salt diet. highdose fludroconisone (1-2 mold). carbenoxolone (1 metabolism of cortisol. as wl licorice activate the mineralocorticoid receptor) Pendred Syndrome AR mutation of pendrin; no electrolytes imbalance under normal conditions Metabolic alkalosis and hypovolemia with thiazide therapy Associated phenotype: sensorineural hearing loss and hypothyroidism with goiter EVALUATION OF ACID-BASE BALANCE Background Acid-base balance is maintained by renal excretion of noninducible titrauble acid (HPO4Z/H;PO¢) and inducible buffers (mainly NH: + H -4 NH4).and pulmonary excretion of CO1 (CQ, + H 10 H H1CO; H HCO; + Ir) Henderson-Hasselbalch equation: pH = 6.10 + log ([HCO;]/[0.03 x ?Co,]) On the ABGs. HCO; is calculated: usually 2 mE/L less than the measured blood CO1 Normal Values of Blood Gas Analysis pH 7.3s-7.44 L 0.02-0.04 10.03-0.05 ABGs Peripheral VBGs Central VBGs Hco; 21 -27 i 1-2 H pCOz 3644 1 3-8 14-5 Step 1:ArteriaI pH Defines the Primary Disorder Acidosis (pH <7.36) or alkalosis (pH >7.44) VBGs has a good diagnostic accuracy for mos: acid-base imbalances Step 2: Metabolic vs Respiratory Disorder Acidosis + low HCO3 -\ Metabolic acidosis Acidosis + high pCO; -> Respiratory acidosis Alkalcsis + high HCO;' -» Metabolic alkalosis Alkalosis + low pCO; -» Respiratory alkalosis Step 3: Compensation Assessment In a simple disorder. the compensatory changes in the same direction of 1° disorder The respiratory compensation of metabolic disorder starts within 30 min and is complete in 12-24 hr The metabolic (renal) compensation of respiratory disorder takes 3-5 d to complete. thus the difference in expected compensation for acute (<3 d) and chronic respiratory disorders (>5 d) Compensation Assessment Primary Compensation Expected Compensation Metabolic acidosis 1 Hco, lPaCOz (hypervendlanion) Metabolic alkalosis Respiratory acidosis Respiratory alkalosis T HCO: . PaCOz (hypoventiiadon) . HCO1 1 mE/L 4» 1.25 mmHg PaCOz = 1.5 x HCO: + 8 : 2 paco, = Hco, + 15 Paco) = decimal number of the pH Down to 8-12 mmHg 1 mEaL ¢ 0.7 mmHg Up co SS mmHg 10 mmHg <-» 1 mEq/L (acute) 10 mmHg H 3.5-5 malL (chunk) 10 mmHg 44 2 mEaL (acute) 10 mmHg H 4-S mErelL (dwronk) . pCO; PCO: 1 Hco, Step 4:Assess for Mixed Disorders Mixed acid-base is present when: 1. Greater or lesser than expected respiratory or metabolic compensation 2. PaCO; and HCO; change in opposite directions 3. TAG in other forms of imbalance:additionaIAG metabolic acidosis In metabolic disorder PaCOz is higher than expected:additional respiratory acidosis pCO; is lower than expected: additional respiratory alkalosis In respiratory disorder HCO; is higher than expected: additional metabolic alkalosis HCO; is lower than expected: additional metabolic acidosis METABOLIC ACIDOSIS Background Daily acid ingestion (50-100 mEq of H*) is balanced by reabsorpdon of HCO; at PCL excretion of H by the distal part of tubule;most of the renal excretion is in the form of Utrarable acids H;PO{ and NH( Renal ammoniagenesis excretes hydrogen ions. NH; + H -r NH4` or hypokalemia due no exit of intracellular K in exchange with extracellular H Wo rku p In pure metabolic acidosls.pH is decreased,serum HCO; is reduced and PaCO1 is reduced as a compensatory mechanism Winners formula: PaCO1 = 1.5 x serum HCO; + 8 i 2 To diagnose mixed acid-base disorders, the degree of PaCO; compensation needs to be assessed: Mixed disorder. arterial pH may not be decreased: 1. If PaCO; is higher than expected: metabolic acidosis + respiratory acidosis 2. If PaCO; is lower than expected: metabolic acidosis 4 respiratory alkalosis 3. These assumptions are valid as long as HCO; is >7 (PaCO; can be lowered only to the range of 8-12) Serum Anion Gap (AG, mEgIL) = Na - (CI 4 HCOs) = unmeasured anions (albumin. PO». orate, sulfate, IgA) - unmeasured actions (K. Ca. Mg, IgG) Normal AG High AG (>9) 3-9 (Variation can occur dependent on the lab) Organic metabolic acidosis (ker.oacidosis; lactic acidosis: ingestions: pyroglutamic acid) Hyperalbuminemia. metabolic alkalosis: t in albumin negative charge Low AG (<3 J Negative AG mpH Hyperphosphatemiaanionic monoclonal IgA Hypodbuminemia: expected AG:2.5 x [albumin] Severe NAGMA: 1 albumin negative charge .. K. t Ca. T mg. lithium intoxication. cationic monoclonal IgG. bromide (pseudohyperchloremia) Na underestimation (severe hypernatremia) Cl overestimation (hyperlipidemia: salicylate intoxication: Bromide) iuco, Serum AG calculation Metabolic acidosis r Calculation of expected PBCO2 with Winters ¢ofmula or decimal digits of the pH PaCO, Measured > calculated PaCO2 Measured < calculated Additional respiratory acidosis Additional respiratory alkalosis TAG: Normal AG: NAGMA AGMA /Urine AG /AAG/AHCOU 1 RTA type 1 hypcaldo steronism (RTA WIG 4) Approach to metabolic acidosis. Super imposed NAGMA Super imposed metabouc alkalosis In NAGMA. appropriate (>200) vs inappropriate (<75) urinary NHL' can be estimated by urine anion gap (UAG) and urine osmolal gap (UOG) Urine anion gap (UAG, Un, + Un - Uci) is used as indirect measurement of the urine NHL concentration, this relation is disrupted in some disorders: (1) urinary excretion of unmeasured anions (DKA-43hydroxybutyrate. ketoaceute; toluene inhalation -v hippurate; proximal RTA -» bicarbonate: Dlactateaacetaminophen - 5oxoproline); (2) Neonates; (3) CKD In the presence of unmeasured anlon.¢he calculated UAG will have a positive value which falsely suggest a low level of NHL excretion. In these disorders UOG is used to estimate NH. excretion ANION GAP MsTAsouc Acloosls (AGMA) I fAG is elevated. /AAG/AHCO; ratio; AAG - calculated AG - expo<ted AG: AHCO3 = 24 - measured HCO3 AAG/AHCOs 1-1.6: anion gap metabolic acidosis (AGMA) In lactic acidosis, due to Intracellular H buffering :he fall of bicarbonate is not equal to the increase in the AG and the expected AAG/AHCO; can be up to 1.6 AAG/AHCO; <1: AGMA + hyperchloremic acidosis (NAGMA) AAG/AHCO; >1.6: AGMA + metabolic alkalosis Etiologies Edologles of AGMA Increased Acid Generation Ketoacidosis" Ingestion Diabetes mellitus. starvation. alcohol Methanol. Ethylene glycol.Aspirin.Toluene (early phase) Diethylene glycol. Propylene glycol Pyroglutamic acid (5oxoproline) dlt chronic acetaminophen ingestion (usually malnourished women) LLactic acidosis Hypoperfusion. aerobic glycolysis DLactic acidosis Metabolism of carbohydrate by intestinal bacteria in patients with show bowel syndrome Metabolism of propylene glycol (solvent for IV lorazepam. automotive antifreeze) Decreased Renal Acid Excretion: CKD 'High acetone level (>100 mg/dL) can falsely elevate sCr (T sCr with normal BUN). Tre a tme n t Address and :rat the underlying process Use of IV HCO; for the treatment of AGMA is controversial; the common practice is to use IV bicarbonate only when pH <7.1 Potential benefits of treating chronic metabolic acidosis with alkali (bicarbonate or citrate) are: 1 dyspnea. improve skeletal grovnnh. i kidney stone and nephrocalcinosis in RTA type 1, slow progression of CKD Potential concerns with bicarbonate therapy includes: T CO: and worsening inna cellular acidosis. T lactate generation though T phosphofructokinase activity. decrease of ionized Ca, hypernatremia. and hypervolemia Bicarbonate Is available in 8.4% 1 mEq/mL 50 mL vials of hypertonic NaHCO; Calculation of the HCO; deficlc The volume of distribution (Vd) of HCOJ Is 50-55% (T up to 70% in severe meta bolic acidosis due to high buffering capacity). HCO; deficit = 0.7 x Lean body weight x (desired HCO; - measured HCO:) LACTIC Acloosls [Ne/M 2014;371:2309) Pathogenesis Lactic acidosis occurs when generation of lactate exceeds consumption Anaerobic glycolysis generates Pyruvaze which is metabolized by Iacune dehydrogenase (LDH) no lactate Pyruvate + NADH + H H lactate + NAD Lactate is consumed for gluconeogenesis and oxidative phosphorylation Hyperlactatemia can occur due to systemic or local tissue hypoxia (type A), the resulting acidemia is autoexacerbated by l of lactate removal by the liver in cases of severe hypoxia and acidemia Hyperlactatemia results from aerobic glycolysis (type B) in hyperdynamic states (et. sepsis. severe asthma. shock, pheochromocytoma) Metabolic alkalosis stimulates 6phosphofructokinase leading to hyperlaccatemia from aerobic glycolysis Lactic acidosis contributes to cellular dysfunction: T cardiac arrhythmias. 1 myocardial contractility.and responsiveness to catecholamines Hyperkalemia is very common when the etiology is 1 Oz delivery: with hyperlactate mia d/t epinephrine stimulation. hypokalemia occurs dlt l32adrenergic stimulation Etiologies of Lactic Acidosis Decrease Local or Systemic O1 Delivery (Type A) Shock Cardiogenic. hypovolemic. septic. severe trauma Severe hypoxemia Lung disorders. CO poisoning Others Severe anemia. vigorous exercise. seizure. shivering. cocaine Aerobic Glycolysis (Type B) Epinephrine stimulation Cardiogenic. hypovolemic. sepzit shock Cancer Sepsis. Pheochromocytoma, Cocaine. Ii;agonists Warburg effecc usually in the setUng of concomitant liver metastases limiting the lactate clearance by the liver Others NRTIs. toxic alcohols (methanol, ethylene glycol). salicylates. cyanide. pmpofol, thiamine deficiency Other Mechanisms DM Liver disease Medormin Propylene glycol Unknown mechanism 1 lactate Clarance Suppression of hepatic gluconeogenesis Metabolized to Dlactate and Llactate Treatment Restore tissue perfusion with volume expansion using crystalloids;albumin can be used as alternative for volume expansion. avoid other colloids Balanced salt solutions (less chloride content) could prevent dilutional acidosis IV bicarbonate is potentially helpful for severe acidemia (pH <7.2). Use with caution (nuacellular acidification.. iCe leading to cardiac contracniliry) DLactic Acidosis Etiologies: short bowel syndrome (carbohydrate metabolism by colonic bacteria). ingestion of propylene glycol (solvent for IV medications notably lorazepam and diazepam) and DKA Episodic metabolic acidosis with neurologic symptoms (confusion.ataxia. slurred speech) Diagnosis: special enzymatic assay for Dlactate (the commonly used lactic acid assay does nor detect Dlactic acid): It cause a combined AGMA and NAGMA (NAGMA is due to excretion of Dlactate with Na and retention of the H) Treatmenc oral antimicrobials. NaHCO: and addressing the underlying fuse KETOACIDOSIS Background Metabolic acidosis secondary to ketone (acetozcetic acid. Bhydroxybutyric acid. ace tone) accumulation: diabetic. alcoholic or fasting ketoacidosis Urine dipstick detects acetoaceute and acetone. no: [5hydroxybutyric acid (can be measured in the blood) Correction of ketoacidosis leads frequently to NAGMA secondary co renal loss of ketone bodies which are considered potential bicarbonate" Fasting Ketoacidosis 13hydroxybutyrate is the main ketone Neonates and pregnant lactating women are at risk dl: T metabolic requirements Alcoholic Ketoacidosis Malnourlshed alcoholic patients. the severe acidosis occurs after :he patient stops alcohol ingestion (alcohol ingestion limits fatty acid lipoiysis and decrease generation of acetylCoA): plasma levels may be low or undetectable Manifestations hypo or hyperglycemia, hypokalemia (GI and renal loss). L PO¢ (i intake and I renal Ioss).i Mg. l OG Diabetic Ketoacidosis Ketone bodies are both Bhydroxybutyric and acetoacetic acids DKA is the result of insulin deficiency, glucagon excess leading to glucose utilization. increased gluconeogenesis, increased glycogenolysis. and Iipolysis Treatment: Correction of the hypovolemia with isotonic solution: Insulin administration Correction of the hypokalemiaz early and aggressive correction is needed in antici pation of worsening of the l K following insulin therapy and volume expansion o <9 Background MSTI4ANOL AND ETHYLENE GLYCOL Methanol and ethylene glycol can be ingested as ethanol substitute. accidently (illicit distillation) or to inflict selfharm. It is Found in: antifreeze and deicing solutions. windshield wiper fluid. solvents. cleaners. fuels Ethanol Fomepizole MethanoI° Ethylene glycol' .| Alcohol dehydrogenase r Fomlaldehyde Glycoaldehyde Formic acid° Glycolate" Tetrahydrofolate r Less toxic 1 Oxalate" metabolites Metabolism of Methanol and Ethylene glycol (Nontoxic alcohol;"Toxic meobolkes). Pathogenesis Formate causes retinal injury (hyperemia and blindness). basal ganglia hemorrhage Glycolate causes tubular injury; oxalateCa crystals causes tubular obstruction The toxic metabolite causes the T AG: the parent alcohol contributes to the osmotic gap (as the alcohol is metabolized the osmolar gap decrease and the AG increase) Folic acid accelerates the metabolism of formic acid Ingestion of 1 g/kg is lethal: toxicity can occur with as little as tsp of methanol C lin ica l M a n if e st a t io n s CNS sedation and inebriation similar to ethanol intoxication than an progress to coma. seizure. and hypotension Methanol poisoning visual blurring, central scotcrnata. and blindness. On eye exam. mydriasis, retinal edema. hyperemia of the optic disc and loss of afferent pupillary reflex Ethylene glycol: oliguria. hematuria.flank pain. tetany (hypocalcemla) When ethanol is colngested. the clinical manifestation is delayed dlt alcohol dehydro genase inhibition Diagnosis Advanced degree ofAGMA (frequently HCO1 <8) w/o T lactic acid Alcoholic ketoacidosis causes AGMA bu! with a lesser degree of acidosis t Osmolal gap (OG) >10 can be seen during the early phase d the intoxication (before the alcohol is metabolized) OG = Measured Posm - Calculated Posm Calculated Posm = (2 x plasma [Na]) + [glucose]/18 + [BUN]/2,8 Limitation of OG measurement: (1) Cannot differentiate among the different alcohols (ethanol, methanol, ethylene glycol, or isopropyl alcohol); (2) a decrease of OG is a sign of metabolism of the alcohol to d1e toxic metabolkes and it is not a correlate of recovery (3) OG increases in critically ill patients due to idiogenic osmoles Solvent screen" does not measure for ethylene glycol Lactate can T in ethylene glycol intoxication (glycolate has similar structure as lactate) Oxalate crystal and fluorescence of the urine with UV light in ethylene glycol intoxi cation Tre a tme n t GI decontamination has a limited role since these alcohols are rapidly absorbed NaHCO; no correct systemic acidosis (in an acidic milieu, tl\e toxic metabolic are in their uncharged form and thus easier to penetrate and cause organ damage), goal to keep arterial pH >7.3 Inhibition of alcohol dehydrogenase: early treatment is important before the fonrnation of the toxic metabolites Fomepizole 15 mg/kg loading then 10 mg /kg q 12h;adiust after 2 dzadjust for HD: Continue therapy until pH is normal and serum alcohol concentration <20 mgldL . Ethanol if fomepizole is unavailableztarget ethanol level 1/3 of the other alcohol: Loading 10 mUkg of 10% ethanol with maintenance of 1 mUkg HD remove both the alcohol and the toxic metabolites. it is indicated in any patient with (1) AGMA regardless of the alcohol level or (2) evidence of organ damage or (3) large methanol ingestions If a toxic alcohol ingestion is suspected but not yet confirm: the threshold to start HD is pH <7.1 (it is unlikely for alcoholic ketoacidosis to cause such an advanced acidosis);a concomitant fomepizole therapy can be started until :he diagnosis is con firmed or ruled our: treating with ethanol for nonconhrmed intoxication is debatable due to SE profile of the therapy ./ toxic alcohol levels every 2 hr of end of HD to determine the need for additional HD; fomepizole is dialyzable and an additional should be given at the sur: of HD PD and CRRT are inefficient at clearing alcohols Treating with cofactors (folic acid. thiamine.and pyridoxine) to optimize nontoxic mez abolic pathways: for methanol intoxication folic acid S0 mg IV q6h; thiamine 100 mg IV or pyridoxine 50 mg IV in ethylene glycol Isopropyl Alcohol isopropyl alcohol is used as disinfectant (rubbing alcohol).antifreeze. and solvent Causes CNS inebriation and depression.a fruity breath odor It does NOT cause an elevated anion gap acidosis; it is metabolized by alcohol dehy drogenase to a ketone Diagnosis: T isopropyl alcohol levels and T OG: isopropyl alcohol does NOT cause tAGMA nor . ;ihydroxybutyrate: ketone in the urine are expected after 2 hr of ingestion (the urine ketone detection can be delayed if the patient receives fomepi zole or ethanol) Treatment; hydration and supportive are.no role for GI decontamination. no Indication for alcohol dehydrogenase inhibitors. HD can help in massive ingestion Toluene Inhalation (Glue SnifTing) Toluene is metabolized to hippuric acid and benzoate leading to AGMA With normal renal function these anions will be excreted with Na. NH4, and K. and the AG is progressively corrected and the patient start developing NAGMA Despite an increase in urinary NHL, UCI does not increase due to the presence of hippurate leading to a positive UAG. NAGMA + * urine pH + T UAG can be misdiagnosed as type 1 RTA: in this disorder UOG is used to estimate NH4 excretion Hypokalemla is frequently present; (1) volume contraction leading to 2 hyperaldo. (2) high distal Na delivery (Nahippurate and Nabenzoate) > Q o NONANiON GAP (HYPSNCHLONEMIC) MeTAsouc AclDosis Causes and Pathogenesis Normal anion gap metabolic acidosis is due to NaHCO; deficit Mechanisms of NAGMA Renal Reduction of acid excreting capacity CKD.distal RTA. type 4 RTA Bicarbonate loss: proximal RTA GI Other Bicarbonate loss: diarrhea, pancreatic fistula, ureteric diversion (ile el loop) Loss of organic anions: recovery phase ofAGMA (DKA. toluene ingestion, and Dlactic acidosis): Na and K Sal: excnedon w/ impaired acid excretion Dilutional acidosis: volume expansion with a nonalkali containing fluid: rare unless extraordinarily large volume is given Addition of HCl:TPN Diarrhea Diarrheainduced NAGMA is frequendy associated with hypokalemia.hypokalemia induced intracellular acidosis.and T NHL excretion and elevate urine pH The more chronic is the diarrhea and the more profound is the hypokalernia. :he higher is the urine pH (can be falsely diagnosed as dRTA or toluene inhalation) Resolution Phase of an AGMA In patients with AGMA and normal kidney function. the renal excretion of ketoacid anions reduces the AG.a NAGMA is generated by loss of the ketoacid anions (potential bicarbonate) with retention of H Ureteral Diversion (lleal Loop) Ureterosigmoidostomy: (1) urine is exposed to colonic mucosa. the Us is exchanged for bicarbonate by anion exchanger (SLC26A3) » bicarbonate loss and NAGMA3 (2) urea in the colon is metabolized to NHL that is reabsorbed in exchange of Na leading to NAGMA lleal conduit: unlikely to cause NAGMA since the urine is not In contact with the epithelium for long before it is drained to an external bag. if NAGMA develops it is sign of malfunctioning of the loop Treatment; NaHCOi administration DISTAL RENAL TUBULAr Acii:>osls (dRTA,TYPE 1 RTA) Causes and Pathogenesis Impaired dismal acid secretion/urine acidification in the presence of NAGMA L Activity of HATPase or increase luminal membrane permeability (leading to move ment of the H from :he urine lumen back to the blood) Hypokalemiaz due to . K excretion which offsets impaired H secretion needed to maintain elecuoneuuality from sodium absorption Etiologies of Distal (Type 1) RTA Autoimmune Sjégren s. rheumatoid ardlri\is. SLE Autoimmune hepatitis. primary biliary cirrhosis Medications Arnphotericin B: reversible dRTA: less wl liposomal formulation Lithium: incomplete RTA (mild to no metabolic acidosis) ifosfamide. ibuprofen/codeine Hypercalciuria Hereditary Hyperparadlyloidism,\hc D intoxication. samoidosis. idiopathic hypeiulciuria SLC4A 1 encoding Cl/HCO; exchanger (AE1 or band3):AD. milder acidosis than AR. presents later in life (young adults). Hypercakiuria. nephrolithiasis. nephrocalcinosis. osteomalacia. and erythrocytosis ATP6V181 encoding apical HATPase: AR: Sensonineural hearing impairment. nephrocalcinosis ATP6VOA4 encoding apical HATPase:AR: No early haring loss Other Obstructive unopathy:l. Na entry in the principal cells 4 . H excretion Medullary sponge kidney. transplant rejection.Wilson disease ldiopathk Diagnosis Urine pH >5.5. Un. >25; positive UAG; L UOG Other causes of persistently elevated urine pH >5.5: diarrhea with hypokalemia. toluene inhalation Urine osmolal gap <150: dRTA Urine osmolal gap >400: chronic dlaMea. toluene Clinical Manifestations Recurrent calcium phosphate kidney stones and nephrocalclnosis.from associated hypercalciuria and hypociuaturia Tre a tme n t Correction of :he acidosis Is indicated in children zo restore normal growth. in adults with K wasting, nephrocalcinosis, osteoporosis. and CaP stones Goal [HCo,] 22-24 NBHCOJ or Na citrate (bicitra) 1-2 mEqlkg/d: K citrate 4 Na citrate (Polycitra) K citrate: for recurrent kidney stones (increases urinary citrate and K moves inm cellularly H exit the cell - . intracellular acidosis) Avoid Na citrate: may increase stone formation Correcting the systemic acidosis will T urinary citrate (acidosis T proximal citrate reabsorption) Incomplete dRTA Impaired urinary acidification and inability to reduce urine pH to less than 5.3 but the net acid excretion is maintained at a rate equal to acid generation by overforma tion of NHL. In chronic condition. patients are not acidotlc. Some patients progress to complete dRTA Urinary citrate -» calcium phosphate stones. osteoporosis Pathogenesis: not well understood. it is related to low intracellular pH in the proximal tubule leading to increase formation of NHL. the acidosis episodes are intermittent Diagnosis with acid load (NH4CI 0.1 g/kg or 3 d of modified diet) -> 1 serum HCO; by at least 3 and urine pH is >5.3 Voltagedependent RTA Dejects in distal sodium reabsorption leading to loss of the electronegativity of the lumen leading to . K and H secretion Etiology: severe hypovolemia. obstructive uropathy (1 NaKATPase pump). lupus nephritis. sickle cell disease. amiloride. lithium • Hyperkalemic RTA PROXIMAL RENAL TUaULAR Acloosls (pRTA,TVPe 2 RTA) Isolated pRTA: defect in proximal bicarbonate reabsorprion Fanconi syndrome: a generalized proximal tubular dysfunction with impaired reab sorpdon of phosphate. glucose. uric acid, and amino acids Patients are in chronic acidbase balance and can reduce the urine pH no less than 5.3 Pathogenesis Edologles of Proxima! (Type 1) RTA Paraprotein Drugs, heavy metals Light chain proximal tubulopathy Ifosfamide, tenofovin aminoglycosides. cisplatin. valproic acid. delerasirox Carbonic anhydrase inhibitors: acetazolamide. donolamide. wpiramate Lead, cadmium. mercury. copper Hereditary Other Dent disease. cystinosis. tymsinemia. galactosemia.Wilson disease. Lowe disease, hereditary fructose inizolerance, mitochondrial rnyopathies. glycogai storage disease (type 1) Mutations Off $LC4A4 encoding NaHCO; cotransporter (NBCe1):AR, isolated pRTA. Eyes. teeth. and cognitive disorders SLC9A3 encoding NHE3:AD pRTA CA2 encoding carbonic anhydrase II (CA II) Renal transplantation.Vit D deficiency. paroxysmal nocturnal hemogiobinuria, Siégren syndrome Variable K excretion dependent on d 1e alkali intake: In chronic stable alkali/acid intake. K level Is normal After alkali therapy dismal tubule Na delivery - t K excretion -» hypokalemia T r eatment pRTA requires a higher load of alkali therapy (10-15 mEqlkg/d) Alkali therapy increases bicarbonawria and T K loss;thiazide can help by inducing volume depletion :had stimulates proximal Na and bicarbonate reabsorption Carbonlc Anhydrase (CA) Inhibitors Acetazolamide. medmazolamide. dorzolamide. topiramate Inhibits intracellular CA II and intraluminal CA IV in proximal and distal tubules pRTA (w/o Fanconi syndrome) + dRTA. L K. nephrocalcinosis. Ca? nephrolithiasis Mixed Renal Tubular Acidosis (Type 3 RTA) Mainly in the Middle East and North Africa,Arabic descent AR. carbons anhydrase 2 deficiency. Guibaud-Vainsel syndrome or marble brain disuse Both pRTA and dRTA, osteoporosis. cerebral calcification. mental retardation, facial dysmorphism with conductive hearing loss and blindness HypoALoosTsnonlsl4 (Tvrs 4 RTA) Pathogenesis Either decreased aldosterone secretion or aldosterone resistance l ENaC activity o L electronegative lumen -» 1 K excretion -» hyperkalemia NAGMA through multiple mechanisms mainly mediated by hyperkalemia 1. K enter the proximal tubular cells -» H exit the cells - intracellular alkalosis -» 1 NHL production from decreased gluuminase 2, Hyperkalemia 1 NHL medullary reabsorption in the thick ascending limb of Henle 3. In the collecting duct. K competes with NHL at the level of the NaK ATPase which leads to decrease the amount of intracellular H available for excretion In summary,the tubule has the opacity to secrete H.but the lack of the luminal buffer prevents excretion of higher load of acid Etiologies of H ypoaldostemnism Hypoaldosteronism. hyporeninemic Diabetic nephropathy. chronic interstitial nephritis. acute GN unSAIDs . Renin + Allinduced aldosterone release Calcineurin inhibitors (75% of transplant patients) Pseudohypoaldosteronism type 2 Hypoaldosteronism. hyperreninemic ACEi/ARBs. Direct rein inhibitor Heparin and LMWH: direct adrenal toxicity 1 adrenal insufficiency autoimmune. infection. HIV Congenital isolated hypoaldostemnismzdelect in aldosterone syndiase Resistance co aldosterone Mineraloconicdd receptor blocker spironohctone. ederesione Epithelial Na channel (ENaC) blocker:amiloride. triamterene. trimeihoprim. pentamidine lMineralocori:icoid receptor expression: calcineurin inhibitors Pseudohypoaldosteronism type 1 Pseudohypoaldosteronism type 1: mutation of mineraloconicoid receptor (AD form) or ENaC (AR form); resistance to aldosterone Pseudohypoaldosteronism type 2.Gordon syndrome, familial hyperkalemic hypertension Diagnosis Mild metabolic acidosis (HCO1 >17). hyperkalemia J Plasma renin aczivicy (PRA). plasma aldosterone concentration (PAC).and serum cortisol after the adminiscranion of a loop diuretic or 3 hr in :he upright position Treatment d/c offending drugs if possible Hypertensive: loop or thiazide diuretics Hypotensive: fludroconisone + high Sal: diet or isotonic fluid METABOLIC ALKALOSIS T pH caused by T [HCOJ]i frequently associated with hypokalemia P a t hoge ne s i s Normally :he kidney has a high capacity to excrete alkali load in de PT Metabolic alkalosis develops as a result of excessive alkali load and/or impaired renal excretion of HCOJ (et, effective hypovolemia) Vol ume depl eti on/ CHF/ ci r r hosi s * Sympatheti c l G FR TAI do 1 Type A imeroelated Proximal tubule: TNa/ H exchange V 1 y pe HATP a s e T N8/HCO3 cotransporl cells: Tv t y ps HATP a S 8 TReabsor pl l on of HCO3 Frindpal cells: T Na r eahsor pl i on (ENaC] -» Elaclronegative lumen TH secr eti on LFIIlgI8¢1 HCA: Mechanism of hypovolemiamediated maintenance of metabolic alkalosis. Hypokalemia is common occurrence due no several reasons: 1. Same pathogenic mechanisms contribute to both disturbances: primary or sec ondary hyperaldosteronism + high distal Na and water delivery 2. Metabolic alkalosis - T NaHCO; distal delivery (nonCl anion + high load of Na) -1 T K se cre tio n 3. Hypokalemia -» K exit and H enter the cell -» intracellular acidosis -»T NH; renal production, ¢ H secretion (T H/KATPase In type A intercalated) and T re a b so rp t io n o f HCO : 1 hyperaldosteronism T distal Na and water delivery + high Aldo -» T K and T H' secretion (distal tubule H/KATPase and HATPase in the typeA intercalated cells) Type B intercalated cells express increased luminal pendrin (HCO;/CI exchanger) with the net effects being secretion of HCO; and reabsorption of Cl The compensatory hypoventilation contributes co the maintenance of the metabolic alkalosis: hypoventilation -» T Pco, -» T intracellular acidosis -» T renal H excretion E t io lo g ie s Mos: of :he etiologies combine a process :hat directly or indirectly generated HCO; with a process of . renal HCO3 excretion to maintain the alkalosis E t io lo g le s o f Me t a b o lic A lka lo sls Etiologles That Help Maintain Metabolic Alkalosis Hypovolemia... arterial blood volume (heat failure or cirrhosis) Hypochloremia hypokalemia:T and ammoniagenesis AKI o r CKD. Hyp e ra ld o ste ro n ism Etiologies that Generate (Directly or Indirectly) HCO1 I n t ra c e l l u l a r H ' s h i f t Hypokalemia G I H lo ss NN NG T su ct io n Gastric H secretion is neutralized by die HCOi secreted by die pancreas. liver, and intesdilea the loss of H leads to HCC: a b so rp tio n Exogenous alkali Antacids in advanced renal failure Mg hydroxide. Ca carbonate (when combined widl SPS) Without SPS.the Mg and Ca vecombine with HCO; in do distal intestine and does not cause acidbase dismrlaance Vlhth SPS. Mg and Ca are chelated by SPS and the her outcome is absorption of HCO; Hypercalcemia. milk or Caalkali syndrome Bicarbonate therapy. citrate after blood transfusion. freebase or crack cocaine Renal H' loss: I distil Na and water delivery + T mineralocorticoid activity 1 hr./peraldosteronism: aldosr.eronesecnting adenoma: Bilateral/unilateral adrenal hyperplasia;familial hyperaldo Other Some diarrhea: villous adenoma. laxative abuse. congenial Contraction alkalosis (type I/glucocordcddremediable aldostercnism. type II and lll).adreno<ord¢al carcinoma 2 hyperaldosteronism: CHE cirrhosis + diuneucs Banter and Gittelman syndrome Pendred syndrome (CIIHCOJ exchanger mutation:AR) Posthyper¢apnic alkalosis chloridorrhea (mutation of the CIIHCO; exchanger -» high CI dionhea) Excessive chloriderich sweat in CF 1 Extracellular volume with a constant total amount of HCO, -» 1 [HCOx]. egearly phase of diuretics Clinical Manifestations Since HCO; moves slowly across the different body compartments. specifically :he brain. symptoms are uncommon in Me: alkalosis Muscular spasms. tetany. and paresthesia (due to 1 ice, L Mg) Etiologyrelated symptoms and signs (hypovolemia. CHE cirrhosis) Compensatory hypoventilation -» TpCOz Wo rku p J U61: help to assess volume ams UN.: nosy increase d/t biaarbonaturia Tre a tme n t Both :he generation and maintenance of HCO; should be corrected For vomiting and NGT suction, H;blockers and PPI L HCI loss Correct hypokalemia: K repletion may connect metabolic alkalosis. volume expansion w/o hypokalemia correction would not correct the metabolic alkalosis Correct hypovolemia. restoring the blood volume with a Clcontaining solution will correct the alkalosis and allows the kidney to excrete the excessive bicarbonate: type B intercalated tells express luminal CIIHCOJ exchanger allowing excretion of HCO3 after restoring euvolemia T Us is marker of resolution of the hypovolemiaz urine pH T to >7 dl: bicarbonaturia CHEF/cirrhosis (edema + low intraarterial blood volume): mineralocordcoid blockers (spironolactone and eplerenone) helps with d1 e metabolic alkalosis and comes :he hypervolemia; acetaxolamide (carbonic anhydrase inhibitor) can be added no :he diuretic regimen (inhibits proximal Na/HCO: reabsorption) Posthypercapnic metabolic alkalosis if nonedematous. volume expansion with Clcontaining solutions (0.9% NS) will correct the alkalosis; If edematous (requires additional diuresis). acetazolamide treats acidosis and corrects the hypervolemia Dialysis will correct :he alkalosis in ESRD or severe AKI HCI (only given through a central line) or NH4Cl is only used in patient with severe alkalosis (pH >7.55) in whom dialysis cannot be done Calculation of the HCO; excess HCO; excess = 0.6 x LBW x ([HCO)] - 24) for men HCO; excess = 0.5 x LBW x ([HCO1] - 24) for women When infusing acid frequent assessment of pH and BMP should be done /Urine CI 1 r 1 <20 mEq/L >20 mEq/L Recent diuretic therapy Vomiting, NGT suclion Posthypercapnea CI depletion (Villous adenoma, laxative. sweating in CF, chloridorrhea) HTN Ongoing diuretics Barter Gitelman hypukalemia (<2) Hypomagnesemia /Serum renin 1 /Serum aldo Ongoing diuretic RAS Fleninsecreting tumor Mal ig rant HTN Cushing syndrome EXQQGFIOUS oorlicosleroid 17hydroxylase detidency Liddle syndrome Chronic licorice Adrenal adenoma Adrenal hyperplasia Adrenal carcinoma GRA Familial hyperaldo Diagnostic approach for me: alkalosis. RESPIRATORY ALKALOSIS Ba c k gr ound Hypervenmilazion (T minute ventilation on vent) -» 1 CO ; - t pH The renal compensation for acute respiratory alkalosis (1-2 d) is 1 HCO3 by 2 mEq/L for every l pCO; by 10 mmHg.for chronic respiratory alkalosis (>3-5 d) is l HCO; by 4 -5 mE q/ L for L pCO z by 1 0 mmHg P a thoge ne s i s t Minute ventilation is sec to T depth and/or race of ventilation Some of the symptoms (et. tuscany. muscle cramps) are due to changes in the binding of Ca to alb: resp alkalosis Te a a l b bi ndi ng 1 ionized Ca Within 10 min, H is released from body boilers (intracellular protein. Hb.and phosphate). In addition. T lactate levels possible from hypoxia from peripheral vasoconsuicticn. Renal compensation takes 2-3 d and includes 1 NHL and T HCO; excretion E ti ol ogi e s Hypoxemia (, pOz -> T minute ventilation): pneumonia. interstitial lung disease. pulmonary emboli. CHE hypotension, severe anemia, high altitude Simulation of the resp centers: psychogenic (eg.anxiety). liver cirrhosis. salicylate intoxication. postcorrection of mer acidosis. pregnancy. stroke. CNS tumor Mechanical ventilation Clinical Manifestations Paresthesias.headache. lightheadedness. due to local and cerebral vasoconstriction (1 PCO: -» lceiebral blood flow):Tetany and carpopedal spasm due to lionized zzlcium Pts are only intermittently aware of hyperventilation (SOB. air hunger), SOB is as rest with frequent sigh (normal 0-3/15 min) exacerbated by anxiety L P04 through Intracellular consumption (intracellular alkalosis -» T giycolysis -> T for mation of phosphorylated compounds), [Phos] as low as 0.5 mg/dL have been reported. severe hypoPhos causes muscle weakness and respiratory muscle weakness Treatment Treat the underlying pulmonary or excrapulmonary etiology (PE.AMI, etc.) For anxiety pos: reassurance. benzodiazepine, and breathing into a paper bag leads to improvement of pCO; levels and pH RESPIRATORY ACIDOSIS 2 4 Background g ; pH and t pcoz: CON is formed through endogenous metabolism and accumulated § when alveolar ventilation is 1 (hypoventilation); CO; + H;O 14 H;CO; H H + HCO; 5 CON is eliminated by alveolar ventilatiomstimuli are 1 P02 and t pCO; o n. Pathogenesis In physiologic conditions, t CON is the major stimulus of the respiratory center In chronic hypercapnia. 1 Oz becomes the major respiratory stimulus;Treat.ment of the hypoxemia in chronic hypercapnic pts can lead to T CO; and 1 pH Renal compensation: T H excretion and retention of HCO; and takes 3-5 d Etiologies Inhibition of the CNS respiratory center: medications (opiates, benzodiazepine. seda tives. anesthesia): obesity hypoventilatiori syndrome: CNS lesion oxygen therapy for chronic hypercapnia; metabolic alkalosis Chest wall and respiratory muscle defect: myasthenia gravis. Guillain-Barré. severe 1 K. severe 1 PO.. spinal cord iniury.ALS. MS. myxedema, kyphoscoliosis,obesity Upper airway obstruction: OSA. foreign body aspiration. laryngospasm Lower airways disease: COPD. asthma. pneumonia.ARDS. pneumothorax T CO; production (associated with impaired alveolar ventilation): fever. thyrotoxicosis. sepsis.steroid.overfeeding. exercise and metabolic acidosis Clinical Manifestations Depeiding on the baseline CO1 (symptomatic at higher PC02 for chronic hypaupnic pts) CNS: level d consciousness (at advanced stages it 1 respiratory drive -> CO; retention). T cerebral blood flow and ICP Cardiac 1 myocardial and diaphragmatic contractility, cardiac instability, and arrhythmia • Hyperkalemia due to respiratory acidosis is mild Treatment Treat the underlying etiology: Mechanical venrilacion if indicated POTASSIUM PoTAssium REGULATION Transcellular Shift 98% of K is intracellular Balance of K between intracellular and extracellular fluid depend on: 1. NaKATPase pumps 3Na out and 2K into the cell: t acUvity by catecholamines. insulin. thyroid hormone;1 by digitalis 2. Catecholamine: B;receptors T :areceptors 1 K cellular entry 3. Insulin: T K entry into the liver and skeletal muscle 4. K load passive K entry into the cell air high K load 5. Extracellular pH: metabolic acidosis T K exit (uncommon with organic acidemia) 6. Hyperosmolarityf plasma [K] T by 0.0.8 for every t 10 of P... (hyperglycemia, hypernatremia. mannitol): solvent drag 7. Exercise: through skeletal muscle ATPdependent K channels Ncrmokalemix exercise -».l, ATP -u Open K channels » lnal T K -»Vasodilation Determinants of Renal Potassium Excretion Aldosterone: T secretion in the principal cells by T de number of ENaC allowing Na absorption creating an electronegative lumen favorable for K secretion through ROMK and BK channels (stimulus for T aldosterone includes K and hypovolemia) Plasma [K]: T K secretion (independent from aldosterone) Dismal Gow T distal flow -» t K secretion; GFR Tubular Potassium Handling Proximal Tubule Loop of Henle Distal convoluted tubule Passive reabsorption paracellular NKCC Basolaceral NaIKATPase - 1 intracellular Na Na entry via NCC -» Electroneuual K into tubular lumen via ROMK Basolareral NaIKATPase -» T Intracellular K -» K secretion via ROMK HIK ATPase (H secretion and K reabsorption) 2Passive Bothaccount for >90% dtime lllnered K is iuhsorbed K secretion Initial and outer medullary CD Principal cells: K secretion nintercalated cells: K reabsorption Inner medullary CD K secretion K secretion in the distal tubules is dependent on Na' reabsorption from the lumen into the peritubular capillary creating a negative charged lumen that potentiates K secretion; this potential is continuously dissipated by :he paracellular absorption of Cl.T his mechanism explains the hypokalemia in pathologic conditions where Na is reaching the distal tubule with an anion other than CI (eg. RTA type 2, carbenicillin induced or tolueneinduced hypokalemia) lAldosterone IENaC activity in the principal cell Hypokalemia coneclion K depletion K load LK secretion ilntraoellular K in TAe1ivity of Hn<+ the intercalated cell ATpase e TAldos1erone tna/KATpase and ENaC aclivi\y TK cellular entry TK raahsorption TK secretion Hyperkalemia correction TColonic secretion HYPERKALEHIA Pathogenesis Potassium adaptation: the efficiency in handling a K load is enhanced if preadapred by a previous K load (the initial smaller load t NaKATPase activity and the density of luminal K channels making the kidney more adapt no handle a higher load) Chronic high K intake is unlikely m cause hyperkalemia unless associated with another K balance defect (impaired secretion or cellular entry) Etlologles of Hypedralemla Increased Cell Release Pseudohyperkzlemia Blood draw technique (hard venipunccure. repeated fast clenching, Light tourniquet) Long specimen storage Thrombocytosis (T by 0.15l 100K pks): /K in a heparinized plasma; nonclotted specimen Leukocytosis (WBC >120K) in CLL; 9 K in plasma and serum: /K in the serum of cloned specimen before centrifugation Hereditary RBC fragility (et. stomatocytosis) Red cell breakdown NAGMA Hyperosmolaricy Insulin deficiency Respiratory acidosis Tissue catabolism Exercise Medications Transfusion of old PRBC; Intravascular hemolysis H enter :he cell and K exit 0.acti< and kexoacid enter the cell widi H md do not fuse t K) Solvent drag (eg. hyperglycemia, sucrose after lVIG. radiocontrast) et, Fasting in ESRD patients Mild effect TLS. Rhabdomyolysis Level of t K depends on the intensity and physical conditioning 82blockers; not wick selective B1 blockers Digitalis overdose (inhibition of NaKATPase) Succinylcholine.aminocaproic acid (K exit the cell) CNI. diazoxide. minoxidil ( ATPdep K channels) Decreased Renal Excretion Hyporeninemic hypoaldosteronism (DN: CNI) l Aldosterone secretion ACEIs.ARBs.and direct renin inhibitors Impaired aldosterone synthesis: chrunk heparii therapy. Primary adruW insufficiency. Severe illness, Inherited disorders (21 hydroucylase deficiency and isolated hypcaldostewnism) i Response to aldosl.erone Minealocordcdd receptor antagonists spiionolacwne,eplaencne ENaC blockers: amiloride. triamterene. trimethoprim. pentamidine Pseudohypoaldosteronism type 1 (AR mutation of the ENaC or AD mutation of the mineralocorticoid receptor) Acquired or congenital defects in Na reabsorpzion by the distal tubule principal cells (voltage RTA): obstructive uropalhy.SLE. renal amyloidosis. and sickle cell disease Progesterone antagonize aldosterone. Pregnancy improves l K. HTN. and metabolic alkalosis in primary aldoszeronism. 1 Dismal Na and water delivery Urererojeiunoslomy CKD and AKI aka Gordon syndrome Drospinenone 3 mg spironolaccone 25 mg Volume depletion CHE cirrhosis Urinary K absorption in die jejunum Pseudohypoaldosnercnism type 2: muracions causing T NCC » Metabolic acidosis. HTN, . K excretion Workup rlo pseudohyperkalemia; review of die history. med: volume status and renal function Transtubular K gradient (TTKG). (UKIPK) + (U°,,../Pm.) is used to evaluate renal K excretion corrected for the movement of water.The presence of urea recycling in the inner medullary segments of the collecting tubules affects U..." and TTKG is not a valid formula to assess renal K excretion (fun of nepal Hwewens z011=201s4n Urinary potassium has limited diagnostic value since it correlates with K Intake 24hr urine K >40 mEqld. spot KlCr ratio >200 mEqlg.TTKG >11 -o e cell release 24hr urine K <30 mEq/d. spot KlCr ratio <20 mEqlg.7TKG <7 -» renal excretion ECG abnormalitieszarrhythmias with K >7 or very rapid rise (sinus bradycardia.sinus arrest. slow idioventricular rhythms,V1zVE and asystole) Tall peaked T wave with a shortened QT interval - t PR interval and QRS duration -» QRS widens to a sine wave Treatment Assess for emergency: (1) muscle weaknesslparaiysis; (2) cardiac arrhythmialconduccion abnormalities; (3) K >5.S with ongoing TLSlrhabdomyolysis: (4) K >6.5 In emergent case. treat with IV Ca. IV insulin + glucose and SBA K removal (diuretics. cation exchangers +I- dialysis if refractory); EKG monitoring: K check Q 1-2 hr Treat the underlying etiology of hyperkalemia Avoid long fasting period for ESRD pos (oral intake t insulin which i K) Therapy of Hyperkalemia Stabilization of the Membrane IV calcium Works within miruaction lasts up to 1 hr Ca gluconate 3 amp (3 g. 10% 30 mL. 14 mEq Ca) via peripheral line or CaCl; 1 amp (1 g. 10% 10 mL 13.6 mEq Ca) via central line over 2-3 min Avoid In digitalis toxicity Drive Extracellular Potassium into the Cells Insulin Bolus 5-10 units of insulin R + 50 mL of 50% dextrose glucose Effect smrrs in 10-20 min. peaks at 3060 min. lasts for 4-6 hr K drops 0.5-1.2 mEq/L Lowers the serum potassium concentration by 0.5-1.5 mEq/L Albuterol 10-20 mg nebulizerz peak effect in 90 min Used as adjuvant to insulin + glucose Sodium Beneficial mainly in metabolic acidosis in acute Kzand in chronic . K bicarbonate in CKD 150 mEq in 1 L of 5% dextrose in water Removal of Potassium from the Body Diuretics Can be used for MM acute and chronic hyperkalemia Dosage depends on the renal function GI cations Patiromer (NEW201§.]72.211) exchangers 8,4-25.2 g qd: give 3-6 hr after or before other po meds Exchanges K for Ca in :he colon sle: constipation. Mg Sodium zirconium cyclosillcaze lns}m zo1s=m:ml Sodium polystyrene sulfonate (SPS) 15-60 g single dose po (4I- sorbitol):50 g enema (without sorbitol) Avoid in postop, ileus or bowel obstruction (s/ez intestinal necrosis) Dialysis HD is more efficacious in K removal than PD CRRT can be used subsequently in patients widl ongoing K release Dialysaie K <2 a/w sudden cardiac arrest (KA 1011591181 Rebound K: K shift to serum after HD. More pronounced after albuterol. insulin and high Na dialysate I/ASN za00:11:znn. postHD .K should not be corrected unless clinically indicated HYPOKALEMIA Pathogenesis Decreased intake Is rarely a cause of hypokalania since renal excretion can be lowered to S mEq/d; Main hypokalemia etiologies are cell entry and renal excretion If lab processing is delayed. pseudohypokalemia occurs in AML (WBC consume K) Etiologies of Hypokalemia Increased Cell Entry Insulin mediated Exogenous insulin in DKA zherapyz refeeding syndrome l32adrenegic mediated Endogenous carecholaminesc alcohol withdrawal. acute myocardial infarction. head injury and xheophylline imoxicazion Exogenous agonists: albuzeroI. zerbuzaline. doburamine. pseudoephedrine.and ephedrine Metabolic or respiratory alkalosis K by <0.4 for every T pH by 0.1 Hypokalemia maintains :he metabolic alkalosis (T HCO1 reabsorpuion) Hypokalemic periodic inherited AD or acquired in hyperthyroidism Sudden entry of K into :he cell leading to paralysis and resp failure J, K (1.5-2.5 mEqIL) precipitated by exercise,high CHO mal Risk of rebound hyperkalemia after therapy paralysis T Blood cell pmducdon Viz B 17 or folic acid therapy in meplobWdc anemia GMCSF treatment of neutropenia O Men Hypothermia. antipsychotic drugs intoxication: chloroquine. Barium (blocks K channels). Cesium Incr eased G astr ointestinal Loss Dianrhea.villous adenoma Lower intestinal losses are high in K Acute colonic pseudoobstruction (Ogilvie syndrome) have high K in the colon lumen due no activation of colonic K secretion White clay binds K in the GI mc: (red clay is high in K and tK) Geophagia Incr eased Ur inar y Loss Vomiting, NGT drainage Gastric secretions are low in K Metabolic alkalosis .i HCO3 Eltmion -» T distal i1 ow -r urinary K loss T Mineralocorticoid activity Diuretics. 1 hyperaldo. renin secreting tumor. RMS Chronic licorice ingestion: inhibition of the 11Bhydroxysteroid dehydrogenase2 (11BHSD2) Apparent mineraloconicoid excess (ruction of 11[3HSD2) T Dial delivery of Na and water 1 polydipsia. diuretics therapy primary hyperaldo. Loss of gastric secretions RTA type 2 (bicarbonate). DKA (B hydroxybutyrate). toluene use (hippurate) and penicillin derivative Lowcalories diet (ketogenesis induces * urinary K loss) Nonreabsorbable anions Others Polyunia. RTA type 1 Hypomagnesemia: K renal loss with open ROMK channels of the DCT Amphotericin B: T K membrane permeability Saltwasting nephropathies: Bartter, Gittelman, reflux nephropathy. SiOgren Liddle: gain of function mutation of ENaC Sweat losses (cystic fibrosis) Dialysis, plasmapheresis 11l\HSD2 Cortisone Conisol Agonist O1 Chronic licorice ingestion mineraloconieoid receptor Apparent mineralocomooid excess No mineralocon\oold acclivity HTN, L K. metabolic alkalosis l renin, 1 aldo Mechanism of AME and chronic licorice ingestion. Wor k up Assessment of acid-base status. Mg level Urine K >30 mEqld. spot K/Cr >13 mEq/g.TTKG >7 -v renal loss Urine K <25 mEq/d. spot KlCr <13 mEq/g.TTKG <3 -» extrarenal loss or cellular entry Cl i ni c a l Ma ni fe s ta ti ons De pe nde nt on the de gre e a nd dura tion of hy pok a le mia Severe weakness. muscle cramps. and rhabdomyolysis (K <2.5): Resp failure. illus Cardiac arrhythmia: PACS, PVCs. sinus bradycardia. paroxysmal atrial or junctional uchycardia.AVB,VI1VF.Torsade de poinne if l K is alw J, Mg Depression of ST segment. L amplitude of theT wave. and T amplitude of U waves Risk for ardvythmia T in elderly pts. organic heart disease. or concomitant digoxin Can precipitate hepatic encephalopathy in cirrhotic patients Effects of Hypokalemia on Kidney Nephrogenic DI: impaired urinary concentrating ability dlt (1) the resistance to ADH is due to L expression of aquaporin2 In the collecting tubules: (2) AWvit y o f N a KZ C I cotransporter of the thick ascending loop of Henle leading to defect of the interstitial corticomedullary gradient the driving force for free water reabsorpdon Electrolytes imbalances: T HCOJ reabsorption (maintenance of metabolic alkalosis). t Na reabsorptiorl (hypertension) Hypokalemic nephropathy: reversible proximal lobule vacuolar lesions develop after 1 mo of hypokalemia. more prolonged hypokalemia (et, eating disorders, laxa tive or diuretics abuse) leads to chronic irreversible interstitial changes with tubular atrophy (more pronounced in the medulla) The patient can still maintain the ability to conserve K Hypokalemia Cellular exchange: exit of K/entry of H Intracellular acidosis Cyst formation Complement activation Tubular damage T T G F B, MCP1. IG BP1 Interstitial fibrosis tNH3 production Mechanism of hypokalemic nephropathy. T r eatment Repletion of K should be cautious in hypokalemia dl: entry of K into the cell: risk of rebound hyperkalemia in hypokalemic periodic paralysis and drymtoxic periods paralysis Hypomagnesemia should be corrected to avoid continuous renal wasting Bblockers (nonselective) is helpful in hypokalemic thyrotoxic periodic paralysis Estimation of K deficit: 200400 mEq total K deficit l [K] by 1 mErelL The total deficit of K needs to be adjusted widi the associated metabolic disorder in DKA. correction of the hyperosmolarity and the insulin deficiency will drive additional K inside the cell. K supplementation should occur for K <4.5;in diarrhea associated NAGMA. the total K requirement need to be adjusted up since the correction of the acidosis will drive K intracellularly Krich food is less effective since it is under the form of K citrate and K phos which have only a 40% retention For chronic hypokalemia from loop diuretic therapy. Ksparing diuretics could be considered as chronic therapy Rarely or citrate (RTA, diarrhea). K acetate. K phos (Fanconi Sd) are used Potassium Supplement KCI IV Should be given in dextrosefree solution to avoid K entry inside the cell Rare 10-20 mEq/hr (max 40 mEq/hr); max IV concentration is 60 mEqIL High concentration is a/w pain and phlebitis KCI PO Solid formulation is preferred; good bioavailability Extended release formulations may result in a ghost tablet in the stool sle: pillinduced esophagitis from osmotic injury Liquid form: 15 mL 10% (1.5 E) 20 mEq KCI In nephrolithiasis, dRTA with hypocitraturia K citrate KHCO: K phosphate Salt substitutes Used in Fanconi syndrome 1 s(= 1/6 teaspoon) contains 10-13 mEq KCI (JAMA 1977;23e;ws) SODIUM AND WATER Determinants of Serum Sodium Concentration (Sn-) Plasma sodium concentration (PN.): a measure of total body solute concentration. does not conflate with extracellular volume: it does reflect the total body sodium to water min. a surrogate for osmolality of the extracellular compartment Pn, = (total body exdungeable Na + :cial body exchangeable K)/total body water (TBW) Serum sodium concentration (S~.):a reflection of water balance Conversely. alteration of sodium balance (high or low intake of salt) leads to changes In extracellular volume Urine sodium (U~.): correlates with the extracellular volume (hypovolemia -» .L UN,) Dehydration (water loss -» T [Na]) at volume depletion P.,,,.and by consequence PN.. is regulated by ADH secretion and thirst Waler loss: sensible (sweat) insensible (thermoregulation) Water load (drinking water) TPm s. TSn. Hypothalamic osmoregulalors Hypothalamic osmoregulaiors 1 lADH secretion iThirsl TThirsl nU»sm Ccncamrated urine Feedback mechanism to maintain P... and [Na]. HY P O NATRE MI A Ba ckg r o u n d Definition: [Na] <136 Usually due zo 1 water excretion and rarely solely from t free water intake Classification Mild (130-135); moderate (125-130): severe/profound (<125) Acute ( <24 hi) ;chr onic ( >48 hr ) Symptomatic: asymptomatic Hypotonic: pseudohyponacremia (or isotonic): hypertonic Hypovolemic: euvolemic: hypervolemic C lin ica l M a n if e st a t io n s Water movement into the brain leading to brain edema acutely Related to the degree and the rapidity of establishment of the hyponatremia Symptoms in acute hyponatremia can be nonspecific like malaise. nausea progressing to headache. lethargy. gait imbalance and In extreme cases seizures and coma Chronic hyponatremia <130 is associated with subtle neurologic symptoms leading to fall. general malaise. and decrease attention span Severe acute hyponatremia can rarely lead to brain edema-induced brain herniation especially in premenopausal women and young children gzip Correction of PM & SNs nu.,,,,. Diluted urine TADH secretion Wonxur OF HYPONATREMIA (;ASN 2017;28:13401 Stepl: Differentiate Hypotonic from Nonhypotonic Hyponatremia Measure P.,,m to rule out nonhypotonic hyponatremia Calculated Pm = 2 x [Na] + [Glucose]/18 + BUN/2.8 (normal: 275-290 mOsmoI/Kg) Measured Pm (done in the lab) reflects the total of all osmolytes in plasma Hypertonic hyponauemia: osmotically active compounds (eg, glucose, mannitol. alcohols) drawing water our of cells Isotonic hyponatremia: waterinsoluble substances (eg. protein and lipid) may interfere with the measurement of sodium.The osmolar gap (MeasuredCalculate Pm) is helpful in these circumstances: a difference of more than 10 is in favor of an additional osmolar substance Treatment of nonhypotonic hyponatremia is centered around the underlying etiology, et. hyperglycemia where indicated Step Z: U.,,m and GFR to Assess the Role of the Kidney Um is expected to decrease in response to hyponatremia. If lvypotonic hyponatremia coexist with low U°.,,. (<100). this can be explained by: 1. 1 polydipsia (usually >12 L): overwhelming the excretion of dilute urine 2. Low dietary solute nuke (eg. malnutrition, alcoholism) :he low total solute excretion limits :he amount of maximal daily urinary water excretion due to reduce delivery of fluid in the diluting segment and creates an environment where even a mild increase of hypotonic intake leads to hyponatremia Step 3:Volume Status Assessment for Patient with High Up" (>100) and Un, U.... >100 in a hyponatremia (elevated ADH levels): true hypovolemia.effective hypo volemia. SIADH, hypothyroidism. and Addison disease lt is sometimes difficult w differentiate clinically hypovolemic hyponatremla from euvolemic hyponatremia (sensitivity and specificity = 50%) (Ami M 44 1995;99:34si Una <30 can be used as a supplement to assess volemia (using a cutoff of 30) Un, diagnostic value is limited in CKD. recent diuretics use.dietary Na restriction . [Na] with isotonic saline infusion trial is favor of hypovolemic hyponatremia (in SIADH with U°,,,. <500. [Na] improves with isotonic saline infusion) Since ADH is a uricosuric hormone.fraction of excretion of uric acid (FE) is a helpful diagnostic tool: FEud >12% is sensitive and specific for SIADH Hypsnonlc I P I 3 $ M3 osmolality Hyperglycemia Mannitol Malloselsucrose MG J u..... u,l,,, <1 0 0 : Low ADH umzlm Un: <30 + hypovolemia Diarrhea vomiting 3° spacing Remote diuretics Una <30 + hy pe wole mia CHF Liver cirrhosis NS /volume assessment and UN.: it recent diuretic or CKD, Una is unreliable and consider etiology based on volume status only Primary polydipsia Low dietary solute intake Advanced renal failure Beer potomania U* 2 3 0 4 hypovolemla Vomiting I adrenal insufficiency Renal salt wasting Cerebral salt wasting Una 230 * euvolsmia SIADH 2 adrenal insufficiency Hypothyroidism Diagnostic approach for hyponamemia based on Pm. Um. Un.. and volume situs. TREATMENT OF HYFONATREMIA noT Z014;Z9i1: Am; mia Z01J; 126:S1) When hypokalemia is concomitant with hyponatremla. the correction of hypokalemia may contribute to the correction of the hyponatremia (the replecion of K helps restore plasma osmolarity by t coral body osmoles) • For acute or severely symptomatic hyponatremia, a bolus of hypertonic saline 3% (100 mL over 10 min x3 as needed to relieve symptoms or the [Na] increases by 6) In hypovolemic hyponatremia, patients will start autocorrecting as soon and the vol ume Is expanded, to avoid rapid correction, it is recommended to combine volume expansion with desmopressin a The limit for correction is 8 mmollUd; Hypotonic fluids and/or DDAVP can be used to relower [Na] if overcorrection occurs Restrict fluid intake (both PO and Iv) to 500 mud below the 24hr urine volume in low Um. hypervolemic hyponatremia and Syndrome of Inappropriate Anddluresis (SIAD) If Um >300-500, consider lurosemide to lower U.,,,,. Urea: induces osmotic diuresis free water excretion. used as second line co fluid restriction; safe and effective (qASN 101B;13:lb17); Even if overcorrection occurs with urea, the risk of ODS and demyelinauon lesions is less Salt tablets increase urine solute load: Usual doses for NaCl tablets are 6-9 g daily ADH Antagonist (Vaptans) (NEW 2015:3711107) Block V2receptors in collecting duct principal cells aquaresis Tolvaptzn (PO): start with 15 mg qd; up to 60 mg. 30 days Conivapan (N): sun with 20 mg over 30 min dlai 20 mgf24 hr: up to 40 rng/24 hl;4 phys NOT indicated in the treaunent of acute or severely symptomatic hyponatremia s/e: overcorrection. liver toxicity On initiation. fluid restriction should be stopped and patient should be allowed access to free water intake to avoid overcorrection; if the target Na is no: achieved after 24 hr of vaptan initiation.fluid restriction will be resumed Treat:lnent of Hyponatremla Conrecdon limit Correction rate Overcorrection Treatment of ODS Severe symptomatic hyponatremia SIAD Hypoyolemic hyponatremla Hypervolemic hyponatremla 8-10 mEqlU24 hr 46 mEdU24 hr Hypotonic solution DDAVP 2-4 us IV Hypotonic solution DDAVP 2-4 pg IV NaCl 3% (100 mL over 10 min) x3 as needed 1" line address :he stimulus of ADH secretion + Fluid restriction 2" line: urea. salt tablets 3' line: lithium. demeclocycline Isotonic volume expansion 1" line:f1uid restriction 2' line: vaptan" or hypertonic saline loop diuretics Only if baseline <120 mErelL Lower [no] by 16 sEq/L Symptoms improve or Na by 6 mErelL Fluid restriction calculation (Un. + Ui()1Sn. >1 - <S00 mud =1 - 500-700 mud <1 -» <1 Ud DDAVP concomitant in patients with high risk of ODS (hypokalemic. alcoholic. malnurridon) 4-8 ug N q6sh High risk of overcorrection with Vapzan 'Ri sk of nonnspcnder s Ur l 2130 mmol / L: Um 2500 mOsml l g: UOP <1. S00 mud 'AvoidVapnn in patients widl liver disease Hy pona tr e m i a For m ul a s Effective Pa, = 2 X [Na] + [glucose]/18; (normal value: 270-285 mOsmol/kg) Since Na and K is the main extracellular and intracellular solutes. respectively: P la s ma [Na ] = (r.ota I body Na 4 tota l body K)/TBW This formula explain why correcting hypokalemia could improve hyponatremia Plasma volume: 93% aqueous (water). 7% nonaqueous (fat and protein) Physlologic [Na] = reported [Na]l0.93 (eg. 143/0,93 = 154 [Na] in 0.9% isotonic saline fluid) Brain Ad ap t at io n t o Hyp o n at rem la Hyponatremia and l Pm -a water flow across the blood-brain barrier -» T ICP -> loss of Na and water into the CSF -» improving ICP within min (acute adaptation) Chronic adaptation srarcs within hours through intracellular K loss (cell swelling sensitive cationic channels) followed by loss of brain organic osmolytes (glutamine. glutamate. Maurine, and myoinositol) that needs up to 72 hr to be complete Loss of Na and water into me CSF Min T ICP and Brain edema Water "OW aaoss the BBB First few hr Loss of intracellular K Within 24 hr and upto 48-72 hr Depletion of brain organic osmoles Brain adapmrion to hyponatremia. The rate of correction of hyponauemia is important whenever the brain has adapted | to hypomonicity (after 48-72 hr of established hyponarremia) Osmotic Demyelination Syndrome (ODS) alw rapid convection of hyponalremia (>8 mEq/L in 24 hr: >16 mEaL in 48 hr) The hourly rare is not a risk factor of ODS unless the daily rate threshold is exceeded Prevention: target a rate of correction of 4-6 mEqlUd in chronic"asymp:omaLk" hyponauemia Ris k Fa c tors for ODS Admission plasma Na ¢ [Na] $120 mEq/L (mainly for $105 mErelL) . [Na] >120 posdiver uansplanz or CDI alter doAvp discontinuation Therapy Hypersonic saline Vasopressin anngoniss . Hypovolemic hyponanremia :razed with volume expansion Adrenal insufficiency creamed with glucocorticoids Holding DDAVP in overtreated Central Dl:Holding diiazide diuretics AucocorrecUon following therapy (rapid renal free water loss) Patient related ESRD on HD » Alcoholism: malnutrition; liver disease: pregnancy . Hypokalemia In hyponatremic ESRD. during dialysis,the rapid T Pm induced by the correction of hyponatremia is counterbalanced by HDinduced L of potassium. uremic toxins including urea (urea does not cross the BBB as fast as water and act as an effective os mole re la tiv e to the bra in c ompa rtme nt) Chrome hyponalremia Rapid hyponatremia correction Normal size Drain depleted from organic osmolytes lB ra ln vo lu me ODS Mechanism of osmotic demyelination syndrome (ODS), Clinical manifestation are delayed (2-6 d), irreversible. or partially reversible: dysarxhria. dysphagia.paraparesis. quadriparesis.and locked in Sd: behavioral disturbances. tremors. araronia and seizures, led1argy.confusion.disorieruaLion.obmndadon.and coma MRI could show Me demyelinacion lesions (delayed finding up w 4 wk) which can allen a n y p a r: o f :h e b ra in a n d sp in a l co rd S o me p ro p o se d p re ve n tive me a su re s: In pus likely to overcorrec: (hypovolemic hyponauemia): DDAVP (1-2 pg IV or SC q6-8h) is given at the sur: of onset volume expansion (NS or hypertonic saline) In pts on therapy where the goal is likely no be exceeded or overcorrected -» sup t h e ra p y + DS W (6 n Uk e ) o r d DA V P Relowefing [Na] to die daily correction limit of 8 mEq/L an l the severity of ODS and even air the onset of neurologic, it is recommended to reiower [Na] by 16 mErelL For patient with baseline [Na] 2120. it is probably unnecessary to relower Na in case of overcorrection. slowing the correction rate is enough in these cases SPECIFIC ETIOLOGIES OF HYPONATREHIA Diureticsinduced Hyponatremia More common with thiazides than loop diuretics because loop diuretics plevent the generation of a conicomedullary interstitial osmotic gradient which limits :he ability of the collecting tubule to reabsorb flee water even it ADH is elevated Thiazideinduced hyponatremia is due to several mechanisms: (1) reduction in diluting function of the distal tubule: (2) an underlying tendency to increased water intake (polydipsia): (3) impaired ureamediated water excretion Hypervolemic Hyponatremia Hyponatremia is an important prognostic factor in CHF and cirrhosis Syndrome of Inappropriate Antidiuresis (SIAD) (NUM 29074$52064) Desalination: since volume expansion does not affect Umm in SIAD. an expansion with isotonic solution results in a net electrolytefree water gain in patients with SIAD (especially if Up, >500) leading to worsening of the hyponatremia Etidogies: drugs. cancer (small cell lung cancer). pulmonary disorders. CNS disorders. hereditary nephrogaiic SIAD (GOF rotation dv2 ieceptontreated with urea; vaptan are ineffective therapy), idiopathic and transient (nausea, pain.anesthesia) Copeptin is produced during the cleavage of die vasopressin prohormone, it can be used as an indirect measurement tool for vasopressin levels Um is an indirect measurement for the ADH concentration. using copeptln in hypo nauemia is o( limited utility (beyond distinguishing primary polydipsia from d1 e other etiologies of hyponauemia) (Endocrine 201a:w.aa4) SIAD has 5 subtypes Type A: vasopressinlcopeptin secretion Is no: related to So: erratic ADH secretion Type B: relationship between So. and Vasopressinlcopeptin is intact but lower threshold (reset osmosis) Type C:vasopressin/copeptin secretion is not related to So.: COHSGUI ADH secretion Type D undetectable vasopressin/copeptin (nephrogenic SIAD) Type E: reverse relationship between So and copeptinlvasopressin (barostat reset) due to increased sensitivity of baroreceptors to increased vasopressin release Cerebral (or Renal) Salt Wasting The same lab profile as SlAD (hyporuuemia. concentmed urine, high Un.. hypouricemia. and t FEud >1176). The FEud does not decrease after coneciion of the hypomuemia: stays >11%;in SLAD the FE,iAde4:iases to less than 11%with the correction of the hypo natieinia (An I Med so 10168528851 Adrenal insufficiency Cortisol deficiency disrupts die negative feedback loop that inhibits ADH release.The increase of conicotropinreleasing hormone production in response to consol defi ciency promotes hypothalamic ADH release leading to hyponatremia (PNAS z000s7.4e 11 Acute Hyponatremia Etiologies always involve a high free water make with additional pathogenesis: postop. exercise. the use of 3.4merhylenedioxymethampheramine (P1DPlA.Ecstasy"). haloper idol. thiazide diuretics, desmopressin. oxytocin.TURPlhysterectomy irritants (glycine. sorbitol, mannitol. and IV cyclophosphamide) Glycine and sorbitol cause cerebral edema: mannitol does not cause cerebral edema (hypertonic hyponatremia) MDMA T ADH release and free water intake in an effort to prevent hyperthermia Hypertonic saline 3% is an effective and lifesaving for hyponatremiainduced cerebral edema Mild Chronic Hyponatremia (qA§N zoisnmzzssi Asymptomatic, >72 hr and [Na] between 125 and 135 mErelL Hyponatremia is alw higher mortality and morbidities in outpatient. inpatient. and ICU settings (neurocognitive deficits, gait disturbances. falls. bone fractures. osteopo rosis) It is not clear if correction of hyponatremia improves outcomes HY P E RNATRE MI A P a thoge ne s i s Thirst reflex tend to correct hypernauemia/hypertonicity for patients with access to free water. For hypernatremia to occur. in addition to the free water loss, the patient has to lose access to free water (eg.AMS. infants, loss of thirst) Etiologies For the etiologies of hypernatremia. :he pathogenesis is a combination of electrolyte free water loss combined with impaired thirst or limited access to free water Nor all fluid loss will induce hypematremia.the Na + K content in the fluid should be lower than the plasma [Na] to induced a net fluid loss and T plasma [Na] Secretory diarrhea: Na + K loss in the stools = plasma [Na] -» no effect on [Na] Osmotk diarrhea. lactulosenomidng, osmotic diuresis. sweating: Na + K loss < plasma [Na] -» T plasma [Na] Hyperglycemia and mannitol therapy initially lead to hyponatremia from to.,. and T water exit from the cells -» Osmotic diuresis -» free water loss and hypernatremia Etiologies of Hypematremia Unreplaced Water Loss Skin Insensible (cransepidermal loss) Sensible: swear (swear is hypotonic to plasma) Vomiting. NGT suction Nonsecnetory diarrhea Urinary Central and nephrogenic DI Osmotic diuresis Decreased Water Intake 1° hypodipsia Defect in thirst; patten: should be encouraged to t water intake Adipsic DI Congenital and acquired CNS lesions Mild volume expansion -» suppression ofADH Treatment by adjusting water nuke based on body weigh: Reset Primary mineralocorticoid excess Osmostat Mild hypernatnemia (high 140s) Water Loss into Cells GI Severe exercise, seizure (uansienr hyperNa for 5-15 min) Na Overload Intake or administration of hypertonic sodium solutions eg. infusion of hypertonic Na bicarbonate solution. hypertonic saline for traumatic brain injury. hypertonic saline during procedures (hydaiic cyst irrigation. abortion). sak poisoning (child abuse, accidental) Cl i n i c a l Ma n i fe s ta ti o n s Acute hypernatremia (<24 hr) can cause irreversible brain damage (osmotic demye libration and cerebral hemonrlrage); since die brain did not have :me so adapt to hypematremia. [Na] should be acutely corrected to normal level by giving die entire water deficit volume within 24 hr The clinical symptoms are mainly neurologic Acute hypematremia: lethargy.weakness. irritability: sei1ures.and coma Chronic hypernacremia (>48 hr): it is difficult to attribute the symptoms to hyperNa itself or to the underlying etiology causing the impaired mental status tlnaVtp,,,,,, Water exit across the BBB Water moves from the Cellular uptake of Na and K Brain 1 CSF to interslilium Cellular accumulation of osmolyles Brain adaptation to hypematremia. volume TREATMENT OF HYPERNATREMIA General Approach Administration of dilute fluid no correct the free water deficit and the ongoing loss In DI. desmopressin is :he main therapy (review polyuria) Free water deficit + electrolytefree water clearance as Free Water Deficit =TBW x ([Na]I140 - 1) Total Body Water (TBW) = Lean Body Weight (LBW)* x 0.6 (young male), 0.5 (young female.elderly male). or 0.45 (elderly female) Another way to estimate: 1 mErelL of T [Na] =Water deficit of 3 mUkg eg.To correct [Na] by 10 point in a 50kg female patient with a sodium of 150 Using the formula: water deficit = 50 x 0.5 (150/140 _ 1) = 1.700 mL Using the estimation: water deficit = 3 x 10 x 50 = 1.500 mL Calculation does not estimate the ongoing free water loss *Fat has lower water content than muscleTBW is lower in obese and elderly Free Water Clearance (Cwo) =V..i¢ x (1 - U.,,..JP,,,..) If (+): the amount of free water that is lost in the urine;ADH absent or ineffective (NDI or CDI) If (-): the amount of free water retained by the kidney;ADH present and effecdye (osmotic diuresis) The cell membrane is permeable to urea: urea does no: contribute to the eH*ecti~»e PM Since the medullary collecting tubules are not permeable to urea and NH3. urea does contribute co the effective U.,,... This discrepancy in the handling of urea between die kidney and the other organs limits the value of Cup in predicting the effect of urine output on serum [Na] especially if solute diuresis is suspected (postobsuuctive. hyperalimentation, high catabolic state) and C4»<=,.=»v-4~»H»° is used in solute diuresis to measure che ongoing renal water loss Electrolytefree Water Clearance (C»4,0) =V,.¢,* x [1 - (UN. + UI()lPN~] The absolute value of free water volume needed to avoid worsening of the hyperna Estimates the contribution of the urinary loss on Pow and plasma [Na] If (.); the amount of electrolytefree water that is loss in the urine: should be added to total volume of (ree water deficit calculation If (-): die amount of electrolytefree water retained by the kidney (kidneys are cor recting the hypernatremia); this amount should be subtracted from the total volume of free water deficit Repletion Solution Oral or NG or PEG mbe free water tube boluses are the preferable repletion access DSW: preferred IV solution. Can cause hyperglycemia especially in DM, leading to osmotic diuresis worsening hypernatremia.Tx: D2.5W or insulin therapy Na (for hypovolemia) or K (for hypokalemia) added .l free water amount in IVF 1 L of 0.45% saline (-154 mOsm): 500 mL of Me water 1 L of 0.45% saline + 40 mEq of KCI (-234 mOsm) 250 mL of free water The Rate of Correction Chronic hypernatremia (>48 hr): lower Na by 10 in 24 hr; max is 12Id Acute hypernatremia (<48 hr): lower [Na] by 1-2 mEqIUhr until [Na] of 140 (Initial rate of DSW is 3-6 mUkg/hr until [Na] reaches 145 and then 1 mUkglhr until [Na] 140) Rapid correction of the of chronic hypernatremia may fuse brain edema. but evidence is not strong (QASN 201m4=s561 Chronic hypematremia causes accumulation of intracellular osmoles as chronic adap tation to avoid of brain volume: rapid correction of hypernatremia creates a hypo osmolar serum compared to the brain and leads to brain swelling mainly in children Slow correction rate (<6 mEqlUd) are associated with higher mortality J [Na] q2-4 hr initially,then adjust depending on cowction rate CALCIUM REGULATION Role: bone structure. muscle contraction. coagulation; cell signaling. secretion. and adhesion Daily intake 1.000 mg. net intestinal absorption -200 mg Bone contains 1.000-1.300 g Ca (>99%) by weight as hydroxyapatite: C210(P04)s(0H)z ECF Ca content is <0.1% of total body stores CaSR in parathyroid gland senses ionized Ca (iCe) and controls PTH secretion Vitamin Do (cholecalciferol, from UV lightmediaxed skin productiomanimal) and vita min DO (ergocalcilerol, from fish. plants) are convened to 25(OH)D2 (calcidiol) in liver; converted to 1.25(OH);D! (calcirriol) by 1a hydroxylase in kidneyzactivated by PTH: inhibited by FGF23 Serum Calcium Regulating Mechanisms (qA91 w1s;10.12s1) Site Inratine Bone Kidney Serum Increasing Serum Ca Decreasing Serum Ca Caki!riol: calbindin.TRPV6 mediated PTH: RANKL -r osteoclastmediated resorption - TCa. POW release Metabolic acidosis: Ca. PO. released from bone I~qM 1971 aomsasl PTH: reabsurprion in TAL DCT; t calciumiol synthesis Volume depletion, :hiazide Metabolic alkalosis T TRPV5 - renal reabsorprion uAs~ z0\oJ1:144m Acidosis: i albumin binding (t iCe) Excreted in the bile Calcitonin: . osteoclast activity -» Lbone resorption umjmwiul 199sa71:Fz1s1 Cakitonin: l robsovption TQ: CaSR -»i reabsorprion Volume expansion, loop diuretics Metabolic acidosis: lTRPV5 -> J, renal reabsorpdon UASN m0s:17=6m Alkalosis: T albumin binding (L iCe) Kidney filters -10 old; reabsorbs 97-99%;excretes 100-300 mg/d; 24hr FEw. 1-3% Renal Reabsorpdon of Filtered Calcium (qAsr4 misiiaiun PCT (60-70%) Passive solvent drag by sodium uanspori; T by volume depletion. zhiazide; x by aceuzolamide. osmotic diuretics Minor active zransporz regulated by PTH and calcitonin Paracellular via claudin16/19, driven by (+) lumen from ROMKI TAL (20-25%) NKCC2: inhibited by loop diuretics Basolazeral CaSR inhibits claudin16/19 via claudin14: . reabsorpnion DCT (10%) and CD ( 594) PTH inhibits claudin14: f reabsorprion was zo17;ii4:en44) Apical TRPV5, intracellular calbindinD2BK: T by PTH Basolazeral NCX moves Ca w blood: T by ihiazides Calcium Measurement ionized Ca (iCe): preferred measurement. unbound. physiologically active form ApH by 0.1 0.08 mmolIL Aica in opposite direction (dlt .\H albumin binding) Serum protein (albumin and lg) level changes serum coral Ca level so maintain iCe level Adjusted Ca = Ca » {0.8 x (4 - albumin in g/dL)} If 1 GFR, unadiusred value may be more accurate (WI as... 201B.8:e017703) Pseudohypocalcemiaz gadodiamide, gadoversetamide interfere wl :oral Ca assay Calcium Balance in CKD KDOQI urge:8,4-9.5:boch below and above Inge are alw t mcmllry (nor 20112e194e> Hypercalcemiaz alw exrraskelecal calcification and cardiovascular morbidity Hypocalcemia: common in CKD;alw t PTH secretion I HY P E RCALCE MI A Pathogenesis and Causes of Hypercakemia PTH PTHrelated peptide (PTHYP) Caldtriol Osseolysis, Bone turnover Renal retention 1 hyperparadlyroidism (HPT). 3 HPT slp kidney transplantation Parathyroid cancer; MEN 1I2A (pituitaryldiyroid cancer FHx). lithium SCC. RCC. breast. ovarian, bladder cancer > leukemia. lymphoma Pregnancy.tends co be mild r€»1a»a;zaus=ss;9s1 Vi: D excess.granuloma (TB, sarcoidosis.ANCA, Crohns). lymphoma Sarcoidosis + vit D (><2) or renal dysfunction ()<4.1) or,Im=¢ so zowasuszI ldiopazhk lAM wi 1997;1§7:2141) Multiple myeloma. metastasis. hypervitaminosis A Pager disease. hyperthyroidism Imam ma zooamswl Thiazide. milk (or CaCO;)alkali syndrome: vomiting or volume depletion worsen metabolic alkalosis renal Ca reabsorpdon Familial hypocalciuric hypercalcemia (FHH):AD CaSR inactivating mutation -r t Mg. Ca reabsorption: T PTH Acquired form:Ab against CaSR Hsu# zo04:as1ss2l immobilization Usually <11. possibly resorpdve mechanism (NEW iveuosiuel Clin ical Man if est at io n s an d Wo rku p AKI (vasoconsnictlon). constipation. weakness. fatigue. memory loss. confusion NDI: 1 aquaporin2 & t medullary Ca deposition -» osmotic gradient impairment Chronic hypercalciuwia (1 HP12 sarcoidosis) _» nephrolithiasis. nephroukinosis - CKD EKG: Short QT interval, prolonged QRS,bradycardia. U waves Hypomagnesemia d/t CaSR activation -) J, renal nabsorpdon Typical Calcium Level (g/dL) by Causes >12 Mal i gnancy. cal ci tr i ol pr oducti on. i ngesti on <12 1 HPl 2 i mmobi l i mi on. FHH. mhi ui de. l i thi um If PTH inappropriately normal (no: suppressed) in hypercalcemia, 1 HPT possible P TH a nd P 0 4 Cha nge s I n Hy pe r c a l c e m l a PTH Po. P os s i bl e Ca us e s PTH P04 | + 1 HP I FHH 7 T a HP T Thi azi de. mi l kal kal i syndr ome 4 l T 1 Var. T Ca l c i t r i oL bone l um ov e r P os s i bl e Ca us e s Mal i gnancy: J P THr E 1, 25V i t D. SIFE/UIFE, FLC Renal retention:24hr FE<;, <1%. Ca <100-200 mud: random CaICr <0.01 (less reliable) Tr eatment Fluid: PO: I V i f sympzomar i c or Ca >13;g°al U O P 1- 2 mU g/ hr : NS to avoi d alkalosis Loop diumics: : f ue l volume repletion Iiude eflecr solely (Am IM 2ao&149:2s9l;may alkalosis RescricrVixamin D and dietary Ca (<400 mg/d) in calcitriol mediated Supplement if 1 HPT deficiency may T PTH Bisphosphonames inhibit osteoclast activity; onse: of action is 2-4 d after administration Bisphosphonate Un in Hypercalcemla (KJ 1008;74:13B5; Na a- no ~¢~-I zuue.r4ssl Dr ug S i de E f f e c t s Pami dr onate Rare collapsing FSGS 60-90 mg over 4-6 hr Zoledronic acid Dose and i nfusi on uAsn 100I:1z:11s4l Cr CI < 3 0 HD: 3 0 m g qd x 3 d Avoi d Cr CI > 3 0 90 mg over 2 - 3 hr >60: 4 mg superior in r ar e dependent $060: 3, 5 mg maligvuncy ATN In 2001441141) 4049: 3. 3 mg u an of z00l ;\ 9sss) 30-39: 3 mg over 15 mi n DenosumabzantiRANKL monoclonal Ab: inhibits osteoclasts and bone resorption s/e: prolonged . Ca: common in CKD. Low dose. eg.0.3 mg/kg w/ vitamin D may be safe (Un lymphamu Mjduma Leuk 1014;14:1207) Gallium nitrate L osteoclast activist:y;AKI reported. Not recommended if Cr >2.5 Cinacalce:: start at 30 mg bid. ticrate up to 90 mg bid: in 1 and 2 HPT HDICRRT: in volume overloaded CKD or severe symptoms: low Ca bath: <25 mErelL bash alw arrest (KA 2011;791118) Pararhyroidectomy In 1 HPT with Ca >1.0 or more above the ULN ucem 2014:99,314»1) HYPOCALCAEMIA Pathogenesis and Causes of Hypocadcemia PTHRe\ated Mechanisms Hypoparathyroidism UCEM z01s;101 ;2273JcEm z0\e10us00) Neck surgery (7596). neck radiation. DiGeorge syndrome CaSRacr.ivaringAb and mutation (AD). IdiopathIc lnfikrative: Wilsons. hemochromatosis. meususis Pseudohypoparadmymidismz T PTH (resistance), L Ca,T POW Hungry bone syndrome (Am j Medl98BlB4:b$4) Abrupt . PTH after parathyroideczomy -a T bone upuke of Ca. POW. and Mg, ¢ renal reabsorpnion of Ca. iintesdnal rabsorpdon of Ca. POW Nadir Ca typically 2-4 d posmop; 1 Ca may last mo Hypomagnesemia CaSRRelated Mechanisms Hypermagnesemia AD hypocalcemial hypoparadiyroidism PTH deficiency and receptor resistance (up 1999:101616) CaSRmediated PTH suppression CaSR acUvaring mutation we/m 19wazsn11sl -» . PTH secretion: inhibition of ROMKINKCCZ -» typev Bartter syndrome wl 1 K. metabolic alkalosis;4 Ca. Mg TCaSR sensitivity no Ca -a ¢ PTH Calcimimerics (cinaczket. Ca in 69% and 60%. respectively UAMA z0\7517:1ss) etelcalcetide) Yitamin D Related Mechanisms . Sun exposure. diet. aging. posunenopause. malabsorpdon W: D deficiency t FGF23 inhibits alcirriol synthesis CKD Loss of calcidiol bound to vitamin Dbinding protein Nephrodc syndrome CYP inducers Other Mechanisms Sequesrradon Bone resorption Spurious irypocalcemia Phenyroin, phenohaibiial. rifampin. INH: metabolize caldiol Pancrealitis. foscarnel. acute respiratory alkalosis Citrate: used in blood transfusion and CRRI;a/W liver dysfunction: . conversion (O HCOxC nl wal Ca. i ice POW: CKD,AKI. rhabdomyolysis,TLS Osteoblastic metastases: breast. pros re cancer Bisphosphonazes. denosumab Assay interference of gadodiamidegadovenexamide Clinical Manifestations and Workup L BR irritability. spasms. oral/distal paresnhesia -» papilledema, seizure. remny Chvostek sign: facial nerve rapping facial muscle contraction; low specificity Trousseau sign: BP curl inflation 3-5 min ) carpal spasm: high specihciry ln5,lm 2011;367) EKG: \QT length PTH Po. 1 1 1 T A Ca level from baseline: narrow T. heart block TdP PTH and P04 Changes In Hyponlcemia Common Causes PTH P04 Common Causes . Mg Hypoparathyroidism t T 1 T Vi: D deficiency CKD Pseudohypopararhyroidism Treatment Correc: low Mg: IV or PO Mg depending on severity. PO access Correct high WE t CaP04 product may cause AKI; still need IV Ca if symptoms Correct respiratory alkalosis Vitamin D: if deficient: 4 Ca requirement by T intestinal absorption Ergocalciferol 50.000 IU weekly x8 wk (mu 100S;3U=129a) or active vitamin D if ESRD In postsurgical lvypoparathyroidism. maintain Ca 8-8.5. 24hr urine Ca <300 mg Lo prevent hypercalciuria induced nephrocalcinosis and nephrolithiasis dlt absence of PATHmediated Ca reabsorption 1ziiaw PM 2011217 suppI1:18) C alcium Supplementation IV: if symptomatic. EKG A. iCe <1.0 mmoUL or total Ca <7.5 Ca gluconate 1-2 g over 10-20 min: if ice in 30 min <1.0 mmollL drip + PO calcium J Ionized Ca. BME Mg, P04 q6h Do NOT mix w/ HCO; or P04 to avoid insoluble Ca salts, IV Ca an worsen dioxin toxicity Ca gluconate 1 g (1 ampule. 10%10 mL) 93 mg (4.65 mEq) elemental Ca Sur: drip with 0.5-1 m hr of elemental Ca (5.4-10.8 mg/kglhr Ca gluconate) and adjust to maintain zonal Ca 9. iCe 1.2 mmollL 1 mg/mL elemental Ca solution: 11 g (1.023 mg elemental Ca) + 890 mL or 12 g ( 1.116 mg elemental Ca) 1.000 mL of NS or DSW Ca chloride 1 g (1 ampule. 10% 10 mL) = 272 mg (13.6 mEq) elemental Ca Use only in unstable patients: sle: infusion site reactions PO if mild, asymptomatic: between mais if P04 is normal or low: with meals if P04 is high s/ezconstipation.. PO (») Ca balance: kidney stone (NEW 200s;354¢669i Ca carbonate Elemental Ca 40% by weight, give tid up to 2-4 old Ca citrate Elemental Ca 21% by weight: avoid in CKD ( Aluminum abso son) PHOSPHATE PHOSPHATE REGULATION (CW of, nehru I.#memes 2013:22MB1) Phosphorus (P): chemical element. always in combo w/ other elements Organic phosphate (POW"): phosphoric ester; component orATE DNA. RNA: intracellular Inorganic phosphate (Pi):fraction measured in ECF; Hpo.*/H,po. u 4:1 as pH 7.4 Typical American diet contains 1.000-1,500 mg/d; recommended minimum 700 mgjd GI absorption: nonsaturable. constant. 60-80% of dietary load: by calcitrioldependent type Ilb Na POW cotransporter (Npdb) + alcitriolindependent paracellular uanspon Total body stores ~900 g: 85% in bone. 45% in soft tissues. -0.01% in ECF ECF is reservoir for all pa exchange. tightly regulated (qAs~ 101s= \05\zs71 Serum Phosphate Regulating Mechanisms um Rn no z01317s:s3s: Aaaa zounmm Site Increasing P04 Decreasing POA lntesdne Calcitriol. » P04 FGF23 via lcalcitriolz nicotinamide Bone Kidney Calcizriol, PTH Calciuiol. J. PO., Thyroid hormone, IGF1. Eddronate. Alkalosis PTH. FGF23. T POW -» 1 rabsorption FGF23 also lcalcitriol synthesis Steroids, estrogens (KI znaann 141) Acidosis (c/Asu z014m1 s27l ACUTE PHO SFHATE NEPHRO PATHY Acute P04 load from tumor lyses syndrome (TLS). sodium phosplure po we zuusneasaz x0 1l](J9:76:1021) or enema we, AM 201Z;172z163) -a AKI Kidney biopsy: CaP deposition in lobular lumen and Lobular cells with (+) von Kossa min Prevention: avoid sodium phosphate agent in high risk paUenrs (CKD. volume depletion): POW binder in established or high risk TLS HYPERPHOSPHATEMIA Causes of Hyperphosphatemla Nonrenal Origin (FEm, >15%) Renal Retention (FE90, <15%) Acute load: N3P04 bowel prep ()A$n Renal dysfunction: inadequate renal excretion : 2005:16:3389). high dose fosphenytoin 2 HPT Tbone release in CKD Transcellular shift: rhabdo,TLS. (rarely) Hypoparathyroidism hemolysis Pseudohypoparachyroidism: PTH resistance ECF shift: severe metabolic acidosis. Vi: D toxicity: T Ca -. PTH hyperglycemia Familial auroral calcinosis: mutations .LFGF23 or anion. soft :issue calcified masses Ac . ly. etidronare Clinical Implication in CKD Hyperphosphazemia is alw T PTH. * FGF23. i calcitriol (directly and indirecdy from t FGF23). Tvascular injury oxidative stress and calcification Sequence in CKD: t FGF23 -» 1 Calcitriol > T PTH -» T P04 UASN 2u 10;21\4z7) I n H D pts, POW >5.5 a/w T mortality by 20% do 3.5-4.5 (nam 2uce;3 s9¢$a4) In nondialysis CKD pts. Po. 3.5-4.0 a/w T mortality by 32% dt 2.5_3 (MSN 100s.16:s20i FGF23: alw morality in HD (new/in z00s13s91se4), ESRD and mortality in CKD UAMA 2011:l05:24]2) Clinical Manifestations and Workup Hypocalcemia: skeletal and extraskeletal CaP precipitation Rarely symptomatic from accompanied hypocalcemia: could be life threatening Pseudohyperphosphatemia lab erior dlt high level of Ig, lipids. bilirubin, liposomal a mp h o t e r i ci n B Tre a tme n t o f Acu te H yp e rp h o sp h a te mi a IV fluid in volume depleted AKI and nondialysisdependent CKD HD:AKVTLS wide symptomatic hypoakenia or Ca x P04 270 mg'ldL' or advanced CKD Tre a tme n t o f C h ro n i c H yp e rp h o sp h a te mi a Diet restrict <1 old (MMA 2009;301:629). then use PO4 binders Goal in CKD: 3.5-5.5 0(¢>001A!»(0200:i;42=s1>:"normal range" (xoico man KI z017.9z26) Phosphate binders: 29941 allcause mortality 22941 CV mortality In CKD5 (al 2oIa.s4.mi P h o sp h a t e B i n d e r s Dr u g s Comment s C a l c i u mb a s e d b i n d e rs Affordable; help control of metabolic atidosis and . Ca sle: FQ and Ca x PO¢. constipation. meohdic allalods Ca acet at e. Ca carbonat e Ca cit rat e N o n c a l c i u mb a s e d b i n d e rs t GI a lu min u m a b so rp tio n (xi ivsa we a n ~ to xicity 1 Mortality in CKD (RR 0.54) (qAsi4 zoieu:zazI J Mort alit y overall (Lancet z0 u. Ja211s81 Sevelamer carbonat e (Renvela° ). l Morality. hypertalcemia. LDL dw Cobased binders S e ve l a me r h yd r o ch l o r i d e ( Re n a g e l ° ) in 2o1zue7; up zoixszm; qAs~2016411.232) s/e: metabolic acidosis (sevelamer hydrochloride) Lant hanum carbonat e l Ml burden lq4wzuoe1i4m; s/ ecdiarrhea; T hone uumcven in rars, accumulates ii the liver W zlussalwy Ni t o t i n a mi d e THDL iqAsn 1n0e:a:11a1) Ferric cit rat e t TsaL Hb (up 1015: 161493) S u cr o f e r r i c o xyh yd r o xl d e 1 pill burden (nor a01s:3a10m 1 Tsar. Hb (nor zoirazmol A l u mi n u m h yd r o xi d e Pat ent POW kiwedng eilecc slealuminum deme\ ch. ost eomalacia; should be limit ed t o a f ew HD: removes 800-900 mg/session: significant rebound after HD (mobilization of FO; occurs more slowly than K, Ca. BUN); can be used in nonCKD (A/xo z01 a11z;4sn Cinacalcei: in 2 HPT/CKD. more pus achieve <5.S lqASN z00a23.m1 i PTHmediated bone resorption. L requirement d active vitamin D may l GI ahsorpdon Parathyroidecromyzl bone resorption: consider if refractory Aceuzolamide in familial :unmoral calcinosis: T renal excretion of PO 4 HYPOPHOSPHATE IA (Am .I Med 1006:1181W4) Causes of Hypophosphatemla Renal Wasting Nonrenal Origin FEI0, <5%. 24hr urine POW <100 mg Firm, >5%, 24hr urine POW >100 mg Transcellular shifts: insulin. glucose. refeeding Fanconi syndrome or 2 HPTlVi: D deficiency t FGF23: genetic hypophosphamemic rickets. oncogene osteomalacia Hepazectomy (jA$N l0\4:1S:761) syndrome, hungry bone. respiratory alkalosis (head injury) l Absorption: GI resections. diarrhea, POW binders. aluminum. Mg CRRT. immediately after HD 1 Chronic alcohol use 1~£1m 1011:37l:1368) Vtamin D deNciencyz L intestine absorption and T renal wasting l Ca -» 2 HPT -» T Ffvo. Nutritional phosphate deficiency: low FEpo, low/normal PTH. calcitriol Fanconi syndrome: PCT damage-» renal wasting of gk. UA.AA. POW; from light chain (LCPT). heavy metals. NRTls. tenofovir. ifosfamide. cystinosis.Wilson disease Genetic hypophosphatemic rickets: xlinked (PHD().AD (FGF23).AR (DMP1, ENPP1) I Oncogenic Osteomalacia (Tumorinduced Osteomalacia) Mesenchymal tumor secreting FGF23: rarely osteosancuma. SCLC, colon a umm zouwiaaan Labs: Ffvo.. T FGF23, J, or inappropriately nl caidtriol.nl or t (by calcitriol) PTH. nl Ca.T AA Imaging: skeletal survey (fractures. osteomalacia). "GoDOTATATE PEI/CT Manifestations: weakness,bone pain. recurrent fractures.Tx: tumor resection Clin ica l Ma n if e st a t io n s Symptomatic if <1: myopathyz seizure, confusion. 1 myocardial contractility (NEW 1977297901) ; diaphragmatic contractility (NEar 1985;313:420). rhabdomyolysis Treat ment Correct any existing vitamin D deficiency: T intestinal absorption. 1 renal wasting PO if asymptomatic: 1-1.3 mmollkgld divided >d:an add skim milk (15 mind POJ48) mL) PhosnaK powder: 250 mg elemental P (8 mmol). Na 6.9 mEq. K 7.1 mEq/packet PhosNaK tablec 250 mg elemental P (B mmol), Na 13 mEq, K 1.1 mEq/tablet IV if symptomatic Na or KP043 max B0 mmol within 12 hr . if P04 <1.5,0.64-1 mmol/kg: if POW 1.6-21.0.32-0.64 mmollkg s/e: precipitation of Ca x PO¢ can muse hypocalcemia w/ tetany Dip yrid a mo le : l re n a l re a b so rp t io n MAGNESIUM MAGNESIUM REGULATION (KI 1997;51:11B0: in 19941417371 Inuke ~350 mg/dzabsorption in small bowel via sarurable TRPM6, passive diffusion Total body stores: 26 g: 60% in bone. 4D% in soft tissues, <1% in ECF 70% of :oral plasma Mg is not proteinboundzfikered in kidney:95% reabsorbed Renal Magnesium Reabsorptlon lqAsn 201s:1a17.sn PCT (20-30%) TA L (5070%) DCT (5-10%) Passive Paracellular via claudin16I19.dniven by (») lumen from ROMK/NKCC2. Inhibited by basolateral CaSR via claudin14 UAS~ z01s26;111. Apical TRPH6: mediated by epidermal growth factor receptor (EGFR) HYPERMAGNESEMIA Clinical Manifestation Symptomatic if >5. progressive neurologic silencing effect; loss of DTR. nausea. lethargy. confusion, paralysis;AV block, arrest 1 Co by CaSRmediated suppression of PTH Treatment d/c administration: if J, renal function IV fluid and/or loop diuretic; HD if severe If symp\:omaxic.Ca gluconate IV 2 g over 10-20 min to stabilize membrane: dialysis HYPOMAGNESEMIW Causes of Hypomagnesemia Nonrenal Origin Renal Wasting re <2%. 24hr urine <10 mg/d . GI absorption: PPI luqm zaus;ass¢1a34). pauromen large bowel resecuon. chronic diarrhea t Bone uptake: hungry bone Alcohol. poor nutrition Complexalion: pancreaxids. transfusion lnuacellular shift: insulin, refeeding ibiauiniinpa I9S&29;644): Bagonist. acute alkalosis. severe burns FE >2%. 24hr urine >10-30 mud Metabolic acidosis: lilzerable Mg Loop and zhiazide diuretics, Bartxer. Gitelman PostATN. poszobsrrucnion. uncontrolled DM Cisplatin. amphotericin. foscarnet Basolaleral CaSR activation: Ca, aminoglycosides (polycadon) - inhibits ROMK and claudin 16/19 . Mg, Ca reabsorpzion Familial hypomagnesemia w/ hypercakiuria and nephnocalcinosis:AR claudin19 muzanion . TRPM6: m (1Asr42004;lS:$49). CsA. EGFR Abs cetuximab, panitumurnab. maruzumab.AR muzadon we Genes 200L31=1711 Chronic alcohol abuse: poor nutrition 4 renal tubular wasting (N5IM 1993:329:19271 If unclear w/ history J FEw I [(UH¢ x P<;,)/(0.7 x P) x Up.] x 100% Clinical Manifestation Terany and seizure (similar [0 i Ca). nysugmus. apathy, depression, azhetosis QRS widening. peakedT waves. prolonged PR (similar to T K). :orsade de pointes . K: t ROMKmediated K secretion in DCT from 1 nuacellular Mg (;ASN 1007;I&2s49) 1 Ca: PTH deficiency and resistance t NODAT UAS~ 2016;27:1793). t rnorraliry in HD we 2ois:ss:1047l Treatment PO if asymptomatic use sustainedrelease or small frequent doses to T absorption Elemental Mg content: oxide (60%6 > OH (41%) > SON (10%) > gluconate (5%): least diarrhea: sle: diarrhea. GI discomfort. Mg: Half dose for eGFR <30 N if symptomatic or <1 mg/dl; 2 g MgSO4 (192 mg, 16 mEq elemental Mg) over 15 min: in symptoms persist infuse up to 8 g over 24 hr; monitor telemetry DTRs For patients with arrhythmias (esp. ventricular). maintain Mg >2 mg/dL Amiloride. triamterene, and spironolactone: for renal wasting or medical conditions requiring diuresis despite hypomagnesemia ACUTE TUBULAR NECROSIS (ATN) Background ATN and prerenal azotemia are the leading causes of acute kidney injury (AKi) • ATN causes 38% ofAKl in hospitalized pts. 76% of AKI in ICU (Ann IM 2007137:744) Causes Main causes of ATN: ischemia.sepsis,and nephrotoxins Ischemia includes any cause of renal hypoperfusion and prolonged prerenal state Hemorrhagic, cardiogenic. hypovolemic. anaphylactic shock Renal artery occlusion (eg, embolic. renal artery dissection) Surgery (especially cardiac. intraabdominal) Nephrotoxins: numerous medicaUons. iodinated contrast media. pigment (hemoglobin myoglobin from hemolysis/rhabdomyolysis), ethylene glycol. synthetic cannabindds Less frequent causes: nephrotic syndrome (especially MCD), hyperbilirubinemia. hypercaltemia Pathogenesis of Ischemic ATN (man R n¢w/vi 2011.71B9l Decreased effective arterial volume in prerenal azotemla leads to activation of neuro hormonal cascade including l sympathetics. RAAS. and vasopressin t Angiotensin II during hypovolemia leads to preferential efferent arteriolar vasocon striction. which attempts to preserve GFR despite J, renal blood flow. eventually afferent arteriole vasoconstricts and overall renal blood flow and GFR drop To prevent excessive vasoconstriction. kidney produces vasodilatory NO and prosta glandins. but this counterregulatory system has its limits Ischemia -o tubular cell apoptosis/necrosis. esp in PT blc high metabolic demands and susceptible micracirculadon: leakage/dysfunction of PT cells - t afferent arteriole vasoconstriction. inflammation. endothelial damage ischemia also injures endothelium causing deranged coagulation and permeability -» ischemic microcirculal.ion.extending AKI damage ATN may cause dysfunction in other organsaanimal models show increase in pulmo nary vascular permeability and cardiac inflammation Pathogenesis of Septic ATN (cin of on Cave 101412ssa1 Occurs even in setting of preserved or increased renal blood flow Sepsis triggers dysfunction in renal microcirculation involving endothelium. vascular tone, abnormal coagulation. oxidative stress, and inflammation Clinical Manifestations and Workup As wide other causes of AKI. praents widl rising creatinine +J- diguria (see AKl definition) Nonoliguric ATN with better prognosis than oliguric FEn. >1%. FEw., >3$%. Urine sodium >20-40. BUN:Cr ratio <20:1 FEn. can be <1% ifATN occurs in cirrhosis or CHF . Urinalysis: usually acellular with <1 g proteinuria. sediment can have muddy brown" casts and renal tubular epithelial casts Kidney Bx: PT slmplificationlflattening. loss d PAS+ brush border. vacuolization Management Correct ischemia and sepsis: discontinue nephrotoxins ATN FOLLOWING CARDIAC SURGERY 18% incidence of AKI. 2-6% requiring HD (qAsn 2o1s ;111s001 Similar pathogenesis as for odier ischemic ATN:alsc mechanical trauma. embolizacion Risk factors: usual ATN risk factors: also: multiple cardiac surgeries in one operation. prolonged bypass time cardiogenic shock (qAs~ zoisnosooi Off pump surgery did not improve rates of AKI requiring dialysis lngpvi 2013;368:1179) Cleveland score may predict need for RRT after cardiac surgery 1;As~ 2005;16:161) 5 points for preop Cr > = 2.1; 2 points for preop Cr 1.2-2.09 2 points for preop balloon pump, emergency surgery, CABG +valve 1 point for female, CHF, EF <35%. COPD. IDDM, prior cardiac surgery 1 point for valve only surgery. 2 points if other cardiac surgery Risk ofAKl requiring RRT: (0-2 ps 0.4%: 3-S pts 1.8%:6-8 pts 7.8%: 9-13 pos 21.5%) PIGMENT NEPHROPATHY RHABDOMYOLYSIS Causes lnqm 1c09:361;62) and Pathogenesis (NEW 2609961162: re 1996;49:314) Category Examples Trauma Crush injuries. exercise. seizures. elecutucution. thermal (hypothermia. hyperthermia. NMS). limb compression from LOC. compartment syndrome. iaimgenic occlusion in OR. thrombosis. embolism Infections Bacterial (Strep. Staph. Clostridium. Legionella.Tularemia). Viral (Influenza A & B, EBb HIV. Coxsackie). Malaria t [Na], 1 [Na],l [K].l [Ca].l [Pow]. lfyperosmolar states Electrolyte Endocrine Drugs and Toxins Genetic and Meiabdic Autoimmune Hyperaldosteronism. hypothyroidism. ketoatidosis Stalins. librates. antipsychotics. antidepressants. antihistamines Recreational: alcohol. heroin. cocaine. amphemmines. LSD. toluene Environmental: he/y metals. insect venom. snake venom. CO Disorders of: glycolysis.glycogenoiysis. lipid metabolism. mitochondria. pentose phosphate pathway. purine nucleotide cycle Polymyositis. dermatomyositis imbalance of cellular ATP causes K/NaATPase and CaATPase dysfunction -» t [Calm Myocyte breakdown releases Myoglobin.CPK. K. POW. purines Massive fluid sequestration in damaged muscles. CaP precipitation and deposition Myoglobin is rapidly filtered (MW 17.8 kDa and not protein bound) Endocytosed by PCT and causes cytotoxicity via hyargxyi radical Piedpitates w/Tamm-Horsfall protein (promoted by acidic urine) forming obstnxdvie ass Vasoconstriction from sequsuadon -> RAAS acdvanion and local inflammatory mediators Clinical Manifestations and Diagnosis May be asymptomatic, Myalgias. red or brown urine. +I- oligoanuria Labs: U/A widi +Heme but no RBCs (Sens,809lS), +I- pigmented granular asts.+l- AKl (FENa often <1%). T CPK (mostly MM isoform. >$-10K to cause AKl.rises within 12 hr of injury and Tm of 1.5 d). T uric acid, T AST/ALT. T LDH. T [K]. t [p]. 1 [Ca]. lacer can see T [Ca] (leaches from muscle). Do not / serum or urinary myoglobin (insensitive). Treatment of Pigment Nephropathy (Intensive Care Med 20011z7803; new 1009;361:62) Address the underlying cause of rhabdomyolysis and hemolysis Aggressive IVF: (1) volume resuscitate in rhabdomyolysis d/t sequestration (1-2 Uhr initially); (2) T urinary tubular flow rate to prevent pigment asts (target UOP >300 mUhr). Continue until CPK <5K or hemolysis improved & able to take PO. Consider urinary alkadinization (pH >6.5) but no clear benefit. Monitor ice and pH If oliguric or volume overload. loop diuretics. No clear benefit from mannitol,and potential for harm (if used. restrict <200 old and OG <55). Medically manage electrolyte complications: avoid repleting Ca unless severe or symptomatic.Allopurinol if uric acid >8 mg/dL HD or CRRT 9nj! for renal failure indications. No role for pievenzive myoglobin clearance wid\ CWHDF An¢A»¢¢uieiaI swi41005;49:a59) or plasmapheresis Risks of poorer prognosis (AKI. need for RRI mortality) include age >50. female. Cr CRYSTAL NEPHROPATHY Crystal nephropathy: acute or chronic kidney injury caused by crystal precipitation; Uric acid nephropathy is Mc Nephrocalclnosisz generalized calcium deposition In the kidney parenchyma and tubules Nephrolithiasis/Urolithiasiss condition a/w renal intratubularlurinary stones.formed from crystals precipitating from the urine Pathogenesis Crysnllizadon is determined by supersaturation (SS) of consdluent molecules SS: depends on the product of the free ion activities d components. promo.er. inhibitor (citrate, Mg. pyrophosphate). and urine pH Urine pH Favoring CrystaII$tone Formation Acidic Urine Alkaline Urine pH if de ndent Uric acid, cysteine, MTX. rriamrerene. sulfadiazine, djenkolic acid Alkalinizadon (citrate. HCO:) might be prevenzive and rherapeuzic CaP, indinavir. auunavir. Ciprofloxacin CaOx AKI. hemamria. auria. renal colic (Hank pain, NN), precipitation an cause morbid urine OXALATE NEPHROPATHY Source of oxalate: dietary (30-6096). liver; Excretion: >90% into the urine. 10-40 mg/d Intestinal Oxafobacter formigenes breaks down oxalate Intestinal oxalate secretion via SLC26A6 and CFTR uA=~2017;242421 Obesity associated inflammation L intestinal secretion (xv z01s.93:109s) Kidney bx; CaOx deposits wl birefringence under polarized Iighc interstitial inflammation Primary Hyperoxaluria t oxalate production of liver caused by mutations of genes encoding hepatic alanine glyoxylate aminotransferase (AGT. type 1). glyoxylate reductaselhydroxypymvate reductase (type 2). 4hydroxy2oxoglutarate aldolase (type 3) Severe hyperoxaluria (usually >80 mg/d) Manifest during childhood or adolescence; ESRD at median 33 y/o Iam/n¢pnw11005251901 Systems deposition -» flecked retina. a mm.mMiomoww. ardiropadiy. fracture Tx: pyridoxine (vit Ba: cofactor ofAGT) and P04 is;/n 1994;331=1ssJ).combin¢d liver and kidney txp in type 1:very high recurrence rate wlo liver up Enteric Hyperoxaluria Causes: pancreatic insufficiency, CE IBD (CD > UC). small bowel resection, ieiunoileal or gastric bypass. orlisnt (lipase inhibitor) lAM :m 2011:171:703) Mechanism: 1. Fat malabsorption -» Ca binds to fatty acids -» 1 free Ca - T free oxalate -» T oxalate absorption -r T CaOx crystal formation in kidney 2. Diarrhea -» metabolic acidosis -» hypocitraturia -o T CaOx crystal formation Impairment of SLC26A6mediated intestinal secretion may contribute WK0 2011;W.s621 Mean urine oxalate 85.4 mild; >50% require RRT up up 7.018:3:136J) T>c lowoxalate diet, T fluid image. K citrate for metabolic acidosis or hypocitramria, PO Ca: reversal of gastric bypass may impnwe renal function (cum Nap rupnu M 1016:61114) Oxalate Loading Causes: ethylene glycol.Vi: C (in) nww201II20I 1:146927l, Iaxadve conralnlng ascorbic acid In 20\7;9l:9B9), methoxyflurane, rhubarb leaves. sur fruit (ummbola). nuts. cocoa. parsley. potato, spinach (KI z01629¢x711). beetroot, almond. chocolate. yellow dock. sorrel. cranberry concentrate rablecs (u,wwf 200l;57:26] Tac d/c oxalate: HD for ethylene glycol. large amount of ascorbic acid (lnuaullau 2016:44za9) ACUTE PHOSPHATE NEPHROPATHY Causes: hyperphosphaturia/hyperphosphatemia from sodium phosphate PO (Hum 11d1u1 20o4;3s;s1s).TLS. enema alw 1 eGFR (Ajxo zo 1s;s7<sor» CaxP >60 mg'/dL* T risk of precipitation in :he renal tubule Kidney bx: inrraluminal tubular and tubular intracellular CaP deposition Tx: dlc offending drug. IVE avoid urine alkalinizacionz RRT if CaxP 270 mg'/dL2 CALCIUM PHOSPHATE STONE AND NEPHROCALCINOSIS Aparke (crystal) >brushize (calcium hydrogen phosphate CaHPO4 2HzO) Causes of Calcium Phosphate Crystals we z01s;71(4)A12) Hypercalciuria M hypercalcemia Hypercalciuria y/9 hypercalcemia Syszemic excess 2 renal handling 1 HPI sarcoidosis.viomin D overdose. Milkalkali syndrome Dysregularion of renal handling of calcium dRTA. medullar sponge kidney. Den: disease. Bauer syndrome. chronic hypokalemia Primary Hyperparathyroidism (1 HPT) 24% of hypercalcemia on thiazide has 1 HPT (}COM 2016; 101: 11ss) If normal serum Ca. hypercalciuria and high PTH. J thiazide challenge (HCTZ 25 mg p o b id x 2 wk); P TH re ma in in g h ig h ma y su g g e st 1 HPT U uawra 1009: 23: 191) Dist a l RTA (d RTA ) Causes: CAI (acetazolamide. topiramate.zonisamide).Sj6gren syndrome . Pazhcgweis: (1) Chronic metabolic acidosis - t Ca. P release from bone: (2) intracellular acidosis -> t miiiochondrial citrine uptake -> t duate realzeorpdon in FCT Ma n ife sta tio n : Ca P sto n e /n e p h ro ca lcin o sis. o ste o ma la cia i u r i n a r y ci u a u e Hypol<alemic NAGMA. severe hypocitraturia. (+) urine AG.constant urine pH >5.8 Incomplete dRTM w/o systemic NAGMA;could be difficult to diagnose K >3.8 + second morning fasting urinary pH <5.3 excludes dRTA (cusp 2017:12:1 son Urinary addificadon :ec NH¢CI 100 mg/kg xi or PO funosemide 40 mg f lludmcordsone 1 mg (xl2007:71:1 :1ol and ./ urine pH hourly x s hi:failure to 1 urine pH <5.3 is diagnostic Me d u lla ry S p o n g e K id n e y Congenital malformation of pericalyceal terminal collecting duct Asymptomatic. dRTA, CaP 2 mixed CaOx stone and nephrocalcinosis. UTI. rare ESRD IVP: paintbrush appearance: CT: calcium stones at calyceal area Tx K citrate to v urine citrate >450 mg/d provided urine pH <7.5 l stone despite p H T f r o m 6 . 4 - 6 . 9 (qAsn z010.s:1663> Diagnosis Swne analysis: kidney bx: tubular, imersnizial. and inuacellular basophilic calcifucarion Characterization of Crystals Blrefringence Under Crystals von Kossa Stain CaP Polarized Light + CaOx, 2,Bdihydroxyadenine + Treatment Correct risk factors: low urine vol, hypercalciuria. hypocitraturia. hyperphosphaturia Correct dRTA w/ K citrate: i Ca. P release from bone. 1 urine Ca, R T urine citrate t Urine pH w/ citrate may augment CaP crystal formation Parathyroidectomy in 1 HPT with nephrvalithiasis/nephrocalcinosis. CrCI <60 or 24hr urine Ca >400 mg with increased stone risk ljcm 1014299135611 URATE STONE AND NEPHROPATHY Pathogenesis and Causes pH decides :he form: insoluble uric acid in low pH: soluble urare in high pH U r l n e pH is more imponan: than hyperuricosuria Tumor lysine syndrome in hematologic malignancy > solid tumor. seizure Exerciseinduced AKI in familial renal hypouricemia (URAT 1 mutation 1 uric acid reabsorption) Clinical Manifestation Usually asymptomatic AKI. random urine uric acidlcr >1 mg/mg; radiolucent stone Preven t io n an d T reat m en t Acute management; volume repletion, rasburicase for high risk for TLS Chronic management: urine alkalinization with K citrate with goal pH 6.5 or above, L animal protein and sak intake CYSTINURIA AR mutation of SLC3A1, SLC7A9encoding PT apical amino acid uansporten rBAT s Cystinosis causing Fanconi syndrome and :ubuiar proteinuria 1st stone 24 y/o. 21% alter 40 ylo; 20% staghorn: CKD (70%), ESRD (9%) (qAsn zo1s:1 &12zs1 Cystinuria may be a/w Ca calculi UASN 2015:16§543); may present w/ sraghorn calculi Dx: family history: stone analysis. hexagonal crystals on urine sediment Cyanidenitroprusside test screening: purple color suggest cystine >75 mg/L J urine cysteine level for diagnosis (>400 mg/d) and estimation of required fluid Intake Bx: rarely done; imratubular cystine crystals (KJ 200s;691127) Tx: T fluid intake to keep urine cystine <1 mmol/L (243 mg/L). urine alkalinization >7.5, low protein. sodium diet.Tiopronin (2mercaptopropionylglycine). Dpenicillamine (can cause MN.crescentic GN) AdENINe PHOSPHORIBOSYLTRANSFERASE (APRT) DEFICIENCY AR mutation ofARRT. purine metabolism enzyme -o T insoluble 2.8dihydroxyadenine (DHA) crystals in urine -» CKD. radiolucent stone (can be misdiagnosed as uric acid) Urine crystals with Maltese crosslike pattern under polarized microscopy Kidney Bx: tubular interstitial deposits with strong birefringence (an be misdiagnosed as oxalate) (NDT z01txzs=19o9) Tx: allopurinol 1 eGFR decline aim 2016:67;4J1l. low purine diet high fluid intake Txp: recurrence is commomfrequently diagnosed by graft biopsy DRUG Po m1in G CRYST AL S AND ST O NES Common risk factors: volumed depletion. high dose use. reduced kidney function Clinical manifesto:ion:AKI with resolution of dlc of dr; frequency radiolucent Drugs Forming Crystals Antivirals Acyclovir Atazanavir Fosarnet lndinavir a/w high dose IV. volume deplecionaganciclevir has lower risk In alkaline urine. Cryscalluria. Stone IA/xo zm 7;10.s7s1 AKI. crystal nephroparhies who Z015;6S:1$21 In alkaline urine. 8% developed urologic symptoms: renal coli: flank pain dysunia placelike rectangles and fanshaped or scarburs: forms lAM :m 19w=1271119) Antibaderlals CiproNoxacin Sulfonamides Other Drugs Sulfasalazlne Triamterene Mechotrexaw (MTX) Ephedrine Pseudoephedrine Dienkol Bean Mg crislllace In alkaline urine. In acidic urine. esp. sulfadiazine Andinflammatory agric used in RA and IBD an form crystals and stones (A/KD 10 I7;70M9) In acidic urine. MTX precipice in the cubules (NEW 10\5d73:15911 Ma huang containing ephedrine W*D 1994311531 Urolirhiasis (nm 1004.1%26!1 Meal in Southeast Asia: dienkolic acid forms needlelike crystal in acidic urine;AKL needlelike crysuls Silicate urolidliasis u up: weusuzsl Tx: d/c offending drug.volume repletion 1 loop diuretics. urine alkalinizadon with goal pH 7 in sulfadiazine, MTX. Urine acidification is no: recommended URINARY STONE DISEASE Conditions Associated with Urinary Stone 1 HPT Sarcoidosis dRTA CF ADPKD Dem disease Horseshoe kidneys Metabolic syndrome CaOx > CaP (W mi 1009;1031e701; consider parathyroideaomy CaOx > CaP CaP. nephrocalcinosis common CaOx; microscopic nephrocalcinosis 92% (NUM 19sa;J 1nsJ) Uric acid > CaOx we CaP CaOx Uric acid > CaOx 1993:27;$13) Clinical Manifestations Acute. colicky Hank pain radiating to d 1e groin: CVA tenderness may be present Hemaruria (9096): absence does no: rlo: Presence w/ flank pain is not dhgnosdc of stone I 26% of pos has persiszenr urereral stone after cessation of pain (I um:201B;19911011) \ workup rlo medicationinduced stone: triamterene. indinavir. atazanavir. sulfonamides, CAI (topiramate). cipro. Mg Trisilicate antacids abuse, guaifenesin. and ephedrine CT: preferred if urological intervention is planned: low dose CT may miss small stone Dual energy multidetector CT may characterize stone composition (Rmnaiqy 2010.1$7394) U/S: low sensitivity, no difference in important missed Dx dw CT (Nt/M 2014:37111100) MRI if pregnant; KUB for flu: IVP: less sensitivity/speciNcity S tra in u rin e to typ e sto n e . u rin e cu ltu re 24hr urine at home before dietary modification and after Frecipitating Factors of Crystals and Stones Type Related Condition A n y t yp e AKI. CKD - 1 HPT.Vil D excess. sarcoidosis.dRTA. hyperdvyroidism.cancer. Dem disease t Na. animal protein intake Hyperoxaluria (<40 mild) Hyperuricosuria (6 <0.B 9 <0.75 old) Hypocizraruria (6 >450 mg/d 9 >550 M8/4) Hypercysdnuria Urea splicing bacteria CaOx Ox intake. i Ca intake 1 hyperoxaluria Pyridoxine (vit B6) del. Small bowl disease or surgery CaOx. Uric T Purine intake. cell lysine. acid uricosuric aden: (probenecid. fenoNbrare. losartan) C a O x CaP T Nondairy animal protein, ; Nondairy animal protein/ Na intake. dRTA, hypoK. Na intake. Citrate. UTI . bowel disease. watching SS CaP and pH CKD (caution urine pH >6,5) Cysteine Genetic mutation Tiopmnin. Penitillamlne Mg ammonium UTI (Proteus. Pseudomonas, Treat UTI phosphate Klebsiella) f High sodium (<100 m a) Acidic urine (>6.5) Basic urine CaOx, CaP High sodium die: l Sodium intake Urlc acid. Cysteine. MTX. Sulfadiazine, Triamrerene High protein die: Alkaliniudon (citrate. bicarb) 1 Prouin imzke CaE Xamhine dRTA. CAI. urea splicing organism (>8) Antibiotic in urea splitting organism UTI MANAG E ME NT Acute Management IVF:T UOP; no A pain. rate of passage (1 emu¢uI 2006;20.71J1 Analgesics: ketorolac > meperidine (A~» HUH: m¢4 1996;2£:151) Passage of stone: small and distal stone u blockers: T passage of ureteric stones 25 mm (BMI 2016:355i6112); no difference in small stone with mean diameter of 3.8 mm kw :m 20I 8;I78:I051) Nifedipine: T passage of urezeric stones (Ann EmerlMe6 zoonsasszl "T m Urologic intervention: >10 mm. infectiomobstruction >4 d.uncontrolled pain Exuacorporeal shock wave lithotripsy (proximaI.<2 cm). ureteroscopic removal. percutaneous nephrolithotomy. open surgery 'i Longterm Management 2 PO fluid >2-2.5 Ud uvwi 199s=1s5=6391 Low Na diet; high Na -o hypercalciuriaz monitor w/ 24 hr vs High K diet: Y urine citrate. pH.volume. i ss CaOx and ss Uric acid <oAs~ z01&11:1 n4l Low protein diet: monitor urine sulfate. PCR Sulfur containing animal protein -» T urine acid loading -» 1 urine citrate Dairy protein is beneficial T urine citrate. 1 oxalate lcpsu 2016;111a341 Low ox diet avoid nuns. chocolate, dark green leafy vegetables. rhubarb. okra. beers High Cz dies: low calcium - T oxalate absorption U um 1012;187116451 Avoid excessive vitamin D: high 1.25(OH);D is alw stone (qAsn 201s;1cr"7l Diuretics with hypocalciuric effectszthiazide. amiloride Citrate Supplementations Used for inhibition of calcium stone formation and urine alkalinization ii uric acid stone Plasma alkalinization T renal Ca reabsorption L stone size. L new stone (Cuchmne Dalahdse So: no 20I 5;CD010057) K citrate: start 30 (urine citrate >150 mold) - 60 (urine citrate <150 mold) mE/d Compliance can be monitored with 24hr urine K amount (should be > dean prescribed amount; should 1 ammonia) It is normal to see K citrate tablet remnant in the stool Side effect; metabolic alkalosis (keep urine pH <7.5 In Ca? sine),t K. NNID Citrate and Bicarbonate Regimens 120 mL (4 oz) contains 5.9 g (-90 mEq) citric acid: urine citric acid by 142 mg/d u um: iwuisuon 5 mEq (540 mg). 10 mEq (1,080 mg) K citrate :ab (UrocirK°) K au-arecitric acid powder 1 packec K curare monohydrate 3.300 mg, citric acid monohydrate 1,002 mg = K 30 mEq. barb 30 mEq (CPU°K°) Solution: 1.100-334 my5 mL = K 10 mEq. bicarb K citratecirric acid (CyvnK¢. VirtrateK°) 10 mEq Solution:500-334 mg/5 mL = Na 5 mEq.bicalb 5 mEq Na dzratecitric acid (BIcil.ra°. cm 2" l Solution:500-550-334 mgl5 mL = Na 5 mEq,K5 mEq. Na citrateK citrateCitric acid bicarb 2 mE (Virtrare3°. Cyzra3°') 1g = 10 mEq:2.Sg= 25 mEq K bicarbonate:F(§)f1erK°. KlorCon/E Lemon juice INTERSTITIAL DISEASES ACUTE INTERSTITIAL Nap:mms (AIN) Interstitial nephritis may be acute, subacute. or chronic. Characterized by renal function and an inflammatory infiltrate limited to the tubulointerstitial compartment. AIN accounts for 12.9% of AKI: prevalence is increasing for 2013:18:112) Causes of AIr who 2014;64.558. al 2010;77.956) Drugs ( 70%): antibiotics (3576. PCN. FQ. cephalosporlns. sulfonamides, vancomycin), PPI (10%), unSAIDs (7%). 5aminosalicylatesa checkpoint inhibitors (KJ 2016;90:638). thiazide, allopurinol. Iamotrigine Autoimmune (-2094): sarcoidosis. Sj6grens.TlNU. lgG4nelated disease. ANCAvasculitis. MCTD. Sweet syndrome Others (10%): infection et, E cd!i.TB, leprosy. histoplasma, Candida. Cryptococcus (Ki 2009;761453). BK virus. Hantavirus; CLL mantle cell lymphoma. idiopathic In 65 Mylo drug (87%) especially PPI (18%) and antibiotic are more common (KI z01 s8714ss1 Antibrush border antibody disease: immune complex TIN d/t andbrush border antibody UASN 20\6:27380) against UASN 20lB:29:644) Clinical Manifestations Druginduced AIN may show triad (fever. eoslnophilia. and rash) in 10% (nor 2004119.81 Usually asymptomatic; NN malaise. arthritis Oliguric or nonoliguric, gross hemawria (596), Dialysis requirement (40%) (KI 101W79956) Laboratory Manifestations Azotemia. pRTA. eosinophilia Urine:WBC 1 WBC casts. eosinophilurla. occasionally bland sediment; microhematu ria common: RBC casts not typically seen. High FENa. lsosthenuria (SG 1.008-1.012). Tubular proteinuria. Nephroticrange proteinuria in NSAID induced MCD or MN Serology:ANA, antiDSDNA. antiRo/SSA. antiLa/SSb. C3. C4,ANCA. lgG4. Other systemic disease based on clinical manifestations (eg, chest imaging for TB. sarcoid) T IgG4 levels. lm/pocomplementemia in lgG4RD; Renal and abdominal masses may be seen Diagnosis Kidney biopsy is diagnostic: interstitial edema. infiltrate ofT lymphocytes and monos/:es > eosinophils. plasma cells and neutrophils. tubulitis: Interstitial fibrosis can be seen wu 7-10 d after inflammation initiation (xi z010n7956i IF: occasionally linear or granular tubular basement membrane (TBM) staining Pathologic Clues in Tubulointerstidal Nephritis Plasma cell rich infiltrate IgG4RD. Sj6grens. SLE, chronic pyelonephritis. HN BK virus, chronic Tcell-mediated rejection Nonnecrozing Drugs: unSAIDs. anzibiozics. thiazide. Iamorrigine. inzravesical granuloma BCG for 1N0s;2\.14z7l. adalimumab we 2010;S6:e17) Necrotizing granuloma Linear TBM IgG staining Granular or semilinear TBM IgG staining Sarcoidosis,ANCA GPA, Crohn disease.TlNU. infections TB we zooe:s 1:sz4). fungal infections AntiGBM disease and MIDD: wl GBM linear staining unSAIDs. allopurinol. phenytoin, mechicillin IgG4RD. MN. cryogiobulinemic GN. Hantavirus. autoimmune (SLE.Si6gren). anribrush border antibody disease. Idiopathic hypocomplemenzemicTIN WKD 200113723a8) Gallium67 scan: Gallium binds [O Iacroferrin on WBC: not sensidvelspecillc Treatment d/c of inciting drug;TreaLment of underlying infection eg.T8. fungus Glucocordcoidsz prednisone 1 mg/kg daily or 2 mg/kg god for 3-12 wk: long duration is not alw improved outcome (cyAn Z01B; 13:1851). Poor response with co delay. severe tubular auophylinnerscirial fibrosis and small kidneys (A/KD 2014.s¢25581. MMF: - Cr in steroid imolerantlrelapsing cases LC/ASN 1006:1:71B) Prognosis Most recover after dl: d causative drug: median recovery time 3 wk in iluoroquinolone associated AIN (map cu, Pix 201891151 Poor prognostic factors: higher degree of interstitial fibrosis/tubular atrophy. small kidneys. longer duration of drug exposure. longer time from AKI onset or bx to steroid treatment We 2014;s4s5sl.The majority of patients do no reach ESRD. Early steroid zreacmen: may improve recovery in druginduced AIN. Chronic dialysis in 44.4 (wl steroid) vs 3.8% (w/o spheroid) (Kl1008:7J=940) TINU SYNDRONE Subset of patients with tubulointerstitial nephritis have uveitis (TINU) HLADQA1*01, HLADQB1*05,and HLADQB1*01 may be associated Monomeric CRP may be pathologically implicated Clinical and Laboratory Features Median onset 15 yr (9-74); female preponderance (Sury Opiiwimii 2001:4e19s) Systemic symptoms: fever, wt loss. fatigue may be present Uveitis: typically bilateral (unilateral or alternating may occur).Timing2 mo before, concurrently,and up to 14 mo after TIN. Slit lamp examination to contirrn diagnosis. TlN: usually AlN. Signs of proximal tubular dysfunction may be seen. On renal biopsy nonspecific interstitial infiltrate. sometimes granulomas present Treatment Renal disease is though: to be selfIimized We 1999;34¢101s) For progressive renal disease. prednisone 1 mg/kg/d (4060 mg) for 3-6 mo followed by a taper (based on response). Limited experience with steroidsparing agents. CHRO NIC TUBULO INTERSTITIAL DISEASE Chronic tubulointerstitial injury can cause interstitial fibrosis. tubular atrophy (IFITA). and macrophage and lymphocytic infiltration I: can happen from primary tubulointerstitial injury or secondary to glomerular injury The degree of IFITA predicts renal prognosis in all type of renal injury Causes Drugs: lithium. Cyclosporine, tacrolimus. cisplatin. indinavir (crystal nephropathy) Toxins: aristolochic acid, heavy metals (lead, cadmium. arsenic, mercury. gold. uranium) Analgesic nephropathy. radiation. obstruction Chronic pyelonephritis.xanthogranulomatous pyelonephritis. malakoplakia Vascular ischemia, renovascular disease Metabolic hyperuricemia. hypokalemia. hypercalcemia. hyperoxaluria. nephrocalcinosis Mesoamerican nephropathy, Balkan nephropathy Progression ofAln and primary glomerular disease Clinical Manifestations and Diagnosis CKD, salt wasting. salt sensitive HTN; RTA pRTA, dRTA. type 4 all possible Nephrogenic DI: decreased concentration ability dlt medullary dysfunction Tubular proteinuria unless secondary to glomerular disease. bland urine sediment Anemia: relatively early stage CKD dl: l interstitial erythropoietin production Imaging: small kidneys w/ indented or irregular contour: papillary calcification in analge sic nephropathy;cysfJc changes in lithium nephropathy; nephrocalcinosis on UIS or CT T r eatment Identify and stop insult If possible: manage CKD: prepare RRT Hereditary Tubulointerstitial Diseases Autosomal dominant tubulointerstitial kidney disease (ADTKD. aka medullar cystic kidney disease). nephronophthisis (NPHP).and cystinosis can manifest with CKD Hereditary Tubulolntersdtiai Disease 0KI>160 xr 101 ssas1s) Disease Gene Pathogenesis and Manifestation ADTKDUMOD UMOD ADTKDHUC1 Mucin 1 ADTKDREN REN ADT KDHNF 1B HNF1B NKCC2 expression water sodium loss -» T FT uric acid absorption. FErrate <5% 1 Urine uromodulin excretion Hyperuricemia.gouL and ESRD at median age 24. 40, and 56. respectively ic;As~ 2013;8:1349) Intracellular accumulation of rnucin1 frameshifi: protein In distal lobule Childhood anemia. hypotension. frequent AKI. T K Tx: avoid unSAIDs. low sodium die: Mamriiy onset diabetes at die young type 5. neW cysts. renal Mg wasting. pancreatic aunphy genial abnomnlides NPHP (AR) NPHP1 10 Retinal degeneration Cyszinosis (AR) crns Fanconi syndrome, photophobia (corneal cystine crystals), CKDIESRD (c/Asn zaaeanil IMMUNOGLOBULIN G4-RELATED DISEASE l8G4: higher rate of dissociation :han other IgG. does not fix complement by the classical pathway. may bind other lgs and form immune complexes Immunoglobulin G4related disease (lgG4RD): autoimmune intiiuatiwle condition that involves multiple organs including the kidney with serum concentrations of lgG4 Virtually any organ may be involved including pancreas. biliary use (sdertasing cholangitis). aorta. Iung.salivary and lacrimal glands.thyroid. pachymeninges.and kidney Clinical Manif est at ion Common in older, male,Asian. and Caucasian Asthenia (26%), weigh: loss (21%), fever (4%) (MHZ an am z0\s9092n From a renal sundpoinr pos present with worsening renal function. or kidney masses Occasionally. NS from concominan: PLAZR Ab (-) MN no z0135sa14ssl Obstructive uropathy from renroperkoneal fibrosis; lgG4RD was 54% (Muadae 2013;92=B1) Workup Azotemia. hypocomplementemia (60%. C3 and C4).eosinophilia (40%) Variable proteinuria. hematuria.and pyuria T IgG4 levels (typically 68fold ULN) in mos: patients Typically needs a biopsy to confirm :he diagnosis Mia ramp 20\z;1s;1\s1).The 3 major histology criteria are: (1) dense lymphoplasmacytic inNltratea (2) Fibrosis, arranged at least focally in a storiform pattern: (3) Obliterative phlebitis IF:TBM immune complex deposits (80%) Nor all features are present simultaneously and some of :he features predominate in some organs (eg. storiform Fibrosis in pancreas. not commonly seen in kidney). Further the number of IgG4 cells may vary Diagnostic Criteria for lgG4related Kidney Disease (at up ~=»»~w 2011;1s:s1s) 1. Kidney damage Abnormal urinalysis or urine marker(s) or decreased kidney function widl either elevated serum IgG level. hypocomplementemia, or 2. Renal imaging (CT Sa n is th e best) a. Multiple lowdensity lesions on enhanced CT elevated serum IgE level b . Dif f u se kid n e y e n la rg e me n t C. Hypovascular solitary mass in the kidney d. Hypertrophic lesion of the renal pelvic wall without irregu la rit y o f t h e re n a l p e lvic su rf a ce 3. Serum lgG4 >135 mgldL 4. Renal histology a. Dense Iymphoplasmacytic infiltration MM infiltrating lgG4 positive plasma cells >10/high power field (HPF) and/or ratio of lgG4positive plasma cells/IgG positive plasma cells >40% b. Characteristic "storiform" fibrosis surrounding nests of 5. Extrarenal Dense lymphoplasmacytic infiltration with infiltrating lgG4positive plasma cells >10lHPF and/or ratio of lgG4positive plasma cells lymp h o cyt e s a n d / o r p la sma ce lls histology IgGpositive plasma cells >40% De f in it e 1 +3 +4 a .b ; 2 +3 4 l.b l 2 4 ,5 P ro b a b le 1+4a.b:2t4a.b;2-5; 34a.b Possible 1+3:2+3: 1+4a. 24a T reat m en t The optimal therapy is unknown (no RCT) CS: 1st line: prednisone 0.6 mg/kg daily for 2-4 wk. tapered over 3-6 MO. Mos: authors favor maintenance 2.5-5 mild for up to 3 yr (co open Rhematol 1011:2367) Azathioprine and MMF: steroidintolerandrelapsing pts (aasziuenxuulugy 200¢;1J4=70s) Rituximab in glucocorticoidrefractory or relapsing pts (Anhnus Rheum 2010<67;1755) Unclear whether renal masses without symptoms need treatment Prognosls In giucoconicoidtreated pus. despite improvement in eGFR,there was progression of renal atrophy on imaging In 2o13:s4:aza> Relapses occur in ~20% pos SPORADIC CYSTIC DISEASES Simple Renal Cysts Benign renal cysts are rare in children. but occur commonly in advanced age Most often simple cysts are asymptomatic and detected as incidenizl findings during abdominal imaging studies; usually of no clinical significance U/S: smooth walls.good sound transmission.and no inrracystic debris II UIS is indeterminate/ CT On CT. benign cysts have homogenous attenuation, no conrrasz enhancement, and smooth walls wirhou: calcifications. I II IIF Ill IV The Bosniak Category Classification on CT Imaging luiuligy zausaswi Features wlo Contrast Features wl Contrast Hanagement Water density (0-20 HU). thin No contrast margins. sharp delineation with enhancement d1 e renal parenchyma. thin and smooth walls. homogeneous No furdier wvflwv or an ukrascncgram Presence of one or few thin No contrast in 6-12 mo septations. small and fine enhancement. or no measurable or akiiiauonsz hypcrdaise cysts masuriig up no 3.0 cm (60-70 HU) perceptible enhancement of septa More complex lesions which cannot Absent. dubious. or hair be included in category II or Ill. like enhancement Multiple septa.walls or septa Continued with nodular or irregular surveillance calciflations. Hyperdense cysts >3.0 cm or with only 25% of their walls visible (exophytic) Wall or septum Conmuea surveillance. Thickwalled cystic lesion, septum irregularity and heterogeneous enhancement he neede biopsy. in nephiemmy septum and wall and/or contents: Gross and irregular calcifications Lesions with all the Endings of Enhancement of wall Require surgery (malignancy in category Ill. and solid component. and/or solid soft parts. independent of finding component(s) 85-100%) of wall or septa Acquired Cystic Kidney Disease (ACKD) Occurs in individuals with advanced CKD or ESRD The occurrence of acquired renal cystic disease increases with the number of years on dialysis,the majority of patients develop cysts after 5-10 yr on dialysis The cysts in ACKD are more numerous than benign simple renal cyst,but share similar radiographic features ACKD is associated with increased risk of malignancy Hypokalemiarelated Cystic Kidney Disease Prolonged hypokalemia due to urinary K wasting (such as in primary hyperaldoste ronism) predisposes to kidney cyst formation Medullary Sponge Kidney A congenital disorder;malformation of the terminal collecting ducts in the pericalyceal region of the renal pyramids, Usually bilateral Etiolcgyn unknown; not clear it the disorder has genetic basis Clinical presentation: mostly asymptomatic. Incomplete or oven dRTA in >80% of pts. Recurrent calcium kidney stones. gross or microscopic hematuria w/ or w/o stones. UTI. flank pain wl or wlo an obstructing stone or UTI. Usually remains undiagnosed or is discovered incidentally by a radiographic study. The diagnosis can be made by IVP or noncontrast CT Prognosis: renal function remains nl in most cases. However,there is a risk of renal injury dlt recurrent stoneinduced episodes of obstruction and/or infections. Treatment; manage UTls and recurrent stones HEREDITARY CYSTIC DISEASES AurosomAL DOMINANT PoLycvsTlc Kinnsv DisEAss (ADPKD) The mlc inherited renal disease affecting 1 in 500-1.000 individuals Accounts for 5% of ESRD population in :he US The penetrate is incomplete: family history is positive in only about 60% of cases Clinical Manifestation The clinical onset typically occurs from the third through the fifth decades of life Massive enlargement of the kidneys due to the gradual development of cysts that arise from the dim! nephron segments and gradually replace normal renal parenchyma. ultimately leading to progressive functional impairment Hypertension: die earliest and most prevalent manifestation: frequently predates the onset of renal dysfunction: Likely caused by activation of die reninangioteisin-aldosterone Flank or abdominal pain (compression by enlarged kidneys) Macroscopic hemamria (cyst hemorrhage). lowgrade proteinuria (tubular dysfunction) Fever and abdominal pain (cyst infection). kidney stones (stagnant urinary Row) Decreased concentrating ability (distorted anatomy of the medulla) Extrarenal manifestations: Gastrointestinal system: hepatic cysts and colonic diverticula Cerebral aneurysms: relatively rare (<10%) Heart: patent foramen ovals (PFO). mitral valve prolapse (MVP) Abdominal wall and inguinal hernia Subcutaneous. ovarian. testicular: seminal vesicle. pancreatic. and pulmonary cysts Diagnosis The preferred diagnostic procedure is renal ultrasound: multiple bilateral kidney cysts in the setting of a positive family history are typically diagnostic Diagnostic Criteria ofADPKD (n r 100% specificity 100% PPM82-100% sensitivity depending on the age group) (MW znonuzosl Age Diagnostic Number of Cysts 15-39 ylo A: least :hree unilateral or bilateral kidney cysts 40-59 y/o At least :we cysts in each kidney >60 lo A: least four cysts In each kidney 10yr ESRD risk can be calculated by total kidney volume (TKV) or kidney dimensions (Available at QxMD app:}Asn z01sa6. 14o) G e n e t ics a n d P a t h o g e n e sis ADPKD is caused by mutations in PKD 1 (75-85%) or PKD2 (15-25%) The proteins encoded by PKD 1 and PKD2.polycystin1 and polycystin2.are compo nents of a multifunctional signaling pathway that regulates key cellular processes including grovnh. differentiation. and orientation of tubular epithelial cells: polycystins form signaling heterodimers that localize to primary cilia of all epithelial cells Direct sequencing: because of high cost. primarily used for the evaluation of atrisk individuals with equivocal imaging resuks. younger atrisk individuals being evaluated for living kidney donation. and individuals with atypical cystic disease Sanger sequencing of all exons and splice junctions of the PKD 1 and PKD2 genes is the method of choice. Mutation screening of PKD2 is straightforward. but PKD 1 is challenging because it is a large gene with its first 33 exons duplicated in six pseudo genes. Current diagnostic sequencing protocols exploit rare mismatches between PKD 1 gene and its six pseudogenes. If Sanger sequencing is ().one should test for structural rearrangements. which occur in <5% of the cases.These can be detected b y a d d i t i o n a l ML P A t e st i n g . NextGen sequencing panels are gaining popularity and will likely replace Sanger se q u e n cin g g ive n th e ir d e clin in g co sts Patients w/ PKD 1 mutations have earlier disease onset and T progression to ESRD T reat m en t No curative ueaunenr. -50% of patients reach ESRDbefore the age of 60 Primarily directed toward complications: HTN, infections. pain,and hematuria Dietary salt restriction: may slow eGFR decline (KJ 2017;91;493) HTN: control w/ RAAS inhibitor In eGFR >60. intensive BP consol (95160-110175) i KTV Increase and urine albumin excretion wlo AeGFR il4Aun(o NS/M 1014;371Q.255) In eGFR 25-60. addition ofARB to ACEI did not aker AeGFR u4ALrn<o new zo\4s1men V a so p re ssin su p p re ssio n n o in h ib it cyst g ro wth f Fluid intake: >3 Ud (C/ASN 201015:-s); difficult to achieve daily for many patients Tolvapun vs placebo L renal function decline in eCrCl >60 uwro NEJM zo 12;a67:z40n Tolvaptan vs placebo L renal function decline in eGFR 25-65 t Liver enzyme (>3x baseline) in 5.6% of the tolvapmn vs 1.2% in the placebo group. These changes normalize after d/c of tolvapizn. Up to 6.8% of patients do not tolerate aquaretic side effects (polyuria. nocturia. thirst) inermse new 20 l7;377:1930) Longacting octreotide: not statistically significant 1 AKW (lim to13;zaz14es) Everolimus: l AKTV w/o effect on renal progression (NEW zo 1o.a6a:.:ol AuTosor4AL Recessive PoLycvsTlc Klonsv DlssAse (ARPKD) ARPKD is a rare AR disorder that usually presents in early childhood The prevalence is approximately 1 in 20.000 individuals ARPKD is invariably associated with liver fibrosis and portal hypertension Both kidneys are enlarged w/ a cystic dilatation of the renal collecting ducts Clinical Manifestacion: Bimodal Newborns can be diagnosed by prenatal US and present with severe renal failure. oligohydramnios. and lung hyperplasia (30% of infants die of respiratory failure) • Older children and adolescents may present with complications of portal hypertension, such as hepatosplenomegaly and bleeding from esophageal varies. Severe systemic hypertension in the setting of renal dysfunction is also common. G e n e t ics ARPKD is caused by mutations in the PKHD gene encoding fibrocystin. a large ciliary protein found in renal and biliary epithelial cells Dysfunction of fibrocystin leads to altered ciliary signaling,which is normally required for regulation of proliferation and differentiation of renal and biliary epithelial cells Tre a t me n t T her e is no cuntive tr eatment for ARKD Infants surviving the newborn period should be monitored closely for decreased re n a l fu n ctio n . h yp e rte n sio n , in fe ctio n s. a n d d e h yd ra tio n Most cases progress to ESRD requiring dialysis or kidney uansplantatlon NPHP is a rare AR disease :had presents as severe chronic tubulointerstitlal nephritis Th e in cid e n ce is le ss :h a n 1 in 5 0 .0 0 0 in d ivid u a ls Clin ica l Ma n if e st a t io n s Low urinary osmolarity (<300 mOsmlkg) d/t reduction in the ability to concentrate urine in early childhood causing polyuria and polydipsia Urinary sodium wasting is also present and may cause hypovolemia Progressive renal failure manifests as poor growth and anemia ESRD develops at a mean age of about 13 yr but can also occur during adulthood The most frequent extrarenal manifestation is retinal degeneration causing early b lin d n e ss,with a n in cid e n ce b e twe e n 1 0 % a n d 3 0 % Dia g n o sis Renal ultnsonography is useful only in the advanced stages of the disease. when renal cysts a re visib le . Kid n e ys a re typ ica lly h ig h ly e ch o g e n ic. Although biopsy findings combined with clinical presentation can be suggestive of NPHR genetic testing is the only definitive diagnostic modality G e n e t ics Mutations in several genes (NPHP1 through NPHP10 and likely many more encoding various clllary proteins) are responsible for NPHP The presence of die NPHP gene products in cilia of various organs (photoreceptor. tubular cells.cholangiocytes) explains extrarenal manifestations in some patients • Molecular testing by sequencing is now available, NPHP genes are included on several kid n e y d ise a se Ne xtGe n se q u e n cin g p a n e ls Treatment No curative OC; Mos: cases progress to ESRD requiring dialysis or kidney uansplancation AUTOSOMAL DOMINANT TUBULOINTERSTITIAL K IdN e Y D ls s A s e (A D TK D ) ADTKD.aka Medullary Cystic Kidney Disease (MCKD). presents as severe chronic tubuloiniersdtial nephritis. similar (O NPHP Distinct from NPHP by its AD inheritance and by the late onset of renal failure Clinical Manifestation Typically present after the third decade of life with advanced CKD Exvarenal manifestations include hyperuricemia and gout The kidneys have echotexzure. but there are no visible cysts by u/s Kidney biopsy: chronic zubuloinrersddal nephritis. :ubular atrophy and mkroscopic cysts in :he medulla or as the corticomedullary iuncdon (similar Findings to NPHP) Genetic Mutations in 2 genes encoding proteins produced by the renal tubular epithelium MUC1 gene: encoding mucin1. a transmembrane protein expressed on the apical surface of mos: epithelial cells.Among other functions, muslin provides a protective barrier to prevent pathogens from accessing the cell. In the kidney. mucin1 is strongly expressed in the loop of Henle. DCI and the collecting duct.A single cyto sine insertion into one variablenumber tandem repeat sequence within the MUC1 gene cause ADTKD. Not detectable by standard genetic tests and can only be tested in a research setting. UMOD gene: encoding uromodulin (Tamm-Horsfall protein).This protein is produced and secreted by TALH. Sanger sequencingbased mutational analysis of the UMOD gene is commercially available and can be used to establish a molecular diagnosis. Treatment No curacive treacmenr for ADTKD Xandmine oxidase inhibitors (allopurinol or Iebuxosrac) should be used for prevention in pts with recurrent gouLThere may be a role for these drugs in slowing CKD pro glession in asymptomatic pos if started early (Qin 20GZ:95:S97) Summary of lnherleed Cystic Dlsorden ADPKD (AO) ARPKD (An) NPHP (AR) PKD1,PKD2 M4401 NPHP 1-12+ Gene (Polycystins1 (Fibfocystin) (Nephrocyslins. (Protein) and 2) other ciliary proteins) Tubules (cilia) Tubules (cilia) Localization Tubules (cilia) Newborns md Children and Onset Adults >30 ylo children adolescents Massively enlarged Enlarged kidneys. cysts Normalsrted Imaging kidneys. multiple visible only in kidneys without large cysts easily advanced disease cyso. increased visible echotexwre Massive cysts char Cystic dilatation of the Chronic Pathology replace normal renal CDs tubulointerstitial renal nephritis parenchyma Urinary HTN.1lank pain. Putter syndrome. Clinical cyst infection, respiratory failure. concentrating Features deject. renal nephrolithiasis. hepatosplenarnegaly. variceal bleeding. failure wlo hematuria. Iow hematuria. low hemawria or grade proteinuria. proteinuria, grade proteinurla. renal failure. lung =~=w=h failure. renal failure. retinal hepatic cysts. hyperplasia. liver llbrosis. portal HTN degeneration cerebral (retinitis aneurysms, PFO. pigmentasa). MVR colonic diverticula blindness ADTKD (Ap) MUC 1 (Mudnl ). UMOD (Uromodulin) Tubules (avid) Adults >30 lo Norrnalsited kidneys without cysts. increased echotextaure Chronic tubulointerstitial nephritis Urinary concentrating defect. renal allure wlo hematuria or proteinurla. hypemnicemia. gouty arthritis RENAL CELL CARCINOMA (RCC) Background Renal mass is frequently found with imaging during AKIICKD w/u 2 6 % o f RCC p t s h a d CK D b e f o re t u mo r nephrectomy (Lancer o»¢ul2006;773sl Risk Factors and Pathogenesis Smoking. H T N , C K D . obesity. Pl: F 1. 6: 1 A cq u i r e d cyst i c ki d n e y disease lqAsn 2007:z:7so): T wl dialysis duration or z011211:ae1 Type (94) Type of Renal Cell Carcinoma Origin Associated Genes and Pathway Clear cell (75-90) PT VHL.TSC 1/TSC2 BAP1 mu aw Res 101111:1061) Papillary (1020) PT Type 1: MET Type 2: NRF2ARE Chromophobe (5) Collecting duct (<1) Medullary (<1) DT CD Medullary Fo llicu lin (FL CN): Bin -Ho g g -Du b e syn d ro me pathway (N£jM 2016;374:1351 Sickle cell t rait > SCD von Hippo-Undou (VHL) gene:encodes VHL protein. E3 ubiquity ligase: proteasome deg radation of a hypoxiainducible factor (HIF). transcription factor of erydiropoietin gene VHL syndrome:AD VHL mutation causing constitutive activation of HIF Odmer malignancies: hemangioblastoma (CNS, retina). pheochrornocytoma. pancreatic serous cystadenomas and neumeidociine tumor. middle ar endolymphadc sac tumors VHL somatic mutation is found in 91% of clear cell RCC (an Canter Ra 200e;14:4726) Tuberous sclerosis: angiomyolipomas > benign cysts, RCC, lymphangioma Skin: forehead papules. plaques. lower trunk, angioiibroma Birt-Hogg-Dube syndrome: mutation of folliculin gene; bilateral mukifocal RCC Clinical Manifestations Hematuria. flank pain. HTN. fever, fatigue. weigh: loss. anemia. hepatic dysfunction Cxosteolytic metastasis. IL6 mediated PTHrp. PG mediated bone :sorption Erythrocytosis: erythropoietin production NS with M amyloidosis. Ig/NN 1/3 of diagnosed with metastasis Diagnosis UIS simple vs complex cyst Contrast CT: standard imaging test; required for Bosniak classification of cystic disease Surveillance of Complex Renal Cysts Bosniak Classification u W z017:19mn) Category: Imagining Features Intervention I: simple cyst II complex cyst with din septations IIF: complex cyst with mulr.iple chin or minimal thickening sepadons wlo masurahk enhancanent III: complex cyst with thickened irregular or smooth walls. contrast enhancing (>1S HU) IV: Ill + solid component. enhancing soft :issue RCC Risk None None F/U 6-18% Surgery or dose FIU 51-55% Surgery 89-91% 80% continued surveillance and 20% (596 of Bosniak IIE 30% of Ill. 62% of IV) under went surgery. mecaszasis, death rare. suggesting surveillance is safe (jUuI2018:1996JJ) Renal Mass Biopsy it Ural 1017.198510) 14% nondiagnosticzvery high sensitivity. specificity. and PPV Consider to rule our hematologic. metastatic. inflammatory, or infectious mass US or CTguided multiple core biopsies Not required if it would not A management (1) young pts who are unwilling to accept the uncertainties: (2) older/frail patients who will be managed conservatively No reported cases of tumor seeding in the contemporary literature RCC Staging and Primary Treatment Treatment Stage TNM T1 ($7 cm, limited to due kidney) NO T1a (54 cm) T1b (>4. (57 cm) T2 (>7 cm. limited to :he kidney) NO T1 or 2,N1 (regional LN) I II Ill PN PN (or RN) RN (or PN if clinically Indlazed) 4 adjuvant treatment T3 (major veins or perinephric tissues) N (advanced) Nephrectomy + merastasectomy or Systemic therapy 3. cytoreductive nephnectomy T4 (beyond Gerota fascia) or M1 (distant metastasis) Nephrectomy Partial Nephrectomy (PN) vs Radical Nephrectomy (RN) WASH um: za11;19&5w1 PN Preferred RN Preferred cT a (54 cm) renal mass Anazomic or functionally solitary kidney bilateral tumors. familial RCC Preexisring CKD. or proteinuria High tumor complexity No preexisting CKD or proteinuria Normal contralateral kidney and new baseline eGFR will likely be >45 Young. have multifocal masses. or comorbidizies Thai: are likely to impact renal function in the future Split radionuclide :wal San an be done co predict posuiephrectomy dialysis requiranent CKD incidence after nephrectomy UASN 201 $.29:207): 7.9% (CKD45). 14.2% (CKD3b5) PN (vs RN) was alw L CKD 4-S (x0.34).l CKD 3b-5 ()<0.15).. mortality (x0.55): CKD Risk Acton: prop renal function. tumor >7 cm. old age Renal function decline occurs within 12 mo after surgery PN was a/w less eGFR fall than RN by 10.5 (qAs~ 201721z.\0s71 AKI postsurgery increasing co 10.4%. alw male. RN, older age. black race. higher comorbidities. preoperative CKD stage (up: of 2016;34:293.e1) Concurrent RN and IVC thrombectomy alw higher incidence ofAKl and CKD Surgically induced CKD has less annual renal function decline than preop CKD (4.7 vs 0.7%). Postop mortality was higher in preop CKD x1.8 (CKD3).x3.S (CKD4). and x4.4 (CKDS) Uu~l20u:1e9.1649) Kidney biopsy review of nontumor tissue by medical renal pathologist in all pts with preop CKD and proteinuria: 15% had renal disease: severe vascular sclerosis (>50% luminal narrowing). global sclerosis >5% and IF/TA >10% was alw postoperative cre atinine elevation wairuviu Lan M44 2013;137$31] Systemic Therapy Rand Toxicity of Systemic Therapy for Advanced RCC IFNn2a (um 2007;]102 lOJ) Anziangiogenic VEGFl:7rosine kinase inhibitors Bevacizumab annul 2(ll7;]70:2103) Collapsing FSGS.TMA TMA (prozeinuria and HTN) HTN could be a biomarker of efficacy UNG 2011;103:763) Scnfenib we 10014512031 Sunizinib man 2857135611s¢n£w10\5:37S:1246) Sunitinib alone no! inferior to nephrecromy + Sunininib (NE/M zo1a1n4wl Pazopanib (1 Cin Onan!201M8:1061) Axkinib (num 2011:mmn Cabozanzinib WSW 201S:J7J:1B141, Lenvaninib Tubulointerszitial nephritis Checkpoint inhibitors Nivolumab + ipilimumab (~=w 20\B.37&1177) Avelumab wl axidnib (NEW 201%38&1103) P e mb r o l i zu ma b wl a xi r i n i b h e l m roTOR inhibimrs Everolimus Temsirolimus IL2 (KJ2016;91k638} zoimmniq AKI(AMC Cam 1014;l4:906) ATN un Once 1013:14:1411) Capilla leak AIN Transplantation • RCC risk: KTR >other organ txp 1e cipient > general population UAMA 1011;306:1891) alw graft failure: kidney function associated >immunosuppresslcn effect UASN 2016;27:1495) Risk factors: black. prolonged dialysis predicting KT: 89% in native kidneys papillary RCC risk is esp high or 20162163a4791 Transmission Risks of Donor RCC WT 201I;I1:1140) Minimal (0.1%) Resected solitary RCC 51 .0 cm. well differentiated Low (0.1-1%) Resected solitary RCC 1.0-2.5 cm. well differentiated Intermediate (1-l0%) Resected solitary RCC T1b 4-7 cm.well differentiated High (>10%) RCC >7 cm or stage II-Iv Screening U/S wu 1 mo of exp. :hen q5y wlo cysts: q2y w/ cysts WT z011:11;a6) Background Common cause of CKD in children with CAKUT (mau nepmu 2016;31;l411) In adults. more common in men due to prostatic enlargement Pathogenesis UTO an occur anywhere in the urinary USC! system Renal tubular lniury is the consequence of mechanical stretching. hypoxia.and exposure to oxygenfree radicals that result (1.um¢4 Res jin 2014:2014:303298) Causes of Acute UTO Oudlow obstruction: mechanical (narrow urethra) vs dynamic (i muscle zone) Neurologic impairment: in sensory or motor nerve supply to detrusor muscle inefficient detrusor muscle. following anesthesia Medications. particularly anticholihergics and sympathomimetic drugs Trauma: Urinary tract infection (UTI) Causes of Chronic UTO Children: posterior urethral valves. ureterovesical. or ureueropelvk junction obstruction Young adults: nephrolithiasis Older adults: BPH. malignancy, nephrolithiasis, retropericoneal fibrosis Clinical Manifestations Acute UTO: hemawria.AKl,+/- pain. abdominal distention. hypertension, UTI Nondilated obstructive uropadiyc happen with volume depletion. hypotension. infilua due metastatic cancer and reuoperkonml fibrosis: Percutaneous nephrostomy tube placement and resolution ofAKl is diagnostic um Fu z010.122uu1 Chronic UTO: may be asymptomatic. Overflow incontinence sometimes. nocturia Discovered during workup of renal insufficiency. Workup Renal UIS: false 1.) rate of mild hydronephrosis wlo UTO is 26%. NPV of 98% Color duplex Doppler: intrarenal artery resistive index >0.7 in obstruction due to vasoconstriction Bladder ultrasound: can ald In evaluating for trabeculation of bladder wall and postvoid residual. as well as bladder wall mass or bladder stone Noncontrast CT scan: recommended for nephrolithiasis when presenting with signs of renal colic (severe flank or groin pain. emesis. gross hematuria) or risk factors (family history or prior renal stone) or in patients with polycystic kidney disease Cystoscopy/retrograde pyelography: if UIS (-) and obstruction is suspected Stenography:Te 99mMAG3 San with IV furosemide to differentiate collecting system dilatation from obstruction Cystoscopy and aerodynamics in patients with suspected oudlow obstruction Differential Diagnosis of Hydronephrosis Peripelvic cysts. exuarenal pelvis.dilated renal veins Hydronephrosis without obstruction: notable in pregnancy Obstructive Nephropathy (~flm i 9s1:104:37s) t intratubular pressure - renal vasoconstriction. rapid ' in renal blood flow and GFR.with interstitial fibrosis and nephron dropout if obstruction is prolonged Chronic obstructive uropathy alw hyperkalemia and dRTA Treatment Dependent on location and etiology of obstruction Oudlow obstruction: clean intermittent catheterization and bladder management Nephrolithiasis: stone and urine analysis for mineral solubility Increase urine How >2 L daily and low salt diet Mass or obstructing stone. nephrostomy until obstruction removed If bilateral chronic renal obstruction is relieved. may experience postobstruction diuresis, monitor for hemodynamic instability if unable to keep up with urine output Prognosis If acute urinary retention is addressed <72 hr. likely complete renal recovery If obstruction remains >2 wk, recovery less likely if not achieved at 12 wk Risk factors for worse prognosis include recurrent obstructive renal disease. hyper tension. diabetes. obesity. and albuminuria REFLUX NEPHROPATHY Background and Pathogenesis limn 1015:J85:371) VUR: the retrograde passage of urine from bladder into the upper urinary tract 1 VUR: incompetent closure of ureterovesical junction (UVJ). which contains a seg men: of the ureter within the bladder wall. Reflux is prevented by bladder contraction compressing the intravesical ureter and sealing it off with bladder muscle. Congenital short intrayesical ureter. LowgradeVUR may improve with pt growth. 2 VUR:abncrmally high voiding pressure in the bladder results in failure of closure of the UVJ during bladder contraction Anatomic (posterior urethral valve) vs functional obstruction (neurogenic bladder) Epidemiology 1VUR occurs in 1% of newborns. incidence higher in neonates with prenatal hydro nephrosis, and in children with febrile urinary tract infections White children are 3>< (than black children): : ,: = 2 : 1 Genetics: familial rate is higher for milder forms of 1°VUR.Although no single gene mutations have been identified certain syndromes may be a/w VUR. eg. renal coloboma syndrome (Cu Genaro 2016217;701 Clinical Manifestations and Workup Prenatal hydronephrosis.with prevalence rate ofVUR of 16.2%; Febrile wl UTI Renal and bladder U/S; Lab: serum creatinine. urinalysis. urine culture Voiding cystourethrogram is the diagnostic procedure of choice. Radionuclide cystog raphy is an alternative method and may be used to monitor pts. Dimercaptosuccinic acid (DMSA) renal scan to detect renal cortical abnormalities Grading of VUR (International Reflux Study Group) Grade I Grade II Grade III Grade IV GradeV Reflux fills ureter wlo dilatation Reflux fills ureter and collecting system wlo dilaution Reflux fills/mildly dilates ureter and collecting system w/ mild blunting of calices Reflux Wllslgrossly dilates ureter and collecting system wl blunting of calices 4 Tonuosiry of ureter Reflux dilates collecting system. calices are blunted wl a loss Mild Moderate Severe of papillary impression: + Ureteral dilation and tortuosiry Prognosis I/ um: 1997;1571646) 1°VUR usually spontaneously resow when age of diagnosis is <2 lo. unilateral I and II resolves in 80% of children by age 5 Ill with bilateral involvement at age 5-10 yr had lowes: spontaneous resolution (20%) vs children presenting at 1-2 yr with unilateral disease (70%) IV: 60% (unilateral) and <10% (bilateral) resolution despite age at presentation V: spontaneous resolution rare.except in 6 infants (30% resolve in 1" year of life) Recurrent UTI:giade III and IV (23%) vs grade I and II (14%) up new 2014:168t8931 General Treatment Surveillance is recommended for mild Glade HIVUR as these usually selfresolve Monitor for symptoms. best in children who are verbal and toilettrained Prophylactic Antibiotics for Recurrent Pyelonephritis and UTI Indications: not toilettrained or have bladder and bowel dysfunction, with any grade: moderate to severe VUR (lll-V); recurrent febrile UTls regardless of grade ofVUR TMPSMX or cotrimoxazole. nitrofurantoin. cephalexin, ampicillin. and amoxicillin. although resistance to E coli UTls do arise (lam z01s¢sas;z11l Stopping antibiotic: reevaluation ofVUR as child grows or after correction ofVUR Prevention of Renal Damage:VUR Correction Indications: IV-V beyond age 2-3, medical therapy failure wl breakthrough infections Open surgical reimplantation (ureteroneocystostomy UNC); permanently corvectVUR vs endoscopic injection (EI) of a biodegradable polymer (can have recurrent VUR) Repeat imaging routine to flu endoscopic correction, and in setting of recurrent UTI UNC more likely to have higher 30d GUrelated readmissions compared to El (4.8% vs 1.1%. OR = 4.76): however. El demonstrated increased odds of repeating antirefiux procedures (OR = 7.13) u haw Url 2017:13:S07.e1) URINARY TRACT INFECTION (UTI) Definition (Imp on at" mum Ain 2014:281) Asymptomatic bacteriuria (ASB): positive urinalysis and culture without symptoms Acute uncomplicated cystitis: urine culture + with symptoms. UTI confined to bladder Complicated UTI: special populations with acute cystitis: urologic abnormalities. immunocompromise. poorly controlled DM, kidney transplant. or pregnant women Pyelonephritisz inflammation of renal parenchyma +I- systemic illness Common Microorganisms Causing UTI Immune competent Enterobacteriaceae: Bcheridvia coli (mlc). Klebsida, Proteus spp Pseudomonas Emerococci and staphylococci (MSSA. MRSA) Staphylococcus saprophylkus Immunosuppressed or immunocompromised Candidaspp and mold Recent broadspectrum antimicrobial use ExtendedSpectrum BetaLactamase (ESBL)producing Enterobacteriaceae Carbapenemaseproducing gram negative bacilli Clinical Manifestations Cystitis: frequency. urgency, dysuria Pyelonephritis: fever (>37.7 C); Chills/rigors, malaise or significant fatigue; costoverte bral angle tenderness; pelvic or perineal pain in men - AKI is rare: reported with solitary kidney and NSAID use swim Dis 1992.1411431 Complications of Acute Pyelonephritis (Infix Ds CM NoihAm 1997.116531 Renal cortical abscess/carbuncle: result from hematogenous spread of bacteria from a primary focus of infection (bacteremia. osteomyelitis. endovascular infections) Renal corzicomedullary abscess: alw underlying urinary tract abnormality. such as vesicoureteral reflux or urinary tract obstruction Emphysematous pyelonephritis: suspect if DM + septic shock.worsening clinical status despite aggressive medical therapy. known or suspected UTO (NE]M 20I 8;378:48) • Xanthogranulomatous pyelonephritis a/w obstruction by struvite stone using destruction of kidney tissue by granulomatous changes wl lipid laden macrophages; frequently require surgical removal of infected tissue nephrectomy Perinephric abscess: abscess between renal capsule and renal fascia, usually alw rup ture of an intrarenal abscess. renal cortical abscess. chronic/recurrent pyelonephritis. +I- obstruction. xanthogranulomatous pyelonephriUs. or renal carbuncle Risk Factors Urinary catheter use. UTONUR. DM. pregnancy. immunocompromised.ADPKD Imaging: CT Scan with or without Contrast Indicated for recurrent symptoms. acute pyelonephritis will\ sepsis. septic shock. known or suspected urolithiasis. urine pH 27.0. new GFR $40 (NEW 1018:37s¢4s) Management (IDSA;Gn lnfea Ds 2011:57;e103) Empiric antibiotics based on severity of illness, risk factors for resistant pathogens. previous susceptibility to antibiotics. local community resistance prevalence Screen and treat all pregnant '2 w/ ASB (IDSA (Ja I»f¢<1 on 101%pmID 30e95zaa) Acute uncomplicated cystitis: nitiofurantoin 100 mg bid x 5 d: superior to fosfomycin (WM 10183319 17s1).TMPSMX DS bid x 3 d.or fosfomycin 3 s ><1 Fluoroquinolones x 3 d are efficacious but can have secondary effects l3Lacnams should be reserved if no other options due to their lower efficacy Pyelonephritis: oral fluoroquinolone (bid or extended release daily) x 7 d (+l- N initial dose). IV ceftriaxone 1 g q24h dose or IV aminoglycoside q24h in lieu of IV lluoro quinolone depending on community resistance patterns. UTI in CKD (C/ASN 200s:1=3z7I Nitrofurantoin: absent in urine if CrCI <20: FDA recommends against use if CrCI <60 Sulfamethoxazole: urine level is subcherapeutic if CrCl <50 Ciprofloxacin. levofloxacin. and trimedloprim: therapeutic level achieved in CKD UTI in ADPKD iA;P Renal 2017313H0773 UTI, infected renal cysts. pyelonephritis: 3060% ofADPKD pts experience UTI Prevention through flushing" of kidneys and preventing stasis through increasing urine volume.vizamin C rich cranberry juice.and usual hygiene measures Treatment targeted to penetrate renal ms, empiric IV fluoroquinolone or cefotaxime or ampicillin plus gentamicin based on resistance panels ?w MINIMAL CHANGE DISEASE (MCD) Most common cause of nephrotic syndrome in pediatric population (2-7 cases/100.000, accounting for -90% of nephrotic syndrome under age 10) Third most common cause of nephroric syndrome in adults (10% of cases) Usually idiopathic, bu: secondary MCD associated with: Neoplasms: Hodgkin disease. NHL leukemia. renal cell carcinoma . Medications: unSAIDs. interferon. gold. mercury. methimazole. penicillamine Infections: syphilis. HIV. mycoplasma Autoimmune disorders: sclerosing cholangiris, sarcoidosis Other renal disorders: loAn (c;Asn Z014:9:10JJ). lupus nephritis (qAs~2016.1 \:§47) Pathogenesis Padwologic Tcell-medlaned circulating factor ("Shalhoub hypo:hesis") (jam l974;7aa0sss1 Activation of Fcell cosdmulatory CD80 (B71) on podocytes is a/w proteinuria in MCD.and may be stimulated by cytokines such as lL13 (sewn ~=¢=»~=4201191324 144 Neplwul 201$130.469). t urinary CD80 during relapses of MCD. but not FSGS (KI 2¢10.78;296). Role of B cells implied by eifectiweness of Bcell depleting agents (rituximab) and asso ciations wide lymphoid malignancies. IL4-mediated mechanism nu 'win zowasiaae). Pa t h o lo g y LM: normal appearance: IF: no staining (unless secondary to other GN): EM: 280% foot process effacement. no electron dense deposits (unless secondary to other GN) Mesangial deposits of IgM 1r¢4n¢vn¢ulzua9;z4;11a7) or C1q may be seen in both MCD and FSGS. and are associated with worse prognosis in MCD C lin ica l M a n if e st a t io n s Acute onset edema (LE periorbital. ascites); GI distress common in children (diarrhea. nausea, pain: attributed to intestinal edema): often follows viral infection or atopic episode Complications: AKI/ATN, thrombosis Wor kup Labs: proteinuria >3.5 G/24 hr.l serum albumin, ' cholesterol (especially triglycerides), hematuria in 10-30% of auks UAW z01 a.14:102l. May present with AKI. Rul e out s e c onda r y c a us e s . a s a bov e Consider genetic resting if age <1 yr. significant FHx. or steroid resisranz disease Tr eatment Prednisone 1 my kg (up to 80 mg) QD or 2 mg/kg QOD (up to 120 mg) for 4-16 wk: if responding, taper over 3-6 mo If unable to tolerate CS or FRISD. use CNI: CsA (3-S mg/kyd divided bid.goal trough 100-150) orT ac (0.05-0.1 mglkgld divided bid goal trough 5-7) x1-2 yn then taper De finitions of Ste roid Re s pons iv e ne s s Steroid resiscam: (SR) Fai l ed to achi eve r emi ssi on whh 16 wk of ster oi d Ster oi d dependent (SD) Relapses 22 during steroid taper or wu 2 wk of dlc of steroid Fr equency r el apsi ng (FR) Relapses 22 wu 6 mo or 24 wu 1 yr of achieving remission For FRISD patients unable (O tolerate CNI. older guidelines suggest cyclophosphamide (2-25 mg/kg PO daily) for 8 wk or MMF (1,000 mg bid) for 1-2 yr (KDIGO GN 1012> Ri:uximab: effective for FR/SD MCD Intro;Asn zo14;zs¢sso; qAsn z01¢1\;710> P r ognos i s In pediatric popul a t i on. 9 0 % of cases are steroid responsive. but 60% develop FR/SD state (I Pediatr 19e1 sss61: MIKE! 1988;85823W: inazau 1W§;l47:202) 20-30% of pediatric FR/SD pa t i e nt s c ont i nue t o have relapses into a dul t hood U mau 2005;147:202. 4:/Asn 2009;4.1$93) 88% of adult onset MCD respond to CS.w/ 56% having relapsing course (AjKo 201726%37) FR/SD patients have good r e na l pr ognos i s but high risk of t r e a t m e nt r e l a t e d complications (osteoporosis, cataracts. infertility) (qAs~100~r421s93). Few will progress to ESRD WND z017;s&6311 Mos t FOCAL SEGMENTAL GLOMERULOSCLEROSIS FSGS is a pathologic lesion that can be caused by a diverse set of diseases Idiopathic FSGS also rolled "primary." usually presents refth nephrotic syndrome (NS) Secondary FSGS: should be interpreted cautiously lt may refer to FSGS with cause (KoiGo GN z01 z). nonprimary podocyte injury excluding genetic FSGS who 2018;62403), or nonnephrotic syndrome wl foot process eifacemem. <80% (nbr 20 l§;]0:375) Most common biopsy diagnosis in US. incidence rising WKD 101s;6a:53 31 Mos: common glomerular cause of ESRD (AJKD 2016:6&533) Male:female incidence 1.5:1 (qA§N 20172125s021 Accounts for 20% of pediatric and 40% of adult cases of NS Conditions Associated With FSGS Infections HIV. Parvovirus B19. CMV. Malaria, SV40 virus. Schistosomiasis. Strongyloidiasis [Ki Rev 201B.]:l4) Malignancies Drugs Hodgkin and NonHodgkin lymphoma Interferon, Pamidronate. Lithium. Heroin.Anabolic steroids, HCV DM (fugaiaiqy z017:se:essl i nephron endowment (unilateral kidney agenesis. ' birth weight) Nephron loss (reflux nephropathy. nephrectomylablation.conical necrosis. residual sclerosis from proliferative nephritis) Hyperiltration (obesity. chronic allograft nephropathy. sickle cell. cyanotic congenital hear! disease. HTN,diabetes mellitus) SLE, HLH, MCTD. giant cell arteritis. adult onset Still disease. sarcoidosis. systemic sclerosis Mostly monogenic mutations of critical podocyte genes Charcot-Marie-Tooth.Alpon.Type I glycogen storage disease. Branchiootorenal syndrome. Partial lecil.hincholesterol Hemodynamic maladaptation Inflammatory disease Genetic mutations Genetic syndromes aqrkransferase deGciency.Spondylometaphyseal dysplasia Pathogenesis Podocyte injury leads to detachment from GBM: parietal epithelial cells (PEC) migrate from Bowman capsule. forming cellular bridges to the capillary wft. eventually causing wft adhesion, loop obliteration. and segmental sclerosis (ACKD 1014221:40e1 Idiopathic: podocytes injured by circulating permeability factor of uncertain identity. likely produced by immune cells. analogous to minimal change disease (Nat no.. wma z01s;1 17sel. Evidence: (1) improvement of proteinuria wl PLEX: (2) resolution of FSGS lesions upon retransdant to nonFSGS recipient one/m 2011:3£6:\648) Adaptive lvyperfiltration: nephron loss leads to distention of individual glomerular capillaries and increased glomerular pressure.causing GBM adaptation, slit diaphragm widening, and podocyte detachment (now ~=»1~=l 1017:3293:405: KI 1017:91:118J) Apolipoprotein 1 (APOL1) and the Kidney APOL1 is a minor component of HDL synthesized in the liver and found in the kidney. endothelium, pancreas. liver. brain. and hear: APOL1 variancs G1 and G2, compared m reference variant G0. confer resistance against zrypanosomal species and are more common in subSaharan Africa (MSN 2011:211098) >50% ofAfrican Americans carry 1 APOL1 risk variant and 13% have 2 risk variants [Sam ~=1~=I201535122) The occurrence of homozygosity Or double heterozygotes for G 1IG2 renal disease in people ofAfnican heritage: 18% of FSGS and 35% of HlVAN U4SN 2011;2L1129) Also alw HTN associated ESRD and sickle cell disease (Acne 2014;11:47.6; up zo 17;119;azs> Pathology LM: at least 1 glomerulus with lesion of segmental (partial) sclerosis. may see tubular microcysts (esp in collapsing variant) IF: typically no staining. Mesangial IgM may be seen.associated with worse prognosis. Clq staining raises concern for Clq nephropathy. a rare variant of FSGS EM: FP effacement typically diffuse (>80%). may be patchy in adaptive FSGS. Mesangial EDD and tubuloreticular inclusions may be seen in secondary FSGS, especially immune complexmediated disease. GBM wrinkling seen in collapsing variant Histologic subtypes help differentiate primary from secondary lesions and may help prognosticate disease course (ACKD 2014414001 Histologist Subtypes of FSGS new 10141140m lo Miianiaua FSGS NOS (68%) Z1 glomerulus with segmental increase in matrix obliterating the capillary lumina.There may be segmental glomenilar capillary wall collapse without overlying podocyte hyperplasia. Collapsing variant (12%) 21 glomerulus with segmental or global collapse of Me glomerular tuft with overlying podocyte hyperplasia or hypertrophy. Mos: likely to progress to ESRD. Tip lesion variant (10%) 21 segmental lesion involving rip domain of glomemlus. Often steroidsensitive. Best prognosis even if SR iqAs~ 7.0 lJ:B:]99) Perihilar variant (7%) 21 glomerulus with perihilar hyalinosis,more common in adaptivelhyperhlu-ation mediated FSGS Cellular variant (3%) 21 glomerulus with endocapillary hypercellularity without foam cells or karyorrhexis Clinical Manifestations Proteinuria. typically nephrotic range (>3.5 old); Idiopathic FSGS usually presents as full nephrozic syndrome: Adaptive FSGS less likely to have full nephrozic syndrome May present as subnephrozic in collapsing and TRPC6related FSGS Workup Urine protein excretion.serum albumin, lipid panel Rule out poizenzial infectious causes (HIV. Parvovirus B19. CMV). inflammatory diseases (SLE. MCTD. HLH.gian: cell arrerizis. adult onset Still disease).drugrelated causes (interferon. pamidronare. anabolic steroids. lithium. heroin) Consider genetic evaluation in patients with significant family hx. steroidresistant (SR) NS. pediatric onse: disease RenalLir nited G enetic F SG S Gene Pr oduct Gene Pr oduct NHPS 1 (AR) Nephrin CD2AP (AD) CD2associated protein NHPS2 (AR) Podocin ACTN4 (AD) Alpha actinin 4 Phospholipase C21 TRPC6 PLCE 1 (AR) (AD) Transient receptor potential cation dlannel 6 Genetic FSGS With Possible Extrarenal Manifestations Gene Pr oduct Associated Conditions INf2° (AD) lnvened or r in 2 WT1 (AD) Wilms tumor 1 Charcot-Marie-Tooth: motor and sensory nerve rnandesmtions wide dismal leg weakness. bot deformities (yes avus. hammer toes) Denys-Drash syndrome:Wilms tumor. male pseudohermaphroditism Frasier syndrome: gonadoblastoma, male pseudohermaphrodidsm mm, MT T L2, MTTY (mino chondrial) Mitochondrial :RNA LMX1b (AD) LIHHboxTF1 LAMB2 (AR) l.aminin be 2 lTGB4 (AR) Beta 4 integrity CD151 (AR) Tetraspanin CD151 SCARBZ (AR) Scavenger receptor class B member 2 MYH9 (AD) Nonmuscle myosin 11a MELAS syndrome: mitochondrial myopathy. encephalopathy. lactic acidosis. strokelike episode Nail-patella syndrome: hypoplastic patella. dystrophic nails. dysplasia of elbows Collagenofibrotic glomerulopathy Pierson syndrome: microcoria. NM junction defects Epidermolysis bullosa Epidermolysis bullosa, sensorineural deafness. nail dystrophy Action myoclonusrenal failure syndrome: ataxia. myoclonus Bleeding diathesis. macrodlrombocyropenia. progressive sensorineural deafness. liver enzyme, cataract Moss common cause of generic SRNS in childhood 'Mon common cause of lamilual FSGS in adults, often subnephmdc (NDT 2011:178B2) Treatment of Idiopathic FSGS . Prednisone 1 mg/kg (up to 80 mg) QD or 2 mg/kg QOD (up to 120 mg) for 4-16 wk or complete remission: if responding, taper over 6 mo If intolerant of or resistant no CS. CNI: CsA (3-5 mgkgld divided bid w/ goal trough 125-175) orT ac (0.05-0.1 mg/kg/d divided bid w/ goal trough 5-10) for at least 12 mo if responding by 6 mo SR FSGS unable to tolerate CNl: dexamediasone and MMF lKl2011rS0:8681 Rituximab generally not recommended for treatmentresistant FSGS. but has been used in small trials to treat resistant FSGS with improvement in protdnuria. relapse rate. and need for IS (jAr 2014152850: Arn] Nephfnl 20l4:3932Z) Conservative care with RAS inhibition. dietary sodium resr.ricdon.and BP control particularly important if incomplete response to immunosuppression Treatment of FSGS With Identifiable Cause Treat underlying disease: eg. ART for HIVAN Treatment ofAdaptiveIHyper1iltrationmediated and Genetic FSGS No role for immunosuppression RAS inhibition, dietary sodium restriction.optimize BP control Prognosis Patients with subnephrotic proteinuria are unlikely no progress to ESRD but are at increased risk of cardiovascular morbidity and morality Patients with nephrotic range proteinuria are more likely to progress to ESRD Tiplesion FSGS associated with best outcomes and most steroidresponsive, more similar to minimal change disease Collapsing FSGS associated with worst outcomes and ESRD Steroid resistance is most important predictor of poor outcome, regardless of histology l;Asn 2004;1S:2169; 201718130551 Transplantation idiopathic FSGS has high rate (-40%) of recurrence after transplant and can recur within 48-72 hr (T~"=v!°M me 2017249111563 qAs~2016;111041) Risk factors for recurrence include younger age. nonAfrican American race. heavier proteinuria and low serum albumin pretransplant. and more rapid progression (D ESRD Surveillance for recurrence necessary with frequent J urine protein excretion Prompt initiation of plasmapheresis t rituximab may improve outcomes for recurrent FSGS; prophylactic treatment may not be effective (fg 1npluntulian 201B1107;e115) MEMBRANOUS NEPHROPATHY (MN) Most common cause of nephrotic syndrome in nondiaberic Caucasian pts Primary MN (PMN) (60-70%) vs secondary MN (30-40%) Pathogenesis PMN is an autoimmune disease in which antibodies (usually IgG4) are produced against a podocyte antigen. most commonly the phospholipase A2 receptor (PLAZR) Abs may also form againstAg rapped in the GBM (eg. bovine serum albumin), or preformed AgAb complexes may in theory deposit from the circulation (not proven in human disease). Complement activation then contributes to podocyte injury. Identified Antigens of PMN MType Phospholipase A2 Receptor (PLA2R) 74)80% of PMN. rare in HBV. malignancy [new200%361:11I associated MN Thrombospondin zype1 domaincomaining 2-5% Of PMN, 10% of PLAZR Ab (-) PMN 7A (THSD7A) (~£Im zoi 4:a71:zzm Expressed in GB cancer & LN meuszasisz 7/25 had malignancy luqm 2016.374.1995) Neutral endopepridase ms//4 2o0za4s.zosal Bovine serum albumin (NE/M 2011:364:1101) Recombinant arylsuifatase B (MW 1014125167s1 Rare: antenatal MN in fetuses of mothers with deficiency of neutral endopepnidase Rare cause of childhood MN Enzyme replacement for Pompe disease Ca us e s of S e c onda ry MN Drugs unSAIDs. gold. mercury Autoimmune SLE, RA. Sj6grens Kidney allograft reiectlon, GVHD [nor z011;zs102s) Alloimmunity HBV (HBeAg, ansHBeAb present on immune deposit) Syphilis. malaria.? HCV (dubious causal relationship) lnfeclion Solid organ tumors (lung. GI. breast. pros re. uterus) Malignancy Hematologic (Hodgkin and NonHodgkin. CLL) Clinical Manifestations Classically NS (80%) less commonly with subnephroticrange proteinuria (<3.5 old), Onset of NS may be gradual compared no the rapid onset seen with MCD. u If AKI is present. consider renal vein thrombosis or rare crescentic MN CKD may be present after years of persistent highgrade proteinuria Thrombosis is more common in MN (7%) vs other causes o( NS. Hypoalbuminemia <2.8 gldL is a significant independent predictor of thrombotic risk (QASN z01z;7:43I Diagnosis: Kidney Biopsy Is Gold Standard LM: thickened glomerular capillary wall with spikes IF: IgG and C3 granular staining EM: subepithelial deposits. foot process effacement In PMN 15% of patients will have glomerular antigenpositive PLA2R staining despite negative serum antiPLA2R antibodies Suggestive Pathologic Features of Primary vs Secondary MN P r i m a r y MN Features S e c onda r y MN Leukocyte infikration in malignancy LM IKI zuas=1(>1s10i IgG4: dominant in PLA2R.THSD7A IgG subtype Tubular basement (TBM) IgG staining Other Ig. C1 q Electron dense deposits Endothelial tubuloreticular () () Subepitheiial, lnmme mbnnous () l8G1. 3 in LN lgG1.2 in malignancy (+) in LN: can have andTBM ab with tubulointerstitial nephritis (+) in classy LN Additional mesangial. subendothelial In LN (+) in classy LN inclusion Serum antiPLAZR antibodies: the presence of has 96-100% specificity for PMN; diagnostic. esp biopsy is connnindicazed and renal function is preserved ous One 2014;9:e1049362 KI 2019;95:429) E v a l ua ti on Serum antiPLMZR level; if negative consider ant.iTHSD7A resting v~d\ere available If history and biopsy are suggestive of secondary MN: age and riskappropriate CBD cer screening, especially in older aduks (age >6S yr) and chose who are andPLAZR negative Recommended Cancer Screening (USPSTF) Colorectal Breast Cervical Lung 5 0 -7 5 l o Biennial mammography 5074 y/o Pap smear q3y 21-65 lo Annual low dose CT for 55-80 lo adults who have a 30 packyr smoking history and currlendy smoke or have qui: within the past 15 yr Serologic testing for autoimmune disease. including ANA and complement levels Hepatitis B and C serologies. HIV. RPR Consider GVHD in patients who have had a bone marrow transplant If nephrotic: high index of suspicion for RW DVD or PE RVT prevalence 30% in nephrotic MN lAmIa¢¢ \900:69:s191 RVT usually asymptomatic. but if acute may present with abdominallllank pain and if bilateral may present as AKI. Raul stenography is gold standard to diagnose but rarely done. No consensus on best radiologic test to use for diagnosis if suspected (CT angio. Doppler ultrasound MRl).depends on local expertise but all have fakenegatives. Treatment Antiproteanuric tx w/ ACEI or ARB: If secondary MN, treat underlying disease If complications of die NS are present then initiate immunosuppression (IS) If proteinuria >4 old persists after 6 mo ofACEI or ARB. consider IS If eGFR <30. KDIGO 2012 suggests against IS (recommendation not graded) Among immunosuppressive regimens. glucoconicoid monotherapy should not be used Immunosuppressive Regimens for MN Treatment Dosing Duration Efficacy Alternating Glucocordcdds (mo 1.3.S) 6 mo 72-93% PRICR Cydophosphamide IV methylprednisolone Relapse: 1025% by (CYC) and 1 gon d 1.2.3followed 3-4 yr glucocorticoids by PO prednisone (aka modified Pont:icelli" 0.5 mgkg daily x 27 d protocol) CYC (mo 2, 4. 6) 2.0-2.5 (nam wnnosc /ASN mg/kg PO daily 1998:9:444: 209798118991 Continuous Cyclophosphamide and glucoconicoids (nor z004.1,1142) Cyclosporine (CsA) (MEN1OR NEW 201938\362 KI z001:sz14a»I Tacrolimus (Tac) (KI2a01:71:914) Rituximab (MENTOR ~£,m zoizael auusu N1HJ1141$) CYC 1.5-2.0 MW PO x 12 mo Glucocorzicoids for first 6 mo: prednisone 0.5 mgkg daily x 6 mo with medwylprednisolane 1 g IV on day 1.2.3 of mo 1. 3.5 CsA: 3.5-5.0 mg/kyd divided bid. :rough 120-200 9; prednisone 5-10 mg QD or QOD Tac: 0.05-0.075 mglkg/d divided bid, up 3-5 2 prednisone 5-10 mg QD or QOD Rizuximab IV 375 mg/kg Qwk x 4.or 1 g Q14d x2 12 mo 92x PRICR. 36% CR Relapse: 28% by 5 yr 12-1s mo (stop if no response by 6 m°) $2-75% PR/CR Relapse: 36% by 1.5 yr 12-18 mo (stop if no response by 6 mo) 76x PRICR Rel-we 47% w zs Y' May repeat at 6 mo 60-65% PR/CR, 27% CR Relapse 28% by 5 PR, partial remission: CR camplexe remission Anticoagulation for patients with known thrombosis. Prophylactic anticoagulation should be considered for padenrs with albumin <2.8. Decision analysis tool can be found at http:/Iwww.unckidneycentenorg/gnrools Prognosis Approximately 1/3 of patients have spontaneous remission. usually widlin the first 6-9 mo Spontaneous remission is more likely in those widi preserved kidney function and subne phrotic range proteinuria. but has been reported in pts MM highgrade proteinunia Complete remission (<300 mg/d proteinuria) and partial remission (<3.5 Yd proteinuria) is associated with a 10yr kidney survival of 100% and 90% 50% have persistent NS: of these. 3040% progress to ESRD within 5-15 yr Proteinuria >8 g/d is a risk factor for progression regardless of GFR (Io 1997:51901i AntiPLA2R Ab titers may predict disease course: low and falling titers are associated with spontaneous remission. while high titers are associated with development of persistent proteinuria iI*5N 1014;24:13S7; An, / ~¢piimI 101S;4170) AndPLAZR Ab titers may be used to monitor response to therapy. Immunologic remission typically precedes fall in proteinuria Transplantation Recurrence: 40-50%. Risk factors: higher prev;xp proreinuria. (+) PLA2R Ab (Tnunspbnladun z011»10a1710) Tx: riruximab or z009;9:2aoo> De novo disease is rare and may be alw DSA and antibodymediated rejection MembranousLike Glomerulopathy With Masked IgG Kappa Deposits (MGMID) Rare secondary form of MN where subepl deposits show C3predominant staining on routine immunolluorescence of fresh tissue (may be misdiagnosed as C3 glomerulopathy). by: reveal strong IgGk staining after protease digestion lx: 2014:B6:154) Mos: commonly found in young women with positive autoimmune serologies.At least one case recurred posttransplant (in Rep 2016;\:199) MALIGNANCYASSOCIATED MN The mlc glomerular disease in patients with cancer Incidence of cancer in MN: ><2.25 We zwnwa9a1 - 9.8 (xi 1006;70:1s101 Reported case numbers: lung > stomach > kidney > prostate > colon, breast cancer [Nat Rev Ncphml 2011:785) Other reported cancer: bladder. pancreas. head.and neck.Wilms tumor. teratoma. ovarian. cervical, endometrial. skin (melanoma. SCC. BCC). pheochromocytoma. hematologic malignancy (Hodgkin disease. NHL CLL.AML CML); =/p HCT 10% of MN: 52% had symptoms of cancer at time of biopsy (xi 200e;701s1n) Risk factors: age over 65 yr and history of smoking >20 p.y. in znoemmisiol Biopsy leukocyte infiltration in 200e70.1s101. IgG1, 2 dominance (nor 2c04;191s741 THSD7A expressed in GB carcinoma and LN metastasis and serum Ab disappeared with treatment (new z01s=374i99s1; 8 of 40 pts with THSD7Aassociated MN was diagnosed with malignancy we 3 mo from die MN diagnosis (jAr 2017;28:S20) Cancer surveillance in PLA2R ().THSD7A (+). or nonlgG4 MN UAS~ 101ma24z1 1: Ac least age and risk factor appropriate screening: may need upper endoscopy. colposcopy and PSA/prostate biopsy lclAsn z014:9zw9) Remission with cancer nemoyal or remission; relapse with cancer recurrence PAUCI-IMMUNE GLOMERULONEPHRITIS Mos: common type of crescentic glomemlonephrids Small vessel vasculitis distinguished from other vasculitides by the absence of immune deposits. ANCA present in 885% of cases (1 Rheumaml 2W1:2B;1S84) Predominantly affects older adults: mlc renal biopsy diagnosis in >80 (CJASN 20n9;4.10731 Incidence 20 uses per million annually, slight male predominance (sen n¢pne12017.37¢41s> Clinical subtypes are defined histologically in the Table below (Chapel . Consensus Cbnferenn Atwas Rheum 10\3z6S1), However. there is substantial overlap between MPA and GPA. Prognosis. genetics, epidemiology. and treatment response are better associated with the specific ANCA antigen rather than histology mm n:vn1»¢w»-mi10141125101 Clinical Subtypes of Paulimmune GN 1~»1~i¢- alien you:ssI: up Z00e4471770l Disease Histologist Features ANCA Microscopic Polyangiizis (MPA) Necrotizing vasculitis widiout gnnulomatous inflammation. Often renallimited Necrotizing granulomatous inflammation. Often involves kidneys. upper and lower respiratory trac: Eosinophil rich necrotizing granulomatous inflammation. Usually involves respiratory tract. about half of cases involve kidney alw asthma and circulating eosinophilia 60% MPO or pANCA Granulomatosis with Polyangiitis (GPA). formerly Wegeners" Eosinophilic Granulomawsis with Polyangiitis (EGPA). formerly "Churn-Strauss 75% PR3 or cANCA 75% ANCA (mossy MPO/pANCA) if renal disease present 26% ANCA if no renal disease present Antineutrophilic Cytoplasmic Antibody (ANCA) Presence ofANCA was traditionally diagnosed by performing IF on ethanolfixed human neutrophils incubated with ptS serum (indirect immunoNuorescence. IIF). Cyioplasmk (C) ANCA pacxem is usually seen MM ab against serum proteinase 3 (PR3) and Perinudear (P) ANCA is usually seen widl ab against myeloperoxidase (MPO). Elevated PANCAJMPO ab can been seen with other autoimmune diseases such as SLE or iniiammatory bowel disease Pathogenesis Distinct genetic associations exist for PR3 vs MPO disease (NEJM 2011:367:2I 4) Formation ofANCA may be potentially triggered through the following Environmental stimuli: silica.asbestos l;As~ 2001;12:134: Ref fun 20081726051 Drugs: hydralazine. propylthiouracil www; Rheum 200tt4:3340s1 Infection (NDT 101017531119. Coin RNeumalal 1010.29:B93) Molecular mimicry 1n¢:m¢42008;14:10as). Epigenetic dysnegulatlon UG 1010;120¢32U9) Loss ofT cell regulation rfmwww 201043064) ANCA causes the development of vasculitis through several proposed mechanisms activation of neutrophils via Fc receptors (!"'"'"*1"11 1994 ;lS]:l171) Release of neutrophil extracellular traps (NETS) containing chromatin and granule proteins that trigger damage to endothelial cells and ANCA antigen presentation to immune system (num M¢4 2069:1$:623) Activation of the alternative complanent pathway and generation d C5a.a nwuophil chemoatuactant and activator In 1007;71:64e; jAN 200910:289) Pathology LM: fibrinoid necrosis of glomerular tufts +I- rupture of GBM. proliferation of epithelial cells forming crescents IF: no staining for Ig. no or mild complement staining (Pauci Immune) EM: no electron dense deposits Affected nonrenal :issue shows leukocytoclastic vasculitis Clinical Manifestations Constitutional: malaise. fatigue. fever, weight loss. night swears. anorexia Renal: rapidly progressive glomerulonephritis (AKl. hypertension. edema. microscopic hematuria. subnephrotic proteinuria over wk to mo) Pulmonary: hemoptysis (from alveolar hemorrhage). cough. dyspnea on exertion. alveolar infiluates on CXR Sinonasal: sinusitis. otitis media."saddlenose" deformity (particularly GFA) Dermatologic: palpable purpura (usually in lower extremities). petechiae, ulcers. nodules. urticaria. ecchymoses. bullae Ocular: iritis. uveicis, episclerltls Gl: bleeding or perforation due to vasculkic ulcers Cardiovascular: pericardltis. myocardids Neurologic: mononeuritis multiplex.cranial nerve abnormalities Comparison of PR3 vs MPO ANCA Diseue PR3 Disease Clinical manifestation (lIdvm Rheum 201b6t3452) Pathology Z003;41539) Recurrence Saddle nose. nasal ulcer/crusting, bone destruction Epistaxis. hearing loss, Subglonic stenosis Lung with cavities Focal GN. Necrosis IA}KD More frequent MPO Disease Renal limited GN Lung involvement w/o nodules Lung involvement wlo ENT disease Global sclerosis. Interstitial fibrosis Less frequent Workup Lab: elevated Cr. hematuria (including dysmorphic RBCs and red cell casts), proteinuria. normal complement levels. eosinophilia (in EGPA).elevated MPO or PR3 ab (or both). positive PANCA or CANCA (O r both) Rule our druginduced causes. esp if dual MPO and PR3 positivity or concomitant ANA positivity Common culprits are propyldmiouracil. hydralazine. Ievamisole, allopurinol. and TnFalpha agents <QAS~ 2015;10:1300) Induction Therapy CYC w/ CS (3d pulse of medlyIprednisolone 500 mg IV, then 1 mg/kg daily prednisone up to 60 mg for 1 mo. then taper off by 6 mo) CYC: in monthly IV doses (0.5-1 W) or dosed orally (1-2 mglkgld). Dose should be adjusted for age >60.eGFR <20.and no avoid neuuwopena lxoico Gn). IV regimen has lower eumularive dose and may be equally effective (qAsn 2013811191 Rizuxlmab (RTX) 375 mg/m' weekly x4 is an acceptable alternative lug;/14 2014361211: 1010:363:221: 101313693417: Ann Rhem Ds 2016;75:1166: KDIGO GN 1012) Plasmapheresis x7 over 14 d for rapidly rising Cr. severe renal impairment (Cr >5.8 mg/dL OR oliguria).AKI requiring dialysis. pulmonary hemorrhage. or concomitant antiGBM disease (MEFEX JASN 2007:1s:z1sa Kolco GN 2012) RCTs of Rituximab (RTX) vs Cyclophosphamide (CYC) Induction Trial RAVE RITUXVAS RTX group RTX 375 mglm1 weekly xi wlo RTX 375 mglm' weekly x4 + CYC maintenance therapy 15 mg/kg IV wl Is: & 3rd RTX CYC group CYC 2 mglkgPOQD foIIowedbyAZA CYCN§or3-émoiollowed byAZA RTX noninferior in inducing remission RTX not superior in sustained by 6 mo (64 vs 5396). 12 mo (48 vs remission at 12 mo and severe Results 3996).and18mo (39 vs 33%) (nqrlI zoimaeszzn 201z,369;4171 PR3 group respond berger no RTX (Ann Rieum Drs 2016:75:1 i's) adverse even's www Zowssa:zin No difference in deadl, ESRD and relapse as 24 mo [Am Rhem o; 101$:74:11781 All RAVE and RITUXVAS groups received corticosteroids Maintenance Therapy 18 mo of maintenance therapy in patients who achieve remission. No further therapy in patients who progress no ESRD without extrarenal disease 0tDIGo GN 10121 Azathioprine (AZA) 1-2 mg/kg/d or Mycophenolate mofetil (MMF) 1 g BID in patients unable to tolerate AZA laI:>IGo GN 2011), MMF has been associated with a higher rate of relapse in a single study (Ann's Rheum 1004511279i Riuiximab 500 mg on d 0 and 14.mo 6. 12.and 18: more effective than AZA (AZA group had HR 6.61 for major relapse) (MAINRITSAN N£)M 2014;371;1771) Trimethoprim-Sulfamethoxazole (TMPSMX) should be considered in addition to immunosuppression in patients with upper respiratory tract disease (KDIGO GN 2011) Relapse Rate 30-50% by 5 yr: Higher with PR3 disease. respiratory involvement. and nasal car riage of S. aurous (in GPA) (Ann IM ZlX)5;8:170% nam 199s;3:1s:16: Ardine Rheilnuld zoiawesol Reappearance or t ofANCA correlates strongly with renal relapse. Fersistently elevated titer is al relapse (KI 2009;63:1079: lASN 2015:26:537; Anlmris Rheum 2004:51269) Persistent hematuria >6 mo (x3.99). but not proteinuria is a/w relapse (qASN 20\&13:251) RTX appears more effective than CYC in recurrent disease (NEW z01s;wx417l Transplantation Wait until 1 yr after remission of extrarenal disease before transplant. Presence of circulating ANCA ab does not increase the risk of recurrence lxoico Gn 1011) Risk of recurrence after transplant is estimated 10% and responds well to repetition of induction therapy (Ki 2007;l 1i1296) Recurrence after transplant may be more likely in PR3 disease (I Neplud 1017;3tt141) Patient and graft survival 92% and 88% at 5 yr. and 68% and 67% at 10 yr, similar to other nondiabetic kidney diseases (Car Open Rneun 2014:16:37) Prognosis Complete remission is attained in the majority (70-90%) of treated patients Untreated disease is associated with 50% mortality at 1 yn Estimated 1 and 5yr patient survival 84% and 76% who z008;41=176) Presence of pulmonary hemorrhage is most important determinant of patient survival (KDIGOGn2011) 20-25% patients will progress to ESRD war 7004;1m19s4) Single most important prognostic marker for longterm renal outcome is Cr for 20041919541 Biopsy predictors of poor prognosis include degree of glomerulosderosls. interstitial fibrosis. and tubular atrophy in 1001:61:17321 ANTI-GBM DISEASE Definitions and Pathogenesis Characterized by ab against a glomerular basement membrane (GBM) antigen. often crossreactive w/ alveolar basement membrane.causing RPGN +I- alveolar hemorrhage AntiGBM disease: kidney involvement alone Goodpastune syndrome: kidney and lung involvement ("puImonavyIenal syndrome") Goodpasture disease: kidney and lung involvement + antiGBM serology Principal antigen: (13 noncollagenous (NC1) region of type IV collagen Trigger for autoantibody production is unclear. but may involve a conformational change (eg. induced by airborne irritants such as cigarette smoke) that unmasks EA and EB epitopes in 2008;64:1108) Antibody binding jin rly along GBM induces crescentic glomenilonephritis HLADRB1 alleles strongly associated with disease susceptibility (KJ 1999s6.16381 Epidemiology Incidence: 0.5-2 cases/million/yn significantly lower than other RPGNs.eg. ANCA GN Two peaks of incidence: (1) young adult males: (2) elderly women Alw cigarette smoking, hydrocarbon. viral URI. alemtuzumab (NE/M zooeaswsel Clinical Manifestations Kidney: hematuria +I- proteinuria usually with rapidly progressive glomerulonephritis. Symptoms include teacolored urine. and those related to kidney failure Lung: hemoprysis due to diffuse alveolar hemorrhage (DAH): Other symptoms include cough, shortness of breath, tachypnea Constitutional symptoms (eg. fevers. fatigue, nausea, weight loss) are largely absent Younger patients may present widi more fulminant disuse when compared m older adults Pulmonary involvement a/w pulmonary irritants, eg,cigarette smite (jam 19aa;83b4;1390) Diagnosis Kidney biopsy: crescentic GN w/ linear IgG (usually lgGl and 3. rarely IgA. IgM) by IF Bronchoscopy (gold standard no identify DAH); Chest CT: ground glass opacities AntiGBM Ab: diagnosis and for lacking disease activity Reasonably sensitive (63-93%) and specific (92-97%) 1!i¢<h¢v» MdMe4 1996;59:521. In a severely ill patient, the clinical manifestations plus (+) AntiGBM ab may be enough to make the diagnosis. ANCA ah: in 15-50%, USU. PIPO, more common in the elderly Disease Variants . Dual (+) andGBM +ANCA disease: 47% d antiGBM disase.6.1% MANCA disease; similar prognosis and clinical features of antiGBM disease. though may be alw clinical features of vasculins and higher chance of relapse and renal recovery (KJ 201792693) Atypical andGBM disease rare: (-) serum antiGBM antibody: usually milder. non fulminant kidney disease; biopsy shows linear andGBM Mining (may be a monoclonal lg). widmut crescents.Thought no be caused by antibodies co an alterative GBM protein (je. not a3 NC 1 type IV collagen). Clinical course more indolent (KI 2016289:897) Treatment If kidneylimited. dialysis dependent on presentation and 100% cellular crescents or >50% globally sclerotic glomeruli. chance of kidney recovery is exceedingly low and is may be deferred lAn IM z001;13410331 Cyclophosphamide: 2-3 mglkg/d PO x3 mo. consider dose reduction in the elderly Corticosteroids: mechylprednisolone pulse (0.5-1 g/d x3) followed by oral prednisone 1 mglkg/d (max 80 mold) tapered to 20 mg by 11-12 wk Plasma exchange: daily for 14 d or until antiGBM ab undetectable Alternative immunosuppressives: insudicienr day to recommend.case reports using azathioprine. mycophenolate. and rituximab Maintenance therapy: not required unless ANCA (+) Prognosis Outcomes in patients who receive appropriate therapy (Ami we 2001;I34:1033): 5yr kidney survival 94% if Cr <5.7 on presentation: 50% if Cr >S.7 but not on dialysis Predictors of ESRD: dialysis on presentation,% interstitial infiltrate.% normal glomeruli lqAsn 201B:13:63) Transplantation Require () antiGBM ab for 6 mo; Recurrence 50% if andGBM ab (+) at time of txp Low recurrence (3-14%). lower rates in current era likely dlt better :xp immuno suppression (KI 2013:83:503: Cal Ylunsploflt zorn:ml Alport syndrome wl large deletions in the COL4A5 gene: at risk of developing do novo antiGBM disease after KT. since the wildtype COl.4A5 in the allograft will be immu nolozically foreizn.Autoimmune conlormerona!.hy" (NUM 2010;363:3431 § -4 is I Ep id e m io lo g y Immunoglobulin A nephropathy (IgAN) is :he m/c glomerular disease (nor 20111zs14141 Disease prevalence varies by ancestry: highest in Asians and norther Europeans. lowest in those with subSaharan African ancestry (Pl.oS Cenex 2011;B:e100176$) In Whites. :he disease is more common in men than in women Pathogenesis Primary IgAN: immune complexes of galactosedeficient lgAl deposit in the mesangium UCI 2009;119;1eea) Galactosedeficient lgAl is a heritable :mir lx 2001;aa79) GWAS have identified multiple susceptibility loci (naG¢nei 1014:46:I 1B7) Up to 5% of patients with loAn have a relative with IgAN Subclinical IgA deposits common in healthy individuals in highprevalence countries. eg. up to 16% in japanese (Ki 1003:63:21861 Secondary IgAN associated with liver ds. HIV. seronegative arthritis (esp ankylosing spondylius). inflammatory bowel ds.and celiac ds (Sem ~»»w- zcueze.zn Liver dysfunction 1 clearance of circulating IgA, -» deposits in mesangium Other causal relationships in secondary disease largely uncertain C lin ica l M a n if e st a t io n s Classically presents with hematuria (macro or micro). subnephroticrange proteinuria and hypertension. Nephrotic syndrome is less common Complements (C3 and C4) usually within normal limits: rarely C3 may be low Recumbent gross hematuria.especially widl URIs (synpharyngitic") may be present AKI during episodes of gross hematuria usually due to pigment nephropathy and resolves once hematuria clan (3-S d): if no resolution of AKI after 5 d.then consider kidney biopsy to evaluate for crescentic disease vs other fuse z Kidney Biopsy The gold standard for diagnosis; reserved for those with hemaruria and one of :he following: (1) proteinuria >0.5-1 Yd: (2) i GFR:and/or (3) newonset HTN '§ Pathology The pazhognomonk finding is mesangial deposits of Ig/X. most commonly polymeric lgAl Oxford Classification of loAn developed no identify prognosrically important. repro ducible features across biopsies: used to generate "NESTC" score Oxford Classification of loAn In z0w;91:1014) Feature Score Clinical Implications Mesangial hypercellularity 0 = <S0% 1 = >50% gloms M1 predicts worse outcomes (vs M0) Endocapillary proliferation 0 - None 1 =Any E1 independently a/w worse renal survival (vs E0) only in studies where patients did not receive IS E1 NOT predictive of outcomes in studies diet included immunosuppressed patients E1 alw improved outcome in those treated with corticosteroids §_egmengl glomerulosclerosis 0 = None 1 =Any Iubulolnzerscicial fibrosis 0 I <25% 1 = 2550% 2 = >50% 0 s None 1 = at least 1 2 = 225% gloms $1 predictive of worse outcomes (vs S0) Podocytopathic features al proteinuria. faster I GFR. bu: better survival with IS Strongest independent predictor of adverse renal outcomes Qrescents. cellular/ iibrocellular C1 predictive of worse outcomes if no IS C1 NOT predictive if IS used C2 predicmle d worse outcome regardless of IS Disease Variants IgAdominant infectionrelated GN staph infection in elderly diabetics UASN 2011.221s7) leAn with minimal change disease: clinically similar to MCD. presents with nephrotic syndrome and usually steroid sensitive. likely reflects dual disease (CJASN 201439 10331 IgAN widi ANCA vasculitis: / MPO and PR3ANCA in crescenric disease Crescenric" IgAN variably defined: range from >10% to >50% crescents Treatment (Recommendnucn Grade Band on KDIGO GN 2012 Gidelines) ACEI or ARBs: for BP control (goal <130/80) and proteinuria reduction Corticosteroids (CS): for patients who do not achieve proteinuria of <1 g/d with first line therapy over 3-6 mo and have eGFR >50 (ZC) Cyclophosphamide (CYC): considered for patients with rapidly progressive renal fail ure. usually characterized by crescendc GN or nephrotic proteinuria (nor 2003;18:13111 Large RCTs of CS w/ or w/o alkylating agents and antimetabolites have not shown consistent benefit Study Key RCTs of Immunosuppression (IS) in leAn Patients IS Protocol vs Characteristics Placebo O u t co me s STOP gAN >7 5 0 mg / 2 4 h r (NEW 2015: prot einuria J7J:Z1l5} De t e r mi n e d b y G FR: No d i f f e r e n ce i n n u m eGeR >6& predni b e r e xp e r i e n ci n g 1 5 despit e ACEI or so n e Q O D x 6 mo loss of eGFR ARB. st at in. BP 4 met hylpred 3 g T clinical remissions in <125f 75 N at mo 1, 3. 5 I S group (UPCR <0. 2 NS a n d RP G N eGFR 30-60: PO wit h st able GFR) excluded CY C + r e d N x3 mo t h e n A ZA I 162 random ized t o I S vs severe inf ect ions in I S group r ed x 3 yr placebo TE S TI NG i t * / m 2017;3184321 . Prot einuria >1 old Me t h yl p r e d n i so l o n e St udy t erminat ed early e G FR 2 0 - 1 2 0 0. 6-0. 8 mg/ kg/ a due t o serious inf ec N P O x 2 mo t h e n t i o n s i n CS g r o u p ized t o I S vs t a p e r e d o ve r (8. 1% including 2 f at al) placebo 6 - 8 mo Fe we r co mp o si t e r e n a l 262 random endpoint s (53% vs 15. 9%). slower rat e of G FR d e cl i n e a n d . p r o t einuria in CS group (1. 31 old vs 2. 19 g/ d) Fish Oils inconsistent benefit Studied doses range between 3,3 and 12 old. KDIGO 2012 suggests 3.3 g/d for those with proteinuria >1 old despite supportive care (20) Tonsillectomy: a/w improved outcomes in observational studies (pardculady from Japan); not superior to CS in randomized controlled trial mot z014.19¢1s46> MMF: several negative trials despite one Chinese study suggesting benet (KJ 2010;77;54J) RTX: in eGFR 30-90 dad not improve eGFR and proteinuria l;As~ 2017¢zs:130sl Supportive care:for AKI in loAn with gross hematuria and kidney biopsy showing ATN and intratubular erythrocyte casts (2C) Prognosis 35-40% reach ESRD by 30 yr from diagnosis Prognosis. from better to worse: episodic microscopic hematuria > episodic gross hematuria > persistent hematuria > hematuria - proteinuria less than 1 old at dx > hematuria + proteinuria greater than 1 old on treatment Most important prognostic indicators. timeaveraged proteinuria. T BR and Tscore Spontaneous remission may occur in patients with minor glomerular abnormalities. In a retrospective study of children with leAn who did not receive IS. 60% achieved 5pgnqnegug remission (paint nwnui 21:13125.711 Transplantation Postzransplant recurrence of gAN up to 30% of patients 10 yr posttransplanL Graft loss due to loAn only 3-4%. Predictors of recurrence posttransplant include precransplanr high levels of galactose deficien: IgA1.earlier age of disease onset. and crescents lAM! :Mala 20 I7;45;99) Maintenance CS aw recurrence in some.but no: all series WT 1011;11:164§) For pos:transplant recurrence. highdose CS may be considered IgA VAscuuTls (IgAV) Wons Rheumtol 2017;69t1862) IgAV is preferred term of Henoch-Schdnlein Purpura (HSP) and anaphylaczoid purpura Small vessel vasculizis afleczing skin (100%. palpable purpura). kidney (70%. hemaruria. proteinuria. AKI). joints (6196). and GI tract (53%. bowel angina. bleeding, ischemia) Some IgAN progress to IgAV in 5 mo-14 yr (Min Nepnrol 101s;31;779) Adult IgAV: cause CKD. unlike selflimiting pediatric gAv (SemnAnlnuis Rheum 10029211499 Kidney biopsy: indistinguishable from IgAN: extracapillary hypercellularity (crescents) 41X: fibrinoid necrosis 32% Skin biopsy. leukocytodastic vasculitis (LCV) with IgA deposition: 30% of all LCV (Mayo Gi Flo: 2014891151 So TxCS:4 CYC wlo benefit (KI 2010;7s;495);possible role in severe (crescent >50%) disease (nor z0a4:19:ase); MMF may be used as CS sparing agent (Ami ~=»»»~l2012:36z271) Lupus NEPHRITIS Renal involvement: 50% of SLE: mos: important predictor of death (Nnewnalaugy 2o0m4e:s4z) SLICC included LN as a standalone diagnostic criteria for SLE (Animas Rheum 101 zs4;ze77) Pathogenesis Risk genes (jAuMirvnun 2013141¢251 and environmental factors (et infections. hormones. UV light. drugs) -» cell death - delay in dead cell clearance -» activation of viral recog nition receptors of the innate immune system, INinducible genes and autoreactive B and T cells (Semn lnvnnopnlNal 1014:36:4431 Nonspecific trapping d circulating immune complexes. in situ formation, or by interaction with f\°2s=iivel1 charged components of the giomenilar capillary wall -> formation and deposition of immune complexes -» die binding and activation of complement -» the ensuing inflammatory cascade TMA w/ or wlo AFL ab can coexist and worsens prognosis Lupus podocytopathies alw heavy proteinuria but no active inflammatory lesions Interstitial or vascular renal disease Clinical Manifestations Variable asymptomatic hematuria. proteinuria. NS. RPGN Workup 1 ESR.l CRR antidsDNA Ab. I C3,C4, CH50:APLA Lab do not always correlate w/ LN class: Bx is frequently necessary Bx if:T Cr wlo alternative explanation. proteinuria >1 old. proteinuria >0.5 Yd with active urine sediment (dysmorphic RBCs or cellular casts) (Aruuws Can be 201L6A:7971 Pathology IF: IgG dominant full, house pastern (glomerular slain 19 lim C3.and C1q codominance) EM: endothelial tubuloreticular inclusion (TRI). subendothelial and subepithelial deposits; extraglomerular immunetype deposits within TBM. the interstitium. and blood vessels Lupus Nephritis Classification l\snmps KI 20l)4:65?511: ;ASN 1004:15:241) I (minimal mesangial LN): nl LM.wl rnesangial immune deposition on IF and/or EM II (mesangial proliferative LN): mesangial hypercellularity w/ Immune deposition III (focal LN): inflammatory injury affecting <50% of :he glomeruli by LM wl cres cents.fibrinoid necrosis. andlor subendothelial immune deposition Classes Ill and IV are subdassified as A MM active lesions of proliferation and necrosis. C with chronic lesions of sclerosis and fibrosis. or AIC widi a combination of these lesions IV (diffuse LN): inflammatory Injury affecting >50% of the glomeruli.agaln classified as A. C. or A/C. This class is further divided into segmental (S) or global (G) depend ing on the extent of inlury to the individual glomerular tuft. greater than 50% in the latter category V (lupus membranous nephritis): glomerular capillary thickening on LM wl sub epithelial immune deposition on EM/IF VI (advanced scleroslng LN):290% global glomerulosclerosis wlo residual activity Upcoming proposed changes to ISNIRPS (Ki z01a:93.7a9) Elimination of IVS and IVG subdivisions Replacing the A/C subclasses wl a modified NIH lupus activity/chronicity scoring General Treatment RAAS inhibition for all pronelnuria >0.5 gig Cr Hydroxychloroquine (HCQ) for all LN: I renal disease and severity Imagine 1016:95:92891) Max 66.5 mglkg IBW (Iipophobic): sle retinopathy (/ophthalmologic exam q 12m) Crescents. interstitial and vascular Lesions:a/w renal progression. mortality (Lupus 2016:1S:1532) Classes III and IV: consider activity and chronicity index for IS decision Ciass VI: prepare for RRT Treatment of Classes III and IV Contraception in active classes III and IV LN Induction Treatment of Classes Ill and IV LN Corticosteroid (CS) Give CS plus any of below regimen unless otherwise specified IV methylprednisolone 250-1,000 mg/d x 3 d -\ prednisone 1 mg/kg qd with open >70% remain on cs 10 yr after (Am ohm Do z01ms~zsn NIH CYC Lowdose IV CYC PO CYC MMF AZA Mulnirarger 0.5-1 gm' BSA qm x 6. q3m x 4, q6m x 2 were 19a6:314¢n4> 500 mg q2w x 6 w/ AZA maintenance = NIH dose 1ELNTArVmU¢ Mew 200z;4e¢z1 z1). Remain same after 10 yr um niim no 10 10.69;61i Works on African American (Access Anil Mum 201444114441 2.5 mg/iq/d MMF MM zaoQ34a11ssl MMF wl target 3 old >< 6 m = NIH CYC lAuds up mozanos) CYC > CS only luqm 19a4.3111s2s): Option for pregnancy CS + Tac + MMF superior to CS - NIH CYC as 24 wk in class V+ (Ill or IV) lAM :m 201S:16218) 2 g,x2 cycles addition to MMF and CS nor superior (LUNAR Aida Riruximab 251 g xl, 2 wk apart Rheum zo 1z;so.1z1sl Induces remission in refractory cases (NDT 201J.N:1M) 2 g + MMF w/o PO CS achieved CR in 52%, PR in 34% (RITUXILUP Am Rheum M 2013:72:12B0) If CYC doesnt induce remission. MMF and vie versa (use Annum Cae Res 1011:64:797) Once remission has been achieved.maintenance treatment should be continued Maintenance Treatment of Classes Ill and lY LN cs MMF AZA CYC Prednisone $10 mg/d with one of below 2 old superior ¢oAZA (ALMS of/m zoI 1;ass:1seo) 2 mg/kgld T Death. Cr doubling and sle (NEW 2004;3§09711; not recommended Relapse: ueat MM induction agent Treatment of Class V Treatment of ClassV CS MMF CYC CNI CS monotheraphy is not recommended ()ASN 1009120901) Rituximab 2 z w/o PO cs induced CR in 38% PR in 24% \>Y 12 mo [Ann khwmbs zoimnzaol - NIH CYC in e4Gcacy and side effect profiles 1xl 201<x7711sz; Lowdose CYC is preferred Remission 83% vs NIH CYC 60%. relapse is common. Promeinuria >5 g/d alw no remission UASN 10a9:z(x9011. OTHER Fonr4s oF GLOMERULAR Lesnon IN SLE Renallimited LupusLike Nephritis (nm z01z4171z71 Renal biopsy with lupus nephritis features wlo systemic SLE Some patients may develop SLE later: needs monitoring Tx: co rre sp o n d in g L N cla ssifica tio n Ne cro t izin g and Crescentic LN with ANCA (C/ASN 2008:3:581) Necrosis and crescents exceeding the degree of endocapillary proliferation Et subendo deposits J ANCA ELlSA;Tx dlc hydralazine if taking;CYC L u p u s Po d o cyto p a th y (q Asn 1 0 1 6 ;1 1 5 4 7 ) SLE + MCD or FSGS. mesangial proliferation wlo endocapillary proliferation. necrosis. and/or crescents. Extensive too: process effacement wlo GCW deposits on EM. Tx: 94% responded to CS wu 4-8 wk. Frequent relapse (56%) (qAsn 2016:11:585) co lla p sin g Glomerulopathy in SLE 1c/As~101u9\41 CG and SLE (positive serologies +I- lupus sx at time of Bx) Co mmo n in fe ma le (7 9 %) a n d A frica n d e sce n t (8 9 %) Geneucs: strongly a/w APOL1 risk allele in AA with SLE (iAs~ 2013I24mI Clinical: massive proteinuria with rapid progression of renal dysfunction Pathology: global or segmental collapse of glomerular capillary tuft, with wrinkling and reuaction of the capillary walls. overlaid by epithelial cell proliferation in Bowman space (xi 1996:§0Ll734) Tx: variable in series. irrespective of concomitant LN on histology. CS. MMF. NIG.and AZA Prognosis: poor 7/13 went onto ESRD within 2 yr time INFECTION-RELATED GLOMERULONEPHRITIS POSTINFECTIOUS GLOMERULONEPHRITIS (PIGN) B a ckg ro u n d Poststreptococcal GN (PSG N), the prototype of PIGN is increasingly uncommon in t h e d e ve lo p e d wo rld » PSGN is more common in children: highest incidence between 4-15 yr old PIGN formally implied antecedent infection and latent period of dwk after infection has cleared (10-14 d for PSGN). Particularly for adults with nonstrep infections. GN often occurs during ongoing infection:thus the preferred term is Infectionrelated GN (IRGN). mlc organisms: Streptococcus (pharyngeal/skin infections). Staphylococcus (skin infections). and rare gramnegative organisms (Pseudomonas, Escherichio.Yersinio, Pseudomol10s) P a t h o g e n e s is Nephritogenic antigens produced by pathogens stimulate an initial immune response. Two streptococcal antigens have been implicated in the development of PSGN. the sueptococcal pyrogenic exotoxin B (SPE B) and die plasmin receptor.a glyceraldehyde phosphate dehydrogenase (GAPDHINAPlr) (KJ 1005;681120) Immune complexes formed in circulation or in situ induce local activation of alternative complement and coagulation pathways and recruitment of neutrophils to glomeruli P a t h o lo g y LM: diffuse endocapillary proliferative GN w/ intracapillary neutrophils (exudative") IF: coarse.granular GBM and mesanglal staining of C3 alone or lg with C3 dominance (st a rry sky a p p e a ra n ce " ) EM: large. scattered subepithelial electron dense deposits ("humps") Clinical Manifestations and Workup Acute GN including RPGN (with HTN).edema (80-90%),dark urinelhematuria In PSGN.typically occurs 10-14 d following infection (pharyngitis. cellulitis. pneumonia) T Cr. Y CH50. C3 (90%), C4 (rare), t ASO (in PSGN). red cell asr.s.proteinurla (usu ally subnephrotic) Treatment and Prognosis Supportive care ofAKl. HTN. and edema Elimination of any ongoing active infection. Patients with PSGN should be :reared with antibiotics to prevent carrier status. though limited evidence that this affects :he course of PSGN.Antibiotics are indicated for prevention of PSGN when used to treat strep tococcal infections in children. Antibiotics should be used prophylacdcally for close household contacts of PSGN patients and in epidemics of streptococcal infections UASN 200s;10:,6551 No clear role for immunosuppnession. though there are reports of success with cor ticosteroids or cyclophosphamide in individual cases of severe/progressive disease In children.complete renal recovery is likely within 2-3 wk. Persistence of low C3 should raise concern for C3 glomerulopathy. In adults. prognosis is guarded. STAPHVLOCOCCAL AssoclATeo GNIIGA DOMINANT IRGN Background and Pathogenesis Risk factors: >S0 ylo. diabetes. malignancy, IVDU. and alcoholism (1ASN z0112z2..ian Common site: skin. respiiar.oiy. hmm deep tissuelbone. urinary tract (Am y~¢pi~ii2o1s=41.9el Causative organisms: MRSA >> MSSA > S. epide/midis/S. haemofyticus >> Enterobacter species. Escherichia species Typically during active infection (often chronic) wlo latency period (And 2015..6ssi61 Proposed mechanism: bacterial toxin (eg. S. aureus enterotoxin) acts as superantigen. bind to MHC molecules _.T cell activation. cytokine release l~w»~»»» an f~n 1011:1m1ai Pathology LH: proliferative GN with endocapillary and mesangial proliferation +I- crescents IF: mesangial C3 dominant or codominant staining with IgA +/- IgG EM: subepithelial hump"like electron dense deposits Clinical Manifestations Renal: AKI. acute GN with elevated Cr. hematuria (including macroscopic), subnephrotic proteinuria and HTN; up to 1/3 have nephrotic syndrome Exuarenal: purpuric rash, signs of active infection Workup Cr. hematuria. subnephrotic proteinuria J C3. C4 (hypocompleineitemia les common dlan with PIGN), ANCA (a/w ciesoentic GN) Evaluate for active infection (blood cx. urine ex,sputum cx) Treatment and Prognosis Treatment of underlying infection and supportive care of AKI. HTN.edema Retrospective studies suggest no benefit from immunosuppression (QASN Z006:11179) Guarded prognosis: many patients have persistent renal dysfunction and up to 33% of elderly pts remain dialysis dependent Risk factors for progression to ESRD and death: age and diabetic nephropathy (;A$n Z011;22:1S7: Median! Z008:B7:l 1: Anil N¢9hlI(201§:41:9B) INFECTIOUS ENDOCARDITIS (IE)RELATED GN In 2015:87:1111) Background and Pathogenesis 6:9 3.5:1.mean age an biopsy 48 Associated comorbidides: valve disease, IVDU. HCV. HIV. DM Affected valves: tricuspid > mitral > aortic > pulmonic Staphylococcus > Streptococcus > Banonella. Coxiella. Cardiobacterium. Gemella Up m 18-24% of IE pos have ANCA (+) (Annrns slew 2014411672 Medan! 2o1a~>s:lzs4»4l Mechanisms: (1) drcuhdng and in situ IC formation; (2) bacterial toxin activation d akena tive complement pathway:(3) bacterial toxin activation ofANCA lading no acdvadon M almemauwe complement pathway via activation of C5a In 201587112411 xmmssos; 2013;e3:m> Pathology LM: necrotizing/crescentic > endocapillary proliferative > mesangial proliferative GN IF: C3 dominant (or isolated) staining. may have (+) IgG. IgM. IgA mining EH: subendodlelial and mesanglal EDD Clinical Manifestations Renal: most common is AKI. may also see hematuria and signs of RPGN Exvarenal: septic pulmonary infarcts (in tricuspid endocarditis).splinr.er hemorrhages. fevers. weigh: loss. murmur. Osler nodes.]aneway lesions. Roth spots Workup Cr, hemacuria. proteinuria. i C3 z C4 (nl in 44%).may have (+) ANCA/ANA Check blood cultures and echocardiogram for evidence of endoardizis T reat men t an d Pro g n o sis Treatment of underlying infection and supportive care ofAKl lmmunosuppression: ANCA (+) and/or persiscenc GN despise antibiotics (OD 19991&10s7; Case in Neill Url 2011421252 lndnn[ Nephrd 201333568: Gln N<PI"°1 Cdse Stud 20\7;5:3Z) Risk of ESRD corvelates wish elevated serum Cr at diagnosis SHUNT NEPHRITIS Background and Pathogenesis Complication of chronically infected yentriculoatrial (VA) or ventricukaiugular (VV) shunts for hydrocephalus. Rarely seen in ventriculoperitoneal (VP) shunts Organisms: S. epidermidislk acnes >> S. aurous >> Pseudomonas. Serration species IC formation w circulating bacterialbiohlm activating complement padiway (nor 1997.1211431 Pathology LM: MPGN or mesangioproliferative GN. may have ATN and red cell casts IF: mesangial IgM. C1q. C3 deposition in 2/3 of cases (Case no n¢p»»ua 20\7=z011=1a¢7149) EM: subendothelial EDD Clinical Manifestations Renal: elevated Cr. hematuria. red cell casts. proteinuria, HTN. edema. may be subacute Weight loss. even arthralgia. hepatosplenomegaly. rash. so of T intracranial pressure Workup T Cr, hematuria. proteinuria. hypocomplementemia, elevated ESR and CRR anemia May have (+) ANCAlCryolRF (nor 1997;1z1143) Infection identification may be delayed dlt to poor growth of S. epidennidis and R acne Treatment and Prognosis Treat infection. removal of infected hardware is frequently necessary (NDT l997;111143) Early dx.slwnt remcwal aiw beuer prognosis (nor 1997;17;1143: Can to NePhlu12017;2017:1B67349) IMMUNE COMPLEX-MEDIATED MPGN Background Accounts for 7-10% of renal biopsies of GN in developed countries Among the leading causes of ESRD from primary glomerulopathies (NEar 201136631191 Commonly presents in childhood and young adulthood 2 causes of immune complex (IC) MPGN include chronic infection (esp HCV). hema tologk disease (eg, CLL NGRS), and autoimmune disease.True idiopathic is rare Pathogenesis AgAb ICS form in glomenulhddier after forming in the circulation or forming in situ fol lowing glomerular Antigua trapping. ICS trigger an inflammatory response and activate complement. leading to disruption of die GBM and endoapillary proliferation. Pathology LM: endocapillary and mesangial proliferation. leading to lobular appearance. Duplication of basement membrane over deposits leads to"¢ram track" appearance of capillary walls. IF: granular deposition of lg and complement in GBM.oMn mesangium. Chronic TMA an mimic MPGN but will have no Ig staining. C3G will have almost exclusively C3 staining. EM: GBM thickening and separation by elecr.ron dense immune complex deposits Clinical Manifestations Acute or chronic GN: hypertension, edema. microscopic hematuria.subnephrotic proteinuria with CKD. Severe cases present as nephrotic syndrome. Wo rk u p Lab: elevated Cr. hemawria. subnephrodc proteinuria. low complement levels C3 or C4 . Seek our secondary causes: Chronic infection: HCV. HBV. HIV. endocarditls. shun: infection. visceral abscess. mycoplasma, parasitic injections Autoimmune disease: Si6grens. SLE. RA. MCTD Hemozologk disease: lymphoproliferative disorders. monoclonal gammopathy. plasma cell dyscrasia (especially in MPGN with masked deposits present) In 101s;ea,a611 Treatment BP control and RAAS blockade as tolerated for all elected patients 2 MPGN: treat underlying causes Idiopathic MPGN: immunosuppression if substantial protdnurla (et. >1 old) or falling GFR Extended courses of corticosteroids have been used in pediatric patienfsahas not been replicated in adults (m ~¢9h.vI 1992;6:113; 19953269 RTX (Clin Ntphml 1012:77Z90: NDT 2004:1931s0: 1007;11:I 351: 0» Neplvmf 20101731350 Rapidly progressive course: cyclophosphamide + corticosteroids (KDIGO GN 1012) Prognosis Pmgvessiverenaldiseasewid\l~erlalsurvival<50%at 10yrflamcb<.Risk facn>rs for pmgres sion: GFR. proteinurh. HTN. age, severity of IFITA. crescents in 2006i69:504: nor 1noz17:1w3) High rue of recurrence after transplant (19-4B%).confounded by studies grouping different categories of MPGN (funspianmuan 1997;6]:152B; qAs~ 7.010:S:2363: pa 2010:77:711) C3 GLOMERULOPATHY (C3G) Background Glomerulonephritis associated with dysregulation of alternative complement pathway Defined on the basis of immunofluorescence: dominant C3 staining Categorization of GN with Dominant C3 Staining In 201345440791 Morphologic appearance Glomerulonephritis with dominant C3 r 1 1 Disease category C3 glomerulopathy Poslinfectious GN Other q C3 GN r Specific genetic forms and/or autoantibodies Specific genetic forms Not otherwise specified for example CFHR5 nephropathy and/or Not otherwise Specified autoantibodies C3G may present as a nonresoiving postinfectious GN. (PIGN may show C3 deposits beyond the acute stage: C3G should be suspected in such uses when dinial resolution is incomplete.) Infection (including with streptococcus) may precipitate CJG. Pathogenesis Hyperactivity of the alternative complement pathway (normally constitutively active at a low level) through hereditary or acquired defects (see table) C3G is commonly associated with a circulating autoantibody called C3 nephritic factor which binds to and stabilizes activated CJ. Other abnormalities of complement acti vation may occur including genetic mutations of complement regulatory proteins and other autoantibodies (see table) Disease presentation and/or flares may be triggered by acute infection Mechanisms of Complement Pathway Disruption in CJG Abnor malit y Genetic mutations or risk variants Descr iption Implicated genes of the complement pathway include CFH, CFI, CFB, CFHRS, C3. and MCP/CD46 Mutations of CFHR5 cause highly penetrant familial Cypriot C3 Nephritlc factors nephropathy (now 2013:1812B2) Risk variants found in <20% of cases of C3G (al 20119440791 AutoAb stabilizing C3bBb.alterr\adve pathway C3 converse CO Nephritic factors ( 50% of cases. DDD > C3GN) AutoAb stabilizing C4b2a, classical pathway C3 convertase Factor H autoAb Factor B autoAb AutoAb stabilizing C5 convertase Prevent CFH from downregulating activity of CO convercase Stabilizes C3 converse; prevents intrinsic and FHmediated deny Monoclonal gammopathies Likely ac! via autoAb activity: eg. one case documented a monoclonal 3. light coin dimer acting as a "miniaumandbody" C5 Nephritic factors to FH (jumnwu 199215145901 Pa t h o lo g y LM: proliferative GN (MPGN endocapillary. mesangioprcliferar.ive.or diffuse prolifera live) IF: C3 dominance and minimal or absent lg In 2014:85:450) EM: presence (DDD) or absence (C3GN) of intramembranous highly EDD C lin ica l M a n if e st a t io n s May range from nephrotic syndrome (hypoalbuminemia. proteinuria >3.5 Yd. edema) to Synpharyngtic hematuria (as seen with PIGN) may be seen reflecting increased activity of the complement system during infectious episodes May present as a nonresolving postinfectious GN Retinal dusen (yellow gnnula on optic disc containing complanent). partial Epodystrophy up Complement Cascade Schematic an u Man c 1é 0 a ( n, 0 ) f or c a l l binding leciln CO Cowc t;1e MCP .13 CFHR5 FH, FI 11 C 5b9 (SMAI Kay components of the complemau cascade an: diagrammed, In grey are various complement components. m back are cumeruses ha: split C] or C5 into their activated brms.and in vivre an lqulazory molecule; Workup Labs: low C3 (40% of uses). normal C4. hematuria, pnor¢inuria.+/- elevazed crasinine J Complement pathway abnormalities: C3nel. Factor H ab. Factor B level, Factor I level, soluble membrane amok complex (SMAC) level J Monoclonal gammopathy screen: SPEP/lFE, serum free light chains Consider genetic mutation analysis: does not currently derange treatment bu: may affect prognosis and risk stratification for pos:transplant recurrence Treatment Immunosuppression controversial: combination of srerolds and MMF may favor clinical remission no 2015:881153: qASN 1018:13:406) Eculizumab (antiCS mAb preventing its clearage): may be afflictive especially in aggressive forms with elevated SMAC levels (qASN 201z17¢74s1 or crescents we 201692941 Plasma (FFP) therapy useful in case reports. eg, FH deficiency In 20as;m4zl Prognosis >50% progress to ESRD within first :we decades of diagnosis (Na: Reueprd201M:6341 Risk factors for progression: baseline eGFR and degree of interstitial fibrosis/ tubular atrophy on biopsy (al 201u2¢4s4;xi Z018;93;977) Posttransplant: 2/3 recur.and 1/2 have allograft failure iIAsn z014:zs:11101.Another cohort showed higher recurrence (10112 in C3GN, NU in DDD) and allograft failure (3/12 in C3GN. 6/7 in DDD) (Aim zommio 304 mm CRYOGLOBULINEMIA Background/Pathogenesis Cryoglobulinsz lgs :hat precipitate at <37C and redissolve upon rewarming Cryoglobulinemiaz the presence of circulating cryoglobulins in serum Mixed cryoglobulinemla (MC): cryoglobulin with 22 Ig clones Pathogenesis of MC: antigen (eg. HCV) stimulation -» B cell clonal expansion -o non neoplastic B cell lymphoprdiferative process -»Ab against Fc portion of IgG (RF activity) » IC formation in vessel walls activate complement -» leukocytoclasdc vasculitis Cryoglobulinemic vasculitis (10-15% of MC): predominantly involves the small vessels. affecting the skin. ioims. peripheral nerves. and the kidneys we: mm 201s; 1zsoso) Types Classification and Fear res of Cryoglobullnemla Components Clinical Features Associated Diseases Type I (simple) Monoclonal Ig. most often IgM > IgG Or IgA Type It (mixed) Monoclonal liM»: w/ RF activity against IgG Polyclonal IgM against IgG Both monoclonal and oligo or polyclonal IgM against IgG Type III (mixed) Types It-Ill (mixed) Hyperviscosity. acrocyanosis. Raynauds. gangrene. arthralgias rarely Wealmess (>80%) Purpura (>75%) Arzhralgias (60-90%) Neuropathy (2080%) Nephritis (7.0-50%) Cutaneous ulcers (10-20%) Sicca (5-50%) "Meltzer triad WaldenstrOm macroglobulinemia Multiple myeloma Bcell lymphoma, MGUS Infection . HCM H8V HN IE Lyme Rickettsio, syphilis Autoimmunity S]6gren§ syndrome . SLE. RA Lymphopmliferative dz idiopathic (essential) Renal Manifestations AKI/RPGN. subnephrotic or nephrodc proteinuria wl microscopic hematuria, NS. HTN Renal injury is the most morbid manifestation of cryo vasculitis. typically manifested as immune complex MPGN. However. only a minority of parents with MC show renal manifestations at presentation w/ as least half developing them over followup. Extrarenal Manifestations Meltzer Mad: purpura, arthralgla (PICPs. P1Ps. ankles and feet). and weakness in 25-80% Skin purpura. ulcers. Ravnauds and acrocyanosis. livedo (exacerbated by cold exposure) Neuromusc: myalgias. peripheral neuropathy with paresthesia. mononeuritis multiplex Pulmonary: rare: include dyspnea. cough. pleuris. rarely diffuse alveolar hemorrhage A smoldering lymphoproliferative process can evolve into NHL 11/mana1 Hepaia z01s:e1on Diagnosis Serum cryoglobulins: measurable cryocrit ar protein concentration Cryocrit: volume percentage of packed ciyoglobulins in blood after centrifugation as 4C: Quantity of cryocrit can correlate with disease severity Draw in prewarmed syringe.transported and centrifuged at 37-40 serum then stored at 4C for up [O 7 d as cryoglobulins precipitate out (hr to d) Fake (-):common hearse of technical collection: repeat assays required if high suspicion False (+): polyclonal cryoglobulins can be transient during infections Immunofixation employed to identify type of cryoprecipitate MC;T RF and cryoglobulins.and ii C4. more variably l C3 and 1 CH50 Kidney biopsy: typically MPGN +I- microthrombi (cryoglobulins appear as pseudo thrombi). EM: subendothelial deposits wl fingerprint pattern substructure T r eatment MC a/w HCV: DAA iHei==-wiv 2016163.408: Gasziueniewiagy Z017:1S3:40G). Can recur despite HCV eradicauon d/t ongoing ab production by Bcells We 2017;7&l011 Type 1 or 2 alw lymphoproliferative disorder treat it based on the type IS: for organthreatening MC to inflammation and cryoglobulin production CS: acute antiinilammatory benelir. Relapses are common upon withdrawal. Rituximab: sustained response. Can be used before or after failure of HCV ueaonent (always screen for HBV confection first) umm Umm 201u4.043i; Cyclophosphamide Plasmapheresis: for severe vasculitis. RPGN, or hyperviscosity U angie 1o 16,31.149) AMYLOIDOSIS Ba c k gr ound Amyloid: extracellular deposldon of insoluble fibrils nesulrjng from abnormal folding of proteins; >25 precursor proteins of amyloid found Overall incidence 1.3-4% of renal biopsies (Am I So: PuMa! 2009939 is) Clinical Manlfestadons of Amyloidosis: Depending on Involved Organ Kidney Proxeinuria (NS common). CKD, NDI, :ype 4 RTA Heart Nonisdlemic HF (nl or low LVEF. restrictive or dilated CMRAflb) Nerves Peripheral neuropathy. carpal tunnel.or¢hosmk hypotension Cooguhtion Easy bruisabiliry, Raccoon eyes, Factor X def GI Malabsorpzion. ulcer. macroglossia joint Ardmralgia Dia gnos is Biopsy fat pad or involved organ: kidney, liver. and heart are commonly involved Congo red stain under polarized light; applegreen birefringence LM in kidney biopsy. diffuse glomemlar deposition of amorphous hyaline material EM randomly arranged fibrils. measuring 8-12 nm diameter Amyloid typing IF staining of monoclonal light chains (AL) and amyloid A (AA) is diagnostic. M protein in serum/urine is not (NE]M 2001:]46:17861. Mass spectrometry gold standard In 10l 7.:B222b) Other rarer forms are derived from following precursors: apolipoprotein CII (AApoCII) qAs~20l 7¢um4:49). l ysozyme (ALys) UASN zol mssan. gel sol i n (Abel ) l x: 2017. 91:964) gzip P rognos i s Prognosis depends on associated underlying disuse and degree of organ involvement Renal involvement carries particularly elevated morbidity Overall survival 80% at 10 yr: renal failure 11% over S yr WKD 1007:49:59) MC: 10yr survival rate <60% la" et Nnwmaiui z0o&ws10sl AL AHYL O IDO SIS Precursor: monoclonal K (20%) or l (80%) LC produced by a monoclonal plasma cell clone in :he BM. Rarely heavy (AH) and heavy and LC (AHL) Only about 10% of padenrs have concomitant multiple myeloma at presentation Localized form: 12% Produced by a local. selflimited plasma cell clone. w/ (-) SIFE/ UIFE. mlc sires: GU nracc. larynx.skin.and upper respiratory yacc Tx is local excision, RTF No systemic progression but recur locally esp In the GU tract w~=»»ov~ nm 2017192.90m Systemic form: affects the heart. kidney. liven and nerves (autonomic/peripheral) Manifesuitions: NS. fatigue. weight loss. bleeding tendency orthosmsis. CHF symptoms Renal Scage and Pmgnosls of Renal AL Amyloidosis (um zounmazsl Definition Stage Dialysis Dependence 3 yr alter dx Proteinuria $5 gl24 hr and eGFR 250 I 0% II Proteinuria >53/24 hr or eGFR <50 7% III Prozeinuria >5 g/24 hr and eGFR <50 60% T reat m en t AutoHSCT eligible (low risk) pts autoHSCT w/ highdoGe melplnhn (Anal IM Z0041140i851 or standard dose mdphalan plus dexamethasone (NEIM 2007;357:10s3) Criteria: physiologic age <70. troponin T <0.06 fig/mL, NTproBNF <5.000 nglL. CrCl >30. NYHA functional class 1 or 2. $2 organs involved. not oxygen dependent AutoHSCT ineligible (intermediate or high risk) pts: combination chemotherapy: eg. melphalan + dexamethasone or CyBorD (CYC. bortezomib,dexamedusone). CyBorD achieved renal response in 25% (Nina 2015;126:mi. Daratumumab: human mAb against CD38 on plasma cells. if refractory (Sim 2017;130:9001 Prognosis orAL Amyloidosis by Treatment Response (am z0\4;1z41azs1 Criteria Definition Renal Progression L eGFR 225% Renal Response l Prozeinuria 230% or 0.5 8124 hr wlo renal progression Difference between involved and uninvohred fLC (d1LC) <4 mgldL wl baseline dfLc 25 mgldL Hematologic Very Good Partial Response (VGPR) Hematologic Complete Response (CR) ESRD Risk HR 4.56 HR 0.15 HR 0.47 () SIFE. UIFE. nl FLC ratio Transplantation 15/19 survived after median flu 41.4 mo (nor 1011:z6:20321 Median graft survival 5,8 yr: Pt survival was 8.9 yr if CR ( SIFE. UIFE. nl FLC ratio) or PR (dFLC <50% of prerx) vs 5.2 yr in NR (dFLC >50% of pretx) WT 1013;1!;433) A A A MYL O ID O SIS Precursor: serum amyloid apolipoprocein A (SEA) produced by the liver. vascular endothelial cells. monocytes. macrophages. It is induced by proinflammatory cytokines including IL1. IL6. and TNFa (Mad Khan 2014;241405) Reactive amyloidosis to: Chronic inflammation: RA, juvenile idiopathic arthritis. spondyloanhropazhies, IBD, FME hidradeniris suppurativa, IgG4related disease <~ElM 7.017¢376=5991 Chronic Infection: bronchieccasis. IV drug abuse. infected pressure sores. osteomy eliris Neoplasm: RCC. lymphoma Organs involved: kidneys. GI rracc (including liver), heart. autonomic nerves Tx: great underlying disease Tocilizumab: humanized andlL6 receptor Ab. inhibits SAA production.Appmved for RA 1 Amyloid load by SAP scimigraphy. i SAA. proteinuria (an Exp Meum 2015;33:S46) In FMFAA amyloid. l proreinuria, ESR. CRP 10wn0mij Nan M 20 I7:Iz\os) Canakinumab: humanized anuIL1 mAb 4 proceinurh in children (haul numb Z016:J 1:6J3) Txp: median graft survival 10.3 yr: recurrence 19.5% or 201J.1314331 ALECT2 AMYLOIDOSIS In 2014:86:370. 2014x6¢m1 Precursor: leukocyte chemotacdc factor 2. a cytokine produced by the liver Etiology of :he hepatic upregulation of this proteins production is unclear Strong ethnic associations: Mexican Hispanics. Punjabis.Alabs. Israelis. Native Americans Organs involved: kidney, Iiver.heart (rare); DM. HTN common CKD. proteinuria (33% nephrotic range). ESRD (39%) over flu of 22 mo Concurrent renal disease on bx: DN (21%), MN (5%) Monoclonal protein in 9.6%: monoclonal protein + amyloid z AL amyloid Tx no specific tree¢ment:Txp: recurrence 1/5 wlo graft demise AFla AMYLOIDOSIS row# 2o13a¢1s\s=;Asr4 z0a942a4441 Precursorzfibrinogen n chain, synthesized by the liver AD mutations with variable penetrate. Family history absent in 46% 4 yr. Txp: 7/12 gray failure in 5.8 yr including 3 recurrence. Combination liver-kidney top Poor prognosis: presenting creatinine 4.1. 62% reached ESRD in appears to be more effective QM 2000:93:169) ATTR Amy Lolnos ls Precursor: transr.hynetin transport teuamer protein that carries T4 and retinolbinding protein; 90% produced by :he liver Accounted for 1.4% of renal amyloid uses submitted to Nephrocor (KI 20\4,e6)378) The most common form of hereditary amyloidosis Mutant forms (>100 known) destabilize the native TTR quaternary structure. leading to mislddinglaggregation of the protein, resulting in amyloidosis VVT (nonrnurant) fonnzaflects che heat in elderly men. Endemic in Fioruigal and Sweden Organ involvement: nervous system. heart. kidney. and Gl uact Manlfesmdon: neuropathy -» micrcalbuminuria 3-5 yr later - oven nephvapaclly 2-3 yr later -» ESRD about 10 yr after neuropathy lqAsr4 1011113371 Tx: liver or liverlkidney txp: tafamidis. aTTR stabilizer. oilers possible improvement cardiovascular outcome (NEW z01a;:n 1007) ABZM Ar4 y Lo1 oos 1 s Precursor: 152 microglobulin, LC of the MHC class 1 molecule.excre1.ed by Me kidneys Clinically affects :he osteoanicular structures. je. scapulohumeral periarthrirjs and carpal tunnel syndrome (Semen our 2017;30:19J). Occurs in long:erm dialysis patients. Cleared by high flux HD membranes along with convection U Lau on m¢4 1991;\1s1i531 Also helpful: use biocompatible HD membranes and ultrapure dialysane to minimize proinflammatory state UASN 1lX)Z;\3972) Treatrnenr time is important: slow imzercompartmenral mass transfer llmins 152 micro globulin removal (KI 200666921431) Higher prevalence with longer dialysis vintage Overall decline in disease prevalence in Europe (n 1997:51:1017) and Asia (nor 2016:J\:s9s) Tx: renal rransplanurion is die best prevention and treatment NONAMYLOID DEPOSITION DISEASES Fibnillary GN and Immunotactoid GN uuz00su»z:14so. qAs~ zmwns; nor z0na7»4131) Fib rilla ry G N (FG N) l mmu n o t a c t o i d G N (I T G N Prevalence <1% of native bx 0 .0 6 % o f n a M b x Marifestation HTN, proteinuria (NS 50% in FGN, 69% in ITGN). hematuria. CKD MG. low C 15-17%. 2% 63-66%. 46% Associated CGodili¢f\s Cancer. MM Autoimmune: Crohns. Graves.SLE. ITP. PBC. Si6grens. ankylosing spondylids. scleroderma Infection: HCV w~ z011;4s=24al.TB. osteomyelitis Lymphoproliferative disease (esp CLL) HIV +/- hep C (at Ntphiul z0112751a01 LM Diffuse proliferative. membranous. Mesangio/membranoproliferative. diffuse sclerosis, crescentic (rare) Membranoprolifemive. diffuse proliferative. and membranous pattern injury IF IgG (esp lgG1 and 4). N and A light chains (mostly polyclonal) and complement Deposits contain IgG or IgM. monoclonal ac or 1. and complement EM Randomly arranged fibrillary deposits: 1 6 -2 4 n m in d ia me te r in th e Micro tu b u le s: 3 0 -5 0 n m in diameter in parallel arrangement, in the subepi and subendothelial space Cryo deposits an be indistinguishable from ITGN mesangium and capillary walls ESRD 44-45% 17% Transplantation 5/14 recurred. 2/5 became ESRD again Recurrence 25% WN 1015;42:I77) - 59% (Am;m¢a iqnsu 2011:47751 1/13 recurred w~201S:41:177) wl MG: 5/7 recurred.3 reoqa. 1 recurved again. 2 died wl hematologic malignancy w/o MG: 0/5 recurred (m zoous:4z0l 1990189:91) Dna] Heat Shock Protein Family B Member 9 (DNA]B9) in FGN A heat shock protein; detected by immunohistochemistry (King 101&3;$6) and mass spectrometry i}Asn 2015429511 in glomeruli with high sensitivitylspecificity May be used for diagnosis. particularly if EM is not available Treatment of FGN:Treat Underlying Disorder Various IS agents have been tried with suboptimal response In group w/ mean Cr of 3.1. IS (CS, CYC. CsA) was not a/w outcome (xi 2003:6314s0) In group w/ mean Cr of 2.1. IS use resulted in PR in 10%.persistent renal dysfunction in 38%. ESRD in 52% ic1As~ z011:s:77$i 6 (5 RTX. 1 CYC)l13 had L proteinuria by >50% w/ stable GFR) WK. 201341:679) RTX use was a/w nonprogression in 4/12: nonprogress had lower Cr (nor 1014129:19151 In crescentic FGN treated w/ CS.CYC.6/8 wen: on to ESRD (I/mn/i4¢1»~iz017.z7..1519 Treatment of ITGN:Treat Underlying Disorder 7/14 (Cr 1.5) had B cell disorder. Chemo#-HSCT led no NS remission in 5 us zoorsziuq A PR of the hematologic disease led to complete renal remission (Ann Henuiul 2007;B6.927) 7/12 w/o MG were treated wl CS+/- CYC. 3 achieved PR (NDT 1017;27:4137) Rar e Nonamyloid Deposition Dlseases Disease P a t h o lo g y Clin ic a l Ma n if e s t a t io n s Fibronectin GP Mes. subendo Hbronectin deposition AD, proteinuria. HTN. ESRD Can recur (an Tiuiiplani zoizzsssi Collagenofibrodc GP Mes. subendo type Ill collagen deposition AR. proteinuria. ESRD Nail-patella Type III collagen deposition in lamina denser AD, prozeinuria. <$% ESRD nail and Upopmtein GP Lipoprotein diiombi w/i g io me n ila r ca p illa ry irin a Proreinuria. T VLDL LDL. app E paella abnormality HEREDITARY GLOMERULAR DISEASES Background • Mutations of genes encoding proteins involved in glomerular filtration barrier can directly fuse glomerular diseases Generic systemic disease (eg. sickle cell disease. generic aHUS) may indirectly cause glomerular injury Monogenic causes identified in 30% of steroidieslstan: NS in <25 y/o IJASN 2015:26:U791 Relatively common generic causes in 19-25 y/o: lNF2,TRPC6, NPHS2 l1Asr4 20151642791 Clinical manifestations: proteiriuria 1 steroidresisxznt NS t hemaruria i CKD Pathology of congenital NS in children: FSGS (5696). MCD (21%), mesangioproliferatiwe GN (12%), diffuse mesangial sclerosis (3%) (QASN 2015110 59z1 lmmunosuppression is generally ineflecdve in generic podocyiopadiymediazed glomerular disease UAS~2015:2b:130) Pathogenesis Deficiency of the enzyme agalactosidase A (nGalA). encoded by GLA on Xq22 Accumulation of globotriaosylceramide (Gb3) within lysosomes in a wide variety of :do Renal Manifestations Proteinuria: nephrotic range uncommon: a/w renal progression (C/ASN 2o1ans:222al pRTAIFanconi: polyuria and concentrating defect in distal nephron involvement ESRD in 14% of cl. 2% of 9 an 38 ylo: alw cardiac even: and stroke (nor 1010'1537691 Multiple renal sinus cysts Renal variant: later onset. renal limited wlo other organ manifestation (KI 100J;64;B01) Heterozygous female: asymptomatic carrier all manifestations including renal mani 2 festations: eGFR <60 (1994). proteinuria >1 g/day (22%) (mu 6¢-1m¢10b 2008;93\12> g Extrarenal Manifestations E . Cardiovascular: nVc muse of death; premature CAD, LVH. arrhyizhmb, mimic hypertrophic cardiomyopathy I3 M Angiokerawmas: ziny painless papules. esp bashing suit area. :elangiecrasia Hypo or anhidrosis. hear intolerance. acroparesthesia in hands and feet Cornea verricillasa (vortex keracopachy) TIA. stroke. neuropathic pain Diagnosis / Leukocyte RxGalA activity in 6: <3% diagnostic. 3-35% requires GLA mucasion analysis: . Not recommended for 9; low to normal regardless of disease manifesucion GLA mutation analysis: diagnostic if known mutation Tissue diagnosis: if genetic test nondiagnostic Kidney Biopsy LM vacuolization of podocytes. DT cells > PT cells,endozhelial cellscglomerulosderosis EM: Zebra or myeloid bod lf osmiophilic inclusions in lamellated membrane stnicuires (enlarged secondary lysosomes) Other causes of Zebra body. silicosis. amiodarone (lu 200e;74:1354), gentamicin (PT cells). chloroquine. hydroxychloroquine IAjKl> 20061488441 Enzyme Replacement Recombinant uGalA: agalsidase ii (Fabrazyme°) 1 mg/ug or agalsidase G (Replagal°. available in Europe) 0.2 mglkg IV q2wk Indicated for all males and symptomatic females even with ESRD 1 Gb3 deposition in mos: cell types including podocytes uAsu zo1n4¢ 137: qAs~ 2017:12:1470) Maximal impact if eGFR >5S (A~» IM 2a07;14u71:1 severe clinical events 0 m4¢G¢»¢ 1016;SJ;49S) s/ez neuualizing antidrug antibodies development; may need dose adjustment and immunosuppression UASN 101819122651 Other Treatments RAASi to treat HTN and proteinuria Migalasuc pharmacologic chaperone, t trafficking of RxGalA to lysosomes -» T aGalA activity: 1 kidney and plasma Gb3: improved LV mass index (NEIM zu1@37s:s4s1 Transplantation 5yr graft survival similar. T death (x2.1$) (rfumpIamauan 200957:N0) Recurrent deposit is common UASN 2002:13:S134) COL4AASSOCIATEO NEPHRQPATHY Background Hereditary diseases caused by mutation of COL4A genes encoding type IV collagen COl.4Aassociated nephropathy includes benign familial hematuria, thin basement membrane nephropathy.Alport syndrome, COL4A associated FSGS (KI 2014.s612sa1 62% of patients with COL4A mutations were clinically not diagnosed with Alpon syn drome or thin basement membrane nephropathy luqm 20195801142) Genetics Type IV collagen: component d basement membrane (BM) in gk>merulus.cubules. and sloan 6 genes are located at chromosome 13 (COL4A 1 & 2).2 (3 & 4).and X (5 & 6) COL4A5 (classic XL) mutation in male or heterozygous female >> COL4A3, COL4A4 (heterozygous AD or homozygous AR) Expression Collagen lY Location Normal XL Alpert Immature GBM. BC.TBM ulu1rx2 + u1u1u2 u1 a1a2 + 01 u1n2 Manure GBM. dTBM u3a4u$ + /13114415 u1u1a2 + 11 a1u2 BC. dTBM. skin BM u1u1a2 + /15415116 at rx1a2 » u1a1 u2 BC. Bowman Capsule: GBM. Glamerular Bm:TBM.Tubular BM; dTBM. rlinalTBr*l Large deletions and nonsense mutations: progress to ESRD faster (90% at age 30). more frequent hearing loss and eye abnormalities Missense mutations: variable course (50% reach ESRD at age 30) De novo mutations: -15% Mutation of lamina B2. component of GBM modify Alport phenotypes (jAsn 201&29:4149) Clin ica l Ma n if e st a t io n s Hematuria, proteinuria: ESRD before 40 ylo:90% in male: 12% in female (MSN 1003;14zwJ). Age of ESRD a/w type of mutation in male ()A$n 2010:2\:B76) Risk factors of renal progression in Xlinked female:gross hematuria. proteinuria Bilateral anterior Iendconus is pathognomonic; dotandfleck retinopathy sphero phakia. corneal erosion Highfrequency sensorineural hearing loss Skin and Kidney Biopsy Skin epidermal basement membrane up stain: (-) In male XL disease: segmental (-) in female is C/w COl.4A5 mutation (+) In COL4A3. COL4A4 mutation LH: normal or FSGS; interstitial (oam cells (nonspecific. present in other proteinuria) IF of collagen: mosaic. skipped a5 in female EM: GBM thinning (early); thickening, laminationibasket waving (late). elecuolucent zone Can have normal GBM appearance in early stage (Hum Anna: 2ma,a1;z19» Treatment RAASi: i progression. ESRD (mau nquvua 1017;31:131). Stan early (n 2012;81=4941 Transplantation No recurrence. LRKT is possible (NDT 200911421s1s1 De novo antiGBM antibody against a5 or 113 detected in 5-10% (cyAsr4 101711z11621 Associated with crescentic GN and subsequent graft failure Commercially available antiGBM as NC1 region Ab does not always detect this Ab Retransplanmionz high risk for graft loss (KI 2004,6s167s) Thin Basement Membrane Nephropathy (Benign Familial Hematuria) Mutations of COf.4A3 and 4: benign side of the spectrum ofAIport (xi 10143611 0611 None or minimal proteinuria unless concurrent FSGS Rare ear/eye involvement Biopsy. diffusely thin GBM 150-225 nM; indistinguishable from early Alport Tx: RAASi especially for proteinuria ANTIPHOSPHOLIPID SYNDROME (APS) Antiphospholipid syndrome (APS):an autoimmune disease resulting from :he presence of antiphospholipid antibody (APLA) which exert a pathogenic role resulting in arre rial and/or venous thrombosis +I- pregnancy morbidity (num R¢vRl»¢umaml2011;1,330) Causes of transient APLA: infection. medications (hydrazine, amoxicillin. minocycline. and propranolol) (Can Rlewnnd Rep 1012;14:71: Lupus 2017185921901 alw autoimmune disease. SLE: APLA is found in about 1/3 of SLE and is an independent risk factor of premature death and progressive renal disease IAP<D 1004143:281 APLA present in 9% of pregnancy losses. 14% of strokes. 11% of Ml.and 10% of DVT I,4/u»¢n¢ Cave Res2013:65:1869) The common final pathway is that of endothelial injury exposing phospholipid binding protein, attachment ofAPLA and the initiation of an inhammatory cascade that activates complement (Blew 2016;127=365), leading to vascular thrombosis and organ dysfunction APLA chronically upregulates roTOR in vascular smooth muscle leading to proliferation and obliterative vasculopathy luzym 1014:37130]) Clinical Manifestation and Diagnosis Diagnostic Criteria o¢APS:21 Clinical + 21 Laboratory uniumo llama 1006;429§) Clinical Cr iter ia Vascular thrombosis 21 arterial, venous. or small vessel thrombosis (imaging or histopathology) Pregnancy morbidity 21 unexplained feral deadl (at or beyond 10th wk of gestation) 21 premature birth (before 34 wk) due to eclampsia. severe prteclampsia, or placental insufficiency 23 consecutive miscarriages (before 10th wk of gestation) Labor ator y C r iter ia: 22 tests, 12 wk apart r T' 1~ n Lupus anticoagulant Anticardiolipin Ab Positivity loG and/or IgM >40 U or >99!h percentile AntiB2 G P1 Ab IgG and/or IgM in medium or high titer (je. >99th percentile) a .. q Renal manifestation: depending on the vessel caliber that is affected Large renal artery/vein thrombosis/infarcdon:sudden flank pain.hema:uria.and AKI Small vessel thrombi in the inzersritiumrsubacute AKII CKD with mild proreinuria Glomerulus: proxeinuria. active sediment +I- renal dysfunction (an Sinful 2005.63 471) Biopsy: acuzely.TMA. and in chronic stages oblirerazive arzeriopanhy. fibrosis and FSGS Od1 er lab: dimmbocynopenia. AIHA. hypocomplemememia (case :up M 24 z017;z0ws797w> 10yr survival probability was 90.7%.The top causes of death: severe thrombosis. infection. and carasuophic APS (Ami linen" of 201517421011) T reat m en t Ancicoaguladon; heparinlwarfarin co maintain INR 2-3 (new 20014349 11331 Rivaroxaban (factor Xa inhibitor) if intolerant of warfarin (lance: Haemuud Z016;3:c426) In SLE w/ APS. hydroxychloroquine 1 secondary thrombosis (Aruvan Rheum 1011261.8631 Transplantation Anticoagulation during the periopenrive period in renal :up to 1. the risk of postLxp thrombosis and graft failure (llansplanralmn 2000:69:1348) roTOR inhibitor: recurrence of APSassociated vascular lesion (NEW 201413718031 CATASTROPHIC ANTIPHOSPHOLIPID SYNONOME (CAPS) Diagnostic Criteria of CAPS: Definite if all 4 (up 1003;I2:sl0) 1. 23 organs. systems. and/or tissue involvement; clinical assessment +I- imaging. Renal involvement: a 50% Cr rise. HTN >180I100 and/or proteinuria >500 mold. 2. Development of manifestations simultaneously or in <1 wk 3. Histopathologic confirmation of small vessel occlusion in >.1 organ or tissue 4, APLA ( )x2 26 wk apart Probable 2 organ involvement + 2 3 4 1 + 2 + 3 » absence of lab confirmation death to the early death 1+2+4 1 » 3 4 . 3rd event in >1 wk. <1 mo.despite anticoagulation VVdespread thrombosis and mulriorgan failure. very high morzaliry In a cohort of 1.000 APS patients followed for a decade. 9 developed CAPS and 5 died. (Am Rumen Drs 2015;741011) Tx: anticoagulation.corcicosteroids. plasma exchange +I- IVIG (l"P"* 1014:231283) For resistant cases. consider the addition of riruximab (AulammuneR¢v2013:11:108S; so; MeumuW 1017:4:145) or eculizumab (Anhriux Rheum 1012;6A:2119; Case My Hemauw 1014;7/4371) HUS AND TTP H eMO L YT lC U R Er4IC SYN D R O ME ( H U S) Background Pathogenesis: ShigaToxin Caused by Shiva toxin producing bacteria ennerohemorrhagic E coli 0157:H7 (mlc). many more Shiga toxinproducing E coil (STEC) and Shigella dysenteriae serotype 1 Complicates 6-9% of STEC cases Food source:beef (cattle GI tract),spinach,Iettuce,sprt>uts.fruit.iaw milk too z01¢xs1;\411i. cookie dough (cm 2012154151 ii. flour (NE/M 1017;J77:1036) Shiva toxin is absorbed by the gun epithelium The toxin binding to the glycoprotein receptor globotriaosylceramide (Gb3), expressed in the kidney and brain -v the toxin entrance into the tissues inflammation. lysine. and destruction Gb3 is also expressed in platelets. causing activation/aggiegation (microthrombi) and thr ombocytopenia in thimbu mwhmi Upregulated complement 2016:100:\597) activity (CJASN 2009;12;1920) » + membrane attack complex (MAC) - endothelial injury and microthrombi formation (Blood 1015;125.3153) Clinical Manifestation and Workup Mainly children w/ abd pain. NM diarrhea that precedes HUS by 5-10 d (NEJM 19951333>64i End organ involvement: kidney and CNS Labs:anemia.schistocytes and helmet cells on peripheral smear. T indirect bilirubin. . haptoglobin, T LDH, thrombocytopenia. renal dysfunction Stool culture (selective media required for 0157:H7 and non 0157 serotypes). ELISA/ PCR of stool for shiga toxin, also serology against the most frequent STEC serotypes Kidney Bx:TMA; cannot distinguish from other causes: not required for Dx Prognosis: in pediatric cases w/ 43% of non0157 serotype. temporary HD needed in 61%.CNS effects (seizures) seen in 25% and mortality rate of about 4% urn 1001418644931 T reat m en t Supportive Treatment: IVF. pRoC if severely anemic or symptomatic. transfuse platelets if clinically significant bleeding occurs. BP control (CCB) if HTN. dialysis as needed Antibiotics (ciprofloxacin.TMPlSMX) have the potential to T production of shiga toxin. Although azithromycin and meropenem J, toxin production WEIM 2000,342119301 Plasma exchange (PLEX): no benefit Eculizumab a mAb against C5 that i production of MAC: In STEC related HUS w/ severe renal (requiring dialysis) and neurologic impairment, early use may improve neurological outcome (NE;M 1011364.1561i Meakine 201S:94.e1000) THRor4soTlcTHRor4aocyTorEnlc PunpunA (TTP) Pathogenesis: ADAMTS13 Deficiency Functional ADAMTS13 (A Disinnegrin And Metalloprotease with aThrombospondin type 1 motif. member 13) activity.This enzyme cleaves large vWF multimers on :he endothelial surface.Accumulation of these structures cause TMA. Heredity disease (<5%):genetic mutation of the ADAMTS13 gene Acquired disease (most):AutoAb against ADAMTS13 Clinical Manifestation and Workup Rare, 3/1 million adults/yr (wav Una Can z0 n=w.1e7sl Diagnosis: i ADAMTS13 activity (<5%), (-) inhibitor before any plasma transfusion Only 5% have all components of the pentad: MAHA. thrombocytopenia <20K. renal impairment. CNS involvement and fever luau 1010.116.4040) Rare severe renal injury 4% AKI requiring dialysis. 6% CKD.no ESRD lal¢¢4A4 2017:1 s9ol Kidney Bx:TMA; cannot distinguish from other TMA; not required for Dx Untreated.a progressive course of neurologic and cardiac deterioration - death Treatment PLEX: immediar.ely;daily until plt >150K and hemolysis markers normalize: removal of a potential inhibitor and replacing ADAMTS13 from the donor plasma Plasma infusion: in case of delay in plasma exchange Concomizann cs (IWPO) 0~4m 1991;3254981 Add Rituximab (RTX). if severe disease or no improvement after a few days of PLEX and CS or in relapsing disease want 2015;125.152sl; ofatumumab (~=1m 101B:378:92) Cyclophosphamide: for disease refractory to PLEX. CS, and RTX (Ink Herms z004»w941 Bonezomib: for refractory disease to all of :he above (NE/M 2011;3681901 Caplacizumab, humanized variable domain of lx against vWF: faster platelet recovery. l TTP related death. recurrence. and thromboembolic event (NE/M zowaurnasi) COMPLEMENT-MEDIATED HUS Atypical HUS (aHUS): HUS not mediated by Shiva wxin: aka diarrhea (-) HUS >50% of aHUS are cornplememmediazed HUS (al z017.91:sz9) Other forms of HUS include coagulationmedicated TMA. eg. DGKE mutations Pathogenesis The complement system is part of our innate immunity that defends us against inlec :ion and maintains internal inflammatory homeostasis.The 3 arms no the system (classic. alternative. lectin) are each tightly controlled by regulatory proteins. In complementmediated HUS. there is disturbance of this balance in the adeemadve pathway. -» pathologic overactivation and ultimately :issue destruction and injury Types Hereditary. gene mutation of die regulatory complement factor(s): complement factor H (CFH.m/c). complement factors I. B. C3. thrombomodulin (THBD).and CD46 (MCP). Often require another hit," eg. infection. pregnancy (C/ASN z007a¢s911. Acquired:Abs to CFH (<10% of aHUS). CFB. Many pts have concurrent mutation(s). Epidemiology and Clinical Manifestations Incidence: 7/million in children (B1H z010.140¢:i7). Can occur sporadically wlo FHx. Age of onset: variable from <1 to >20 y/o. 60% were adult onset Adults progressed to ESRD (4 6 %), d e a th (6 ,7 9 6 ) w/i th e 1 st ye a r o f disease. re g a rd le ss o f d ie typ e o f complement dysregulation (CjA$N zo13x;ss4). Ischemic injury to organs: renal (mlc).gangrene of fingers and mes,hean. lung. Gl.death (Nat Rev Nephml Z014;1ll1174) Wo rku p Labs:TMA (MAHA, thrombocytopenia). Complement mutation and Ab in select labs: nl complement levels do not exclude complementmediated HUS Diagnosis of exclusion: rlo STEC,TTP (normal ADAMTS13). other causes ofT MA Kidney Bx:TMA Cannot distinguish from other causes LM: mesangiolysis. GCW duplication. vascular onion skinning.: Nbrln thrombi IF: fibrin staining thrombi; no immunoglobulin (In) and C3 staining EM: endothelial cell swelling. subendothelial electron lucent space Eculizumab AntiC5 monoclonal Ab. FDA approved. Efficacious in 80% of pts that were either PLEX dependent or refractory genetic testing not performed (n6/M 2013;3681169) C5 blockade with eculizumab can predispose to encapsulated bacterial infection. Pos should be given meningococml (both quadrivalent x2 and serogroup B). pneumococcal (PCV13 and PPSV23), and Haemophilus influenzas type b vaccine. Penicillin VK 500 mg bid or erythromycin until 2-4 wk after last meningococcal vaccine Optimal duration therapy is unclear. Attempts to d/c the drug can lead to relapse. d/c can be considered in seroconversion of CFH Ab (KDIGO KI 2017935191 When stopped after 18 mo therapy 31% (72% of CFH. 50% of MCR none of no variant) relapsed during 22 mo flu. Roan we 2 day of drug was therapeutic (qAsn 2017;1Z50> Other Treatments lmmunosuppression if Ab (+): cyclophosphamide 1/qxo 201ass9m2 xoico KI 1017.91519) Plasma exchange (PLEX): use if eculizumab not available. About half respond (compieteiyl partially). Pos w/ CD46 mutation do not benefit (rom PEx since 90% of episodes resolve whether they received plasmatherapy or not LC/ASN 2010.5;l844). Pts w/ ab to CFH do better with the addition of immunosuppression (CS wl cyclophosphamide or RTX) who 2gl0:$§;923; our run zootzasel. Transplantation Before ecullzumab use. recurrence was -80%. esp w/ CFH mutation Laura 100s;10812677 Eculizumab +I- PLEX: prevention and tx of recurrence in allografLTleatment may have to be lifelong (qAs~ 2011;6:\4881 A/r zoiznuaavl. Combined liver-kidney Txp (rarely done): liver produces modulating proteins. Perioperatilely. there is an intense upregulation of the complement systan. often leading to allograft demise with widespread microvascular thrombi in the liver sinusoids and kidney graft Wr z00s5=114sl. Perioperative F'Ex +I eculizumab may circumvent dis problem (mau ~¢vl=-il2014;29:477). GENERAL HYPERTENSION About 103 million us adults have HTN (ACC/AHA;ACC 201B:71:e1Z7) 45.6% prevalence of HTN among US adults >18 yr; pharmacologic treatment is rec ommended for 36.2% of US adulr.s: 53.4% of Pts receiving treatment for HTN have BP above goal (cauuauni 2018;137:109) As of 2010. 80.7% are aware of the diagnosis of HTN UAMA 201ik30:2043) Prevalence increases with age: >twothirds of US aduM >60 yr of age have HTN HTN is prevalent in B085% of pts with CKD:prevalence of HTN T inversely with GFR Risk of CVD doubles for every 20/10 rise in BP above 115/75 (una:2002;3&19031 Risk factors for primary HTN: age. obesity. family history. black race. excessive dietary sodium i»»==\<=.8'-w alcohol intake. physical inactivity. reduced nephron mass HTN in black pls is more common.develops earlier in life, is more severe. and is associated with greater risk of CV complications in comparison to whites Complications LVH, HF w/ reduced EE HF w/ preserved EF. ischemic heat disease. ischemic stroke. intracerebral hemorrhage. CKD, ESRD 2017 ACCIAHA Definitions of Hypertension UACC 201t71»127) Normal BP SBP <120 and DBP <80 Elevated BP SBP 120-129 and DBP <80 Stage 1 HTN SBP 130139 or DBP 80-89 Stage 2 HTN SBP 2140 or DBP 290 Isolated systolic HTN SBP >130 and DBP <80 lsokced diastolic HTN SBP <130 and DBP 280 Pathogenesis Hundreds of generic risk variants have been identified: number of risk alleles corre lates with likelihood of developing primary HTN: effect on BP is modulated by envi ronmental factors High sodium intake leads to t intravascular fluid volume.cardiac output.peripheral vascular resistance, and BP;elevation in BP leads to T renal perfusion pressure and T excretion of excess sodium and fluid (pressure natriuresis"). If sodium excretion is impaired (aging, obesity. kidney disease) -> HTN Other factors: reduced compliance of large conduit arteries. impaired endothelium mediated vasodilation (T PVR). T activation of local reninangiotensin systems (heart. kidney, adrenals, vasculature),T activity of sympathetic nervous system Evaluation Ensure proper measurement technique: patient sitting widi back supported for >5 min and arm supported at level d heart; length of BP cuff bladder >80% and widdi >40% of dr cumference d upper arm; take average of 22 readings (additional if readings vary by >5): measure BP in both arms: assss for postural hypotension Exam: optic fundi. thyroid. heart. lung. kidneys. peripheral pulses. neurologic system Testing: electrolytes. Cr. glc. Hb. lipid profile. U/A. UACR. ECG. echocardiogram Evaluate for causes of secondary hypertension BP Measur ement Strategy C omments Cr iter ia Ambulatory blood pressure monitoring (ABPM) Device takes BP measurements at regular intervals over 12 or 24hr period (15-30 min during daytime and 3060 mi during sleep) Predicts CV outcomes independently of office BP: stronger predictor of all cause and CV mortality than office BP (NEW zoiezmsoel Reference standard for confirming diagnosis of HTN w. :m 101s¢1s3r/s) Daytime average 2130/80 OR nigh: time average 2110/65 OR 24hr average 21251275 Home BP monitoring (HBPf1) May predict CV outcomes as well as ABPM Multiple mouing and e~ening measurements should be taken over a period 21 wk Alternative method of confirmation if ABPM not available Repeated readings 2130/80 Oncebased BP measurements (OBPM) Can be done routinely (manual or semi automated) or via automated oscillomeuic BP (AOBP) device (ukes multiple consecutive readings while pt See above: based upon average of 22 readings at 22 o1&ce visits is sitting and resting alone. better approximates daytime A8PM) - Secondary Causes of HTN (amuuuin 10aa11171a101 Lifesryie factors Obesity. excessive dietary sodium intake. heavy alcohol nuke Medications unSAIDs. sympathomimedc agents (decongeszanrs. cocaine), amphetaminelike stimulants. oral contraceptives. glucocordcoids. herbals (ephedra). licorice (l metabolism of cortisol). Curls. ESAs. VEGF ligand inhibitors. antiangiogenic TKIs Renal disease CKD. acute GN. vasculitis. HUS Renovascular dz Endocrine disorders Renal artery sxenosis Primary hyperaldosteronism. pheochromocytoma. Cushing syndrome. hyperparathyroidism, reninsecrezing rumors Monogenic HTN syndromes Glucocorticoidremediable aldosteronism (GRA). Liddles. pseudohypoaldosteronism type 2 (Gordons). syndrome of apparent MC excess (AME). congenital adrenal hyperplasia (CAH) OSA (discussed below).aonic coarctarion. intracranial rumors Other Evaluat ion of H T N in C KD Masked HTN Nondipping Elevated ambulatory but normal clinic BP ("isolated ambulatory HTN") a/w * longterm risk of sustained HTN and higher risk of allcause (HR 2,83 vs 1.80) and CV (HR 2.85 vs 1.94) mortality than in Pts wl sustained HTN in large registrybased study (NUM z0\a;37e1 s09l Occurs in 15-30% of US adults with normal oNce BP More common among prs wl CKD: 70% of pos wl controlled clinic BP in the AASK Cohan had masked HTN: masked HTN was aw LVH and proteinuria and lower eGFR 1H»~w~»»w~ zooesaizol Absence of the normal (10-20%) nocturnal decline in BR may be related to impaired ability to excrece sodium during daytime Up to 80% of pts with CKD are nondippers Risk factor for LVH. HE proxeinuria. CKD progression Independent predictor of CV events and CV and allause mortality in Pts wl resistant HTN Chronotherapy can restore normal dipping (discussed below) Tr e a tm e nt Lifestyle As: wt loss (maintain BMI 18.5-24.9 kg/m').die:ary sodium restriction (<2.4 old or 104 mmol/d Na or 6 old NaCl), DASH die: (rich In fruits. vegetables, and lowfat dairy products). T physical activity (230 min/d. 5 d/wk). moderation of alcohol intake DASH diet + dietary sodium restriction: high sodium (3.5 g or 150 mmol/d) -> low sodium (1.2 g or 50 mmol/d) DASH diet a/w L 7 in SBP: high sodium control -» low sodium DASH die: a/w is in SBP (N£IM 2010.361:z10z) Pharmacologic dwerapyc in -2/3 of HTN. 22 drugs are required to achieve target BP Tre a tme nt a nd Bl ow up 1 ;Ac c a o1 a m1 2 1 ) Normal BP Encourage healthy lifestyle As w maintain normal BR reassess in 1 yr Elevated BP Recommend healthy lifestyle As. reassess in 3-6 mo Sa ge 1 HTN If 10yr ASCVD risk <10%: healthy lifestyle As. reassess in 3-6 mo If clinical ASCVD or DM or CKD or 10yr CVD risk >10%: start 1 BPlowering medication. monthly followup until goal achieved Stage 2 HTN Recommend healthy lifestyle As and 2 BPlowering medications of different classes. monthly followup until goal achieved z qo H HYPERTENSIVE NEPHROSCLEROSIS Background 2nd m/c cause of ESRD: usually a/w longstanding HTN (HTNattributed nephropad\y") In black pts,r.here is a high incidence of renal disease progression despite intensive antihypertensive therapy (3fold T risk in incidence of ESRD among African Americans with HTNattributed nephropathy dw European Americans) Pathogenesis Apolipoprotein L1 (APOL1) risk variants are significantly associated with kidney dis ease (FSGS and HTNattributed nephropathy) in black Pa. OR 2.57 In 20131834141 Chronic HTN - medial hypertrophy and intimal thickening -» luminal narrowing of large and small arteries and glomerular arterioles; ischemic injury global glomeru Iosclerosis nephron loss. compensatory glomemlar hypertrophy and hyperGltra :ion -» rise in inuacapillary pressure -» FSGS; ischemic injury -» severe interstitial nephritis BP Targets and Choice of Antihypenensive Agent Population Goal BP and Benefit Choice of Agent CKD and others with known CVD or 10yr ASCVD risk 210% Target <130/80 (Acc t¢A;Acc N1&7I:e127) In 250 y/o wl T CV risk (excluding Pos wl DM. oven HE stroke. or 21 old prozeinuria). intensive treatment (SBP <120) is a/w l in allcause moruliry (HR 0,73) and Ml.ACS. stroke. HE CV death (HR 0.75) dw standard treatment (SBP <140) (shunT ~=1m z01 s.am1o:l In CKD subgroup (eGFR 20-59): intensive BP control is alw 1 in all cause mortality (HR 0.72) and CV outcome (HR 0.81). No A in kidney In pos who require 2 drugs: Benazepril-amlodipine 1 CV morbidity. morulizy (9.6 vs 11.896, HR 0.80) and 1 CKD progression (HR 0.52) dw benazepril outcome (25096 . in eGFR or ESRD) (SPRINT ASr 10\7;2&Z812) HCTZ 1A€COMPIJS14 nqfa 1n0eus9z4m Chlorthalidone 1 me of HF and CVD outcomes. but no A in primary outcome (fatal CHD. nonfatal MI) or morality dw lisinopril. amlodipine Al.uIAT (MMA zo0z.zs8m1l In ps wlo baseline CKD: t incident CKD (HR 3.5) and AKI (HR 1.64) but early 1 eGFR may be reversible hemodynamk effect(9*$N Z01&13:I575) In metaanaiysis of RCTs: intense BP lowering is a/w 14% i risk of allcause mortality in Pa widl CKD stages 3-5 (WM IM 20177171:1498) CKD with proteinuria More intensive BP control alw 1 risk of CKD progression in pts with: >1 old proteinuria in longterm flu of ACEi or ARB L rate of progression to ESRD in Pts the MDRD study (Ann :m z00s;14z34zI proteinuria; benefit extends no PU w/ advanced CKD: no benefit and . adverse effects wl combination ACEilARB lo~rAnGs1 we N08:)S&1$47] In pa wl albuminuria ACE or ARB In pos wlo albuminuria:ACEi. ARB. thiazide. or CCB In pts who require >1 drug ACEr or ARB Q longacning CCB >300 mg/d proteinuria among black pts in cohort phase AAS( (NUM 1010l]63:918) and in longterm flu 1 ESRD in pos wl >1 old pmteinuria (Msn lOI7;18t67 l) Diabetes (with and without CKD) Target <130/80 (AccrA»4A;Acc 201B:7\:l127) In¢ype2 DM CvDa22adn»tiomlrisk lectors for GQ imenswe comrd (SBP <120) a/w no A in CV morbidity/ morulimy or allause mortality but slgnbiiam m wal (HR 059) a1d nonhnl sunle (HR 0.63) dw sundard dwipy (<140) (Accoar>epr4gpu zola=Jea;1slsl Intensive BP conunl 1 incidence d microdbuminuria (HR 0.84) but no A in renal failure Of 1ezinopazhy of zolzsl so wl >500-1.000 mild ADPKD Target $130/80: in young pts wl intact kidney fun. urge: <110/75 may L CV events and me of is: growth In pos 15-49 yr w/ eGFR >60. low BP goal (95160-110175) alw 1 A in total kidney volume. LVMI. urinary albumin excretion. no overall A in eGFR dw standard (120170-130180) (HALTPKD NE[M 2014;]71:1155) General population wlo above conditions ACC/AHA: clinical Lrial evidence strongest for <140/90. but <130180 may be reasonable yAcc 201B:71:e127] JNC8: <150l<90 in 2 6 0 lo. SBP <140 in <60 ylo up 2014;311:S07) Isolated syscolk HTN: may need tO Black and elderly respond beuer so nhiazide:ype diuretics or longacting CCB than ¢oACEi or ARBs accept SBP >140 to keep DBP >60 HYPERTENSION IN ESRD Background Prevalence of HTN in dialysis Pts is high>50% and up co 86%1A~»}m¢4 100s;11s:2911; the majority are :reared with antihypertensive agents but not controlled DeGnicions: 1wk avenge predialysis SBP >150 or DBP >90 OR 44hr interdialytit ambulatory BP 2135/85 OR use of any antihypertensive medications In 10-15% of Pts. BP paradoxkally increases during dialysis ("intoadalytic hypertension"): this is ails volume overload. interdaiylic hypertension.and increased shonteam morality Pathophysiology Volume overload is the major fuse of HTN in dialysis Pts;T activity of RAA6 and SNS: arteriosclerosis. T in intracellular Ca2,t in endotheliumderived vasoactive substances ESAs: incidence of HTN correlates wl dose but not RBC mass or viscosity: may involve T in vasoactive substances such as endothelin; more likely wl IV than SC Evaluation There is uncertainty about how to accurately measure BP in dialysis Pts BP Measurement Strangles Highly varialsle inaproverdmezagleepoorlywidiiuuvhlyUc alnbdawry BPmaybe t but predialysis BPL Predialysis and postdialysis BP measurements Ambulatory BP monitoring (ABPM) Home BP monitoring (HBPM) dq,1en¢1ilg on Me degree and race d duafiluation Gold standard for diagnosis bu: generally nor used clinically Measurements men over the 44hr interdialytic interval Amb. BP T by 2.5 for every 10 hr elapsed after HD Correlates more closely with ABPM and better predicts longterm outcomes (CVD, allcause mortality) Home BP T by ~4 for every 10 hr elapsed after dialysis Tr e a tm e nt Guidelines are scarce target predialysis BP <140190 and postdialysis BP <130/80 iKVOQ¢A1»<D 2005:45:51)C no recommendations made by KDIGO up 20!3;B3:377)i using incerdialytic home BP to target BP <13S/85 may be more reasonable No doubleblind RCTs evaluating :he target BP or optimal agen: in dialysis pts Giving anrihypenensive drugs at nigh: may occurrence of inrmdialytic hypotension Tr e a tm e nt S tr a te gi e s Nonpha rma c ol ogi c Dietary Na resticrion <1.5-2 old Na no target imerdialytic we gain (IDWG) <2-3 kg Optimizing die dialysis prescription (1) Individualize dialysare Na; Hypertonk dialysaze may allow t Huid removal and improve hemodynamic stability BUT leads to T whirs: and T inrerdialytic WI gain (2) Increase length and/or frequency of dialysis: A from conventional co frequent/nocturnal HD is alw L BR number of andhyperrensive medications, and LV mass Optimizing the management of dry weigh! Dry weight should be achieved via gradual reduction in post dialysis weigh: (0.2-0.5 kg/session) no :he lowes: tolerated weigh: that J, sis of hypo or hypervolemia Reducing EDW can improve BP in majority of Pls Probing EDW can 1 ambulatory BP even in Pts w/o oven sis of volume overload (Hyperwaniun 11109;5}:5001 P ha rma c ologic Well tolerated but may T risk of hyperkalemia and anemia ACEr or ARB L In LV mass: no large RCT has demonstrated benefit on CV events or mortality Lisinopril, enalapril, benazepril are dialyzable and should be given Dihydropyridine (DHP) CCB Bblocker after dialysis: other ACEi and ARBs are not Effective and well tolerated; not dialyzable and do not require supplemental dosing Openlabel RCT showed CV events with atenolol vs lisinopril (nor 2o14;29¢sn»:A:enolol is moderately dialynblezcan be given MR antagonist (MRA) TIW after HD (25-100 mg) 36wk RCT showed SPL welltolerated at $25 mgdajly, T me of K >6.5 mEq/L at 50 mg daily In z01s¢d°e 10.101sl " Metaanalysis suggests benefit on CV and allcause morality but lowquality evidence We 10154681591) RESISTANT HYPERTENSION Background Defined as BP Mat remains above goal despite adherence to treatment with 23 anti hypertensive agents of different classes prescribed at optimal doses. ideally including a diuretic. OR BP at goal but requiring 24 agents (aiaiIauan 200B;117:510) Epidemiology iHn=¢iteiuion 201\;57:\076) Using data from NHANES from 2003 to 2008: (1) 8.9% of US adults with hyperten sion and 12.8% of US adults on treatment with antihypertensive drugs met criteria for resistant HTN; (2) 72.4% of all drugtreated adults with uncontrolled HTN were taking drugs from <3 classes: (3) 85.6% of adults with resistant HTN used a diuretic but 64.4% of those used the weak thiazide diuretic HCTZ Prevalence of resistant HTN in nephrology clinics may rise to >50% Adults with resistant HTN are more likely to be older, nonHispanic black. and have higher BMI,albuminuria, CKD.CAD, HE stroke. and DM P a thoge ne s i s Factors do T prevalence of resistant HTN in CKD: impaired Na handling. chronic fluid overload. T activity of RAAS and sympathetic systems. impaired NO synthesis and endodieliummediated vasodiladon. arterial sdflness. inflammation, renovascular ds Definitions of Resistant Hypertension Apparent resistant HTN True resistant HTN Pseudoresistant HTN Uncontrolled BP despite being prescribed 23 antihypertensive agents or controlled BP despite being prescribed 24 agents Uncontrolled BP despite adherence with 23 antihypenensM agents at optimal doses or controlled BP despite adherence with 24 agents Appearance of treatment resistance Causes: poor adherence to therapy. complicated dosing regimens: suboptimal dosing of medications. inappropriate combinations of agents. physician inertia; improper BP measurement technique. White coat HTN difficult to compress calcined arteries in elderly: white coat HTN Elevated BP during clinic visits with normal BP in nonclinic settings and absence of target organ damage (isolated clinic HTN") Pts an at lower cardiovascular risk compared with persistent HTN but white coat HTN may not be benign. alw HR 1.79 for allcause mortality in large registrybased study 1n£/m z01s.3n.1 solI Refractory HTN Occurs in 15-30% of pts with elevated office BP Mon common among patients with resistant HTN BP unable to be controlled despite optimal medical therapy under die care of a hypertension specialist Evaluation Accurate measurement of oNce BP attention to environment. body and arm position. and appropriate cuff size: obtain avenge of multiple measurements at least 1 min apart Confirmation with ABPM or HBPM Identify contributing lifestyle factors: age, obesity.family history. black race. excess dietary sodium intake. heavy alcohol intake. reduced nephron mass Identify substances that interfere with BP control: unSAIDs, sympathomimetics. stimu lants. alcohol, oral contraceptives. glucocorticoids. natural licorice. herbal substances Screen for secondary causes of HTN Treatment Optimize volume status Adequate RAAS blockade Chronotherapy Dietary sodium restriction and use of appropriate diuretics: Chlonhalidone 25 mold is twice as potent as HCTZ 25 mgld.has a much longer duration of action. and is effective at a lower GFR Use of loop diuretics in advanced CKD Combining loop diuretic with thiazide or lowdose Ksparing diuretic Use of mineralocorticoid receptor blockers (MRBs. spironolactone and eplerenone) as addon therapy: Addition of spironolactone 25-50 rngld is superior dw placebo (-8.7 1 In home SBP).doxazosin (4 .0 3 .),and bisoprolol (4 . 4 8 ) esp. in Pts wl low plasma renin;low incidence of hyperkalemia though Pts had GFR >45 lPAYHWA!2 linier zoisaaazns9l Bedtime dosing of BP medications can restore the nomtal dipping p a r e r . improve nocturnal and 24hr ambulatory BP control. reduce proteinurh. and may be a/w l risk of CV morbidity and mortality UAW 2011:2Z;13131 HYPERTENSIVE EMERGENCIES Background Hypertensive emergency: significantly TBP (SBP 2180 and/or DBP 2120) with s/s of acute. ongoing, endorgan injury: requires immediate BP reduction Severe asymptomatic HTN ("hypertensive urgency"): BP can be lowered within hr to d BP usually severely elevated in pts with chronic HTN but can develop at lower BPs in Pts without preexisting HTN if there is an acute rise in BP (je,acute GN or pieeclampsia) Pathophysiology Release of vasaconsukting substances (angiotensin II. notepinephnine) -» abrupt rise in vascular resistance -> endothelium releases vasodilator molecules but dlis compensatory response is overwhelmed - endothelial damage and furdier rise in BP As MAP increases (esp >180).cerebral vascular autoregulation is overwhelmed -» cerebral vasodilation and edema - hypertensive encephalopathy Clinical Manifestations and Evaluation Symptoms chest pain (Ml or aortic dissection):back pain (aortic dissection); dyspnea (pulmonary edema or HF): neurologic sx. seizure, or AMS (hypertensive encephalopathy) Exam: ./ for BP A between arms (aortic dissection): T JVR $3 (HF): flame hemor rhages, exudates. or papilledema on funduscopic exam (hypertensive retinopathy) Causes: renal (acute GN, vasculitis. HUS. renal artery stenosis): endocrine (pheochro mocytoma.Cushings): CNS (head iniury.cerebral infarction. cerebral hemorrhage); drugs (cocaine. sympathomimetics. Curls. ESAs. sudden withdrawal of antihypertensive medications): other (preeclampsiaJeclampsia.TTP) Reversible Posterior Leukoencephalopathy Syndrome (RPLS or PRES) Associations: HTN.TlR HUS. eclampsia,vasculitis. immunosuppressive drugs (CyA.Tac) Imaging MRI shows symmetric white matter edema in posterior cerebral hemispheres Tre a tme n t Hypertensive emergency: admission to ICU for monitoring and parenteral therapy MAP should be i by 10-20% in die first hr and addtl 5-15% over next 23 hi:after 24 hr of BP at target levels.oral medications an be started and N mediations tapered oil Tre a tme nt Approa c h for Cl l ni c a l S c e na ri os Acute ischemic stroke Hypertensive encephalopathy Labeialol and nicardipine (fursline). Ninroprusside (secondline) Lower BP if Z2201120 (or 21851110 if IPA candidate) Nicardipine. clevidipine, fenoldopam, niuoprusside. Iabetalol. enalapril. hydralazine Loop diuretics, vasodilators (niuoprusside, nitroglycerin) Avoid hydralazine (T cardiac work). Bblockers (i contractility) Nitroglycerin. nicardipine. esmolol (T coronary perfusion. 1 MVO;) Acute MI Acute aortic dissection First: Bblocker to L HR and wall shear stress (esmolol. labetalol) then vasodilator (nitroprusside or clevidipine) SBP should be rapidly l to 100-120 (within 20 min) Pregnancy (pre eclampsia. eclampsia) Methyldopa. hydralazine. Iabezalol. fenoldopam nicardipine IV magnesium sulfate for prevention of eclampsia Delivery of baby and placenta AKI (acute hypertensive nephvosclemsis) Calcium channels blockers and Rxblockers (preserve renal blood flow):fenoldopam (causes renal arterial dilation > maintains or increases renal perfusion) Dr ugTr veaunent Drug Mechanism Dose Adverse Effects Sodium nitroprusside Arterial and venous dilawr Sun ac 0.25-0.5 max B-10 ug/kg/min Nitroglycerin Venous > arterial dilator 5-100 up/min Cyanide toxicity if Rx prolonged >24-48 hr Headache. reflex tachycardia Clevidlpine Shortaczing CCB 1-21 mglhr Reflex tachycardia Nicardipine CCB Reflex tachycardia laberalol B and ublocker 5-15 mg/hr 2080 we bolus or 0.82 mglmin infusion Fenoldopam Dopamine1 receptor agonist 0.1-1.6 pglkglmin Bradycardia. bronchospasm Headache. flushing, Hydr azine Vasodilator 10-20 mg IV bolus Reflex tachycardia . IOP ANTIHYPERTENSIVES F eatur es and Dose o( Andhyper tensives Class Feacunes AC Et and ARBs Beneficial efleccs in proreinuric CKD. HE pos:MI Synergistic eifecc with diumics Remains beneficial in advanced CKD (NEW2M;]§(;U\) Contraindicated during pregnancy sle: K ACEi 1 formation of angioiensin II (All), vasodilation (dl: 1 kin in levels) sle: cough. angioedema (rare) due to kin in levels Lisinopril: 10-40 mg (1:Id) Benalepril 1040 mg (1-2>Id) Fosinopril: 1040 mg (1-2x/d) Ramipril: 2.520 mg (1-2xld) Quinapril: 10-40 mg (1-Zxld) ARBs Impair binding olAll to AT1 receptor Losarlzn: las effective ac BP lowering dun oder ARBs. T uric acid excretion and L plasma uric acid levels Inhibit apical NCC in DCT sle. K. J. Na. t Ca.. uric acid. glucose intolerance Most effective at GFR >50,tin 10 hr; reasonable choice in frail older Pts <10 above goal BP Losarran: 50-100 mg (1-lx/d) Valsartan: B0-320 mg (1>Jd) lrbesartan: 150-300 mg Telmisanan: 4080 mg Candesar¢an:8-32 mg Azilsamn: 4080 mg Thiazides <~+;1m za o mw sa ) HCTZ (rhiazidezype) Dose Start at 25 mg/d and citrate Io 50-100 mild: can be given 1-2 x/<1 Can be effective to GFR of 3 9 4 0 : i n 5 0 6 0 hr, 2 x more pote nt than HCTZ; greater L in nighttime and 24hr BP; l HE CVD IAU.HAT #mi 2007:zae:19sn Star: as 12.5-25 mg/d and t i m e (D 50 mild Mezolazone (xhiazidelike) Retains efiecxiveness at GFR Sun as 2.5-5 mg/d. ckrace to 10-20 mg/dc can giveTlW Loop diure tic Inhibit apical NKCC in THAL sle: L K. rash. AIN. otozoxiciry as high doses Normal renal fxn. Bum.1 mg = Euros. 40 mg = tors. 20 mg Severe CKD: Bum.1 mg = furos. 20 mg tors. 20 mg Maximal response in severe CKD: 160-200 mg IV. Should be given 2-3x/d Bioavailability Maximal response in severe CKD: 50-100 ms lVlPO: Can be given 1-Zx/d Chlorthalidone (thiazidelike) (NEW 19981339:J07) <30 mUm in; TM 14 hr Funosemide Torsemide 100%;tm ~3-4 hr Maximal response in severe CKD: a-10 mg IVIPO Bumetanide Erhacrynic acid Only nonsulfa diuretic but T ototoxieity Ks pa ri ng diuretics Act in the principal cells of the CCD Spironolactone Competitively inhibits MR. Tm >15 hr (SPL) (active metabolite). sle: gynecomastia. 1 libido dl: nonselective binding to steroid receptor 25-100 mud; risk of hyperkalemia is predicted by baseline eGFR $45 mUm in and baseline K >4.5 mEqIL Competitively inhH>its P1R.tm 3-6 hr; t specificity for MR. 1 incidence of sle but more expensive and may be less effective than SP1. Inhibits ENaC. sle: crystalluria. stones,AKl Starr at 25 mg/d. drrare to 50100 mg/d in daily or divided doses: risk of Amiloride Inhibits ENaC;prolonged to (100 hr) in CKD:few side effects Scar: as S mg daily and drrare to Ca lc ium channel blockers Inhibit Ltype cab channel sle: peripheral edema. constipation, gingival hyperplasia (dose dependent) DHP (amlodipine. Potent vasodilators. s/e:as above plus headache and flushing edema is more common. Amlodipine: longer to (30-S0 hr vs 2-7 hi):studied in ALLHAT and ACCOMPLISH trials Negative inouopes. less potent vasodilators. May : proteinuria. s/ea: above plus L CO. HR. Cause T levels d CYP3A4 substrates (incl. CNI) Eplerenone (EPL) Triamzenene nifedipine) NonDHP (diltiazem, verapamil) Bblockers sle: hyperkalemia, T Glc and TG. bradyardia. ischemic sx wl acute withdrawal, depression. t weight Selective (p.1) Atenolol: excreted by kidney: to prolonged in CKD Atenolol and metoprolol are water soluble and dialyzable; should be administered postdialysis Nebivolol produces NOdependent vasodilation (atenolol. bisoprolol. metoprolol, nebivolol) hyperkalemia as above 37.5-75 mg/d in combination pills wl H C T Z 10 mg daily AModipine sur! as 5 mold (15 mg in small prs).¢iu1ce to 10 mg/d after 7-14 d. Nifedipine: Sir: 3060 mg/d. da me w 9 0 -1 2 0 ma . ma y need no be given rwke daily Dilciazem: 120-360 mold VerapamiI: 120-480 mold Wsodiladng pmperdes. Carvedilolz no impact on glycemk control. may v renal vascular resistance and T renal blood How and GFR Carvedilol: 12.5-50 mild (2>¢Id) Labezalolz 2001.200 mg/d (2-3,/d) t HDL and insulin sensitivity May have benefit in men wl BPH. sle: postural hypotension. dizziness. In ALLHAT,doxazosin alw t risk of CHF UA/M 1001;28&2981) sie: sedation. dry mouth. sexual dysfunction. withdrawal hypertension (esp w/ clonidine). Methyldopa is safe in pregnancy bu: rarely used in other servings sie: headaches, fluid retention. reflex tachycardia sl e:as above pl us dr ugi nduced l upus 25-100 mgldose (2-3>(Id) and ANCApositive vasculitis Minoxidil s/e: as above plus hirsudsm Indications for Specific Drug Classes Indication Drug Class HF Pos:MI ACEi,ARB. diuretic. Bblocken MRA Aerial 6brillaxion DM Proreinuric CKD Fluid overload BPH /Osteoporosis ACEi. Bblocken MRA Bblocker. nonDHP CCB ACEi.ARB. diuretic. iiblocker. CCB ACEi.ARB. nonDHP CCB Thiazide diuretic, Iaop diuretic. Ksparing diuretic ablod<er Thiazide diuretic Background A sleeprelated breathing disorder characterized by repetitive partial (hypopnea) or complete (apnea) cessation of airflow caused by collapse of the pharynx during sleep repeated arousals and hypoxemia Common but frequently undiagnosed disorder An independent risk factor for HTN: in generaI.the more severe the OSA.the more prevalent and severe the HTN Moderatelsevere OSA is a/w widl nearly3fold T risk of incident HTN lnqm zouasazmal OSA may be present in >70% of Pts wl resistant HTN Epidemiology Prevalence is 10% in middleaged individuals (-5% in women, -15% in men) Risk factors: obesity craniofacial or upper airway soft tissue abnormalities. age. male gender. smoking.» family history Prevalence T w/ T BMI and markers of obesity (neck circumference.waisttohip ratio) Presentation Common presenting complaints: daytime sleepiness. fatigue. snoring. restless sleep, poor concentration, mouing headaches. nocturia Common exam findings: obesity.crowded oropharyngeal airway. HTN Frequent apneic and/or hypopneic episodes can end with arousals with spikes in BP lasting several seconds » T the risk for"nondipping" HTN.a strong predictor of CV risk: nearly 90% of Pts w/ nondipping HTN patterns may have OSA Complications: T mortality. sustained HTN. pulmonary artery HTN. HE stroke. insulin resistance. impaired daytime functioning. impaired cognition. depression Diagnosis Screening in Pts w/: Excessive daytime sleepiness; snoring + 22 additional clinical fea tures of OSA: resistant HTN; unexplained pulmonary HTN;secondary pciycyzhemia The STOPBang questionnaire can help idenzify Pro w/ OSA STOPBang Questionnaire laId 1012410a16s) T Do you snore loudly! Do you often feel ¢ired.fatigued. or sleepy during daytime? o P Has anyone observed you stop breathing during your sleep? Do you have or are you being treated for high blood pressure? s B I BMI >3s Up/ml n Age >50 yr old Neck circumference >40 cm 8 Gender: Male? 01 pos. nsponsas = low risk. 3-4 pos. responses = intefmediane risk. 58 pos. responses = hgh risk d OSA: probability of moderatefsevuu OSA = 36% for score 23. 60% for score 27 Polysomnography (sleep study) evaluation performed in a sleep disorders un: is :he gold standard for an accurate diagnosis of OSA Criteria: 25 obstructive respiratory events per hr of sleep in a P: w/ 21 associated symptom or comorbidity OR 215 eventslhr regardless of symptoms or comorbidities Apneahypopnea index (AHI) 5-15 eventslhr = mild. 15-30 eventslhr = moderate, >30 evencslhr of sleep or 02 saturation <90% for >20% of total sleep time - severe OSA Treatment Behavior modificationweight loss. exercise.and avoidance of :he supine sleep position. alcohol, and medications that can worsen daytime sleeping or cause weigh: gain CPAP to stabilize the airway and prevent hypopnea and apnea events due upper airway collapse is the mainstay of therapy Surgical procedures to relieve nasal obstruction (turbinate reduction.septoplasty rhi noplasty). upper airway obstruction (uvulopalatopharyngoplasty [UPPP]. tonsillectomy. adenoidectomy), and lower airway obstruction (somnoplasty) Successful treatment of OSA can lead to a modest bu: clinically significant i in BP and neducdon (rather complete elimination) of the need for antihypertensive medications Among Pts w/ OSA and resistant HTN, use of CPAP is a/w greater i in 24hr mean BP | (3.1) and 24hr DBP (3.2) dw no CPAP and f percentage of Pts displaying a"dipper" pattern at 12 wk (35.9 vs 21.6%. adjusted OR 2.4) up 1013=310n40n Number of hours of CPAP use alw greater in 24hr mean B 24 hrlnight likely needed Predictors of a greater BP response to treatment with CPAP: OSA severity, presence of excessive daytime sleepiness. presence of uncontrolled HTN RENAL ARTERY STENOSIS (RAS) Baekgr ound RAS: narrowing of one or both main renal arteries or their branches Renovascular HTN: . BP resulting from renal arterial compromise. often due to occlusive lesions in the main renal arteries Ischemic nephropathy: CKD that results from atherosclerotic RAS due to diminished renal blood flow to the poststenotic kidney RAS is an anatomical descriptor: the presence of lesion(s) does not necessarily translate to the lesion(s) being responsible for BP or renal dysfunction If systemic hypertension is related directly to an arterial lesion. then relief of the obstruction. presumably. should lead to reversal or improvement of the hypertension Ep id e m io lo g y Atherosclerosis accounts for 90% of cases of renal artery stenosis (discussed in this section):hbromuscular dysplasia (FMD) accounts for -10% (discussed below) Risk factors for renoyascular atherosclerositic lesions: DM. HLD. aortoiliac occlusive disease.CAD.and HTN Prevalence of atherosclerotic renal artery stenosis ° wl age. may rise as high as 30% among Pts with CAD and to 50% among elderly Pts or those wl diffuse atheroscle rotic vascular diseases; 10-15% among patients with endstage kidney disease Pathophysiology Decrease in renal perfusion pressure -» activation of the RAS. impaired sodium excretion. activation of the sympathetic nervous system.T intrarenal prostaglandin concentrations. L nitric oxide production -» renovascular HTN Initially plasma renin activity t due to activation d the RAS: but when HTN is sustained. plasma renin activity L Advanced vascular occlusion (>70-80% stenosis) -» hypoxia widiin the renal cortex -» activation of inflammatory and oxidative padiways -» irreversible interstitial fibrosis and loss of renal function (ischemic nephropathy") Presentation Renovascular disease is more likely to accelerate or impair control of preexisting HTN than to cause newonset HTN Features that suggest renovascular hypertension: resistant HTN. onset of HTN (>160/100) in a Pt >50 yr. presence of diffuse atherosclerosis. atrophic kidney or asym merry in kidney size. absence of family history of HTN. recumbent flash pulmonary edema. unexplained refractory HE acute rise in serum creatinine (z50X) after the administration of ACEi or ARB. presence of abdominal bruit Atherosclerosis usually involves the ostium and proximal 1/3 of the main renal artery and perirenal aorta: segmental and diffuse intrarenal disease may also be seen Stenosis is progressive in the majority of patients Diagnosis Testing is indicated in pa w/ clinical findings suggestive of renovascular disease who have a high likelihood of benefiting from an intervention should a clinically significant srenoric lesion be found Renal arteriography is the gold standard but less invasive options are available / Modality Diagnosis of Renal Artery Stenosis Features Duplex Doppler ultrasonography Provides both anatomic (direct visualization of the main renal arteries) and functional assessment (systolk flow velocity via Doppler) of the severity of stenosis Nonirwasive and relatively inexpensive: bu: time consuming, may be CT or MR angiography Captopril stenography technically difNcull. operator dependent Accurate and noninvasive: better for proxdmal disease May be limited by pt.related factors (presence of cadmium or scents) Toxicity associated with use of contrast media in pts with CKD Oral captopril is given 1 hr before a marker of glomerular fikradon. such as DTPA is injected - ACE inhibitorinduced decline in GFR in the stenotic kidney and equivalent increase in GFR in the contralateral kidney - A between kidneys is enhanced Functional test to compare RBE GFR between the two kidneys Low predictive accuracy for renovascular hypertension Can be unreliable when baseline kidney function is abnormal as Measurement Of peripheral plasma renin activity (PRA) asymmetries in renal flow and function can be present for reasons other than renovascular disease PRA measured 1 hr after the administration of oral captopril - Pts w/ a functional lesion should have an exaggerated . in PRA Low predictive accuracy for renovascular hypertension PRA is in only 50-80% of pts wl renovascular hypertension PRA may be suppressed by high dietary Na intake. bilateral renal artery disease. volume expansion.various medications Tr e a tm e nt Treatment goals include: blood pressure control (rather than reversal). preservation or salvage of kidney function. and prevention of flash pulmonary edema Options include (1) medical therapy with ACEr or ARB other agents as needed. (2) percutaneous angioplasty +I- stent placement). (3) surgical revascularization Revascularization vs medical therapy alone (1) In 1,000 Pts wl adierosclerotic renal artery stenosis widl 260% narrowing and sys tolk HTN despite 22 antihypertensive medications and/or eGFR <60 no A in pri mary outcome (composite of dam from CV or renal muses. CVA. Ml. hospitaliza don for CHE progressive renal insufficiency. or die need for permanent RRT) between those randomized to medical therapy alone vs medial dtevapy plus stent (CORAL NEIM 2014;3741J) (2) In 800 Pts w/ average 76% stenotic occlusion of the renal arteries and entry serum creatinine >2,0 mg/dL randomized to medical therapy with or without stem ing - no A in blood pressure control. kidney function. heart failure hospitalizations. or mortality over a median followup period >2 yr lAs1rzAL new zcoraernrsai Features that suggest benefit from revascularization: short duration of BP elevation: inability of optimal medial therapy to conuol Be intolerance of optimal medical therapy. including ACEi orARB: progressive CKD in a pt with bilateral renal artery stenosis or unilateral srwosis to a solitary kidneys recumbent flash pulmonary edema: refractory HF Risks of revascularizationz renal artery dissection. thrombosis, perforation; restenosis. AKI due to atheroembollc disease; reaction to ndiocontrasr: agent Calculation of the renal resistive Index (RI) may help predict the outcome after revas cularization: t Rl is alw greater degree of intrinsic renal damage. Rl ([1 - (enddiastolic velocity + maximal systolic velocity)] x 100) 280 identifies pts wl renal artery stenosis in whom angioplasty or surgery is not likely to improve renal function. blood pressure. or kidney survival (Ne/M z001:344:4ro). FlaRomuscuLAn DYSPLASIA (FMD) Ba ckg r o u n d FMD is much rarer than atherosclerotic diseasecaccounts for <10% of cases of RAS Classically.diis disease has been described as a cause of HTN in younger females.some times first presenting during pregnancy Prevalence drops markedly with age:among pts with renovascular HTN. FMD accounts for up to 50% of cases in children but <15% of cases in adults Among adults. FMD is far more common among females (10fold higher prevalence) Pr e se n t a t io n FMD =dpi==lIy affects the distal 2/3 of the renal artery and its branches ("soing of beads") Extracranial cerebrovascular (carotid. vertebral arties) involvement is common Only rarely does FMD lead to complete or segmental occlusion of d\e renal arteries. wick most individuals presenting w/ normal kidney function but significantly elevated BP Diagnosis Duplex ultrasonography. CTA.and MRA (less preferred) are noninvasive options Renal aneriography (dagiia1 subtraction angiography [DSA]) should be the first diagnostic tat for Pts at high risk for FEDassociated reno vascular hypertension.as this imaging modality allows for simultaneous treaunent wrih percutaneous transluminal angioplasty T reat m en t FMD and uncontrolled HTN: conventional balloon angioplasty Rate of restenosis following angioplasty ranges from 12-34% over followup intervals of 6 mo-2 in but restenosis does not always lead to recurrent hypertension Likelihood of cure of HTN is more likely in Pts w/ FMD than in those w/ atheroscle rotic renal artery stenosis (60% vs <30%) HYPERALDOSTERONISM Ba ckg r o u n d Aldosterone: hormone primarily involved in the regulation of extracellular volume and potassium homeostasis Sites of action: epithelial cells in distal nephron > colon. salivary glands. and swear girds Regulators of secretion: plasma K+. All. ACTH Binds to cytosolic mineraloconicoid receptors -v T number of open ENaC channels in apical membrane of CCD principal cells -» T sodium reabsorption electronegative lumen creams a laivorable gradient for poizssium secretion via ROMK. BK channek Primary aldosteronism (PA): reninindependent hypersecrecion of aldosterone. non suppressible by sodium loading Ep id e m io lo g y Prevalence of PA: 4% in primary are clinics. 40% among Pts referred to HTN specialty clinics; 43% among Pos wl severe HTN. Prevalence of elevated aldosterone to renin :ado (ARR): 46% in primary care clinics. 20% in specialty clinics UMM 101e101:1ss<n Causes of PA: bilateral idiopathic adrenal hyperplasia (IHA: 60-70%). unilateral aldosteroneproducing adenoma (APA: 3040%). less common: Unilateral hyperplasia: familial hyperaldosteronism type I (GRA). type II. and type Ill: and adre nocortical carcinoma Somatic muradons cause aldosterone hypersecretion in 50% ofAPAs: KCNj5 (most common. -40% of APAs). ATP 1A 1, ATP2B3. CACNA 1D. CTNNB 1 Presentation Persistent volume expansion, severe & resistant HTN. hypokalemia (in <50% of pts). metabolic alkalosis. hypernauemia (mild). hypomagnesemia (mild) T CV morbidity/mortality clw pts wl same degree of BP elevation: ¢ LV mass and myocardial fibrosis.. LV function. risk of arrhythmias, Ml. stroke. CV death Renal effects: T GFR due to glomerular hyperNkration, T urine albumin excretion Pts widl APA: usually younger (<50 yr). T aldosterone secretion rates, plasma and urinary aldosterone concentrations. more severe HTN and hypokalemia Evaluation Casedetection testing w/ plasma aldosterone to renin ratio (ARR = PAC/PRA) should be performed in Pts with: severe HTN (SBP >150 or DBP >100). resistant HTN, HTN and spontaneous or lowdose diureticinduced hypokalemia. HTN and adrenal inciden talorna. HTN and sleep apnea. HTN and family history of earlyonset HTN or CVA at <40 ynand HTN with firstdegree relative w/ PA Screening for PA should be done in all Pts w/ resistant HTN. regardless of K level. although the likelihood of positive results T in pts w/ hypokalemia PAC and PRA should be measured in a mouing blood sample while seated Definition of abnormal ARR is assay dependent: PRA is generally undetectable (usu ally <1 ng/mUllr): PAC is >15 ngldL in most pts w/ PA,ARR >20 is suggestive of PA: ARR >30 is the most commonly used cutoff Antihypertensive medications can be continued during testing as long as pt has been on stable doses for >3 wk (1) EXCEPT mineralocorticoid receptor blockers (MRBs, spironolactone. and eplere none) which should be stopped for 26 wk unless Pt is hypokalemic and PRA is suppressed (2) ACE inhibitors and ARBs can T PRA thus a detectable PRA or low ARR does not exclude PA: undetectable PRA will be strongly suggestive of PA ( 3) Bblocker s can l PRA and ARR but PAC >15 still suggestive of PA (4) Drugs with minimal effects on PRA and PAC: verapamil, hydralazine.ablockers 2 as 5 Dlagnosls of PA Findings Diagnosis 1 PRA,T PAC.. ARR Suspect primary hyperaldosteronism Proceed to confirmatory resting (see below) If spontaneous hypokalemia.undeteci:ible PRA. and PAC >20 my dL confirmatory testing may not be required T PRA. T PAC.ARR <10 Suspect secondary hyperaldosteronism (renovascular disease. diuretic use. malignant HTN. reninsecreting wmor [rare]) 1 PRA and 1 PAC wl HTN and hypokalemia Suspect Liddle syndrome OR nonaldosterone mineralocorticoid excess (syndrome of apparent MC excess [AMEJ. Cushing syndrome, chronic licorice mot ingestion. congenital adrenal hyperplasia) Confirmatory resting to demonstrate inappropriate aldosterone secretion (1) After consumption of a high sodium diet for 3 d. if 24hr urine collection shows UM >200 mmolld.then urine aldosterone >12 pg/24 hr is confirmatory (modern practice): (2) IV saline suppression test or fludrocortisone suppression test (cumbersome. difficult to implement): (3) captopril challenge test (high false negative rate) Subtype classification is the next step once primary hyperaldosteronism is con firmed. to distinguish a unilateral APA from bilateral hyperplasia and to exclude adrenal carcinoma Studies for Subtype CIasMcation Adrenal CT Preferred imaging modality Superior spatial resolution dw MR with contrast Imaging findings:APAs usually appear as small hypodense nodules (<3 mm diameter); in bilateral hyperplasia.adrenal gland may appear normal or nodular; adrenal carcinomas usually >4 cm in diameter and have suspicious imaging phenotype Limitations: imaging findings may be misleading: absence of a mass does nor exclude adenoma (can be missed if lesion <1 cm): solitary unilateral adenomas may be nonfunctioning and cannot be distinguished from APAs Adrenal vein sampling (AVS) Gold standard zest to distinguish whedier excess aldosterone production is unilateral (ie.APA that is a candidate for adrenalectomy) or bilateral (je. IHA that should be treated medically) Sensitivity and specificity (95 and 10014) superior to adrenal CT Indications: pts with PA who are candidates for surgical management and have adrenal CT showing normal findings or bilateral abnormalities or unilateral abnormalities in pts >3S yr: may not be needed in pts <35 yr w/ spontaneous hypokalemia. marked hyperaldosteronism. and unilateral lesion dw adenoma on CT Limitations: expensive. invasive. technically diiiicuk Method: J conisol to confirm successful cannulation of both adrenal veins:wl cosymropin infusion, the adrenal vein to IVC cortisol ratio is typically >5:1; J aldo and conisol hom 3 sees: right adrenal vein, left adrenal vein.and IVC; then compare adrenal vein cortisolcorrected aldo ratios (PAGconisol): ratio >4:1 suggests unilateral aldosterone excess: >10:1 in mostAPAs; ratio <3:1 suggests bilateral adrenal hyperplasia Treatment Treatment goals: reverse cardiovascular morbidity caused by aldosterone excess. normalize serum potassium, normalize BP For unilateral disease (APA or unilateral hyperplasia). Rx is laparoscopic adrenalectomy For pts wl bilateral hyperplasia or in Pts with unilateral disease who are not surgical candidates or unwilling to have surgery. treatment is with MR antagonist Unilateral adrenalectomy » marked L in aldosterone secretion and cornectlon of llypokalemia in nearly 10054; HTN improves in nearly 100% and is cured in 35-80% Postoperative management: / PAC and PRA to assess biochemical response. d/c potassium supplementation and MR antagonists. and lower other BP medications; risk of T K postop d/t hypoaldosteronism 2/2 chronic contralateral adrenal gland suppression Adnenalectomy more likely to cure HTN in Pts withzyounger age. shorer duration elf HTN. use of $2 antihypertensive agents. t ARR,T urine aldosterone.lack of FHx of HTN Spironolactone or eplerenone.titrate dose to achieve midnormal serum K Ksparing diuretits (amiloride. triamterene) are an alternative but do not address the CV morbidity caused by persistent hyperaldosteronism and activation of the MR Rare Entities of MR or ENaCtlndueed HTN Liddle syndrome AD: ENaC function and Na reabsorption in CD: classic triad of HTN, hypokalemia.and metabolic alkalosis at young age: J. PRA and l PAC Tx: amiloride or tniamcerene Glucocorticoid Remediable Aldostervonism _ Familial hyperaldosteronism type 1 Syndrome of apparent mineralocorticoid excess (AME) AD; ACTHdependent activation of aldosterone synthase; typical onset of HTN <age 21: 1 PRA and T PAC Tx: glucocorticoid AR: deficiency in 11DHSD2;T cortisol binding [O MR: T urinary free cortisol [0 cortisone ratio,J. PRA, L PAC Tx: amiloride or triamterene or MRA +I dexamediasone PHEOCHROMOCYTOMA Background Neuroendocrine tumors derived from chromafNn cells of the adrenal medulla that hypersecrete catecholamines (epinephrine. norepinephrine. and/or dopamine) Paragangliomas or extraadnenal pheochromocytomas" arise from chromatin cells of the sympathetic paravertebral ganglia in the thorax. abdomen. or pelvis Rare form (<0.2%) of secondary HTN Presentation Classic symptoms:palpkations.headaches.dlaphoresis.and paroxysms of hypertension Pts do not always present w/ all of these. but paroxysms of BP spikes are common feature Pheochromocytoma can occur at any age There are no known risk factors except for the presence of certain genetic syndromes including: multiple endocrine neoplasm (MEN) type ZA or 2B. von Hippel-Lindau (VHL) syndrome.and neurofibromatosis type 1 (NF1) "10% tumor" because it was commonly thought that 10% of pheochromocytomas are malignant: -10% are bilateral: 10% are pediatric; 10% are extraadrenal: and -10% are familial: but more recent data suggests that up to 25% of pheochromocyto mas are inherited Evaluation Indkations for testing: classic symptoms. onset d HTN at young age. resistant HTN. FHx of pheodiromecyioma. presence of familial synd, or adrenal incidemaloma (>10 HU on CT) Testing for plasmafree metanephrine levels has become the most efficient screening test A positive screen for plasmafree metanephrines should be followed by more involved 24hr urine tests for fractionated metanephrines and catecholamines After biochemical confirmation: imaging studies w/ CT or MRI to locate the tumor II imaging is negative '"IMetaiodobenzylguanidine (MIBG) nuclear scan or "Ffluorodeoxyglucose (18FFDG) positron emission tomography (PET) scan should be done to search for adrenal tumor too small to appear on CT/MRI MIBG also indicated for palagangliomas or large tumors (>10 cm) due to T malignancy risk FOGPET Is more sensitive than CT/MRI and MIBG for metastatic disease Genetic testing should be considered for Pts wl: paraganglioma, metastatic or bilateral or multifocal dz. + family history. syndrome presentation. onset at young age (<4S yr) Treatment Once a tumor is found. it must NOT be biopsied;can lead to a pheochromocytoma crisis and possibly death Definitive therapy is surgical removal of the tumor; adrenalectomy if tumor is in the adrenal gland: specialized approach required for paragangliomas Most pheochromocytomas can be removed Iaparoscopically except for large tumors (>68 cm) and those that are clearly malignant Perioperatively: combined u and Badrenergic blockade to control blood pressure and prevent intraoperative hypertensive crises Pedoperative Medical Management of Pheochromocytoma xxadrenergic blockade Given 2 wk preoperatively to normalize BP and expand intravascular volume (co prevent severe hypotension after minor ieinoval) Nonspecific uadrenergic blockade Phenoxybenzamine: preferred. conventional drug; longacting and irreversible; initial dose is 10 mg once or twice daily -» increase by 10-20 mg in divided doses every 48-72 hr as needed to control BP » final dose is often between 20 and 100 mg daily: side effects are common and include ordiostasis. nasal stuffiness, fatigue. and retrograde ejaculation (men) Selective u1adrenergic Prazosin. terazosin. doxazosin blockade Associated with fewer adverse effects and lower costs Badrenergic blockade Initiated AFTER adequate nblockade to control nclvycardh: usually 2-3 d preoperatively; NEVER first because this an lead to unopposed aadrenergic receptor stimulation. hypertensive crisis Calcium channel blockers Metyrosine Alternative regimen: can also be used as addon drug or as intravenous infusion Intraoperasively (je. nicardipine) inhibits catecholamine synthesis: may be used in combination with ablockade for short period to further stabilize BP FoIlowup:Annual biochemical messing to assess for recurrent or mezastadc disease CARDIOLOGY CANi:>iORSNAL SvnoaomE (CRS) Classification of Cardlorenal Syndrome Type 1 Type 2 Type 3 Type 4 T s Acute HF leading to acute kidney injury Chronic HF leading to chronic kidney disease Acute renal failure presenting with fluid overloadlHF Chronic renal failure contributes to hem disease (je. associated with LVHI diastolic dysfunction. coronary artery disease. arrhythmias) Systemic disorder causes both cardiac and renal dysfunction (je. sepsis) Background CR :the interaction between kidney and CV systems where acute or chronic changes in one organ leads to adaptive (or maladaptive) changes in the other organ system Risk factors for HF and renal insufficiency overlap. 38-55% of patients had DM (more frequent wl worsened renal function). 70-80% had a lo HTN. and advancing age was more common with increasing cneatinine (ADHEREJ cne Fdi 1007;13;422). Chronic HF is al CKD.Among 80.098 pts wl HF 63% had any renal dysfunction with 29% being rated as moderate to severe." Mortality was higher in those with renal dysfunction wl a stronger effect in those w/ worse renal function (RR 1.48 for any impairment and 1.B for mod-severe dysfunction) (yAcc 2006;4711987) Pts admitted with acute decompensated heat failure (ADHF) may experience worsening renal function (WRF). 27% of 1.004 pts with ADHF experience WRF yacc 2004.43.61). High Rsided venous pressures correlated best (Mc zoomsrsssi WRF may occur in the setting of diuretic use. although some pts may show improvement. In a study of 443 patients ADHF. only 10% worsened wl diuresis while 27% improved. Larger BP drop was predictor ofWRF with cardiac index (Cl) and change in RA pressure not being predictive (Et:/Hwt rm12013;1$:43J).The fre quency ofWRF with diuresis varies between studies. ranging from 10-40%. In ESRD patients. LVH is very common (>70%) and 40% carry a diagnosis on CHF Pathogenesis NeurohormQnal: reduction in cardiac output leads co arterial underfilling -» activation of the RAAS. sympathetic nervous system. and endothelin release -o arteria) vasocon striction with a reduction in renal blood flow Reduced cardiac oq§p115: perhaps an overstated contribution to GFR decline,as changes in intraglomerular pressure work to maintain GFR.at least when Cl >1.5. In 575 patients MM PA athetefs in place. :heine was no association between Cl and GFR or WRF UACC zoiesnisstan effect that was confirmed when looking at UNOS registry of patients listed for heart transplantation (;Acc 201614»818741 V_€D9LI§L9ngg§xi9n: backward flow from RV dysfunction -» venous congestion in an encapsulated kidney - mechanical compression with T in interstitial and intratubular pressure -» L GFR. In addition. there is a redistribution of blood How from the cortical tissue (where glomeruli are) to the medullary compartment. In human studies of HF with renal dysfunction, there is a stronger correlation with RA pressure than Cl. an effect that may be modified by systemic arterial pressure.With lower SBP sensitizing patients to a reduction in GFR alw venous hypertension (Hun few Rer 201B;23;29\) Renal adapution to HF: in the setting of chronic hypoperfusion.the iuxtaglomenilar apparatus hypertrophies. glomerulus may undergo ischemic type atrophy with associ ated progressive interstitial fibrosis or"thyroiditation" where tubular atrophy is out of proportion to the degree of fibrosis.These effects an Iikeiy worsening by elevated levels of neurohormonal factors (eg.AlI) and cytokines (eg.TGFB) Cardiac adaptation to AKI:AKI is a/w fluid retention that results in increased LV end diastolic pressures. In addition.alteration in Cal. K. HCO;.all i cardiomyocyte connactility and predispose to arrhythmia. Cytokine release from inlury renal tubules have independent effects on mitochondrial oxygen consumption as well as increase pulmonary capillary bed permeability, Cardiac Idantation to CKD: chronic fluid overload and HTN lead to progressive LVH. Elevations in RAAS markers,alterations in FGF23 signaling through the IGF receptor and oxidative stress all contribute to cardiac fibrosis and impaired relaxation. leading to the rates of CHF >40% in the ESRD population Treatment Loop diuretics: standard of care for ADHF even in renal dysfunction.Torsemide and bumetanide have lower inuapatient and interpatient variability in absorption. Torsemide (cl: furosemide) is a/w 1 readmission rates 17% vs 32% (Am}M¢4 2001;111:51]) IV loop diuretics are preferred. In one study there was no difference in outcomes at 72 hr between continuous vs bolus. However highdose group (received x2.S their home dose) were x2 as likely zo be able to convert to an oral regimen ac 48 hr than lowdose group (continued on their home dose given IV) (Doss new 10113641971 Add a thiazide diuretic (hydrochlorothiazide, chlorthalidone. or metolazone). spironolactone, or CA inhibitor if refractory edema despite loop diuretics ACE ihhibition: a mainstay of therapy in HF w/ reduced EF and improves long.term survival. However. its use in these patients has not resulted in reduced risk of renal insufficiency lnotropic support: dopamine.dobutamine. or milrinone (requires dose adjustment for CrCl. may 1 BP with vasodilation) may be considered in persistent CHF despite maximal dose diuretics and/or evidence of low output state Prognosis of HF With Associated Renal Dysfunction Lower eGFR in HF is consistently alw worse mortality t RR independent of EF: eGFR 30-59: 1.13: eGFR 15-29: 1,85: and eGFR <15: 2.96 (Open Heart N 1&8:¢0003241 WRF during treatment of acute HF is a/w a worse prognosis.wid\ an RR of 1.48 Mm eGFR declines by 11-15 and 3.2 with a decline >15 DetongesUon (despite WRF) may be a/w improved survival (annum zoi0 iuzosi Prognosis of Renal Failure With Associated Cardiac Disease In ESRD pts the presence of HF alw a doubling of mormliq at 2 yr - 16,6% vs 33% (USRDS 1018 Annual Day Report) Compared to the general population. patients with CKD are less likely to undergo rensculariution and have worse outcomes after cardiac catheterization and CABG. However. revascularized patients do better than those who do not undergo these procedures (reviewed in CAD and CKD) CononAny ANTEIW DlssAsE (CAD) Background Patients with CKD have much higher rata of CAD than the genes population: 39.4% of adults >65 yr old have CAD compared no 15.6% in those wir.hou: CKD Even young paniamrs are at risk for CAD. Among patients aged 2040. 18% on HD carry diagnosis of CAD (USRDS 2017AfuunI Dan Rayon). as opposed to only 0.6% of general population 4c~um=w» 1015;131:e29) Albuminuria on its own is a marker of T risk of CV death. Hazard ratio for CV death (compared to Um <10 mglg Cr): 11-29 = 1.63. 30-299 = 1.82, >300 = 4.77;an effect do was present zhroughour all stages of CKD lcxo Conw4num.IAn¢e¢ 1010;37§;2073) Pathogenesis Risk Factors for CKD + CAD Hypertension Smoking Hyperlipidemia Diabetes Age Metabolic syndrome Uremiaspecific Factors Inflamma[l9n . Phos. - PTH Carbamoylzdon of LDL FGF23 Indoxyl sulfate Asymmetric dimechylarginine Risk factors for CAD and CKD overlap. but uremia plays a role as well Treatment of CAD in CKD CKD not on HD Srazin Use Metaanalysls showed a 1 cardiac morality RR 0,8 lAM :m 20I1;I$7151) Simvasratin 20 mg qd Ezezimibe 10 mg qd: 17% risk . for major atherosclerotic events. driven mainly by 1 ischemic stroke and revascularizations 4SHANP was 10l 1i]77:2I8l) No clinical benefit in 1255 dialysis pts wl DM(4)new100$;3$3:238) Subgroup pts w/ starting LDL >14S had l primary endpoint (HR 0.59). cardiac death (HR 0.48) (4oqAs~ 20111611319 No difference in primary outcome at: 3.8 yr (AURORA NEWzau9=ua1a9si B lo o d P re s s u re Co n t ro l No RCI Observational day suggest a U or Jshaped curve widl T mortality at lower or higher BPs. PreHD BP dw the best di f f er enc e j am z o\ a: J 47: r s s s ol outcomes differ between studies and Target <130180 (140/90 if UACR <30 mg/g) range from SBP 130-159 with DBP ( K D I G O C K D 2 0 1 2 ) . or perhaps 120/80 60-99 (al 2012;8Zz570) (SPRINT ngu 2015:373:1103: piss z017;1ezs12i cl) Percutaneous Coronary Intervention (P 4 CV events wl similar efficacy as in nonCKD wl 17% risk L per 5 of . SBP wlo class CKD p a wl NSTEMI a re mu ch le ss like ly to undergo PCI (41% st age 4, 20% st age 5) even though CKD pts who undergo PCI are twice as likely to survive to discharge U W 201817 ¢00m 01 I n pt s w/ eGFR <60. drug eluung scent s (DES) vs bare met al st enrs (BMS). revealed a . a llca u se mo rta lity (RR = 0 .8 ).i ca rd ia c deat h and t arget vessel revascularizat ion ( I l ner taw l oi 201B.3l :319) Coronary Artery Bypass Graft Surgery : Mortality, risk of myocardial injury. deep t issue inf ect ion, prolonged I CU st ay. v ent i l at i on ( N D T z 0\ az s as s 4i t Renal progression at 3 mo (compared to PCI or medical t herapy). but no d iffe re n ce a t 2 yr.Th e mo ra lity risk a t 24 mo was lower (3.9%) dw PCI (14.5%) or medical t herapy (16. 4%) (CnmnAmry Ds 201&19;B) Angiographic success is similar between HD patients and nonuremic controls. but longterm survival is much worse for ESRD patients. with a 3-4 fdd T mortality at 1 yr Similar to CKD not HD population, ESRD patients receiving DES have a 18% relative risk reduction in death and a 13% risk reduction in death. MI, and target vessel revascularization yAcc 201&61:1459) (CABG) Inhospital mortality (12.2 vs 1096). mediasninitis (3.6 vs 1.2%). stroke (4.3 vs 1.7%) 1oullum 2(100.102:297!l Despite T early monalkya ESRD Po undergoing CABG have lower 1 yr mornlity compared w ESRD pos wl CAD who do not undergo CABG.and lower risk of revascularization compared xo patients undergoing PCI Prognosis After ACS (NSTEMI or STEMI). CKDnon HD patients have a higher mortality at 180 d (10.3% vs 3.4%). CAD risk factors are also more common in CKD.after adiusunenr-each 10 .. in CrCl T 180 d morralizy with RR = 1.1 (Grtulamiun 1001:106:974] There is a graded decrement in 2yr survival patients with CAD, widl worse outcomes among patients with worse CKD. 2yr survival: no CKD:87.476, Stage 1-2: 81.1%. Stage 3: 77.6%. Stage 4-5: 67.4% mans Z018 AnnuaI Day Kwon) CARDIAC CATHETERIZATIO N Backgr ound More than 1 million cardiac catheterizations performed in :he US annually Since risk factors for CAD and CKD overlap, many patients requiring catheterization o have underlying renal dysfunction. Stage 3A: 17%. 3B: 91%. 4-5: 2.9% gAil 2014a:¢00us01 .4 Reported rates of AKl after cardiac cath range from 3-20% depending on patient risk factors, procedural factors (eg. contrast dose).and definition of AKI used From 2001-2011. number of postcatheterization AKI cases has f 3fold UAHA 1016540027] 91 Pathogenesis of Kidney Injury Renal hypoperfusion in ACS. hypotension related to cardiogenic shock Cholesterol emboli from procedural manipulation of vasculature RBC breakdown products/pigment related to hemolysis from IABP or lmpella device Ris k F a c t o rs o f K id n e y I n ju ry CKD Graded increased risk by starting eGFR with values <30 mUm in alw Diabetes 1.5-2x increased risk compared to nonDM with same eGFR Age Each 10 yr increase alw relative risk 1.1-1.1 for CIN h i g h e st r i sk o f A K l o r A K I D Hemodynamics CHF (at presentation or prior). hypotension.and need for intraaonic balloon pump, all independently increase risk ofAKl Indication STEMI >> NSTEMllunstable angina >> elective procedure Contrast High osmolar >> Low or soosmolar Contrast volumexnaOnine Clarance ratio: risk dAKar begins no increase as ratios between 2 and 3 Others Hyperglycemia (w/o diagnosis of DM). anemia. proteinuria (independent of eGFR). unSAIDs. multiple myeloma (possible), complex coronary lesions Predicting AKI after Catheterization Risk of CIN ranges from <1% to >50% in individual patients Stratification can identify patients who benefit from additional interventions (see below) to reduce risk of AKI. or identify patients in whom catheterization should be deferred IAHA (ulddine for ac: ;Acc 1011;S8:14) Many prediction equations exist but were generated on data obtained prior to renal sparing interventions. newer contrast agents. and low contrast volume PCI Mehran Risk Stone includes 11 clinical and procedures factors and has been externally validated (acc 2004:44:1393) National Cardiovascular Do Registry (NCDR) AKI score was developed using >900.000 patients and has been validated in US and overseas.with AKI defined by the Acute Kidney lniury Network criteria. using a modern ueatrnent cohort. 11 clinical characteristics for AKI and 6 clinical characteristks for AKIDialysis UAHA 1014;3:e0013B0) Prevention Modifiable risk factors with the largest impact are volume ams and volume of contrast used. Volume resuscitation avoids hypotension and prevents renal vasoconstriction that could be worsened with contrast administration. Frequent examination required as shine administration can be limited by CHF symptoms Intervention for AKI after PCI Fluid Randomized trial data limited but suggest N better than unrestricted oral hydration (though oral salt loading may have benefit). Regimens vary ranging from 3 mUg for 1 hr to 1 mU kg for 6 hr prior to cath.continuing postprocedure at 1 mUkg for 4-6 hr Type of IVF NaHCO; solutions have theoretical benefit of altered urine LvEDpguided fluid Direct measurement of LVEDP during cash detects underfilling as well as avoids giving fluid to patients already ac risk for HE LVEDPguided fluid administration reduced risk ofAKl by 60% Acetylcysteine Free radical scavenger with mixed results in RCTs. Unlikely to be effective. IV preparation has 3-5% risk of anaphylactoid reaction. Prophylactic dialysis Several studies have shown NO benefit of dialysis or hemohltration prior to contrast or postcatheterization dialysis to remove contrast in hopes of reducing renal toxicity (ln»}I4ed 1011;11.661 5BUH5 Mixed results when compared to NS alone. though patients likely to be initiated on statin at time of discharge legandless.nuy be worth Diuretics Diuretics alone do not . risk of AKI and may worsen. Forced diuresis matching IVF to urine output using RenalGuard system Access Radial access may reduce risk ofAKl over femoral access; OR 0,57 pH - lower free radical generation -» lower AKLClinic trials comparing to NS have been mixed with () welldesigned trials (new201&]78:603) (POSEIDON lance! 2014;]83:1B14) initiating prior to contrast exposure may lessen AKI (MYTHOSWC Cntimt In 10115,901 (0.35-0.91) (Am}cnuzo17:1m141) Evaluation DDx: prerenal AKI from hypoperfusion/cardiogenic shock.volume depletion in patients who have postprocedural bleeding. cholesterol emboli syndrome Unlike other nephrotoxic AKI, urine Na and FEn. is frequently low or unchanged from prior to procedure (NE}M 1989;320¢149) Cholesterol embolilrenal atheroemboli: presentation is usually subacute over 1-2 wk w/o improvement.Approximately 213 will have eosinophilia and 1/3 will have reduced complement levels. Skin findings of livedo reticularis. digital infarcts, and new neurologic deGcits are strongly suggestive but not always present. Prognosis In hospiizl mortality for AKI 5-10%.with mortality forAKlD 20% UAHA 2016;55¢001739) At 1 yr. risk of death remains higher in patients who experienced postcath AKI. as are rates of reinfarction and target vessel revascularization (Cn CmUiniwclnierv2015;8:s00247§) Of all. patients with a 50-99% increase in creatinine between days 3-7. 28% will con unue to have elevated creatinine 3 mo later.Those with more severe early AKI. >50% will have sustained loss of function and a more rapid rate of decline in renal function between mo 3 and 24 after exposure Kl 2010:78B03) ATRIAL FIBNN.LATIO N ( AFIB) Background The annual incidence d being newly diagnosed widi AFlb * as renal function declines:40% of stage 4-5 CKD pts wall develop AFib over 2 yr (usaos 1017AilmI Dao Revoll) 18% w/ CKD had AFib (25% >70 lo). ><2-3 of nonCKD picnic AHA zoirkis9.1I01) AFib is al a 67-80% T in rate of J. of renal function. including progression to ESRD Patients with CKD and AFib are at higher risk (or stroke than patients with either condition alone, with those on dialysis having the highest risk. Proteinuria itself is ailw an almost 50% increase in risk lAT MA awl¢Inn 2009;119:1s63) Pathogenesis AFib and CKD share common risk factors. In addition.CKD contributes to HTN (largest populationbased risk factor for AFib).yolume expansion + LVH -» t left atrial volume. electrolytes abnormalities. myocardial fibrosis. and adierosclerosis-all of which may contribute to die T risk. Patients with CKD have slower atrial appendage emptying. T frequency of spontaneous auial appendage echocontrast T platelet aggregation in response to cAMP and ET1. markers of inflammation and activation of tissue factor pathway. all of which have been alw an T risk of thrombotic events (;Acc Z016:6B:145Z) T r e a t m e n t C o n sid e r a t io n s In addition to having an t risk of thrombotic events, ESRD pts are at higher risk of hemorrhage,wl x10 T risk of intracranial bleeds and x3-4 T risk of GI bleeding In nonendstage CKD pts, balance of risks and benefits favors warfarin use (HR of thrombotic event 0.7 and death 0.65). However, multiple cohort studies in ESRD patients suggests no reduction in stoke (in some studies. higher risk). no reduction in mortality, and a consistent increase in risk of bleeding (Own 201e; 149.9s11 Data regarding Novel Oral Anticoagulants (NOACs) is dialysis patients are limited since most are at least partially eliminated by the kidneys and patients with advanced CKD were excluded from randomized trials.Apixaban at a dose of 2.5 mg BID appears to show similar pharmacokinetics to the 5 mg BID dose in patients with normal renal function UASN 2017;282241) but efficacy studies are not available yet SunkEn CAnoiAc DEATH (SCD) AND AICD Background Wadi eadx sage d CKD. patients experience higher morality rats (no CKD:43. sage 1-2: 79.sizge 3:97.smge 4-5: 170 per 1.000 patientyr).And among those wide ESRD.40% at these deaths are amibured no SCD/Arrhynhmia lusaos 7.017Ann\»l Dao R=o°f4 Common in 15: 2 wk of chronic dialysis (c;Asn 201116:zs4z) Pathogenesis Rates of ischemic hear: disease approach 40% in dialysis patients.At least part of the elevated risk of SCD related to ischemic events from underlying atherosclerosis. as SCD risk is higher in patients with known CAD and diabetes. Electrolyte fluctuations lead to abnormalities in cell membrane stability and polarlza tion. Low K dialysate (<2 mEq/L) was alw )<2 t risk of SCD in zoonwasm1011:79=21a) Low Ca baths have been a/w QT: prolongation and cardiac death (qASN 2013.8:7971 Abnormal fluid balance leads to development of CHE and rapid removal of fluid during dialysis may lead to myocardial hypoperfusion and microvascular ischemia. Increased rates of fluid removal (>13 nUke/hr) are alw T allcause and CV mortality (Ki 1011991501 The combined impact of additional fluid and electrolyte overload manifests in HD pts as an ' risk of morality during the long (72 hr) interval between dialysis sessions. Compared to other times during the week. the 72hr interval is al a 36% T CV mortality, 23% T in allcause mortality. and a 90% T risk of dysrhythmia i~€lm 201 l:J6S:1099) Prevention Avoid 0 or 1 K lx: 2001;m3s0. 2011791181. <2.5 Ca and high bicarbonate (Doors um 2013;62:738) dialysate;Avoid digoxin (in 2010321:15S0) ii blockers: in ESRD wl cardiomyopathy, addition of carvedilol was alw a 21.5% | in mortality over 2 yr u/irc 20oa=4114ssl.Among >40.000 pts followed in :he Gambro dialysis system. B blocker was alw an T likelihood of surviving arrest (qASN 2007:2491). However. other observational trials have given inconsistent results We 201B;71337), Use nondialylable p blockers (carvedilol) instead of dialyzable p blockers (atenolol. acebuwlol. bisoprolol. or metoprolol) ac/Asn 1018:13:604; ;As~ 2015216387) ACEr/ARBs: fosinopril did not I CV events in ESRD w/ LVH lFoslmAI. xizoos;1o13\si Automated Implantable CardiovertervDelibrillator (AICD) Remains controversial in patients with renal disease Patients with renal failure have higher arrhythmia event rates but also higher rates of competing death Patients with CKD and eGFR >30 likely benefitThose with eGFR <30 or advanced age are much less likely to benefit (qAs~ 201S;10;l 119) ldeally.should be placed on side opposite AV access to reduce venous congestion and allow venoplasty or venous stent placement if needed to maintain access patency PULMONOLOGY Interorgan crosstalk between the kidneys and lungs IS not limited topulmonary-renal syndromes.AKl/CKD may affect lung function and acute/chronic lung disease may affect kidney function. Reduced lung function is a/w several factors that may contribute to the development of CKD: hypoxia ( HIF1u. RAS activation. SNS activation); RV dysfunction (1 perfusion due to T renal venous pressure): chronic inflammation (A;xo 1017;70c615) Impaired lung function is common in CKD. In CKD (eGFR 15-60 or ACR 230). 15.6/9.8% had obstructivelrestricxive lung function. In pts w/ ACR 230. OR for obstructive lung function 1.42 and OR for restrictive lung function 1.43 (niIAnes Ain: 2016:68=4141 Reduced baseline lung function (esp. ; Xpredicted FVC) was alw T risk of incident ESRD and t risk of CKD progression lAxic Also 20 17:7a675) AcuTe Lun¢s Inlulw (ALI) AKI is common in patients with ALl:AKlN stage 1: 54.1%. stage 2: 12.3%.stage 3: 15%. AKI defined by change in Cr may be masked in presence of fluid overload.When adjusted for fluid balance. incidence ofAKl increased to stage 1: 61.8%. stage 2: 19394. stage 3: 17.2% Patients with AKI that was only diagnosed after adjusting for fluid bal ance lead similar mortality to other patients with AKI. and higher mortality than those without AKI (Ados Network sAcrT on Care mm 2011.]9:2665). ALI managed wl low tidal volume (46 mUkg) ventilator strategy Low volume respiratory acidosis -> acidemia. Patients in ARDS network study less likely to develop AKI if treated with low tidal volume,Treatment w/ HCOi may worsen acidemia in this setting. so earlier initiation of RRT may be needed to prevent complications of acidemia p:jAsn 2(l(8.3:57B) In AU,conserva6i»e fluid strategy (CVP <4, PCWP <8) alw improved oxygenation index and lung injury vs liberal fluid strategy (CVP 10-14, PCWP 14-1B). Baseline Cr good in bodi groups (Cr 1.24 vs 1.29) and no difiiefence in new for RRT betweai groups (10 vs 14%). Impact on course of preexisting AKI or CKD not studied (FACTT NE/M 200sJs41zs641 Inhaled NO. used in ARDS.a/w T AKI (RR 1.52) in dosedependent fashion. Risk MMI not present with low or medium cumulative dose. or when iNO used in absence cARDS. Possible mechanism: reactive nitrogai species -» oxidative injury icunailCaft z01s. \$.1371 Prone positioning may be used in severe ALI » t intraabdominal pressure. but no effect on renal perfusion or renal function wew-A»d¢2001:92:\126) COP D The prevalence of CKD is T in COPD. occurring with 2-3x Frequency dw pos wlo COPD. Presence of achexia and muscle wasting in COPD may mask diagnosis of CKD. as patients may have low GFR with normal creatinine. In pts with COPD exacerbation. more advanced CKD a/w T rnorraliry (lm 1 corn zmsnazoln AKI more common in COPD (1.4 vs 0.6%). esp. among patients with preexisting CKD or CHEAKI occurring during COPD exacerbations alw T short.term mortality urn! COPD 2015;10;2017: 2013;B:1271 T Inflammation -» enW lhl dysfunction _ albuminuria. UACR higher wl more advanced COPD and albuminuria in COPD alw t mcruliq loa m1s;1 41w iw f i mu n sn w zi C O PD a n d D ia lysis COPD is common (75% prevalence) in ESRD on dialysis. Mortality is higher Mr ESRD w/ COPD (RR 1.20).esp. in active smokers (RR 1.28). COPD pa w/ ESRD are less likely w receive a KT (RR 0.47 for aW smokers, 0.54 for nonsmokers) WN 20\1;u;M. COPD HD paUenu are more likely to have prolonged inzradialytic hypoxemia.which is associated with risk of hcspicalizarion and T mortality (clAw 101s;11.616l Wim standard HCO; dialysate, Pco, T. HCO; T and pH r during HD. PO; l and Aa gradient T during treatment M m lah so 2011:41:3\S) Fluid removal >3% of body weight during HD may T FEV1 and FVC temporarily in COPD (Hmnulal i! zoisaofeai COPD pts sining on CAPD may have L WC.lVC,LTLC that ieversu within 2 wk. without changes in PO w. mo or pH ( 19u;u:s74) SMOKiNC AND IMOPATHIC NonuLAa GLOHERULOSCLEROSIS (ING) Chronic ischemiclhypoxlc conditions can cause ING wl nodular mesangial sclerosis wl accentuated glomerular lobularity. mimicking diabetic nephropathy. MPGN, dys proteinemias. organized glomerular deposition diseases (/ASN 1007=18:20321 ING linked to chronic HTN and cigarette smoking. Patients more likely no be older. white, male: 95.7% with HTN and 91.3% wl lo heavy cigarette smoking. Nephrotic range proteinuria common (70%) but NS uncommon (21%). Mean time from biopsy to ESRD 26 mo. T IFlTA and vascular disease alw progression to ESRD. Smoking ces sation and RAAS blockade aw better survival (Human nntnulqy 2oo2.nam Smoking may cause ING via T AGEs.1 oxidative stress, T angiogenesis. T sympathetic activation (JASN 2007;18:2032) PULMONARV HYPeaTENSlON (PHTN) PHTN is common in CKD, and CKD is common in PAH, PHTN (PAP >25 mmHg) occurs in 23% of pt w/ CKD.and severe PHTN (PAP 245-50) in 7-29% of HD pos. PD < HD. likely due to differences in comorbidinies lA/KD 20 1a1717s1 xv Z01 J.e=ee1l PHTN in CKD , v morzalicy (RR 1.4 CKD, 2.3 ESRD, 2.1 after KTx).. CV event (RR CKD 1,7. ESRD 2.3). CV morzaliry (RR 2.3) We z01a:n75) CKD occurs in 4-36% of PAH. Prevalence of CKD higher in PAHassociared connec :ive tissue disorder: esp. SSc. CKD in PAH - t risk of death (num ci<z017:17:.a). In pos with PAH and CHF exacerbazion.AKl is common (2394). more common if CKD (OR 3.9) and alw T mornalicy (OR 5.3) U ci~llia¢r¢,im 201147533) Mechanisms of CKD: SNS activity T RAAS aczivicy -» pulmonary/renal vascular remodeling T RA pressure » t renal vein congestion; t endothelial dysfuncuon in uremia -» T pulmonary vasoconstricrionc I PCWP mum of 201711738: KJ 20 u:a:m) OasTnucTlvs SLEEP APNEA (OSA) Common in ESRD (>S0%) with similar prevalence in HD and PD. No studies on whether CPAP reduces CV risk and mortality in ESRD patients with OSA. although switching to nocturnal HD alw improved symptoms (See 0m12013;16:2731 More common in CKD. seen in up to 65% Nocturnal hypoxemia in OSA is alw more rapid decline in GFR. Possible mechanisms: endothelial cell dysfunction, stress. RAS activation (c/As~ 201I:8: 1S02) oxidative T Risk of albuminuria independent of the presence of DM or HTN. T UACR may correlate wl severity of OSA.Treaunent of OSA with CPAP is alw a l in UACR (Aledkme1016:95:26). Risk factor for developing HTN (risk increased nearly 3fold in OSA). OSA is a common fuse of resistant HTN. OSA patients wadi resistant HTN treated with CPAP show improvement in BP (. 4.7811.53) uwwiwm 20161511531 C v s nc Fm nos ls ( C F) Nephrocalcinosisz 23.2% on uls. 92% on biopsy mf*1 m2w;u;n= new im:3i9.263) Nephrolichiasisz 3,063%. Possible mechanisms: far malabsorption -o T GI oxalate absorption -> hyperoxaluria -» 7 CaOx saturation in urine: hypocitraluria l O. forrnigenes in GI tract -» J, breakdown of oxalate in GI tract -> T GI oxalate absorption -» hyperoxaluria - T CaOx saturation in urine (A)K0 2003¢42:11 Prevalence of CKD (stages 3-5) in CF 23%. Disease prevalence doubles with every 10yr increase in age. imdiing 19.2% in patients over 55. Risk of CKD greater in CFrelated DM. but not widi increasing pulmonary exacefbaticns of CF (AIRCCM 10019541147i CFrelated DM: microalbuminuria in 14-21%. Patients wl CFrelated DM more likely to have microalbuminuria and less likely to have retinopathy than patients with DM1 II Cyst Fibiuils 2000;7:S15; Dabeles Care 1007:3(M056) Other causes of intrinsic CKD:AA amyloidosis. loAn (qASN 2009;4:921) AKI in CF most commonly druginduced from nephrotoxic antibiotics (aminoglycosides. polymyxin B.colistin). unSAIDs used in pediatric patients. may cause AKI if acutely volume depleted la Can Hanan: 200e=1 z3o9). AKl rarely due to acute oxalate nephropathyzfat malabsorption - t GI oxalate absorption -» hyperoxaluria » T calcium oxalate deposition in kidney luff 100a;a119011 SARCOIDOSIS (Ap(o z0as;4a£54>» Granulomas and maaophages make 10 hydmxylase » T 1.25(OH)2 vitamin D (ddtriol) Hypenakiuria: Um >300 mild. 50% (mlc renal manifestation); t calcitriol -» 1 PTH -» L tubular Ca* reabsorption Hypercakemix 10-209411 cakitxiol -» T Gl Ca* absorpdonf bone iubsorplion -» ' Ca" Prednisone 20-40 mold can improve hypercalcemia and hypercalciuria dh L macrophage 1a hydroxylase activity Noncaseadng granulomatous interstitial nephritis: 7-23% on autopsy. mos: uses clini cally silent Treatment with prednisone 1 mykg/d for 6-12 mo improves renal function but most left with CKD. Relapses uncommon (1S%). more likely no occur after prednisone d/c. but also respond to prednisone (Meda: 1009;BB:98). ESRD rare; KT safe if ESRD develops, but sarcoid GIN can recur in KT (nos of 201440 Renal tubular dysfunction: common: polyuria from Calinduced NDI.CDI in neuro sarcoidosis: piTA. dRTA, or Fanconilike syndrome from tubular damage from T Cal or GlN.Tubular abnormalities improve with steroids. TUBERCULOSIS ExuapulmonaryTB more common in HlV or organ transplants. 27% of extrapulmonary TB are GU. GU TB occurs in 2-20% of pts with pulmonary TB. GU TB primarily involves the collecting system and less commonly causes parenchymal lesions. TB seeding of GU tract an occur widi primary infection or racti~»ation.TB bacilli form granulonias in medulla -» rupture into tubular lumen widi exaction into collecting system. Descending infection can lead KO papillary necrosis. ureteral stricture and obstruction. hydronephrosis. and renal dyslunction.Typically unilateral: if bilateral an lead to ESRD. Urinary symptoms common. systemic symptoms uncommon Labs sterile auria and gross or microscopic hematuria Renal parenchymal lesions:AA amyloidosis from chronic iniiammationz lnnerstitial nephritis; postinfectious GN Diagnosis of renalTB: isolation of TB from urine culture or tissue biopsy Treatment; antiTB antibiotics. If obsuuctlon present and renal dysfunction reversible. may require ureteral stenting or nephrostomy. Partial or total nephnectomy may be required in UP to 55% (A~»1f~» M 44 we 2013:B8:54) IN Te N STi Ti AL L u n g D l ssAss (IL D ) CKD is common in IPF. with 30% of patients having eGFR <60. CKD more common in older patients and patients with HTN. CKD associated with .. DLCO and 1 distance on 6min walk test. eGFR independent predictor of survival in IPF after adiusdng for age and PFls aw-wili" 2017:94:3461 ILD alw ANCA: usually >65 lo. MPO (+); pulmonary fibrosis occurs concurrendy or predates by several mo to 12 yr: usual interstitial pneumonia is the m/c radiological pattern; ILD has an adverse impact on :he prognosis (Auiuaivmn Rev 1017;!6:712) roTOR InhibitorAssociated Pneumonitis 1r-~=--salini-=w~ z004;77121s: Ann it 100611448051 Transplat Pwr 1018;159331 In up to 4.3% of :xp pts receiving everolimus and up to 11-17% receiving sirolimus Not related to drug levels; S0% of cases occur after >6 mo of drug exposure Symptoms: cougltfatigue. levers.and dyspnea. Pulmonary infiltrates are common and resemble BOOR No formal diagnostic aiteria. so r/o infectious etiology BAL shows lymphocytic alveolitis. Treatment: permanent withdrawal of roTOR inhibitor +I- steroids Clinical and radiographic recovery zypically occur w/i a few weeks of drug dlc DIFFUSE ALveoLAr HEMORRHAGE (DAH) Caused by disruption of tile alveolarapillary basement membrane: small vessel vasculitis can cause injury co glomerular capillary wall together causing pulmonary renal syndrome Lifethreatening condition requiring prompt diagnosis and treatment Conditions Associated With DAH With Renal Impairment r~Elm 2u11;:67:1540) . ANCAassociated disease.AntiGBM disease. SLE +I-, antiphospholipid syndrome HSR mixed cryoglobulinemia. polymyositis, progressive systems sclerosis. MCTD HIV. disseminated cryptococcosis, Legionnaires disease. CMV. strep or staph infection . Uremic pneumonizis: cardiogenic pulmonary edema dl: HTN and/or volume overload Clinical Manifestation and Diagnosis Hemopzysis may be absent in ~1/3 of cases: should suspect vnth radiographic opadcies (either localized or diffuse) and falling Hb level: PFT:T DLCO Confirmed when lavage aliquots are progressively more hemorrhagic / ANCA, antiGBM,ASLO. CO. C4,ANA. RE cryocrit.APLA,and blood culture Biopsyi lung, skin (if rash present). or kidney Tr e a tm e nt Invasive or noninvasive mechanical ventilation. correct coagulopachy transfusion pm Pulse glucoconicoid + PLEX: empirically when autoimmune conditions are suspected PLEURAL EFFUSION Nonmalignant pleural effusion + renal failure 1yr morzaliry is 46% (do z017;1s\.1099) 20% of hospitalized HD pts. commonly from hypervolemia (fmusglanxllnc 1007;39.8891 Pkuroperitoneal leak in PD: 1.6-1098; pleural fluid/serum glucose >1 (nbr 2011;27211121 Urinothorax: caused by obstructive uroparhy (pelvicureteral, bladder outlet, pelvic mass). GU procedure. trauma; pleural fluid Cr/serum Cr >1 (An»1m¢a s¢z017;Js4;44) Transudadve: hypervolemia. nephrodc syndrome. HE pleuroperitoneal leak Exudadve uremic pleuridc. parapneumonic effusion EXTRACORPOREAL MEMBRANE OXYGENATION Background Extracorporeal Membrane Oxygenation (ECMO) provides gas exchange for hypoxemia I and hypercarbia as well as hemodynamic depending on configuration and indication Venovenous (W): respiratory support Venoanerial (VA): respiratory and hemodynamic support ECMO use has increased dramatically in recent yr. from 253 in 2006 to 4.297 in 2016 iecis r-gsm. 1rz0171 AKI during ECMO AKI is common. ranging from 2986% (pooled estimate 55.6%) with renal replacement therapy (RRT) required in 7-86% (pooled estimate 46%) (Am Thom: sw:2014;971610) AKI requiring ECHO is a/w with high mortality (78% vs 20% nonAKl) (NDT 1006;11:ZB67) Pathogenesis of ECMOAssodaned AKI (c¢1uw¢i Abu 1016.4s0) Patient Factors ECMO Related Hypotension.SIRS. Nephrotoxins. Hypoxia, CKD Blood flow changes. RAAS dysregulation Blood-air interface. Cardiorenal syndrome, Homo/ myoglobinuria,Aor¢ic disseWon (VA). Embollsm (VA) In 50-60%. renal failure precedes :he initiation of ECMO fnaiaucni Cae M44 101617:115n In severe ARDS, ECMO use was a/w more days free of RRT and renal failure (EOUA num 2018;378;1965) Renal Replacement Therapy (RRT) during ECMO RRT frequently initiated earlier for control of volume status In one survey. indication for RRT was fluid overload in 43%. prevention of fluid overload in 16%.AKI in 35%. and electrolytes in 4% (A$Aloj 20121581407) While intermittent HD and PD can be used during ECMO. CRRT or SLED is recommended at least Initially until patients are stabilized CRRT can be used via a separate double lumen dialysis catheter but central access may be taken by other catheters (cannulate for ECMO plus catheters for medication administration) and placement may be risky if on systemic anticoagulation Hemofilter may be placed inlihe with ECMO circuit distal to ECMO roller pump (providing blood flow) with the venous return line proximal. Effluent needs to be continuously measured with replacement fluid administered to maintain the net filtration balance. In practice. this configuration provides less accurate assessment of fluid balance and more nursing work lqAsr4 2011;7I 32B) CRRT machine can be spliced into the venous limb of ECMO circuit directly If a centrifugal ECMO pump is used, place the CRRT machine after the pump because of the risk of air entrapment. Return line of CRRT must be prior to oxygenator to trap air or clots (cow Cae 10149816751 High blood How used for ECMO an tause high pressure on CRRT circuit. Line pressure adaptor or placanent of CRRT access line * return line before the pump has been tried without air embolism event (ASAIOJ 2017;63:4G) Prognosis Adult patient survival to discharge in setting of ECMO AKl ranges from 25-45% with slightly better survival when respiratory failure is the indication iscLs R=¢»1'"y Report.112017) PostcardiotomyAKl requiring ECMO is alw high mortality x30.8 in AKlN stage 3, x12.6 in RIFLEF (Emf Caldiadwiu( So: 101&37:3341 Renal prognosis among aduk ECMO patients requiring RRT is poor.widi 74% continuing to requiring dialysis in one study for 2013:7.8:86) Among 200 pediatric ECMO 4 CRRT patienis.68 survived to discharge widi 18 requiring continued dialysis (mau on Core Med 201 111211s31 In pts who survive episode of AKl on ECMO, CKD is common: 12% have proteinuria and 19% have HTN at 8.2 yr. though eGFR >60 lqAs~ 2014910701 GASTROENTEROLOGY GASTROINTESTINAL SYMPTOMS inn iv Nephfd 1010;61480) 8 § 5 g 5 O Most common symptoms include nausea. vomiting.abdominal pain, constipadon.and diarrhea; divided into organic (causal lesion) and functional (no histopathologic) basis and influenced by psychological factors. visceral hypersensitivity and altered GI motility Prevalence: 70-79% of pos wl CKD and ESRD; trend toward increasing Sx w/ duration of renal failure: similar rare of sx in CKD. HD. and PD Etiology: uremia/ureinic retention molecules. comorbid anxiety.and depression Constipation Prevalence: 63% HD patients and 29% PD patients Etiology: l activity. L fiber. l liquid. phosphate binders. and other comorbidities Tx: la1ati\¢es.stool softeners.enemas;avoid magnesium and phosphate laxatives and enema Gastroparesis Prevalence: up to 36% of padenrszr prevalence vs general pop Etiology medications. DM; related no intraabdominal fluid in PD Clinical Sx: nausea. vomiting. abdominal pain. bloating. and weigh: loss Tx: meroclopramide and erythromycin: t dialysis doesnc help GASTROINTESTINAL BLEEDING (Nat Rev Ntpllld zo1 o.¢4ool Background Prevalence: (+) fecal occult -19% Causes: anglodysplasia. GI erosions. ulcers. divertlculosis. and mesenteric ischemia Upper GI Bleeding T Upper GI lesions in renal failure vs general pop Duodenal lesions in 61% of ESRD patients wl (+) fecal occult Angiodysplasia and GI erosions most common cause of upper bleeding; angiodysplasia -20-30% of episodes of upper GI bleeding and cause Y: of recurvenx episodes of upper GI bleeding in patients with ESRD lAM IM 19as;1uzsaal No higher risk of ulceration or H. Pylori T Acute upper GI bleeding w/ estimated frequency of 21 bleeds per 1.000 patient years: cause 3-7% of ESRD deaths: anticoagulation and andplatelets are not a risk factor Lower GI Bleeding Angiodysplasia and colonic neoplasms are common causes; angiodysplasia 20-30% of episodes of lower GI bleeding and are the m/c cause of recurrent lower GI bleeding diverticulosis and diverticulitis in PKD vs general pop Pancreatitis (Na: Rn Nepal 1010z614B01 Prevalence: T pancreatic abnormalities: T risk of acute pancveatitis, PD > HD • Etiology: similar causes general pop in HD. In PD: chronic exposure to icodextrin and high dextrosecontaining dialysate are risk factors Diagnosis: L clearance of pancreatic enzymes with renal failure -> look for amylase >3x ULN. lipase >30O kg/L (>60 IU/L). in PD distinguish from peritonitis: effluent amylase level >100 UIL: inhibitory effect of icodextrin on serum amylase levels Tx: no heparin w/ PD and HD to i risk of pancreatic hemorrhage; stop icodextrin If new Acute Mesenteric Ischemia imp Rev nepal z010.s24a01 Incidence: higher in HD: frequency 0.3-1.9%Ipt/yr; 14% of HD pts on autopsy Etiology: typically nonocclusive; intradialyzic hypotension w/ atherosclerosis Common Sx: abdominal pain. fever. guarding. leukocytosis. bloody diarrhea or rectal bleeding: can mimic peritonitis Dx: colonoscopy. CT with an opaque enema. surgery, vascular calcification on imaging Prevention: avoid excessive UF and normal fluid balance with acute abdominal pain Monaliry rates from 33-73% Encapsulating Peritoneal Sclerosis (no: no mam:20104:4410: ia 2010=172s041 Peritoneal thickening - encapsulation of the bowel and obstructive ileus in PD pts Incidence: up to 4% of PD pos: >15% in pvs on PD for >15 yr Risk factors: PD vintage. prolonged exposure to high glucose dialysate. repeated peritonitis, PD -> HD conversion, and no RRF Clinical Sx: early satiety, abdominal fullness. obstructive symptoms. UF failure Diagnosis: abdominal UIS and CT are not sensithfe or specilic.gold standard laparotomyl laparoscopy -> peritoneal thickening encases intestines Tx: tamoxifen: nesting peritoneum w/ switch to HD: morality rates 20-93%. T when on PD for >15 yr INFLAMMATORY Bowel. DisEAse (IBD) (Ioun»»c=wu¢2o1e.1azzs» Kidney Bx findings: gAN > interstitial nephritis > arrerionephnosclerosls > acute lobular injury > proliferative GN > AA amyloidosis lqAsn 101491551 Nephrolithiasis Prevalence: 12-28% in IBD: ileocolonic disease > leal disease (Crohns > UC):t in Ca Ox and UA stones Pathogenesis Alkali los: with diarrhea - metabolic acidosis -» aciduria - UA stones Low urine volume (especially with colon surgery) - CaOx and UA stones Bile Sal: malabsorption 4 enteric hyperoxaluria (>45 mg/d) (Ca binds to fa: and not oxalate) . oxalate reabsorbed - oxalate stones Less Oxafobacter formigenes - L intestinal oxalate catabolism -» oxalate stones Risk factors: bowel surgery. ongoing diarrhea Tx t liquid intake and citrate to alkalinize urine G lo m eru lo n ep h rit is T IgAN in IBD: mucosal inflammation and chronic immune stimulation -» dysregu lated IgA (qA$N 201419:165) Other GN: IgM nephropathy. membranous. mesangiocapillary, FSGS.AntiGBM disease GN T w/ intestinal disease activity T u b u lo in t erst it ial Nep h rit is ( T IN) 5ASA and sulfasalazine - CINlchronie interstitial fibrosis >TNFalpha ) Related to underlying disease vs Tx, seen in pediatric population wlo Tx 5ASA Associated TIN Prevalence; CKD in 1-7.I1.000; 10% of cases progress to ESRD Nonspecific sx, +I- malaise.fever, skin rash. eosinophilia; idiosyncratic often w/ 12 mo of saning Tx: d/c:szeroids improves function in 4085% if dx within 10 mo and only 1/3 if dx after 18 mo AA Amyloidosis lncidence:0.3-10.9% in CD and 0-0.7% in UC: dx 10 yr after IBD diagnosis Clinical Signs: m/c AA manifestation renal (9096): Proceinuria. nephrotic syndrome Tx: control underlying IBD Soolun PHOSPHATE BOWEL PREP (no: 0. ¢~¢phvu z01ae 4aoi Pathophysiology and Risk Factors T Serum [Po.] + volume depletion -» T intratubular [POW] -» precipitation and :issue deposition of CaP salts -i luminal obstruction + direct tubular epithelial injury Risk factors for AKl:Age, HTN, volume depletion. CKD,ACEi/ARB. unSAIDs. Diuretics Clinical Manifestation and Diagnosis 1-4% w/ oral sodium phosphate prep develop AKI U/A often bland sediment. modest proteinuria; Normocalcemic Renal BX: Interstitial pattern of CaP deposition won Kossa stain Prevention Avoid use in patient with CKD Use balanced electrolyte solutions containing polyethylene glycol for bowel prep proTon Purr INHIBITOR lx: Rep 1017;1297) Pathophysiology and Risk Factors AIN »AKI,also linked to CKD and ESRD I through unresolved AKI Duration of exposure up to 720 d uAs~2016:27;3153) Clinical Manifestation and Diagnosis AIN: idiosyncratic. not dosedependent. recurrence an occur wl 2nd exposure 2-3x TAKI: 1.2-1.8)< t CKD l x f ne p 1017929n UIA: +I- sterile pyuria, +I- prot/einuria with AIN; Renal Bx:AIN Prevention dlc if possible: consider H2 receptor blockers lranicidine or famotidine) SHONT BOWEL SYNDROHE E RouxenY Gastric Bypass.Jejunoileal bypass -\ Rapid intestinal transit -» fat malay sorption l, soluble Ca in the GI trac: and insoluble CaOx -> 6x T absorption of solu ble oxalate and oxaluria up Bacterial overgrovnh. fermentation of unabsorbed carbohydrates -> t Dlactate Risk factors: CKD and HTN are risk factors for AKl Clinical Manifestation and Diagnosis lntratubular deposition of CaOx crystals with giantcell reaction and tubular damage + interstitial inflammation and fibrosis; CaOx nephrolithiasis;AKI and CKD Dlactic acidosis: AMS. slurred speech, seizure.anion gap metabolic acidosis Prevention Consider restrictive procedures if CKD, eg. sleeve gastrectomy So 1:»1ur4 POLYSTYReNE (SPS) +I- SORBITOL Pathophysiology: cation exchange resin -4 inreszinal necrosis Clinical Manifestation and Diagnosis Ileal and colonic necrosis w/ bov.h oral and real SPS-sorbkol reported Incidence of bowel necrosis 0.4% Lon nehru z016;as:3a) Risk Factors Sorbitol containing sodium polystyrene CKD. recent surgery. ileus. opiate use. bowel disease and obsuucdon. use as enema Prevention Use laxatives without sorbitol or alternative potassium binding resins Electrolyte and AcidlBase Disorder In GI Diseases (qASN 2naa;310s1) (Normal stool:0.15 Ud Na 20-30 K 55-75 CI 15-25 HCO; 0) GI Scare F luid C omposition Electr olyte AcidlBase VomiringING suction 0-3 Ud. Hypotonic Na 20-100 K 10-15 ci 120- 160 HCO ; 0 1-3 Ud. Hypotonic Na 50-100 K 15-20 C l 50- 100 H co; 10 1-20 Ud. Hypotonic Na 40-140 K 15-40 CI 25-105 HCO x 20-75 1-5 Ud. Hypotonic Na 3080 K 15- 60 C l 120- 150 H co, <5 1-3 Ud, Hypotonic Na 70-150 K 15-80 CI 50- 150 Hco, Unknown 1-1.5 Ud Na 115-140 K s-1s C I 9 5 - 1 2 5 H co ; 3 0 Hypokalemia: renal loss Metabolic alkalosis None +I- Menbolic alkalosis Hyponaxremia Hypokalemia Menbolic acidosis Hypokalemia +I- Hyponanremia Metabolic alkalosis Hypokalemia Metabolic alkalosis Hyperkalemia w/ acidosis Metabolic acidosis: HCOa loss Metabolk alkalosis: Cl loss.vol depletion Inflammatory diarrhea Secretory diarrhea Congenital chloridorrh . Villous adenoma Ileostomy drainage (new) Ileostomry drainage (adapted) 0.5-1 Ud Na 40-90 K 5 C l 2 0 H co ; 1 5 - 3 0 HEPATOLOGY HEPATORENAL SYNDROME (HRS) A variety of causes ofAKl/CKD exist in pos wl cirrhosis/decompensated liver disease The approach to dilhrential diagnosis ofAKl and CKD can be challenging,as renal biopsy | is difficult to perform in cinhotic pts due to concerns about bleedingcoagulopaizhy Relying on complement testing or FEel is problematic due to the altered physiology of advanced cirrhosis Pathogenesis Release of vasoactive mediators by failing liver leading to splanchnic vasodilation and renal vasoconsMcdon: portal hypertension -» T nitric oxide production -» splanchnic arterial vasodilatation- hypotension -\ baroneceptor activation -» T renin.All.AIdo. NE,vasopressin renal vasoconstriction - impaired Na excretion - ascites impaired H20 excretion - hyponatremia -» l RBF - progressive renal dysfunction Precipitants: bacterial infection, GIB. SBR CKD. acute alcoholic hepatitis. large volume paracentesis with no albumin repletion (NE/M 199k341=403) Clinical Manifestation and Diagnosis Classification of Hepatorenal Syndrome uiqnuinligy 1996:1!164:2015a61'i86) T ype ( T iming) Findings Type I (<2 wk) Rapidly progressive renal failure. Doubling Scr. >2.5 mgldL UOP <400-500 mud. bland urinalysis. <S00 mglg prvoteinuria No response after 2 consecutive d of diuretic withdrawal and volume expansion with albumin Often precipitant factor(s) Absence of shock, infection. urinary obstruction. nephrotoxlns Type II (indolent) Steady and progressive impairment of renal function Related to diuretic resisianr ascites Bland urinalysis and <500 mg/g proteinuria Chronic kidney disease Differential Diagnosis: Other Common Causes of AKI in Cirrhosis Volume depletion: large volume paracentesis particularly if done without albumin replaae rent. bleeding, over diuresis. Responds quickly no holding diuretics and vokirne expansion ATN: prolonged prerenal azotemia.bleeding. shock. nephrotoxins. prolonged renal ischemia in HRS lA;Ko 19azz13szl. Expect muddy brown ;asts.AIso bile casts (below) Glomerular disease: hepatic IgA nephropathy. hep C associated MPGN. expect an T UPCR.active urine sediment Abdominal compartment syndrome: massive ascites. high bladder pressure. bland UA Prevention Use of albumin with large volume paracentesis (8 YL of ascites removed) Primary prophylaxis of SBP with riorfloxacin . HRS (Cusimenwuiqy 2007;13J81a1 SBP pls should receive concentrated albumin (1.5 g/kg on d 1.fdlowed by 1 g/kg on d 3), Albumin was a/w lower renal impairment (8.3 vs 30.6%) and mortality (16 vs 3S.4%) (On Gasunemerd 14¢f1°1°12013:11123) SBP pts should dlc nonselective B blocker <G¢=~»=~~=»-ww 2014;146:16B0) Management (I Hpazol 1016.647171 Hold diureticszvolume expansion with crystalloid solutions as initial fluid choice in volume depletion (10-20 mUkg) Albumin 1 Ykg (up to 100 g) on d 1 then 20-40 old + vasoconstrictors V a s oc ons c r i c r or s f or HRS T HRS r ever sal :han al bumi n onl y (23. 7 vs Teriipressin 15.2%) (6anuemelnlu¢y 201445015791 t Renal r ecover y dw ocl r eozi del mi dodr i ne (70.4 vs 28.6%) iuepuwllgy zo1s»z=s¢m No e pi ne phr i ne w / MAP god T 1 0 - 1 5 m m Hg Si mi l ar outcome w/ r er l i pr essi n U Hqmnl l Oc zre otide (1 0 0 2 0 0 ug SQ TID or IV in Octr eor i de i nhi bi t gl ucagon. spl anchnk 1011156:1Z93) $0 kg/ hr ) and Mi dodr i ne (7. 5 mg and 1 dose at 8hr inzervals up no is mgTlD) vasodi l ator Up to 3 d. can be aaempzed pr i or no nor epi nephr i ne Other:TlPS. liver transplant. hemodialysis as bridge co transplant Lu£Gj 20173811001 Re na l Re pl a c e m e nt The r a py Withhold RRT unless there is reversible component or a plan for liver transplantation l ocal Coe 201Z:16:R23) Q 30d and 1yr morality 73% and 90% U Cammi Hmm# z004:19:13649 1; 64mo mortality is 84% if not listed for liver =XP vs 39% if listed for liver txp (qAsr4 > 2019:1l&16) § Hemodialysis an T ICP worsening hepatic encephalopathy: CRRT preferred 8 BILE CAST NEPHROFATHY (Kl 2015;87:§09; WIG 20\6:12:27) 4 Can occur when bilirubin level >25 mg/dL Pathology demonstrates pigmented casts occluding tubular lumens, pigmented granular casts seen on urine sediment Renal manifestation: direct toxicity to :he nephron leading to elevated Scr levels. pig mented bile crystals on urine. natriuresis, and [32 microglobinuria Dx: T bilirubin.bland u/a.trace protein and AKI.jaundice.renaI biopsy Tx: directed at bilirubin reduction which may improve renal function 1 hemodialysis I gA NEPHROPATHY SECONDARY To LIVER DlSEASE (Sem al Nepal 109818271 loAn occurs in association with liver cirrhosis and portal HTN due to poor clearance of In/\ by hepatic Kupffer cells :hat circulate and deposit in the kidney. Most frequendy bu: not exclusive seen widl alcoholic liver disease. Renal manifeszadon: proteinuria. microscopic hematuria Renal biopsy mesangial proliferation with IgA deposits Tx: :r ear under l yi ng l i ver di sease ABDOMINAL COMPARTMENT SYNDROME UTHIMG 2000:48874. ;Acc 1013.61485) Definition: sustained intraabdominal pressure (IAP) >20 mmHg and abdominal perfu sion pressure (APP) = MAP - IAP <60 mmHg causing new organ dysfunction Epidemiology: occur in liver Lransplanrarion. massive ascites. abdominal surgeries. i nt r a pe r i t one a l bl e e d. pa nc r e a dds Renal manifesracions: renal vein compression - 1 venous resistance - impairs venous drainage -» progressive reduction in renal blood (low both -» t renin.All.AIdo. NE. vasopressin - l Un, and Uci -» T abdominal pressure -» renal dysfunction/ATN Dx: / intraabdominal pressure by bladder pressure: 1 mmHg = 1.36 cmH to Tx: reversible if recognized and decompression is done early (large volume paracen tesis. surgical decompression): Larger APP :60 mmHg ACETAMINOPHEN-INDUCED NEPHROTOXICITY (KID 2015:11:316) Renal injury in :he setting of acetaminophen toxicity Epidemiology: acetaminophen remains mlc cause of acute liver failure in the US.ATN can occur in up to 10% of patients. Renal Manifestations of Acetamlnophen Toxldty ATN: possible mechanisms include direct tubular damage from the wxrc metabolite Nacetylpbenzoquinoneimine Anion gap metabolic acidosis: 5oxoproline (pyrogiurzmic acid) (qAs~ z0 I4;9,191) DX clinical.biopsy often not needed Tx: supportive management of acetaminophen intoxication KIDNEY TRANSPLANTATION IN ENDSTAGE LIVER DISEASE Indications for Liver and Kidney Dual Organ Transplantation (C]A$V2017;12:84B) CKD: GFR <60 for >90 consecutive d and eGFR or CrCl $30 at or after registration on kidney waiting list or Dialysis (in the setting of ESRD) AKI: dialysis for 6 consecutive wk or eGFR or CrCI $25 for 6 consecutive wk Metabolic disease: aHUS from mutations factor H or factor I. hyperoxaluria.familial nonneuropathic systemic amyloidosis, mediylmalonic aciduria may be cured by dual organ transplant CKD must be verified by a nephrologisr Evaluation of MELDNa score (Acxo z015:zz=391) ELECTROLYTE AND ACID-BASE DISTURBANCES IN CHRONIC ALcoHoLUse DiSOROER MM 20 l7:377:1]6B) A variety of electrolyte disturbances occur in patients with chronic alcohol use Most severe w/ proteincalorie malnutrition and vitamin deficiency Hypophosphatemia (<Z.5 mgldL) Causes: phosphate deficient diet. deficits in body stores. increased urinary excretion. vitamin D deficiency Clinical presentation: skeletal muscle weakness.:t rhabdomyolysis. metabolic acidosis. hemolytic anemia. respiratory failure To: oral supplements preferred: 42-67 mmol phosphate over 6-9 hr not to exceed 90 mmol/d: IV 10-15 mmol. Check calcium and magnesium levels Hypumagnesemia (<2.0 mg/dL) Causes: intracellular shift from correction of acidosis.administration of glucose containing fluids leading to insulin release. loop dysfunction and acute pancreatitis Clinical presentation. neuromuscular irritability weakness.anorexia. nausea.tremors. arrhythmias. apathy T>c oral supplements preleried. slow oral replacement 2-8 tablets (S-7 mEq/tablets)/d. parental administration over 8-24 hr, to maintain Mg >1.0 mgldL in pts with arrhyth mias or neuromuscular irritability. Proper replacement of Mg paramount in die effec tive correction of hypokalemia and hypocalcemia deficiencies Hypocalcemia (<B.5 mgldL) (AmI 200e;JJs119a) Causes: intracellular shift from correction of acidosis and administration of glucose containing fluids leading to insulin release Clinical presentation: neuromuscular irritability.weakness, tremors. arrhythmias. Trousseau sign, Chvostek sign Tx: oral supplements include calcitriol 0.25-0.5 ug twice a day and oral calcium car bonate 1-4 old. IV calcium gluconate 1-2 g can be infused over 20 min Hypokalemia (<3.5 mErelL) (Dpi Akal<>iR¢»2001.2I;73) May occur in nearly 50% of hospitalized pts with alcoholuse disorders Causes: inadequate PO intake. GI and urinary losses. Coexisting hypomagnesemia can cause kaliuresis Clinical presentation: weakness, paralysis. arrhythmias Txcoial suspaision is pieierred; if N KCI is needed give 4080 mE/L as rare <20 mEqlhr; administer K before bicarbonate in acidemia disturbance Sodium Disturbances vcxo 201512z 376) Hyponatremia: Na <135 mEqIL commonly seen in about 17% in patients MM chronic alcoholuse disorders-causes: poor solute intake, hypovolemia, release of vasopressin - T urine osmolality -r free water clearance - hyponatremia Cllnlcal presentation: fatigue. nausea. dizziness. vomiting, headaches, confusion. coma Pseudohyponatremia: alcohol consumption is often associated with hypertriglyc eridemia. hence pseudohyponatremia may occur Beer potomania: vasopressinindependent mechanism of hyponatremia in individu als who drink large quantities of beer without adequate food intake Reset osmostat syndrome: abnormal osmoieceptcr activity due to defective cellular metabolism. Persistent hyponauemia Usom <100 mOsm/kg and natriuiesis >40 mmol/L Hyponatremia in Cirrhosis: dlt hemodynamic changes resulting in an impaired ability to excrete water.Vasodilatation~ activation of endogenous vasoconstrictors T ADH release -» L free water clearance -» hyponatremia Alcoholic Ketoacidosis Seen in malnourished pos w/ chronic alcoholism after 1-2 d of drinking cessation Present in 25% of pa admitted w/ alcoholrelated disorder Responds quickly to holding diuretics and volume expansion Presentadonzabdominal pain. NN tachycardia. HTN.: pancreatitis and volume depletion (*"/M¢4 1991:91:119) Dx:AG metabolic acidosis. due to ketoacids and fact acid. T Bhydroxybutyi-ate Tx: directed at correcting hemodynamic instability and ketogenic pmcess.Volurne expan sion with 5% dextrose in 0.9% NS. Repletion of coexisting electrolyte abnormalities. Lactic Acidosis Favors the conversion of pyruvate to lactate If lactate is >3 mmol/L; consider alternate diagnosis; sepsis or thiamine deficiency Tx: volume expansion with 5% dextrose in 0.9% NS Hyperchloremic NormalGap Metabolic Acidosis Lowered bicarbonate concentration due to loss of ketoacid salts in urine. which is counterbalanced by an equivalent plasma chloride HEPATITIS B VIRUS (HBV) HBV infection affects 2 billion worldwide. HBVrelazed renal disease is rare in :he US and Western Europe dl: the lower prevalence of chronic HBV infection and lower likelihood of childhood infection dl: widespread vaccination. HBVrelated glomerular diseases are mlc in endemic areas with high chronic carrier incidence (hepb.og) HBVAssociated Membranous Nephropathy (MN) Laboratory and Histology Findings of HBVAssociated MN ran nephml 201118459 H BVR e la t e d MN Pr imar y MN Younger onset age High occurrence of microscopic hematuria and renal failure, more nephrotic Severely low C (C3 and C4). Neg antiPLAR2 LM: more segmental glomerular damage. mesangal proliferation, rulzuloinrersddal elanor IF: polyclonal immunoglobulin and polytypic complement: Granular IgG, CO. and some IgM staining along :he GBM HBeAg in immune deposits IME/M 197%100:8144 EM: extensive poclocyte foot processes effacement Steady and progressive impairment of renal function Proteinuria 2 nephrocic syndrome. * hematuria. - antiFLAR2 More severe hyperlipidemia LM: thickened capillary wall and GBM IF: granular IgG, C3. and some IgM staining along the GBM EM: subepithelial immune deposits: extensive podocyte too: processes effacement Other Renal Manifestations MPGN: microscopic hematuria (dysmorphie RBC and RBC casts). 1 C4 2 1 C3. normal RF. proteinuria 2 nephrotic syndrome. i GFR and HTN PAN: necrotizing vasculitis of small and med vessels. T ESR. T CRR neg ANCA.Nw HBe antigenemia and high HBV replication. HBsAg/Ab detected in vessel wall wjriuu 1978;90:619). Can lead to renal infarct. variable degrees of i GFR and HTN. Less commonly IgA nephropathy (advanced liver disease) and FSGS Diagnosis and Workup Hepatitis serologies in all patients with CKD Kidney biopsy no confirm a glomerular process. For PAN. a diilerent tissue site may be biopsied for diagnosis (skin, nerve. muscle) or renal angiography Treatment and Immunosuppression Acute hepatitis B: supportive treatment Antivirals: tenofovir or entecavir. Lamivudine or adefovir monotherapy cause resistance Tacrolimus may have synergistic effect with entecavir (Am jYmnslR¢s 2016:B:1S9J) MN: 50% children spontaneously remit IFN l proteinuria (¢~~~=~»¢=f=¢=¢v 199s:10~rs40) Antivirals therapy 1 proteinuria, T HBeA,g clearance (lnbiidj Gmuwiwa 1010=1617701 immunosuppression is generally not recommended Mild PAN: antiviral therapy plus short course of immunosuppression (prednisone 0.7-1 mg/kg QD, tapered over 4-6 mo) and PLEX (2.5-4 Usession x6-10. QD or QOD over 2-3 wk) www anew 2004:s1¢4m Moderate-severe PAN: antiviral therapy and PLEX + prednisone + cyclophosphamide (oral or IV) (Anhnus Nlem 2001944661 ESRD About -1% of dialysis patients are seropositive for HBsAg Nosocomial transmission is a risk in HD pts. Machine segregation and proper cleaning and disinfection procedures among H8sAg + pos at HD is essential in the prevention in HBV incidence (Semn Oval Z00§;18:$2) Regular 2-3 mo monitoring of liver enzymes and albumin. liver US annually All pts with ESRD should receive HBV vaccination and have HBsAb titers monitored HBsAb + after vaccination is alw 1 allcause mortality in dialysis pts (man 2017135:814) Kidney Transplantation and HBV All HBVinfected pts should be further evaluated prior to transplantation in order to determine risk of reactivation (HBeAg. serum HBV DNA, and preferably a liver biopsy) HBsAg+ a/w 1 allograft survival. No change in patient survival (hnnspiant Proc 201s;47=94z1 There are cases of de novo HBV from receipt of kidney from infected donor Isolated HBcAb + pts are prophyfaxed with lamivudine posttxp to prevent HBV reactivation with IS irlunipimn hue Z007;3&3121; Can Open own Timsplml zoosn uses; HEPATITIS c VIRUS (HCV) HCV infection affects 2.8% of the worlds population. HCV infection is a risk factor for proteinuria and/or impaired renal function (cm,n n¢phml2012174101 incident CKD and prevalent CKD lqAs~101247¢$491 HCV infection HCV infection doubles :he risk of progression to ESRD (l4¢W"1l°IY 101541114951 HIWHCV confection: high risk of CKD progression wxo 2009254:431 HCV . the risk of morbidity and mortality of dialysis patients (/vuviH:94n 2007:14:697) Renal Manifestations Maced cryoglobulinemia syndrome (MCS): 30.1% of HCVinfected pts have circulating cry globulins (c¢=~~~~~~v 2016;1SQlS99). Symptomatic MCS anil -2% uwu Hoi: zoaa7 nasl Up to 90% of MCS is due to HCV MCS caused by type It or Ill cryoglobulinsz polyclonal IgG and monoclonal IgM or lg/l (type II) or polyclonal IgmllgA (type III).The IgM has RF activity against Fc portion of the polyclonal IgG. HCV RNA and antiHCV antibodies have been identified in cryoprecipitates (no/vi 1m.31s4ss) Renal manifestations d HCV MCS: nephritic syndrome. HTN.mar/ also halve NS or RPGN Symptoms: palpable purpura, arthralgias. neuropathy. weakness . C3. J. 1 C4. +RF and +cryocrit Biopsy: MPGN pattern on LM with mesangial and subendothelial proliferation. Pseudothrombi" are classic. IF positive for IgM, IgG.and C3. EM shows subendo thelial deposits w/ fingerprintlike substructure Mesangioprt>lillaatlve GN:deposits/proliferation in mesangium. Mild hematurh/proteinuria Membranous nephropathy proteinuria 1 nephrotic syndrome. normal C3/C4. normal RF PAN: 19% of HCVassociated vasculids; more severe. variable degrees of l GFR and HTN. Small. medium vessel disease (ANCA neg). T ESR, t CRP nufan Cannes 201\;63=4z7) IgA Nephropathy: can be seen in HCVinfected patients with cirrhosis Fibrillary and Immunoxaccoid GN: several cases reported. Hematuria/proteinurialrenal insufficiency with normal C3lC4 and RF US/AN 1990.9122441 FSGS: :he mlc lesion seen in pauiem: coinfected w/ HCV and HIV (a» Nfpniu 7.01327ns51 Renal manifestations may be underdiagnosed.autopsy studies and kidney biopsies taken at liver :xp show GN In 45-85% (Inter M44 1999237834 AM :m zcoe4144.1as> Diagnosis and Workup All patients evaluated for CKD be screened for HCV Evaluate for proteinuria. hematuria. HTN. eGFR. cryogtobulins. complements. RF Kidney biopsy recommended if there is hemarurialproteinuria Treatment of HCV Infection J CrCI.or GFR prior to HCV treatment IFN and RBV are renally eliminated. lFN associated with collapsing FSGS and drug induced lupus. RBV must be dosereduced for CKD, can cause hemolytic anemia. Because of lack of efficacy and because IFN/RBV so poorly tolerated. only 1% of HCVinfected dialysis patients ever received ueatlnent (Amy new#2o1ne405i Directacting antivivd therapies (DiAs) target the HCV viral proteins widl cure rates >95% DAys have many drug-drug interactions (an Phamacy Dew Div 2017:6,147] D AA T r eaunent O ptions for H C Y Drugs Use Comment Elbasvir - Grazoprevir (Zepatier°) Tesv.ed in Stage 4-5 CKD/ESRD Genotype: 1a. 1 b. 4 Ombiusvir 4 pariraprevir + ritonavir + dasabuvir ( Viekin PMI Sofosbuvir + simepnevir Tested in Stage 4-5 Cured 94% of patients with advanced CKDIdialysis s/e: headache, nausea, and fatigue acsunru Lance: 10 15886115371 sle: anemia, nausea. fatigue. diarrhea. headache. peripheral edema (C°""=°1°°l°l7101&1sa1s901 Genotype 1a and 1b sie: insomnia. photosensitivity (simeprevir) CKDIESRD Genotype 1b,add ribavirin for pos wl 1a Sofosbuvin-ledipasvir Genotype 1a . 1b, 4 sie: headache. fatigue. nausea Sofosbuvir-daclalasvir Genotype 1-3 sle: headache, fatigue. nausea Sofosbuvir-velpansvir Genotype 1-6 s/e: headache. fatigue. nausea Glecaprevir-pibrentasvir Genotype 1-6 Cured 9B% in advanced CKDIdialysis. No treatmentrelated SAEs (NEW10\773773144B) (M=vyf°=°) Treatment of Cryoglobulinemic Glomerulonephritis lnipfmalqy 2016;63;468: 1016:641473; Gm Gauunenlemd Hepalol 20I 7;15.5751 DAAs are safe and effective; curing HCV in >90% patients with MCS D»°iAs alone lead to nomnlizadon d complement. and reduction d cryo level in die majoiiny DAAs cause complete or partial remission of MCS in 70% :r ear ed with DiAs lmmunosupplession (Riuiximab, steroids 4- PLEX) should be added in patients w seven systemic vasculitis (pulmonary hemorrhage. CNS vasculitis. RPGN) or nephrodc syndrome Riruximab does no: reduce antiviral efficacy (Aida 2010416943) and does no: lead to heparins flares or increase in uremia (Andrus Rheum 20\2;64:843:2011:64:835) Management of Patients With HCV and Kidney Disease Presentation Treatment Asympwmatic hemaruria Normal kidney function Minimal proteinunia Suspected GN DAA therapy DAA therapy Subnephrodc proteinuria Suble renal function. eGFR >30 Suspected GN Subnephrotic proxelnuria Stable renal function. eGFR <30 Nephroxic syndrome Rapidly P , . ressive GN (5%) DAys recommended for eGFR <30 grazoprevir + elbasvir giecaprevir + pibrennsvir Biopsy -» Rizuximab steroids. DAAs Biopsy - PLEX. Ricuximab + Steroids. DAAS Rend Side Effects of DAAs Sofosbuvir is no: FDA approved for eGFR <30. however analysis of offlabel use sug gests reasonable safety and efficacy (um nu 2017137974) Sofosbuvir linked to increased rates ofAKl mum in patients with eGFR <45 compared to those with eGFR >45 (um I( zoo s;36¢a07) Lupuslike immune complex-mediated GN: sofosbuvirbased therapies (va up 201a111351 FSGS may occur wir.hlafter DAAs (H=»=~~=w zo11=e4¢¢se¢~.t;m z017;a76:z394) ESRD HD is a major risk factor for HCV. HCV prevalence is 10-13% in US dialysis patients HCV outbreaks are still reported in dialysis units due to breakdown in infection con. trot techniques iImJAfvfofl¢"= 2015:3B:471) HCV associated with 1 survival on dialysis uwrai Heps 2007:14.697) and T morbidity (t hospitalizations.T transfusions. 1 QOL) on dialysis lclAsn z011:1z:2s7) Liverrelated deaths t in HCV+ dialysis patients UASN 200n11:1a9s) Kidney Transplantation and HCV HCV is a/w T NODAT. T de novo glomerulopathya T chronic allograft nephropathy. 1 allograft survival, 1 patient survival postKT (An 200§:5:1452;200\;1:171) INbased therapies for HCV can provoke acute rejection trialupialuaiian 19B&45:401) No T acute rejection risk with DAAs (al 2018915601 Sofosbuvir/ledipasvir: 100% elective in KT recipient wid genotype 1/4 (Am IM 2017.16a109) Transplanting HCV positive kidneys (genotype 1 or 4) into HCV negative recipients followed by pos transplant elbasvir/grazoprevir treatment may be safe. and is under active investigation mum 2017:376:Z394) Timing of Kidney Transplantation HCV infection dramatically i waittime for KT WT 2010.1&12J81 Current recommendations are to treat HCV ;fig transplant in patients on dialysis waiting for a deceased donor transplant in centers utilizing HCV+ organs Timing ofTreatment of HCVInfected KT Candidates on HD In 201&9nss01 Favors Treating PreKT Excellent cure rates for all genotypes i liver disease progression nosocomial transmission in dialysis units 1 posttransplant de now GN 1 NODAT risk l Favors Treating PostKT Excellent cure rates for all genotypes Does no: T risk of rejection i KT waidist time T orpn utilization (i discard of HCV+ organs) l cost by shortening time on dialysis HEMATOLOGY Possible Hematologic Manifestations of Rend Conditions AKI + anemia: hemoglobin 1 hemosiderin pigment nephropathy from hemolysis. light chain cas: nephropathy wkh myeloma.TMA. lupus nephritis. undiagnosed CKD AKI + :hrombocyzopenia:TMA including anziphospholipid syndrome. HIT with renal artery ischemia, lupus nephritis. Hancavirus infection, leptospirosis AKI + eosinophilia:AIN. renal adieroemboli GN + eosinophilia: EGPA NS + eosinophiliz parasitic infection, et. Strongyloides szercoralis (Ra Rep 2018;3114) Potassium Charges in Hematologic Conditions K Hemolysis. tumor lysine syndrome Spurious: leukocytosis dl: cell fragility (a. Cn.mA¢w zuommosl. zhrombocywsis (./plasma) upco l99B;l1:116) LK Hemaropoiesisz GMCSE folaze, vitamin B11 Lrearment Spurious:AML (T cell uptake) HEMOGLOBIN AND ERYTHROPOIESIS Hb: heme (iron + porphyry, synthesized in BM and liver) + aglobin + Bglobin Anemia is defined as Hb <13 (d) and 12 (9) (WHO.KDlGOAnemin z012) Erythropoiesis:The Production of RBC at Bone Marrow Erythropoietin (EPO).a glycoprotein is produced in kidney peritubular Interstitial fibroblastlike cells (90%), liver and brain pericytes L local oxygen tension inactive HIF prolyl hydroxylases » Y HlF -» T EPO -» binds to EPO receptors on erythroid precursor cells -» T erythroooiesis T Loal oxygen tension active HIF prolyl hydroxylases 4 hydroxylated HIF binds to Von Hippel-Lindau (VHL) protein -> ubiqukinarion and degradation of HIF -» i eryzhropoiesis Roxadusrac HIF prolyl hydroxylase inhibitor T Hb in CKD ND and CKD SD (NE/M 2019;PMID lII400891 J13401 16). Need long :erm safety dana, eg. RCC risk A N £ t4 IA oF C K D Diagnosis of exclusion: rlo other cause of anemia T as GFR declines: 113 (6)-2/3 (Q) at eGFR 15 ln14Anes/vu- IM z001.\s2:1401; pAsru am MUM Open 2aa4;1011s01); l 3% in Hot allw t 7% death (ac zoouamssl Pathogenesis EPO deficiency and resistance: level is not low in CKD. bu: inappropriate Acute and chronic inflammation: t IL6. lL1.TNFa. INFy -» .L erythropoiesis Hepcidin: 1 by chronic inflammation. lL6 and L renal clearance of hepcidin Inhibitor of iron tiansporten ferroportin - functional iron deficiency Folate, vitamin Be nutritional deficiency 2 HD removal -w ineffective erythropoiesis and 4 survival of RBCs Blood loss during HD and phlebotomy Uremic bleeding: abnormal hemosrasis in CKD dl: defects in platelet function Aluminum toxicity: BM accumulation -» microcytic anemia Clinical Manifestations Dyspnea at vest/on exertion.fatigue. L QOL LVH (strongly alw hasphaization, morality) Hb variability is a/w morality (NDT 2010.2s=3701: Ayer 1011:5711661 Diagnosis and Monitoring J Hb quo mo in CKD3-S including pts on PD: qlmo in CKD5 pts on HD ./ Iron profile iron.TIBC.and ferritin (reflects storage) periodically rlo other causes of anemia:/ stool occult blood, res. MCV. platelet, monoclonal protein/ folate.vitamin Be if t MCV. J res. LDH. and hap to to rlo hemolytic anemia J PBS if accompanied by thrombocytopenia to rlo TMA Homocysteine and methylmalonic acid levels elevated in CKD (NE/M 1013;36B:149) IRON DEFICIENCY Goal and Strategy Consider iron initiation ifTsat $30% and ferrite $500 in CKD (KDIGO Anemia 2012) lV iron if ferrite 500-1.200 and Tsar $2596: T Hb and Tsar lows,/Asn z0o7;Is;97s) and L ESA requirement (DRIVEILjA$N 100941913121 iron sucrose high dose (400 mg monthly unless ferrite >700 orTsat 240%): l ESA dose, vs low dose 0400 mg monthly reactive to ferrite <200 or Tsat <20% (NE}M zo1nso44n Iro n Ad mi n i stra ti o n In nonCKD. multiple PO iron dose is inefficient dlt T hepcidin. QD or QOD dose is recommended (aim 201s¢126=1se1i. Hepcidin is further T in CKD: consider QD or QOD PO iron is generally ineffective in dialysis pts Ferric citrate (?0) approved for hyperphosphatemia in dialysis pts and IDA in nondialysis CKD. 1 IV iron and ESA requirement in dialysis pos UASN 101s1zs¢493: 2015;16:Z578). T Hb and Tsar in CKD (;As~ 1017;Z8:l851: um 201$;65:NB) IV Iron Agents and Dose Iron sucrose (Veno4er°) HD: 100 mg HD x10; PD: 300 mg on d 1 and 15. then 400 mg on d 28; Nondialysis pts: 200 mg x5 Sodium ferric gluconate (Ferrleci¢°INulecit°) Ferumoxyrol (Feraheme°) Iron dextran (INFeD°l DexFerrum°) Ferric carboxymaltose (lni=¢0f¢r°) Ferric pyre phosphate citrate UM¢c HD: 125 mg HD x8 510 mg xi then 510 mg in 3-8 d IV or IM:test dose require¢05 mL (25 mg).wait for 1 hr then 100mglhendose 1.000mgx1 or 100mgx 10 750 mg x 2 (at least 7 d apart) Added to dialysate: reduced ESA and IV iron dose (KA zo1s;sa11sn Side Effects of IV Iron Infection: bacteremia x2.5 in HD pos with Tsar 220 and ferritin z100 (an N»1ioo»s z004;3e;w90); injection is a/w high ferritin In z01 w61s4s1 No direct evidence of t mortality, CV event. iniecdon. and hospitalization at a systemic review and mereanalysis lqAs~ 2018;l3:4$7) Iron overload: deposition i injury in liven heart. pancreas. gonad. and skin. rare with iron administration. bu: possible Lem; Hmml0l Z01 l89:B7) L POW w/ ferric carboxymalrose (mc n4pn~4201J;l4=167):anaphylaxis wl iron dextrin ERYT HNO PO ISSIS ST IMUL AT INC AG ENT S ( ESA) BeneGr.s: J, RBC transfusion.l iron overload. improve QOL. LVH (qASN 2009445755) ESA Regimen and Dose Epoetin a (Epogen°. Procrit°) Epoetin aepbx (biosimiiar. Rencrit°) (qASN20181111200 Darbepoetin u (Annesp°): x3 longer half life than Epoetin u SCIIV r.iw; sur! with 50-100 uniulkg $GIV q1-4wk; in with 0.45 up/kg qwk or 0.75 Wks q2wk in dialysis pa and 0.45 kg/kg quo wk in nondiaiysis pts SCIIV q2-4wk: start with 0.6 uglkg q2wk gzip Methoxy polyethylene glycolepoetin p (Mircera") Peginesatide (Omontys') Withdrawn for anaphylaxis and death Epoetin and Darbepoetin Dose Conversion Total Weekly Weekly ToW Weekly Epoetin a (dw, units) Aranesp (pg) Epoetin a/Aranesp Mircera (ug) <2.499 6.25 <8.0001<40 120 quo or 60 q2wk 2.5004,999 12.5 5.000-10,999 25 8.000-16.000/4080 200 quo or 100 q2wk 11.000-17,999 40 18.000-33.999 60 >16.000l>80 360 quo or 180 q2wk 34.00089,999 100 290.000 200 Clinical Trials on ESA Use With Hb or HcrTarge¢ NHCT (U5) HD pos Mth CHF or CAD. Hot larger 42% vs 30%. 28% T death CHOIR (U$) CKD (eGFR 15-SO): Hb target 13.5 vs 11.3. 34% T death, MI. CHF. CVA (num zoos:ass:zcasl Pos:hoc: inability to reach target Hb and high doses of ESA were each a/w death. MLCHF. CVA (DOI the high Hb) (KI 10ae.14.7<m CKD (eGFR 15-]5): Hb urge: 13-15 vs 11-12.5 no difference in CV event: improved QOL; T HTN and headache (NE/M 2ccs.assz011l CKD (eGFR 20-60) widl T2DM; Hb target 13 vs rescue if <9 no difference in death or CV event and dash or ESRD; T nonfanl or nonfatal MI (NEW 199a=J39§84. K1 zmzewsl CREATE (Europe) TREAT (lnzernadonal) CVA (NEW zco9;sm01~>) ESA dose can be increased no avoid blood transfusion Recommendations (or Target Hb With ESA lxmcu Menu 1011) For nondialysis CKD w/ Hb <10. choice of starting ESA is individualized For ESRD. use ESA (D avoid Hb drop <9 Do not use ESA to keep Hb >11.5, but ok to individualize for QOL if pt aware of risk Do not use ESA to keep Hb >13 Side Effects Hypertension: endothelial cells express EPO receptor -> T endothelin - vasoconstriction T Mortality and/or tumor progression or recurrence in pts with breast, head/neck, lymphoid. cervical and non-small cell lung cancer (FDA): insufficient evidence on tumor response (Cachvne omuw Sys Re 1012;12:CD€03407: M Canal 1012;106:1149) Highdose ESA a.lw T Incidence of cancer diagnosis (NDT 1016;32:1047) AVFlAVG thrombosis (new 199e¢339:sa4l Pure red cell aplasia (dlt antiEPO Ab) with Epoedh a (Eprex°.available in Europe) ESA Resistance Iron deficiency (could be alw blood loss). infection. inflammation. inadequate dialysis Hyperparathyroidism (A}KD 10091518131 Can Nepluul zo1 l;16:99) INTRAVASCULAR HEMOLYSIS WW z01o.ss¢7aiz 2015:65:337) TMA: glomerular endothelial injury: MAHA (1 hapto,T LDH. reti.a>schis:ocytes) + thrombocytopenia (could be absent making it difficult to diagnose wlo renal biopsy) Free Hb from intravascular hemolysis is bound to haptoglobin: glomerulus cannot 6Mr Once haptoglobin is deplezed.flee Hb is filtered: reabsorbed by megalith-cubilin in PT AKI by direct heme effects (renal vasoconsuiction. mitochondrial toxicity, cell damaging enzyme activation) and/or intratubular Hb cast and tubular obstruction Hemosiderin: FT cell deposition (brown on PAS. Prussian blue Q) :AKI BLOOD TRANSFUSION Indication In CKD. should be determined by symptoms and clinical conditions (acute hemorrhage. unstable myocardial ischemia), not Hb threshold (KDIGO Anemia 2012) A restrictive threshold, Hb level 7 is recommended for hemodynamically stable hospinilized adult patients UAMA 1016;316:1025) Side Effects Volume overload. t K. transfusiontransmitted infection. immunologic sensitization on transplantation candidate. iron overload. transfusion reactions,TRALI Acute (<24 hr) and delayed (5-7 d) hemolytic transfusion reaction - AKI TX: IV fluid z loop diuretics according to volume status Transfusionassociated circulatory overload (Am 1m¢42013;116e29) Risk factors:CKD (x27). HE hemorrhagic shock:alw T mortality (x3.2).hospiulACU stay Leukocytereduced blood still increases sensitization (lvansplanmau 2011:93:41s) Iron overloadzchelators are required for conditions requiring chronic transfusion Defer.sirox:AKI and Fanconi syndrome are common (mm n¢inmi 1011:27:2115: nor 2011r1s:z37e app z014;167:434). reversible wl dlc w/o longterm kidney injury laps 2011;154:lB7). Dosedependent hypercalciuria (Bone 2016;8S:S5). CaOx stone (Ann Heinalnl 10139Z2s3).Avoid in renal dysfunction Deferoxamine:AKI from tubular injury l~or 200a;23:10s1i Defeniprone: no significant renal side elect; preferred in L GFR (n£)M 201B¢379:2140) SicxLe CELL DlssAse (SCD) Background Glu toVal substitution as 6th AA of 13globin chain of HbA -» sicided hemoglobin (HbS) SCD Genotypes: HbSS. HbSC.HbSBthalassemia, HbSD, HbSE. HbSO Sickle cell anemia = HbSS (homozygous): most common and severe form of SCD • Affects millions worldwide. ml in ancestry from subSahara Africa. Latin Americal Caribbean. Saudi Arabia. India. Italy. Greece, and Turkey Renal disease was attributed to cause of death in 16% ireduv lined Cancer 101J.w: 14e2) Pathogenesis (no: lu new# 2015;11:1611 HbS molecule is insoluble upon deoxygenation causing rigid deoxy HbS polymer in RBC Leads co hemolytic anemia.inflammation,vasoocclusion.endorgan damage, and death Renal vasculopathy -» medulla h/popefusion + cortex hyperperfusion + vasoconsulction C lin ica l M a n if e st a t io n s Crisis: vaseocclusive painful,aplastie, sequestration.and hemolytic Acute chest syndrome (ACS). pulmonary HTN. asthma, myocardial ischemia. HE CVA Renal disease develops in 5-40%;CKD -» ESRD in 4-12% immune 100594:3531 AKl during vaseocclusive episode <5%, a/w ACS and pulmonary HTN for 2010.152524> Glomerular hyperfiltration-» T GFR,albuminuria. protieinuria -o glomerulopathy. CKD Kidney biopsy: FSGS > MPGN >Tr4A (m<¢s¢»¢ 10\o1sa~ma1 AKI. ns and red cell aplasir parvovirus B19/FSGS (lance: 1995;346:475: app 2010=149=za9) Proximal tubule hyperfunction -» T uric acid and Cr secretion: Crbased equation overestimate GFR (pies One 201m»699z2),t PO. reabsorption -v hyperphosphacemia Dis ml tubule and collecting duct: metabolic acidosis.l K secretion (incomplete dRTA). enuresis, hyposthenuria 2/2 impaired urinary concentration (Max Uosm after 8 hr HxO de pri v a ti on 4 0 0 4 5 0 mO s ml k g) Interstitium: hematuria (common). papillary necrosis (painless gross hematuria). renal medullary carcinoma.chronic interstitial disease -» CKD Renal infarction: gross hematuria. pain,vomiting.fever. renlnmediated HTN, T LDH . Dx : c ontra s t CT. ra dio is otope s c a n.c ontra s t MRI Treatment Fluid for volume depletion: blood transfusions: may T level panel reactive antibody Potential l, proteinuria with ACEI (Caduvne Diabase Sys: Rev 2015:CD0091911 Hydroxyurea for 6 mo 1 albuminuria l;As~ 1D16:27:lB47) Blood transfusion with Hb goal 10 for stroke.TIA.acute chest syndrome and preop AlloHSCT: curativezsickle nephropathy is an indication iuianuiuiqua 2014598s111 Prognosis ESRD alw x2.8 1yr mortality we 1012:1s9n60) HD. high 5yr mortality (46336 vs 6.4%) from cardiac Ernest and septic shock low chance to get transplantation (MH 1016;174:1481 Kidney Transplantation Better survival than being on dialysis 6yr survival 70%. improved but lower than other disease (NDT 2013;2a=10391 Vascular occlusive crisis on graft (Human rauiuiqy 2011142110272 al 1008;74:1219) is possible Sickle Cell Trait (SCT) Heteitazygous sklde cell muiadon on one allele of [3globin chain of HbA. producing HbAS Albuminuria x1.86, CKD x1.57 up 1014:312:21151. ESRD x2.03 (IAS~2017=ua1a01 Microscopic hematuria. papillary necrosis HD patients with SCT requires higherdose ESA (;ASN 201411518191 Medullary Renal Cell Carcinoma in SCT Rare, aggressive form of RCC: almost exclusively in young SCT patient Hemawria, flank pain. palpable mass: survival 4-16 mo (IJiulily 100717a878) Dx: contrast CT or MRl;ultrasound can miss E RY THRO CY TO S I S Polycythemia: t red cell mass . Hb >1B.5 or packed cell volume >0.52 (6): Hb >16.5 or packed cell volume >0.48 (9) Clinical Manifestations: Hyperviscosity Chesdabdominal pain, myalgias. weakness. fatigue. HA. blurry vision, paresthesia Causes and Pathogenesis un] n¢pl\\I 2013:37:333) Excess EPO production (so 2018:347l6667) Tumors: renal cell carcinoma. hepatocellular carcinoma. hemangloblastoma Gastric carcinoma. parathyroid carcinoma. pheochromocytoma, uterine leiomyoma PKD (from epithelial lining of renal cysts). hepatitis (Am]Med$¢i 1984;287:56) Chronic hypoxia (via HIF1); OSA. R- L cardiac shunt. chronic pulmonary disease. high altitudes. carbon monoxide poisoning. smoking. hemoglobinopathies Polycythemia Vera: acquired ]AK2 V617F mutation in 95% RAAS Activation: posttransplantation. RAS. chronic severe hypotension Idiopathic: rare. treated with phlebotomy and close attention to iron levels PostTransplantation Erythroeytosis Incidence Hb >17 decreased from 18.7-8.1% (a»Tfaiaa4unr 2009:13;B00) Risk factors: male. simultaneous pancreas kidney transplantation Wr 20l0:1&9ll8). primary disease; PKD and GN Pathogenesis: muitifactorialzactivation of RAAS (angiotensin II type 1 receptor activation stimulates EPO mediated wydirvid prdiferadon).local renal hypoxia. hematopoietic growth factors. eg. IGF1. serum soluble stem cell factor. endogenous androgens Tx:ACEI or ARB. phlebotomy P N w ANTICOAGULATION Nonvalvular Atrial Fibrillation (NVAF) in ESRD Prevalence ofAF 10-15% in ESRD l;Asn 1a11:12;349) 1yr mortality in HD patients with AF is twofold that of HD pos in sinus rhythm AF risk scores have poor predictive value for stroke for the CKD/ESRD population and underestimate woke risk (qAs~ 1016;11:2085) Anticoagulation for NVAF in CKD and ESRD For eCrCI 30-50. noninferior efficacy in prevention of CVA and rhromboembolism and Iikeiy superior safety of DOAC compared [O warfarin lKolGo an Ileon 12019.39 11141 Convicting recommendations on anticoagulation in CKD 4-5.AHA supports for CHAR;DS;VASc score >2, KDIGO does not support Anticoagulants for NVAF yacc m01ws=zzn; we zmsn L:om lOl1;I2:1\76) Dr ugs ( Pr otein Bound) Warfarin (99%) ND( dialyzable Renal elimination <1% CYPZC9 metabolism to inactive meuboliue Dabigatran (35%) 50-65% dialyzable Renal elimination 80% of dose Rivaroxaban (95%) Not dialyzable 35% renal elimination CYP3A4/5 and CYPQ12 metabolize 50% no i1acdw¢e metabolite Apixaban ( and) 7% dialyzable 34)40% renal clearance CYP3A4/S mexabollsm to Inactive meobolire Comments CKD ND ESRD Overanricoagulazion: xi .2 in CKD and x 1.5 for ESRD UAS~ 2oo9:zwml INR variability in ESRD: <4S% of time Lherapeutic (Hedvl Z01l;l0]:8lB) CKD: L CVA (qAsn Z°\6:ll12W§) ESRD: 30% * major bleeding wlo 4 stoke/mortality (Gia:201$;149951) Stop in calciphn/Iaxis Major bleeding t 48% in ESRD lcauniun zoisnavzni HD WH 2015:\69:603) or idarucizumab WE!" 1017;377:431) can be used for reversal in bleeding No adjustment Avoid for primary prevention (KDIGO n 2011:sa571> CrCI 15-30: 75 ms BID CrCI <15: avoid Avoid Noninferior to warfarin in CrCl 230 (nocxE\=AF is;/u 201 \;Jus=seJl t 38% major bleeding in ESRD;no T wl 15 mg daily <a¢n»u- zomuwn) CrCI 15-50: 15 mg daily CrCI <15:avoid 15 mg daily: I 10 mg daily we 101516630 Nonlnferlor to warfarin in CrCI 225 (ARISIOTLE new N11:365!981) 1 bleeding dw warfarin (CJASN z01a \I:w1~n Guulludun 201B;138:1S19) Cr >1.5 and ZW lo or <60 kg 1.5 mg BID CrCI <15: avoid 5 mg BID: ! 2.5 mg BID we 2011a&1241) Prophylactic Anticoagulatiori in Membranous Nephropathy Pts with MN have increased risk of thrombosis (KVI PE.and DVT) No RCT addressed question of prophylactic as Risk faccor:Alb <2.8 a/w RR of 2.5 for thrombosis. x2 Increase for further 1 albumin of 1. Proteinuria does not correlate with risk (qAsn 201 z7431 Broad spectrum of clinical practice regarding prophylactic anticoagulation in MN Alc if low/intermediate bleeding risk and albumin <3 lx:10141as1i41z1 Alb <2.0 w/ prophylactic dose LMWH or lowdose aspirin;2.0-3.0 wl lowdose aspirin was successful (C1ASN 1014:9.47B) AnticoagulationRelated Nephropathy (WarfarinRelated Nephropathy) T Cr by >0.3 wlo other obvious etiology in the setting of INR >3.0 in case of warfarin 33% of CKD and 16.5% of noCKD had T Cr w[i 1 wk after INR >3;a/w 1yr (31.1 vs 18.9%) and 5yr mortality (42 vs 27%) and CKD progression In z0 n¢s4x1a1l 5/9 did no: regain baseline kidney function (Aixo 2609454111219 More common wu 8 wk of starting warfarin Gross or microscopic hemacuria air an anticoagulant overdose. minimal proteinuria Dx: r/o other causes of AKI (esp RPGN); Bx in Cr does not improve with moderation d anticoagulation; consider risks of bleeding and dwombaemboiism while off anticoagulation Bx: giomerular hemorrhage with RBCs and numerous occlusive RBC casts in tubules Dabigatran caused similar pathology in rat (NDT 10141n228) Rx: d/c or moderation of anticoagulation MONOCLONAL GAMMOPATHY (MG) Background Monoclonality: the abnormally high proportion of one type of light chain (LC) or heavy chain (HC) on serum/urine immunofixation or FLC assays M protein: monoclonal protein; B]P: urine M protein The type of monoclonal protein determines d1e type of kidney disease lnqm 19911324;1s451 lg do not cross GBM. LCs are filtered and reabsorbed by PT cubilin-megalin complex lgG3: strongest complement activation, highest (+) charge sFLC >ULN a/w t mortality (x1.45) and ESRD (x3.25) (mapan nu¢2017:<n:1671l CD19,CD20 (+) B cells differentiate into CD27. CD3B. CD138 (+) plasma cells HEMATOLOGIC CONDITIONS (lnncet Ondnl 2014:15:¢$38: NEW! 2006:J55:2765) Mu lt ip le Mye lo ma ( MM) Diagnosis: clonal BM plasma cells 210% or exuamedullaq plasmacytoma AND any of the myeloma deNning event: . Evidence of end organ damage char an be amibutM to MM: Ca > 11 or > 1 higher than :he ULN, Renal insuMciency (CrCI <40 or Cr >2, LCCN). Anemia (Hb <10) Bone (osteolwc lesion; MRI or CT more sensidw than plan radiography) Biomarkers: donal BM plasma cells 260 M 2100 or $0.01 or >1 focal lesions on MRI 17% of newly diagnosed MM had eGFR <30 I 201329134n Renal biopsy. 3/4 showed MG associated renal disease: LCCN 33%. MIDD 22% Amyloidosis 21% (Aim 2012:s9:7u) Tx: auwHSCT if eligible. Proreasome inhibitor (bone. aril ixammjh), immunomod ulamq drugs (knalidomide. pomalidomide). cytotoxic 4ens.and CS. Mmmmunnb and elowzumab J. disease progression or death (NW N1&3N:S\&1015;373:611) Morality in ESRD:86.7.41.4,and 34.4/100 personyr in the 1st 3 yr (WN mlmrwn Other Hematologic Conditions Causing MG Smoldering MM (SMM): serum M protein IgG or IgA 23 gldL or BJP >S00 mg/24 hr and/or clonal BM plasma cells 104M wlo myeloma defining events or amyloidosis Waldenstmm Macroglobulinemia (WM): serum monoclonal IgM and 210% BM | lymphoplasmacytic infiltrate: hyperviscosity syndrome; almost always B cell (CD 20+) Clinical manifesmdon of IgM subtype of lymphoplasmacytic lymphoma (LPL) Renal biopsyQAL Amyloldosis > IgM deposition/cryoglobulinemia > lymphoma infil uation > LCCN, MIDD up 2016;175:623:c1As~ 101841311037) Chronic lymphocytic leukemia (CLL): MPGN (20%) > interstitial infiltrate (12%) >TMA (12%) > MCD (10%) innmttalqea z01s;1001 1s0) Monoclonal B cell iymphocytosis (MBL): B lymphocytes <S.000l1IL w/o Iymphadenopathy MG of Undetermined Signillcance (MGUS) Dellnition: serum M protein <3 gldL.clonaI BM plasma cells <10%. no elo CRAB or amyloid that can be attributed to the plasma cell proliferative disorder 1-2% of adults: more common in older age.female.African American Progression to MM or lymphoid disorder -1%/yr (18% at 20 yr. 28% at 30 yr) Risk factors (RF): M protein >1.5 g/dL. abnormal FLC ratio. Progression in IgM/non IgM MGUS at 20 yr: 5s/30% (2 RF),41/20% (1 RF), 19/7% (no RF) (nom201B:37B1241) ilu pts wid\ IgM MGUS. M protein >1.5 my dL or abnormal FLC ratio wl labs annually flu pts with nonIgM MGUS. M protein <1.5 mgdL and normal FLC wl history and PIE MG of Renal Significance (MGRS) ll1(mG Consensus Row Nor Rev n¢pnmI 201<r1s¢4s) Any B cell or plasma cell clonal lymphoprolilleiation wid\ both of the following diaracterlWcc One or more kidney lesions that are related to the produced monoclonal lg The underlying B cell or plasma cell clone does not fuse tumor complications or meet any hematologic criteria for specific dweraplr: including SMM, smoldering WM. MBL Frequently more than 1 type of renal diseases coexist MG of Clinical Significance (MGCS) uuw4201&m:14n) MG with related organ damage (kidney. nervous system. or skin) that would otherwise mee: criteria for MGUS DIAGNOSIS AND Woaxuv t Ca in MM: Igs have Cobinding sire: may T :oral Ca:./ iCe T Globulin (total protein _ albumin). Low complement in PGNNlD,immunotactoid AG: L In T IgG (+ charge), t in ' IgA ( charge) (clAw 101l;6:1814} Urine albumin to protein ratio (UAPR) <25% in LCCN. Sensitivity 0.98. specificity 0.94 vs >25% in amyloidosis and MIDD (qAs~ 1012:7:1964) Urine dipstick: hematuria and proteinuria. Nor sensitive to BJR 3% Sulfosalicylic acid precipitation: detects albumin. BjR and lysozyme SPEP: M protein on 1>> Ll Low level Ann be missed. 1 fraction in LC disuse is common. SIFE: more sensitive than SPER quantitative FLC: reference i</) ratio varies according to renal function. NonCKD (0.26-1.65). CKD (0.37-3.1). HD (0.69-2.57), PD (032-2.35) (cjAsn z00a;311ea4l UPEPIUIFE detects BJP Cryoglobulin, RE C3, C4: HCV. SSA, SSB (Si6grens) RF:ab against the IgG Fc portion: can be (+) in MG Fat pad biopsy or aspiration: used for systemic amyloid diagnosis and typing. Fat pad or other organ amyloid - proteinuria >0.5 g/d w/o other explanation (DM or hypertension) is diagnostic for renal amyloidosis WW 2005;793191. Underutilized and can obviate the need for invasive kidney biopsy (Mn ma z011:49s4s). BM biopsy: evaluate lymphocyte or plasma cell clone. May detect amyloid. Kidney biopsy: frequently only way to prove MG is responsible for kidney disease Mass spectroscopy types amyloid from formalinfixed paraffinembedded specimen Unnecasary if diagnosed as AL amyloid. MM.WM. or CLL and in AKI wl FLC >1S0 mg/dL AL amyloidosis a/w factor X deficiency /factor X before biopsy (Biased 2001197218851 Pseudoabnormalities in lab: 1 Na. CI.Alb. BUN: T Ca: L or f Cr. CQ, po. (xi 20123116031 LIGIIT CHAIN CAST NEVHNOrATHY (LCCN) Tamm-Horsfall glycoprotein: synthesized at TAL. binds to LC to form LC cas: aka myeloma kidney:>95% has MM, rarely CLL and B cell lymphocytosis Urine dipstick (sensitive co albumin) protein discrepancy Urine albumin/protein ratio: usually <10%,<25% sensitive and specific (qAsn 1011;7;19641 Not otherwise unexplained AKI with LC >150 mg/dL is diagnostic for LCCN: consider kidney biopsy if <50 mgldL (Lam Omni 1014:15:eS38: Not no nqmmi 20111B:43) Kidney biopsy: eosinophilic distal tubular easts with IF staining of associated Ig chain. Local inflammation with giant cells Tx: MM treatment. IV fluid: l LC concentration and correct hypercalcemia PLEX: remove LC: didnt improve outcome (Ann :m z00s.143=177) High cutoff HD: remove LC (c/i$~ zoom.74s);didnt ' HD dependence up z017=J1&20991. Unavailable in the US. L FLC is linearly a/w renal recovery:60% reduction by day 21 alw 80% renal function recovery Pt survival is al renal recovery ()ASN 201l.Z2:11291. Survival on dialysis: 16 mo; 28.9 mo in AL amyloidosis, 18.4 mo in MIDD (qASN 20161\1A31) LIGHT CHAIN PROXir4AL TUBULOPATHY (LCPT) UASN 2016;2711555) aka LC Fanconi syndrome; mlc cause of adult Fanconi; Fanconi in 38% MM 25%. smoldering myeloma 15%. MGRS 53%. rarely B cell lymphoma or CLL Biopsy: crystalline or noncrystalline inclusions of LC in proximal tubular cells CRYSTALGLOBULINEMIA (ISSN 2015:16:515) Monoelonal crystals in vessels or glomeruli; kidney infarction Painful purpuric nonblanching rash (occlusive vasculoparhy), corneal. BM deposition LM: inrracapillary crystals; IF: monoclonal Ig: EM: parallel linear array MONOCLONAL Im4ur4ocLosuun Dsposmon DisEAss (MIDD) LC >> LHC, HC. I( > J.; M protein 90-97%, MM 34-59% (qAsn zo1r7.zJ1;el¢¢az019.ms1¢) NS. CKD; heart. liver involvement: low complement level in HCDD LM: nodular mesangial sclerosis. MPGN IF: diffuse linear GBM,TBM.and mesangial monoclonal LC or HC EM: unorganized (nonfibrillary).finely granular powderylpuncure EDD Tx: borzezomibbased regimen. melphalanconditioned autoHSCT (Aland 2015;126:2a0$) Hematologic response was alw good renal out:ome Txp: no recurrence with sustained remission (Bland 2015:126;2805) Prognosis: pt and renal survival MIDD > MIDD + LCCN - LCCN; 33% ESRD. 29% death after 4 yr up* lyvnghamu 2015;563357) PGNMID (1ASN 20o9;zoz0ss) Proliferative GN w/ monoclonal immunoglobulin depositszglomerular injury related to monoclonal Ig deposition that cannot be assigned to any other conditions lgG3 >> G1 > G2 >> G4. s: > 1.: IgA In z0 n:91no). IgM (WM) who 201$;66:756) Monoclonal protein in -3094: BM clone -3098: hematologic malignancy $-3574; can develop during f/u; 22% progressed to ESRD LM/IF: endocapillary or mesangial proliferative GN. MPGN (lgG3) > MN (lgGl) (QASN 2011:6:1A09>. EM: mesangial and subendothelial deposits Tx: clonedirected therapy: B cell lymphoma treatment (eg. RTX + prednisone) for B cell clone. MM treatment (eg, CyBorD) for plasma cell clone (Vu 2018;94:1991 Transplantation Monoclonal protein (+) 4/11 of recurnm MPGN vs 2/15 nonrecurrence (no 20 m77:n1) Recur w/ same IgG deposition w/ native PGNMID wlo monoclonal protein (cum wnmzzl Recurrence caused graft failure in 11/25 (44%) during7yr flu (KA 2018:94159) Filgrasdm (GCSF)induced crescenzic RPGN (}ASN z016227:1911) RENAL LESIONS WITHOUT MONOCLONAL IMMUNOGLOBULIN DEPOSITION TMA with MG (au 201791690 Direct or indirect endothelial injury by monoclonal protein 13.7% ofT MA patients had MG: 21% in z 50 y/o.x5 50% progressed no ESRD vs 33% TMA lo MG coG with MG (awe 1011.129 14m IgG x (71%) > IgG 7. (2278); MGRS (60%).smoldering MM (3094). symptomatic MM (4%) Renal survival was worse in C3G 250 lo w/ MG than w/o MG Bortezomibbased regimen induced hematologic response:A/w better renal outcome GENERAL MANAGEMENT Fluid: imporvznt in T Ca.volume depletion. and LC cast nephropathy BP: /orthoslasis in AL amyloidosis. Avoid overdiuresis and ablockers. Consider midodrine. RAAS blockade: little evidence supports its use for albuminuria Clonedirecred therapy may improve renal prognosis. No RCI AutoHSCT in eligible PLS Nauru 2018:122:3583). Plasma Cell Directed Treatments Cyclophospharnide Requires adjustment based on renal function s/e: hemorrhagic cysnius (give with MESNA). SIADH No renal dosing, require HZV prophylaxis Bortezomib (V) s/e:TMA Mph AKI wH n16=91:EJ4s). peripheral neuropathy. thrombocytopenia CrCI >50: 25 mg qd 30-50: 10 mg qd <30: 15 mg q48h ESRD: 5 mg qd after HD Lenalidomide (R) sle: birdl defects. rash. myelosuppnession Dexamethasone (D) Melphalan No renal dosing High dose: 100-200 mg/mzaszandard dose: 10 mg/m' CrCI 10-50: 75% <10: 5096: HD: administer after HD PD: 50% CRRT:75% HEMATOPOIETIC STEM CELL TRANSPLANTATION Background Hematopoietic stem cell uansplanmtion (HSCT) is classified into autologous HSCT (autoHSCT) and allogenic HSCT (altoHSCT) by donor type All autoHSCT requires myeloabladve regimen to replace abnormal replace hemato poietic system. AlloHSCT can be done with myeloabladye (causing pancytopenia). reduced intensity.or nonmyeloablative (lymphopenia w/o significant cytopenia) regimen AKI Mortality of pa with AKI requiring dialysis 83% In 2o0s;s7:1wa) AKI and mortality decreasing; Cr x2 50 -» 33%, x3 18 -» 10%. dialysis 8 - 5% from reduced intensity of conditioning regimen. reduced hepatic SOS. seven GVHD. iniecdon. amphotericin use (num 20i0;363:2091) CKD CKD3-5 after myeloablanive altoHSCT 17%: ESRD 4% (nor z01o,zs 278) Risk factors: hlo AKI. GVHD. 245 ylo. baseline eGFR <90. HTN. highdose TBI In£iM 1016:374:2}56) CKD risk was similar in reducedintensity and myeloablazhre doHSCT (as/wr 2UOS.14.6$8) All renal biopsy: MN (36%) >TMA (21%) > MCD (12%) lAvA»~¢¢ Pau1¢120I4:2I:330) Types of HSCT and Associated Complications Indications AKI sos Causes of AKI Typespecific causes of AKI Causes of CKD TAutologous Myeloablative Allogenic Myeloablative Allogenic Nonmyeloablative MM.AL amyloidosis. WM.AML. lymphoma + 4+ Leukemia. lymphoma. MDS. aplasdc anemia. sickle cell anemia 44+ 4+ +44 Hyporension, volume depletion. sepsis.TLS,TATMA. drugs TAutologous GVHD CNI zoxidcy, acuze GVHD Chronic GVHD. MN. CNI :oxiciry TAutologous GVHD (One Type of Engraftment Syndrome) Within days of neutrophil engraftment in autoHSCT. usually 8-20 d after HSCT Fever. rash. pulmonary edema, weight gain. capillary leak Biopsy of involved organ: skin. colon: mononuclear cell infiltrates AKI Is common; 28% required dialysis. 72% recovered (Am) Hfnwwl 2011;87=511 Tx: IV corticosteroid (BSMT 2015:11:2061) SinusoioAL OBSTRUCTION SYNDROME (SOS)NENOOCCLUSIVE DlssAse Risk factors: myeloablation (busulfan. cyclophosphamide. and TBI). preexisting liver disease. age. specific treatment (eg. gemtuzumab. ozogamicin) 4aam12016124001 Less common with less intensity conditioning Pathopmiology: thrombosis. sinusoidal obstruction. portal HTN. microvascular intrahepatic portosystemic shunting Clinical presentation: hepatorenal syndrome (t bilirubin, ASK ALT. PI 1 urine sodium), hepatomegaly. fluid retention. weight gain Doppler U/S: reversal of portal vein How Tx: defibrotide TransplantAssociated Thrombotic Microangiopathy (TATMA) lamr 201s:s::119) 30-35% of alloHscT;45% of all biopsy proven TATMA was autoHSCT mum iiiuiii z014,z 1.as01. a/w high morality. Risk factors: GVHD. HLA mismatch. highdose TBI. CNI. genetic (Blow 201s=117=9891 Clinical manifestation:AKI. proteinuria. edema. HTN Arteriolar C4d deposition (Transpkniauan 20131962zm TX: conservative. eculizumab (riunqiimpow so 2016Z54:1B1). rltuximab Other Causes of Renal Dysfunction Recurrent hematologic disease associated (amyloidosis. MIDD). lymphoma infiltration Pigment nephropathy from ABO incompatible HSCT; BKV nephropathy (nor 2013:ze:6z0) Nephrotic Syndrome After AlloHSCT lumr z016=n297s> MN (6$.S%): PLAZR Ab (+) is rare > MCD (19%) > FSGS (7.7%) 87% was a/w acute or chronic GVHD:often a/w immunosuppression reduction Tx. reinidation of immunosuppression. rituximab Renal Transplantation Kidney from HSCT donor or combined txp (NEW 20G8;358:362) may allow iS dlc ONCOLOGY Tur4oR Lvsis SvnonomE (TLS) Background and Pathogenesis Spontaneous vs induced wmor cell lysine by cytotoxic therapy (chemodlelapy;Ab therapy or radiotherapy)-> Release of intracellular electrolytes (K and Phos) and nuclei acid Nucleic acid is metabolized as below by xanzhine oxidase (XO) and orate oxidase (UO) Water solubilityc xamhine < uric acid < allantoin UA: precipitation in the distal par! of the renal tubules in acidic urine (acute UA nephropathy), renal vasoconstriction Hyperphosphatemia: calcium phosphate (CaP) deposition in the renal tubules (alw hypocalcemia); the deposition starts when Ca x P >60 mg*1aL' Xanthinuria: XOl used for TLS prophylaxis can cause accumulation of xanthippe -> Xanthine stone. Xandiine nephropathy (cum, an 19B1:412273) CairoBishop Definition ofTLS we 2004.1z7s) Laboratory TlS:2 or more lab changes within 3 d before or 7 d after cytotoxic therapy UA 28: K 26; P a4.S: Ca 57 or any change 225% ClinicaITLS: laboratory TLS +AKl. cardiac arrhythmlalsudden death or a seizure Risk Assessment U a- anal 2uue.zs:z1s7l Risk Factors of TLS PatientRelated TumorRelated Precreaunenr UA >7.5 High tumor cell proliferation rate CKD Chemosensilivizy of :he malignancy Volume depletion Acidic urine Solid tumors: rare: mainly when tumor diameter is >10 cm Hematologic WBC >50K:Aggressive NHL;ALL: Burkitt lymphoma/leukemia Veneroclax for CLL; Obinutuzurnab for diffuse large Bcell lymphoma: Dinacidib/Alvccidib for ALL or AML TLS Risk Stratification lqu mo,\4ms1s) High risk (>5%) Inter mediate r isk ( 1- 594) Prophylaxis IV fluid v rasburicase IV fluid AML WBC > 100K Burkina lymphomailleukemia. lymphoblastic lymphoma Burkitt leukemia Stage IIL IV lymphoma LDH 2 2X ULN WBC 25-100K LDH 2 ZX ULN Early stage lymphoma + LDH <2X ULN ALL WBC > 100K LDH 2 2X ULN CLL Adult Ttell lymphoma. DLBCL. peripheral Tcell, transformed or mantle cell lymphoma Aduk bulky, LDH > ULN Child $Ug€ 11IIN LDH z 2X ULN Others Intermediate risk renal dysfunction.T UA. K or P04 allcpurinol All others Fludarabine. rituximab WBC > 50K Adult nonbulky LDH > ULN Child stage lllllv. LDH < 2X ULN Child anapestic large cell lymphoma lllllv Lymphoma I leukemia + renal dysfunction Some solid tumors* Treatment IV fluid to maintain UOP 80 to 100 mum': lurosemide only for hypervolemia Urinary alkalinization no longer muzindy recommended! Ca? deposidon.Could consider initially in padenzs with lvypenlricemia w/o hyperphosphatemia (et. spontaneous TLC) Blockers of UA formation through XO inhibition: allopurinol or Febuxosran Used mainly when UA is still <8.Allopurinol 100 mg/m' qBhr. Metabolism of UA Lo allantoin (water soluble) using exogenous UO: rasburicase 0.2 mg/kg once daily for 5-7 d or 3 mg daily (/G6PD activity) Sle of rasburiase anaphylaxis widl repeated courses. mezhemaglobinemia in G6PD def RRT if Ca x P 270 mg'/dL2;AKl with elecuolyres imbalances or hypervolemia CHEMOTHERAPY Background In oncology patients. GFR estimation using BSAadjusted CKDEPI is accurate for medication dosage. MDRD tends to underestimate GFR (j au- ami 2017;35:2798) Nephrotoxicity is potentiated with: volume depledon.usage of other nephrotoxic agents. obstructive uropathy 5yr incidence of AKI in cancer patients receiving systemic therapy: multiple myeloma (2694). bladder (1996). leukemia (15.4%) u~c» zo18 m1o 304231601 Cisplatin Mechanisms: organic cation uansponer2 (OCT2) mediated cellular toxicity primarily of :he $3 seg of the proximal tubule.vasocons:ric¢ion, proinflammatory effect Progressive AKI. hypomagnesemia, salt wasting, Fanconilike syndrome.TMA (when combined with neomycin or gemcitabine). anemia secondary [O epo deficiency AKI is dose dependent. nonoliguric 4, Dose: 25% for CrCl 46-60: 50% for CrCI 31-45 (Can¢efTnalRev 1995;21;J3) Agents to decrease toxicity: (1) amifosdne (organic thiophosphate): concerns about possible interference with :he antitumor efficacy of cisplatin: (2) sodium lzhiosulfate for prevention of systemic toxicity of intraperitoneal cisplatin I f o s f a mi d e The metabolite chloroaceizldehyde is directly toxic to the tubular cells The metabolite atrolein causes hemorrhagic cysUtis (ifosfamide and cyclophosphamide) Partial or complete pRTA/Fanconi: hypophosphatemia.glucosuria. bicarbonaturia. aminoaciduria. tubular proteinuria (T beta2microglobulin excretion). K wasting d RTA. n e p h ro g e n ic DI The cumulative dose (>60 x/m'). nephrectomy and concomiuint dspladn T nephrotoxicity Me t h o t r e xa t e ( MT X) Precipitate in acidic urine for high doses MTX: transient afferent arteriolar constriction Preventlon:50% of dose in CrCI 10-50 and avoid in CrCI <10; avoid drugs inhibiting MTX clearance via OAT1/3: unSAIDs. PCN. salicylates, probenecid.gem8brozil.TMPSMZ, N fluid: Urinary alkalinization (target pH 27) before starting infusions; leucovorin Leucovorin: reduced form of folic acid; competitive inhibitor of MTX Leucoworln Dose Based on Serial Serum Methotrexate Levels and AKI Condi ti on Normal elimination MT X L e v e l Al te r Adm i ni s tr a ti on 101ll*1 as 24 hr.1 pM at 48 hn and <01 lIM as 72 hr Le uc ov orin Dos e PO. IM. IV: 15 mg q6h x10 beginning 24 hr after die sun of infusion Delayed late elimination >0.2 l,iM at 72 hr and >0.05 pM as 96 hr Continue 15 mg (oral, IM or IV) q6h until <0.05 pM Delayed early elimination and/ or AKI 250 uM at 24 hr. or 25 pM as 48 hr. or a doubling of serum creatinine at 24 hr 150 mg N q3h until <1 .uM.then 15 mg q3h until <0.05 l,IM Glucarpidase metabolizes folic acid: used in patients with AKI leading to delayed MTX elimination co decrease systemic toxicity HD: limited utility due to the high volume of distribution of MTX leading to rebound Me di c a ti on Pa thoge nesis and Clinical P re s e nta tion . P re v e ntion a nd The ra py P la tinum CarboplaUn Less AKIIATN than Cisplatin . Mg: Sal: wasting Calves formula* to estimate Cisplatin AKI. RTA, L Mg TMA (combination with IV fluid, lower dose. amifostine Oxalipladn Rare ATN No adjustment for GFR >20 Cyclophosphamide SIADH with high IV dose Hemorrhagic cysrkis Dose reduction far CKD IV fluid. MESNA Nitrosoureas (carmustine. Iomustine, Chronic interstitial nephritis (aikylalion of tubular cell proteins - Glomerular sclerosis. interstitial fibrosis) Delayed noxicizy (onset several mo or yr :her stopping :he medication) Forced diuresis Slreproxocin Chronic inzerszicial nephritis Proteinuria (65-75%) Proximal tubular damage Forced diuresis Ifosfamide pRTA, dRTA Nephrogenic DI (polyuria) Hemorrhagic cysriiis IV fluid, Nacerykysreine. MESNA Toxicity can be delayed the dose neomycin or gemciubine) Alk y la ting Age nts semusline) O the rs Minomycin C Mezhozrexare (h ig h d o se 1 -1 5 a m') TM/N cumulative dose dependent. delayed clinical onset (few mo) Inkarubular deposition of crystals SIADH Gerncitabine Cumulative dose dependent TMA IV fluid Urine alkzlinization (keep urine pH 27.0) Cabazicaxel AKI . hemor r hagi c cysti ti s Lenal i domi de AI N I nter fer on Pr otei nur i a (MCD, FSGS) TMA ( m os dy w i t h CML) . ATN Al l tr ans r eti noi c aci d Capi l l ar y l eak wl edema. ( ATRA) . I L2 wei gh: gai n and AKI . Aka "di ffer enl i adon syndr ome" I n ATRA BIOLOGIC AGENTS Bevacizumab Risk factors for sle: CKD. renal cell carcinoma Usually mild asymptomatic proteinuria; only 2-6% develops nephrodc range proteinurla Histology<TMA: local binding of :he podocyteproduced VEGF leading to aVEGFR medicated glomerular endothelial damage (NEW 100e;3$*r205) HTN wfl days of starting the dierapln the mechanism of HTN seems to be independent from the proteinuria (T peripheral resistance; i Na excretion: .L NO production; 1 Endothelin1) Rapidly of the HTN onset depend on the potency of the VEGF inhibitor HTN is a surrogate for anticancer efficacy TMA rare. reversible in most cases after stopping the drug. Eculizumab is a potential therapy for persistent TMA Medication VEGF Pathway Blockers AntlVEGE bevacizumab. afiibertept Tyrosine kinase inhibitors: axitinib. pazopanib, sorafenib, sunitinib An ti EGFR Cetuximab. panitumumab. necitumumab, matuzumab Others Rituximb (antiCD20) Bosutinib Crrzotinib Ibnninlb Vemurafenib and dabrafenib Ch¢CIQQint inhibitors: PD1 (pembrolizumab. nivolumab) PDL1 (atezolizumab. avelumab. duryalumab) AntiCTLA4 (ipilimumab.* tremelimumab) Epacadostat PathogeneslslClinic.l Presentation Prevention and Therapy Proteinuria. ns. HTN.TMA. reversible posterior leukoencephalopathy (RPLS) AKI with sunitinib or sorafenib Proleinuria monitoring Hold for U,..,. >2 old Discontinue for NS Hypomagnesemia dl: wasting. (sunnite of better outcome) - i Ca. K Reversible after stopping the therapy TLS.PRES AKI. CKD AKI AKI AKIICKD (mainly with Vernurafenib) AIN (Immunenelated adverse effects) Monitor kidney function Monitor kidney function (first few weeks) Oni fluid Prednisone The medication can be resumed after prednisone therapy lpiliinumah camblned will anocher checkpoint inhlbhors like niwaklmab (andPD1Ab) induces AIN wish aggressive inilzruion of cytaloadc l1¢dI;:he1py requires camhlnadon on sword and/or MMF (KI 2016:9&63€). ELECTROLYTES AND Acne-BAs£ IHBALANCES Hyponatnemla Pseudohyponarremia Tumorinduced SIADH Paraproreinemia Small cell carcinoma of the lung and other organ, Head and neck cancer Therapyinduced SIADH Cyclophosphamide, ifosfamide: occurs and resolves within 24 hr of drug discontinuation Melphalan, Vina alkaloids (Vincnisdne. vinblasdne. vinovellaine). Methotrexate Therapyinduced sak wasting Cisplatin. carbopla:in: Sal:wasting through direct tubular damage mainly the loop of Henle Nephrogenic DI ifosfamide Pseudohypokalemia Tumor related Leukocytosis ACTH secreting tumor: SCLC. thymus or bronchial carcinoid. thyroid medullary carcinoma, or neuroendocrine tumors AML (M4 and M5): lysozymemediued tubular Injury Leukemia blast crisis: cell build up Light chain proximal rubulopadiy (LCPT) In monoclonal gammopathy Therapyrelated GMCSEVit B12: cell buildup Therapyrelated wasting Cisplatin AntiEGFR inhibitors (ceruximab and paniv.umumab) disrupt TRPm6medicazed distal reabsorprion of Mg I lyp e ma t n e mla Hypokalemla Hypomagnesemia Humeral Oszeolytic tumor Hyper calcemla PTHrp: squamous cell carcinoma (lung. head and neck), renal cell, ovarian. breast. and esophageal cancers 1,25(OH)1Vit D: lymphoma, dysgerminoma PTH (rare): parathyroid, lung (small. squamous cell). d thyroid papillary carcinoma, ovarian cancer Osceosarcoma, MM. solid (breast) cancer with osceolydc metastasis Proxima! tubulopachy Tumorinduced osteomalacia Hypophosphatemia Ifosfamide, cispkzin, imacinib FGF23 is release by the rumor (hemangicpelicy\omas.gam cell tumors. and osteoblastamas) .I ding to phosphamria AGMA pRTA (NAGMA. glycosuria. aminoaciduria.. K. POW) Metabolic Acidosis Lactic acidosis: leukemia, lymphoma,Warburg effect lfosfamide: NDI and dRTA can accompany Cisplatin Lich: chain proximal tubulopazhy (LCPT) in monoclonal dRTA gammopamhy lfosfamide INFECTIOUS DISEASES SsrslsAssoclATsn AKI AKI is common In sepsis. and incidence increases with higher severity of sepsis (>50% in patients with septic shock) llnlj infer m 1009;13:176) AKI typically occurs early in clinical course (often wu first 24 hr of presentation) UASN 1003;14;1021) and is a/w T morality. although outcomes are improving over time (A]KD201§.65:B70l Although septic AKI is alw T morality and T length of hospitalization dt nonseptic AKI lm Care zooe.1 zR4n, it may carry better renal recovery prognosis in survivors (qA§N2007:2:431) Pathogenesis and Workup AKI results from both impaired glomerular filtration and lobular dysfunction l RBF only if L cardiac output. otherwise T or normal Lon can 200591R363) Altered intrarenal blood flow and microcirculatory changes can lead to J. glomerular capillary pressure independent of RBF 1 GFR (lu 2017;91:45) Systemic inflammatory response syndrome. tissue hypoxia. 1 perfusion -v tubular cell apoptosis/necrosis FEn, >1% and "muddy brown" ass on microscopic sediment Prevention and Management Although maintenance of MAP to preserve renal perfusion pressure is key. no advan tage to raising MAP about 65-70. except in subset of patients with chronic HTN (NEW2014:310:1S83) Use of dopamine to increase RBF does not reliably protect against AKI Prophylaetic fenoldopam results in smaller T SCr. but not 1 mortality Aggressive IVF is alw inferior outcomes (Ki 200~m:4z2) and conservative fluid administra tion strategy after initial resuscitation may be renoprotectiwe (umune Cnem¢4 z01e42.1 a9s1 Balanced cryszalloids may provide marginally better renal outcomes compared to NS in critically ill adults (NS has supraphysiologic chloride concentration). although benefit for balanced crystalloids is small (major adverse kidney event [death, new RRT. or persistent renal dysfunction] 14.3% for LRldasmalyte vs 15.4% for NS. p = 0.04: no difference in need for new RRT or persistent kidney dysfunction) SMART new zoiaanxzvy Artificial colloids (eg, HES) ahv tAKl and T mortality: should be avoided (NEW 10113611141 No evidence to support highvolume hemohltration to clear inflammatory mediators (lnleidne Care m¢420138911535) Ideal timing of RRT initiation is controversial: early initiation does no: appear to provide increased survival or better renal outcomes in septic critically ill patients with AKI In patients Who require RRT, d\ere is no benefit to highdose RRT over lowdose RRI and efliuent flow rare of 20-25 mUkglhr is considered sufficient (Table) . Consider higher-dose RRT if refractory acidosis or hyperkalemia Key Cllnlcd Trials Regarding RRT Management Study Companson Primary Out come Fi n d i n g s A TN Hi g h i n t e n si t y RRT 6 0 d mo r a l i t y No dif f erence in (NEW z0a855mn ( 6 xl wk HD o r morlaliry. RRT CWHDF wi t h dependence. 3 5 mUkg l h r e f f l u e n t ) organ f ailure vs l o wi n r e n si cy RRT ( HD 3 x/ wk o r CWHDF wi t h 2 0 mUkg l h r e l l i u e n z) RE NA L (NEW 2wt u1=1sz1) CWHDF wi t h e f f l u e n t 9 0 d mo r t a l i t y No dif f erence in mo r t a l i t y RRT f l o w 4 0 vs 2 5 mUkg l h r d e p e n d e n ce . lengt h of h o sp i za l i u zi o n 2o\ x; ». 1sss) I VOI RE (lnwnne Cure m¢4 Hi g h vo l u me HF vs 2 8 d mo r za l i r y No d i f f e r e n ce i n st andard HF in mo r a l i t y. crit ically ill pat ient s h e mo d yn a mi cs wi sh se p t i c sh o ck a n d AKI ELAIN (lW* N16;3I§2190) AKIKI INEJM 2016z375:\21) IDEALICU wire 20IB:J7%I431) Early vs late RRT inidadon in critically ill pazienrs with stage 2-3 AKI (primarily surgical patients) 90d mortality Early vs lane RRT inidacion In critically ill pazienu with stage 3 AKI (80% patients had sepsis) 60d monalicy Early ys lace RRT initiation in early septic shock and failurestage AKl by RIFLE criteria 90d mortality Early RRT 1 mor:ali:y.l RRT durazion.l length of hospitalization Extended followup: early RRT L mortality and T renal recovery ax 1 yr UAW m1nm01 n No differences in mortality, RRT dependence. length of hospinlizadon Stopped orly: no difference in mortality, ICU days. vent d. Delayed -» L RRT time A N T I MI C R O B I A L S An ti b i o ti c D o si n g i n AKI Patients with AKI display variable alterations in antibiotic pharmacokinetics. so close drug monitoring is required to ensure drug efficacy while avoiding increased drug toxicity (Cm Can an 1006;211255) Intravenous route is preferred due to variability in oral drug absorption Although some antibiotics will experience i clearance in AKI. thirdspacing of fluids. hyperyolemia.and 1 drugprotein binding can T volume of distribution -» t dose needed to reach therapeutic drug level (Cm Care Med 2009;37a40) Early renal recovery can lead to underdosing dlt T renal drug clearance In patients requiring CRRT. antibiotic clearance is highly variable concur z01s;19:a4).and suggested dosing may be inappropriate due to (Nat RevNephlul 20l 1:7226)2 . Heterogeneity in extraction coefficient: due to variable drugprotein binding Mode of clearance (hemodialysis vs hemoliltration vs hemodiafiltration): convective methods increase clearance of larger solutes Filter adsorption differs based on filter composition Variability in dialysis dose delivered: dosing recommendations are based on stan dardized dialysis dose. but there is practice pattern variation in CRRT dosing; in addition. only 68% of patients receive prescribed dose of dialysis Consider antibiotic characteristics Concentrationdependent antibiotics (C) require high peak levels: may require increased dose due to factors above. and avoid RRT immediately after dosing Timedependent antibiotics (T) require prolonged time above MIC: consider prolonged intermittent antibiotic infusions or continuous infusions Pharmacodynamic Profile and CRRT Monitoring ofAntlblodcs Drug CRRT Monitor ing/Consider ations Vancomycin (T) Daily serum concentration. redose for level <15 mg/L Continuous infusion may be superior in CRRT UA¢lun¢mb Oianadnf 2013;6828$9) Linezolid (T) No established drug level monitoring parameters. although there is large variability in pharmacokinetics in patients receiving CRRT (Imnmnu aienavw z016:11:4a4) Daptomycln (C) Although trough concentrations correlate with peak levels, not routinely checked, as adequate peak levels achieved MM 8 mg/kg q4Bhr Lou Cae Me4 201 189119) Increase serum CK monitoring frequency (institutiondependent) No data available Cehzroline (T) Tigecycline (C) Nonrenal elimination. poorly dialyzed. No adlustrnencs required U a» Mdm1¢¢=IN1M2:l3N1 P w U Piperacillin mobamm m No puri ne drug level monitoring. Higher doses (12 g/d) associated with achieving drug targets, and extended infusion preferred regardless of dose (qAs~ 1016;1 l:\)I7l Cefepime (T) No routine drug level monitoring, although variability in pharmacddneiics in pacienvs on CRRT u~vw»w==»~~»= z0\s;4ew1>l results in risk of Cefnzidime Limited day (case report) lA»uwvuA¢¢m Oumiam 2017.6l:100164) undeureazing inlecdon or risk d neurologic side effec is Avibaczam (T) Meropenem (T) No routine drug level monitoring. Consider loading dose prior to dose reduction for CRRT given pharmacokinetic variability um I Kldy Dx 10 I4:63(1):1701) Gentamicin (C) Peak drug level monitoring 30 min after dose delivery (goal 6-8 kg/mL or 8-10 kg/mL depending on severity of sepsis) and redose when level <2 kg/mL (or <3 kg/mL depending on institution and severity of sepsis) (J avow 2012;24:107) Amikzcin (C) High loading initial dose (225 mglkg) preferred.with peak drug level monitoring (xo adjust dose) and extended dosing interval (goal trough <2.5) (Minden We oieniiim 10164049011 Polymyxin B (C) No routine drug level monitoring. No dose adjustment needed for patients on CRRT 4/umienb Oimain 2013:681674) Coliszin (C) No routine drug level monitoring. Potential role of loading dose (in) Annrmcwb IB 10\5:4&337) Peak drug level monitoring 30 min alter dose delivery (goal 6-8 purL or 8-10 pglmL depending on severity of sepsis) and redose when level <1 kg/mL (or <2 kg/mL depending on insdtudon and severky of sepsis) Tobramycin (C) Ciprofloxacin (C) No routine drug level monitoring. Given reliance on achieving desired AUC/MIC ratio for elhcacy. consider exceeding recommended dose in severe infection (can nm of 2005;41;\159) Rend Complications of Antimicrobials Risk factors of antibioticrelated AKI: CKD. DM.advanced age. other nephrotoxins Direct tubular toxicity (ATN) is most common mechanism of injury Crystal formation (sulfa.acyclovir) more likely to occur in volume depletion Acute interstitial nephritis can complicate therapy with any antibiotic. but commonly widi penicillin antibiotics or fluoroquinolones. Classic AIN triad of "rash, even and pyuria" occurs only in the minority. Need high index of suspicion or kidney biopsy. Dlactic acidosis due to bacterial overgrowth of acidproducing enteric bacteria 4 anion gap metabolic acidosis AntibioticAssociated Renal Toxicity (num lu ~=»~w auovsnsal DruglCIass N ephr otoxicity Trimethoprim Sulfamethoxazole AIN: ENaC inhibition o hyperkalemia. volume depletion induced hyponatremia WKD zoixsziissi Trimethoprim . tubular Cr secretion 4 T SCr wlo AGFR ATN: L Aquaporin 2 - hypernatremia (nephrugenic DI) T Membrane permeability to cations -» hypokalemia. hypomagnesemia. nephrogenic DI. distal RTA Amphoterlcln B Aminoglycosides L Microsomal protein synthesis, mitochondrial injury (especially in proximal tubule) » ATN. L K. POW. L Mg. Fanconi syndrome luiiiwaia we Glanulliet 1999;431003) t CaSR -» Bartterlike syndrome (L K. metabolic alkalosis) Linezolid Mitochondrial toxicity » lactic acidosis INfJM 1005.35323051 Proximal tubule ribosome injury v Fanconi syndrome Lactic acidosis t 5oxoproline, pyroglutamate o anion gap metabolic acidosis AIN: penicillins and other BIactams can provoke allergy Tetracyclines Penicillins Fluoroquinolones AIN: crystal nephropathy (Ciprofloxacin) Vancomycin Cellular uptake ATN Vancomycin cast formation -» ATN UASN 201723:111!I Polymyxin B Tubular cell apoptosis -»ATN Rhabdomyolysis: possibly via plasma membrane disruption (mvw cur on Gunn 2010c46.613) »» ATN Daptomycin Antibiotic Toxicity if Inappropriately Dosed for Renal Function DruglCIass Toxicity in Renal Failure BIactams Neurotoxicicyn encephalopathy seizures Aminoglycosiries Ozoroxiciqn AKI Vancomycin AKI HUMAN IMMUNODEFICIENCY VIRUS (HIV) Prevalence: 38.8 million worldwide and 833.000 in the US (wu HIV 20 1s,3.¢z611 HIV causes primary kidney diseases and is also a risk factor for progression [O ESRD AKl is common in HIVinfected patients (sepsis.ARVtoxicity) was 201$:29;1061) Glomerular diseases may result from direct infection of podocytes causing HlV associated nephropathy (HIVAN). immune complexmediated glomerular disease and endothelial inlury causing thrombotic microangiopathy (TMA) (not Rev n°p"iu z01s;\1:1S0) Incidence of HIVAN decreasing with widespread use ofAR11 although prevalence is increasing as patients live longer (1ASN 2005,16:241z1.The incidence of FSGS increasing in such patients (NDT 2011:27:2349) Increasing survival of HIVinfected patients leading to rise in CKD from other comorbidities (DM and HTN) found in HIVinfected patients and ART nephrotoxicity W o r ku p a n d E va l u a t i o n Recent HIV diagnosis (HIVAN) vs chronic HN (immune complexmediated GN) Rate of GFR decline: rapid (HIVAN) vs subacute (immune complexmediated GN) Risk factors: HCV coinfection. high viral load Workup HIV activity (CD4 count. viral load), Ula, proteinuria quantification Fanconi syndrome (glycosuria without hyperglycemia, NAGMA, hyperphosphaturia): drug toxicity especially tenofovir disoproxil fumarate (TDF) Kidney biopsy. recommended for suspected TMA. nephrotic proteinuria. or atypical presentations of other renal lesions (typically does not change management) HIVASSOCIATEO GLOMERULAR Dis£AsE - Glomerular Diseases Associated With HIV I mmu n e Co mp le x HI V A N Me d ia t e d G N TMA Advanced HIV. Black race/APOL1 Variable stage of HIV we 101358115141 No racial predilection Advanced HIV ($Om4Iln\murlnl 2UUM8L3JTI NS.fast GFR decline. large echogenic kidneys on UIS GN (p ro te in u ria . 1 pit. MAHA (often nl ADAMTS13) Be vw Collapsing FSGS. microcystic tubular dilation, tubulitis TRls (IFN fo o tp rin t) I mmu n e co mp le x G N (variable: lupuslike. Ig o r. MP GN. IRGN. MN, ITGN, FGN) Thrombosis. Ischanlc glomeruli and tubules. RBC fragments Treatment ART, RAASi. GC for A RT » l- GC PLEX and CS if low ADAMTS1 3 ,ART No n lg A N fo rms h a ve Mixed Risk factors genotype (MSN 2011:17;1\29) Clinical findings hematuria). low complement rapid progression Prognosis Poor widiout ARV better outcome than loAn. HIVAN (NDT 2016;31:Z099} The :erm HIVassociated immunecomplex kidney disease (HIVICK) is not recom mended for its heterogeneous disease spectrum and potential nonHIV reversible causes [KDIGO KI 101B9]:54$) HIVAssoclATeo TUBULOINTERSTITIAL DlseAss 11-26% of kidney biopsies from HIVinfected patients show mbuloinzerstirial disease ac/Asn 10105179812013;8:930). Of diese: 70% have a second major diagnosis. M of AIr attributable to drugs Hematologic (je, lymphoma) and infectious (TB. MAI) etiologies should be considered Immune Reconstitution Inflammatory Syndrome (IRIS) 1s¢~-~~~=i~~ zooaamsssm Systemic inflammatory response that typically occurs in setting of ART initiation early in course of opportunistic disease (and severe immunocompromised) Kidney Bx: granulomatous inflammation Tx: steroids Diffuse Infiltrative Lymphocytosis Syndrome (DILS) In 1007711191 Multiorgan lymphocyte infiltration that occurs in xetdng of uncontrolled HIV infection: commonly affects salivary gland . Kidney Bx: CD8+ lymphocytic infiltration Tx;AR1Z steroids Anvenss RENAL EFF£CTS oF ART Small T Cr w/o true renal dysluncuon dl: L tubular cr secretion: dolutegravir (integrase and OCT2 inhibitor) up an nwmmi 201J:7ss90). cobiciscat (CYP3A4 and MATE inhibitor) UAIDS 20 izs1:32). T Cr >0.4 should be evaluated for its fuse (NIH hapsl/aidsinlo.nlh¢ovI). Nucleoside/tide reverse cranscripase inhibitors (NRTIs) stavudine and didanosine may cause lactic acidosis and rhabdomyolysis. Rarely used in developed world. Proximal Tubulopathy Tenofovir disoproxil fumarate (TDF) and Adefoyir inhibit mitochondrial DNA 7polymerase and fuse renal tubular mitochondrial toxicity and Fanconi syndrome. TDF is most common cause of Fanconi syndrome. Secreted by OAT1 (basolateral) and MRP4 (apical) in the PT (Lab :in z011:91=ssz> Lab: L PO¢.glucosuria,aminoaciduria. nonalbumin proteinuria was 20151z9194n Kidney Bx: tubular damage; EM w/ change in mitochondrial shape. enlargement, or depletion TDF causes osteopenia d/t hypophosphatemia. 1 1ahydroxylase activity, and loss of vitamin D binding protein in urine Early detection and dlc may prevent further decline of renal function U10 2011107113591 Tenofovir alafenamide (TAF): newer formulation wl safer renal and bone sle profile due to 90% lower serum tenolovir levels. Less renal adverse events and proteinuria with TAF than TDF (;Alos 20162711s301 Z :: Crystalluria Protease inhibitors (lndinavir and Atazanavir) can cause nephrolkhiasis and inrrazubu lar crystal formation. Indinavir caused renal colic in 8%,Atazanavir (case reports) Radiolucent stones comprised of the medicine We IM 1997:127:119) HIV DrugAssociated Nephrotoxicity Jun in ~=I»~~I 201s:11¢1soi Drug Class Comments Tenofovir NRTI Didanosine Lamivudine. Stawdine NRTI ATN from mitochondrial toxicity Proximal tubulopathy (TDF>>TAF) w/ tubular proteinuria: failure no reabsorb low MW proteins Fanconi syndrome: phosphaturia. glucosuria. acidosis (insulNcient ATP to power sodiumglucose cotransponer and perform ammoniagenesis) Renal osteodystrophy: PO 4 wasting. loss ofVinmin D binding protein, low 1uhydroxylase production Biopsy:ATN and characteristic mitochondrial enlargemenddismnion Treaunenc drug discontinuation - good prognosis Fanconi syndrome. Lactic acidosis. Rhabdomyolysis NRTI NNRTI RTA Nephrolithiasis um) M 44 So 20163518131 Pl Crystals. stones,AKI Efavirent lndinavir.Atannavir KIDNEY TRANSPLANTATION Transplantation improves survival compared to HD in HIV+ patients with ESRD HIV viral load should be undetectable prior to transplantation No increase in HIV progression after transplant is;/A 201ck361220041 Safety and efficacy of HIV+ no HIV+ transplantation established IN£]M 20155372;6131 Drug Interactions Generally continue with same pretransplant ART regimen CYP4503A inhibited by CNI and Pl: expect to use 20% of typical CNI dose via extended dosing interval (fiunsplonmuon 1999;se¢a071 Avoid MMF - zidovudine or sravudine myelosuppression. 1 zidovudine efficacy WT 10099Suppl45263) Outcomes Pr a graft survival worse :han nonHIV. bu: similar no other highrisk INEJM 10\(x:ss:.004> Increased rates of rejection compared to HIVnegative recipients Worst outcomes if HCV coinfected UASN 20l5;26:ll2Z) DIABETES MELLITUS D IA s e Tlc K lons y D is e A s E (D K D ) Background Most common cause of CKD and ESRD in die US (USRDS) Abeu: 34 of diabetic patients develop DN Albuminuria with strong predictive value for CKD progression Microalbuminuria on spot morning void: HR 4.4 for progression (NEW 1001;345:B611 A/w allcause morality, CV events an all GFRs UAMA 2010230314n1 Moderately increased albuminuria (microalbuminuria): 30-300 mg/g or mg/d Severely increased albuminuria (macroalbuminuria): >300 mg/g or mild Of diabetes with eGFR <60. 16% have microalbuminuria. 61% macroalbumlnurla Of those with microalbuminuria. 20% progress in 8 yr. 50% stable. 30% improve Possible to progress directly to ESRD without evidencing oven proteinuria Pathogenesis and Risk Factors Hyperglycemia and advanced glycation end products drive diabetic complications: glomerular hyperfiltration UASN 2017;28:102]) ;Afferent arteriole resistance from tubuloglomerular feedback (TGF) inhibition. NO bioavailability. hyperinsulinemia . Efferent arteriole resistance from TAII. endothelin 1, ROS lnflammationlfibrosis from cytokines and growth factors (eg.TNFa.VEGF.TGFll) Direct podocyte effects.eg. nephrite expression.podocytespeciic insulin signaling Older age.African ancestry. smoking.and obesity increase risk for DKD No single gene has been identified.familial clustering is common Screening Annually from DM2 diagnosis. annually S yr after DM1 diagnosis / Cr. eGFR calculation. urine microalbumin to creatinine ratio (UACR) (ADA.KDIGO) Workup and Diagnosis Urinalysis: bland sediment. although hematuria can be seen.especially in severe DN Urine protein measurement Dipsticlc affected by urine concentration. usually "+" indicates >300 mold 24hr collection: gold standard Spot UPCR and UACR: acceptable and easier for patients. accuracy affected by creatinine generation (large muscle mass. cachexia) Urine microalbumin sensitive for low levels of albuminuria Protein electrophoresis: distinguishes albumin and nonalbumin proteins (light chains) Biopsy ac,IAs~ 2013;8:1718) Of biopsied diabetic patients. 1/3 with DN. 1/3 with nondhbetic renal disease (NDRD). and 113 with both DKD and NDRD mlc NDRD:ATN. FSGS. lgA nephropathy. HTN glomerulosderosis Kidney Biopsy Decision In Patients With DM Pursue Biopsy Defer Biopsy CKD of show duration Rapid worsening of GFR Vasculitit symptoms New onset nephritis/nephrosis Stable proteinuria Inactive sediment Known retinopathy Low C3IC4 Monoclonal mmopa Pathologic Classification of Dlabetlc Nephropathy unsuzoiwsssy I: GBM thickening III: nodular (Kimmelsdel-Wilson lesion) sclerosis (<50% global glomerulosclerosis) II: mesangnalexpansion IV: advanced sclerosis (>§0% global glomerulosclerosis) Interstitial fibrosis and small vessel disease frequently coexist UASN 1010:z1s56l Treatment Nephrology referral: GFR <30. UACR >300 mg/g. 25% drop in GFR (KDIGO) Lifestyle changes: exercise. BMI <25; no clear benefit w protein restriction BP goal <140190 :Ace l<olGoilnc). <130/80 if proteinuria 1KD°GO1. <130/80 (1017 ACC/AHAI Every 10 mmHg drop In SBP L mortality (x0.87).albuminuria (x0.83). CV events (x0.89), stroke (x0.73), retinopathy (x0.87) llAMA z01 s;m¢w3) Diuretics usually necessary to achieve BP control. loop preferred in advanced CKD (eGFR <30. or heavy protelnuria) RAS inhibition:first line for BP and proteinuria conuol; i intraglomerular pressure ACEi or ARB: renoprotective UDNT num 2001:345:851: RENAAL N£jM 2001:345:861) w Y Q 30% Cr: acceptable. /BMP, risk of AKI T wl diuretics. unSAIDs or volume depletion T >30% Cr: consider workup for renal artery stenosis Continue in advanced CKD unless *. K (try l dose + diuretic) or sudden ' eGFR Not recommended for primary prevention in normotensive. UACR <30 mglg ACEi +ARB a/w worse outcomes and no benefit lON1AaGE1: new 2013;369:1892) MRA + ACEi or ARB for further antiproteinuric and antiHTN: can initiate K s4.S and eGFR 230; T K frequent: lowK diet. loop diuretic. no NSAlD. close BMP monitoring Glycemic control: strict control prevents onset of microalbuminuria (NEW 1993;129:977) A1c <8% appropriate in CKD to avoid complications of hypoglycemic (ADA. KDIGO) A1c correlates widi Hub and pH.an be confounded in CKD due to anemia, acidosis . Fasting and postprandial fingers\jcks generally more reliable than Alc Proteinuria control: 1 50% albuminuria. i 18% CV event (at~AAi. KI z004:6s:-:09) . CCB: nonDHP more andproteinuric than DHP (KI 20041651199\l Pentoxifylline L eGFR decrease.albuminuria [MSN 201 $:26:220) CV comorbidities: statin with LDL goal <100, smoking cessation, aspirin 81 Liraglutide Lixlsenaride Semaglutide a gluc os ida s e inhibitors G LUCO SE DISARRAY IN PATIENTS O N DIALYSIS Susceptible to hyperglycemic episodes No urinary glucose excretion posrprandially. adsorption of insulin by dialyzer Hypoglycemic episodes -» counrenegulatory hormones :had are poorly cleared Susceptible to hypoglycemic episodes No renal gluconeogenesis. no renal clearance of insulin - prolonged halflife Recommended target for Hgb A1 C: 6-8% (nm Rev ~=1~~°lw 201s¢11¢:02) Treatment no glucoselree dialysare Aim for p:s glucose to be wnl before HD to prevent shifts during trearmenn Titrate insulin to nutritional status as malnunridon/inflammacion -> Tinsulin resistance Increased pr selfmonitoring on dialysis days no catch postHD hyperglycemia DIABETIC KETOACIDOSIS (NEjM 10151372:546) Pathophysiology Insulin dehciencylresistance -\ impaired peripheral tissue glucose metabolism. T f===v acid oxidation and lipolysis, T glycogenolysis and gluconeogenesis Fatty adds overwhelm Krebs cycle and excess Acetyl CoA - Acetoacetic acid Loss of ketones in urine -» ECF contraction v AG acidosis when ketoacids retained in severe volume depletion Clinical Manifestations and Workup NN abd pain. AMS: / Insulin use. ischemic symptoms. ingestions. infection Exam: volume depletion (orthosiasis. flat neck veins, dry axillae). hyperventilation Labs:+urine/serum ketenes,AG acidosis. sGlu usually 400-800 although can have euglycemic DKA especially in setting of SGLT2 inhibitors Tre a tme n t Monitoring: hourly glc, q2hr BMR cardiac monitor Volume resuscitation: bolus 1-2 L NS via largebore access; continue fluids 250-500 cdhr Potassium repletion . If K <3.5. hold insulin until repleted >3.5 If K <5.0. 40 mEq KCI with each L of NS If K >5.0, monitor q2hr Phosphate repletion:avoid.unless phosphate <1.0 mg/dL.then 20 mEq Naphos If pH<6.9, 100 mEq NaHCO; in 500 cc w/ 20 mEq KCI and repeat until pH >7.0 Insulin: 0.1 u/kg regular insulin lV bolus. then 0.1 ulkyhr continuous Infusion Repeat bolus if sGlu does not drop >50 mgldL in Grst hr Once sGIu <200 mg/dL change IVF to D5 36 NS at 250 cclhr When AG acidosis resolves. start subq rapid acting 0.1 ulkg q2hr Overlap 2 hr of insulin GTT with subq plt stopping GTT Treat potential underlying disorder: infection.ACS. intoxication METFO RMIN ASSO CIATED LACTIC ACIDO SIS P a thophy s i ol ogy conversion of glucose to lactate in GI tract and inhibiting mitochondrial respira tory chain complex 1 -» 1 lactate use in hepatic gluconeogenesis Diagnosis History: NN abd pain.AMS. dyspnea: documented metformin use when eGFR <30 Exam: tachycardia and hypotension in setting of severe acidosis Labs:AG acidosis. negative wlu for infection or other causes of severe lactic acidosis Treatment (Cru Core Med 201554317161 Volume resuscliadon with isotonic IVF if hypotensive: avoid bicarbonate administration 1 glkg IV dextrose if hypoglycemic Dialysis if: lactate >20. pH <7.0. shock despite fluid resuscitation, ongoing AMS >2 hr P a t h o p h ysio lo g y Chronic interstitial inflammation and effect of hyperinsulinemia on WNK4 signaling lead to low renin levels and hypoaldosteronism (NEJM z01s;373:$4a).Volume expansion from CKD can elevate aural natriuretic peptide which directly inhibits renin and h yp e rka le mia in d u ce d a ld o st e ro n e se cre t io n , Hypoalldosteronism - * Na absorption -» L lumen electronegativity -v l K/H excretion Hyperkalemia -» impaired excretion of ammonium H re t e n t io n Dia g n o sis r/o a lt ca u se s o f h yp o a ld o ste ro n ism: Primary adrenal insufficiency: chronic interstitial nephritis: HlV.Tb. sarcoid. EBV/CMV Drugrelated: unSAIDs. Curls. heparin,ACEl/ARB, Ksparing diuretics. trimethoprim Labs: nonAG acidosis, hyperkalema +UAG. urine pH <S.5, low plasma reninaddosterone Tre a t me n t If plw HTN or edema. low K diet with thiazide or loop diuretic If not then patiromer (potassium binding resin) ELECTROLYTE DISORDERS IN DIABETES (NEJM 2015;373:548) Dysnatremia: inua -i extracellular fluid shifts and osmotic diuresis from hyperglycemia Hyperkalemia potassium shifts due to insulinopenia and acidosis.Type IV RTA Hypomagnesemia: renal Mg wasting due to osmotic diuresis Hypophosphatemia renal Phos wasting due to osmotic diuresis HypermagnesemialHyperphosphatemia: in DKA due to acidosis and insulinopenia HYPERLIPIDEMIA CVD is alw death in ESRD (50% of deaths. 20% of which is related to CAD) Dyslipidemia is alw incidence and progression of kidney disease Risk srranificadonz 10yr risk for atherosclerotic cardiovascular disease (ASCVD) (Cu lu wn 2014;1Z&511; available AHA/ACC websir.e. app (ASCVD Plus. QxMD') HMG CoA Reductase Inhibitors (Stalin) Intensity of Stains (mg) (ACGAHA o-ww z01m 39=\04q L LDL goal Low Mo d e ra t e Hig h <30% 30-49% 250% A t o rva : 1 0 2 0 A ro n a : 4 0 -8 0 Rosuva: 510 Simva: 20-40 Prava: 40-80 Lover: 40 Fluva: 40 BID or XL so Rosuva:20-40 Srarin dose Simva: 10 Prava: 10-20 Lover: 20 Fluva: 20-40 Picava: 1. 2, 4 Bold: Recommended dose for CKD 3-5. including CKD SD or w/ KT IKDQGO Lipid sum 2 (18 ylo) and 1 (40-75 ylo) Prevention ofASCVD (AcclAHAa.mliun z01%1m104el Co n d it io n s Tre a t me n t Multiple major ASCVD or 1 major ASCVD + mu ltip le h ig h risk co n d itio n s* Maximal tolerated statin: if LDL 270 add ezetimibe :hen PCSK9I Histo ry MA S CV D e ve n t High or moderate srazin LDL 2190 Maximal tolerated surinz if LDL >100 add ezenimibe :hen PCSK9l Moderate satin; if multiple ASCVD risk (50-75 lo) high statin LDL 70.189 and DM LDL 70-189 and 10 yr ASCVD 220% High snazin LDL 70-189 and 10 yr ASCVD 27.5 co <20% Moderate szadmconsider risk enhancers" and coronary artery Ca score LDL 70-189 and 10 yrASCVD 25-<7.5% Selective moderate sauna risk discussion considering risk enhancer' LDL 70-189 and 10 yr ASCVD <5% Lifestyle and risk discussion LDL <70 Assess lifetime risk CKo>4 (eGFR 15-59) is one of hi¢risk conditions* and risk enhancing heron' S t a t in M yo p a t h y Dosedependent. lowes: with prava and iiuvastatin Prava, fluva. pitava. and rosuvastatin are less affected by CYP3A4 inhibitors Drugs causing myopathy with statin: Cyclosporine. gemfibrozil. protease inhibitors S t a lin a n d A K I No L kidney failure but 1 proteinuria and rate of eGFR decline W02016:67ea1) Preoperative use is not alw l postoperarJveAKl Isa rep z017:7:10091) Szatin should not be recommended solely for renal protection and proteinuria H yp e r lip id e m ia in C KD Cholesterol level is predictor of mortality in HD pts: lowest in 200-219 (KI 2002:61:i887) Prayastatin 40 mg 28% . CV death or recurrent nonfatal Ml in CrCI <75 w/ previous MI (cAns Am :m 2003;1:a:98);23% i new MI. CV death. or cardiac intervention in eGFR 30-60 (mean ss) (PPP aannxan z004:110:1ss1) Simvastatin 20 mg + ezetimibe 10 mg 22% l 1st major atherosclerotic event in non dialysis Cr >1.7 <3 >1.5 9: no effect in dialysis population lsr.lARpi»»<=i 1011;377:2181) Simvasnatin + ezetimibe: better than simvastatin alone (MSN 2017aa30341 Atorvastatin 20 mg did not lower CV death. nonfatal Ml.and stroke in HD pts with T2DM.There was 18% i cardiac events (40 NEW 1005;353=23B). If LDL >145. 31% 1 cardiac death. nonfatal myocardial infarction, or stroke lcpisn z011:6:1a1¢) Rosuvasladn 10 mg did not lower CV death,nor\fatal MI. or nonfatal spoke and allcase mortality in HD pts (AuroRA num z009;3se1 i9s). In post hoc analysis of DM pts. 32% reduction in cardiac events (AURORA/ASN 1011:22:1335) Pharmacologic Treatment of CKD (xouco ups42013) 18-49 lo. CKD Srazin if CAD. DM. prior ischemic stroke or 10yr risk >10% 250 ylo. eGFR 260 Sratin 250 ylo. eGFR <60 Skin or srarin/ezenimibe ESRD If pr is already on a satin. continue in. Do not routinely iniziane it OBESITY Background and Definition By BMI (kg/m1): overweight 25-29.9: class I 30-34.9; class II 35-39.9; class III 240 Prevalence increasing;33.7 (2007-2008) -» 39.6% (2015-2016) (}M4A 201e;J19¢\713) Waist circumference is alw mortality in CKD who 20\1;5B:\77) a/w low GFR and albuminuria in 2017;911224). inflammation who 10l7:70:B17) Risk factor of ESRD: overweight x1.87, class I x3.57. class II ><6.12 (Am. :m 1004144911 M e d ica l C a u se s o f O b e sit y Cushing (including iatrogenic), hypothyroidism. PCOS. hypothalamus injury Atenoiol. metoprolol, propranolol. MAO inhibitors.TCA, paroxetine. lithium. escitalo pram. clozapine. olanzapine, risperidone. valproate, divalproex. mirtazapine, progestins. insulin, sulfonylureas. thiazolidinediones, meglltiriides (émdnuon 10122125116951 N o n su r g ica l T r e a t m e n t Bdiavioral intervention: dietary changes (energy deficit 2500 kalld). physical activity. selfmonitoring and inperson counseling (uspsTF AM in 20121157373; ;Acc 1014:63229B5) Orlistac lipase inhibitor;AKI (ArtN :m 1011:171:703), oxalate nephropathy We 2007:4e 1s3) Phentermine: used with topiramate: sympathomimetit;T BR HR: avoid In glaucoma Topiramate: cause hypokalemia. distal RTA -» nephrolithiasis Liraglutide: I, new albuminuria (NE;M 2017:377¢s39> Lorcaserin: serotonin agonisu: no signMcanz CV side effect luzw z0\s=m1101): improved renal function and albuminuria (GmWauun 1019;139366) QBESITYRELATED GLOMERULOPATHY (Nat Rev nepal 2016:11:453) Glomerular hyperNkrarion -) glomerular hypertrophy > podocyte hypertrophy UASN 1011111254 - podocyte deuachmenr -» FSGS Bx: glomerulomegaly, FSGS (perihilar common), segmental foot process effacement Proteinuria: subnephrodc (52-9094). normal albumin, NS is uncommon (<6%) Tx: we loss. RAASi induce proreinuria reduction >nonobese l;Asn 101112111211 Prognosis: 10-33% progressive renal failure and ESRD G As Tnl c BY P AS S S unc s k v Indications (Arcs Guideline Ohwlr 201111511 BMI 240 w/o excessive risk o( bariatric surgery BMI 235 widl 21 severe obesity related comorbidities:T2DM. HTN. HLD. OSA. obesity hypoventilation, NAFLD, NASH, pseudotumor cerebri, GERD. asthma, venous stasis. severe urinary incontinence, debilitating ar thritis. considerably impaired QoL BMI 30-34.9 with diabetes or metabolic syndrome may be offered Types of Surgery Malabsorptive: biliopancreatic diversion with or without duodenal switch Restrictive: adiusrable gastric banding and sleeve gastrectomy Malabsorptive + restrictive hybrid: rouxenY gastric bypass (RYGB) General Effects of Bariatric Surgery Lower mortality (1.3%) in 4.3 yr than matched cohort (2.3%) uAmn01ma 19;zm T Remission of HTN. DM. HLD (;AMA 10189194911 Deficiencies of iron.vitamin Biz. D.and thiamine. Gallstone. sagging skin T Additional GI op (x2.0), op for obstruction (x10.S), peptic ulcer (x3.4) (mAMA 101&319:291) Renal Effects of Bariatric Surgery Postoperative AKI 8.5% (T 50% Cr or dialysis requirement). Risk factors are higher BMI. HLD, intraop hypotension and preoperative use of ACEilARB lCMSN z001:z41s1 Renal function predicts postpp complicaiion:4.6 (CKD1) .. 9.9% (CKD5) mm z01z=2Jaes) 1 Proteinuria, albuminuria (Pedau ~»pnfa z009;24=a51; cu- n¢w-i1 zuce.704941 Q g 27 kg weight reductions with RYGB: 1 absolute mGFR (1 glomerular hyperfiltration). unchanged mGFR adjusted for BSA. T creatininebased eGFR (overestimation dlt 1 muscle mass), unchanged cyscatin Cbased eGFR (mc mur z0 i7;1s:s21 Improvement in KDIGO CKD risk categories 1/ASN 2018;1911B9) At median flu of 4 yr. 58% L eGFR decline 230%,S7% L ESRD or Cr doubling of 10149011641 6 C a l c i u m Ox a l a te N e p h r o p a th y as Saponification of calcium/insoluble calcium oxalate complexes formation -» excessive u reabsorption of oxalate by the gut Malabsorptive procedure T urine oxalate excretion. oxalate nephviopathy (KI 2007:moa clAsn anceansvel kidney sine and CKD (x1.06] lx: zo1 s:s7.aa9) CKD-MINERAL AND BONE DISORDER Definition (KI Suppl ZOl0;7H $10) Systemic disorder of mineral metabolism. bone. and vascular calciticaUons Abnormalities of Ca. PO 4. PTH,vitamin D metabolism Renal osteodystrophy refers to the bone component of CKDMineral and Bone Disorder (CKDMBD) and is a spectrum of disorders in bone 8um9295 minerallation. and volume in CKD Background Linked to vascular calcificauon: the leading cause of mortality in dialysis patients Clinical outcomes in CKDMBD are increased risk of CV events and fractures Risk of CKDMBD and (-) clinical outcomes T with severity of CKD (usually eGFR <40) CKD: t risk of falls 2/2 frailty and sarcopenia,1 fragility fracture and related morality (2.5x 1yr mortality rate after hip fracture) compared to general pop WKD z00013e2111s) Renal osteodystrophy is a form of osteoporosis: osteoporosis is defined as a disorder of bone that increases risk of fracture Pathogenesis Phosphonls retention with 1 ionized Ca and vitamin D -» 2 hyperparathyroidism In early CKD.T fibroblast growth factor 23 (FGF23) peptide -» suppression of 1nihydroxylase 4 1 calcitriol producdcn -» T PTH -a phosphaturia with further GFR decline -» hyperphosphatemia v oszeoblastlc transformation of vascular smooth muscle 4 vascular calcification Vascular calciGcatlon: media >intima -> vascular stiffness and LVH. FGF23 linked to LVH and CV events (atherosclerotic and death) in CKD UAS~1014a5=3491 RENAL OSTEODYSTROPHY (xl Suppl z010.7&s10) A d yn a mic B o n e Dise a se Very low rate of bone formation (1 SD below normal mean,<20 yg'lum'/yr bone for mauon) secondary to PTH suppression by inflammatory cytokines 4 low osteoblast a ct ivit y a n d b o n e f o rma t io n ra ms 5 5 % o f HD p a u e n t s u m 1 0 1 1 1 2 6 2 1 3 6 8 1 In cre a se d in cid e n ce wh e n PTH <1 0 0 p g ./mL (PPV >9 0 %) T Serum calcium secondary to reduced bone uptake; l alkaline phosphatase Some evidence that it is associated with increased risk of arterial calcification Ost eomalacia Low bone turnover with abnormal mineralization Previously from deposition of aluminum containing binders; now 4 incidence (3%) (IBMR 1011;26:1 asa) Hyperparathyroidisrn (34%) High bone turnover disease" t rates Iormadon and resorption PTH >600 pglmL Secondary to calcitriol deficiency, hyperphosphaternia. hypocalcemia. and excessive FG F2 3 i n e a r l y CK D Re la tive ly L o w P TH Associated with T mortality (Ushaped mortality curve with T PTH) secondary to cal dumbased binders. dialysate bath. assay differences. excessive active Vit D repletion Vit a m ln D D e f icie n cy 1.25(OH)1D3 active metabolite secondary to worsening CKD. Supplementation associated with improved survival in CKD and HD patients .> 25(OH)D (<30 fig/mL) associated with T mortality in HD patients. supplementation wick nutritional/inactive D2 (ergocalciferol) or D3 (cholecalciferol) results in reductions in PTH that are more appreciable in patients with less severe CKD Hyperphosphatemia and Hypophosphatemia Phosphorus <3 and >6-7 associated with t mortality Hypercalcemia and Hypocalcemia Both associated with increased CV morality Hypocalcemia ( PO» retention, i calcicriol. PTH resistance) -\ T PTH -i abnl bone r e mo d e l i n g Hyp e rca lce mia -» e xtra ske le ta l ca lcifica tio n Increased Alkaline Phosphatase (Hyperphosphatasemia) Linear ailw allcause and CV morality (pyrophosphate hydrolysis - vascular calcifica don) and hip fracture risk in HD pts (nor z014;2*ms3z).¢ w/ vitamin D and calcimimetics OSTEOPOROSIS Definition Disease of low bone mass. disrupted bone architecturee,and skeletal fragility Osteoporosis: dual energy xray absorptiometry (DXA) Tscore 22.5 SD below young adult mean OR fragility fracture Low bone mass (previously osteopenia):Tscore 21-2.5 below young adult mean Normal:within 1 SD of young adult mean Background US prevalence 9.9 million. 2 million fractures annually lomipalus on 2014415:23591 CKD: lower bone mineral density (BMD) and 2x the facture risk of age matched conuols ESRD: up to 40% prevalence of fragility fractures Screening All postmenopausal women and men >50 should be evaluated for fracture risk DXA recommended for all women 265 or <65 with equal or greater fracture risk on Fracture Risk Assessment Tool (FRAX): 10yr risk 29.3% lusrsTF Ann IM 2011=1s4¢Jss1 FRAX is available at sheMeld.ac.uMFRAX Clin ical Risk F act o rs f o r F ract u re Advanced age. previous fracture. family hx of fracture. low body weight Risk Factors for Osteoporosis-Related Fracture (Office of the Surgeon General US 2004) Lifestyle Alcohol abuse, immobilization. low calcium intake,vitamin D deficiency. smoking. hypervitaminosis A CE osteogenesis imperfects. porphyry. Marfan syndrome. Ehlers- Genetic Danlos syndrome. hemochromatosis. homocysdnuria. Gaucher disuse. glycogen storage disease Hypogonadal states Anorexia nervosa. panhypopituilanism, premature maiopause (<40 yr). hyperprolactinemia. androgen insensitivity.Tumer syndrome. Klinefelter syndrome Endocrine Cushing syndrome. DM. hyperparathyroidism, thyrotoxicosis. central obesity GI disorders Celiac disease. IBD. malabsorption. PBC. gastric bypass. pancreatic Hematologic Hemophilia, leukemia/lymphoma. multiple mydono. sidle cell disease. thalassemia Rheumatologic RA. SLE. ankylosing spondylitis Neurologic and musculoskeletal Epilepsy. MS. muscular dystrophy. Parkinson disease. spinal cord injury stroke Medications Aluminum, anticoagulants. anticonvulsants. aromatase inhibitors. barbimrates. chemodielapeutic rigs, depomedroxypnogesterone. glucocorricoids (>2.5 mg/day prednisone for >3 mo). GnasH agonist. methotrexate. PPls. SSRls.TZDs. dvyroid hormones. P2lB1l\il nutrition Miscellaneous HIVIAIDS, amyloidosis. COPD. CHE ESRD, sancoidosis. posttlansplant disease bone disease GlucocorticoidInduced Osteoporosis iAA Andrus Rhemalal 2017.s91sz11 Monitoring and prevention for patients taking >2.5 mg/d prednisone for >3 mo Osteoprotegerin inhibition & T RANKL synthesis -» osteoclast proliferation Inhibited gonadotropin secretion-» i androgens and estrogens 4 l bone resorption T O st e o b la st a p o p t o sis + 1 b o n e f o rma t io n High fracture risk during early rapid bone loss phase (first 3-6 mo) and subsequently correlates to dose and duration of glucocorticoid treatment Clin ica l Ma n if e st a t io n s None until there is a fracture (often no preceding trauma) Vertebral fracture most common (2/3 asymptomatic. usually incidentally found on other imaging, signs: height loss and kyphosis) Workup and Fracture Risk Assessment iOnwnawsis i! 2014:Z51159) DXA for BMD of hip and spine:spine BMD has limited use in CKD to predict fracture risk 2/2 extraosseous calcification and focal osteosclerosis Vertebral imaging (lateral T and Lspine Xray or lateral assessment on DXA) in setting of low bone densitylrisk factors to assess for vertebral fracture (indication for ueaunent) FRAX: calculator to estimate 10yr probability of major osteoporotic or hip fracture for untreated patients age 40-90. Can be used with or without BMD at the femolal neck Bone turnover markers: not routinely used. possible role in monitoring response to D( Evaluation for secondary etiologies if recent/multiple fractures or very low BMD TREATMENT (Nut Rc n¢vl\mI 20119681; C]ASN 101849629 Conventional osteoporosis meds effective in mild CKD when CKDMBD excluded (normal PTH, Ca. and FO 4) Insufficient evidence for fracture reduction in stage 4-5 CKD Initiate treatment if eGFR <30 with fragility fracture or osteoporosis (KDIGO HBO 2017) Exdude adynamic bone disease prior to bisphosphonaves (theoretical L In bone formation) Exclude hypaparadvyroid hone disease in patients with CKD prior to anabolic treatment Nonpharmacologlc Treatment Die: (1,200 mud calcium. 800-1.000 IUld Vic D). lifestyle (exercise and fill prevention) In CKD patients. lim: calcium intake w 500800 mg daily. replete 25OH it D to 30 and manage metabolic disturbances a/w CKDMBD (hyperparathyroidism. hypocalcemia. hyperphosplutemia, vitamin D deficiency) prior to starting treatment for osteoporosis E s t ro g e n 1 Fractures. initiate within 10 yr of menopause given CV risk. Dosereduce In CKD. Avoid estrogenprogestin combo dltvTE. CVA. CAD,and breast CA risk Selective Estrogen Receptor Modulators (SERMs) Raloxifene L vertebral fractures in eGFR <45. t Lspine BMD in stage 4-5 CKD TVTE risk and 1.4x higher serum levels in CKD (KI 1003;63:1169) B isp h o sp h o n a t e s 1 Fracture rate by 50% In postmenopausal osteoporosis WM 2009;177;$14). effectiveness cor r elates with degr ee of bonetumover Fracture reduction comparable in mild CKD.but data lacking in stage 4-5 CKD (small ¢ BMD in ibandronateueated HD patients) iA-J n¢pnmI 2012;zs:23s) Prevents resorption by binding mineralized bone surface-half bound with remaining half excreted unchanged by the kidney Cleared by HD. Teriparatide: Recombinant Human PTHI/4 Peptide A n a b o lic e f f e ct wit h d a ily S Q in je ct io n s T BMD and 4 fractures in mild CKD. T BMD in adynamic bone disease (lGdney alan4 pvus Ne 2 0 1 0 :3 ]:7 .2 1 ). No e vid e n ce to su p p o rt u se in CKDMBD. De n o su ma b Monoclonal ab against RANKL (osteoclastdiflerentiation cytokine) Antiresorptive. nonrenally excreted. no restriction with CrCI <35 i Vertebral fracture in mild CKD um 1011216518291 Risk of severe symptomatic hypocalcemia in late stage CKD (Jane 20n:z7147I). No evidence [D suppor t use in CKDMBD. Strontium Ranelate: Incorporated into Bone in the Place of Calcium Used outside the US for postmenopausal osteoporosis Renaliy cleared, no safety data to recommend use in CKDMBD Osteoporosis Pharmacotherapy in CKD we no ~.ui,.l2.01as=ee1: KI zoiuwal Dru g Co mme n t s Alendronate No t re co mme n d e d fo r CrCI <3 5 F DA L a b e l Risedronate No : re co mme n d e d fo r CrCI <3 0 2013 Ibandronale No r re co mme n d e d fo r CrCI <3 0 2013 Zoledronic acid No t re co mme n d e d fo r CrCI <3 5 2013 Teriparatide Caution in recent urolithiasis 2009 2013 Be n e fit in CKD.lcw PTH a n d lo w BMD Denosumab Risk of hypocalcemia in CrCI <30 May be useful KO :neat hyperealcemia 2013 Calciwnin No renal adjustment Probably safe,weak effects. no dm in CKD 2012 Raloxifene No renal adjustment Pilot data with beneficial elfecls in HD patients 2007 Estrogen Limited dam in CKD 4-S;appropriate in premenopausal 2011 women with CKD and amenorrhea PROGNOSIS AND MONITORING 8-35% excess monaliry within 1 yr of hip fracture (osoapwus lm 1009;2¢1633) Monitoring eGFR >30: BMD testing 1-2 yr after initiation of therapy q2yr thereafter eGFR <30: quo mo serum calcium. phos.25(OH)D: calcium 10 d after sraning denosumab Annual Cr monitoring on bisphosphonates Repeat DXA may be useful for response to tx (not for assessing fracture risk) . Markers of bone turnover not recommended r' PRIMARY HYPERPARATHYROIDISM Definition and Pathogenesis 1 Hyperparadryroidism (PHPT): one or more paradvyrold glar\d(s) secretes excessive PTH with elevated or highnormal serum calcium and replete vitamin D Adenoma (80-8595). hyperplasia (10-15%).carcinoma (<1%) 2 HPT: renal failure (impaired alckrlol production and hyperphosphatemia).vitamin D deficiency (may be present in PHPT and lower serum raldum to normal range),meds (lithium. thiazides). calcium malabsorpt.ion.renaI calcium loss. inhibited of bone resorption 3 HPT: aker longstanding 2 (glands remain llyperfunctioning despice correction of 2) Normocalcemic PHPT: variant with normal total and ionized calclum.elevated PTH. and no 2 causes. Progression to hypercalcemia (19%), renal stones. fracture. decline in BMD.and hypercalciuria (40%) over 3 yr (ICE/* 1007;3S:123) Familial hypccalciuric hypercalcemia (FHH): benign mild Ca elevation 2/2 AD inacti vating mutation in the parathyroid and kidney calciumsensing leceptor (CaSR) PTH inhibits NHE3 and bicarbonate reabsorpcion in PI Clinical pRTA is uncommon (KI 198$;2&187) Clinical Manifestations Mos: commonly asymptomatic hypercalcerniaz asymptomatic nephrocalcinosis Renal stones in 55%. osteoporosis in 63%. vertebral fractures in 35% UCEM 2015;100:1309) Nonspecific SX related to hypercalcemia: weaknas.ano4exia. fatigue. polyurialpolydipsia. cognitive/neuromuscular dysfunction Parathyroid bone disease: osteitis ibrosa cysdca (<5%) excessive osteoclast activity - subperiosteal bone resorption in middle phalanges, tapering of distal clavicles, bone cysts, brown tumors (fibrous tissue and poorly mineralized bone) - bone pain. Reduced cortical BMD and increased risk of fracture. CV HTN, LVH, diastolic dysfunction, coronary atherosclerosis Atypical: parathyroid crisis (1-296) symptomatic severe hypercakernia (man 17.5 mg/dL) Workup Serum calcium: repeat to confirm. Most <1.0 mg/dL above ULN PTH: elevated in 80-90%.wn1 10-20%. No performance differences between 2nd gen "intact" and 3rd gen"whole molecule" 1-84 assays UCEM 10 14:w3s10) Creatinine: for calculation of CrCl; 60 is the threshold of parathyroidectomy 24hr urinary calcium: elevated (>200-300 mg/d) in 40%. correlates with risk of renal complications. FEW < 0.01 senslspec of 85%/88%, PPV 85% (can Enaaawmi 1a0816917u1 25Hydroxyvitamin D (25OH vit D):<20 may lead to a falsepositive dx of PHFI Repletion increases urinary calcium excretion. Differential Diagnosis for PHPT PTH PHPT FHH PHPT wlVit D deficiency Z HPT dlt Vit D deficiency Normocalcemic PHPT Ca t or high nl T NI, T (15-20%) T t nl T nl or 1 t nl Vitamin D Urinary Ca Nl.lownl.or L NI 4 l nl T or high nl 1 Low nl or ' 1 nl Genetic testing (Ca$RAP2$1, GNA11) for FHH. Indications: positive family hx. young age. multigland involvement, concern for multiple endocrine neoplasm (MEN 1) Renal Imaging: u/s. Cli or plain film for stone and nephrocalcinosis detection Bone mineral density (BMD): decreased particularly at cortical sites (forearm and hip). not required for dx. Imaging for vertebral fracture recommended if DXA negative for osteoporosis dlt increased risk Neck imaging (ultrasound, technetium99m sestamibi scan. dynamic CI MRI) not indicated for dx. used for surgical localization SurglcalTreatment: Parathyroidectomy Symptomatic hypercalcemia or nephrolithiasis Indlcadons for Parathyroldectomy in Asymptomatic PHPT up z0149&ass1) Me Renal Bone <50 CrCl <60. 24hr urine calcium >400 mg/d with increased stone risk. nephrolithiasis or nephrocakinosis on imaging swdy DXA T score <2.5 as lumbar spine. total hip. femoral neck, or dislzl 113 radius OR Venebrad fracture by xray, CT. MRI.or venehral fracture assessment on DXA Serum Ca >1 mg/dL above the upper limit of normal Medieal Treatment For nonsurgical candidates or failure of cure after surgery Dietary Ca 1.000-1.200 mold: dietary Ca & vit D def T PTH: should not be restricted Vit D repletion (goal >30 fig/mL) J, PTH (17%) and T Lspine BMD (2.5%) ()C£m 201439:1072) Thiazide: 1 PTH. urinary Ca ()CEM z017;10231270). Monitor serum Ca level. Cakimimetics: serum Ca >1 above ULN. Cinacalcet normalizes Ca in 75%. no change in BMD. preferred in patients with nl BMD (SurfEnda¢Ilrlo12015;171527) Bisphosphonates: osteoporosis and/or fracture risk Improves BMD without change in senim calcium. Combo therapy with cinacalcet can be used to reduce serum Ca levels but has not been studied in RCTs. Estrogen-progestin: significant increases in BMD in postmenopausal PHPT. Not ret ommended 1stline tx dlt breast cancel: stroke. and CHD risk. Prognosis Surgery as the only definitive therapy Significant increases in BMD and reduced risk of renal stones (NEW I 999;34\:\249) Comparable BMD improvements with bisphosphonates alone www 20109s16sJ1: Reduced fracture risk observed but not demonstrated in RCTs No change in postop renal function ucw z014.99:u4sl Excess mor tality (RR 1.7 male. 1.8 female) 2/2 cardiovascular disease persists after surgery. unclear relationship to severity of underlying disease (Eur 1 cl»n< Invest 1998:28:271) Small nonspecific differences in postop neuropsychiatric sx that favor surgery URIC ACID (UA) Background UA H Urate + H. pKa 5.75:po:en:iaI no crystallize in acidic milieu (pH <S.5) UA is the result of metabolism of purine in the liver; diem can provide ~40% of orate UA excretion via the GI tract (1/3) and the kidney (2/3) <5% protein bound; most UA is littered as the glomerulus PCT Handling of UA Process (Proportion of UA, PCT Segment) Transporter Reabsorption ( 99%, $1 ), pos secretory reabsorprion (40%. $3) URAT1, OAT4 (apical) GLUT9 (basolateral) Secretion (507é. 52) OAT1 . OAT3 (basolateral) MRP4.ABCG2. NPT1, NPT4 (apical) URAIZ rate anion exchanger; OAT. organic anion transporter: GLUT. glucose uansponer: MRR multidrug resistanceassociated pro¢ein,ABCG.ATP banding cassette sbfamily G member: NPT. sodiumdependef! phosphate rransponer FEud 10%: >20% in ATN Females have lower levels by 1-1,5 (estrogenmediated renal orate excretion) (Hum neama zo13:2e1asal.Af¢er menopause level males level (Aland: Red ho 2GGB;10:R116) Pathogenesis of Clinical Conditions Associated With Uric Acid Hyperuricemia: 85-90% underexcretion; 10-15% overproduction (Aninus umm 2001447:6101 Hyperuricemia is risk factor for renal and cardiovascular diseases (potential mechanism: activation of the RAAS, 1 NO. l glutathione formation an antioxidant and dysfunction of intrahepatic fructose metabolism) CKD progression: T oxidative soess. endodlelial dysfunction -> systems and glomemlar HTN:alr.eration of RAAS-» T renal vascular resistance. l renal blood flow (nor zoinemn Autosomal dominant tubulointerstidal kidney disease (ADTKD). aka medullary cystic kidney disease can be cause by munitions of UMOD. REN. and MUC 1 gene: familial CKD/ESRD.chronic tubulointerscitial nephrirjs, CKD. and hyperuricemia/gout Hypouricemia associated with uricosuria may be associated with recurrent exercise induced AKI resulting from muiztions in URAT or GLUT9 uansporters Factors Al¥ecting Uric Acid Level Diet Medication Pathologic conditions Hyperuricemia Hypouricemia Alcohol, red meal. seafood. high fructose die: Thiazide. loop diuretics. niacin, lowdose ASA. CNI. pynzinamide. ethambutol. pancreatic extract (for CF) Volume depleLion.Wc Be def. pre eclampsia Lowfat dairy products. coffee. plays proteins Allopurinol. febuxcstac Losartan. fenofibrate Mutation of URAT1. GLUT9, pRTA.SIADH.cerebralsak wasting HYPERURICEMIA Clinical Manifestations and Management of Hyperuricemia DiagnosislLabs Pathogenesis Prevention/Therapy Acute Url: Acid Nephropathy IV fluid (HCOi controversial) AKI + UA >15 UA overproduction:TLS. XOI. rzsburkase Urine UAIcreat >1 seizure Lesch-Nyhan Sd Chronic Urate Nephropathy CKD » Deposition of sodium orate CKD management UA >9 for Cr s1.5 crystals in the medullar UA lowering agents UA >10 for Cr 1.5-2 interstitium - chronic UA >12 for Cr >2 interstitial fibrosis DDx: lead nephropathy Uric Acid Nephrolithiasis Cli stone analysis Low urine pH. high urine UA Urine alkalinization UOP >2 Ud XOI in hyperurkosuria (no RCT) Gout UA can be nl within 2 wk of Deposition of orate crystal Acute attack :reared wl an acute attack acute gouty arthritis (starts colchicine. steroid (intra Urabe crystals on polarized mostly at night dlt low articular/po) or unSAIDs light microscopy body temp) UA <6 (<5 stophi) w/ XOI Chronic gouty arthropathy Tophaceous gout (connective tissue deposits) Asymptomatic High Uric Acid 2/3 of T UA is asymptomatic The degree of T UA is alw T Consider of of male wl UA UA >8 risk of gout and >13.female wl UA >10 up IM 1018;178;1516; nephrolithiasis Uncertain role of UA in A]KD 2015.66945) CKD progression General Management Goal: lower UA levels by s1-2lmo Weight loss. purine restricted diet Die: modifications: ' coral calories. refined carbohydrates.saturated far. meat and fish, T lowfat dairy products. plant proteins Cherries reduces recurrence of gout;Vit C (500 mild) reduce UA levels by 0.5 Xa n th i n e Oxi d a se In h i b i to rs (XOI) Initiate w/ antiinfiamrnatory drugs to prevent acute iiareup Do not use w/ 6mercaptopurine and azathioprine; metabolism is inhibited by XOI Allopurinol: a/w lower incident renal disease than febuxostat (Ann Meum on 2017;76216691 Stan w/50 mg qd in CKD4-5: 100 mg qd othewvise: uptitrate dose monitoring toxicity (can exceed 300 mild) (ACR Guiddmes Animas cm an 1012;64:143) Allopurinol hypersensidviry (dosedependent): high risk if +HLA8*5B01: / in Han Chinese.Thai. Korean. African American ¢s¢~» Anhms Rheum 2011;4s=s94):AKI. fever. rash. eosinophilia,T LFTs Other s/e: vasculids.AIN. xanchine or oxypurinol crysralluria and urolirhiasis Febuxostan star: wl 40 mg qd: No crossreactivity w/ allopurinol s/e:T all cause and CV morality or ailopurinol in pts with coexisting CV conditions (NE/M 201&17s:1100): T LFTs. myopachy and rhabdomyolysis in CKD \qAs~ 20174117441 AntiIn(Iammatory Drugs Treatment of acute gout and initiation of XOI Colchicine.cor:icosceroid unSAIDs U Rheumatol z01&4s12nl HYPOURiCEMIA Background Low serum UA <2 mg/dL Hypouricemia is pathological in conditions alw renal umm reabsorption defects (je, hypouricemia due no hyperuricosuria) Etiologies Decreased UA production: . XOI therapy, liver disease Hereditary xanthinuria (deficiency In XO): xanthippe stones treated with hydration and urine alkalinization. myopathy Purine nucleoside phosphorylase (PNP) deficiency: recurrent infections UA oxidation: rasburicase Decreased UA tubular reabsorption Fanconi syndrome. volume expansion, SIADH. Sal: wasting Familial renal hypourlcemia: nonAshkenazi Jews and Japanese. mutation in URAT 1 or GLUT9 leading to decrease orate reabsorption. GLTU9 more severe symptom atology than URAT1. recurient nephrolithiasis and exerciseinduced AKI ExerciseInduced AKI in Familial Renal Hypouricemia UA is an antioxidant and AKI is due to an oxidative stress induced by exercise: other potential etiology could be due to the increase of uric acid excretion that is exacer bated by exercise leading to intratubular UA pretipitadon Some patients were successfully treated with allopurinol Prognosis is good with recovery of renal function RHEUMATOLOGY Many autoimmune disease (AID) present wir.h renal manifestations. eg. SLE; conversely lupus nephritis may develop w/o systemic manifestation of SLE Rheumatologic Conditions and Kidney Systemic diseases/conditions SLE, systemic sclerosis. IgA vasculitis (HSP). associated with kidney Cryoglobulinemia. ankylosing spondylitjs (loAn) involvement Allergic interstitial nephritis: SiOgren syndrome Medicationassociated AID immune checkpoint inhibitor AID causing AA amyloidosis (NEWZOl8;37B:1$8) AID 3/w 60% ofAA amyloidosis. RA (33%) is mlc (NEW 2007;3$6:136Il Treatment of rheumatologic conditions allw kidney involvement unSAIDs: vasoconstriction. interstitial nephritis. papillary necrosis Allopurind: interstitial nephritis. DRESS Sulfasalazine interstitial nephritis AntiTNF agents: lupus nephritis. pauciimmune crescentic. Renal disease affecting course of rheumatologic conditions ICmediated (nor z0os5n 14001 Exacerbation of gout by diuretiWCKD SvsTEmic ScLERosls (SSC) An autoimmune disorder causing vasculopathy and fibrosis of skin and multiple organs Skin: edema and redness -» :hickening sclerodacryly. fingertip pitting ulcer ClassiNcadon of SS: Based on Skin Involvement Limited cutaneous 5Sc (lcSSc) Skin imolvemem on extremities distal no elbows and knees >face CREST syndrome: calcinosis cuds (soft Ussue calcification). Raynaud Diffuse Cutaneous SS: (dcSS:) Skin involvement on trunk. disvaLand proximal extremities and face Scleroderma renal crisis: more common Restrictive cardiomyopathy phenomenon. Esophageal dysmoziliry, Sclerodactyly. and Telangieciasia PAH >pulmonary fibrosis Andcenuomere Ab Anniiopoisomerase1 (Sci70) Ah AntiRNA polymerase ill Ab Vascular involvement Raynaud phenomenon. telangiecizsia Albuminuria (25%), intermediate MW proteinuria (31.3%) a/w GI involvement and dcSSc (on Nepnra z00a:1rn110): MPOANCA crescentic GN (Gln r4¢pw 2W7;68:l8$) Penicillaminez used as antifibrotic; a/w MN, MPOANCA GN (I Rheumami zuoe,J3:1 see) Myeloablative autoHSCT improved eventfree and overall survival (nf,1M 201S;37&3$) Scleroderma Renal Cnsis (SRC) Prevalence: 5-10% of systemic sclerosis w»»~»»a=d»=w 1009;4&ii3zi Risk factors diffuse SSc. CS 215 mg/d prednisone (Andris Rheum 19ss,41=1sn),an¢iRNA polymerase Ill Ab (25% risk vs 2% if -) (Nheumambgy 1D09;48:1570), fine speckled ANA Less common w/ anticentromere Ab (QW 2007:100485) AKl not explained by other causes. malignant HTN: abrupt onset or worsening of HTN, t PRA, retinal hemorrhage and exudates TMA: MAHA (schistocytes.' relics. 1 hapto.t LDH.. indirect bill) + Lplt Urinalysis: normal or mild proteinuria with few cells or casts Kidney Bx:TMA. onion skin hypertrophy from intimal proliferation and thickening vascular thrombosis. glomerular ischemic collapse,and peritubular C4d deposits a/w poor renal outcome (Hum Panini 2009=40aaz) Treatment indefinite ACEr (T patient and renal survival) (Ann ii 199e11a:351:2au0.133¢w0;. ARB unproven: avoid glucocorticoidsal PLEX (nor 1011;1714398) Prognosis ESRD (54%), death (41%) despite ACEi on 45.8 mo flu (Rnmmawlqy 101L5 114ao); Kidney may recover in up to 18 mo of dialysis on ACEi (Am IM zuaaiauooi Transplantation: wait for 6-1B mo for recovery; patient survival is better than on dialysis 90.1% (vs 81.1%), 79.5% (vs 54.6%) as 1 and 3 yr :Alf 1004;4:2017)C 2V0id CNI in; llheinnalal 1 w4;aa90) and highdose cs RHsunAToIo ARTHRITIS (RA) (umm Dis an Nadl Am 201B:44:57 1) Background eGFR <60 more common (25-34%) dun general population (A}XD 2014163:2062 On Rnwnalal 1017:36:2b73)I chronic inflammation mediated CVD and metabolic changes Hydroxychloroquine use is a/w 1 CKD Ieyasu 201813:701) Rheumatoid Factor: IgM antibody against IgG Fc portion; elevated in various conditions: Rheumatologicz RA. type II & III cryoglobulinemia Aging, infection (endocarditis. HBV. HCV.TB) sarcoidosis. silicosis. asbestosis. PBC Me th o tre xa te (MTX) MTX is excreted by glomerular Filtration and tubular secretion Rheumatologic dose d MTX does not abuse crystal nephropathy as in oncology high dose MTX cause bone marrow suppression in CKD imp: fal 1006:28;95) CrCl 31-50: reduce dose by 50%; CrCI s3lk contraindicated (ACT Annnzluiw zouaiswszl Glomerular Disease AA amyioidosis (17.2 yr) and mesangial GN (129 yr) 2lB a/w longer disease duration d can MN (3.8 yr) (Afdv-» NM 1ws;J&z4z); Fat pad aspiration can diagnose AA amyloidcsis Drugs a/w MN, bucillamine. penicillamine. gold.and auranoGn are now rarely used Sl6CNEN SYNDROME (SS) Background and Extrarenal Manifestations Lymphocytic inhltntion around epithelial dum d exocrine glands (salivary. lacrimal) gland Sicca syndrome: keratoconjunctivitis sicca (dry eyes). xerostomia (dry mouth) Secondary form (alw RA. SLE. scleroderma) has exuaglandular findings: ILD. cutaneous vasculitis. peripheral neuropathy t Lymphoma (NHL) x6.S, in primary and secondary form (tiu ad 10C8=111;40291 (+)AntiRolSSA.AntiLalSSB Kidney biopsy:TlN (71%) >> MPGN (8%). cryoglobulinemic GN, FSGS (QASN 200~h4:1423) Tubulointerstitial Nephritis (TIN) in Sjiigren Syndrome CD4+T lymphocyte dominant; Granulomatous TIN is me (qAsn z009.414231 Tx: prednisone.AZA. rituximab, MMF iamc Mutallndrekt Damn 20ie17¢11 Other Renal Manifestations No CKD4 progression to ESRD (qASN 100%4;1423).The other study showed 11% ESRD (A/uvmi Rheum 201J;6$.1M5) GN a/w T death. CKD. lymphoma (Artemis Nnfwn 2013;6$:z94s1 Cryoglobulinemit GN: 32.5% (m/c noninfectious cause):22.5% S16grens only: 10% SlOgrens + hematologic malignancy (;ASN 2016217112131 S1Ogrens wl cryoglobulinemia has T mortality (x4.36) than wlo (kleumawligf 2016:§5:1443) dRTA >> pRTA: absence of HATPase in CCT UASN 1s9zJ;ze4);Ab against CAII iAni}m¢4 inns.11&1a1); severe hypocitraturia -» CaP nephrocalcinosis; stone 4/24 (c/Asn 2009;4¢1413) Hypokalemia dRTA. sodium wasting (QIM 199ms;s1zl; rarely Gitelman syndromelike metabolic alkalosis with antiNCC Ab we z00e:s2:1163) Nephrogenic DI: polydipsia can be attributed to xerostomia VASCULITIS Large Vessel Vasculitis Takayasu arterials: renovascular HTN >50% Gian: cell aneridsz rare renal in»olvemencANCA GN may present (~~=»~w¢u 2014:s3w) Medium Vessel Vasculitis Polyaneritis nodosa: alw HBV frequently; renal artery microaneurysm -» rupture. peri renal hematoma, renal infarctions; mild proteinuria. CKD. HTN (dl: RAS activation) Skin: redform (angulated) purpura 1 palpable purpura Small Vessel Vasculitis IgA vasculitis (HSP). staphassoclated IgA dominant lRGN.ANCAassociated GN. cryoglobulinemia Renal manifestation: GN with hematuria and proxeinuria Skin: palpable purpura. telangiecusia. ulcer urticaria Skln biopsy: Ieukocytoclastic vasculiziszdirecc IF should be performed IgA deposition in IV. IgM deposition in cryoglobulinemia. pauciimmune in ANCA PAIN MEDICINE ANALGESIC NEPHROPATHY CKD due to years of consuming as leas: 2 analgesics. usually containing codeine or caffeine (A;XD 1996:27:16112 can also occur with single agents Most cases were due to phenace:in.rnuch less common since banned in 1983 by FDA Phenacetin also linked to urochelial malignancies Chronic acetaminophen: possible (NEW 2001:34S:1B01)I aspirin: unlikely UAMA 1001;186:315) unSAIDs cause AKI and worsening of preexisting CKD. but unclear if CKD (Ann :m 2004=\64:1s1t Am/ m¢4 2oo7;1zazs0) uses incident Pathogenesis 1AIKO 19964n5s391 Phenacetin metabolized no acetaminophen and other metabolites.which concentrate in renal papilla. causing damage by lipid peroxidation: most damage in renal medulla Aspirin potentiates effect of acetaminophen by further depleting glutathione. which n o rma lly d e to xifie s a ce ta min o p h e n Clinical Manifestations,Workup, and Treatment Renal papillary necrosis. chronic interstitial nephritis. 1 urinary concentrating capacity (KI 1007:72:517) Often clinical diagnosis based on history.bland urine. minimal proteinuria Noncontrast CT: indented kidneys and papillary calcifications but low sensitivity, especially in absence of phenacetin (5-26%) (MSN 2006;17:1472) Sensitivity of ultrasound likely even lower sensitivity, but frequently firstline imaging Urinalysis with spot proteinuria (usually <1.5 g) (KI Z007:72:517) Tx: no specific treatment other than stopping offending analgesics P rognos i s If analgesics are stopped. eGFR can stabilize if there is not heavy proteinuria or CKD is not advanced. heavy proteinuria can develop due to nephron loss Monitor patients with a history of phenacetin use for transitional cell malignancy N s r H noTox lc 1 Tv oF unSA ID s Mostly associated with AKI but can worsen preexisting CKD and may muse incident CKD: no established sale dose/duration in setting of CKD. risk higher with lower GFR Topical unSAIDs with far less systemic absorption than oral.fewer side effects (See Anhwx Rheum 1016;45:51911 case reports of renal failure after topical use. not well studied in CKD.c a nnot routine ly re c omme nd c urre ntly COX2 inhibitors: risk of AKI may be lower with celecoxib than naproxen or other nonselective unSAIDs (RR 1.5 vs 2.4 and 2.3. respectively) rAm} £via¢mIaI 2006:164:881) Pathophysiology and Risk Factors Inhibit renal prostaglandin (PG) synthesis; PG -o renal afferent arteriolar vasodilation and natriuresis. in normal circumstances. not very important In setting of hypoperfusion. renal PG needed to counteract excessive renal vaso constriccive effects ofAIl and SNS to preserve renal blood flow and GFR . unSAIDs blodt PGs. leading no vasoconstriction. renal isclleinia.L GFR. and fluid retention AKI risk factors CHE cirrhosis, nephrotic syndrome, hypercalcemia. volume depletion (all conditions that lead to decreased effective arterial volume): also CKD. elderly Concurrent ACEI/ARB + diuretic v unSAIDs combo increase risk (5m}101J;346 ¢8525> Clin ica l Ma n if e st a t io n Hemodynamically mediated AKl,ATN,AIN, MN. MCD. chronic tubulointemitial nephritis. hypertension lNE;M 19B4:310:563) Usually minimal proteinuria (<0.5-1 g).wlth acellular urine; heavier proteinurla suggests MN or MCD. or from preexisting CKD; sterile pyuria suggests AIN Electrolyte Derangements Hyperkalemia: UNSAIDmediated decrease in aldosterone release. hyporenin state from d e cre a se in P Gs.a n d a n y co n cu rre n t re n a l fa ilu re Hyponatremia: increased ADH activity from decrease in PGs.and concurrent renal f a ilu re wh ich limit s f re e wa t e r cle a ra n ce Treatment Supportive. volume replerlon. hokl UNSAIDs/ACEIIARB: may need biopsy if no improve men: in few days. or if atypical labs such as >1 g proneinuria or cellular urine :had would suggest a lesion other than ATN (eg, membranous.AIN) PAIN CONTNOL IN CKD AND ESRD (ScmmOal2014;27:188) Mo s: data in HD. prevalence 21-81%. similar in PD and nondialysis stage 5 CKD: narly 73% in one study of CKD 1-5 paciencs (cm n¢w-u1 z010;7:4:z94) Adjunctive nonpharmacologic therapies (kg,exencise, behavioral Maw) should be tried Pharmacokinetics of analgesics are different in CKD vs nonCKD General Approach to Chronic Pain Modified WHO Analgesia Ladder (1Asr4 z00s;w1:19s) Step 2 Acetaminophen Hydrocodone. oxycodone. tramadol Step 3 Hydromorphone. methadone. fentanyl. oxycodone Step 1 Avo ld u n SAIDs. me p e rid in e (ca u se s se izu re s) If ineffective add tramadol, or switch to lowdose opioids with slow titration if needed Ne u ro p a t h ic P a in Common in CKD given high prevalence of DM Tac sun wl SNRI or gabapendn/pneigahalin; cautiously use TCA: open need combo dierapy Lidocaine patches if localized; addon acetaminophen +I- opioids/tramadol if needed C a r p a I T u n n e I S yn d r o m e 9-63% incidence in ESRD. increases with duration of time on dialysis: due to deposition of B2microglobulin amyloid. extracellular calcification. and ischemia related toAV access T>c usually splinting. cs injection, or surgical decompression for sevenelrefractory cases ADPKD Pain due to enlarging cysts. scones. cyst hemorrhagehnfection. polycystic liver disease Tx: consider surgery if mediations/conservative therapy fail, cyst aspiration. sclerodierapy Dialysis Removal and Renal Dosing of Analgesics isemi ouzo14a7;1sa; Me d i ca t i o n Re mo va l C o mme n t s a n d Ma ximu m D o sin g A ce t a mi n o p h e n HD: yes; PD: no No dose changesfrstline analgesic Co d e i n e HD: no: PD: unlikely No t re co mme n d e d . Me t a b o lize d t o mo r p h i n e d e r i va t i ve s; ca n ca u se CNS / r e sp i r a t o r y d e p r e ssi o n . h yp o t e n si o n Tramadol e G FR 1 0 - 3 0 : $ 0 - 1 0 0 mg B I D eGFR <10 or HD: S0 mg BID: dose after HD Morphine HD: yes (parendacrive mefabolices); PD: no No t re co mme n d e d . Me t a b o lit e s Hydrcmorphone HD yes (active metabolite): PD: Better talented than morphine. fewer toxic Fenranyl Buprenorphine Oxycodone Methadone HD/ P D: n o a ccu mu l a t e i n CK D ca u si n g se d a t i o n . co n f u si o n . r e sp i r a t o r y d e p r e ssi o n . myoclonus ! met abolit es Inactive metabolites, safe to use if monitored HD/PD: yes Generally saf e t o use HD: yes; PD: ? Generally safe to use. case reports of toxicity HD/PD: no Similar plasma levels as nonCKD, may help wit h neuropat hic pain. generally saf e Gabapenlin sle: CNS depression, myotlonus if overdosed CrCl <1$:dose after HD: 300 mg QD:stzn 100 mg after HD or 100 mg QOD if not ESRD; CrCl 15-29: 300 mg BID: CrCl 30-49: 3 0 0 mg Tl D; Cr Cl 5 0 - 7 9 : 6 0 0 mg T I D Pregabalin HD/ PD: yes QGFR <15: dose af t er HD: 75 mg QD: st art 25 mg alter HD or 25 mg QOD if not ESRD e G FR 1 5 - 3 0 : 1 5 0 mg Q D eG FR >30: 150 ms B I D P w u Duloxedne 30-60 mg daily: eGFR <30: do no: use TCA (amitripryiine, nomipryline) Use cautiously esp, in cardiac patients, can Topical capsaicin Useful for local pain (eg. knee osteoarthritis) cause QT prolongation and arrhythmias. start low (je. 10 mg QD): nortripcyllne may be better tolerated with less sedation PSYCHIATRY, SLEEP MEDICINE, AND NEUROLOGY CHRO NIC L IT HIUM T O XICIT Y Lithium (Li) commonly used to treat bipolar disorder. mania. and depression Pathogenesis Li freely filtered at glomerulus; absorbed as various points in nephron uAsr4 201s;21=1 San In proximal tubule. small amount of transcellular and paracellular reabsorption In thick ascending limb. paracellular movement due to favorable luminal gradient cre ated by potassium efflux into tubule via RO MK channel In distal tubule/collecting duct. reabsorbed by principal cells through ENaC.causes nephrogenic Dl (NDI) by downiegulating aquaporin2: Dl also caused by increased prostaglandins. which inhibit aquaporin2 expression Hypercalcemia due to hyperparathyroidism. raising threshold for calcium sensing receptor in paradiyroid gland (lame 2012;an721; Jam 1984:59:354) C lin ica l M a n if e st a t io n s Nephrogenic DI: polyuria/polydipsia.hypernatremia.dilute urine. nocturia CKD: chronic cubulointerstitial disease. renal microcysi.s.can progress to ESRD (15% in Li users. 68x higher than general population) UASN 1018;1731 ssn Typioliy subnephrodc pnoieinuria (<1 old usually). but can develop FSGS and increased proteinuria; also rarely nephrotic range proteinuria with MCD Hyperparathyroidism with hypercalcemia-up to 25% (KI 2003;64:58S1 Wor kup / BMR UIA with spot proteinuria and osmolality. PTH. UIS: microcysts Renal bx: proximal tubular atrophy and chronic interstitial fibrosis. FSGS. microcyszs originating from distal tubule/collecting duce. distil tubular dilacadon In lB03:64:5B5) 8 é N ephr ogenic D I ( N D I ) First option always dlc Li if possible NDI can improve if treatment begins prior to onset of severe concentrating defect Preferred: if continuing Li. start amiloride 5-10 mg daily, competes with Li for ENaC. blocking entry into principal cells and T urine osmolality, if concenuating defect not severe 1NE/M 19a5=31z4asl; monitor Li level as can T due to amilorideinduced volume depletion and increased proximal tubular reabsorption Other options similar for any fuse of NDI: (1) unSAIDs which 1 prostaglandins and concentrate urine, but contraindicated with CKD: (2) low salt diet/thiazides -» hypo volemia,causes i proximal urinary reabsorption.and i urine output. monitor Li levels closely: (3) Acetazolamide (experimental) <~2Jm z016:.7s.100el CKD Stopping Li can stabilize or modesdy improve renal function if CKD not advanced. otherwise can still progress. may be a "point of no return" around eGFR <40 where renal function continues to decline even if Li is stopped (KJ 2003;s4=sB$) 7/9 patients with Cr >2.5 progressed to ESRD despite stopping Li ()ASN 10t10.11:1439) Greater proteinuria alw poorer prognosis and higher rates of ESRD. possibly due to superimposed FSGS UAS~ 2000211:1419) O ther T r eatments Hypercalcemia treatment: if severe consider cinacalcet (App) 2006:48:8J 1) Cautious use ofACEllARB and thiazides which T Li levels: monitor levels closely. usually need empiric Li dose reduction ANX IE TY in CKD (s - D°» ,=» » 1 0 1 5 :1 8 :4 1 7 ) SSRIs can be used for generalized anxiety disorder Benzodiazepines can be used, most hepatically metabolized and no dose adjusunen: needed: Chlordiazepoxide has active merabolices -» 50% dose reduction: other ben zodiazepines would start lower than usual dose PsvcHosls in CKD (Semn n4¢vi=»= 2015:19:417) Aripiprazole and quetiapine have similar pharmacokinetics in CKD and nonCKD Risperidone should be dose reduced with CKD due to active metabolite Haloperidol not well studied but unlikely to need dose adjustment Monitor for side effects including prolonged QTc D EA N £SSIO N IN C K D Prevalence 22% in both dialysis and nondialysis CKD. and is associated with increased mortality (Ki 2013:a4:17/: kw 1013:62:493) Adverse outcomes in CKD patients with depression may be due to increased inflam mation. nonadherence. autonomic/endocrine imbalances Likely underdlagnosed; routine screening controversial. unclear if treatment improves outcomes; depression scales should be adjusted with higher thresholds in ESRD (eg, Beck Depression Inventory threshold t (rom >9 to 14-16) Lu 100616116629 T reat m en t RCT data lacking. ideally should be combination meds/behavioral changes Underrreaced (<50% on meds) in ESRD (xl zoos;sm 1se2) Nonpharmacologic rreacmenc limited dm show bench: for CBT and exercise Meds: SSRI generally firs: line; in generaI.any medication should be started at low dose with slow cirrarion Antidepressants In CKD 00201u1z47= Apu:1009:s¢741; Aw N 1) nynuevy 2014;40:510) Medication Dose and Comments SSRI Ciulopram Ciulopnm: start 10 mild: active metabolites. cautious use if eGFR <20 Fluoxecine Sertraline Paroxedne although probably safe based on small studies lAM rea z001=29=e1n Fluonnedne: sur: 20 mg/d: no renal dose adjusunenl. use uudously because long halfIife.smalI studies showed safety in ERD an my-uw m iv 1997a7:7\) Senralinez sun S0 mg/dzactive metzbolire bu: no renal dosing Paroxedne (immediate release) accumulates with eGFR <30. Starr at 10 mold, increase slowly co max 40 mg/d Class sle: nausea. hyponaznemia. sexual. HA. ? bleeding Rdadve good safety record was cardiovascular disease SNRI Venlafaxine Duloxenine Trazodone Bupropion Mirtazaplne Venlafaxine: toxic metabolites. avoid if eGFR <10.l dose by 50% for eGFR 10-50;stan ER 37.5 mg/d;side effects: HTN. sexual Duloxetinez in 30 mg/d: do not use if eGeR <30;side effects: nausea. dry mouth. fatigue No dose adjustment but start low (150 mg immediate release) in divided doses:can be used for insomnia (start 25-50 mg QHS); side effects: sedation. priapism. dry mouth Toxic metabolites. can fuse cardiac dysrhythmia Nor recommended for CKD Antidepressanrlanxiolytic effects; sedating properties: accumulates in ESRD. use with caution (Hum f»<~i#w~»°t=I 19ss4imxsn TCA Amitriptyline Can have cardiac side effects including QTc prolongation and anrhrythmias. Nortripqrline Desipramine and anticholinergic effects; use with caution Stan with low dose (10 mild) and increase slowly Can be useful for neuropathic pain SL EEP D l s o n o s n s : n C K D Insomnia and Poor Sleep Quality (Semm ~¢l»v1 Z015:3$:]S9) Prevalence 2040% and increases even in early CKD:a/w somorbid conditions including fatigue. depression. and anxiety; may increase risk of mortality in ESRD (NDT 1008;13:998) Conuibutcrs: comorbld conditions (eg.CHE depression).mediations. pmrims. pain, dialysis schedules. physical inactivity. nocturia. substance abuse History: if heavy snoring. restless legs, parasomnias. refer to sleep specialist to rule out more serious sleep conditions (et, OSA) Nonpharmacologic treatment preferred over medications Start with trial of slip hygiene. treat comorbidities. modify any culprit meds Cognitive behavioral therapy has efficacy in ESRD W 2011m¢41s) Pharmacologic treatment; limited data in CKD, always start at low doses No dose adjustment for nonbenzodiazepine benzodialepine receptor agonists such as zolpidem. zaleplon. eszopiclone (hepatially metabolized) Melatonin receptor agonist ramelteon not well studied in CKD. no dose adjustment Benzodiazepines and trazodone can be used as well (see above sections) Restless Leg Syndrome (RLS) Definition: an urge to move legs during periods of rest. usually worse at night, accompanied by discomfort. and relieved by movement Distinguish from periodic limb movement disorder. characterized by increased limb movements in sleep Prevalence: much higher in ESRD than general population (30%),significantly lowers quality of life (KI 2013;85112751; nondialysis CKD similar to general population Risk factors in ESRD: low iron/hemoglobin and diabetes :so mea zo\411s11sn) Treaunent (xi 2013:B51275) Improves with transplantation (Mor aims 2002:17:1072) Fix iron stores/anemia. remove SSRIITCA (may exacerbate RLS). dopamine agonists (firstline medications). gabapentin/benzodiazepines (secondline) Sleep Apnea Syndrome in 200s;10 1sa7i Definition: disturbed sleep from periods of apnea -» oxygen desaturation and arousal Prevalence: >$0% in ESRD vs 2-4% in general populationzt risk of CVD Different phenotype in general population. usually obstructive. in ESRD even distri bution between centrallobsuuctive/mixed; possibly due to uremic toxins.volume overload, altered chemoreceptor sensitivity affecting respiratory control Treatment; CPAR nocturnal hemodialysis (NEW 1001;344:1021. transplantation Hanging style STROKE AND CEREBROVASCULAR DISEASE CKD is an independent risk factor for stroke; T risk 41% with eGFR <60 raM/ 1010341:c4149) Dialysis patients have 10x T risk of CVA and carotid endanerectomy vs general popu lation. ischemic stroke most common. embolic most common subtype; high mortality and worse neurologic outcomes We 1009;54146a Neuinlqy 20iua1909) Perfusion abnormalities, subclinical white matter disease. brain atrophy.and silent infarcts more common in CKD. especially dialysis (Sunni Nepnid z01s;as:311) Besides traditional stroke risk factors. nontraditional risk factors more common in CKD (anemia, inflammation, oxidathre stress. uremic toxins. sleep dysregulation) Stroke Prevention in Setting of Atrial Fibrillation (A fib) A fib common in CKD. exact management unclear Warfarin use appears to reduce stroke risk, but may increase bleeding risk in CKD. particularly in dialysis patients. and anticoagulation risk needs to be individualized (WI 201§;]50:h246: WM 1014131 l:919) Warfarin may have other adverse effects in CKD;associated with T vascular calcifica tion in animal models, by interfering with matrix gla protein. which is a potent inhibi tor of vascular calcification: also T risk for calciphylaxis (Mai Dd z014;17=371 Novel anticoagulants require dose adjustment in CKD. none well studied in ESRD where warfarin Is still drug of choice: in retrospective cdion study apixaban 5 mg BID reduced risk of suoie. bleeding, death vs warfarin while apinahan 2.5 mg BID reduced risk of bleeding but not deadilsuoke vs warfarin (cranium. zmaiaeiswi Stroke Treatment Therapies less likely so be utilized in CKD (Seam n2p"ml 2015,zs23111 No dose adlusunent for tPA. but outcomes less favorable in CKD (nnuulqy 101381:17a0> COGNITIVE DECLINE AND DEMENTIA Epidemiology: even mildtomoderate CKD is a risk factor for cognitive decline Cognitive impairment in 30-60% of HD patients ()A$n 2013;24=3s3) Manifests as a vasculamype dementia with impairment in memory and executive function (m Rey Neural 1009:5:542)i may also raise risk of nonvascular dementia Pathophysiology: Tradrdonal and nomradltional (anemia. Inflammation,oxidative stress. uremic toxins. sleep dysregulation, endothelial dysfunction) risk factors clustered in CKD L cerebral blood flow.t subclinical cerebrovascular disease on MRI Potential improvement after transplantation (NOT 200s;21:327s) NEUROPATHIES (Not Rev Neuld 20025:5421 Ure mic Ne u ro p a t h y On ly in E S RD, p re va le n ce 6 0 -9 0 %.ch ro n ic p ro ce ss Clinical Manifestations: symmetric lengthdependent polyneuropatlvy. starting with sensory deficits. paresthesia. loss of ankle reilexesz can eventually involve motor nerves mu scle a tro p h y a n d we a kn e ss Differential: diabetes. paraprotein disease.vasculitis. inflammatory demyelinatlng neuropathies (associated with FSGS and membranous. usually much more acute) Dia g n o sis: n e rve co n d u ct io n st u d ie s Treatment: ensure achieving adequate clearance on dialysis: transplantation may re ve rse symp to ms. p a in ma n a g e me n t Carpal Tunnel Syndrome isemm Op: 1014:171881 Common in ESRD: 9-63% prevalence. increases with duration of time on dialysis Clinical manifestations: sensory symptoms initially (numbness. paresthesia) which can progress to muscle atrophy in medial nerve territory; can worsen on dialysis Pathophysiology: multifactorial; deposition of B2microglobulin amyloid. extracellu la r ca lcifica tio n . isch e mia re la te d to AV a cce ss Treatment: usually splinting. corticosteroid injection. or surgical decompression for se ve re /re fra cto ry ca se s Aut onomic N eur opat hy 6 0 % o f p a t ie n t s wit h CK D Clinical manifestations: has been detected even in early CKD Intradialytic hypotension. orthoslasis. erectile dysfunction, cardiac arrhythmias Higher resting HR. lower HR variability predict ESRD and hospitalization UASN 1010.211s601 Treatment: may improve with transplantation (he et Oialruiupianmnac 1979:16:261) Midodrine for intradialytic hypotension S ild e n a fil fo r e re ctile d ysfu n ctio n . has most day for CKD: consider holding on dialysis days if imradialytic hypotension ACUTE UREMIC ENCEPHALOFATHY Due m buildup of uremic toxins: result: in irritability. confusion, headache. nausea, tremor. asterixis, myoclonus. coma (in severe cases). treatment is dialysis Treaunent is dialysis. overly aggressive dialysis on initial treatment with high BUN can precipitate dialysis disequilibrium syndrome DIALYSIS DISEQUILIBRIUM SYNDROME (Semin D041 200822049J 1 Clinical manifestations: headache. nausea. fatigue, seizures/coma (severe cases) Risk factors: old age,very high BUN. initial treatment, neurologic disease Padlop physiology: cerebral edema due to osmotic shifts; rapid decline in plasma BUN causes water to shift intracellularly: also possibly from paradoxical CSF acidosis induced by rapid correction of serum bicarbonate levels with dialysis Prevention: slow, gentle dialysis aiming for no more than 40% urea reduction during first session: et. 2 hr, blood flow 200 mUm in. with small Winer: IV manniml/hypenonic saline for prevention. but data limited; increases dialysate sodium 143-146 mEq/L may b e h e lp f u l if h ig h risk Treatmenc supportive. reduce dialysis blood flow: terminate dialysis if significant symptoms; IV mannitol or hypertonic saline may be useful: key is prevention UREMIC MYOPATHY Up to 50% of dialysis patients; proximal muscle weakness/wasdng. especially legs Pathophysiology unclean! role for hyperparathyroidism. vitamin D deficiency. uremic toxins, malnutrition, muscle biopsy nonspecific Trearmenc correct metabolic disarray. nutritional sums. anemia DRUGINDUCED ENCEPHALOPATHY IN CKD Numerous common medications implicated. especially when incorrectly dosed H2 antagonists: infrequently causes altered mental status and delirium. improves with withdrawal (Am1 m¢a so zoosaaozal Baclofen: presents wl altered mental status. respiratory depression. somnolence; avoid with eGFR <60. no safe dosing guidelines in CKD; treatment is daily dialysis (Semn ons 101538: 525) Gabapendn: entirely renally cleared: useful in CKD for neuropathic pain, uremic pruri ms. restless legs: improper dosing can lead to accumulation causing myodonus,altered mental status, coma (pm Med z009110.1901 Acyclovir We 1992;10:647) and valacyclovir in PD: celepime CEREBRAL EDEMA AND RENAL REPLACEMENTTHERAPY (Semin Dal 2D09;22.16§) Cerebral edema and elevated intracranial pressure can be seen with trauma, hemor rhage. stroke. liver failure. tumor, infection Pathophysiology intermittent HD (HD) can worsen cerebral edema by removing solutes from plasma. causing an osmotic gradient favoring movement of water intracellular also rapid correction of plasma bkalbor\ate,which cannot readily cross bloodbrain barrier can combine with hydrogen ions - CON formation -» diffuses into CSF > inuacellular acidosis -> generation of intracellular osmoles and water mo.~ement intracellularly CRRT preferred over iHD. due to less osmotic shifts and greater cardiovascular and intracranial pressure stabilit aim for lower clearance than usual If HD must be used: start low blood flow (50 mUm in increasing to maximum 250 mUm in). short sessions (2 hr), daily treatments, cool dialysate (35C). higher dial ysate sodium (up to 10 mE/L higher than plasma). lower bicarbonate dialysate Hypertonic saline boluses an be used during HD or CRRT to maintain sodium 145-155 SODIUM DISORDERS 57% in one series. with 20% developing sodium <130; more commonly due to SIADH than cerebral Sal: wasting (69% vs 75%) (an Eniiuainal 1006;s4¢1s0);although true incidence unknown given diagnostic challenges Cerebral salt wasting usually within 10 d. resolves by 3-4 wk (nor 1000:15:262) Comparison of SIADH and Cerebral Salt Wasting SI AD H Cer ebr al Salt Wasting Elewcedz >40 Elevared;>100, often higher Elevated: >40 Elevaced;>100,of:en higher Usually low Euvolemic/slightly hypervolemic Typically normal Usually low Hypovolemic 1 Skin wrgor, hemoconcencrarion. T BIJN/Cr ratio. ordiosrasis. relative hypotension Pathophysiology Inappropriate ADH secretion Response w IV normal saline challenge Does not improve. may even worsen if Um >300 as infused sodium is excreted bu: some water is reiainedc Um does no: change significantly Unknownzl syrnpathelic reducing FT Na absorption, possible unidentified nacriureric factor (nor zoa0.1s= 1s21 Should improve hyponanremia as restoring volume :urns off ADH, causing excretion of dilute urine;of note. :his is no: always the case as there may be coexisting SIADH Urine sodium Urine osmolalizy Serum uric acid Volume scacus Physical exam/ Other Lab Treatment Fluid restriction or vasopressin antagonist; however if SAH, cannot fluid restrict dk risk of vasospasm. give hypertonic saline to ensure volume and sodium correct ($6 T R4 hr) Volume expansion widl IV normal saline; +I- fludrocorzisone: given diagnostic difficulty with SIADH, star: hypersonic saline if sodium not improving Transsphenoidal Pituitary Surgery (1 Nwmrug 2007:10666: Fiwwr 200/:9:93i Both SIADH and DI can occur postoperatively though DI more common Associated win\ classic triphasic pattern. although incidence of this parer is low 1. Polyuria and hypernatremia from CDI (19% Incidence: usually first 48 hr ) 2. Hyponatremia from release of stored ADH (994 incidence: 4-7 d postop) 3. Hypernatremia from CDI when stored ADH depleted TX: depends on phase: DDAVF during DI.fluid restriction or hypertonic saline during SIADH Monitor sodium 1 wk following surgery as outpatient to check for SIADH 80% of DI resolved at 3 mo at one center OBSTETRICS PREG NANCY AND KIDNEY Weight gain: 1-1.5 kg during 1s¢ zrimesrer (12 wk).0.45 kglwk during 2nd (13-27 wk). and 3rd ¢rimes¢er (28-40 wk) (nor 199e;1J:Jz4»6). Overweighdobese mothers gain more weighs; underweight gain less weigh: (cam G/~<~2015:1zs:773) 1 SVR.t CO. l MAP (nadir as 18-24 wk);glomerular hyperfilr.rnion.t GFR by 37-4098; 7 Kidney size by 1 cm.dilaxation of the collecting duct R > L (qAsn 101271073) Adverse pregnancy outcome is lower with eGFR 120-150 lcusu 2017,111048) Effects of T Progesterone (LH Surge ~4 wk before Delivery) and its Binding to Mineralocorticoid Receptor (MR) 1 Aldostemnism Anragonisdc; Potassium rexemion Antagonistic; Resolution of HTN and hypokalemia Geller syndrome GOF murazion of MR: progesterone and spimnolactone become Normal agonist; HTN and hypokalemia (Saenze NU0.1a9=119) . PT reabsorption: glycosuria. amino aciduria. tubular proteinuria w/o true pathology Hypokalemia and metabolic alkalosis: dl: vomitingzl serum albumin Gesradonal DI: vasopressinase produced by placenta: polyuria throughout pregnancy. recurs w/ each pregnancy. responds to both DDAVP and AVP Other DI: alw HELLR acute fatty lMr: 3rd trimester; decreased metabolism of vaso pressinase; responds only to DDAVP Preterm and early term birth is alw later CKD likely dlt i nephron (aw 201%3A5:I13461 MEDICATIO NS IN PREG NANCY Hyperiipidemia Amkoaguhrion Warfarin Dose requirement is increased dl: T volume of distribution, hepatic metabolism. GFR. and l albumin and drug protein binding Medicat ion during Breast f eeding For a list of medication use in breastfeeding. please refer to the LactMed Database: https:l/toxnet.nlm.nih.govlnevnoxnet/lactmed.htm Era la. capto. and quinapril do not pass into breast milk: warfarin is safe for brezsdeeding Most andhypertensives are present at breast milk; kbeizlol and nifedipine acceptable; avoid atenolol HYPERTENSIVE DISORDERS oF PREGNANCV (HDP) Gestational Hypertension New onset of HTN (SBP 2140 and/or DBP 290) at 220 wk of gestation in the absence of proteinuria or new signs of endorgan dysfunction HTN at <20 wk is chronic HTN. not gestational HTN alw sustained HTN and CV disease later in life (j i4lp¢ne1¢ z010:zs:m) Tre a tme n t BP control may prevent maternal endorgan damage BP control may l placental perfusion:a/w 1 birth weight (/canel Gynuea\lCan z00zz4:941) Tight control (DBP goal 85) not alw 1 pregnancy loss. highlevel neonatal care. maternal complication including preeclampsia (NE/M 10155:l721407) Sak restriction close to delivery is not recommended to avoid volume depletion Ca (>1 g/d): 35% HTN and 55% l preeclampsia (a<n~»e Daahase Syxrkev 2010¢cooo\os9) Weight loss during pregnancy: not recommended; gain goal (kg): 11.2-15.9 in BMI <25; 6.8-11.2 in BMI 25-29.9; <6.8 kg in BMI 230 (be Cyan Gwen:20ae111701 Weight loss after deliveryt recommended lAM) 2017;35B113014) BP conuol in mild-moderate HTN: unclear benefit (Cotluune Daiaiaase synnezoimooozzszl Severe HTN: >150/95 lest; EurHeor]10\1:32:]147) 160/105 lncoc. onus G>~<~ 1013;11211221 should be treated w/ antihypertensive Avoid UNSAIDs:frequently used for peripartum analgesia Folkrw up no later than 7-10 d postpartum; if severe wfl 72 hr (aeu¢¢Gyn¢¢al201B;1J1;e140) Pr ognosis HTN development wu 10 yr is 14% (vs, 4% in nonHDP) (BM) zowlaseiaon Half of postpartum stroke occurs wu 10 d of discharge (own Cyndi z018:1:70) Chronic HTN (x2.8).T2DM (x1.7). hypercholesterolemia (x1.4) (Ann IM 2018;1691141 PREECLAHPSIA Pathogenesis Placental hypoperfusion inducing soluble fins-like tyrosine kinase 1 (sFlt1. soluble VEGF receptor 1. sVEGFr1): circulating antagonist toVEGF and placental growth factor (PIGF): t sFLT1/PIGF (no 20162374¢131 Deficiency of Apela/ELABELA, placental angiogenesis mediator (Soenre 1017;387:7071 Endothelial dysfunction (1 NO.t endothelin); injury of multiple organs Definition iAcoG Geaelme Cami Gynecol 201].122l122) BP >140190 after 20 wk of gestation, previously normal BP AND one of following Proteinuria >300 mg/24 hr or spot urine prodcreat 0.3 gig Platelet <100K; Cr >1.1 or doubling in the absence of other renal disease Liver transaminases >x2 the normal; pulmonary edema: cerebral or visual symptoms Severe Features:Any of Following (Acoc Goaan Obslet Gynecol 1013.112:1IZ2) BP >1601110 x2 >4 hr apart on bed rest Platelet <100K; Cr >1.1 or doubling in the absence of other renal disease Liver transaminases >x2 the normal or RUQ or epigastric pain not explained otherwise Pulmonary edema. newonset cerebral or visual symptoms Clinical Manifestations AKI:TMA (endothelial injury) Seizure (eclampsia). cerebral hemorrhage. hepatic rupture, pulmonary edema. bleeding related to thrombocytopenia. abruptio placenta. or fetal growth restriction 10-20% HELLP (hemolysis, elevated liver enzymes and low platelet) syndrome ml cause of prematurity Diagnosis in ESRD is challenging: proteinuria and renal function cannot be evaluated Uterine and umbilical artery Doppler U/S:t pulsatility index » fetal growth resuiction Risk Factors and Prevention Risk assessment is available: https:I/fetalmedicine.org/research/assess/preeclampsia Recovered AKI ()<4,7) l;Asn 2017:2a1su61. fetal APOL1 risk allele Luc 201&103=3671 Aspirin Prophylaxis for Pneeclampsla lusvsrf An IM 1014:15um High risk factors Renal disease. hlo preeclampsia. esp. accompanied by an adverse outcome.mulr.ifetal gestatiomchronic HTN.Type 1 or 2 DM. SLE.APS Moderate risk factors Nulliparity. BMI >30 kg/m*. mother or sisters ho preedampsia. African American race. low socioeconomic status. 235 ylo. low birth weigh: or small for gestational age. previous adverse pregnancy outcome. >10yr pregnancy interval Aspirin 81 ml qd if 21 high risk factors or several moderate risk actors from 12 wk no 510 d befog expected delivery Aspirin 1 delivery w/ preeclampsia before 37 wk in high risk group (NEW 1011;377:6131 Ca supplementation (>1 old): 55% l preeclampsia (Cachmne O0mnm¢ Syn an 2010;cD0010591 Weigh: loss loam: Gym#2010:116667)I bariatric surgery UAMA zucasoimssl Monitoring and Diagnosis U/S w screen for feral gmwdw reslrictiomif present umbilical artery Doppler velocimetry Kidney biopsy not always necessary T reat m en t CS for lung maturity if <34 wk with severe features M8SO4 pre and postpartum for severe features to prevent seilure;/ DTR. J Mg in mother and baby: half dose for ESRD mother BP control:antihypertensives for severe HTN >1 $0/95 - 160/105 Delivery (placental removal): only definitive treatment; consider regardless of gesladon age if uncontrollable severe HTN,eclampsia. pulmonary edema.abruption placentae. DIC. nonreassuring feral srazus IACOG GudelneOhuxn com: 2013;127;1 ml Prognosis cm esp wu 5 y x3.9 (delivery < 34w) x2.8 (delivery 34-36w) usu z019;365:II51 q T ESRD x5;x9.2 if preterm; X7.1 if preeclampsia in 2 pregnancies (PLuS Med 2019e1001A7$) | 415% had HTN 1 yr after severe preeclampsia uqpenenwi 1018271149\) alw dementia, esp. vascular type fam;1018;363k4109) Regarded as riskenhancing factor ofASCVD (ACC/AHA Cnmlmn 101213941049 A K I I N PR EG N A N C Y Absence of 1 Cr during pregnancy is sign of renal dysfunction AKI requiring dialysis: 1/10.000; 4.3 vs 0.01% died: T preterm birth. low birth weight. small for geslzdonal age, 69% experienced complications (preedampsia.TMA. HF. sepsis. or poszparwm hemorrhage) UASN 2015:Z6:J085). Possible Causes of AKI In Pregnancy (KJ up zmuam 1st Septic abortion. hyperemesis gravidarum 2 nd-3rd Preeclampsia/HELLP (after 20 wk),TTE complementmediated HUS (aHUS). acute fatty liver of pregnancy LN.APS Anyri me Acute fatty liver of pregnancy 1 anzkhrombin activity:AKI 14-90%. HTNlpreeclampsia 26-70% U Cone: Go¢=<»l Res 2014:4as41> GLOMERULAR DISEASES AND PREGNANCY Background Proreinuria, t BP and CKD are a/w adverse outcome Pregnancy can potentially worsen proteinurla. HTN. edema In NS In leAn w/ Cr 51.2. pregnancy was not alw difference in kidney function (Ajxo 1010:S6;sOe) Infant Survival Rates (X) law zmvntauzl leAn MN 70-100 67-76 FSGS MCD 55-94 71-76 NS during Pregnancy In 1017.91,1464) Causes: FSGS > ION. MN > Fibrillary. PIPGN. C3G. MCD T preterm,preeclampsia (27 vs 3.4%). Csection Kidney Biopsy during Pregnancy T complimion Zhan posrpanum (7 vs 1%); major bleeding as 23-26 wk laps 2011114411) Bx after az wk gestation is nor. recommended (kw \9B7:94:932) ATYPlCAL HUS (aHUS) AND PREGNANCY Alternative complement activation. Pregnancy is frequent triggering event. Not all patients have genetic muutions Risk factors: hlo HUS. aHUS (26%) UASN 20199910201 Common between 36 wk to postpartum; similar severity wl nonpregnancy aHUS; r ar e death: 27-57% ESRD l qAs~ 2017;1Z:1137; or z01s:93:4so; I As~ 1018:19:1020) Overlapping features with preeclampsia including biopsy finding (TMA) aHUS does not resolve with delivery vs preeclampsia resolve with delivery Eculizumab: used in pregnancy safely; no ESRD out of the 22 cases (KA z018:9J<4$0) SLE AND S16GREN Svnoaor4E AND Pos<snAncv Background Risk factors of active nephritis during pregnancy: active disease wu 6 mo before con ceprion, hlo multiple flares, dlc of hydroxychloroquine (Rheum Of an Nom»Am 1007;33:137), past kidney disease. low C4: low C3 or dsDNA Ab alone are NOT (c;Asn 2017:I 2:940) Risk factors of adverse pregnancy outcome: (+) lupus anticoagulant. antihypertensive use. thrombocytopenia. mammal severe Rare. disease activity. high BMI (Am :m 201s;16321531 Clinical Manifestation/Prognosis Fed and Maternal Pregnancy Outcome In SLE (%): T premature Births and Material HTN With LN and APIA (+) (QI*$N zowxznwy 25.6 Spontaneous abortion 16.0 SLEHare 16.3 IUGR 12.1 HTN 16.1 Stillbirth 3.6 Nephritis 7.6 Neonatal death 2.5 Preeclampsia 0.8 Premature births of all live binhs 39.4 Eclampsia Neonatal lupus: heart block and rash caused by SSA and/or SS8 Ab transfer from mother: all mother w/ SLE. Sjégren syndrome should be screened for fetal heart block All mother of fetus with congenital heart block should be screened for SSA. SSB: asymptomatic mother can progress to SLE and/or Sjégren (Ann Rheum Dis z0o9¢se;a2a) Prevention and Treatment Recommend against conception within 6 mo of active class Ill and IV LN /antiphospholipid Abs in pregnant women with suggestive APS history HCQ in SLE: ¢ flare (Am nam on 10 1s011a5s1 HCQ in refractory APS: alw T live births in refractory APS lmiiuannwn Ier 101s;14;49e) Active LN class III or IV: treat with CS - azathioprine CKD AND PREGNANCY Pregnancy Outcome in CKD Preterm and early term birth is a/w later CKD likely dlt 1 nephron in: 2019;36s1113461 Infertility and sexual dysfunction are common in advanced CKD and ESRD In CKD adverse maternal events happened in 11.5% (2% in nonCKD control). Premature birth 13% (vs 6% in nonCKD) (qAsn z011:s:2sa7) CKD alw preeclampsia (x10.36). premature delivery (x$.72). small for gestational age/low birth weight. Csec. and failure of pregnancy (qA$N 2015;l019641 CKD stage shift or RRT start was: 7.6% (CKD1). 12.6% (CKD2). 16.2% (CKD3). 20% (CKD45).Adverse outcome is a/w HTN and proteinuria UASN z01s:26:z011). 1 proteinuria in DN during pregnancy. Insulin is recommended during pregnancy. in CKD wl Cr >1.4 pregnancy L GFR 6 mo postpartum in 3196; progression was highest in Cr >2.0 and uncontrolled HTN (NEJM 1996;J35:116) Laboratory Changes in CKD HCG: 36.7 koa,degraded and excreted by kidneyzcan be elevated in CKD w/o preg nancy Ultrasound should be used to diagnose pregnancy. Elevated HCG level may lend to misdiagnosis of molar pregnancy (cwmuupuun z01ssn41 AFP: i level is used to screen fetal Down syndrome: can be falsely elevated in CKD General Management Delay conception until txp if <35 y/o. Risk discussion if >35 lo (jueplnul 1011:25:450). ESRD AND PREGNANCY Pregnancy Outcome in ESRD Live birzh/1,000 personyr: dialysis (1.26) <Transplan:ed (16) < General population (6017); PD (1.06) < HD (2.54);among pregnancies on dialysis 79% achieve live birth; 53.4% preterm.65% low birch weight i~4»,.*i!r z01 a:1a:z7s) HD has lower incidence of small for gesmtional age than PD (nor 1016;31219151 High BUN in 2D09:75:1217) and shorter dialysis for 201s;31:191s) is a/w adverse outcome General Management Iron. Epoetin alfa (C).and darbepoetin (C) can be used: ESA requirement goes up Cholecalciferol 4,000 lU is safe UCEM 201 J;9872337). May need PO Ca for hypocalcemia POW binder is usually unnecessary d/t high intensity dialysis: use Cobased binder Noncalcium binder and active vitamin D are no: well studied Hemodialysis Intensive HD with goal predialysis BUN <50 (18 mmoIIL):weekly KW 6-8: requires daily HD ~36 hi/wk May need Mg and POW supplement and 3 K, 3 Ca bath for low level d/c intensive HD Assess DW weddy and T based on expected weigh: gain (1-1.5 kg during 1st trimester I and by 0.5 kg/wk in 2nd and 3rd trimesters) and physical examination Avoid hypotension to keep uterine blood flow Heparin can be used Peritoneal Dialysis May need to 1 fill volume and T frequency: may need HD conversion for clearance KIDNEY TRANSPLANTATION RECIPIENTS AND PREGNANCY Delay conception to 1 yr after KI stable graft function, minimal proteinuria Higher risk of preeclampsia (27.0 vs 3.8%). gestational diabetes (8.0 vs 3.9%). Csection (56.9 vs 31.9%),and preterm delivery (45.6 vs 12.5%) w1201I.11¢2aesl Pregnancy does not affect graft or patient survival (rfamplaluuuan 2006;B1:660) CNI: relatively safe; need to dose. 20-40% for T hepatic metabolism Tacrolimus " gestational DM MMFIMFA: switch to AZA RADIOLOGY CONTRASTINOUCEN NEPHNOrATHY (CIN) CIN:20.5 rise m serum Cr or a 25% t in serum Cr occurring within the first 24 hr after contrast exposure and peaking up to 5 d aker (n£,IM 1018:]78603) 2-5% in patients was no risk factors: 10-30% among diese as risk lsmai NePhml7.0\1:31:JM) Ri sk Fa ct o r s Patient factors: CKD. DM. CHE hypovolemia. concomitant nephrotoxic medication u sa g e a n d mu l t i p l e mye l o ma Procedurerelated factors: higher dose of contrast. multiple contrast studies performed within shon period. ionic contrast. hyperosmolar contrast IV contrast may have no or low risk (Am Mm m¢4201B;71:44: wider 2017;28S¢4141 Risk prediction tools for CIN from coronary angiography (;Acc 2004;44,1393: Am Hahn] 1008;155:2W) are available at QxMD° app P a t h o g e n e si s Renal vasoconstrktion -» medullary hypoxia -» ATN (mediated by efliects of viscosity by alterations in nitric oxide. endothelln. andlor adenosine) Direct cytotoxic effects of contrast agents on tubular epithelial cell -v ATN (mediated and by reactive oxygen species partly) yAcc 1008;s1:1419) Cellular events occurs within first 60 min after administration of the contrast agent with greatest risk in the first 10 min (AJKD 1996 n1s4: Ain 1000:183:167]) Clin ica l Ma n if e st a t io n s Rise in creatinine. generally within 24-48 hr after contrast exposure The creatinine usually peaks and then starts to decline within 3-7 d Severity range from nonoliguric transient fall in GFR to severe renal failure requiring dialysis in generally 1% <A~1 cmu 200w0n06a1 Urine sediment -) muddy brown granular/renal tubular epithelial cell cast Absent or mild proteinuria (contrast agents may induce false positive proteinuria) FEn often <1% (as opposed to ischemic/toxininduced ATN) A persistent nephrogvam on intravenous pyelogram or contrastenhanced CT scan may be suggestive of CIN in man 1997;70:B97) P r e ve n t i o n o 9 ° Avo id vo lu me d e p le tio n a n d u n SAIDs No proven benefit of holding ACE inhibitors/ARBs who 10114915751 Avoid repeated studies that are closely spaced (within 48-72 hr) Contrast lowest effective dose (<30 mL if diagnostic. <100 mL if diagnostic + interven tion); low or soosmolar (lodixanol is nonionic and isoosmolal) (KDIGO AKI 10121 Volume expansion with isotonic NaCl in pt at risk (KDIGOAKI 20111 Outpatient: 3 mUkg starting 1 hr preprocedure and 1-1.5 mUg/hr during and for 4 - 6 h r p o st p r o ce d u r e Inpatient: 1 mUkglhr for 6-12 hr pre. intraprocedure,and for 6-12 hr postpmcedure Preventive Interventions Intervention LvEDpguided vs standard IVF R¢$ul¢§ LVEDP guidance 1 ClAKl and bereft sustained through 0.9% NaCl vs 1.26% NIHCO3 Similar rate of AKI, dialysis ac 90 d or persistent kidney Nacetykysneine Conilicring or no beneNz we z004.4>1; lm Hed]1€0&151:140¢ fnfsenvs new }01B:37&603 ) Sxarins Support use of suers in statinnaive patients RRT No beneii: l,4mim¢4 Z012:115:66) 6 mo (FOSHDON lance: 1014:18J:I814) impairment and death iraiseiwe new zomaruon Higher dose superior zo lower dose (}ACC Z0\4:\14:1195; An IM 2016;1(>4.406) NSPHROCENIC SvsTsmlc Flsnosls (NSF) Mos: gadolinium containing agent: are excreted by kidneys. Low renal function prolongs halflife of gadolinium. NSF is a iibrosing disorder seen exclusively In paniencs with CKD or ESRD due to exposure to gadolinium containing conzrasr agents (NDT 2009;z4£s6) Characterized by marked expansion and fibrosis of dermis leading to thickening and hardening of skin overlying trunk and extremities Incidence of NSF in patients with renal dysfunction may vary from 0.19-4% (1A$n 2006:17:235*k Curr Open Rheumaml Z003:\5:7B5) ACR CIassl6cation of Gadoliniumbased Agents Relative no NSF Group I The greatest number of NSF cases Group II Few. in any, unfounded cases of NSF Group Ill Limited data. but for which few. if any unconfounded cases of NSF reported Gadodiamide (Omniscan°) Gadopenreraze dimeglumine (Magnevist°) Gadoversezamide (op¢amAnK°l Gadobenate dimeglumine (MuI:iHance°) Gadobucrol load=vis¢°l Gadoreraxe acid (Dourer) Gadozeridol (ProHance°) Gadoxerare disodium (Eovis\°) Pathogenesi s Inciting event is tissue deposition of gadolinium - direct stimulation of bone marrow co produce CD34» fibrocytes -> aberrant activation of circulating fibrocytes ac c u mulation of fibrocytes in the tissues and producion of collagen l oc al ti s s ue fi br os i s A c t iv a t io n o f T G F b e t a 1 p a t h wa y Associations: use of ESA. placement of dialysis cadieters, chronic liver disease. hepa torenal syndrome. peritiarisplant period after liver transplant Clin ica l Ma n if e st a t io n s Skin manifestations: fibrotic. indoorated papules.plaques. or subcutaneous nodules. Lesions are symmetrical, bilateral. and centrifugal in distribution. May give "cobblestone" woody" or pear dorang¢ appearance umjbomniagama12001;2]:38J) Systemic manifestations: muscle induration, joint conuacture. involvement of lungs. diaphragm. myocardium. pericardium. pleura. sclera. and dura mater A fulminant form w/ liexion contlacnures and immobility in 5% (CwOph Rixmaiul 2003:1$:7B5) Course: death (28%), no improvement (28%), modest improvement (20%) (see Alumina M um 1006; 35: 118) Workup Elevation in serum CRE serum femtin. ESR.and reduction in serum albumin Skin lesions can be visualized by ["F1FDG wholebody PET Skin biopsy: proliferation of dermal librocytes in early lesions. marked thickening of the dermis. with a florid proliferation of fibrocytes and long dendrite processes in fully developed cases Immunohistochemistry: CD34 and procollagenIo spindle cell infiltration Prevention US FDA recommends avoidance of gadolinium in patients with eGFR <30. receiving dialysis. or with AKI lu,s, FM s»4 Drug Adniininrnian s¢91¢mu¢. zo07l If study has no be performed in atrisk paziencs.avoid Group 1 agents Lowest dose of gadolinium char is needed should be used in asrisk patients Elimination of gadolinium with PD is much lower than with HD (Mad Rudi! 1998:$:491) Gadollnium is effectively cleared by HD (Ana And z001:41:m; now M44 z00e;24=44s) HD soon after the procedure and a repeat HD wu 24 hr can be considered among prs on HD but no proven benefit (Ace Ciimmme¢ on 9 fw MY Conrrasx Midi 2017> Treatment No proven therapy lmatinib, oral and topical steroids. plasmapheresis. exuacorporeal photopheresis. UVA phototherapy have been studied with inconsistent results Intensive physical therapy to reverse disability from joint contractures Restoration of renal function with kidney transplant can slow or stop disease pro gression Renal transplantation may offer benefit in patients who are candidates for transplantation We 2005;46:763: nor 2011;u;1099: Gnfiumpiani 200B:Z2;803) Prognosis NSF has a chronic and unremitting course in mos: patients More severe and rapid progression of the skin disease is alw a poor prognosis DERMATOLOGY Pathogenesis Oxidative suess. inflammation. recurrent skin trauma Arteriolar blood flow. endothelial injury; PTHinduced ischemic skin necrosis Inhibitor of vascular calcification: fetuinA (reduced in CUA pts) (nor 201733z11s1 Impaired Vit K dependent carboxylation of Matrx Gla Protein. inhibitor of vascular alclNauon 4 dermal arteriolar calcification (pisu z0\7:za:17171 Clinical Manifestations Dysesthesia only in early sage; pmritic surrounding area Painful vidaceous. plaquelike subcutaneous nodules;sometimes Iivedo redcularis pattern Ischemic. necrotic ulcers with eschars. can be infected Site: frequently abdomen. buttock. and thigh: possibly acral and penile 1 yr survival SO% l;AAz> 2001;$6:569). Mortality >80% wl ulcer in 2002;61:2210). Diagnosis Skin biopsy: arteriolar medial alcilication (von Kossa stain).thrombosls of dermal vessels. ischemk necrosis w/o vasculitis; biopsy may complicate wl ulceration. infection. bleeding Xray using mammography technique WKD 100e48;659). bone scan T reat m en t dlc VKA; DOAC safe alternative (IMJ Dur anal 2011:56:106sI Low Ca bath (2.25-2.5 mErelL) d/c calcium containing binder vitamin D analogues Lower pos Mth noncalcium containing binder to keep phos <5.5 and CaxP <55 Cinacalcet PO to L PTH <300; L CUA x0.31 levon qAs~ 201s;\oa00).eteIcaIce¢ide IV Sodium thiosulfate Nzandoxidant;25 g (diluted in 100 mL of NS).infused over 3060 min during the last hr of each HD session: effective In 70% lmpniuiag 20185n6691 s/e:AG metabolic acidosis. NN bad taste w/ periorbiizl tingling lmralesional sodium thiosulfate (}AMA Devmainl z01J:14n46) Hyperbaric oxygen (nepnfmqy 2015;10.444). bisphosphonates (uefwlqia 2012:321329) Surgical debridement. parathyroidecwmy alw L mortality (Man avi he 2016;91:1384) Vitamin K 10 mg TlW clinical trial ongoing (NE/M 101&378:1704) UREMIC PRURITUS 42% of prevalent HD pts alw 17% higher mortality (mm nor 2ooea 1=349sl 18% are very much or extremely bothered by itching (cows qAsn 2017;11:1000) t Wim inadequate dialysis. anemia,T BUN. PTH, CaxR Mg. CRP. IL2, l albumin Polyarylethersukone > polysulfone membrane dialyzer (ac Nephrnl Z01$;\6:184) alw xerosis: dry skin from sweat gland atrophy Affects quality of life and sleep; fatigue. agitation, depression Pathogenesis: systemic inflammation, calciNcarion, opioid receptor imbalance T reat m en t Adequate dialysis. control CaxR PTH; topical capsaicin. topical tacrolimus If occurs during HD only.consider changing heparin formula:ion.dialyzer Glycerollparaflin emulsion esp. in xerosis (dry skin) (C1ASN 1011:6:748) Gabapentin who 1017;70:638). pregabalin is boner than doxepin lnfmmulnz 201711.6a) Nalfurafine (ac opioid agonist. unavailable in USA) ACQUIRED PERFORATING DERMATOSiS (5,}n¢¢m¢i¢l 1995:\3§:67I) Similar to the primary perforating dermatosis. Kyrle disease Common in CKD. DM. and African American; 11% of dialysis pts Skin biopsy: ulcer craters showing perforation of both collagen and elastic fibers Pruritic domeshaped papules w/ cenuul crusts on the drunk & extensor limb surfaces Treatment: topical steroid. retinoid DRUG REACTIONS WITH EOSINOPHILIA AND SYSTEMIC Sv nr r ons (D R ESS) Drugs Causing DRESS Xamhine oxidase inhibitorszallopurinol >> febuxosrat (A/M 2017;13fxe67) Antiepilepricsz phenytoin. carbamazepine. oxcarbazepine, lamotrigine Sulfonamides. sulfasalazine; vancomycin. dapsone. minocycline. lenalidomide Clinical Manifestation 2-8 wk air use of dIe culprit drug symptoms may persist after stopping offending drug Renal involvement interstitial nephritis;40%; higher (68%) renal involvement with allopurinol cases; baseline CKD ()<24) is risk factor (Ann Demuml 2010¢146113731 Maculopapular rash. purpura. exfoliative dermatitis, lymphadenopathy Fever. facial edema. hepatitis. pneumonitis, myocardids. hemophagccytosis. shock. death Eosinophilia. atypical lymphocytosis. elevated aminotransferase (ALT) Differential Diagnosis: StevensJohnson Syndrome/Toxic Epidermal Necrolysis Similar offending drugs: allopurinol, antiepilepdcs. sulfonamides AKI from volume depletion/hemodynamic change: extensive mucosal involvement • 4-28 d after use of the culprit drug: leucopenia instead of eosinophilia Treatment dlc offending drug: systemic corticosteroids for incersddal nephritis El Fisgón Morboso et al. OTHER SKIN CHANGES IN CKD Xerosis: dry skin from sweat gland atrophy Uremic frost crystallized urea from swear evaporation (NE}M 2018:)7%669) Lindsays nails (halfandhalf nails): distil pink nail bed and proximal white band: found in CKD (NEW 2015;372:1748) Skin Changes and Associated Renal Pathology Skin Manifestation Renal Pathology Purpura: nonblanchable red-purple. 3-10 mm (<3 mm petechiae:>10 mm ecchymoses): RBC leakage; leukocyioclastic vasculitis (LcV) on skin biopsy Skin ulcer Livedo neticularis: mottled. reticulated: congested venules Small vessel vasculitis: lgAv. staphassociated IgA dominant IRGN (cm nipuiuzaixnsuzl. ANCA GN, cryoglobulinemia (immune thrombi in small blood vessel) TMA: APS,TTP, Crystalglobulinemia Pyoderma gangrennsum Maculopapular rash ANCA GN (Ammmn Re 101731e11138) Medium vessel vasculopathyc APS. SLE. PAN. cholesterol emboli alw Raynaud phenomenon Acute Interstitial nephritis 'LCV: will fusel vasculitis wld\ neuuuphil influale;44% has real iwelvemen: lgAVlHSP (30%).ANCA (10), cryogiobulinemic (4%) (Mayo Can Proc 2014;89:1515) Genetic Conditions Affecting Skin and Kidney Conditions Skin Manifestations Renal Manifestations Tuberous sclerosis Hypopigmenied spots. molar angioiibromas. periungual fibromas. connective :issue nae vi. cafeauIain spots Angiomyolipomasz hemaruria. RP bleeding 59% CKD3-5 aim z01s=6616381 Benign cysts, lymphangiomas. RCC VHL disease Capillary malformations. hemangioma Clear cell RCC Fabry disease Nail-pardla syndrome Telangiectasias and angiokemomas at groin and hip; Hypo or anhidrosis Hypoplasmic nails. webbing. absence of dismal dorsal phalangeal skin creases Proteinuria w/ lamellaced lysosome membrane strucmvesz myeloid (zebra) bodia Proteinuria. CKD with type III collagen deposivjon in lamina denser and/or FSGS Renal Manifestation of Dermatologic Diseases Psoriasis leAn ><4.75 in mod-seven disease (as w11;17613ss1 Hidradenitis suppuraziva M amyloidosis. Can progress to ESRD. Tx: Infliximab new umm ma 200e:\9:¢32) Mesangioproliferarive GN (in Uid n¢»m=i z01z441s091 OPHTHALMOLOGY Ag e re l a te d Ma cu l a r D e g e n e ra ti o n (AMD ) mlc cause of blindness in the developed world; x3.2 in eGFR <60 (jA$N zaawrsoe; Drusen: extracellular deposits between Bruch membrane and the retinal pigment e p ith e liu m (RP E ). E a rly sig n o f A MD. CFH, alternative complement pathway regulator variation.Y402H is alw AMD VEGF produced by RPE - T CFH -» regulate alternative pathway Us 2017112721991 Dry AMD: geographic atrophy of the retinal pigment epithelium: degeneration of lightsensitive cells and supporting tissue + vision loss Wet AMD: choroidal neovascularization; rapid and severe visual loss and retinal edema Clinical manifestations: loss of vision.visual distortion lntraviueal antiVEGF Ab for wet AMD: rarely may be associated with TMA (HTN. proteinuria.AKl) in native lA;xo 1011157:756) and txp kidney (Tamara-maui" zoissnaazi Diabetic Retinopathy (DR) mlc cause of visual loss worldwide; x2.0 in renal dysfunction (}ASN 2004;1 s;z469) T1DM (+) DN almost always have microvascular disease, such as DR and neuropathy T2DM (-) DR is a predictor of nondiabetic renal disease. (+) DR is a predictor of ESRD (Diabetes No Chi Prey 2011314981: (+) DR does not necessarily predict DN Nonproliferative DR: cotton wool spots. intraretinal hemorrhages. microaneurysms P ro life ra tive DR: n e o va stu la riza tio n Clinically significant macular edema: retinal thickening and macula edema Treatment: photocoagulation for proliferative DR. severe nonproliferative DR; intra vltreal antiVEGF for proliferative DR and clinically significant macular edema H yp e r t e n sive R e t in o p a t h y Grade 1: generalized arteriolar narrowing: 2: Focal narrowing and AV nicking/nipping 3: 2 + exudates. hemorrhages. and cotton wool spots; 4: 3 + optic disc swelling Grades 3 and 4: alw malignant HTN, requiring urgent or to prevent irreversible damage Retinopathy, microaneurysms. retinal hemorrhages. soft exudates. and AV nicking were alw renal dysf unct ion UASN 1004: \ s: z4e9) Uveitis with Tubulointerstitial Nephritis Causes sarcoidosis. SiOgren syndrome.TlNU.ANCA vasculitis Anterior uveitis: pain. photophobia, ciliary i1 us: more systemic involvement Po ste rio r u ye itis: flo a te rs, re d u ce d visu a l a cu ity Tubulointerstitial Nephritis and Uveitis (TINU) 1-5% of IN. common in adolescent (median 15 lo). 9: typically bilateral and anterior uveitis: 58% developed uveitis aMrTlN dx: easily misdiagnosed iqAsr4 z0i491zn Modified can target Ag Ieyasu z011:6m); predict late onset uveitis ic1As~2o1419.zn Eosinophilia, pyuria. pRTAlFanconi:T Urine B2microgiobulin WMA apnu\ahia12015;133=140) Prednisone 1 mglkg topical corticosteroidslcyclopleglcs for uveitis May spontaneously resolve. CKD in many cases despite steroids (Norma z<Ma:1:111l. Ocular Effects of Hydroxychloroquine (HCQ) Corneal deposits: reversible w/ dlc of HCQ Retinopathy: Bulls eye matulopathy with a central patchy deplgmentation surrounded b y a co n ce n tric p ig me n ta tio n Risk factors: HCQ dose >400 mud, cumulative dose >1.000 g, >5 yr use, renal or liver dysfunction, concomitant tamoxifen. retinal disease. obesity (HCQ is lipophobic) Pretreatment and annual fundus examination: dlc HCQ if there is retinal damage Ocular Mmliestadon of Renal Condldows C3G Keratoconjunctiwitis sicca (2 Sjbgren), retinal vascukapathy w/ cotton wool spot. optic neuropathy. scleritis. anterior uveitis Drusen. retinal pigment epithelium detachment, choroidal GPA Conjunctivitis. corneal ulceration. episderitis/scleritis. optic neuropathy Alport syndrome retinal vasculitis, and uveitis Anterior lenticonus (20-30% of Xlinked) SLE neovascularimion Subcapsular cataracts. perimacular granulations Fabry disease Cystinosis Nephronophdmisis CKD Corticosteroid Hemodialysis Conceal opacity (corner veniclllata). subapsular cataracts Corneal cystine crystals/photophobia Retinitis pigmentosa (tzpetoretinal degeneration)Iblindness Narrowed retinal microvasculature (qAsn 2011;61872) Glaucoma. carrack. central serous chorioretinopathy T Intraocular plessure;Tx: hypertonic sodium. mannitd (n:/M 19nisa0z1. glucose W*D zo14;sa1so0) GERIATRICS Background Adjusted ESRD incidence rate highest in population >75 ye,though declining since 2010 iusaospfgy For age >65 yo risk of ESRD exceeds risk of death only once eGFR <15 UASN zo07:1&z7ssi In the elderly.frail population dialysis may not provide survival advantage dt optimal medical management and is a/w a functional decline (qAsn 20 n;7:1as; NEW 2009;361:153t 2009;361:1612) Kidney Changes in Ageing (;ASN 201738407: 2017:28liB38) Structural changes in healthy aging conical volume loss. increase in simple renal cysts. T glomerulosderosis (upper limit vary with age; nor 2015:30z034, mlunie nz Q»mo'), T inter stitial Fibrosis. T tubular arroplvy. i arreriosderosis.decrease in nephron number Normal GFR decline with aging is 0.75 mUmin/yr Tubular dysfunction: 1 sodium reabsorpzion and potassium excrexion.and 1 urine concenuacing abilicy Increasing susceptibility to AKI particularly ischemic and toxic ATN LiFE EXPECTANCY AND PRoGnos»s Modality HD Prognosis by Modality Prognostic Information Remaining life in yr age 75-79: ESRD 3.2 (male) md 3.5 (female) vs Gai Population 9.8 (male) and 11.4 (female) usrds.org Quartiles of life expectancy in yr: Age 75-79: 0.5 yr (lowest). 3.7 yr (highest) Age 80841 0.4 yr (lowest). 3 yr (highest) In 20I1n261) Median survival >6S yo in yr -Vent + dialysis (HD):0.9; post CPR + HD:0.8:feeding we 4 HD: 0.4 UASN 20141151431 Nursing home population, cumulative mortality: 24% (3 mo). 41% (6 mo). 58% (12 mo) we znos=ss11szol 5.7% of prevalent ESRD patients age 75 and older are on PD (usrds.org) Retrospective study of French PD registry and patients >76 yo showed median survival of 27 mo (NDT 2011125:1S$I Mortality benefit of PD over HD modified by age. HD many be favored alter 90 d in age >65 yo UASN 1010.z1:499I No difference in 12mo survival and hospiulizadon rate and QOL at 6 and 12 mo between HD and PD patients age 70+ (mu oumx2oo2:1z4e:I Medical manzgemenr Median unadj survival 37.8 mo KRT and 13.9 mo medial management lCI*5N1N0%4¢16\11 Low comorbidity: median survival 36.8 mo RRT and 29.4 mo medical management High comorbidity: no survival benefit RRT vs medical management (NOT 2011:2s,160e) Renal supportive care dink: men survival 20 mo. median survival 16 ma RRT padencs: man suwinl 36 mo. median survival 46 mo (qAsr47015310u01 Transplantation Age 70+: adjusted nelazive risk d deadi 41% lower in nransplam vs wait listed puma. Risk d deadi among transplant neeipiems higher than was listed until 125 d after surgervTrar\splan: recipient survival worse than waidisned until 1.8 yr after uansplant.Ai: 4 ynadjusted survival d iransplanr recipients 66% compared wid 1 5196 for waiting list andidaza. Subgroup analyses shamed a signiNcantuansplantsunrival benetitforaga 70 to 74 yr. ages 75 and olden DM and HTN. ECD kidneys lrliiiplimuia zmw:iuss) Gait speed & timed get up and go res: predictive of mortality in CKD UASN z01 aa4az2) Other prognostic risk factors for morcaliry (see palliative care chapter) FRAI LTY A physiologic stare of increased vulnerability no stressors that results from decreased physiologic reserves. High vulnerability for adverse healdl outcomes including disability. dependency, falls. and mortalizy Characterized by slowness/weakness. poor endurancelexhausdon. physical inaczivicy. unincendonal weight loss Sxarcs early in CKD and increases as eGFR declines. High prudence in CKD. Independent RF for deadi. hospiulizacion. and need for dialysis lqaw 2013810911 .44l<o 1012409121 HE MO DI ALY S I S V AS CULAR ACCE S S Fistula first may not be appropriate in the elderly with a limited life expectancy, Patient centered approach that considers risk to develop ESRD. overall survival. risk of primary access failure. patient preferences, and quality of life should be considered. AV F O lder age is risk factor for 1 failure (up zoo3;4z 1001= ;ASN 1006;171n04; qAs~ 200a:3:4a7) Higher prevalence of CAD and pAD;both risk factors for 1 failure uAsr4 zc0e:17a204: x: 1005167:2461) Lower cumulative survival ofAVF up=< so 2007;45:4204 [lia¢A<¢ess z009;101991 alw with repeat vascular access placement compared to AVG (QAM 2015:10:I791) alw HD initiation mm a catheter compared to AVG (/ASN 201$:26:448) Patient factors affecting AVF placement. even among pts wl AVF + catheter, may explain 2 2/3 of the mortality benefit observed in pts w/ AVF ()ASN 2017118:645) Timing placing anAVF >6-9 mo predial7sis is not alw greater success and is associated with increased number of vascular procedures UASN 20\5;16:448) AVG AVG use has declined with a concomitant increase in AVF and catheters in this pop ulation 1c;Asr4 1M7:21M3: Aim 2003;42:1013: la elnadal IM z01z16=2331 AVG survival superior to AVF survival. in the first 18 mo after iCC€SS placement. when primary failure rates included (CJASN 1010:5:243Bl Some studies show no morality benefit of AVF over AVG msn z01m4:1297: Semis Dial zoomason. others have shown some small benefit to AVF (qAsr4 2015;I0:1791) H e m o d ia lysis C a t h e t e r Higher morality than AVF and AVG (p\sn 2013=z411 z971 Majority of patients start with a catheter UASN 10IJ;l4;1297:jASN 2017;21:645) MEDICAL MANAG EMENT /CO NSERVAT IVE CARE Defined as planned holistic patientcentered care that includes intervention to delay the progression of CKD and minimize risk of adverse events and complications.as well as shared decision making.advanced care planning. active symptom management. and psychological and social support Does not include dialysis in the treatment plan (KDIGO KI Z015:88447; C[ASN 2016;11:19091 Guidelines recommend Informing all patients of this treatment option in addition to RRT. include toolkit up>A/Asn Revsed Guldulina.Shared Decision Making. we z010;s.2zao; Palliative care can mn concurrently with curative treatment FLow SHEET For MANAGING ELDERLY PATIENTS Wm 4 Ao vAn csD CKD 1. Assess goals of treatment, including patient preferences 2. Estimate prognosis and outcomes 3. Shored decisionmaking process Fuel prognosis or putnem Dftivmncs low no dialysis N ona lo law mat wns a poor prognn- . a good functional mama. or parent p d o an o a f o r d alyss Medical ITl&f\8g€M8fll/COI\5GfV8liV€ Pr oceed wi th r enal r epl acement ther apy pl anni ng care Transphm canddah w Dialysis planning: Tr anspl ant r efer r al PD vs HD Ti mi ng of access Shoul d take i nto account competi ng r i sk of ESFI D vs death Calheief sparing approach may favor AVG in those with a more Iimixe¢ prognosis PALLIATIVE CARE Ba c k gr ound High health care utiliurion and low hospice use compared no other end organ failure lA:<h IM 2011:171:661) High symptom burden, high prevalence of uncontrolled pain, and low healthrelated quality of life we 19852312255311As~ z00s¢1¢¢z4s7¢ Acxo 1007;14azi De f i ni t i on Palliative care is an approach to care focused on improving quality of life of patients and their families facing a lifethreatening illness through prevention and relief of suf 1 :: fering by means of impeccable assessment and treatment of pain and other problems. ,E physical. psychosocial. and spiritual (http:llwww.who.indcancer/palliative/definition/) Ca n mn c onc urre nt with c ura tiv e ue a rme nr Guidelines recommend palliative care services and advanced care planning to aIIAKl. C K D , an d ESRD patients who suffer from their disease burden (CJASN 201lk&1300) Identifying Patients Most Likely to Benoit (qAsn z01<xs¢114n:1Asn 1a0u=11:1>409 Identifying Factor Measurement High mortality risk Age 275 yr Dementia High comorbidity score charlscn comorbidity Index >8 lqisu z0\<xs:z3s0) Marked functional impairment; Kamofsky performance score <40. noriambulatory wow 1994:2):4631 Serum albumin <2.5 Frailty Surprise question-No: provider would not be surprised if patient died in 1 yr Cohen score (CJ*5N 2010.591 Malibu at of<mD°l Berger score (Cl*$N 1011;7110)9) High symptom burden Dialysis symptom index Edmonton symptom assessment sale Palliative care outcome Scale-Renal (Qiailiuulihtiarie 199*kB:2191 Difficulty with determining goals of care Pain assessment Advanced care planning 8 Q = Q 4: w Nephrology Palliative Approach Advanced Care Planning UAS~ 2000;11;1z4<z qAsn z01o.s:zaa0i Purposezhelp :he patient understand their condition. identify GOC.and prepare for future decisions needed as the condition progresses over time SpecMc goals: written advanced directives including health care proxy or power of attorney. DNR or POLST form when appropriate When: when considering RRI with sentinel events,when question raised by patient or families. no to the surprise questions. routine are plan Treatment of Symptoms: pain assessment scale and distinguish nociceptive vs neuropathic pain -WHO Ladder for Analgesic Therapy UASN 10047131981 P a in S c ore (# ) Mi l d (1 -4 ) Mo d e r a te (5 -6 ) S e v e re (1 -1 0 ) Treazmem Acetaminophen £Adiuvan: for neuropathic pain Hydromorphone or Tramadol *°Adiuvanr for neuro pain Hydromorphone' t'Adjuvanc for "WM pa in Dose Acetaminophen: max daily dose 3.2 Yd Hydromorph: 0.5 mg q4h pm Tramadol: 25 mold to 75 mg BID 0.5 mg q4h standing Adminisxrarion route Oral Oral KO start and IV PO standing. IV PRN PRN Morphine s hould not be us e d in CKD a nd E S RD A bowel regimen should be prescribed with opiates Pmritus: gabapentin effective in CKD and ESRD. dose adiusz for GFR Reference: . Mdnqs upponi 1 e um . or g. .who.int/cancerlpalIiadvelpainladder GENERAL CONCEPTS OF RRT ULTNAFILTNATION (UF) Hemodialysls (HD)IHemofiltration (HF) Driving force: hydrostatic pressure gradient across the membrane.transmembrane pressure (TMR mmHg) UF coefficient (K.,. mUhr/mmHg): water permeability of dialyzer HD pump applies TMP = desired UF (mUhr)/K.,l (mUhrlmmHg) High flux dialyzer (K¢ >20) requires lower TMP to achieve desired UF Peritoneal Dialysis (PD) Driving force: osmotic gradient between dialysar.e and blood.cleated by glucose (1.5%. 25%. or 4.75% glucose),or a poorly absorbed wtohydrace polymer icodexuin in dialysane UF rate is maximum at the beginning of dwell and decreases as glucose is absorbed CLEARANCE Diffusion Concept Types of Cleamce Convection Movement of solutes across a semipermeable membrane along a concentration gradient between the blood and dialysate Removal Modality compartment Small solute HD (predominant). PD Movement of solutes across a semipermeable membrane resulting from "solvent drag" during UF of plasma solutes across a semipermeable membrane Middle and some large salutes HE PD: hemodiafiluation (HDF) Types of Solutes (MW) Small solutes (<500 D): urea (60). Cr (113), Na. K', H.glc, HCO!. lactate Middle solutes (500-5,000 D): insulin,Vit Biz (1355).aluminumldeferoxamine complex (700), vancomycin. aminoglycosides Large solutes (>5 kD): PTH (9 kD). 132 microglobulin (11.8 kD). rnyoglobin (17.8 kD). in LC (22.5 kD). u1 microglobulin (33 kD). A LC (45 kD), albumin (68 kD) Protein bound solutes: indoxyl sulfate. pcresyl sulfa¢e.pcresol glucuionide ipinimhnwraiiiry ;As~ 1013;z4:19a1>; homocysteine, indoles;only small portion of ironbound form can be cleared by HD Determinants of Convective Clearance UF replacement fluid (RF) is infused to allow for increased total UF to achieve con vective clearance.yet maintain desired net fluid balance Sieving coefNcienr; the ratio of the concentration of the solute in the ultrafiltrate over the plasma; important factor in middle MW solutes; 1 in small MW solutes Determinants of Diffusive Clearance Flux (J): the rate of solute movement is based on Fick principle Flux (J) I Diffusivity x Area x Concentration Gradient Diffusivity (D. permeability): dependent on membrane composition (pore size. pone density. membrane thickness. membrane charge). solute. and solvent Area (A): effective membrane surface area (typically 1.7-2.0 ml) The mass transfer coefficient (K.A) = permeability (K,) x surface area (A) K.,: membrane and solutespecific constant KaA determines maximal clearance at infinite blood flow (Qb) and dialysate flow (Qd) Actual diffusivity is affected by stagnant fluid layer Qb and Qd . Concentration gradient: dependent on dialysate solute concentration, Qb. Qd. stagnant fluid films. geometry of flow (parallel vs antiparallel) Floor. small salutes clearance is dependent on Qb and Qd; higher flows help to maintain the concaitration gradiait across which diffusion occurs. up to optimal flows which. in turn, is determined by the K.A of the dialyzer Time: large solutes clearance is dependent on length of treatment (ie.contact time across the dialysis membrane) dlt slow diffusion and to a lesser extent by the K,A d die dialyzer High Flux Membrane High rare of water transfer. the ultrafiltntion coefficient (KJ) >20 mUhr/mmHg Removes 10-15 kD (middle and some large) solute: does not remove albumin Backfiltration of bacterial endotoxin from dialysate into blood is possible No A in mortality and hospitalization rate memo ne1I.4 200z;347120101 Survival benefits in DM or patients w/ albumin $4 IMPOJASN l 009;2(k645) High flux membranes use is a/w 1 CV morralicy 0.93 lcuanw Damien syn in zoizcocosoul and low CV event in pts with AVF and DM lacE;As~ 201312410141 OtherTerms Used forTypes of Membrane High permeability: higher clearance of the middle solute (eg, 52microglobulln) B2microglobulin clearance >20 mUm in: high flux membrane High ellieiencyz high urea clearance >210 mUm in and urea KaA >600 mUm in High cutof? (HCO): remove 100 kD solutes. et. Ig LC (C1ASN 100%4:745). rnyoglobin: Cons: albumin loss Medium cutol? (MCC): remove 15-45 kD solutes; less loss of albumin than HCO Greater clearance of large solutes (eg, 2. LC) than high flux (nor 201713111651 Sua s TITuTion FLu lo Dialysate Electrolytes and buffer containing fluid used to generate concentration gradient Produced by adding acid and base concentrate to treated water Separated by dialyzer from blood Replacement Fluid (RF) Electrolytes and buffercontaining sterile fluid that is given to replace fluid removal Administered into systemic circulation before or after hemoiiltration Prefilter RF: less extracorporeal circuit (filter) clot: preUlter RF flow rate is added to plasma water flow rate. lowering Valuation fraction Postfilter RF: more efficient clearance For m s oF R R T Forms of RRT Column Title Fluid Clearance Comment Hemodialysis (HD) Dialysare Diffusive >> Convective Hemofikmion (HF) Hemodiafillradon RF Convective Diama¢e and RF Diffusive and Convective Cgnyecdye clearance proportional no UF amount Small solute clearance correlaze wl UF rate Nor used for maintenance of RRT (HDF) HDF: online ultrapure substitution fluid (dialysate and RF) production the cost No 1 mortality. CV events (vs low flux HD). High volume HDF lmorxalityz CV event (CONTRAST ;Aw 2012;23:1087) No 1 monaliry. CV events (vs high Hux HD). High volume HDF l overall and CV mortality for zoizzamy Mortality, hypotension. hospitalization (vs 92% high flux HD) when convective volume 23-24 Usession (ssl1ot /ASN 20!3:24:487) Feritoneal dialysis (PD): utilizes the peritoneal membrane to facilime fluid and solute transfer between dialysate in the peritoneal cavity and the bloodstream Modalities Available in Hospital Setting Only Continuous venovenous HD (CWHD): slow form of HD Continuous venovenous hemoNltration (CWH): slow form of HF Continuous venovenous hemodiafiltradon (CWHDF): combined CWHD + CWH Slow continuous ulzrafilcrarion (SCUF): UF only. No dialysatelRE Minimal convective clearance In decompensated HE T Cr, adverse events in SCUF group. dw diuretic group (NEW 1012;36712296) RRT INMATlON IN CKD The IDEAL Study we/m 2010.a6316091 828 pts in Australia and New Zealand (mostly white patients) were randomized based on BSAcorrected CrCl by Cockcroft-Gault equation to early (10-14) vs late (5-7) initiation of dialysis. Clinicians were allowed to initiate dialysis based upon die presence of ureinic symptoms and volume overload in addition to CrCLThe mean CrCl was 12 in the early start group vs 9.8 in the late start group. The median time to the initiation of dialysis was 1.8 and 7.4 mo after randomization in the early and late start groups. respectively At a median followup of 3.6 yr, there was no difference in survival between groups or in cardiovascular events. infections. or dialysis complications NKFKDOQI and KDIGO we z0\s;se:aa4.i(oico coo 20n1 Based primarily based on assessment d s/s alw uremia. progressive deterioration in clinical status refractory to dietary intervention, inability to control blood pressure. volume overload. or metabolic abnormalities with medical therapy Not based on a specific level of kidney function in the absence of symptoms Canadian Society of Nephrology (CMAI 1014218621121 Intenttodefer dialysis until a clinical indication is present or eGFR has declined to 6 mUm in or less (even in the absence of symptoms). whichever occurs first European Renal Best Practice Advisory Board (nor zoinzezoszi In patients with an eGFR <15 mUm in when a clinical indication arises When close supervision is not feasible and in patients whose uremic symptoms may be difficult to der.ect,a planned in of dialysis while still asymptomatic may be preened General Indications of RRT Initiation in CKD The optimal time of dialysis initiation in CKD is controversial Most patients will develop uremic symptoms with eGFR 5-10 mUmin.Younger pts and those without multiple comorbidides may remain asymptomatic at lower levels of eGFR. Uremic pericarditis or pleuritis. uremic encephalopathy Declining nutritional staws (anorexia. weight Ioss.evidenced by decrease in dry weight and serum albumih level) Persistent or difiicuktotreat volume overload. refractory HTN or recurrent admissions for HF Metabolic acidosis. hyperkalemia.and hyperphosplutemia refractory to medical therapy Cognitive impairment (consider timelimited trial of dialysis to see if AMS improves) Other uremic symptoms: nausea. vomiting.pruritu$. fatigue, pain, muscle cramps. sleep disturbance. altered use, sexual dysfunction RRT INITIATION IN AKI The initiation of RRT in patients with AKI prevents uremia and immediate death from the adverse complications of renal failure Emergent indications: K 26.5. metabolic acidosis wl pH <7.1.fluid overload especially with increasing oxygen requirements in patients who are oliguric or anuric; uremic pericarditis or uremic encephalopathy; certain intoxications (eg. methanol, ethylene glycol. lithium. medormin) Elective indications: K >6.0 or metabolic acidosis w/ pH <7.2 despite optimal medical therapy. repeated positive fluid balance despite aggressive attempts at diuresis RCTs have compared strategies of early vs delayed Initiation of RRT (in the absence of emergent indications) in critically ill patients with AKI wid\ the majority of them not showing a difference in mortality at 60 or 90 d. the risk of dialysis dependence, length of ICU Ol hospital stay. or recovery of renal function (AKu<l n£/m 1016237521223 A/Rcavl 1018198458: BMC *11l"l°=ly 2017;18:78) However in the delayed inidadon groups (48-72 hr) a significant amount of patients did not receive RRI the majority of them because they recovered renal function. but a few of them died before RRT was initiated (low likelihood that this would have been prevented with dialysis) w8/m 2018:379:1431:NE}M 2016:375:122) In hemodynamic insrability.ACS. acute brain injury.or fulminant hepatic failure CRRT may be a better option compared to intermittent hemodialysis RRT MODALITY DECISION Kidney transplant when feasible is the best option for ESRD. However. if a decision to star: dialysis is made. adequate patient education and shareddecision making are key factors in determining what is most suitable for the patient. Patient should be informed about pros and cons of incenter HD and home dialysis modalities (peritoneal dialysis. conventional. shortdaily.or nocturnal home henodialysis) Companson of InCenter Hemodialysls vs Peritoneal Dialysis He mo d i a l ysi s ( HD) Frequency 3 - 4 h r o n ma ch i n e i n a Benefits IACKD Less pazienr responsibilit y d i a l ysi s u n : xi t i me s/ Wk 201 l;\8:4Z8) Opport unit y f or socializat ion Mo r e f r e q u e n t mo n i t o r i n g Pref erred in bedbound pat ient s. t hose wit h mu l t i p l e co mo r b i d i t i e s Risks (Acre z0\ 1: ie4za) iniziazion CCP D: cycl i n g ma ch i n e a s n i g h : L o we r co st . p a t i e n t a u t o n o my. adapt ed t o lif eszyie Higher saiisf aczicn and qualit y of lif e Pref erred in young. high f unct ioning p e o p l e wi t h r e si d u a l r e n a l f u n ct i o n Maint enance of residual renal f unct ion A cce ss co mp l i ca t i o n s I nf ect ion (perit onit is) Ce i u a l i e n a u s md i e n e r s L o ss o f UF ( me mb r a n e f a i l u r e ) (CVC): iniect icn Pat ient and caregiver burnout ( l za cwe l n i a yt h I u mb o si s. Body image piiohlem wide PD at het ier VUTOUS stenosis Higher dropout rate mostly due to Fist ula: body image problem Access and dialysis P e rit o n e a l Dia ly s is (P D) CA P D: 4 ma n u a l e xch a n g e sl d A l l o w 2 - 3 mo f o r f i st u l a t O mat ure bef ore use: u su a l l y a r o u n d 2 wk f o r graf t bef ore use perit onit is or inadequat e dialysis Ro u t i n e P D: st a r t 2 - 4 wk a f t e r ca t h e t e r i n sa n i o n t o a l l o w f o r a b d o mi n a l wa l l t o h e a l b e f o r e u se Ur g e n t P D: st a r t wi t h i n 2 wk CVC an be used immediat ely Training t ime No t r a i n i n g n e e d e d Usu a l l y 1 - 2 wk CV co mp l i ca t i o n s Angina. MI , and st roke can S a f e r f o r p a wi t h l o w B P a n d CV b e p r e ci p i t a t e d b y l o w B P Marked K changes can lead disease Mo r e g e o d e f l u i d r e mo va l t o ca r d i a c a r r h yt h mi a s Other co mp l i ca t i o n s A cce ss ma l f u n ct i o n A cce ss ma l f u n ct i o n Di se q u i l i b r i u m syn d r o me Hyp e r g l yce mi a a n d we i g h : g a i n Mu scl e cr a mp s Encapsulat ing perit oneal sclerosis Lack of vascular access Absence of a f unct ional perit oneal wi t h l o n g : e r m P D ( > 5 yr ) Absolut e Concraindicarions um I n¢pmul I n t o l e r a n ce t o HD p r o ce d u r e |so me mb r a n e ( e t . e xt e n si ve abdominal adhesions. p l e u r o p e r i t o n e a l co mmu n i ca r Jo n ) 10113011 : A ct i ve a b d o mi n a l wa l l i n f e ct i o n 739794) (cellulit is. abscess. perit onit is) z Severe inrescinal disease (et . I BD. ischemia) S e ve r e me n t a l i mp a i r me n t L a ck o f su i t a b l e h o me e n vi r o n me n t A K l i n p r e g n a n cy Relat ive Conzraindicarions (Inc } Nephvd zolI aownsml S e ve r e h e a t f a i l u r e Severe ischemic heart disease Ost omy. abdominal hernias. mult iple abdominal surgeries Fr a i l t y o r p h ysi ca l i mp a i r me n t Th r o mb o se d ce n t r a l ve i n s Poor personal hygiene Needle phobia S evere malnut rit ion L o n g d i st a n ce t o cl o se r Mo r b i d o b e si t y dialysis unit Me d i ca t i o n n o n a d h e n e n ce G E RD o r i l e u s CONTINUOUS RENAL REPLACEMENT THERAPY Introduction A renal replacement therapy (RRT) modality for acutely ill or hernodynamically unstable patients unable to tolerate intermittent hemodialysis (iHD) Continuous renal replacement therapy (CRRT) offers the advantage of gradual correction of fluid electrolyte abnormalities in renal failure due to slow flow rates. smaller dialysis dialyzer surface areas, and extended duration of therapy used in dlis form of RRT As a result. this is the preferred modality in unstable patients particularly in the ICU Indications (Gun 101%15S:616) Acute indications are the same as those for initiating any form of RRT Severe acidosis (PH <7.15). diuretic resistant fluid overload. uremia and certain drug intoxications. and poisoning cases The role of early initiation of CRRT in AKI is not established,There is currendy no strong evidence to support the early introduction of CRRT. the choice d one modality over anodien or a specific clearance dose CRRT has been used for the removal of toxins with large volumes of distribution effectively with rebound: metformin 15w/0w mean Pharmaznlunn 201 z:i7:z49), lithium. methotrexate. dabigatran Tvrss or CRRT Slow Continuous Ultraliltration (SCUF) Primarily designed for volume removal with slow UF rates. SCUF does not provide meaningful clearance of solutes and is used in volume overload states. eg.refractory CHF Continuous Venovenous Hemohltration (CVVH) A convective method of CRRT where hydraulic pressure across die dialyzer mem brane ultraNlters plasma war.er.The clearance delivered is directly proportional to ultrafiltration volume. Replacement fluid (RF) can be added [O the circuit either before the blood enters the dialyzer (predialyzer) or after it leaves the dialyzer (postdialyzer) . Predialyzer RF dilutes die blood entering the circuit somewhat decreasing the concentration and thus the clearance of solutes. Predilution is die primary cincuk setting used in the United States. Postdialyzer dilurjon maintains concentration and thus efficiency but the higher hematocrit at the end of the dialyzer resulting in decreased plasma volume increases risk of dialyzer clotting Continuous Venovenous Hemodialysis (CVVHD) Employs diffusive clearance where dialysate is circulated in a countercurrent fashion to facilitate maximal diffusion from the blood side.The diffusive clearance delivered is proportional to the dialysate Row rate. Diffusive clearance is less effective at removal of larger molecules including so called "middle molecules." Continuous Venovenous Hemodiafiltration (CVVHDF) Uses both dialysis and RF which allows for both diffusion and convection clearance. This modality limits the loss of clearance by limiting the volume of RF used by adding dialysate fluid used to dilute die blood entering the dialyzer. Newer circuits allow for the use of both pre and postdialyzer addition of RF allowing for considerable custom ization of the circuit. PRESCRIPTION CRRT differs from intermittent RRT in several respects as below . Blood flow rates: much slower. 100~300 mUm in Dialysate flow rates: when dialysate is used, the flow rates are much lower at 20-25 mUkg/hr (eg. for a 70kg person. 1.5-2.0 Uhr with CRRT vs >24.0 Uhr with HD). Since fluid is continuously removed at a low rate with CRRT. :here is less chance of hemodynamic instability RF flow rate: when prescribed,this is done ac a rate similar co dialysate and expressed as mUg/hr Net ultrafiltration rate: race of goal her Huid removal from the patient expressed as mUhr. Ne: ultrafiltration rate is determined by patients volume slams. CRRT pre scriptions are writxen either to maintain net even balance or negative balance. Total UF volume is the sum of :he RF (including the volume of fluid used for anticoagulation) and the net UF volume removed from the patient Effluent volume is the sum total of the zonal ult-afiltrate and the dialysate fluid (if used) that is discarded Given the rehuVely low flow ralzes and assumed sieving coeflident of 1 (ie.dl=at the equal concernation of solutes in do blood is equal to due effluent) Br low MW substances. small molecular clearance is: U oWE U: effluent concenr.ration.V: effluent volume. P: blood concentration It is equal the total effluent volume (V) in mUkglhr as UIP = 1 Howevelz predialyzer RF decrease the U/P ratio by l the solute concentration entering the dialyzer compared to the solute concentration in the patient.T RF races and i blood flow rates lower dIe clearance delivered (wjmfcqans 1012;3sA\3). Doss Currently delivered dose of CRRT recommended is 20-25 mUg/hr (KDIGO AKI 2012) When prescribing RRT as supportive therapy for AKI. a weekly KW of >3.6 is rea sonable and translates co an approximate goal of 20-25 nUke/hr The prescribed dose may need no be increased to ensure :had the urge: dose is acnnlly delivered. Dose reductions may be required in die presence of severe metabolic alkalosis (given die high concentration of bicarbonate in r.he dialysane solutions). or if time primary indiadon was volume managemevi: in die absence of metabolic derangements. Time off CRRT usually lowers delivered dose by 20-30% per day Eflluen: volume underestimates die total dose especially when sieving coeflicien: is <1 and in prefilter CWH and CWHDF In these cases. :he X decrease in clearance is = 1 - [Q,/(Q, + QaF)] where Q, is blood flow rate and die Qnr is die replacement flow rate Delivered dose is effluent volume x [Q\J(Qb + Owl] CWH is do preened mochliny to rerncfve large MW substances lnduding myoglobin in cases of severe dubdomyolysis (WM 2ao°n61:16z7; Co-ae orwaae so an zowcooosssei ANTICOAGULATION Anticoagulation of the CRRT circuit is necessary to ensure viability of the circuit and :void blood loss :had result when the circuit clots Unfractionated heparin: low dose. 300 units/hr: traditional circuit anticoagulation Regional citrate anticoagulation: pts ac high risk of bleeding or in postoperative seeing The administration of citrate predialyzer to dielate all the calcium and repletion of calcium before returning the blood to the patient Citrate is metabolized to bicarbonate and an contribute to metabolic alkalosis Failure to metabolize curate In liver failure or shock can result in metabolic acidosis Hypocalcemia may occur when there is an imperfect balance between the amounts of citrate administration and calcium repletion Citrate anticoagulation is now the preferred method (cm Care Med 201s:43:16221 Anliooagulation (citrate of heparin) Prefnlter replacement Hued (for CWH a nd CV V HDF) Counterwrrent dialysate (for CVVHD and CVVHDF) Calcium (only with curate anllcoagulation) Postfiner replacement fluid (for CV V H a nd CWHDF) PRACTICAL CONSIDERATIONS Good vascular access with a double lumen catheter placed in a large blood vessel is necessary to ensure adequate flow. Lower blood flow rates make recirculation an infrequent concern. Patients with ESRD and a working fistula need a catheter as well as long term cannulation of the fistula is considered unsafe (camnb ruphml 1007;15e17s) Given the slow rare of removal, HD is the preferred treatment modality for the management of acute hyperkalemia (cy co 2015;19:s9) Large variance between the prescribed and delivered dose of dialysis is common for ICU patients due to the device being turned oil for a variety of reasons.This should be taken into consideration by checking the total effluent volume for the preceding 24 hr and taken into prescribing subsequent flow rates.AIternatively. increase the prescribed dose by 20-25% (Cm cm 20152m91 COMPLICATIONS EIectrolyteIAcid-Base Complications Hypophosphanemia is common especially when feeds are held. Unlike HD, the gradual rare of removal allows phosphate to move from the intracellular compartment Can potentially delay ventilator weaning. Either PO and slow IV repletion of phosphate is often necessary (Semi Did Z018;J 1;7.1]) Metabolic alkalosis results commonly from diffusion of bicarbonate from the dialysate solution or from direct mixing of the bicarbonate in the RE Bicarbonate concentration in most fluids is 32-35 mErelL and this may impact the prescribed flow rates. Hypocalcemia and hypomagnesemia are uncommon occurrences given the presence of calcium and magnesium in fluid solutions. Hypocalcemia when using citrate antico agulation requires an increase in the calcium supplementation rate. Sodium concentrations in most dialysate and replacement fluid is 140 mEq/LThis is of concern when initiating a patient with either hyponatremia or hypernatremia on CRRT which may result in a rapid change in concentration of serum sodium which should be avoided In re 2019:4;$'h ~=v-=f- Ci" Ina 2014;1za.3941 Inadequate Drug Dosing When possible.drug dosing should be donated either using clinical response or therapeutic drug monitoring. Most d"»s= require at loin some dose adjusunents for patient on CRKT and subtherapeutic drug concentrations are common [see Did 101*17:441) Drugs with a small volume of distribudon.low protein binding, low mdecuhr weight are impacted to a great extent but the amount of drug removed depends on the delivered dose of clearance and whedier the clearance was convective (greater drug removal) or diffusive. Dialyzer size and membrane may also impact d is (on Can ma z012;4a1s1J1 Circuit Clotting: A Frequent Complication and Can Result From Inadequate anticoagulation Inadequate vascular access -» frequent alarms -> cessation of flow in the circuit High filtration fraction: the goal filtration fraction is <20% Filtration fraction = ultrafiltration volume/plasma water flow rate Plasma water flow rate = blood flow rate (1 - Hct) + predialyzer RF rate This can be lowered by decreasing the rate of ultrafiltration or increasing the plasma | water flow rate (by adding predialyzer RF or Increasing die blood flow rate) Oth e r C o mp l i ca ti o n s Catheterrelated complications include catheter infections. bleeding, and clotting Anticoagulation of the circuit an T the risk of bleeding especially in susceptible patients Given the ability of glucose to diffuse from the blood to the effluent. rare instance of normoglycemic ketoacidosis have been reported Hypothermia resulting from the use of fluids in large volumes at room temperature is primarily a concern in pediatric and small adult patients. Fluid warmers should be considered in these situations iAgo 1998:3 2:1023) Thrombocytopenia has been reported; usually responds to cessation of therapy or the use of a dialyzer with a different membrane type (AM pliarmmu\er 101B;52:1204) DISCONTINUATION The most important predictor of successful cessation of CRRT Is urine volume at the time of cessation panicularty achieved without diuretics (ox Cane m¢4 z009;37:1s76) Standardized protocols for initiation and discontinuation of CRRT have been associated with lower morality lcpisn 2017:11:218) HD INITIATION AND PRESCRIPTION Indications AKI, CKD: for conuol and correction of fluid and electrolyte imbalance that cannot or no longer be managed conservatively by diet and medications. for control and correction of acidbase abnormalities. and for the uremic syndmfne Early (eGFR 10-14) vs late (eGFR 5-7) HD scar: did not result in improved out comes at 1 yr of followup (IDEAL new 20103616091 Intoxication: lithium, ethylene glycol. methanol, aspirin. phenytoin, barbkurates. theophylline FirstThree Hemodialysis Sessions Low intensity to prevent dialysis disequilibrium: avoid UF >2 L for 1st session Examples of FirstThree Sessions of HD Initiation Time (hr) Qb (mUm in) Qd (mUm in) Needle, Dialyzer 1 s: 2nd 3rd 1.5-2 2.5-3 3-4 150200 250-300 300350 400 500 600 17 G, Low K.,A dialyzer 16 G 15 G. High K°A dialyzer DIALYZER Dialyzer K°A = permeability x surface area: dewmines maximal clearance Currendy available dialyzers are hollowfiber (capillary) TYPE Cellulose Substituted (modified) cellulose Synnheric DlalyzerType by Membrane Material Biocompatibility Example Low lnlermediare High Cuprophane Cellulose accuse Cellulose diaceune Cellulose niacecaze (Excel¢ra°) Polysulfone (F. FX. OprJflux°) Polyethersulfonem Polyarylethersulfone (Revaclear°) Polymethyl medlacrylate (PMMA) Comment Lowflux Hi8hflux Highflux Protein adsorption esp. PMMA Reflect dialysate impurities Polyacrylonitrile membrane: ches: pain and dyspnea in pts on ACEI. Unavailable. Sterilized by gamma irradiation. ethylene oxide. or electron beam FLu lf REMOVAL AND ULTRAFiLTRATiON (UF) Estimated Dry Weight (EDW):Various definitions EDW is the optimal weight patients should reach after HD The weight at which the pt is asymptomatic wlo signs of volume depletion or overload The weight at which patient is norrnotensive without antihypertensive medications Failure to achieve EDW is alw ED visit and hospitalization UASN 2018;2H1781 Methods to Assess EDW Empiric (trialandenar"ItraditionaI method) lowest postHD weight tolerated with out inoaduiyrlr hypotension (IDH) or symptoms (cramps. NN dizziness. near syncope) Blood volume monitoring (BVM): monitoring of relative contraction of intravascular volume due to hernoconcentration from UF of the blood to help determine the maximal rate of UFtolerated and the lowest postHD weight achievable without the development of IDH Bioimpedance measurement measure d trial body water (TBW);not in muune clinical use DW assessment protocol J mortality: orthostatic BP may help (qAsn 2019;14:3B$) UF Amount and UF Rate (= UF amount/dialysis treatment time) UF rate >10-13 nUke/hr We 2016:ss911:K1z011:79a$01 and IDWG >4 kg (annum 20011196711 are alw mortality Strategies to Lower UF Rate Increase treatment time (duration of each session or frequency) Decrease interdiaiytic weight gain (IDWG) Restrict fluid intake (including IV fluid for inpatient) co <1 Ud Restrict sodium intake Loop diuretics: . intradialytic hypotension. hospitalization (c/Asn 201%14:95) Lower dialysate sodium gradually to 135 as tolerated HEmoolALvsls PRESCRIPTION arm flow (ob) Prescription of Maintenance Hemodiadysis 400450 mUm in 200 mUm in: initial. reswarc hyporensiorncerebral edema (CRRT pldlemd) Dialysare flow (Qd) Length 600800 mUm in for high flux dialyzer Should be 1.5-2 x Qb for optimal clearance Frequency zx3Iwk for minimal residual renal function Initially <50 kg: 3 hr. 50-90 kg 3.5 hr. >90 kg 4 hr Adjust based on adequacy, UF requirement, lab (K. PO4) Incremental HD based on RRF is an option who z0l4x>4:1e1) Needle Max Qb:300 (17 G),400 (16 G).450 (15 G) Ultrafiltration (UF) UF amount: Commensurate with EDW UF modeling Higher UF rate (when the patient is at a higher volume and capillary rein is presumably more rapid) - Lower UF me Various profiles available: stepwise. linear. or exponential decline Rarely lower 9 higher UF rate for intradialyric HTN wons in late par: Dialysate Temperature Sodium (132-155 mEq/L) 36.5C: Low temperature (35-35.5°C) promote perkaheral vasoconstritdon and aid in hernodynamk stability during HD: sic cramps,d1iIIing Low Na: 1 BR IDWG (HmM 7.007.29;14:3): may cause cramps. NN High Na: may stimulate dlirst and T IDWG Rapid Na reduction may cause cerebral edema Rapid Na rise may cause osmotic demyelinadon; safe correction limit is unclear: 15-20 [Semis Owl2011:24r407) In severe hyponatremia CRRT with customized substitution fluid or postfilter hypotonic fluid may be considered (C/ASN 201&1J17871 Sodium prowling (modeling) Higher dialysate Na (Lo allow for higher UF me) Lower dialysate Na Various profiles available: stepwise. linear or exponential decline Stepwise prowling is eiieczive 4H¢m¢¢0il»»i 201742113121 s/ez potential Na loading -» T thirst and fluid intake with higher IDWG; alw t allcause & CV mortality (QASN zoimwaasi Potassium (0-4 mErelL) 4 rarely used in advanced CKD Potassium prowling Calcium (2-3.5 mEq/L) Higher K initially -> lower K later in treatment allows for gradual fall in Bicarbonate (3040H1541/L) 35: typical: adjust to have preHD HCOJ level 21-22 (Ayn:1004;44=s611 High dialysate bicarbonate BP (nor z009:z4:97a1, t death (AP(D z01J:6z13a) 3:preHD K <42 2: PreHD K 4-6 0-1: preHD K >6: alw cardiac arrest lx/ 101 l;7%2l8: cIAs~ 2o1zwns5 1 serum K UASN 1017;28:}441) with less K gradient (nor 1018:33:1107) 2.5 typical 3.0-3.5: hypoalcernia in hungry bone syndrome after parath/midectomy 2.0: hypercalcemia; a/w low BR sudden cardiac death (qAs~ 10 I3:9197) Heparin Anticoagulation Prevents cloning within the dialysis circuit AVF/AVG: 25-50 ulkg: 60% bolus at initiation then 40% as infusion over duration of HD: held las: 60 min of therapy for hemostasis (eg. 1.000 u bolus + 500 u/hr) TDC: 50-75 u/kg heparin; 60% initial bolus: 40% as maintenance infusion - held last 30 min before completion of HD (eg.2.000 u bolus + 1,000 uR\r) Akernativelyn the entire dose given as a bolus at the in of HD HeparinFree Dialysis Indication: active or recent Gl bleed. hemorrhagic or ischemic stroke. surgery w/i the past 24 hr or a known/suspected allergy to heparin, HIT Options 1. Periodic flushing of the dialyzer with 50-100 cc NS every 15-20 min 2. Citrate infusion into the arterial side of the dialyzer (to bind Ca and inhibit pro coagulant factors) w/ Cafree dialysate and repletion d akium on the venous side 3. Citrate containing dialysate;./ ionized calcium (iCe) after HD in (2) and (3) Dialysis CatheterThrombosis Prevention: 4% sodium citrate or tPA lock Tx: tPA (alteplase. tenecteplase) to each port for 3045 min: if it does not dissolve thrombosis. catheter exchange MBD AND HEHOGLOBiN IN DIALYSIS PATIENTS Conslderadons In MBD and Hb Management in Dialysis Patients Conditions Considerations High POW (>5.5) Dietary restriction: 750-1.000 mg/d r P04 binder dose;/ compliance and timing: right bdore or wl men Readdress the need for active and inactive vitamin D R/o rhabdomyoiysis.hemolysis.wmor isis syndrome Pseudohyperphosphatemia high Is. ball. or lipid Low PO 4 (<3.5) Lower or stop POW binder If PTH is high. sun or increase act we vtamin D If PTH is within goal. consider lowdose active vitamin D (but High PTH (>600-770) maintain PTH within goal) Control PO¢ If Ca x P >70, avoid active vitamin D and consider PO cinacalcet or IV etelcalceNde if Ca is not low: consider parathyroidectorny If Ca x P $5-70. start low dose or titrate up active vitamin D If Ca x P < 55. start or titrate up active vitamin D Low PTH (<150-170) Lower active vitamin D dose and dlc inactive vitamin D If slp paradiyiioidectomyn do not dlc active vitamin D for low PTH-tiuate active vitamin D to maintain serum Ca 28.4 If Alk pos is low. possible adynamic bone: stop act vitamin D and convert Ca containing P04 binder so nonCa containing one. consider low Ca bath High Ca Convert Ca containing POW binder to nonCa confining binder Readdress the need for vitamin D malignancy. granulomas. hypothyroidism. immobility If PlH is above goal, consider :inacalcet or etelcalcedde Rlo: Low Ca Use albumin corrected Ca level; Control high P04 Stop calcimimetics (PO cinacalcex or IV etelcalcetide) if it is given If P04 is controlled. consider active 2 nutrient vitamin D High Hb Lower (Hb 11-12) or stop (Hb >12) ESA dose Low Hb (<10) Start of increase ESA dose to avoid transfusion lnithl ESA dose: epoetin 100 ulkgTlw or darbqacetin 0.45 Was/wk ESA resistance: requiring >7S u/kg epoetin 3 x/wk (225 Wk.;/wk) Rio malignancy (RCC, HCC. hemangiohlasmma). polycythemia Vera or equivalent dose rlo other causes of anemia including iron deficiency (could be alw blood loss). inflammation. malignancy.folate or vitamin Bn deficiency.TMA. inadequate solute clearance. hyperparathyroidism (Aim 1cc9;sa¢ezai Proactive iron sucrose high dose (400 mg monthly unless ferrite >700 orTsat 24058) 1 ESA dose dt neactiwe low dose 0400 mg monthly reactive to ferrite <200 or Tsat <20% wpm z0193a0444 PTH Initial Active Vltamln D Dose (TIW for W) Based on PTH 300-600 600-900 >900 Parecakizol (IV) Doxercalciferol (IV) Calcitriol (Iv) Calcizriol (Po) 0.04 ugly 0,025 ug/kg 0.015 pg/kg 0.07 vs/*G 0.04 pkg 0.025 kg/kg 0.1l18/l<8 0.055 pglkg 0.035 pglkg moral weekly IV dose and divide into a daily PO dose Examples of Dose Adjustment Based on Senal monthly PTH Change in PTH PTH <1S0 PTH 300-600 PTH >600 Fall >60% 25% 125% 125% 1 25% Mainzaln Maintain 1 25% Maintain T25% 1 Fall 40-60% Fall<40% Examples of ESA Dose Adjustment . Hb >0.5/wk . Hb <0.S over 2 wk Hb >12 l 25% Hb 11-11.5 J25% t 25% Hb 11.5-12 1 50% hold until <11.5 and then resume at a 1 dose ( 25%) HD ADEQUACY Adequate HD Solute clearance. BR and volume status are considered SOLUTE CLEARANCE Urea Reduction Rate (URR, %) URL = (pre HD BUN - post HD BUN) X 100 pre HD BUN Limitations: does not consider urea volume change and generation. inability to incor porate the patients residual kidney function; cannot compare ueatrnents widl different frequency Should be 265% (68% if no UF during HD); KDOQI not recommending the use Normalized Urea Clearance, Kt/V Dimensionless, urea clearance normalized co distribution volume of urea K = Urea clearance: z = Dialysis time:v =Volume of distribution of urea Single Pool Urea Clearance, spKtN Per treatment normalized urea clearance based on the single pool variable volume urea kinetic model estimated by Me Daugirdas II equation UASN 1993>1:\20s.»vailable a¢QxmD'p: *PK*=-Ln(R-0,0osxn+(4-3.s><alx UF olu e L v m <) post.HD weight (kg) R _ postHD BUN r = dialysis time (in hr) p re H D BU N spKtN should be >1.2 with target 1.4 (KNOQ1A;KO 201s;ss=aa4) ::: 3 9 o Equilibrated Urea Clearance, eKt/V 5 Similar to spKt/V except uses a postHD BUN drawn 30 min after the completion of < HD to allow for tl\e initial rapid rebound and transcellular reequilibration of urea eKt/V should be >1.05: approximately - spKtN 1.25 Computed from the spKt/V and session length (t) using. for example. the Tattersall equation (KI 199s;$02094): r = session duration (min) C = time constant. specific for type of access and type solute being removed. For urea. C should be 35 min for arterial access (AVF/AVG) and 22 min for TDC Standard Normalized Urea Clearance,stdKtlV An estimation of geglgly urea clearance on continuous or intermittent therapy On intermittent therapy, use the Leypoldt formula to calculate s:dKt/V (Semen Dial 2004.17:142,cakulator is available at www.h¢kn.<am) Typically used for treatment prescriptions other than 3x/wk dlaiysls sessions stdKtN should be 22.0 if residual renal function is not measured or negligible A spKtN of 1.2 delivered 3 x/wk yields a stdKtN of 2.0 Normallzed Urea Clearance from Residual Renal Function, KtIV,,.,,l K: urea clearance from 24hr urine prior to the first HD of the wk and the predialysk BUN (can pu: urine volume in dL and multiply by 0.07 = 100/1.440) Urine urea (mg/dL) x Urine volume (dUd ay) X 100 mL x predialysis BUN (mg/dL) dL day 1M0 min t:1 wk= 60x24x7- 10.080 min V: the urea space. or :oral body water (TBW) as: (a) dry weight TBW 0.6 (in men) or 0.5 (in women) (b) alternatively. use the WatsonV formula KfJV.,.\l >2.0 indicates sufficient residual renal function to not require dialysis No residual renal function (RRF) is alw mortality RR of 17.66 compared to KtN,,,.,l >0.84 (dw C..,.. 3.5 mUm lf in 70 kg man) uAs~1oo4;1s=1os1l Total Weekly Ktlv stdKt/V + Kt/V,,,,.l should be >2.0:for PD total KdV >1.7 is considered sufficient Example 50yrold man male produces 10 dL of urine/24 hr with a urea nitrogen of 405.7 mgldL. His EDW is 71 kg.Treat.menr.s are 3.5 hr with 2kg inzerdialytic weight gain and preBUN is 75 mg/dL and a postBUN is 25 my dL. Estimated TBW or urea space is 0.6 x 71 kg = 42.6 L = 42.600 mL Residual urea clearance = (405.7 x 10175) x 0.07 = 3.79 mUm in . Kt/V,\,1l = (3.79 mUm in x 10.080 min/wk)I42,600 mL = 0.90 Calculation ofTotaI Kt/V x3Iwk Method Daugirdas II formula* 1.27 2.07 Leypoldt formula* 2.97 Kl:N,,,.l + $tdKt/v spKn/V s:dKcN Tool x2/wk 1.27 1.37 2.27 Use online alcularor Conclusion: this patient could Mac xlfwk as this point Normalized Protein Catabolic Rate (nPCR,glkgld) Estimate of dietary protein intake based on the assumption of a steady state equi librium between dietary protein intake and protein catabolism Can be estimated based on interdialytic (ID) BUN and interval (Nina n.»ef 1991=1s=1sn nPCR= 0.22 + 0.036 X ID rise in BUN X 24 + Urine urea nitrogen (g) X 150 ID interval (hrs) ID interval (hrs) x weight (kg) Can be esrimamed based on preHD BUN and spKtN if there is no significant renal urea nitrogen excretion, C... <2 mUm in (1As~ 1996:7,700) nPCR = pneHD BUNI[a + (b x spKtN) + (¢'§plWV)] >a1wk Ho a b c 1st 36.3 5.48 53.5 + 0.168 x2Iwk HD 2nd Jed 1st 2nd 25,8 16,3 48.0 33.0 1.15 4.30 5.14 3,60 56.4 56.6 79.0 83.2 nPCR at least 1.0-1.2 glkg/d: optimal nPCR is 1.2-1.4 glkgld Inadequate dialysis is associated with poor oral intake and decreased nPCR Renal urea clearance corrected nPCR and its changes are a/w high albumin and low mortality (C]ASN 2017;11:1109) Clinical implication of Solute Clearance Weekly timeaveraged BUN (TAC..,.) 50 (vs 100) was alw less hospitalization in nondiabetic ESRD wlo residual renal funetion.TAC.,,, is an imperfect measure of urea clearance alone as confounded by and not separated from urea generation rare (nPCR) (NCDS NE]M 19B1:30$1176) spKtN >0.80.9 was a/w less hospitalization ¢ncos Vu 19es=1s.szq spKt/V goal of 1.65 (vs 1.25) and high flux dialyzer did not improve mortality and hospitalization rate (HEMO new 2002:347,2010) High flux dialyzers (K.,¢ >20 mUhrlmmHg) did not improve overall mortality. lt produced survival benefits in DM or patients w/ albumin 54. presumably related to better middle molecule clearance (MPO )Asr4 2009;10.64S). High flux dialysis alw low CV event in pts with AVF and DM leGs 1Asn z013.z4110141 x6 vs x3/wk HD for 12 mo (srdKnN 3.54 vs 2,49) resulted in L death or 1 LV mass progression (HR 0.61). t access intervention (xi .71) lrHn new z010;zea:nsn. 3.6yr followup showed . mortality (x0.56) (FHN ;As~ 20163z7:-9:40) CAUSES OF INADEQUATE DIALYSIS Cau ses o f In ad eq u at e So lu t e Clearan ce Lower Qb than prescribed: inappropriate needle position; small diameter needle Inadequate treatment time: late arrival. early termination Dialysis noncompliance Access recirculation: inflow and oudlow stenosis Causes of Inadequat e Fluid Removal Overestimated DW: volume overload: large interdialytic volume gain Inadequate treatment time Dialysis noncompliance. excessive dietary sodium. and fluid intake Dialysis associated symptoms: cramping. hypotension HD WATER TREATMENT Water for HD is pretreated through a series of purilicauon steps before it is used [O dilute the dialysate concentrate to generate the final dialysate solution Chlorine dioxide. chloramine: added in municipal water supply to prevent bacterial (eg, Legionella) growth Conventional HD requires 600-B00 mUm in (100-200 Usession) of dialysate flow The process consists of having water pass through a series of membranes and filters C omponents of Water T r eatment Heating Multimedia filters Warmed xo 25 C (77F) for optimal RO membrane performance Remove large particulate matterscaka sediment filter aka sediment Glter Water softener Remove Ca". Mg". iron. and manganese lon exchange resin: exchange with Na Prevents Ca" scaling on RO membrane Carbon Glter (activated carbon) Remove chorine, chloramines. organic contaminants Usually 2 in series. the lstworker" rank and the 2nd polisher" tank Empty bed contact time (EBCT) should be 210 min High pH of water [O . copper. lead and chlorine cause lefliciency of carbon filter J Chlorine. chloramine between 1st and 2nd carbon tank at each shift Reverse osmosis (RO) membranes Remove inorganic (aluminum. zinc. lluoride.copper).organic contaminants. bacteria, viruses. endotoxins Uses high pressure. rapid filtration of the water across a 300Da pore membrane to generate the deionized water Chlorine can damage RO membranes J Conductivity of product water continuously Remove ionized contaminants, do not remove bacteria. endotoxins Exchange cations for H and anions for OH Either 2 tanks (cation and anion exchanger) or combined in 1 tank J Resistivity continuously Remove any remaining bacteria and bacterial products (endotoxins) Cartridges alters with pone size <1 um in diameter Deionizers (optional: used with RO membrane) Ultramicron filter Bact eria and Endot oxins Pyrogenic reaction is esp. a/w dialyzer reuse and high flux dialyzers The presence of low levels of bacteria and endotoxin are alw chronic inflammation and potential i risk for accelerated atherosclerosis and CV morbidity/mortality Cytokineinducing substances: endotoxin. pepzidoglycans, bacterial DNA and its fragments lead to chronic inflammation: T ESR. hsCRR IL6 which may contribute to accelerated atherosclerosis. CV disease. ESA resistance Ultrapure water is required for high flux HD or HDF to reduce risk of backfikrazicn of bacterial products Bacwerla and Endotoxin Limits in Wanr Used for HD CMS (AAMI 2004) Europe, AAHI 2014 Ultrapure <200 <2 <100 <0. 1 <0.2S <0.03 Bacteria (CFUlmL) Endotoxin (EUImL) Potential Water Contaminants Contaminant Chloramines Aluminum Fluoride HzO2 Copper. Zinc Lead Cyanozoxin Water Contaminant Potential Cause Manifestation Hemolysis. medlemoglobinemia. Short EBCT Chlorine contamination -r carbon ESAresistant anemia fiber failure Damage RO membrane Dementia. myoclonus. seizures. Acid concentrate pumped via low pH incompatible tubing delirium. ESAresisnan: anemia, osreomalacia Pruriws. headache. nausea. Sawrared deionizer hypo¢ension.Vflb Incomplete rinsing Merhemoglobinemia Hemolysis Meal pipes Abdominal pain. myopazhy Pipes Contaminated water Neuronoxiciry. hepawxoxiciry HD COMPLICATION DIALYSIS DISEQUILIBRIUM SYNDROME Epidemiology Risk Factors: high BUN. low bicarbonate. CKD (>AKl). brain injury (stroke. seizure. trauma). eerebrai edema (hyponauemia. hepatic encephalopathy. malignant hypertension) Rarely wl CRRT with high intensity (effluent flow 40 mUkg/hr) (NE/M 2009;361:1627) or significant osmolality drop (cit 2013:67516) Pathogenesis Intracellular osmotic equilibration in ESRD or AKI of relatively long duration - Rapid osmolytes and fluid shim at the initiation of dialectic therapy -»Osmotic disequilibrium across cellular membranes and fluid shifts into cells -»Acute cell swelling and, in die brain, cerebral edema Clinical Manifestations Range from mild (headache, nausea) to severe (confusion. restlessness. altered senso Q :z rium, blurred vision. seizures, coma, brainstem herniation.and death) MRI: demyelinating white matter injury Prevention Initial HD URR <]*09lS wadi low Qb (150-200 mUni\) and short ueaunem titles (15-2 hr) based on body weight (and esdmaued :oral body water or urea space). UF <1 L Followed by gradual updzrazion of dialysis time (usually 30 min increments) and blood flow (50-100 mUm in) until HD adequacy is achieved +I- mannltol 75 g IV during EM 1-3 HD session Treatment Mild L Qb; consider d/c of HD according to indication Severe:dlc HD, IV fluid. consider mannirol 10-75 g. 23% hypertonic saline 5 mL Seizure: airway protection. lorazepam 4 mg IV or diazepam 5 mg IV TYPEA DIALYSIS MEMBRANE REACTION Pathogenesis IgEmediated type 1 hypersensitivity reaction (anaphylaxis) to ethylene oxide NonIgE mediated anaphylactoid reaction to acrylonitrile membrane + ACEi use Clinical Mahifestation Typically.wichin :he hrs: few min of initiation of dialysis Burning as d1 e access sire, chest pain. dyspnea. bronchospasm, urticaria. hypotension Treatment Stop dialysis immedianelyado not return the blood in the extracorporeal circuit • Epinephrine. IV steroids. and H1blockers; proper sterilization for prevention TYPE B DIALYSIS MEMBRANE REACTION Pathogenesis Akemate pathway complanent activation: PMN sequestration in the pulmonary vascular bed and degranuladon with release of inflammatory cytokines Clinical Manifestation Typically.within the firs: 30-45 min of initiation of dialysis: Chest and back pain More common with the modified cellulosic membranes Chan synthetic membranes Neutropenia during the event and have a posrdialysis rebound necrophilia (common occurrence not clinically significant in the absence of systemic symptoms) Treatment Symptomatic. supportive CRAMPS Frequent cause of HD early termination and inability to achieve dry weight Causes: below DW. high interdialytic weigh: gain (dietary noncompliance). high UF rate. hypotension, hyponatnemia, hypovolemia, carnitine deficiency Tre a tme n t a n d Pre ve n ti o n NS. 25% mannitol $0-100 mL. 50% dextrose 25-50 mL Readdress DW dietary counseling to educate on weight gain <1 kgld Higher sodium dialysate or Na modeling If fluid removal is needed, * treatment time and/or frequency to .l UF rate Vitamin E 400 IU HS lAm/n»¢n010:17:4ss). Carnitine 300 mg PO bid we 2cae;sz;9e2l Quinine: may cause severe allergic reaction and TMA: not recommended INTNANIALVTIC HYrOTENSlON (IDH) Background and Clinical Implication Minimum SBP <90 a/w mortality UAS~ 201s:16;724) lDH in >10% of HD t CV mortality 22% lqAs~ 2014 1124i alw residual renal function loss (xi 2002;621046). cerebral ischemia (al 201$;B7:1109). access thrombosis (}A$N 201 l:11:l516) Myocardial stunning: recurrent myocardial ischemia, regional wall motion abnormalities lqAsn 2ca83:i9> - fibrosis -> dysfunction ac/Asn 200924:914: xi 201994:6411 HD early termination, T EDW _. chronic hypervolemia -| LVH, HF (swan nm12016:z9;41s1 Causes Contraction of the intravascular volume which occurs when the race of UF exceeds the rate of capillary refill from the interstitial space reaching a critical point where die patients CV system can no longer compensate to maintain systemic BP UF rates >13 mUg/hr (H¢ma¢allnz2018;12:170); volume depletion below DW Hlgh predialysis osmolality reno 101516614991 Paradoxical withdrawal of reflex vasoconstriction UC' 1992;9016$7) Dialysate: acetate. low Na. low Ca, high Hco, vasodilation (nor z009=24397a1 Bleeding, distributive (sepsis. adrenal insufficiency). cardiogenic. obstructive shock Clinical Planlfestation Asymptomatic. lightheadedness. NN cramps. hoarseness (thinning of vocal cords). vagal symptoms (yawning, Sighing) (qAs~2014:9:708) Stroke. myocardial and bowel ischemia. shock Treatment Stop UF. headdown (Trendelenburg) position. 1 Qb If solute clearance is not an issue Administer NS.hypertonic saline, albumin or mannitokaddress causes Prevention Strategies to Prevent IDH Ulrrahlxrariun (UF) L UF rare <13 mUg/hr: . dialysis Mme. additional HD session LIDWG: restrict fluid (<1 Ud) and Na intake; lower dialysare Na may . thirst: loop diuretics if UOP >200 mud rqasu 1019:144ls) UF profiling/modeling: greater UF earlier when :he patient is more volume overloaded and a lower UF rare laze in HD as die parien: approaches the EDW and is more prone to lDH Osmolalizy change Reassess volume status and EDW: may need to T EDW Na profiling/modeling: high Na dialysaze to prevent fluid shift into cells: stepwise profiling is effective (Hwan: Ml 2017;21:312) sle: may cause () Na balance and izhirs: leading to lDWG:rou:ine use is alw mormaliry ac;/isn zo1'zi4¢3as) Sequential UF: UF wlo dialysis for 1-2 hr while BUN concenuavion remains high;followed by HD with no or less fluid removal Low Qb ieyasu 2018.1].1197) Vasaconsuicrion dlc antihypertensive or dose after HD L dialysate temperature (3535.5 C): promote vasoconstriction to maintain BE . IDH mm 100s.z 1:1as3: qAs~ 10l6:ll:442), 1 regional wall motion abnormalities lcusu 2(l06:1:1Z16) High dialysate Ca for 1ca'n497n; may cause (+) Ca balance Low dialysate bicarbonate (NDT zuatuany Midodrine: a1 agonist: 2.5-10 mg 15-30 min before HD: removed by HD; additional small dose can be given during HD: SBP of 12.4 Ivor 2U04:l9.1S53)1 no additional effect (O cool dialysate WM 1999=ns20). s/e: urinary retention. supine HTN Droxidopa; NE prodrug no benefit wl sle u=~=~I~=»~1 my 2015;111m) Others Avoid food intake during HD; manage anemia Blood Volume Monitor (BVP1): helps determine the maximum rate of UF that a patient can tolerate before developing IDH: monitor for the relative contraction of intravascular volume (goal <8%/hr or 16%/session). No clear benefit IC}ASN zoI 7;1zi031:201*xI4.ass). Switch to PD High predialysis BP does not prevent IDH (w-~=» at PM z00s;103:<un INTRADlALYTlC HYPERTENSION Background and Clinical implication Common: z1.3/100 HD session (li[AmlOrluns 201113s10z11 3 alw Tambularory BP url/~$~ z011;6:14>e4> t Short:erm morzalicy. hospizalizadon (An-11#www 201813113291 t Longterm adverse CV events and death WKD 10091548B81. K11013;8479§) Pathogenesis and Causes Volume overload: inadequate dialysis (NOT 201tn15:3355) u D : Acrivadon of the RAAS ;t SNS. removal of antihypertensives. high sodium dialysaze ESA T endothelin1 (ETLvasoconstrictor); endothelial dysfunction (C/ASN 101141016) Low SaO1 -o sympathetic activity. ET1 (nor z0maz;1o40) Dietary Sal: and high [Na] no 2012:81.40n. Serum KO dialysate sodium gradient wi1 ~=¢~=l 2D13;3B:41J) Management of Interdialytic Hypertension Early Late 1 Target EDW 1 Dialysate Na T Ancihypertensives If being used. dlc Na prohlinglmodeling J, Dialysaxe Na: 5 mEqIL below serum level IAlxL>201s¢es=4s4l Add or . nondialyzable RAAS inhibitor (ARB or fosinopril) SNS blockade (¢x and Badnenergic blockade) Carvedilol 50 mg bid: . EI1 release \qA$N 1012113001 Consider addition of RAAS blockade (ACEi/ARB) and/or SNS blockade (carvedilol) PERICARDIAL DISEASE Causes Inadequate dialysis solute clearance > volume overload Clinical Manifestations Dyspnea. pleuriric chest paimfever. pericardial rubs Tachycardia (in ramponade: can be absent in uremia). cardiac ramponade.deach Workup rlo other causes: infection (Tb. fungal.vinl-Coxsackie. enteroviruses. adenovirus. echoviruses. CMV). MI. hypothyroidism. malignancy. autoimmune (SLE. MCTD) EKG: diffuse ST elevations. PR segment depression. lowvoltage QRS complexes Echocardiography: pericardial effusion Tamponade physiology respiratory variation in transvalvular velocities Treatment Pericardiocemesis: tamponade. large effusions (usually resistant co intensive dialysis) 101s;za91) Intensive dialysis: wlo tamponade.daily heparin free HD or PD . failure is alw admission temp >102F. rates, admission SBP <100.JVD, PD only because of hemodynamic ins\zbilil:y.WBC >15K. large effusion <A~»J mea 19841763s1 u N4pnmI PULMONARY HYPERTENSION Cause: chronic volume overload or t venous return to the RV from a high flow AVF or AVE typically in >2 Umin Echocardiogram to evaluate for elevated RV pressures Treatment Auempr no reduce DW: banding of AVF to reduce flow through the access Am EMBOLISM Cause Air leak within :he exuacorporeal circuit Symptoms Chest pain, dyspnea/wheezing, tachycardia. hypotension (can progress to overt shock) Treatment Terminate dialysis Place patient in the left lateral decubitus position and in Trendelenburg (to trap air in RA/RV) Monitor oxygen saturation: supplemental high flow oxygen Echocardiogram and/or Chest CT angiogram (if needed) to tonearm air embolism Vasopressors for shock. mechanical ventilation for respiratory therapy HYPERKALEMIA Background Hyperkalemia is more common in pts on HD (K > 6 5%) (KI 2003;64:254) than PD High preHD K alw morality iqAs~ 2007:z:999: Aixo z011;s<n6s) Low (<2) K dialysate use is a/w cardiac arrest In 2011:n:2\& QA$~ zo11:7ns) HD diffusive clearance is decided by serumdialysis K gradient: reduced after 2 hr of HD and after using hyperkalemia treatment for intracellular shift HD pts have x2-3 colonic K secretion mediated by All/aldosterone (Senor DmlZ014;27:571): ~35% of daily intake is removed by colonic secretion (CJASN 201&13:155) Each HD session removes $0-100 mEq K according to dialysate K, time, Qb Causes of Hy pe r k a l e m l a I n HD P a ti e nts (semi of z01+.11s71: qisn 2018:1J:155) T Intake Dietary indiscretion. znnsfusion. IV or PO supplementation `Transcellular shift Metabolic acidosis Cell lysine: hemolysis, rhabdomyolysis, puma. minor lysine Prolonged fasting DI: Linsulin secretion High Na dialysare l;Asn zeoainzasn Inadequate HD Recirculation: Missed, shortened, or low dose (Qb. Qd) HD I Renal K excretion In pts with signihcanr residual renal Iunction: RAAS inhibitors, loss Colonic K secretion of residual function Constipation: 1 wet stool weight. RAAS inhibitors P re ve n t io n Prolonged fasting: D10W S0 mUm in + regular insulin 10 U/L if diabetic Dietary K restriction: 2-3 g (51-77 mmol) diet; dlc RAAS inhibitors Potassium exchange agents: sodium polystyrene sulfate. patiromer (NEW 2015:372:211). sodium zirconium cyclosilicate (new Z015:371:2221 Tre a t me n t Prior to HD: dextrose + insulin; NaHCO; only is not effective in HD pts; albuterol 1 0 -2 0 mg n e b ;Ca g lu co n a te 1 g IV if E K G ch a n g e s HD: low K bath according to preHD potassium; long session K profilingzlrom moderate (2 mEqIL) to low K (1 mE/L) less arrhydimogenic (NDT 209813114152 IASN 2017:2B:]441) HE MO LY S I S Ca u s e s Contamination: chlorine/chloramine (inadequate removal by carbon membranes), copper. nitrate, bleach. formaldehyde, peroxide Mechanical trauma to RBCs due to a malfunction of the blood pump, kinked cube Hig h Ro w t h ro u g h n a rro w n e e d le Hypotonic dialysis from erroneous electrolytes mixing, overheated dlalysate All other causes of hemolysis: mediation induced.TMA, autoimmune hemolysis Clin ica l Ma n if e st a t io n Chest pain, dyspnea. back pain. bradycardia due to severe hyperkalemia Port wine appearance of blood in venous line, pink plasma in centrifuged specimen Acute anemia Tr e a tm e nt If severe. dlc HD; do not remm hemolyzed blood to patient: J K. Hb.LDH. redo count to .é THRO MBO CY TO P E NI A s Ca us e s Heparin induced rinsing of the circuit (Hensndailn 2017;21:E30). catheter lock 2 Election beam sterilization of membrane (MW 201113061679) ,§ Treatment of HeparinInduced Thrombocytopenia Q I d/c heparin: / heparinPF4 Ab by ELISA and confirm with serotonin release assay Consider nonheparin anticoagulation for 23-6 mo if (+) thrombosis HD anticoagulacion heparin free HD. argatroban (KI Z004:66:2446) Apixaban approved for Afib/ESRD (uanauan z01e;\1a:1s19) can be considered Bivalirudin can be removed by HD HD VASCULAR ACCESS Background Vascular access patency is crucial for patients with ESRD.A significant amount of hospitalizations in ESRD patients is related to vascular access problems.Also. diamis catheter infections are associated with higher morbidity and mortality In 2016, 80% of patients of ESRD in the US were using a catheter at hemodialysis (HD) initiation.After 90 d, 69% of patients were still using catheters.The percentage of patients with a functional or maturingAV fistula at time of HD initiation was increased from 28.9% in 2005 to 33% in 2015 (USRDS 2018 Annual Data Report) The US has higher rate of grafts and dialysis catheters compared to japan and many European countries within 5 d of first dialysis treatment (al 100]:63:3Z3) Optimal vascular access planning should begin when eGFR <20 mUm in Vihdiout early planning patients often end up requiring placement of temporary dialysis catheters with increased risk of infections and higher mortality Types of Access Types of HD Vascular Access Access Time to Use Arteriovenous fistula (AVF): connection between native artery and vein. typically constricted with endtoside vein to artery anastomosis Aneriovenous graft (AVG): a connection between an artery and a vein using a prosthetic graft Dialysis central venous catheter (CVC) Aldiaugh someAW may be ready for emulation at 30d.alongerdme(upto6mo)maybe needed Mom they provide reliable HD access [KI 2005;67:2399) Can usually be cannulated within 2-3 wk Immediate use AVG (widiin 24-72 hr of placement) is an option ()in¢Aam zoo 1;17¢14s) Can be used immediateiyn but require verification of pager positioning prior to use Selection of the Appropriate Dialysis Access The choice of optimal access for an individual patient depends on multiple factors: timing of referral, personal preference. life expectancy. comorbidities. frailty, patient anatomy, institutional resources. and surgeon experience Factors that can Influence Vascular Access Selection Repeated venipuncture. peripheral IV catheters, CVC. PICC lines (um 1/41 201*r.pmlo 311s88461: previous dialysis access; history of neck/thoracic surgery or CABG Cardiac devices (AICD. pacemakers. CRT) May lad to phlebitis.venous sclerosis.stenosis and thrombosis which may interfere with Mum AVF placement In CKD 3S.avoid PICC UASN 201z7:16s4¢qAs~ zn16:n:\4J41 Dorsal veins of the hand are the preierted location for phlebotomy or peripheral access Internal jugular vein is :he preferred location for central access use lnzew Rural 200&I 141091 May lead to central vein stenosis Create AVF in contralateral upper limb Avoid central venous catheters If possible. avoid transvenous leads Consider leadless pacemakers. subcutaneous leDs, or epicardial leads (lllaxktess 201s.19,sz11 Potential for early kidney transplant Estimated life expectancy Preemptive transplantation is alvnys preferred if feasible Adverse ellecrs of posttlansplant outcomes on dialysis dwerapy are duration dependent No mortality diilenence between HD or PD prior to transplant lrmplun no 200<x41=11n For elderly patients with frailty, functional and cognitive impairment or severe comorbidities always discuss palliative care If a trial of dialysis is desired. may benefit from a CVC.AVG or assistedPD us niwisasy Use or AVF AND AVG Background An AVF is a direct surgical anastomosis between an artery and a vein Advantages ofAVF: lowest morbidity and mortality. lowes: need for intervention. and it has the best longterm patency WKD zo0¢4ais1; KI 200s;s7;2s9~x qAsn 2010§¢1 1s7). In most patients k should be the initial hemodialysis (HD) access (Ajxb 2006=4s suppl 1:S116). Disadvantages of AVF: longer maturation time. potential for vascular steal syndrome. aneurysm formation AVF are more likely to experience primary failure (access never usable or failed widiin 3 mo of use) than AVG In order to be usable, several characteristics must be present in an AVEThese include adequate blood flow. adequate maturation. reliable repeated cannuladon.and accessi bility in sitting position. In order to determine the best location to create an AVE evaluation should start dismally in the forearm of the nondominant arm and then move proximallycA radiocephalic AVF (1st choice. Figure 1) should be done it feasible.Alternative vessels may be used if needed (Figures 2 and 3) AVG or prosdxetic bridge grafts are surgically created artificial conduits that connect an artery to a vein and are superficially tunneled under the skin to allow easy cannuladon The conduit can be looped (Figure 4) or straight (Figure 5). Forearm looped grafts are preferred (law SW 101§:62:l7.$B), In older patients or those with poor vascular anatomy an AVG may be preferred.There is no clear AVF patency advantage in pts >6S yo compared to AVG (see Dai 200742asosl. AVF may be more difficult to cannulate than AVG. particularly during initial use. Timing ofAVF Creation and Time to Use Evaluation for vascular accts include clinical exam and vascular mapping by Doppler US A number of events take place before a successful AVF is created: referral to surgery. surgical evaluation. scheduling for surgery. a period of maturation. and the possibility of a need for salvage procedure to achieve usability which may be followed by another waiting period before the AVF is finally declared suitable for use Although a minimum time for AVF maturation may be 1 mo, we generally try to place AVF 6-12 mo prior to anticipated dialysis When created at least 4 mo prior to starting HD there may be a lower risk of sepsis and mortality (1As~ 2004:15:1936) Minimum time for maturation in older pos should be longer (>3 mo) UASN 20151164481 Polyteuafluoroetlvyiene (PTFE) AVG can typically be cannulated in 2-3 wk Polyurethane AVG can be cannulated in as little as 24-48 hr if needed U\'as<A:t:ss 1011:11.248). Concepts ofAVF Maturation Once an AVF is created. the blood vessels involved are subjected to marked changes in hemodynamic forces and increases in wall shear stress that trigger vascular remodeling, resulting in an increase in vessel diameter and wall thickness which are needed for a successful cannulation (]lhs<A¢cess 2014:15:291) Blood How through the AVF will increase providing adequate delivery to the dialysis machine. In addition, appropriate AVF depth. length. and location. which contribute to successful cannulation. are critically important. Evaluation ofAVF Maturatlon A thorough evaluation of a new AVF 4-6 wk after creation should be considered mandatory to assess for AVF maturation and to detect problems as soon as possible Physical exam by an experienced practitioner has >80% accuracy for predicting AVF maturation (K 4¢l\1l°ly 2002:215:S9) Rule of is: More Likely to Be Useable ifAVF Meets Following Criteria at 6 wk A&¢r Creation n(DoQIA;xD 1n0e¢4a511s) Depth External diameter Blood flow <0.6 cm below skin surface >0.6 cm >600mUm in Are line Venous line I x Ax..ry win B¢ld\i. vlerr CoD\lJic\!il auic vain Bradlill angry EndIOSian lnaslorloin " 4 I Figure 1. Bruhiocephak AVE (From Zdenock GB. ef. Figure J. Bradxiehasik AVE (From Zclenodc Manny of vnsadar and endawscula surgery. 1 so ed. 2006) GB. ¢d..Maslely ofnscudav and enduvnswlar surgery. in et 2006) Separate indslan :91 if! Endxo8169 anwomow Bladliil lfllly Flgun 4. Brachialanlxuhiul forearm bop AVG, PTFE. poly\nnlIuo1uedmenl. (From Zelaneck GB. ed..Mouery of vuimlar and endouwWaf swguy. 1so ed. 2006) Figure S. Brulicaxilary soaighc AVG. (From Zehnock GB, ed..Masury ofvasmlar and udomuulal surgery. he ed. 2006) Physical Exam of HD Vaxular Access liwxiees zornrxn History Difficulty placing needles. low KtN low Inflow stenosis blood flow Prolonged bleeding after removal of needles. high venous pressure during HD. large Oudlow stenosis aneurysms Inspection ipsilateral arm swelling ipsilateral arm and face swelling Bilateral arm and face swelling Enlarged veins on chest Long scar In forearm or arm No collapse of AVF with arm raise Aneurysm with paimenlargemenf. skin erosion Cold and pairNul hand.gangrene of fingertips Palpation Compression of loop AVF Hyperpulsatile access Compression of access with palpation between arterial anastomosis and occluding Finger (Augmentation test) Auscultation Highpitched predominantly systolic bruit Subdavian vein stenosis Brachiocephalic vein stenosis Superior vena an stenosis Central vein stenosis Transposed or superficialized AVF Outflow stenosis impending rupture Steal syndrome Pulsation felt in arterial p o rtio n Outiiow stenosis Poor augmentation suggests inflow stenosis Stenosis If there are abnormalities in die routine exam of the new AVF do has failed co mature. this should be further evaluated as soon as possible. usually using duplex US and/or contrast angiography Some parameters such as AVF internal diameter and volume flow are typically assessed by U/S (qAsn Z016;111817) Surgical Procedures for AVF Maturation Superficialization: used often in obese patients and those with deep veins Transposition: used mainly in AVF using the basilic vein.since this vein is more medial it re q u ire s la te ra liza tio n Translocation: with a vein uansloation AVE a vein is removed from its normal anatomic location to another location and thus requires the creation of aW anastomosis and aVA anastnmosis.The construction of a vein translocation AVF is similar to the placement of an AVG.The only difference is that a native vein is used instead of prosthetic material. Ca n n u la t io n Te ch n iq u e AVF: rotating site (rope~ladder) technique with sharp needle or constant site (but tonhole) with blunt needle. Constant site cannulatjon offers some advantages: less hematomas. less need for interventions. However. it may be associated with higher infection rate and more difficult cannulation compared to rotating site technique (NDT 101(k15:215; qAsn 1012;7:l6J2) AVG: must use routing site technique with sharp needle AVF FAILURE Primary Failure AVF that has never been usable for dialysis or that fails within the first 3 mo of use. lr is essentially a failure of maturation lqAs~ zuasmm). The primary failure rate for the brachialbasilic transposed AVF has been reported to be the lowest. followed by the brachialcephalic,and then the radialcephalic with the highest rate (C]ASN 1009;4:86) Failure in :he first mo is often due to technical errors in fistula construction or vessel selection UASN w91:3111 Late Failure Mawre AVF that fails after at least 3 mo of normal usage. Usually caused by stenosis (venous or artelial).flow stasis (excessive Rsuula compression after HD or due no §l¢°pi'\8 position). hypotension or hypovolemia. lrypercoagulabilityendodmelial injury we 199741) Evaluation ofAyF The best validated and mos: widely recommended method for access surveillance for detecting hanodynamically signitiant stenosis is monthly access Bow (Qb) measurement In one study access with >35% decrease in Qb had a 14fold increased risk d d1r ombosis compared to those without change W 1998:S4i1714) Several techniques are available for Qb measurement ultrasound dilution, conductivity dialysance, duplex UIS. Measurement of static and dynamic pressures is less effective for access monitoring. The mlc indications for AVF intervention are inadequate blood flow during dialysis, thrombosis, and failure to mature. Specific endovascular interventions include angiog raphyn thrombectomy. angioplasty. and stenting all of which are performed with fluo roscopy in a dedicated facility by adequately trained sniff. Surgical interventions are now rarely needed. Signs and symptoms suggestive of access dysfunction are edema. decreased delivered dialysis dose, excessive negative pressures. prolonged bleeding time after needle withdrawal Percutaneous Balloon Angioplasty Angioplasty is indicated if the stenosis is >S0% and is associated with clinical or phys iologic abnormalities u<l>OQI App: 2006;4B:Sl76) in AVF the mlc stenosed site is the "swing point" or "iuxtaanastomotic area." the portion of native vein mobilized during creation of the AV anastomosis (Can Nepluul 2003;6835) Treatment of stenosis increases access blood ilow and longevity, reduces access thrombosis and reduces vascularaccess related hospitalizations We zaastswz) Successful angioplasty is defined as no more than 30% residual stenosis and resolution of physical indicators of stenosis II(ooQI ~»<1> zu0s;4s;s17al Stents There is no clear access patency benefit of primary stem use versus angioplasty alone within a stenotic access or cenual vein ac/Asn 1008:3:699) Stalls should be considered in the setting ollailed balloon angiaphsxy (an elastic lesion).whe1 dveiealefewren1ainingacc5ssites.ifd\epadauisnotasuvgizzlandiclalneforanewaccess or when an outflow vein ruptures after balloon angioplasty (nmluugy 1997304943) CompucATlons oF AVF AND AVG Local Complication Easy bruising: hematomas may also result (rom improper cannulation technique Skin rashes:allergic reactions no iodine, Betadine.anrJbiotic cream are not uncommon Prolonged access bleeding should raise suspicion for elevated intraaccess pressure and outflow stenosis Infections Bacteremia frequently occurs during cannulation without actual AV access infection Dialysis pts with uncomplicated catheterrelated bacteremia are treated with systemic antibiotics for 3 wk.Those with metastatic infection (eg, endocarditis or osteomyeli tis) should receive 6 wk of antibiotic therapy We z0095s41.1 Venous Hypertension Usually occurs in pts with central venous stenosis or valvular incompetence May present as edema. skin discoloration.dilated collateral veins. Although mild extremity swelling is common following access surgery it usually sub sides. If the problem persists beyond 2 wk an underlying problem should be suspected | Aneurysm and Pseudoaneurysm True aneurysms: abnormally dilated focal regions of a blood vessel that contain all the | layers of the vessel wall Pseudoaneurysm: a focal disruption of the vessel widi a collection of blood outside the vessel that is contained by fibrous tissue Complications: rupture. infection, bleeding.erosion of the underlying skin, difficulty with cannulation Hand Ischemia (Vascular Steal Syndrome) Placement of AVF can reduce perfusion of the more dis ml extremity as a result of shunting of arterial blood flow into the AVF Ughs<Aaest 1011:12413> More common after creation of a high flow upper arm AVF than a more distil AVF (iurjllmr Endavmc Surg 2004;27:1) lr on cause paresthesias, sense of coolness. loss of sensation. weakness. Symptoms often worsen during HD. Tx: if symptoms are severe and persistent pts may require MILLER banding. distal revascularization, and AVF ligation High Output Heart Failure and Pulmonary Hypertension In addition to dyspnea on exertion and fluid retention. pts may have a hyperkinetic precordium and wide pulse pressure in the high output state.Access should be hypertrophied. located in the upper arm,with high (>2 Umin) access flow rates. The Nicoladoni-Branham sign can be elicited by brief manual compression of the AVE The response to this diagnostic maneuver is an immediate i in pulse rate and an T in BE which occur as a result of the sudden restoration of normal blood flow to the systemic circulation coincident with occlusion of the AVF Definite diagnosis of high output Slllé requires right hun cadleterization. High cardiac output. lownormal systemic vascular resistance and pulmonary HTN are character istic (nemuaial in! 1011;15:104) Evaluation of other etiologies of high output heart failure should be done Tx: lAVF inflow by banding techniques or surgical ligation of the access Coronary Steal Symptomatic steal from an internal mammary artery CABG from an ipsilateral upper extremity AVF can cause myocardial ischemia lA}KD 2002;40:B52) Thrombosis Infections and Seromas Occur more frequently with AVG than AVF Advantage Can be used immediately. Does not require cannulation. Option if an AVF or AVG is contraindicated (eg. severe heart failure). or if die expected duration of dialysis is less than 1 yr Used temporarily with a failing AVG or AVF until these are repaired Disadvantage 1 infection, sepsis, and mortality and die development of central venous stenosis or thrombosis. which comprises further access in the upper limbs In 1ooz;a1¢3os> The annual Medicare expenditures for pts with a CVC average approximately $20,000 more than for pts with an AVF (USRDS 2006 Annual Data Report) Location of Catheter The right internal jugular vein is the preferred vein for HD access because the vein takes a straight path directly into the SVC (jiuxunuv aaau 2013:24:129§) In cases of occlusion of all central veins. alternative sites for catheter insertion are the IVC which can be accessed via a percutaneous translumbar approach (J!'°°< Inue new 2013;14=997) or the hepatic vein (A~l\i=< so; 2013:27:332) Types of Catheter Tunneled dialysis catheter (TDC) or nontunneled dialysis catheter (NTDC) TDC dual lumen, composed of silicone.polyethylene. PU. PTFE and contain a subcu taneous cuff for tissue ingrowth to immobilize the catheter below the skin surface NTDC are preferred for pts who require emergent HD TDC are associated with lower rates of infectious complications and greater blood flow rates compared with NTDC.Tissue ingrovnh into the cuff seals off the catheter tunnel and reduces risk of infection Irv nr 1008;23;977) Realtime UIS guidance is recommended for venous access during the placement of CVC. Once inserted, positioning of the up of the catheter open needs to be verified by imaging. Duration of Catheter Due to the increased risk of infection over time. the duration of use of NTDC Is limited. Usually <2 wk for IJV catheters and <3 d for femoral catheters. If there is a longer anticipated duration of dialysis a cuffed TDC should be used The overall survival ofT DC is variable when used as a permanent access. One study showed 74% 1yr and 43% 2yr catheter survival (nor 1992;7;I 111) Care and Maintenance of Catheter Before and after each use dialysis CVC should be disinfected with chlorhexidine. flushed with saline to evacuate residual blood and locked with antithrombotic prophylaxis to prevent catheter malfunction Common solutions to lock TDC are normal saline. heparin.4% sodium citrate.tPA The available data do not support use of routine systemic antithrombotic prophylaxis for HD catheters to prevent catheter dysfunction Ul'¢lscAccess 2016;17:S41) Antibiotic coating appears to be effective in preventing intravascular catheter infections in the short term. but no data is available in the long term (Car cmm¢4 2009.37.702) Complications of Catheter Placement Bleeding. usually due to arterial puncture or venous laceration Pneumothorax, air embolism.cardiac dysrhythmias.atrial perforation. pericardial tam ponade Catheter Infection Exp site infections: Ioallzed cdlulids confined to 1-2 on where the atlieter exits the skin Tunnel track infections: involves space surrounding the catheter >2 cm from the exp site Risk factors for catheterrelated bacteremia: poor personal hygiene. use of occlusive transparent dressing, accumulation of moisture. nasal and skin colonization with Staph aurous and bacterial colonization of HD catheters mlc organisms of dialysis catheterrelated bacteremias are coagulase negative Szaphyiococcus. s. aurous. Enierorocci and gramnegative rods we z004.4411s) Patients often present with fever or chills. Patients with severe sepsis can develop hemodynamic instability. altered mental status or acidosis. The diagnosis of dialysis catheterrelated bacteremia requires one of the following: Concurrent positive blood cultures of the same organism from catheter and peripheral vein Culture of the same organism from both the catheter tip and at least one percuta neous blood culture Cultures of the same organism from two peripherally drawn blood cultures and an absence of an alternate focus of infection Broad spectrum antibiotic coverage should consist of vancomydn plus either tobramycin or cefepime.Antibiotic regimen should be modified based on sensitivity Catheter Removal in Infection NTDC removal: in all bacteremia TDC removal: in severe sepsis. hemodynamic insiability.metastadc infection (eg, endo carditis or venebral osteomyelitis). exitsite or tunnel infection. persistent fever or bac teremia >72 hr after initiation of antibiotics. bacteremia used by S. aurous, Pseudomonas. fungi or mycobacteria. or mukidrug resistant organisms (lon Gudeline an vnfea Du z(10m9;1) In this setting. a temporary NTDC is placed for shortterm dialysis access until the bacteremia resolves.Then.a new TDC can be inserted. If there are absolutely no alternative sites for catheter insertion catheter exchange Over a guidewire can be performed nu 1998;53117921 In pts without indications for immediate removal ofT DC the principal options are guidewire catheter exchange or instillation of antibiotic lock solution as adjunctive therapy to systemic antimicrobial treatment we 2007so:zs9) CentralVenous Stenosls Stenosis of superior vena cava (SVC) or brachiocephalidsubclavian vein Risk factors: subclavian catheter (ASAIOJ Z00$;51;77), duration and number of prior cath eter. pacemaker younger age at dialysis initiation lqAsr4 2019:PNID J0765534) Often these are initially asymptomatic. but the stenosis may manifest after the creation of a peripheral AVF in the ipsilateral exrnmiq It may present as edema or elevated venous pressures on dialysis (KI IW;33:11%) Severe extremity edema may lead to patient discomfort. skin ulceration, and infec dion SVC syndrome: SVC stenosis or obstruction or bilateral brachiocephalic vein occlusion Presents with edema of bod: upper extlemides.face. neck along with multiple dilated collateral veins over chest and neck Prevention: avoid catheterization especially subclavian including FICC (<JAs~20141I:14341 C a th e te r H a l fu n cti o n Adequate catheter function is the ability to sustain a Qb >300 mUm in lt is often suspected when blood cannot be wid\dllwn from the catheter or saline cannot be infused into icalso when during dialysis there are high prasures and low flow rates The mechanism of the obsutiction may be mechanical (kinking or improper positioning of the catheter tip) or thrombotic (catheterassociated thrombus or a fibrin sheath) Exp o sed T DC Cu f f A TDC with an exposed cull can be easily pulled out The exposed cuff also suggests that the catheter tip is no longer at the proper location and delivery of blood through the catheter may be inadequate PD CONCEPTS PERITONEAL TRANSPORT Peritoneal Membrane Anatomy The peritoneal membrane is semipermeable Mesothelial cells with microvilli cover the peritoneal cavity Microvilli increase the surface of exchange In females. the fallopian tubes and ovaries are connected to the pentoneaI cavity (during menses PD fluid may turn red given the appearance of hemoperitoneum) In PD. due perkoned membrane serves as d1e dialysis membrane; surface area of 1-2 my The peritoneal cavity serves as the dialysate compartment The lymphatic system drains the peritoneal cavity TheThl*ee Pon Model In mu£§m Comments Pore: Size Large Small 100-250 A 40-50 A Ultrasmall 2.5 A <10% of solute removal >90% of solute removal + 60% of water transport Aquaporin1, transport water only Large pores < Aquaporins << Small pores an number Nearest capillary hypothesis (pun of run 19%:16:1z1) Capillaries closer to the mesothelial cells have a greater contribution to transport across the peritoneal membrane Transport is dependent on surface area. distance from mesothelial cell layer and the extent of perfusion of capillaries (increased capillary perfusion in peritonitis) WATER TRANSPORT Osmosis Osmotic gradient is created by :he additives to the PD solution. glucose. or icodexmn 40% of water moves through aquaporin1 channels 60% of water moves through paracellular transport between cells. je. via small pores Hydrostatic Pressure Hydrostatic pressure gradient is the difference between intraperitoneal pressure and peritoneal capillary pressure Higher when patient is supine compared to standing SOLUTE TRANSPORT Diffusion Based on Fick lava transfer rate of a solute is determined by The diffusive permeability of the membrane to a solute The surface area available for transport. je. the surface area of the peritoneal membrane and capillaries The concenuauon gradient; solute moves from high to low concentration The concentration gradient: highest at the beginning of a dwell -» fastest removal In PD.creatinine,urea. K. H. and phosphate are mainly moved by diffusion Convection Occurs wid\ ultrafiltration and is determined by: The mean concentration of the solute. je. the dialysate fluid concentratlon.The higher the dialysate concentration - the higher the gradient between the dialysate and blood -» faster movement of water across pores. Of note. dextrose from the dialysate fluid is absorbed during dialysis and therefore the concentration gradient is reduced as dwell time is prolonged Water flux: depends on the number of small pores and aquaporins which varies among patients The specific solute reflection coefficient of the membrane: ranges from 0 to 1. Reflection coefficients closer to 0 indicate faster transport Dwell time je. show and frequent dwell times are the most effective because longer dwell times allow for equilibration of solutes between blood and dialysate Barriers to Effective PD Effective surface area of peritoneal membrane available. je. number of capillaries and area In contact with dialysate Intrinsic permeability of the peritoneal membrane that allows sduces to be uansported je. number of pores Peritoneal fluid is absorbed at a rare of 1-2 mUm in (WwW oiPerlmneaI Dhlyshln Handbodr °fDI°*tl*1. 3rd ed. 20012B\) PD PRESCRIPTION Peritoneal Dialysis (PD) Solutions Advantages of kodextrin over Dextrosebased Solutions 1/3 of icodextrin is absorbed through lymphatics over 12 hr ¢ can be used for longer dwells because oncozic pressure is maintained for ulnraflltration Greater UF in high transporters (AJKD Z002:3%861) Improved glycemic control UASN 2018;141B89) PD MODALITIES PD modalities Continuous or Intermittent Manual or Automated Continuous Ambulatory Peritoneal Dialysis (CAPD) Multiple exchanges during the day followed by a night dwell Automated Peritoneal Dialysis (APD) Combined with Day Dwell APD with Morning Day Dwell CYCLER CYCLER DRY APD with Evening Day Dwell CYCLER CYCLER DRY Continuous Cyclic Peritoneal Dialysis (CCPD) A cycler performs multiple nigh: dwells followed by a day dwell 7 am 10 pm (From Daugirdas JT. ed., Handbook of Dialysis. so et. 2015) Nocturnal Intermittent Peritoneal Dialysis (NIPD) A cyder performs multiple nigh: dwells: No day dwell is used Day Dry" APD (n 1pD) CYCLER CYCLES DRY PD PRESCRIPTION Patients Choose the Modality that Fits Their Lifestyle CAPD needs less training than APD APD oRers more flexibility for maintaining a good lifestyle Calculate the Required Total Dialysate Volume Daily Kr/vw.. Kt = 24hr dialysate volume x D,.,.,lP.,,. D: the urea concentration in 24 hr effluent dialysate collection . P: the serum concentration of urea V.,..: the volume of distribution of urea total body water = ideal body weight >< 0.6 in male. x 0.5 in young female The target is weekly Kt/V...., 21.7 = daily Kt/V,,.. 20.24 in anuric patient The initial prescription usually assumes that the patient has average membrane uaris port and that the plasma and dialysate urea are in full equilibrium; D ,.,. Pm Daily Kt 24hr dialysate volume eg. in a man with ideal body weight 70 kgV,,,,, is 42 L Required Kt is 0.24 < 42 L = 10 L of urea clearance per day. 10 L is the amount of dialysate that should be drained per day to achieve the goal weekly KtN 1.7. In a patient who has residual kidney function. residual renal KW should be calculated. This is :hen subtracted from 1.7,The resultant number will be die target KW used to calculate the dialysate amount. Determine the Fill Volume per Exchanges and the Number of Exchanges The initial fill volume is usually 30-35 mL of dialysate per kg per exchange. or 1.500 mum' of BSA per exchange. or 2.5 U1.73 m1 of BSA per exchange The initial (ill volumes should not increase intraperitoneal pressure >1B cm H20 In patients with residual renal function.it is possible to avoid a daytime dwell Determine Ultrafiltraticn Needs The initial dialysate composition depends on die volume status of the patient and their residual kidney function Euvolemic patients with residual kidney iunttion can start with 1.5% dialysate In hypervolemit patients. 2.5% dialysate can be initially used UF can be increased by using diah/sar.e with higher dextrose concenuation. by decreasing dwell time. increasing dwell volume. and increasing the number of exchanges Adjust Prescription Based on: The total UF (diaiysate and urine). changes in body weight. volume sums Uremic symptoms and dialysis adequacy 4 wk following prescription,/ peritoneal transport rate PERITONEAL TRANSPORT RATE MONITORING Pentoneal MembraneVariablllty Variability in peritoneal membrane transport between different individuals Changes in efficiency of peritoneal membrane over time Therefore. PD prescriptions should be individualized Tests to Evaluate PD Transport Rate Multiple tests have been advocated: Peritoneal equilibration test (PET) Standard permeability analysis (SPA) Peritoneal dialysis capacity (PDC) measurement Dialysis adequacy and transport test (DATT) Peritoneal Equllibration Test (PET) PET is the mos: commonly used rest The PET is a 4hr standardized rest with several steps It should be done no earlier :han 1 mo after initiating PD. PFT can also be performed after bouts of peritonitis as well as with UF failure. A dwell of 2 L (200 mUm in for 10 min) of 2.5% dextrose dialysare is used Drain 200 cc at 0.0,5. 1. 2,and 4 hr: 10 cc are sampled and the rest is rein fused The dwell is drained at 4 hr.and tonal volume of dialysate is calculated. Uluafiltrate is then inferred. use D/F DIP aeainlna 1.1 0.9 0.9 0.7 0.7 0.5 0.5 0.1 glucose ego sodium 1.1 1.00 0.9 0.90 o.a0 0.1 hours W high HA hlghavevage LA bwavungo L low Peritoneal membrane lranspon types are based on 4.hr equilibration ratios low Una. creatinine. glucose. and sodium. (From Daugirdas JI ed.. Hlndheck of Die}ysis. Sth QUO. 2015) 4 hr after the dwell, sodium. potassium.urea.creatinine.glucose.and :oral protein are measured in both d 1e serum and the dialysate High transporters remove waste products fast but are not effective at UF Tx: short dwells and frequent exchanges. je. CCPD Low transporters remove waste products slowly but are effective at UF Tx: longer dwells and less frequent exchanges, je. CAPD Peritoneal Membrane Failure The peritoneal membrane properties change over time.This is related to the exposure to dialysate and to inflammation in the membrane. Peritonitis increases the risk of membrane failure. Peritoneal membrane failure is defined as a UF <400 mL after a dwell time of 4 hr using 4.25% dextrose solution in die absence of any catheter malfunction or fluid leaks Type I membrane failure is characterized by high solute transport Tx: shortening dwell time and doing more frequent exchanges Type II membrane failure is characterized by decrease solute transport and water transport . Tx: dlc of PD and switching r.o HD Type Ill membrane failure is due to lymphatic absorption Tx shorter dwell time and using 4.25% dextrose or icodextrin solution PD ADEQUACY Adequate Dialysis Effective dose :had maintains fluid balance and prevents metabolic complications Measurement ofAdequate Dialysis Factors Affecting PD Adequacy Residual Renal Function (RRF) PD prescription should be adjusted as residual renal function decreases over time Higher RRF is associated with decreased odds ratio for death (Ajxo 1999832523: CANUSA,lASN 2001:11:2158) ACEi (Ann :m z00::u9:10s) and ARB we 2004;4310sq may help to preserve RRF Higher solution osmolaiity increases UF and can increase solute clearance by convection Higher fill volume can increase solute clearance Higher frequency of exchanges can t the concentration gradient between dial/sate and blood which leads to better solute clearance Peritoneal transport type (described below) Patient position the supine position T the peritoneal surface area available for exchange Catheter malfunction Fill and ExchangeVolume Can be estimated using the following formula:V,,.. =V + ((18lAP)I2) x 1.000 mL Vi: the maximum dwell volume tolerated by the patient IAP: the lnuaperitoneal hydrostatic pressure which should be <18 cmH1O in the supine position. lAP is lowest in the supine position. highest in the sitting position and intermediate in the standing position. V: the intraperitoneal volume Daily dwell volume = [kl/v xV]lt x DlP.,.. (V = volume distribution of urea.t = time in d) PentoneaI Transport Type Fast Transporter: require short dwells.ie. PD regimens that include frequent exchanges Slow Transporter: require long dwells and high fill volumes. je. CAPD or APD PD COMPLICATION PERITONITIS Background and Pathogenesis Presentation: abdominal pain. cloudy effluent fluid Bacterial peritonitis: effluent WBC >100 cell/pL with >50% neutrophils Maiorlty Grampositive organisms: S. epidelmidis > S. aurous > Enterococcus Fungal or mycobacterial peritonitis: lymphocytic predominance of the effluent WBC Candida albicans is the most common organism in fungal peritonitis . Recent antibiotic use is a risk factor Mycobacterial peritonitis: lymphocytic predominance of the effluent WBC PCR is more sensitive and can yield faster results than acidfast smears Eosinophilic peritonitis:>10% eosinophils in effluent fluid Related to allergic reaction. drug exposure,fungal and viral infections lcodextrinassociated sterile peritonitis: (-) peritoneal cultures Can occur any time after exposure to icodextrin Cloudy effluent with macrophage and eosinophil predominance Workup PD fluid total cell count and differential. Gram skin and cultures If the suspicion for peritonitis is high and cell counts are low. resend cell count and culture alter a dwell time of at least 2 hr Swab of the catheter exit site if there is purulence Treatment Stepwise Treatments of Bacterial Peritonitis 1 Empiric antibiotics while awaiting cultures: Vancomycin (15-30 mg/kg every 7 d) or lstgeneration cephalosporin (1e.cefazolin 15-20 my/kg daily) for grampositiye organisms Aminoglycoside (je, gentamicin 0.6 mg/kg daily) or 3rdgeneration cephalosporin (je, cefotaxime 500-1.000 mild) for gramnegative organisms 2 3 4 Followup daily effluent counts If clinical manifestations of peritonitis persist beyond 48-72 hr or if effluent cell counts remain positive for >5 d 4 treatment failure and need for catheter removal Antibiotics are narrowed when culture sensitivities are back Antibiotic course usually 2 wk: Sxapn aurous and Pseudomonas are heated for 3 wk IP administration of antibiotics is superior to IV administration in treating peritonitis. No specific antibiotic appears to have superior efficacy for preventing treatment failure or relapse of peritonitis (Cochrane Dunham So: Rv 2014;CD005284). Oral antifungal prophylaxis (lluconazole or nystatin) with each antibiotic course may g reduce the risk of fungal perinonicis (Coduune Database SW Rev 20\7:CD004679) Relapsing peritonitis: 2 peritonitis episodes caused by the same organism or 2 sterile peritonitis episodes within 4 wk of each other Refractory peritonitis: peritonitis that persists for >5 d Indications of PD catheter removal: relapsing or persistent peritonitis (Cndlmne DemOns: Syn an z014;cD00s1s4). pseudomonal peritonitis,and fungal peritonitis (high risk of death) Mycobacterial peritonitis: 6-9 mo of isoniazid. pyrazinamide. olloxacin.and IP riiimpin followed by a maintenance antimycobacterial regimen EXITSITE ANDTUNNEL INFECTION (ISFD Guidelines his Didlnl 1017:]7:141) Exitsite infections purulent discharge at the catheter-epidermal interface Tunnel Infection: :he presaice d inlhmmacion (erythema. edema. iendemess. or induration) or collections along :he tunnel Exitsite infections or tunnel infections can occur at dl! same time Investigation includes sending any drainage from the site for gram stain and culture Catheter care should be continued during treaunent of an exitsite Infection. Please refer to catheter care in the PD Catheter" chapter Empiric antibiotic therapy of exitsite and tunnel infections includes oral antibiotics that cover S. aurous. Patients who have a history of MRSA or R aeruginosa should receive oral antibiotics that cover those organisms. 8 3 z e Consider nysutin (or prophylaxis against fungal peritonitis If the culmres grow P. aemginosa, then patients should be given two antibiotics for coverage. one of which being an oral fluoroqulnolone. Of note, quinolones should no: be given at the same time as phosphorus binders. Duration of therapy for exitsite and tunnel infections is typically 2 wk.except in cases of P. aeruginosa where the duration of therapy is 3 wk Exit sires should be observed closely to evaluate response to therapy J U/S of :he tunnel to document clearance of any fluid collections Remove the catheter if fail to respond to antibiotics after 3 wk of therapy and in patients whose exitsite or tunnel infection progresses to peritonitis A new catheter an be replaced immediately after removal of an infected catheter in patients MM exitsite and tunnel infections only In those with concomitant peritonitis. a new catheter should be placed no sooner than 2 wk after catheter removal. MECHANICAL CompucATlons Hernias Can develop secondary no increased inu1abdominal pressure Encapsulating Peritoneal Sclerosis Sclerosis of the peritoneal membrane -n bowel encapsulation and intestinal obstruction The causes are not well understood bu: longer duration on PD is a risk factor. Many patients present after stopping PD. Clinical manifestations: partial or complete bowel obstruction. hemopeiitoneum. abdominal masses.abdominal pain. poor ultiaiiltration among others CT is the imaging modality of choice: peritoneal thickening and calcifications. bowel thickening. tethering. dilatation, obstruction, and loculated ascites Tx: discontinuation of PD.supportive care in use of bowel obstruction, nutritional support. Enterolysis an be considered for recurrent or severe symptoms. PD Cadwetewrelated Mechanical Complkadons Impaired dialysate flow Pain Leakage of dialysate Hydrothorax Can be seen during inflow or drainage Can be related to constipation -» laxative regimen Can be related to catheter rip migration -»AbdominaI Xrays can detect migration Entrapment of the catheter by the omer tum Fibrin - add heparin to the diaiysate From abdominal irritation of die catheter up From the dialysate flow against the bowel Can be related to high dialysate volume -» 1 dialysate volume Can be related to weak abdominal muscles » supine exchanges PD catheter migrates into the pleural space -> a communication between die pleural space and die abdomen Presents with respiratory distress and lung collapse. High glucose in die pleural effusion is a clue to die diagnosis TX: temporary discontinuation of PD or diaphragm patching Hemoperltoneum PD catheters may erode into mesenteric vessels or internal organs Other causes of hemoperitoneum include: menstruation. ovarian cyst rupture. renal cyst rupture.carcinoma in the abdomen. abdominal organ infections,splenic rupture, and sclerosis peritonitis . J effluent counts. culture. amylase and CBC. Ha >2% is suggestive of intraperimneal bleeding and requires further workup of intraabdominal bleeding. Oral contraceptives can stop bleeding related to menstruation TX: rapid exchanges (2-3 hr) MM 500 units of heparin per liter of dialysate.This pre vents clot formation that can result in catheter malfunction ME TABO LI C CO MP LI CATI O NS Metabolic Derangements With PD and Causes Hyperglycemia Absorption of glucose from the PD solutions Hyperlipidemia Nor completely understood. possibly due to hypoalburnlnemia and hyperglycemia Hyponaznemia Fluid overload and low dialysate sodium Hypokalemia Low dialysace potassium concencrazionlcontinuous diaiysisluse of diuretics Hypercalcemia High dialysace calcium concentration Hypermagnesemia High dialysare magnesium concentration Hypoalbuminemia 1-2 g losses/L of drained dialysace PD CATHETER Relative Contraindications to PD Catheter Placement Previous abdominal surgeries: abdominal wall hernias T y p e s o f C a th e te r s Tenckhoff (mos: widely used). Missouri swan neck.Toron\:o wesr.ern catheter P D Ca the te r S e gm e nts Inrnperitoneal The section inside die peritoneal cavhiy widi side holes no drain due dialysare No difference in function between srnight innapericoneal segments compared to coiled Double cuff Superficial curl is in the subcutaneous portion of die abdominal wall Deep cuff is in the rectus abdominis muscle Exuaperironeal The section within d1 e abdominal wall and outside :he body Preplacement Recommendations Laxatives to avoid postoperative constipation Antibiotics prior to PD catheter insertion: cephalosporins iisro reno niiiiin 10173711411 Pre/perioperative intravenous vancomycin may reduce the risk of early peritonitis in :he first few wk (<1 mo) following PD catheter insertion but has an uncertain effect on the risk of exitsite/tunnel infection (Cotkrune Dawbose Sir Rev 20I 7:CD004679) Periplacement Care (but before use) PD adieus are flushed widi dialysate followed by immediate drainage to maintain patency Heparin is flushed to avoid clots Catheter is covered.Traurna and change of dressing should be avoided for at least 1 wk PD is started at least 10-14 d after catheter insertion Showers should be avoided until the exit site is healed Urgent start PD is started 24-72 hr after PD catheter insertion.This is done in patients who need dialysis urgently but want to avoid hemodialysis. Early in PD is started 72-14 d after PD catheter insertion Both urgent start and early start PD should be done by trained staff, using low volume exchanges in the supine position PD Catheter Maintenance Wash PD exit site daily with antiseptic. either chlorhexidine or povldone iodine Topical antimicrobial agent should be applied daily: Mupirocin. Gemamicin Nonocclusive dressing should be used to cover the site Catheter should be immobilized with tape to prevent injury to the site If patients report trauma to their catheter site -v 3 d of cephalosporins Patients should avoid baths and swimming Pets should not be in the room when exchanges are being done. windows and doors should be closed Mechanical and infectious PD catheter malfunction causes 50-70% of patients to switch to hemodialysis. RECIPIENT EVALUATION Background Kidney Txp l death and T survival compared to remaining on dialysis 1n£;M 1999;341:1725) Preemptive txp: the optimal treatment for ESRD.Waiting time on dialysis is one of the strongest independent modifiable risk factor for txp outcomes (Tuwgiainunn 200z74:um Transplantation Evaluation Referral Early referral is important to avoid the development of comorbldities associated with dialysis and to increase chance for preemptive transplantation (nunxplanauan 100174 1377) Refer all medically appropriate pts w/ CKD stage 4.5 (eGFR <30) (A/xo 2007:sos901 Patients can begin to accrue wait time on the waitlist once eGFR or CrCl 520 or when they are receiving chronic dialysis therapy (http:/lo ptn.transplanLhrsa.gov) Goal of Evaluation To assess patients medical. surgical.social.and psychological suitability for transplant To educate the patient about the risk vs benefit of transplant To discuss donor options: living vs decased donor. Kidney Donor Profile Index (KDPI) >85%. Public Health Service Increased Risk (PHS IR) ISDEI combines a variety of donor factors (age. height. weight. edmicityt HTN, DM. cause of death. Cr. HCV siams. donation after circulatory death status) into a single number that summarizes the likelihood of graft failure after DDKT (eg.a kidney MM a KDPI of 85% is expected to have shorter longevity than 85% of recovered kidneys) PH idendhes donors at increased risk of transmitting HBV. HCV. and HIV Contraindications of Transplantation :Aim 2007sos90) Chronic illness that shortens life expectancy significantly; Poor functional staws Reversible renal failure. Chronic or active infection (needs treatment prior transplant). Active malignancy: needs treaunent prior transplant and must be in remission Uncontrolled psychosis; active substance abuse: ongoing noncompliance Cardiac Disease Cardiovascular disease is the leading cause of death after kidney transplantation Se. Sp of noninvasive cardiac tests in CKDlESRD pts are very low (knpeniisan 2003147;1631 Immunosuppressive agents can worsen HTN, hyperglycemia.and dyslipidemia.and thereby accelerate CAD (calcineurin inhibitors.sirolimus,steroid) Asymptomatic for CAD:23 risk factors (age >60. DM. HTN. dyslipidemia. obesity. lo angina pectoris. LVH. previous cardiac events. smoking history, (+) family history. HD duration 22 Yf)9r 21 CAD risk equivalent (DM.ad\erosderosis in other vascular beds. history of spoke) . noninvasive cardiac stress test (s¢t~i om:10101231598 Symptomatic for CAD.type 1 DM complicated with ESRD,ordiorrlyopad1y with reduced EE (+) noninvasive cardiac stress test -» coronary angiogram (.) Coronary angiogram -» If amenable. revascularization before txp (A/KO 2007;5&a901 Preuansplant LVH and elevated LA volume are associated with reduced survival after kidney transplantation (Ymnspiam Ro 20141310) -| Echocardiogram should be obtained in those with suspected valvular disease or CHF - Patients with severe inreyersible cardiac dysfunction should not be listed for kidney transplantation alone (may be candidates for combined heartkidney transplantation) (GMAJ 1005;17J:S1) Infectious Disease J HIV. HBV, HCV. tuberculosis. CMV (risk stratification). EBV. toxoplasmosis J If from endemic areas foncoccidomycosis. histoplasmosis. strongyloidiasis HIV Not an absolute contraindication. Needs HIVspecialist consultation. Should be on stable antiretroviral regimen. should have no detectable viral load. and should have CD4 count >200 cellslmm' Protease inhibitor can increase serum concentration of calcineurin inhibitors Shortterm outcomes comparable to general kidney Dup patients. Higher acute rejec tion rate. No increase in HIVassociated complications (u6/m 201(k3612004). For H Ninfected ESRD patients. kidney transplantation is associated with a significant surviral benefit compared with remaining on diadysis.Adlusted RR of mortality at 5 yr is 79% lower after kidney transplantation compared widi dialysis win so; 1017Jts¢s04I. Liver Cirrhosis HBV, HCVpositive patients should undergo liver biopsy and hepatic venous pressure gradient measurement (>10 mmHg clinically significant portal HTN) Pts w/ cirrhosis and portal hypertension needs evaluation for combined liver-kidney txp (AIKD 2007;50:B90l.A contraindication for KT alone due to increased mortality HCV qua Rev ~.¢n~l 201 s:11:m): needs hepamlogy referral HCVinfected patients have a lower mortality following KT c/w mortality on dialysis HCVinfected renal transplant recipients have worse patient and allograft sunmral after transplantation compared with noninfected recipients An HCVpositive organ may reduce waiting time substantially -» Consider postponing antiviral treatment until after transplantation co maintain eligibility for an HCVpositive organ as long as disease severity does not warrant earlier treatment HBV (www Hemi 10179 10541: needs hepatology referral lmmunosuppression t HBV reactivation -a HBsAgpositiverecipients are at high risk Both, patients with chronic HBV (HBsAgpositive) as well as resolved HBV (HBsAg r\egative.antiHBcpositive) should be initiated on antiviral therapy around die time of transplantation iGuw\=ev~wv1°ly 2015:148215) The use of antiviral therapy to prevent reactivation has improved longterm patient and graft outcomes -| Similar Syr patient and graft survival when compared to HBV negative recipients (qA$N 2011:6:l481) Ma l i gna nc y Immunocompmmised padeuvs are at increased risk for recurrent and de now malignancy All padems need ageappropriate screening. If malignancy is diagnosed.r.he cancer should be :reared and cured before transplantation. Mlnlmum Tumo»»Fr¢e Waiting Period (vi lU0$;173:§1; .quo zoouwol Cancer Mi ni m a l Wa i t Ti m e Ca nc e r Mi ni m a l Wa i t Ti m e Bladder In situ: none Breast Early in situ: 2 yr Prostate At l a s t 2 y r Renal Smal l , i nci dental r umor s: none Invasive: 2 yr Other : 5 yr Cervix In situ: <2 yr Colorful Duk e s A or B1 : 2 - 5 y r lnvasive:2-5 yr O t he r : 2 - 5 y r Other : 5 yr Lymphoma 2-5 yr Basal cell None Lung At l east 2 yr Mel anoma 5 yr He ma tol ogi c Di s e a s e WK0 2 0 0 7 :5 M9 0 ) -15-20% of ESRD pts have hypercoagulable scare (et, activated protein C resistance. factory Leiden gene mumion, prothrombin gene mutation, and APLA) History of thrombosis (DVD PE. recurrent dialysis access cloning), and/or recurrent spontaneous abortion/preeclampsia -» J hypercoagulability workup Plan pre. peri.and poswperanive anticoagulation: hematology referral for bleeding risk G l om e r ul a r Di s e a s e Transplant should be delayed until disease is quiescent. Not absolute connzindicazion. Risk of Primary Kidney Disease Recurrence (qAsn 10ua=JB00) Di s e a s e Ra t e Di s e a s e Ra t e Pr i mar y FSGS 20-30% MP G N Type 1: 20-30% MN 10-30% ANCA G N l g, 1n Z( ) 6 0 % AndG BM di s e a s e 15% SLE 2-10% HUS I TTP Noni nfecti ous: 60% Ty pe 2 ( DDD) : 5 0 - 1 0 0 % 17% Ne ur ol ogi c Di s e a s e History of corwulsion: avoid andconvulsanls which an interfere with CNI metabolism (carbamazepine.fosphenytoin. phenobarbital. and phenytoin may decrease serum concentrations of calcineurin inhibitors) -> neurology referral History of CV/*a needs neurology evaluation. Modiflable risk factors should be addressed. P ul m ona r y Di s e a s e Smoking cessation. CXR & PPD/IGRA (QuantileronTB Gol°"> -» isoniazid if indicated. History of extensive smoking and/or any signs of obscrucnive or restrictive lung disease -> PFTICT chest -a pulmonary referral P s y c hi a t r y Mild cogllimre impairment is not an absolute contraindication. esp wl good social support Stable and controlled mental illness is nor a contrainditazion Complia hte s hould be doc ume nte d prior tra ns pla nta tion Substance abuse should be eliminated prior transplantation Needs psychosocial evaluation In conjunction with a transplant social volker to assess support network, determine suitability. and develop a plan to avoid adverse nntnrnnlznrainn ntvrhnsnrial nutnnmes LIVING DONOR EVALUATION Living donation: 25% of uansplancs performed in the US in 2016.The rate remains stable. compared to rising deceased donation since 2011 (Air 201a21s suppl 1:18) Racial disparities in donacio.: Junors: 12.3% black (36.4% waidisr pts) vs 65.1% white (33.2% waitlist pa) WT 201a.is s-4w 1.1a) Commercial donation, a common practice in some countries. comprises 10% of uansplants. I: had fallen after d1 e Declaration of Istanbul on Organ Trafficking and Transplant Tourism (Lancer zcweanfs; KI 2019;95757) Superior outcomes compared to deceased donor transplant: 10yr graft failure 34.2% vs 51.6% and 10yr deathcensored graft failure 18% vs 26.2% WT 2o1&is Suppl 1:18) MEDICAL EVALUAT IO N Informed consent mandated by UNOS: evaluation process: surgical procedure: alter native treatment for recipient: medical and psychological risk; financial and insurance factors; voluntarism and the right to opt out of donation at any time J The operative cardiac. pulmonary. bleeding risks and anesthesiarelated complications H&P. includes focus on kidney disease history and risk factors:AKIl CKD. DM. HTN. gestational DMIgestational HTN. hemawria. proteinuria. kidney stones. UTI. congenital genitourinary anomalies. medications review including unSAIDs. PPI. herbal supplements. genetic or familial kidney disease. family history of HTNIDM Social history including adequate support. psychiatric disease history and behaviors meeting Public Health Service (PHS) highrisk criteria Compatibility r.esting:ABO typing (x2) including groupA subtype: HLA typing for MHC Class I (A, B. C), Class II (DR DQ. DR). Donor specific AntiHLA anubodies in recipients. ID screening: HIV. HCV. HBV. CMV. EBV. Syphilis,TB testing w/in 28 d of surgery Ageappropriate cancer screening 'UNOS requires mGFR or merCI Hematuria (KDIGO Tiuiupianiarian 2017;101 as 9991 1s1) Persistent x2-3 of 2-5 RBCJhpf. rlo infection (UA). malignancy (cystoscopy). nephro Iithiasis (stone panel).glomemlar disease:TBMN, I N (kidney biopsy). TBMN does not preclude from domdon (in absence of proteinuria and with normal BP) HTN (numplanmuan 2017;101 as mapu \:$1) J Office BP xl, If indeterminate. confirm w/ AB , Not an absolute conmindiudon if controlled on 1-2 antihypenensives w/o endorgan damage (LVH. albuminuria) Imaging MRI or CTA. In case of functional and anatomical disparities.the kidney with smaller size and/or lower function kidney is to be procured Additional considerations: dependent on each transplant center preference and based on the individuals lifetime ESRD risk. Obesity: BMI >40:absolute conuaindiadon, In the general population. BMI >30 alw CKD msn 1006;17:169S; up zwasrwi AMD 2005:46:587). 3.57 fold T in ESRD (Ann :m zm;1u=z1) and 1.16 we 201437414111 in otherwise healthy potential donon.albu minuria, and glomerulopathy Smoking relative contraindication at most centers despite association with renal inluq.AWised w quit before donation Ifwwww 20172101 as 991 1:51) DM is an absolute contnindiodon. Screening widl 2hr GTT orA1C. Role of APOLLO testing is unclear.Tes:ing is advisable among young donors ofAfrican ancestry with ESRD family history although precise risk is not quantified.APOL1 highrisk genotype donors have lower eGFR pre and post donation compared to lowrisk black donors w/ 0-1 risk variant (57 vs 67. 12 yr) UASN 201839 13091. Surgical Technique: handassisted laparoscopic donor nephiecwmy (LDN) widely used compared so open nephrectomy (ON). LDN is 51 min longer but has less blood loss. shorer hospital sraya and time co rewrn to work compared to ON (rimpluni nu 2013;45:65) OuTcomEs S h o r tte r m Ou tc o m e s 90d mortality is 0.03% up 20109039591 Perioperative complications encountered in 6.8% of donors: 4.4% GI. 3% bleeding. 2.5% respiratory. 2.4% surgical/anesthesiarelated injuries. 6.6% other [A/y 1ol6ns1a4a). Similar rates compared no patients undergoing cholecystectomies or appendectomies bu: lower than nephrectomies for cancer (qAs~ 2013;B:17I3). L o n g te r m Ou tc o m e s Physiologic changes post donation: 50% immediate reduction in GFR with subsequent compensatory hypertiltration by increased RBF and thus SNGFR ultimately leading to 30% GFR decrease . Physiologic adaptationzat 36 mo post donation, 1.47 mUmin/yr increase in GFR in donors vs 0.36 mUminlyr decrease in healthy controls WM 2015;s6114).And 0.20 mUmin/1.73 m'/yr at 12.2 t 9.2 yr (NEIM z0o9.aw4s9l, No accelerated loss of kidney function of-~»v¢»~»»»~ z001;n;444) At 12.2 e 9.2 yr after donation. among zss donors: 85.5% GFR 260 men zo0nso¢4s9} Proteinuria: same estimate across studies: 12% (N = 4.793. 7 yr) lx: z00s;70 1a01); 12.7% (11% >300 mold. N = 255, 12.2 1 9.2 yr) we/M zuo~r 3so.4s9l: 13% (3% with >1 old. N = 331, 18 mo-16 yr) (A/xo z01s:66: 114). lt correlates to longer time since donation [NgIVI z009.3s0.4s9> and HTN WM 201s;ss;1141. HTN: developed in 321% (NS/M z009;:iw4s94491 to 38% (TusplanlaUol 200127z4441 of nor mownsive donors. Risk similar to age matched nondonors in men but lower in women rnantpunmuan z001:7z:444l. 85% of white HTN donors had BP <140/90 at 6 and 12 mo after donation but readings are higher d1 an normotensive donors. Cr. UACR were similar (hongblantown 2W4;7B:276). CV events: no difference in deatncvD events between donors and nondonors at 6.2 yr after donation (Tl\l»1=1vIvrivw 1G0&B63399). In Norway, the risk increases among donors by x1.4 an 15.1 yr (K12014;86:1621. Older donors: in the US. 5.717 donors with age >55 from 1996-2006. Compared to agematched donors (mean age 59) with median followup 7.8 yr. no difference in mortality or combined outcome death/CVD (As z014;14.1ss3l. Pregnancy: gestational HTN/preeclampsia are more common among living kidney donors (11%) than among nondonors (5%. OR 2.4): Preterm birth (8% vs 7%1 and low birch weight rates (696 vs 494) are similar IN£/M z01 s1m2u41 Quality of life: donors physicalhealth summary score and mentalhealth summary score are above the US population norms INE/M 2009;3w.4s9). In Canada. Scotland. and Australia both scones are comparable WT 201l:l 1:46J). ESRD rate 1.8/10.000/yr vs 2.68I10,000/yr in the general population (flu 22.5 yr) in white dominant donors MM zucmasofassi In another study. ESRD rates in donors 30.8110.000 vs 3.9110.000 in matched non donors.Aldiough higher than :he controls. the risk remains low I/AMA 2014.111:s191 The 15yr risk in donors is x3.5-5.3 higher than the estimated projected risk of non donors. Longterm ESRD risk varies by age at donation and race (NEW 101&374411) Obesity: BMI >30 86% T risk of ESRD compared to nonobese donors no 2017991;699) Life expectancy similar to nondonors (hansplaninuan 1997164876: NS/M 2009¢3s0459) Other Considerations Kidney paired donation: incompatible donor/recipient swap for matched kidneys. Chains often initiated by nondirected donors.The National Kidney Registry facilitated 1,748 transplants,d\lough 344 chains. 78 loops from 2008-2015/2016 (4[rzo\7:17,z4sn Financial impact from oval to 3 mo after donation: median outolpocket expenses Can $1254 (5312589) and the median for lost donor productivity costs: can $0 (01908) (12 centers in Canada 2009-2014) lIAsn z01s.29¢2a47) Potential donors are more willing to take potential health risk compared to potential recipients and health care professionals (K12005;7311S9) Kidney donors on the waidisc 56 donors were listed as of 2/2002 (Tiumpianianun z00z74:1349), From 1993-2005. 102/8.889 donors were on the waidist Black donors 14 3% of donors but 44% of donors reaching the waitlist lfmnnlnzu 2007846471 IMMUNOLOGIC TESTING AND MONITORING PRETRANSPLANT IMMUNOLOGIC EVALUATION Background ABO blood type antigens and the human leukocyte antigen (HLA) system provide the major immunologic barriers to renal transplantation Transplant across ABO barriers is generally contraindicated (an be done in experi enced centers. bu: at increased cost and risk of rejection) HLA Antigens Class Expressed by: Control the Action of Class l (A. B, C) Class II (DR DQ. DR) All nudeared cells Antigenpresenting cells B cells CD8+ cy:otoxicT lymphocytes CD4- helper" T lymphocytes HLAA, B. and. DR are the primary antigens considered for HLA matching between recipient and donor: 2 alleles at each locus I 6 antigens total.A recipient will there fore have 0-6 HLA mismatches" with a particular donor Significance of HLA Matching T #S of HLA mismatches are associated in a stepwise fashion Deceaseddonor KTR with decreased longterm graft survival lnunspianmusn z016;10a1094) Aside from zeromismatch donorrecipient pairs (who have :he best longterm graft survival). the number of mismatches has Livingdonor KTR little effect on graft survival T h e Se n sit ize d Pa t ie n t Patients may have preformed antibodies to HLA antigens as a result of prior transplants. pregnancies. blood transfusions.and (rarely) viral/bacterial infections Such patients are referred no as "sensitized," and comprise approx. 1/3 of patients awaiting renal transplant in the US Preformed donorspecific antibodies (DSA) is associated with T incidence of AMR and 1 allograft survival compared to DSAnegative pts WT 2C0s;s324) Cnossmatch (XM): tests reactivity of recipient serum against allogeneic cells or HLA molecules (see table); can be performed against a specific donor or against "panels" of cellslamigens representative of the general population Antibody Detection Methods luqm zo1 eJ14s40l Assay Components Readout Sensitivity C o m p le m e n t dependent cytotoxic ( CDC) XM Donor lymphocytes. recipient serum. and complement 76 killing of donor cells F l o w cyt o m e t r i t XM Donor lymphocytes. recipient serum. and lluoresteinlabeled antibodies against human IgG Binding of antibodies to donor Low (requires high Ab levels for positive result) Intermediate Recipient serum. beads coated with purified HLA molecules tagged with unique. identifying lmmunofluonescente Binding of antibodies to beads (quantized as MFI): allows precise definition of DSA specificity " Vir tual" XM ( via solidphase assays. et. Luminex°) lymphocytes (quantified as mean fluorescence intensity orMFI") High (can detect low Ab levels) Immunologic Testing Prior to Deceased DonorTransplantation 1. HLA typing of recipient 2. Use solidphase assay no detect and define andHLA andbodia present in recipient serum 3. Lis("unacceptable" HLA antigens based on centerspecific MFI threshold. Recipients will not receive offers for donors who possess unaccepizble antigens. Calculate the calculated panelreactive antigen (CPRA): CPRA reflects the probability of a CDC XM+ based on the listed unacceptable antigens and their frequency in the general population (pts with CPRA >80% are considered "highly sensitized" and given higher priority for HLAmatched kidneys) 5. Final crossmatch: CDC crossmatch performed just prior to transplant using fresh serum from recipient Immunologic Testing for Living Donor Transplantation 1. HLA Typing of recipient and donor 2. Solidphase assay co detect and define andHLA abs present In recipient serum 3. Perform CDC.flow,and virtual XMs Crossmatch Test Interpretation Crossmatch Interpretation (Nepluniig N11;16:17.5) (4 CDC Tcell XM (+) CDC BceII XM () CDC Tcell XM (+) CDC Bcell XM (+) CDC Tcell XM () CDC Bcell XM (*) flow XM DSA to HLA class I, 4- class II High risk olAMR and Is a contraindication to transplant. unless DSA an be reduced with desensitization protocols DSA to HLA class II OR low level class l DSA OR nonHLAAbs High risk of AMR and is a contraindication to transplant, unless DSA can be reduced with desensitization protocols Possible false (+);tes¢ should be repeated Poses an intermediate risk of AMR-> may benefit from netxp desensitization and require posttxp irrmunosuppression and/ or monitoring Wt 14104,4.10331 (+) DSA by solid phase assay ( )flow and CDC XM T Risk of AMR and graft hilune compared with negative DSA UASN zaizaaansn Crossmatch Pitfalls and Limitations Falsepositive flow XMs may be caused by nonspecific lg binding no Fc receptors on donor lymphocytes. Riurxinmab dwerapy in redpienrs may also muse falseposiUle flow XM. Antigens such as MHC class Irelated chain A (MICA) and angiotensin II type I receptor (ATTAR) have been implicated in graft failure but are nor routinely detected by :radi tional XM pladorms POSTTRANSPLANT IMMUNE MONITORING Presence of DSA. whether formed prior to or after txp. is alw inferior graft out comes. De novo DSA formation (after transplant) occurs in 13-30% of previously nonsense sized pts. De novo DSA formation associated with late acute AMR. chronic AMR, transplant glomerulopadmy. and L graft survival or 2012:12:1157; qAs~ 101B:13:182) Risk factors for de novo DSA: high HLA mismatches (especially DQ). inadequate immunosuppression. and graft inflammation of any cause (QASN 201&1]:181) Posttransplant DSA monitoring (using solid phase assays such as Luminexs). with protocol biopsies for high immunologic risk patients. is recommended to guide immunotherapy and permit early intervention (fonxplonuzrlun 2013:95:19) PostTmsplant DSA Monitoring Highrisk: pts with preexisting DSA Lowrisk: nonsensitized. 1st top Months 1. 3. 6. 12. annually thereafter Protocol biopsies are recommended in the first yr to screen for subclinical AMR. At least once 3-12 mo posttxp. and/or whenever a significant change in maintenance immunosuppnession is considered. suspected nonadherence. graft dysfunction. or before transfer of care to another transplant center KIDNEY ALLOCATION Deceased donor transplantation provides a significant survival advantage over dialysis There are large regional variations in the median time no transplantation While preemptive listing prior to starting dialysis is preferred given outcomes for preemptive transplantation. only a minority of patients are preemptively waitlisted Discards are higher on the weekend even after adjusting for organ quality (KI 1016:9m15n Inappropriate unilateral kidney discards is common (qASN 201B;lJI 18) Kidney Allocation System (KAS) (Tunxpbnrlle z 017,31 61) The new KAS was implemented to imprtwe organ utilization. reduce racial disparities in waitlisting, introduce longevity matching and prioritization for the most sensitized patients Allocation time starts from start of dialysis or what added to the waitlist. whichever is earlier: Can be preemptively listed if the measured or calculated GFR or CrCl $20 s Kidney Donor Risk Index (KDRI): estimate d the relative risk d postuanspWt graft failure Variables: age. height, weight. ethnicity/race, HTN. DM, cause of death. Cr, HCV. donation alter circulatory death (DCD) Kidney Donor Profile Index (KDPI): simple mapping of the KDRI to a cumulative % scale using all kidneys procured for op in the preceding calendar year in the US eg, KDPI 85% has higher gray failure risk than 85% of all donated kidney Estimated PostTransplant Survival (EPTS) score: assigned to all waidisted patients Variables: age. dialysis vintage. DM. number of all previous transplant 0-10076; lower scores alw longer survival: pts wl $20% are prioritized to KDPI <20% Calculated panel reactive antibody (CPRA) score: the percentage of antibodies in the recipient serum to the donor pool.This is monitored on a monthly basis. Allocation Points for Adult Transplantation Candidate Characteristics Points Given Allocation time Prior living donor Sensicimion (CPRA. %) 1ld 4 0.08 (220.<30). 0.21 (230.<40)....17.30 (297,<98). 24.40 (298,<99). 50.09 (>99.<100). 202.1 (100%) Single HLA-DR mismatch Zero HLA-DR mismatch 1 2 Priority was also established for blood group 8 candidates to accept blood group A2 Outcomes of KAS KAS has resulted in a signiiant decrease in racial disparities in access to uansplanudon t shipping times dl: more national sharing for high KDPI kidneys -» t cold ischemia time, DGF Despite prioritizadomandidates with CPRA 298% continue no have long wait list times The discard rate continues to rise and is approximately 20% post KAS Reference https:l/opu1.rransplanLhrsa.gov/learn/professionaleducation/kidneyaIloca:ionsyst.em/ I Policy 8: allocation of Kidneys and Frequently asked questions ALLOGRAFT DYSFUNCTION Def init ion and Background After excluding volume depletion: >25% rise in serum Cr and/or new proteinurla >1 g Cr >1.5.0r ACr between 6 mo -a 1 yr aM graft failure regardless of cause (xi zoouzzn) Improvement w/ empiric reduction in CNl is insufficient (unless extremely elevated) since many patients have more dlan 1 diagnosis (ie.AMR + CNI toxicity) Most surgical complications (je. subcapsular hematomas. lymphoceles) are only seen early and can usually be detected on U/S Causes and Workup Time After exp 0-3 mo Differential Diagnosis of Allograft Dysfunction Possible Causes Parenchymal: ATN. acute cellular rejection (ACR). antibody mediated rejection (AMR), druginduced TMA.AlN. CNI toxicity pyelonephrids. Recurrent FSGS. subcapsular hematoma Urologic: bladder outlet obstruction (BPH, blood clot), uneteral (ischemic stricture. blocked stem. blood dot. extrinsic compression from Iymphocele). urine leak Vascular: transplant renal artery stenosis (TRAS). anastomotic eden\a.technical. fibrous contraction.vascular compression from lymphocele. pseudoTRAs. iliac vascular disease. venous stenosis 3-12 mo Parenchymalz ACR.AMR. BK virus nephropathy. recurrent glomerular disease. CNI toxicity (acute or chronk).TMA. pyelonephrids.viral interstitial nephritis.AIN Urologic: ureteral strictures (ischemic or BK virurla related). kidney stones (frequently asymptomatic) Vascular:TRAS or pseudoTRAS >12 mo Parenchymal: chronic AMR. mixed ACR/AMR. recumnt glomerular disease.chronic CNI toxicity BK virus nephropathy Dominant role of noncompliance (Alf zoiznzaesi Workup CBC, BMR LFTs. IS levels, BKV DNA PCR. LDH. haptoglobin. donorspecihc antibody (DSA) via Luminexs or Flow crossmar.ch.urine proteinlcreaUnine. UIA with urine cul ture.and appropriate serologies if original disease was GN Renal transplant UIS with dopplers of renal artery and vein Renal bx: usually required unless UIS diagnostic; LM. IF +C4d staining (marker of C activation in AMR). EM helpful for recurrent disease and some cases olAMR Treatment and Prognosis Depends in underlying cause of dysfunction (covered individually in dles e pages). reversibility, and degree of interstitial fibrosis Each 0.5 change in Cr a/w a 2.5 fold l RR of graft failure (KI 100161¢3\11 Later changes in Cr (>1 yr out) are less likely to be reversible than earlier changes since degree of Fibrosis tends to be worse and the causes of dysfunction may be less likely to respond to treatment DELAYED GRAFT FuncTion (DGF) Deilnition DGF: need for dialysis within 7 d of zransplamation for any reason Slow graft function: dysfunction do does not require dialysis. Has inconsistent defi nition in swdies 1 25% in serum Cr between POD 1 and 2 or serum Cr >3 on d 5. Similar mechanism to DGF but less severe. Primary nonfuncrion: dialysis never stopped or eGFR <20 ac 3 mo Background 20-25% of deceased donor recipients 5-6% of live donor recipients.Associated with 25% graft failure at 1 yr. usually related to severe event, je. allograft thrombosis Associated with 40% increase in relative risk of allograk failure. increased rejection risk and 6 fold increase in risk of Chronic Allograft Nephropathy W72011;11:1179) Pathogenesis and Risk Factors Donor factors: preexisting ATN-prehospital down time. hypotension/hypovolemia alw brain death.donor DlC,1 terminal Cr. DCD,age Ex vivo factors: prolonged cold ischemh time (CIT). perfusate soludan choke, pump versus off pump uanspon (particularly if CIT >24 hr or DCD donor) (91 So; z013;\0<m1l Recipient factors: age. DM. obesity. l PRA,African American. males Wf 1010;\0.19B1 Preexisting donor quality with ischemia reperfusion injury related to redox species. followed by abnormal local C regulation. release of DAMPs -» activation of innate immunity -» cellular infiltrates. tubular degeneration with apoptosis/necrosis Clinical Manifestations Oliguriaanuria. persistent elevation in Cr. fluid overload T K:from l K excrerJon.absorbing blood in surgical bed.tissue destruction Workup Daily CBC. LFls. BMR and IS levels Renal U/S q3-4 d initially, as UOP increases during recovery occasionally unmasks ureteral or bladder outlet obstruction. evaluate renal arterial velocities for stenosis Renal biopsy after 7-10 d (earlier in patients with DSA) for reiection.TMA due to IS. early recurrence of FSGS Treatment Induction with thymoglobulin versus no induction or basiliximab may reduce risk slightly bu: allows for delayed introduction of CNI uAs~ z009;2a 1:asi Delayed adminisuauon of CNI has no impact on DGF rare. bu: may shorer duration of HD dependence (T/ansglanluuan 2009s8n 1011 For persisteit DGE reasonable to attempt conversion to belatacept. avoid conversion to rapamycin/mTOR inhibitor; prolongs recovery UASN 2003;14¢1031) Preoperative dialysis ineffective at preventing DGF (Tiunspiamadun 2009:B8:1]77) Prognosis 7 Graft failure 2.5 fold in standard donors or z00616.11 so) t Both ACR and AMR. persists beyond duration ofATN. likely due to bodi allograft factors and expansion of alloimmune response during what was initially nonspecific innate immune activation (al 201Sa94:BS1) RECURRENT GLOMERULAR DISEASE Background Nearly all glomerular diseases can recur in :he allograft. For most. the rate of recur rence and allograft failure from recurrence is lower than allograft causes from other q :: 3 C Impact of GN recurrence increases over time: 1-3% of biopsies in the first 6 mo but 16% of all biopsies beyond first yr or zoiznfsaal Risk factors for recurrence: younger recipient age, DDRTx. steroidfree regimen (pie dominanrly for IgA), more HLA mismatches reduces recurrence risk (Ki 1017;9z46\) Recurrent Glomerular Disease AfterTransplantation (NDT 10141%5: KI 70179244611 GN Type leAn MN FSGS MPGN type 1 C3GN/DDD Lupus ANCA AntiGBM Clinical Recurrence 10-15% (>50% hismlogically) 5-30% 20-40% zmsox >80% 5-30x 20% Extremely rare Graft Failure 5-10 yr After Recurrence 1040% 5-40% zo-40% 30-70% 30-70% <10% 7% Unknown IgA Nephropathy (loAn) Histologist recurrence is more common than clinical disease and early graft failure is rare. However. recurrence leads to worse outcomes beyond 10-15 yr Earlier age of onset and crescent are alw recurrence (AmjNeph¢ul 1017;45:99) Steroid withdrawal a/w an t rate of recurrent disease in several studies. In USUNOS data. maintenance steroid use alw 1 risk of allograft loss due to recurrent loAn (RR 0.66) but no difference in overall patient or graft survival (rruiapiInr zoleai nr51 Thymoglobulin induction alw L recurrence in single center studies rruupianirurri nueasnsos) Membranous Nephropathy (MN) Presence of antiPLA2RAb in serum preuansplant increases risk of recurrence 3-4 fold. with 73% recurrence if positive. 33% if negative serologies (rraapinawan z016:i001710) In those with recurrence,adding rituximab (with continued maintenance immunosup pression) resulted in complete or partial remission in 75% WT 2009;9128001 Focal Segmental Glomerulosclerosis (FSGS) Risk factors for recurrence: younger age. rapid time to progression to ESRD. white race > nonwhite race. and prior recurrence in allograft >80% chance if first allograft failed from recurrent disease (nor z010;2s=2s) Recurrent cases suspected to be related to soluble factor. ~7J3 will have partial or complete response to plasmapheresis and plasmapheresis use associated with better longterm outcomes II Yranspfanr 201 §;201563961B) Prophylactic PLEX or RTX did not reduce recurrence tfwnwltmtlitn 201B;10Z:e11S) ApoLlo risk variants recipient do NOT predispose to recurrent disease.but deceased donor carriers of risk alleles associated with increased risk of graft failure Wr zoiz\2m4) De novo FSGS after transplantation: a/w viral infections (CMV. Parvovirus B19. HIV), ischemia (ie.transplant renal artery stenosis).and CNI toxicity ComplementMediated (Atypical) Hemolytic Uremic Syndrome (aHUS) Unlike diarrheaHUS, aHUS associated with genetic abnormalities in alternate comple ment cascade has a high recurrence and graft failure rate. depending on mutation. Eculizumab prophylaxis may prevent recurrences in some cases (Air 1010:10:1517) Recurrence and Graft Failure Rate of tHUS wrz01a1a1sm Mutation CFH C3 CFI MCP Recurrent disease Graft failure 76% 86% 57% 80% 92% 85% 20% 17% DE Novo THROMBOTIC MICROANGIOPATHY Background De novo TMA In patients whose original kidney disease was not related to TMA 0.B-3% of KTR. most commonly in the 1st several mo after transplant lA)KD 2003;42z105e) Approximately 30% have renal limited disease which has a better prognosis but can only be diagnosed by renal biopsy WND 2003:41:471) Pathogenesis Similar to native disease dough etiology of injury different: endodlelial inlury and swelling with detachment from basement membrane leads to localized thrombosis. hemolysis. and platelet consumption. Progresses to mucoid edema and onion skin appearance of vessel walIs.Wid1 time.glomeruli develop thickened endothelium, mesangial interposition.and double contours (nonimmunologic MPGN changes). Calcineurin inhibitors (Cyclosporine >Tacrolimus) contribute to endothelial iniuiy. roTOR inhibitor use associated with TMA as well but less frequently Sirolimus have been rarely a/w TMA. particularly in combination with Cyclosporine AMR. ischemiareperfusion injury. DCD also risk factors lAIr 2010. 10.1$17) Infection: work as triggers: CMV. Parvo B19. HCM in addition to the diarrheal associated HUS forms more common in native renal TMA (or vi urn" Transpiam 10\4;1naJ1 Clinical Manifestations Systemic form: renal dysfunction. thrombocytopenia. anemia. low haptoglobin. elevated LDH. fevers. hypertension Renal limited form: renal dysfunction, hypertension. elevation in resistive index on UIS. nominimal evidence of hemolysis on blood tests Workup AntiHLA ab screen. crossmatch with donor. anticardiolipin ab. lupus anticoagulant. ADAMTS13 level, CMV PCR. Parvo B 19 PCR Renal biopsy is diagnostic. Presence of C4d staining in peritubular capillaries strongly suggests AMR. presence of tubular vacuolization or arteriolar hyalinosis in nonafiected vessels suggestive of CNImediated injury T reat m en t CNImediated TMA: controversial. Cessation of CNI adequate in mos: cases but places patient as risk for neiection. FLEX has been used while excluding other causes. Switching CNI no an roTOR inhibitor has been reported. Careful monitoring for renal toxicity is recommended. Belatacep: has been used as a replacement for CNI WT 100m424) AMR related: neat underlying rejection with steroids. PLEX. +I- rituximab.proteasome inhibitor. Some refractory cases have responded Ra eculizumab (nam zuatnuosszi Prognosis Renal limited has better prognosis than systemic TMA (0% VS 38% graft failure) From 1990s. de novo TMA has 50% graft failure rare at 3 yr we 2003;41:10$8). though the advent of belatacept has increased therapeutic options In contrast. recurrent TMA has graft survival rare of only 20% at 1 yr SURG ICAL AND URO LO G IC CO MFLiCATiO N Background 6% of renal uansplants, mos: occur within first 6 mo after surgery Ureteral scents reduce incidence of urine leaks and obstruction bu: may increase cost of transplant and require cystoscopy for removal 3-6 wk posttransplant UrinomalUrine Leaks: 1-3% olTransplants Pathogenesis Mos( common sire of leak is ureter-bladder anastomosis. though leaks from midureter and renal pelvis also seen Renal failure accompanied by enlarging fluid collection (usually adjacent to allograft and bladder). chemical peritonitis and ileus are frequent. occasionally leakage from wound. May only manifest as delayed graft function or immediately after ureteral spent removal Diagnosis: (1) sample fluid collection for electrolytes and creatinine. If urine leak. then creatinine and K will be higher than serum. (2) nuclear medicine renal scan can also be diagnostic in cases where fluid inaccessible Treatment: the majority of urinary leaks require surgical correction, Dlstal leaks with minimal extravasation and clinical stability may respond to Foley insertion for 5-7 d. Lymphocele: 1-16% of Transplants Pathogenesis: inadequate ligation of lymph vessels near iliac vessels or hilum -o lymph collection accumulates between :he transplanted kidney and bladder Small Iymphoceles are frequent but usually asymptomatic. larger collections present few wk to mo after transplantation.A bulge near the surgical wound sometimes with extravasation of lymph and edema of lower limb ipsilateral to the graft may be seen. Rarely. compressive symptoms such as urinary urgency or hydronephrosis and allograft dysfunction may occur Diagnosis: renal ultrasound showing the colleWon with associated compressive effects. Fluid sampling to rule out urinoma (serum creatinine/potassium are similar to serum). T>c expectant treatment for small lymphoceles. Drainage or laparoscopidopen surgery (marsupialization) for larger and recurrent collections. Llreteral Stricture: 3-6% ofTransplants Pathogenesis: usually ischemia due to inadequate distal blood flow in ureter. though fibrosis from local BK virus replication and rejection is also suggested or z00d63a521 Risk factors: donor age. DGE abnormal vasculature Renal insufficiency with hydronephrosis on UIS despite decompressed bladder Diagnosis: renal U/S or CT urogram usually suffice. If the diagnosis is uncertain, and antegrade pyelogram needs to be performed Tx: decompress collecting system with nephrostomy lo reverse AKI and perform pyelogram. Stem placement can temporize. dilaiztion with stenos or balloons frequently ineffective: success 28-80%. Most need surgical reimplantation (a. Twsplai 201519161 Allograft Pyelonephrltis: 10-15% of Transplants in FirstYear Pathogenesis: reflux from surgical bladder anastomosis. RF: Female sex. diabetes. UTls prior to transplant. immunosuppression, ureteral stent AKI. fever. pain over allograft. frequently h/o UTI symptoms preceding allograft pain. Occasionally asymptomatic and found on biopsy done for graft dysfunction Diagnosis: usually made clinically,eonfirmed with urine cukure. blood cultures frequently positive as well. CT AIP can suggest diagnosis but not specific as perinephric suanding is common after all renal transplant surgeries. Tic broad spectrum IV Abx pending sensitivkles. continued treaunwt for 2-3 wk Patients with 2 episodes in 6 mo or 3 episodes in 1 yr should be investigated funder by urology Many benefit from suppressive andbacwials.such as methenamine 1 g BID plus vitamin C Prognosis: single episode of pyelonephritis does not impact longterm allograft function 1nw$p Infect of 2016;18:647). Pyelonephrids may predispose (O subsequent rejection and recurrent episodes can lead to allograft failure. Asymptomatic Bacteriuria: 35-40% of Transplants UTls and episodes o( pyelonephrizis frequently preceded by periods of asymptomatic bacteriuria but most do no: progress xo symptomatic disease Randomized trial of creating asymptomatic bacteriuria NOT associated with reductioh in UTIs. hospizalizacions.or pyelonephritis or zo1e;1 s:z94zl T NANSPL ANT RENAL ART ERY ST sn o sls Background Different etiologies than native RAS and more likely to respond no treatment with improvement in renal function and BP conuol Incidence 2% in US transplant population by 3 yr (reported range 1-20%) with risk factors: donor age, recipient age. hlo DM, ischemic heart disease (Am 1 rhphmi 2ua~u04s9l PseudoTRAS: similar presentation to TRAS but location of vascular obstruction is in vasculature proximal to anastomosis. common iliac or early external iliac artery Ecology by London of Stencils wr 7M4;l4:\J3) RAS Type Location of stenosis Mechanism A Anastomosis Bend/kink in artery as any point Surgical emote--sewn coo :ightba fibrous conuacdon Malposiiioning of kidney leads no a kink (like a bent straw) causing reduction in blood flow. may be missed if only do Huoioscopvy in one orienmion Pos:Anaslomosis Adierosclerozic disease. compression from fluid colIecdon.twisr in artery related to orientation during sewing. weak association widl rejection Proximal w arterial anastomosis iliac artery atherosclerotic disease.clamp injury B P PseudoTRAS Pathogenesis Goldblan 1 Kidney 1 clip model of hypertension Reduction in lumen size by >S0% (usually >70%)WlTH a mean arterial pressure gradient >10 mmHg across lesion. Renal hypoperfusion -» L GFR and sodium retentlonlvolume expansion - HTN. Renin, angiotensirtaldosterone levels usually in normal range C lin ica l M a n if e st a t io n s Graft dysfunction our of proportion to biopsy findings: delayed graft function Hypataision requiring multiple fuss m control; Edema wlo protdnuria/liypoalaurnlnemia Audible bruit over allograft (low sensitivity and specificity) Wor kup Renal UIS with Doppler: operator dependent. sensitivity/speciUcity -85% Anastomosis >200 cm/s, acceleration time >0.1 s. iliac to renal artery gradient >1.8 Nuclear medicine: sensitivitylspecificity -70-80% . Separation in rate of appearance of tracer in allograft vs artery (Hilson Index) CTA and MRA sensitivitylspecificity 95% but require contrast Angiography: gold standard T r eatment Angioplasty alone-patency rate 3069% at 10 yr ()Vas< Sw:2013;57216211 Angioplasty with stent-patency rate >80%. DES = BMS Vascular reconstruction-best ueatment if within Erst 1-2 wk of operation when stent placement could rupture anastomosis and cannot wait. Late attempts at surgical convection associated with graft loss Prognosis Untreated TRAS associated with high rates of graft failure WT 2014;1411331 Creatinine decreased 2.9> 1.6 when angioplasty done for graft dysfunction Angioplasty for HTN without graft dysfunction and/or fluid retention unlikely to lead to clinical improvement (je, if no graft dysfunction. it is unlikely that stenosis is physi ologic) gwiu SungZ013;§7:1621) ACUTE CELLULAR RE]ECTION (ACR) As immunosuppression has intensifled.cellular rejection rates have been decreasing for pas: 30 yr. now consistently below 15% for living donor recipients (Air 1004:4:37B) Early detection and treatment are crucial, as complete reversal of rejection can improve prognosis to level of nonnejectors Pathogenesis Migration of passenger dendrltlc cells (or native immune cells having processed alloantigens) migrate to 2 lymphoid organs. stimulating immune cells via direct (or indirect) allorecognition. Many become circulating efYectorT cells that infil :rate the allograft -» interstitial inflammation/tubulitis/rejection (NEW 2010;363114s11 Innate immunity respond to tissue "damage associated molecular patterns (DAMPs)" including redox species. nucleic acids. extracellular matrix components among others leading to macrophage and dendrite cell activation as well as upregulation of adhesion molecules -» attraction of adaptive immune cells and milieu for cell activation rather than energy W12016;16:3338) BiopsyBased Definition Recommended adequacy: 2 separate cores (-90% concordance among samples). 210 glomeruli.and 22 arteries - Minimal adequacy. 7-9 gfomeruli and 1 artery Grade Acute Tcell Mediated Relecdon Inna Com-in Afr 201m1wa) Histologist Cnteria Borderline Fool of wbulkis (Bo) + minor interstitial inflammation (60-1).0r IA moderatesevere interstitial inflammation (i2-3) + mild tubulids (11 ) Intersddal inflammation involving >2S% of nonscarred cortex (82) v IB Interstitial inflammation involving >25% of nonscaned cortex (ii 2) + IIA IIB III severe wbulixis (G) mild w moderate intimal aneritis (vi) 1 any Vt Severe intimal aneritis (v2) : any ill Transmural aneritis and/or fibrinoid necrosis (y3)1 any ill moderate zubulitis (12) Addltlonal Notes Gene expression profiles suggest that not all borderline inflammation is alloimmune in nature (no Rev ~w»~=/ z01a:1zs34l Arterials lesions may also be related to antibodymediated rejection Tre a tme n t Borderline it is no: clear that all patients need [O be treated. though most centers will treat borderline rejection associated with allograft dysfunction using methylpred nisolone 500 mg IV x 3. followed by corticosteroid taper IA methylprednisolone 500 mg IV x 3, 250 mg IV x 1. then oral CS taper IB: center dependent-many use Thymoglobulin at 10.5 mg/kg total dose In addition to CS. However, in select patients. IV corticosteroids as above may be adequate depending on comorbidities and infectious risk IIAIIIB: thymoglobulin 10.5 mg/kg in divided doses with IV CS Ill: thymoglobulin 10.5 mg/kg in divided doses with IV CS Prophylaxis Mucosal candidiasis: nystadn SS TID-QID. clotrimazole troches 10 mg TID (N.B. drug interaction with alcineurin inhibitors) for 1-3 mo Pneumocystis: uimethoprim-sulfamethoxazole 1 SS QD or 1 DS TIW for 1-3 mo.or dapsone 100 mg QD for 1-3 mo or atovaquone 1.500 mg QD for 1-3 mo CMV: valganciclovir adjusted for renal function for 1-3 mo in intermediate and highrisk Prognosis Severity direct correlation between the severity of rejection and long term graft sur vival at 8 yr (control = 97.676, borderline = 93.396, IAlB - 79.696, IINB + Ill = 73.690 lfrunsplmvluOon 1014974146) Reversibility: if creatinine returns to baseline after treatment, longterm outcomes equal those without rejection (though more severe rejections less likely to reach baseline) (Tuns9laMlun 1997;63:1739) Time: late rejections have a worse prognosis than early rejections. Usually have more advanced Fibrosis and less likely to be reversible if,°»w»11vl¢»1¢iv» 201437111461 Repeat rejection is common. particularly when associated wid\ noncompliance ANTIBODY-MEDIATED REIECTI0N (AMR) &rlyA!1R (<3 mo): 10% door fuse biopsies done in dIe First 6 wk after surgery almost :Mays in sensitized patients. If donor spediic ab (DSA) at time of uansplant. risk is 2040% depending on strength. If no hlo sensitizing events. risk is <5% (A]r 2012;12;JS8) Late AMR (>3 mo): usually from de novo DSA fonnation.frequendy presents as chronic active AMR (CAAPIR) with slowly progressive rise in creatinine. and progressive pro teinuria from transplant glornerulopazhylgiomerulitis, CAAMR make up majority of renal biopsy results beyond first yr after uansplanr. Pathogenesis Circulating antibodies bind no target on endothelial cells.The mos: frequent targets of antibodies are HLA molecules (MHC classes I and II),though antiangiotensin receptors. antiMICA Ab. endodlelial Ab.and others have been described (nm Rev Nfpluul 20ts;12:4e4l.Antibody then cause lnlury through changing intracellular signaling, local activation of complement,and attraction of inflammatory cells. Endothelial injury can be sufficient to lead co local thrombus generation (TMA) though chronic activation leading to increase matrix deposition and muldlayering of peritubular capillaries is more common Concomitant cellular rejection is common (304014): alw rapid 1 renal function Definition Recommended adequacy: 2 separate cores of tissue. 210 glorneruli, and 22 anerles Minimal adequacy: 7-9 glomeruli and 1 artery AntibodyMedlated Rejection: all 3 criteria must be met for diagnosis (Banff cewe Arr 10\l:18:Z7J) Active AntibodyMediated Rejection 1. Histologist evidence of acute tissue injury (21) Micnovascular inflammation: glomerulitis (g>0) and/or peritubular capillaritis (ptc>4)) Aneritis (v>0) Acute thrombotic microangiopathy without other apparent cause Acute tubular injury without other apparent fuse 2. Evidence of antibody interaction with endothelium (21 ) Linear C4d shining in periwbular capillaries (C4d22 by IF. C4d20 by IHC) At least moderate microvascular inflammation (g + ptc 22;g must be 21 ifTCMR) 3. Serologic evidence of donorspecihc antibodies Chronic AntibodyMediated Rejection 1. Histologist evidence of chronic tissue injury (21 ) Transplant glomerulopathy (cg>0) Severe peritubular capillary BM multilayering (EM) Arterial intimal Fibrosis wlo other apparent cause 2. Evidence of antibody interaction with endodtelium (21) Linear C4d staining in peritubular capillaries (C4d22 by IE C4d20 by IHC) At least moderate microvascular inliammation (g + ptc 22:5 must be 21 ifTCMR) 3. Serologic evidence of donorspeciNc antibodies Cllnlcal Manifestations Acct AMK rapid decline in kidney function (or lack of recovery from DGF) with fluid | retention and J, UOR occasionally ahv thrombocytopenia/anemia and features ofT MA Chronic AMR: slow progressive decline in kidney function associated with proteinuria Measuring DSA ComplementDependent Cytotoxicity Crossmatch (CDCXM): recipient sera + donor lymphocytes + complement 4 antihuman IgG Ab.Technician uses a vital dye to determine if cell death has occurred.With +CDCXM, >90% risk of hyperacute rejection and precludes transplantation Flow Crossmatch (FXM): recipient sera + donor lymphocytes. run through a How cyclometer with fluorescent marker antibodies against human IgG.T cells (usually antiCD3). and B cells (usually antiCD19) to assess presenceabsence of binding as well as cell type. Strength of antibody can be assessed by dilution or expressed at mean channel shift"-a measure of brightness compared to background. +FXM at time of transplant predicts a higher risk of AMR (20-50%) and ACR (20-50%) as well as higher risk of graft failure at s yr ¢A;rz014:14;1s73) Limitation: does not :ell target specificity (which HLA antigen is target) and many false posidws. Requires donor cells which may no: be available during posttransplant phase. particularly if deceased donor Beadbased Multiplex (eg, Luminex° Assay): recipient sera + polystyrene beads coated with HLA peptides.place in flow cyclometer widl iiuorescent andIgG antibodies. Read our is expressed as mean fluorescence intensity-"MFI" that is semiquanzitacive assessment of Ab concen:radon.AIlows identification of Ab but may detect levels that are not clinically significant. Modification of assay co include complement C1q bind ing or generation of C4d may lead to better discrimination of high risk Ab (NEW 1013;369:1215) Tre a tme n t Reverse inflammation: highdose intravenous corticosteroids +I- Thymoglobulin Antibody reduction strategies: Plasmapheresis daily or every other day is effective, many centers replace with Ivlg after treatments to prevent hypogammaglobulinemia. Duration is determined by level of antibody assessed through FXM or Luminex° testing High~.1ose Ivlg (2 g/kg in divided doses) has been used with some success Rituximab: antiCD20 Ab to depletes Bcells in hopes of reducing DSA-random ized trial showed no difference in graft survival as 1 yr compared to control but did low DSA (fumplatntwn 2016;100:391) Proteasome inhibition (bortezomib x 2 cycles of 4 doses) was no different from placebo in a European trial uAs~ 2018:Z9:591) Limit complementmediated injury: Terminal complement blockade with Eculizumab prevents membrane attack complex formation. Many case reports suggest utility for treating refractory AMR, and reduced AMR rates when given prophylactitally to highrisk patients but 1 yr outcomes show significant chronic Abmediated injury (A/r 2011;I1:z40s) C1 esterase inhibition has also been successful or 201621631s961 Anticytokine therapy: tocilizumab blocks IL6,a key component in maturation ofT. B.and plasmacells.dl of which are involved in progression of AMR. Use in transplant patients has led to increased transplantation rates in sensitized waitlisted patients as well as patients with AMR posttransplant Wr 1017;17:23B1) Prognosis Overall 1yr graft survival: 80-96%. 5yr graft survival: 65-75% C 1q binding: antiHLA Ab :had bind to C1q (thus activating complement locally) are associated with a worse 5yr graft survival 54% vs 93% (NEW zoimmzusi Time (O rejection: early AMR (<3 mo) has a better prognosis than late AMR (>3 mo). 4yr graft survival of 75% vs 40% (Tunsplomauon 201J;96:791 Proteinuria, transplant glomerulopathy.and presence of interstitial inflammation/ concomitant cellular rejection have all been associated with more rapid disease pro gression lTI=»=¢rl°m lmmunolqy 2014;31:l40) INFECTION AFTER KT Background Infectious complications occur in >1/3 of patients in the 1st yr with UTls and viial infections are the most common causes Infections are the 2nd leading cause of death in KTR (USRDS Annual Report 2010) Risk factors for infection after transplant: donor exposures. prior and recent recipi ent exposures. prior and current immunosuppression (IS) regimens, recent treatment for rejection (A/r 2017;17:556) <1 mo Timeline of Common Infections After Kidney Transplantation (KT) 1-17. mo >12 mo Wound infection. UTI. Dialysisaccess infection, C. drfiidk colics BK poiyoma virus Herpes viruses: CMV.EBV. HSV,VZV MulUdrugresistant organisms: P]P MRSA.VRE.ESBL Cryptococcus Donordenived infections (uncommon) Communityacquired pneumonia UTI Fungal infections Late reactivation of herpes viruses DONORDERIVED INFECTiON$ Unexpected transmission of infections from donor is rare. and may be alw signiiunt morbidity and mortality. May occur with living or deceased donors (AlT 2013213 Sup9i 4=22) Kidneys from deceased donors with premorbid bacteremia can be used for trans plantation with minimal risk for disease transmission if prophylactic antibiotics are used. Kidneys from bacteremic donors have an increased risk of DGF but similar patient and graft survival (rimaplainawi 1999;sa:1 Io7: Cui ruiapum Z0l6;30:415) Kidneys from donors wl bacterial meningitis may be used or 2011;\1:1123) Rabies, parasites, lymphomas.and leukemias (via lymphotropic viruses) when donors w/ encephalitis w/o a proven cause were accepted as organ donors Possible Transmission from Donors Slnungyloides s!ercaIulis from donors who lived in endemic areas (je, Cenual and Soudi America). Serologic screening of donors atrisk and prophylaxis with ivermectin in recipients when donors test (+) can prevent transmission lA}r 1015;1S:1369) Trypanosoma cruz from donors who lived in endemic areas (je. Central and South America). In donors who test (+). regular resting of recipient by PCR. hemoculture. and serology can identify disease transmission early (reported in 13%).and prompt treatment with benznidazole can L morbidity alw Chagas disease or z013;13z4181 CYTOMEGALOV1RUS (CMV) INFeCTlON Risk of CMV disease is related to donor/recipient serologic match: Highrisk: D+/R-, intermediate rislc D+lR+,and D-/R+, lowrisk: DlRA/w T acute/chronic rejectiomgraft failure. EBVassociated PTLD. other opportunistic | infections (fiuneplanlauan 2013:96333) Clinical Manifestations CMV syndrome: fevers. malaise. weight loss. diarrhea. arthralgias. leukopenia. thrombocytopenia, transaminitis Tissueinvasive disease: GI (mlc tissueinvasive disease in KTR;colitis > gastritis: CMV viral load may be negative; in clinical suspicion is high. need biopsy with staining for CMV), pneumonitis. nephritis. hepatitis. retinitis (can 1:ifm on z00e;44»£40) Prophylaxis Valganciclovir (900 mg QD, adjusted for CrCI) significantly reduces risk of CMV posttransplant. Also a/w i in other viral (HSV.VZV) and bacterial infections Duration: minimum 6 mo if highrisk; 3 mo if intermediate risk.consider 3 mo if Iow risk (funiplunlnman 2013;96333) Longer duration (200 d vs 100 d) alw 1 CMV infection in highrisk WT z010210x1zza1 Risk of infection air stopping prophylaxis.esp in 1st 3 mo and high risk:/ CMV titer Treatment PO val@ndclo»rir (900 mg BID adjusted for CrCl) and N gancidovir (5 mglkg qlladiusted for CrCl) equivalent: consider IV if tissueinvasive disease or significant GI symptoms. Treat until viral load undetectable x 2 wk.then start secondary prophylaxis. Consider dosereduction of antimetabolite during/after treatment of CMV W1 z007:7110s) Resistant CMV Infection IT1uvuplonmuan 2011.91.217: can Infer o» 2017;6$:571 Occurs in 1-2% of kidney transplant recipients ° Risk favors:for resistant CMV include D+lR. longer duration of antiviral exposure Treatment: cidofovir and foscarnet; mortality rate up to 11% in resistant CMV VAMCSLLA ZosTsn Virus (VZV) INFECTlON Wr 1009t9$108) Disseninazed infection: vesicles and crusts not limited no a dermatome: 2/3 had visceral involvement; morizliry (alw AZA and visceral involvement) 17% inunspiani he: 2011:44:1B14) Visceral involvement; DIC. hepadris, pneumonitis, pancreatitis. meningoencephalitis. vasculopazhy; may develop wlo skin lesion (nbr 2011:16:365) Antivirals for CMV prophylaxis reduce risk ofVZV reactivation Tx: acyclovir N if disseminat.ed,visceral or facial involvement: valacydovir PO if limited to single dermatome; Consider decreasing or holding anzimetabolite until all lesions healed EPSTEIN-BARR Virus (EBV) In=scTlon EBV mismatched (D+/R-) recipients have higher risk of EBV uremia. up to SM in 1st yn It may be asymptomatic. may be alw mononucleosislike symptoms, or may progress to PTLD. Late persistent EBV uremia may be a/w T risk of solid cancers I*/T 20 un3165e Tinnsplamnuan 2017;10.l473) Risk of PTLD 24x higher in EBVseronegative recipients Jan we on 1995520r13461 Monitoring in EBV D+lR-: J viral replication at least monthly for 3-6 mo. then every 3 mo until the end of die 1st yr. Resume after acute rejection tx (KolGo Afr 2009.9 sw¢lJ,S1) EBV D~lR- recipients with increasing EBV viral load should have immunosuppression reduced. which is aw i risk of developing PTLD WT 2013;13 suppl3:41) Use of rituximab in EBV D+/R recipients with asymptomatic increasing EBV viral load may reduce risk of developing PTLD WT 2011;1110581 Antiviral prophylaxis for CMV does not reduce the risk of developing PTLD We 2017;\7710) BK POLYOMAVIRUS INFECTION Lbiquitous poiyomavims; establishes latency in GU tract and an reactivate in semng d IS BK viruria occurs in -30%. BK uremia in 15-20%. and BK nephropathy in 1-10%. BK viruria can cause hemorrhagic cystitis (more common air HSCT) or irritative voiding symptoms. Only sign of BK vireinia/nephropathy typically t crmtinine (new 2o0z 347:4aa. Trasplnnlnhun 2013:9s94k BMT 2008;41:363) Viral replication in urine and blood is most common in 1st yr posttransplant Risk factors: T IS (most imponant).1 age. male gender: diabetes. Caucasian. ureteral stent. donor/recipient serologic mismatch BK nephropathy is an early complication that adversely affects allograft survival up 10064691653 new 200z=14714ss1 Kidney Bx: intranuclear viral inclusions. interstitial infiltrates. and lymphocytic tubulitis (may be difficult to distinguish from acute rejection): immune staining +SV40.7 Severity of BK nephropathy by Banff criteria alw worse graft survival l;As~ 2018t296801 Screening for BK viremia.wi¢h L in IS if persistent uremia. can i risk of nephropathy. Screening minimum q3mo in 1st 2 yr, then annually through 5th yr. Screening should be resumed after treatment for rejection (Arr 2013.13 iu¢914:i79) Despite L in IS if viremic, development of BK uremia alw T risk of allograft failure (framplanlalian 2013:15:949) Tx:firstline treatment is l in Is.Typlcally..L /eliminate antlmetabollte.then 4 CNI trough if uremia persists. Other therapies include switch from tacrolimus to cyclo sporine,switch from CNI to mTORi.switch MMF to Ieflunomide.add cidofovir W12013:13 wppM:1 WE qAsn 20143932 As 2015;15:1014) HsrATms c IN=ECTION Virus (HCV) Hepatitis C infected patients who remains on dialysis are as higher risk of death than :hose who receive a kidney transplant (T'°I=VI\"l11¢\°'\ 20 u;9519431 AntiHCV antibody positive KTR have lower allograft survival rates and T risk of dash compared co antiHCV antibody negative recipients (*)T 2005:5:1452) Management of HCV (4) KTR: Live r Biopsy and Porn! Pressure Help Guide No significant fibrosis (stage 0-2), no live DDRT w/ HCV+ or HCV-. then DAA post donor transplant No significant Fibrosis. has live donor DM then transplant with HCV- kidney Significant fibrosis (stage 3-4). portal HTN SLK. Not a candidate for KT alone. Significant fibrosis. no portal HTN DM and KT w/ HCV kidney vs SLK UASN 2016:272238) In patients w/ compensated HCV cirrhosis and hepauopord venous gradient <10 mmHg. KT alone may be performed with similar patient and gray survival dw HCV4 recipient wlo cinriiosis (Tmwiuniaun zonnsasol Historically. the use of interferonbased regimen to neat hepatitis C in KT patients was alw increased risk of acute humeral rejection and should be avoided WT 20031374) Posttransplant treatment with DAA for 12 or 24 wk achieves sustained virology response at 12 wk in most HCV+ KTR and is well tolerated. with an acceptable safety pro6le (Ann :m 2017;166:109) Transplantation of kidneys from HC\Lposhlve deceased donors into HCVnegative recipients. followed by the use of DAA. has been peiiormed as a way to address the organ shomge. Showterm results show 100% sustained vimlogic response widl excel lent allograft function we 2017;376123943 AM :m 1018;168:$33) HIV INFeCTlON In selected HIV+ pts wl ESRD (CD4 >200ImL'.viral load undetectable on stable and retroviral regimen). pt and graft survival are high at 3yr (88% and 74%), although slightly lower Chan among all US recipients. HIV infection remained well convolled and where were few HIVassociated complications (NUM z01o.u>a:z0o4l.The slightly lower sur vival in HIV+ recipients may be due to HCV coinfection. as HIV+ and HCV- recipients have similar patient and allograft survival compared with HIV recipients (KJ 20158&3411 Protease inhibitors: interaction with Tac and CSA. and dose and frequency of antirejec tion medications may need to be reduced. T allograft loss. especially during the 1st yr postuansplanL and are a/w t death.A nonproteaseinhibitorbased ART regimen is preferred in potential KTR if feasible (Arr z017;171:m4l KT from HlVpositive deceased donors may be an acceptable treatment option for HlVinfected patients, with patient survival of 84% at 1 yr. 84% at 3 yr. and 74% at 5 yn and allograft survival of 93%, 84%. and 84% INEJM z015;s716131 PNEUMOCYSTIS HROYECII Pnsur4onlA (P]P) Can occur anytime post transplantation. though it is rare in patients Mo remain on P]P prophylaxis. Low eGFR and lymphopenia are risk factors (Anil #ma cmmul 201 a;4441s). PJP transmission posttransplant an be nosocomhl. Standardized prophylaxis protocol and airborne droplet precautions on uanspdant unks and clinics may help decrease nosocomial transmission In 2013;B4:240) Unexplained PTHindependent hypercakemia in a renal transplant patient who presents wiM subacute respiratory complaints should raise concern for P1P (m zoisnanon FUNGAL INFECTIONS Invasive fungal infections: occur in -1.3% of KTR in the 1st yr posttransplant Invasive candidiasis and aspergillosis are the mos: lirequent cause (cm MM of 201tnsa1101) Candiduria in KTR is alw reduced patient survival race. However; treatment of asymp tomalic candiduria does not appear to improve outcomes (an uuia no 2005;4Q 1413) U R IN A R Y Ta A C T infe c tion (U TI) m/c infectious complication.all UTls in transplant recipients are complicated UTIs Risk factors:female.T age, ESRD due to reflux. DDRT. T immunosuppression For patients with allograft pyelonephridmfeverslallograft tenderness may persist for several days despite appropriate antibiotic choice Recurrent UTls defined as >3 in 12 mo or >2 in 6 mo. can occur in up to 32% of patients. Recurrent UTls typically nested with longer course of antibiotics and require evaluation for stru aural/functional abnormalities WT 2015:1S11021) High prevalence of ESBL organisms. especially if recurrent UTls (rmmpl 1pn Do 2012;14¢5951 No RCTs to guide duration of therapy: 7-10 d for first UTI (longer if ureteral stent in place). 14-21 d for allograft pyelonephritis or UTI with bacteremia Asymptomatic bacteriuria develops in 50% of transplant recipients (XI z010.e7=77/1 Treatment does not 1 rate of UTI, nor improve renal function WT 2016116:2943) INFECTiOU$ DIARRHEA Diarrhea is a frequent posttransplantTwo mlc etiologies are medications (mycophe nolate > tacrolimus) and infections. Evaluate for infection before L mycophenolate dose as 1 mycophenolate dose -» T risk of reiectionlgraft failure lriulnplarlauai zooeaziuzl Common causes of infectious diarrhea: viral (CMV. EBV. adenovirus. Norovirus). bac terial (C. difficile). parasitic. Infectious etiology identified up to 70% of cases with molecular testing (runugiiluiuan 2014:9s:a0sl C. diffkilez 3.5-16% of hospitalized KTRs.8-33% will have as least 1 relapse. Initial Rx 10-14 d: if on Abx for coinfection with other organism, continue for 1 wk after other antibiotic stopped. Consider longer duration with relapses/vanco taper. Consider pro phydaxis if hlo C. diff and requiring new course of antibiotics lffaieplanaiaan 2014;9s¢sos1 Norovirus: 17-26% of severe diarrhea. may have significant weight loss. Main treatment if transient . in IS. Nimzoxanide may be effective in some uses. If viral shedding and symptoms persist. mycophenolate may need to be dIced lnnmplimiuan 1014:98:B06) METABOLIC COMPLICATION AFTER KT Newonss1 DiAaETES AFTER TNANSPLANT (NODAT) Epidemiology and Clinical Implication 20-30% in the 1st yr after kidney transplantation (KT): Risk attributable to KT alone is highest in the 1st 6 mo after txp i Patient and longterm allograft survival. T risk of major CV events. inlection.and sepsis Diagnosis and PostTransplant Screening Symptoms of diabetes plus random plasma glucose 2200 Fasting glucose 2126 x2. weekly )< 4. at 3 mo. 6 mo. then annually posttxp A1c 26.5% (test only valid after 3 mo posttxp;Alc cannot be used in conditions that change RBC turnover), J at 3 mo.q3mo for 1st ynand at least annually thereafter Risk Factors and Pathogenesis Traditional: age >40. BMl z30.AA. Latino, Fllx of DM, personal he gestational DM. IGT Transplantspecitic: infection (CMV. HCV), poswp hyperglycemia (fasting glucose >200). . Mg. decased donor. increased HLAmismatch. PCKD. immunosuppressive agents Immunosuppressive Drugs and Risk of NODAT NODAT Risk Mechanism Corticosteroids tT Reduce peripheral insulin sensitivity Curls Ta c t t Cs A t Direct toxicity to pancreatic Bcells Si . Ii us T Reduce ripheral insulin sensitivity Treatment Lifestyle modificationzfirstline therapy 2ndgen sulfonylureas. repaglinide,and DPP4 inhibitors have proven efficacy in KTRs SGLT2 inhibitor: appears safe and LA1: and weight (Dobelei cm 20\9;4z10en Metformin: limited data: appears to be safe in stable KTRs with eGFR >4S Insulin as needed to attain A1 c <7% Prednisolone reduction to 5 mg/d alw improved glycemia (nor 2001;16;s19) Mixed data re: benefit of complete/early steroid withdrawal on risk of NODAT Belazacentbased regimens aw a lower incidence of NODAT (Tlw\=pl¢\w¢i¢H z0\1;91.976> Lmn ABNORMALITIES AFTSN KT Treatment Spins L MACE by 21% and cardiac death or nonfatal MI by 29% (Al.£kT Air zo0s5:m9) Siadns for all adult KTR. If <30 w/o DM. CVD. individualized decision (KDOGO Lipid 10131 CsA (bu: not tacrolimus) inhibits hepatic metabolism of stairs. raising levels Goal is to attain a large: statin dose rather than a specific LDL value (see table) Ezetimibe is probably effective in statinintolerant KTRs. but data is limited Avoid librates T adverse events. a/w graft dysfunction (A/xo 2004244:s431 .2011 FDA: concomitanc use of CsA and simvasutin :s contraindicated; howaven if satin cannot be changed dl: cost and patient is stable. may monitor CPK and LFTs q612mo C K D -MB D A s nonr 4 A Lm s s A FTER K T Pathophysiology Regression of structural changes in the parathyroid gland (hyperplasia. adenoma) an rake mo to yr; resolution of uremia improves endorgan resistance to PTH Persistently T PTH + PTH responsiveness/healthy allograft 4 .1 R T Ca: similar to 1 hyperparathyroidism (HPT) . FGF23 levels in the early posttxp period also promotes phosphaturia CS: .L bone formation of osteoblasts. T bone resorption of osteoclasts. t RANKL EidemioIo*sTand Clinical Implication ersistent is common after KT >80% of patients have PTH > 65 and >40% have PTH >130 at 1 yr posttxp. despite good renal function (TIunsphniauvn zols; 10c»1a4> High prelransplant PTH level is a/w graft failure (T/amplamauan 200s=01:352) L PO¢:40-90% of pts during the first 3 mo.gradually improves thereafter (NDT 2004;1r1za11 T PO4A/w top failure and mortality we 2017:1aJ17) T Ca: approx 1/3 of patients during 1st yr. usually within the 1st 3 mo 1 25OH vit D is alw interstitial Fibrosis pro ression and low raft x s function UASN ZOlJ:24:B31) Posttxp CKDMBD abnormalities are alw T fracture. allograft dysfunction/loss. pro gression of vascular calcification. and mortality Monitoring J Ca, Phos w/ routine labs;/ PTH. 25vit D q3mo for 1st yn diet q6-12 mo Mereafter (more frequently if abnormality or if receiving vitamin Dlcalcimimetic therapies) T reat m en t Consider paradryroidectomy before txp if iPTH 2800 despite adequate medical therapy Avoid POW supplementation unless severe (<1.0. or symptomatic <1.5). as it may T PTH . PTH wlo T Ca: replete 25OH vit D no >20 no zuom7s:s4s1 If PTH remains elevated, :rear with activated vit D T PTH w/ T Ca Cinacalcec may 1 iac level (our zoca;23:104s) Pararhyroidecromyz superior Ca and PTH reduction no cinacalcer UASN 1016427124871 HYPERTENSION AFTER KT Backgr ound >90% d CNIoated transplant recipients have HTN (<5% normotensive wlo medications) Risk factors: male. recipient age. donor age. DM. obesity. presence of native kidneys. delayed graft function. previous acute rejection. Curls and steroids, CKD in transplant Complications: increased risk of CVD. graft failure, and death Risk of graft loss t by -15% with each 10 t in SBP at 1 yr postTx loewi 2000.1s36:m Lowering SBP to $140 by 3 yr is a/w significantly improved 10yr graft survival (RR 0.79) and L risk of CV death (RR 0.73) (A/r 200s:s:zns) Pathogenesi s Immediate postTx period: volume overload, graft dysfunction. ischemia, CNI toxicity CrIs (CsA >Tac) a activate SNS. upregulate endothelin, inhibit NO oxide -o systemic and renal (afferent arteriolar) vasoconstriction, t NCC activity (Nat M44 z011;17:1304) Glucocorticoids (je. prednisone >10 mold); sodium and water retention due to partial activation of mineralocorticoid receptors Activation of the RAS in the native kidneys and/or a failing allograft Evaluation J graft dysfunction. CNI toxlckyc recurrence of primary disease. postbx AVF Transplant Renal Artery Stenosls (TRAS): important to Identify Presencationzworsening or refractory HTN and/or unexplained graft dysfunction. HE f l a sh p u l mo n a r y e d e ma Risk factors: operathle trauma. athevosclerosls of transplant renal artery or iliac artery. CMV in fe ctio n . d e la ye d g ra ft fu n ctio n of complications. should be reserved for refractory HTN) UASN 2004;15:134) T r eatm ent TalgetBP is basedcn presencedproleinuriaand addidanal comorlaidides (DPLCVDLHF) Guidelines for Target BP Guideline Recommendation KDOQI <130180. if prouinuria. l goal may be appropriate we zc04:4351) KDIGO s130Is80. irrespective of the level of urine albumin (KI 20I!:BJ:377) EBPG <130I85 lo prozeinuria, <125/75 w/ promeinuria (NDT 100Z17125) Choice of drug class should be based on time air Txp.use of CrIs. presence/absence of persistent albuminuria. and comorbidizies D r ug Tr eatm ent D H P C C Bs ( am l odi pi ne. ni f edl pi ne) N onD H P C C Bs ( di l ti az em . v enpam i l ) AC Ei , AR Bs May ameliorate vasoconstriction induced by Curls CCB alw i graft loss (RR 0.75) and T GFR (man A 4.45) dw placebo no R x uw i ugl m i i auun N 09:8877) Nifedipine t GFR at 1 and 2 yr dw lisinopril ¢f~.»»=~w~~~ 2001;mnn Pot ent I nhibit ors of CYPJA4. cause p l a sma l e ve l s o l Ta c. CsA a n d sirolimus; effect occurs in 48-72 hr; close monitoring of CNI or r o TO R i n h i b i t o r l e ve l s i s r e q u i r e d Cause As in GFR whkh may interfere with do of acute rejection (esp. in first 6 mo postTx);can exacerbate hyperkalemia (RR 3.76 for incidence of hyperkalemia w/ACEi dw CCB). esp. in Pts on CrIs:an exacerbat e anemia (Tunsplanlnnnn news 7) Losarun an lower plasma uric acid levels in Pts widl gout Despite beneficial effects on proteinuria and HTN. no longterm benefit on graft, patient survival has been shown in RCTs Wa it 3 -6 mo p o stTx b e fo re sta rtin g ACEi o r ARB. if in d ica te d gzip Diagnosis: PRA may be relatively low due to volume expansion and high PRA is non specific; Doppler U/S has 87-94% sensitivity and 86-100% specificity; spiral CT: MRA: arteriography (risk of AKI due to contrast or thromboembolism) Treatment: conservative therapy w/ ACEi; PTA +I stenting (can restore perfusion in 70-90% but may recur in up co 1076); surgery if PTA unsuccessful or stenosis inac cessible to PTA (successful in 63-92% but recurrence rate up to 12% and high risk MALIGNANCY AFTER KT Ba c k gr ound Overall cancer risk rare is elevated in solid organ transplant (SOT) patients Standardized incidence Ratio (SIR) cl: general population is 2.1 (JAMA z011:30s:1s91I SIR of Mallgnancles in Transplant Recipients UMM 1011;30s:1a9\) I nf e c t i on Re l a t e d Noni nf e c t i on Re l a t e d Kaposi sarcoma 61. 46 Nonmel anoma ski n Liver 11. 56 Ki dney 4.65 Vulva 7.6 Thyroid 2.95 NonHodgk i n l y m phom a 7.54 Mel anoma 2. 38 Anus 5.84 Lung 1.97 Hodgki n l ymphoma 5.84 Urinary bl adder 1.52 13. 85 Penis 4. 13 Pancreas 1.46 Or ophar ynx i ncl udi ng tonsi l 2.01 Col or ect um 1.24 Stomach 1.67 Prostate 0.92 Cer vi x 1.03 Breast 0.85 Cancer (20%) is 2nd leading cause of death after CVD (24%) UAMA am 201614611 Cancers may occur de novo (eg. NMSC and Kaposi sarcoma).donorrelated (eg. RCC. melanoma. or choriocarcinoma). and recurrent cancers Impaired immune surveillance Is thought to be :he major underlying pathogenesis coupled with higher rates of oncoviral infections Risk Factors and Pathogenesis Smoking Historic cancerrelated death T 1.4x if quit before op. T 2.6x if continued smoking (ruepiwnaaan 20\e10fm7) History of prior cancer Kidney and thyroid cancers alw kidney allograft failure uAsr4 201s:z 7149s) General Screening and Prevention Strategies Smoking cessation Updating pressansplant recipient malignancy screening Screening postvransplant for skin. breast. colorectal. cervical cancer per USPSTF EBV IgG seronegative recipients of seropositive organ should have protocol EBV PCR monitoring throughout first year and beyond G e ne r a l Tr e a t m e nt 1 IS;Chemorherapy; Radiation: Removal of affected organ as indicated Pembrolizumab (amiPD1 Ab) caused cellmediated rejection l~glm 20laJ74¢s9s); CTlA4 i nhi bi tor . i pi l i mumab. di d not U an once 2014;32:c69) NONMSLANOr4A SKIN CAncers (NMSC) Ba c k gr ound Basal cell carcinoma (BCC) and squamous cell canzinoma (SCC) are the most common malignancies in solid organ transplant recipients lemma Sre 2012384622-1630) Aldiough mortality risk is low, it has die highest incremental risk of death compared g 4; ;2 to general population (><29.8) UAMA ann:1016224631 Risk Factors Cumulaui»e ultraviolet radladon exposure.Age at txp (>50 yr lx T risk). Dungeon of top. Immunosuppression: type (llA has 1.Sx risk of SCC) and Dose: high accumulated dose ofAZA. CNl.and steroids T risk of SCC 4.6x (Amjannemaiafwll 2018) Type of organ transplanted: higher risk of NMSC if utilize more intense immunosup pression such as combined heart and kidney transplant compared to kidney alone History of previous NMSC increases risk for subsequent NMSC Screening and Prevention Selfexam AND Heakh care provider skin exam annually (KDIGO Tmnglviuuon 2009) Sun protection education (Use of highspF sunscreen decreases SCC. BCC) Sirolimus L 56% risk NMSC vs CNI (Ami 2D14;349296s79). But a/w higher mortality (qAsn 2016:11:lB4§) 3N Treatment In aggressive SCC. reduction of immunosuppression Consider change to MMF from AZA. or roTOR inhibitor from CNI. systemic retinolds (Am I an o¢-mmlA¢lil 2018) POSTTRANSPLANT LYre PHOPNOLIFEaATIVe Dlsonosn (PTLD) Background Incidence 1% at 10 yr posttransplant with majority (>80%) occurring in first yr post transplant (mau n¢Iniu 2014:29(91151n Cumulative incidence over S yr is 1-3% in kidney transplants The maioriry are EBVdrivenaup to 30% are EBV negative Risk Factors IS after SOT is a/w marked T risk of malignancy UAMA 1004294113211 Negative EBV serostatus of the recipient at the time of kidney transplant Prior malignancy Time PostTransplant, EBV naive occur early.whereas EBV IgG seropositive recipients develop -10 yr pos:transplant (T/aiisglniuallon 2013;5:470) Clinical Presentation Nonspecific constitutional symptoms: B symptoms (fever. weight loss. night sweat) Lymphadenopadiy and organ dysfunction: extranodal masses (>1/2). CNS disease (20-2538), infiltrative lesions of the allograft (20-25%) 1 Hb. Plt.WBC. i LDH. Ca.uric acid. monoclonal protein in urine or serum Allograft dysfunction: hydronephrosis. renal vessel stenosis, graft infiltration Prevention No role of antiviral prophylaxis or z011:17:1701 Workup and Management of EBV Reactivation (AIT 2013;13¢41) Initial reactivation with elevated EBV PCR over 2 wk Reduce immunosuppression. monitor EBV PCR once weekly until negative In the following settings of EBV uremia. r/o PTLD via CT imaging or PET scan, and pursue excisional biopsy when appropriate: Persistent EBV uremia, or high asymptomatic EBV uremia w/wo I IS Any EBV uremia with associated symptoms Treatment (MH 10101496932 National Comprehensive Cancer Network Guidelines) Goals: endication of PTLD and preservation of graft function Tumor histology staging with WHO criteria EBV status of tumor established (EBV+ tumor may respond best to reduction of IS. EBVnegative lymphomas unlikely to respond) Reduction of IS (where alterative organ supports possible. eg.dialysis) Immunotherapy with CD20 monoclonal antibody rituximab (Effective in CD20+ PTLD) Chemotherapy: Anthracyclinebased: CHOP (cyclophosphamide. doxorubicin. vintristine. prednisone) Care must be taken in patients with impaired cardiac function Platinum drugs are nephrotoxic and even in normal renal function. care should be taken Fludarabine is renally excrend. monitor renal function Radiotherapy Surgical management CNS Involvement; radiation therapy.surgical removal.and methotrexate (if renal function preserved) Prognosis Ly ca 0rWI}013:1Dt1N1) Patients with PTLD had 5yr survival race of 53%. 10yr survival rate of 45% Multivariable analyses revealed than age >55 yr.semm creatinine >1.5 mg/dL. LDH, disseminated Iymphoma.brain localization, invasion of serous membranes. monomor phic PTLD. and Tcell PTLD were independent prognostic indicators of poor survival RENAL COMPLICATION IN OTHER ORGAN TRANSPLANTATION CKD AFTER NONNeNAL Soup ORGAN TRANSPLAnTATION (NRSOT) CKD is a known complication pos: NRSOT CKD prevalence reported as 5 yr after transplantation was 21.3% for intestine recipients. 18.1% for liver recipients, 15.8% for lung recipients. 10.9% for hear recip ienv.s. and 6.9% for heartlung recipients ESRD occurred as a rate of 1-1.5%/yr among NRSOT recipients (NUM z003:349931) Risk Factors for CKD Post NRSOT mew 1W3:349:9J1: ;ASN z001:1e¢a031: Tnmnglant Rev 2N 1$:2%17§) Pretransplanr factors Older age. 9, preexisting CKD. DM. HTN. HCV Perkransplam factors Renal hypoperfusion: LV dysfunction. hepatorenal syndrome Perioperadve AKI: hypotension. hypovolemia, iodine contrast. nephrotoxic medications,atheroembolic disease Calcineurin inhibitor toxicity Acute: vasoconstriction of afferent arterioles. Chronic: interstitial fibrosis. nodular arteriolar hyalinosis. glomerulosclerosis. thrombotic microangiopathy Nephrotoxic antibiotics. ongoing transplant organ dysfunction. BK nephropathy (rare) Pos:transplant factors Treatment NRSOT recipients with eGFR <30. protelnurla >500 mg/d or rapidly declining GFR should be referred for renal evaluation. Management of complications of CKD (eg. anemia. metabolic acidosis. bone and mineral disease) should follow guidelines for nontransplant pts U Halt u", Tmmplam 201D:29:914; Lnerfnmspl 2013:19:3). BP iargers and management should follow those for the general population. CCBs are most commonly used. but ACEIIARB should be used if proteinuria and may be pre ferred in DM. In patients on mTORi.ARB may be preferred to ACEI due to lower risk of angioedema u Hear! hmlTnmsplani z01<z2~r914; iierfonspl 2013:1n: ClASN 2010:5:703). C o n ve rsi o n fro m C N I to mTOR i alw T GFR. However. conversion to mTORi also a/w T acute rejection in liver trans plant and high discontinuation rate due to side effects. mTORi conversion associated with improved GFR in heart and lung transplant recip ienrs. mTORi may slow progression of cardiac allograft vasculopathy lrmmplaluiuon 101611006111 1016;10041558) P a t ie n t s wit h p re e xist in g p ro t e in u ria o r CKD ma y h a ve wo rse n in g re n a l fu n ctio n after conversion to an mTORi law aauwmi 101711735811 Heon lung Trasplant 1009;7.81564) DiALvsis AFTER NRSOT HD is the mos: common RRT modality in NRSOT patients who develop ESRD PD has been used in heart and lung transplant recipients. who might be very sensitive KO volume changes and fluid shifts associated with hemodialysis In thoracic transplant recipients showed higher rate of hospitalization with HD vs PD (231.4 vs 72.7/100 patient yr), higher rate of dialysisrelated infections with PD (0.36 vs 0.08lpatien¢ yr), and no difference in mortality (he MM z01s;Js9sl Kl1:>n£v TRANSPLANTATION (KT) AFTER NRSOT Early referral for KT evaluation is essential given high mortality rare while on dialysis KT is alw small T mortality peritransplant in NRSOT However the mortality rate is i significantly after 141 d and remains sustained for 5 yr postrenal transplant (NE/M 1W];3491931) 5yr overall graft survival for KT in hear or lung recipients is lower than with primary KT However deathcensored gray survival is comparable and KT i risk of death com pared with dialysis by 43% in heart and 54% in lung recipients. Liver transplant recipi. e n ts with ESRD have a 44-60% reduction in morality compared witll remaining on dialysis (Air 2009;9$784 um Tmnspl 2011;19:3) URINF SEDIMENT IMAGES Dysmorphlc RBCs. RBCs of diflenenz size, RBC cast. Typically seen in giomerulone shape. hemoglobin content. with fraglnenndon phrids or vasculitis. and budding. Seen in gkamerular bleeding. Hansel shin. WBC cast (KI 1008;73:980). Frequently seen in inzersririal nephritis. presence of eosino phils suggests allergic origin. May also be seen in glomemlonephriris. Hansel stain. Renal epithelial cell in AKI. Multiple vac uolazed renal epithelial cells in fosamet nephrotoxicicy (ATN). Hansel szain. » 8 Triple phosphate (stluvite) crystals (KJ zoIs;ua:20sl. Coffinlid shaped Triple (ammoni ummagnesium) phosphate crysnls (stru vile) seen in infected alkaline urine with uneaseproducing bacteria. Urabe crysnls In 201181:118Il, Rosenes and rhomboidshaped crystals M uric acid in pink urine after recurrent seizure. after pro pofol anesthesia.Also seen in hear stressrelaxed Mesoamerkan nephlupazhy. . _ Sulla drug crystals (re 20 1s;a1sss; "Shock of wheat" appearance of Suifamthoxazole crymls seen in acute kidney injury following high dose Sulfamthoxazole-Trimedroprim therapy. RENAL PATHOLOGY IMAGES Wir9A Mesangial prolilerulve GN, H&E 924: -5 .auf Crescentic GN widl fibrinoid necrosis (ormw).JMS Immune thrombi in cryc\d¢bulinemk GN. PAS FSGS. rip lesion variant, H&E MPGN. H&E Nodular mesangid sclerosis. PAS Acute thrombotic microangiopathy in giom erulus. H&E Acute tubular necrosis, PAS Acute interstitial nephritis. PAS H14 Strongly bireiringenr cadmium oxalate crystals. H&E. polarized Iigh: Arypkzl asks of myeloma/light chain as! nephropathy. PAS II T Granulomatous interstitial nephritis. PAS Mucoid Intimal edema of a mediumcaliber artery; scleroderma renal crisis H&E Cholesterol emboli (arrow) in a large artery. Granular mesangial staining (loAN) H&E .4 S Linear GCW shaming landGBM dIsease) MIDD ., "";`.4 . . *w Subepidmdial electron dense deposits Suhaldomhelial electron dense deposit = ~ Mac °e~'=»=».».=. Armed fibrils (8-10 nm) '1.. n } 13" I. Fibrillary deposits (16-20 nm) Annularuibular suhszniaure in cryoglohuli nemk GN UNITS AND MOLECULAR WEIGHTS Unit Conversion Substance (MW) BUN (14 x 2 : 28) Urea (60) Creatinine (113) Calcium (40) Phosphorous (31) Magnesium (24.3) Glucose (180) Uric acid (168) PTH Total cholesterol 25OH vit D 1.25(OH)1 vit D UPCR UACR Unit Conveniomx Factor Below Conventional Conventional Unit to Sl SI Unit mg/dL 0.357 mmolIL mgldL mmol/L 0.167 mg/dL umollL 88.4 mg/aL 0.25 mmol/L mg/dL mmollL 0.3229 mg/aL mmollL 0.41 mgldL mmol/L 0.055 mgldL u mol/L 59.485 pg./mL 0.106 pmoVL mgldL mmol/L 0.026 nglmL 2.496 nmolIL pg./mL pmoIIL 2.6 g/g Cr mg/mmol 113.6 mglmmol gig Cr 113.6 SI to Conventional 2.8 6 0,0113 4 3.1 2.43 18 0.0168 9.4 38.67 0.4 0.38 0.0088 0.0088 'Urea 1 mmollL = run 1 mmol/L; BUN 1 mg/dL= Urea 2.14 meat Sodium Chloride 58.44 glmoI: Na 22.99 glycol + CI 35.45 glycol NaCl 3% = 30 g/L = 513 mErelL: 3% 100 mL = 3 g = 51.3 mEq Na + 51.3 mEq CI NaCl 2% = 20 g/L = 342 mErelL: 2% 100 mL = 2 g = 34.2 mEq Na + 34.2 mEq CI NaCl 5.1 g = 87 mEq (2 g) Na + 87 mEq (3.1 8) CI NaCl 5.8 g (1 teaspoon) I 100 mEq (2.3 g) Na + 100 mEq (3.5 g) CI NaCl 1 g= 17.1 mEq (393 mg) Na + 17.1 mEq (606 mg) Cl Sodium Bicarbonate 84.01 g/mol: Na 22.99 glycol + HCO; 61.02 glycol NaHCO; 8.4% = 84 mg/mL = 1 mEq/mL: 23 mg Na + 61 mg HCO; per mL 50 mL = 50 mEq Na + 50 mEq HCO3: almost same Na contents with 3% 100 mL NaHCO; 650 mg = 7.7 mEq Na + 7.7 mEq HCO; NaHCO; 4.8 g (1 teaspoon) = 57 mEq (1.3 g) Na + 57 mEq (3.5 g) HCOg Potassium Chloride 74.55 glmolz K 39.10 g/mol + Cl 35.45 g/mol KCI 1 g = 13.6 mEq (530 mg) K + 13.6 mEq (470 mg) Cl Protein Size Abumin Myoglobin Hemoglobin ISG 68 17.8 68.8 150 Proton Size (kDa) 192 microglobulin Cystatin C or light chain 1 light chain 11.a 13.3 22.5 45 ABBREVIATIONS primary secondary betablocker change in mental status 1 betahydroxysteroid dehydrogenase type 2 fludeoxyglucose F 18 18FFDG 6mercaptopurine 6MP associated with alw amino acid AA Association (Cr the AAMI Adyancement of Medical lnstrumentadon antibody Ab arterial blood gas ABG antibodymediated ABMR rejection abnormal abnl ambulatory blood ABFM pressure monitoring antibiotics abx American College 01 ACCP Chest Physicians angiotensin convening ACE enzyme angiotensin convening ACEi enzyme inhibitor anticardiolipin antibody ACL acute cellular rejection ACR acute wwiiary synditume ACS adrenocorticouophic ACTH hormone autosomal dominant AD ADAMTS13 a disintegnin and metal loprozeinase with a thrombospondin type 1 motif.memb¢f 13 ADH ADTKD antidiuretic hormone autosomal dominant AlloHSCT ALT AME AML AMR ANA ANCA Ann IM APC APD APLA APOLLO APS AR ARB ARDS ARNa AHUS AIDS AIHA All AIN AlT AKI AKID alb aldo ALI acute interstitial nephritis American journal of Transplantation acute kidney injury dialysis requiring acute kidney injury albumin aldosterone acute lung lnlury transplantation alanine aminotransfense apparent mineralocorti coid excess acute myelogenous leukemia antibody mediated rejection annnuclear antibody ancineutrophilic cytoplasmic antibody Annals of internal Medicine antigenpresenting cell automated peritoneal dialysis antiphospholipid antibody apolipoprotein LE antiphospholipid syndrome autosomal recessive angiotensin receptor blocker acute respiratory distress syndrome angiotensin Receptor Neprilysin Inhibitor ARV ASA antiretrunral aspirin ASCVD atherosclerotic cardio vascular disease aspartate aminotransferase asymptomatic acute tubular injury acute tubular necrosis autologous hematopoietic stem cell transplantation aneriovenous. aortic valve atnioventricular block arteriovenous liswla arteriovenous graft arteriovenous malformation alathioprine alkaline phosphatase because blood culture AST asx ATI ATN AuwHSCT tubulointerstitial kidney disease acidfast bacilli atrial Fibrillation anion gap antigen anion gap metabolic acidosis atypical hemolytic uremic syndrome acquired immunodeficiency syndrome autoimmune hemolytic anemia angiotensin II allogenic hematopoietic stem cell AVB AVF AYG AVM AZA A¢ bl: BCx B)P BK BKV BM BMD BMI BMP BNP BP BPH BT BUN Bence lofts protein maxiK channel BK virus bone marrow bone miuenl density body mass index basic metabolic panel MIPS naxriuledc pqmae blood pressure benign prostatic hypertrophy bleeding dmc blood urea niungen biopsy carbon monoxide/ compared w cardiac Output chronic obstructive pulmonary disease cyderoxygenase calcium pyrophosphate crystal deposition calculated panel reactive antibody COI1\PIEl¢ remission. complete response creatinine creatinine clearance compared with/ consistent with complement C3 glomerulopathy C3 glomerulonephritis CCB CCD CD CDC carbonic anhydrase coronary artery bypass grafting coronary artery disease carbonic anhydrase inhibitor congenital anomalies of the kidney and urinary tract calcium oxalate calcium phosphate continuous ambulatory peritoneal dialysis calciumsensing receptor complete blood count calcium channel blocker cortical collecting duct collecting duct complementdependent CDI cytotoxicity central diabetes insipidus CAD CAI CAKUT CaOx CaP CAPD CaSR CBC ceph. CF CFB CFH CFTR CFU CH50 CHF CHO Cl CIAKI CIN CKD ND CKDT CKDEFI CLL CML CMP CMS CMV CNI CNT Cephalosporin cystic fibrosis complement factor B complement factor H cystic Fibrosis transmem brane conductance regulator colony forming units total complement activity congestive heart failure carbohydrate cardiac index contrastinduced AKI contrast induced nephropathy cold ischemia time creatine kinase chronic kidney disease dialysisdependent chronic kidney disease nondialysis dependent chronic kidney disease nondialysis dependent chronic kidney disease wid\ a kidney transplant Chronic Kidney Disease Epidemiology Collaboration chronic lymphocytic leukemia chronic myelogenous leukemia cardiomyopathy Centers for Medicare & Medicaid Services cytomegalovirus calcineurin inhibitors connecting tubule COX CPPD Cr CrCI CRP CRRT Creactive protein continuous renal replacement therapy C RT cardiac resynchronization therapy CS corticosteroids CsA Cyclosporine A cesarean section cerebrospinal iluid computed tomogram computed tomography angiogram connective tissue disease Csection CSF CT CTA CTD CTLA4 cv cytotoxic Tlymphocyte associated antigen4 CVVH cardiovascular cerebrovascular accideit cardiovascular disease central venous pressure cardiovascular system continuous V¢l10V€I1OU§ CVVHD hemofiltration continuous venavenous CVA CVD CVP CVS CVVHDF cx CXR CyBorD CYC CYP cys d dlc DAM Ps DBP DCD dcSS¢ DCT DDAVP hemodialysis continuous venavenous hemodiaNltration culture chest radiograph cyclophosphamide. bortezomib. dexamethasone cyclophosphamide Cytochromes P450 cysraun C day discontinue. discontinuation due to dopamine directact.ing antiviral disuse alveolar hemorrhage damageassociated molecular patterns diastolic blood pressure donation aker circulatory death diffuse cutaneous systemic sclerosis dlscal convoluted tubule tdesamino8Darginine vasopressin dense deposition disease deceased donor kidney transplantation Ddx def DES dFLC DGF DHP dHUS differential diagnosis deficiency enzymelinked drugeluting stent enzymelinked immunosorbent assay electron microscopy epithelial sodium channel electrophysiology erythropoietin encapsulating peritoneal sclerosis :he involved and uninvolved light chain delayed graft function dihydropyridine diabetes insipidus disseminated inuavascular coagulation diabetic ketoacidosis diffusion capacity of die lung diabetes mellitus diseasemodifying anti rheumatic drug diabetic nephropathy direct oral anticoagulant dyspnea on exertion diffuse proliferative glomerulonephrids drug racdon widi eoslnophilia a systemic symptoms dRTA Epo EPS diarrhea associated hemolytic uremic syndrome DRI immunoassay difference between direct renin inhibitor distal renal tubular acidosis disease donor specific antibody deep vein thrombosis dry weight diagnosis dual energy xray absorptiometry elo EAV EBPG evidence of eRecdv»e arterial volume EBV ECF ECG EpsteinBarr virus extracellular fluid electrocardiogram extracorporeal mem brane oxygenation electron dense deposit ethylenediaminetet EPTS ERBP ESA ET1 EKOH EU erythropoiesis stimulating agen: erythrocyte ggdimgnggign rate endstage renal disease hemodialysis dependent endstage renal disease endothelin1 alcohol endotoxin units EULAR the European League ESR ESRD ESRDHD flu F DA EDD EDTA EGFR eGFR eGFRcreat cys estimated dry weight ejection fraction esophagogastroduode noscopy epidermal growdt factor receptor estimated glomerular filtration rate estimated glomerular filtration rate using creatinine and cystatin C eGFRcys EGPA estimated glomerular filtration rate using cystadn C eosinophilic granuloma tosis with polyangiitis U.S. Food and Drug Administration fresh frozen plasma FGF23 fibroblast growth factor 23 iibrillary glomerulone phritis family history free light chain fibromuscular dysplasia familial Mediterranean fever lluoroquinolone FGN FHx FLC FMD FMF European Best Practice raacetic acid EDW EF EGD Against Rheumatism followup FFP fracture risk assessnnent tool Guidelines ECHO Estimated Posttransplant Survival European Renal Best Practice FRC FSG FSGS FTT G6PD GBM GCA GCSF GCW GERD GFR GGT GI as gk glom GLP1 GMCSF functional residual apadty fasting serum glucose focal segmental glomeru losdemsis failure to thrive glc6phosphate dehy dragenase glomerular basement membrane giant cell aneritis granulocyte colony stimulating fatter glomerular capillary wall gastroesophageal reflux disease glomerular ikration rate ygluumyl uanspq:d¢se gastrointestinal gastrointestinal bleed glucose glomeruli glucagonlikepeptide1 granulocytemacrophage colonysumulating facwr GN GNR GnRH GOF giomerulonephritis gramnegative rods gonadotlopinreleasing hormone gain of function GP GPA glomerulopathy granulomatosis with polyangiitis GPC GRA giamposiuve cocci aldosteronism global sclerosis genitourinary graftversushost disease hour headache haptoglobin hematoxylin & eosin stain history and physical examination hlo HZRA Hb HBcAb HBeAg HBsAb HBsAg HBV HC HCC HCDD hCG HCQ Hot HCV HD HDL HELLP HIF HIT HLH history of H2receptor antagonist hemoglobin hepatitis B virus cone antibody hepatitis B virus envelope antigen hepatitis B virus surface antibody hepatitis B virus surface antigen hepauiis B virus Heavy chain hepatocellular carcinoma heavy chain deposition disease human chorionic gonad ouopin hydroxychloroquine hematocrit hepatitis C virus hemodialysis highdensity lipoprotein hemolysis. abnl LFTs. low pIn heat failure. hemohltra :ion hyperosmolar hypergly cemic state hypoxia induced factor heparininduced throm bocytopenia hemophagocytic lymphohistiocytosis hypotension high power held hyperparathyroidism heart rate hematopoietic stem cell transplantation HSP HSV HTN HUS Henoch-SchOnlein purpura herpes simplex virus hypertension hemolytic uremic syndrome history l&D IABP IBD IBW lCa ICD ICP ICU IDA IDWG IE IF IFITA IFN is IgAN IgAV IGF1 lgG4RD IGRA IGT HD incision at drainage intraaortic balloon pump inflammatory bowel disease ideal body weigh: ionized calcium implantable cardiac defibrillator intracranial pressure intensive care unit iron deficiency anemia interdialytic weight gain infective endocardltls Immunofluorescence interstitial fibrosis and tubular atrophy interferon Immunoglobulin Immunoglobulin A nephropathy Immunoglobulin A vasculitis Insulinlike growth factor 1 Immunoglobulin G4related disease interferon1 release =35=1 impaired glucose tolerance intermittent IKMG hemodialysis indirect immunofluores cence testing the International Kidney and Monoclonal Gammopathy Research Group ILZRA interleukin2 receptor IIFT ILD IMCD IMI antagonist interstitial lung disease inner medullary collect ing duct inferior myocardial infarction INH INR IP IRGN ITGN ITP intlanasal idiopathic nodular glomerulosclerosis isoniazid international normalized ratio intraperitoneal Infectionrelated glomerulonephritis immunosuppression International Society for Peritoneal Dialysis immunotactoid glomeru Ionephritis idiopathic thrombocyto penic purpura IUGR intrauterine growth restriction IV IVC IVD U IVF l vIg intravenous inferior vena cava intravenous drug use(r) Intravenous fluids lntrannous immuno globulin luxtaglomerular MAHA ones medienamine silver jugular venous distention jugular venous pulse potassium Kidney Allocation System KDIGO KDOQI KDPI KDRI IcSSc LCV LCDD LDH LDKT LDL LE LFTs LHC LHCDD LM LMW LMWH LN Loc LOS lpf LPL Kidney Disease: Improving Global Outcomes (Guidelines) Kidney Disease Outcomes Quality Initiative (Guidelines) Kidney Donor Profile Index Kidney Donor Risk Index Kidney lntemational Kidney International Reports kidney transplantation kidney transplant recipients kidney-ureter-bladder xray left atriumllongacting/ lupus anticoagulant light chain light chain proximal tubulopathy limited cutaneous systemic sclerosis leukocytodastic vasculitis light chain deposition disease lactate dehydrogenase living donor kidney transplantation MAOI MAP MATE MBL MC MCD mCrCl MCTD MCV MDMA HDRD MDS mes MG mGFR MHC ml MIDD min light and heavy chain deposition disease light microscopy low molercular weight mo lowmolecularweight heparin MPGN lupus nephritis loss of consciousness length of stay MR MOA MPA MRA MRI lactated Ringers left ventricle LV enddiastolic pressure left ventricular mAb MAC MACE hypertrophy most common. most commonly monoclonal antibody membrane attack complex malor adverse cardiac event Modification of Diet in Renal Disease myelodysplastic syndrome mesangial monoclonal pmmopadvy measured glomerular filtration rate MGUS lowdensity lipoprotein lower extremity liver function tests light and heavy chain low power Edd lymphoplasmacytic lymphoma microangiopathlc hemo lytic anemia monoamine oxidase inhibitor mean arterial pressure multidrug and toxic compound exclusion monoclonal B cell lymphocytosis mineralocorticoid minimal change disease measured creatinine clearance mixed connective tissue disease mean corpuscular volume 3.4methylenedioxy methamphetamine (Ecstasy) MRSA MTb roTOR MTX MVP MW N/V NAFLD monoclonal gammopadvy of uncertain signifi cance major histocompatibility complex myocardial infarction monoclonal immuno globulin deposition disease minute multiple myelonna mycophenolate mofetil measles. mumps and rubella membranous nephropathy month mechanism of action microscopic polyangiitis. mycophenolic acid membranoproliferative glomemlonephrius mineralocorticoid receptor mineralocorticoid recep tor antagonist, magnetic iuonance angiography magnetic resonance imaging mezhicillinresistant s. aureus Mycobacterium tuberculosis mammalian (mechanistic) target of rapamycin methotrexate mitral valve prolapse molecular weight nausea and/or vomiting nonalcoholic fatty liver disease NAGMA NaPi NASH NCC NCX NDI NGT NHANES NHE NHL NKCC NNRTI NODAT NPO Np! NPV NR NRSOT NRTI NS NSAID nonanion gap metabolic acidosis sodium phosphate cotnnsporter nonalcoholic steatohep atitis sodium chloride cotrans poner sodium calcium exchanger nephrogenlc diabetes insipidus nuclear factor d activated T cells nasogastric tube the National Health and Nutrition Examination Survey sodium hydrogen exchange nonHodgkin lymphoma sodium potassium chlo ride cotransporter normal nonmelanoma skin cancer nonnucleoside reverse transcriptase inhibitor newonset diabetes after transplant nothing by mouth NaPi cotransporters negative predictive value no response nonrenal solid organ transplantation nucleosidelnucleotide reverse transcriptase inhibitor normal saline: nephrotic syndrome nonsteroidal antllnllam NYHA matory drug nephrogenic systemic fibrosis New York Heart OAT OCT Association organic anion zranspona organic cation NSF transporter OSA OTC plw PA PAC PAD PAH PAN PAS PASF PCI osmolal gap Organ Procurement and Transplantation Network obstructive sleep apnea overthecounter present(s) with primary aldosteronism plasma aldosterone concentration peripheral artery disease pulmonary arterial hypertension polyarteritis nodosa periodic acid-Schiff stain PA systolic pressure percutaneous coronary intervention PCN penicillin PCOS polycystic ovary syndrome PCP Pneumocystis jimved pneumonia PCR protein catabolic rate. polymerase chain reaction proprotein conyerase subtilisin/kexin type 9 inhibitor proximal computed tubule 13valent pneumococcal conjugate vaccine pulmonary capillary PCSK9I PCT PCV13 PCWP PD PE PET PE: PFO FFT PG PGNMID PHPT PHS PI PICC PiT wedge pressure peritoneal dialysis pulmonary embolism positron emission tomography physical examination patent foramen ovate pulmonary function test prostaglandin proliferative glomerulo nephritis with MOI\O clonal immunoglobulin G deposits primary hyperparathy roidism Public Health Service protease inhibitor peripherally inserted central catheter inorganic phosphate transporter P]P Pneumocystis yimved pneumonia FKD PLEX plt PMHx PML polycystic kidney disease plasma exchange platelet past medical history progressive multifocal Ieukoencephalopathy polymorphonuclear leukocyte pneumonia paroxysmal nocturnal PMN PNA PND PNH pn5 PO POD PPD PPI PPSV23 PPV Ppx PR PRA ¢ly=pn=a paroxysmal nocturnal hemoglobinuria peripheral nervous system onl intake. by mouth postoperative day pufifigd protein derivative proton pump inhibitor 23valent pneumococcal polysaccharide vaccine positive predictive value prophylaxis partial remission. partial response plasma renin activity panel reactive antibody PR8Cs packed ned blood cells RZV PRES posterior reversible encephalopathy syndrome sle pRTA PSGN pr PT PTA proximal renal tubular acidosis post streptococcal glomerulonephritis patient proximal tubule. pro thrombin time percutaneous translumi slp mis SBP subeladinoid l~e~°~h=s= spontaneous bacterial peritonitis/systolic SC SUb(UCZl\€OUS see squamous cell carcinoma sickle cell diseasdsudden cardiac death SAH blood pressure SCD nal angioplasty PTH P TH r P PTLD PTT PVR parathyroid hormone parathyroid hormone related protein posnransplant lymphop roliferative disease partial thromboplastin time pulmonary vascular SCLC SCT small cell lung cancer stem cell toansdanmion Se sensitivity sFLC SGLT senim free light chain sodium glucose cotrans poner syndrome of inappropri ate ADH serum immunoelectro phonesis serum immunofixation electrophoresis standardized incidence ratio resistance every before every meal daily every bedtime e4ery odle r day RANKL quality of life rule in rule out rheumatoid arthritis. right atrium nenin-angiotensinaldosterone system renin-angiotensinaldosterone system inhibition receptor activator of nuclear factor StevensJohnson syndrome systemic lupus erythematosus kappa[s ligand RAS RBC RBF RCT RI renal artery stenosis red blood cell renal blood flow randomized controlled trial rheumatoid factor. risk factor resistive index. renal RO MK renal outer medullary RF insufficiency SMX SNGFR SNRI SNS sos potassium channel ROS RP RPG N RR RT RTA RTE RTX RVT Rx RYGB residual renal function renal replacement therapy radiation therapy renal tubular acidosis renal tubular epithelial rituximab renal vein thrombosis therapy RouxenY gastric bypass slow low efficiency dialysis simultaneous liver kidney transplantation superior mesenteric artery soluble membrane attack complex smoldering multiple myeloma sulfamethoxazole single nephron gfomeru lar filtration rate serotoninnorepinephrine reuptake inhibitors sympathetic nervous system sinusoidal obstruction syndrome specificity reactive oxygen species. review of systems retroperitoneal rapidly progressive glomerulonephritis relative risk. respiratory serum protein electro phoresis scleroderma renal crisis supersaturation Sjogren syndrome systemic sclerosis selective serotonin reuptake inhibitor rare RRF RRT recombinant zoster vaccine side effect status post symptoms and signs svc superior vena cava SVO; mixed venous oxygen SVT supraventricular saturation tachycardia symptom(s). symptomatic syndrome type 1 diabetes mellitus T2DM Tac TAL type 2 diabetes mellitus Tacrolimus Thick ascending limb of the loop of Henle TBMN TCA TCC Tdap TEE temp TG TGF TIA TIBC TIN TINU TIW TKV TLS TMA tuberculosis tubular basement membrane dtii hasemait membrane nephlopadly tricycle antidepressant uansltional cell carcinoma tetanus. diphtheria. pertussis transesophagol echo temperature triglycerides tiubuloglomerular feedback transient ischemic aback total iron binding capacity tubulointerstitial nephritis tubulointerstitial nephri ds and uveitis three times a week total kidney volume tumor lysine syndrome thrombotic microangiopathy TMP TNF TP TPN TRALI TRAS TRI TRP Tsar TSH TTE TTKG TTP TURP trimethoprim wmor necrosis factor total protein total parenteral nutrition transfusionrelated acute lung injury transplant renal artery stenosis wbuloreticular inclusion transient receptor potential tnnslerrin saturation thyroid stimulating hormone transthoracic echo transtubular pqgggium gradient thrombotic dirombocy topenic purpura trinsurediral resection of the prostate treatment transplantation rhiazolidinediones urinalysis ultrasound uric acid urine albumin to creatinine ratio urine anion gap urine albumin urine albumin to protein ratio ulcerative colitis urine calcium UCI UCx UF UFH UGIB UIFE UK ULN UN: UNOS UOP UPCR UPEP Uprot URI USPSTF USRDS urine chloride urine culture ultrahltration unlractionated heparin upper gastrointestinal bleed urine immunohxatjon electrophoresis urine potassium upper limit of normal urine sodium United Network for Organ Sharing urine OLIIPUL urine protein to creatinine ratio urine protein electrophoresis urine protein upper respiratory tract infxn U.S. Preventive Services Task Force United States Renal Dam System UTI UTO VBG urinary tract infection urinary tract obstruction Vd volume of distribution VDRL VEGF venereal disease research laboratory (test for syphilis) vascular endothelial VF VHL vit VKA VOD VT VTE VUR vWF vzv wl wlo wlu WBC WH O growth factor ventricular fibrillation Von Hippel-Lindau vitamin vitamin K antagonist venaocclusive disease ventricular tachycardia venous thromboembolus vesicoureteral reflux von Willebrand factor varicella zoster virus with without workup white blood cell (count) World Health venous blood gas Organization week Waldenstriim macroglobulinemia worsening renal function water restriction test weight Xlinked Y ylo zeaL xanthippe oxidase xanthippe oxidase inhibitor year year old zoster vaccine live Note: Page numbers followed by f and c denote figure and :able respectively. AA amyloidosis. 722, 912, 9S3 Abdominal compartment syndrome. 914-915 A[}2M amyloidosis, 723 Acetaminophen. 955 Acetaminopheninduced nephrotoxicitya 915 Acetazolamide. 413. 432 Acetoacetic acid. 46 Acid-base balance. 43 in alcoholuse disorders. 915-916 in GI diseases. 913 Acquired cystic kidney disease (ACKD). 5.11 Acquired perforatihg dermatosls. 969 Activated charcoal, 334 Acute cellular rejection (ACR). 1113 Acute decompensated heart failure (ADHF), 315. 91 Acute fatty liver of pregnancy 964 Acute interstitial nephritis (AIN). 58-59. 937 Acute kidney injury (AKI). 1.24-128 Acute lung injury (ALI). 96 Acute mesenteric ischemia. 911 Acute phosphate nephropathy. 431 Acute tubular necrosis (ATN). 215. 51. 9.14 cardiac surgery and, 51 Acute uremic encephalopathy. 9S9 Acyclovir. 960 ADAMTS13 deficiency. 728 Adefovir. 938 Adenine phosphoribosyltranslerase (APRT) deficiency. 55 Adolescents and young adults (AYA). transition of care for. 1.33 Adrenalectomy. 814 Adrenal insufficiency. 317-318. 425 Adrenal vein sampling (AvS). 8.14 Adrenocorticotropic hormone (ACTH). 318, 812 Adynamic bone disease. 9.45 AFib amyloidosis. 723 Allibercept. 933 Agalsidase B. 725 Agerelated macular degeneration (AMD). 970 Air embolism. 1017 AKIN criteria,AKl, 18 AL amyloidosis. 215, 722 Albumin. 11 Albuminuria. 939 i Albuterol. in hyperkalemia. 418 Alcohol dehydrogenase inhibitors.48 Alcoholic ketoacidosis. 47. 916 Aldosterone. 812 ALECT2 amyloidosis. 723 Alemtuzumab, 324-325 Allele, 217 Allograft pyelonephrids. 1111-1112 Allopurinol, 5 14. 951 Alltrans retinoic acid (ATRA). 932 ix1 microglobulin. 11 Alphaglucoside inhibitors. 941 Alport syndrome, 122. 221. 710 Aluminum. 331 Aluminum hydroxide.432 Ambulatory blood pressure monitoring (ABPM). 8 1. 84 Amikacin, 936 Amiloride. 434 for nephrogenic DI. 17 Amitriptyline. 957 Amyloid. 721 Amyloidosis. 721-723 Anabolic steroid. 331 Analgesic nephropathy. 954 ANCAassociated vasculitis. 122 Anemia. 920 Angiography. 29 Angiotensinconverting enzyme inhibitors (ACEr). 39-311 for hypertension. 85 Angiotensin receptor blocker (ARB). 39-311 Angiotensin receptor neprilysin inhibitor (ARNI). 311 Anion gap metabolic acidosis (AGMA), 45 Antibiotics for UTI, 63 Antibody agents. 323 Antibodymediated rejection (AMR). 1114-11 15 Anticoagulation in membranous nephropathy. 925 nephropathy related to. 925 for NVAE 924-925 Antidepressants. in CKD. 957 Antidiuretic hormone (ADH). 16. 112. 113. 25 in hyponatremia. 422 AntiGBM disease. 122. 710 Antihypergiycemic agents, 941 Antihypertensives. 87 Antiinflammatory drugs. for gout. 951-952 Antimicrobial prophylaxis. 3.29 Antineutrophil cytoplasmic antibodies (ANCA). 77. 78. See also Pauciimmune glomerulonephritis Antiphospholipid antibody (APLA). 727 Antiphospholipid syndrome (APS). 727 Antiproteinuric therapy. 76 Antithymocyte globulin (ATG). 324 Anuria. 19 Anxiety. 956 Apheresis. 333 Apixaban. 95. 925 Apneahypopnea index (AHI), 810 Apolipoprotein 1 (APOL1).72 Apolipoprotein L1 (APOL1).83 Aristolochic acid, 330 ART. adverse renal effects of, 938-939 Arterial pH. 43 Arterioyenous 6 stula (AVF). 973. 1020 Arterioyenous graft (AVG). 973. 1020 Aspirin. 335. 954 for preeclampsia, 963 Asymptomatic bacteriuria. 1112 Atrial fibrillation (AFib), 95. 958 ATTR amyloidosis. 723 Automated implantable cardioverter dehbrillator (AICD). 96 Autonomic neuropathy. 959 Autosomal dominant polycystic kidney disease (ADPKD). 512-513, 956 Autosomal dominant tubulointerstitial kidney disease (ADTKD). 59. 514. 950 Autosomal recessive polycystic kidney disease (ARPKD). 513 Axitinib, 933 Azathioprine (AZA). 321. 79 B Baclofen. 960 Bacterial peritonitis. 1031-1032 Bariatric surgery. 944-94S Bartter syndrome, 41-42 Basiliximab. 325 Bath sales. 331 Beer potomania, 916 Belatacept. 325 Belimumab. 325 Benign familial hematuria. 726 Benign variant. 219 IIBlocker. for hypertension. 85 [3hydroxybutyric acid. 46 [32 microglobulin, 11 Bevacizumab. 932 Bicarbonate therapy. for AGMA, 45 Biguanides. 941 Bile cas: nephropathy. 914 Bilirubin, in urine. 23 Biochemical tests, 217 Biologic agents. 932 Birt-Hogg-Dube syndrome. 515 Bisphosphonates for glucocorticoidinduced fracture. 318 for hypercalcemia. 429 for osteoporosis, 948 BK polyomavirus injection, 1117 Bladder pain syndrome. 110 Blood gas analysis, 43 Blood transfusion. 35. 922 Blood urea nitrogen (BUN). 21 Blood volume estimation. 116 Body fluid comparunenrs. 111 Bone mineral density (BMD),949 Borcezomib. 729. 928 Bosniak classification 511. 515 Bosutinib. 933 Breastfeeding. medications during. 962 Bumeranide. 313 Buprenorphine, 955 Bupropion. 957 C Cabazitaxel. 932 Cadmium, 331 CAKUT. 221 Calcify uremic arteriolopathy (CUA). 968 Calcineurin inhibitors (CNI). 31 B-320 Calcitonin, in hypercalcemia. 429 Calcium. 428 Calciumbased binders. 432 Calcium kidney stones. 511 Calcium oxalate nephropathy. 945 Calcium phosphate crystals. S4 Calcium supplementation. 431 Canakinumab. 722 Cannabinoid hyperemesis syndrome. 331 Cannabis. 331 Caplacizumab. 729 Captopril renal scan, 29 Captopril stenography. B11 Carbon Hker. 1013 Carbonic anhydrase (CA) inhibitors. 312. 411 Carboplatin, 932 Cardiac catheterizations, 93-95 Cardiorenal syndrome (CRS). 91-92 Carpal tunnel syndrome. 955 Catastrophic antiphospholipid syndrome (CAPS). 727-728 diagnostic criteria. 727 treatment. 728 Catheterrelated bacteremia. 1025 Cefepime. 936 Ceftaroline. 936 CefazidimeAvibactam. 936 Central diabetes insipidus (CDI), 15. 16-17. 112 Central venous stenosis, 1025 Cerebral edema. 960 and renal replacement therapy, 960 Cerebral salt wasting, 425. 960 C3 glomerulopathy (C3G). 718-720 C3 nephritic factor 71B Checkpoint inhibitors. 933 Chlorothiazide. 313 Chlorthalidone. 313 Cholesterol emboli syndrome. 94 Chromosomal microarray (CMA). 218 Chronic kidney disease (CKD). 129-131 Chronic lymphocytic leukemia (CLL).925 | Chronic tubulointerstitial disease. 59 Chvostek sign, 430 Cigarette smoking. 331 Ciliopathies. 221 Cinacalcet in hypercalcemia. 430 in hyperphosphatemia, 432 Ciprofloxacin, 936 Cirrhosis. 913-914 Cisplatin. 930-931 Citalopram. 957 Citrate supplementations. 57 CKDMBD abnormalities. after kidney transplantation, 1120 CKDmineral and bone disorder. 944-945 Clearance convective, 101 diffusive. 101 Clevidipine. 87 Cocaine. 331 Cockcroft-Gault equation. 22 Codeine. 955 Cognitive decline. 958 COL4Aassociated nephropathy. 726 Colistin. 936 Collagenofibrotic GR 724 Collapsing glomerulopathy, in SLE, 715 Collecting duct Colloids. 32 Compensation assessment. 43 Complementdependent cytotoxicity crossmatch (CDCXM). 11 1 S Complementmediated HUS. 729-730 Congenital chloridorrhea. 913 Conivaptzn, 314. 423 Constipation. 910 Continuous ambulatory peritoneal dialysis (CAPD). 1027 Continuous cyclic peritoneal dialysis (CCPD), 1028 Continuous renal replacement therapy (CRRT), 128. 105-107 and drug therapy. 38-39 Continuous venovenous hemodiahltration (CWHDF). 102, 105 Continuous venovenous hemodialysis (CWHD). 102. 105 Continuous venovenous hemofiltratlon (CWH). 102. 105 Contrastinduced nephropathy (CIN). 966 Convection. 101. 1026 Convective clearance. 101 COPD. 96-97 Copeptin. 16. 425 Coronary artery bypass graft surgery (CABG). 93 Coronary artery disease (CAD), 92-93 Corticosteroids (CS). 317-318 in antiGBM disease. 710 in cryoglobulinemia. 721 in idiopathic FSGS. 74 in loAn. 712 in MPGN. 718 Cramps. 1015 Creatine. 21 changes in serum level of. 21 estimated GFR (eGFR), 21 Crescentic glomerulonephrids. 213 CREST syndrome. 952 Cryocrit. 721 Cryoglobulinemia. 720-721 Cryoglobulinemic glomerulonephritis, 122. 215 Cryoglobulinemic vasculitis. 720 Cryoglobulins. 720 Crystalglobulinemia. 927 Crystalloids. 32 in septic shock. 117 Crystalluria. 938 Crystal nephropathy. 53-55 CT scan. renal, 29 Cyclophosphamide (CYC). 322-323. 78. 79. 928. 932 in antiGBM disease. 710 in loAn, 712 in MN. 76 in thrombotic dirombocytopenic purpura. 729 Cyclosporine (CM). 318 in MN. 76 Cystatin C-based eGFR, 2 1 Cysteamine. 41 Cystic diseases hereditary. 512-514 sporadic. 511 Cystic fibrosis (CF). 97-98 Cystinosin. 12 Cystinosis. 12. 41. 59 Cystinuria. 55 Cytomegalovirus (CMV) Infection. 1116-11 17 D Dabigatran. 335. 924 Dabrafenib. 933 Daclizumab. 325 Daily nitrogen balance. 25 Damage associated molecular patterns (DAMPs). 1113 Dapromycin. 936 Daracumumab. 722 DASH died. 82 Deferasirox. 923 Deferiprone. 923 Deferoxamine. 923 Dehydration. 111-1 13 Deionizers. 1014 Delayed graft function (DGF), 119 Deleteriousness prediction. 219 Dementia. 958-959 Denosumab. 947 in hypercalcemia,430 De novo :hrombodc microangiopazhy. 11 10-1111 Den: disease. 12 Depression. in CKD. 9S7 Dermatologic diseases, renal manifestation of. 970 Desipramine. 957 Desmopressin for central DI, 17. 112 challenge, 15 for nephrogenic DI, 17 Dexamethasone. 929 Diabetes insipidus (DI) central. 15. 16-17. 112 nephrogenic, 15. 17. 113 Diabetic glomerulosclerosis (DGS). 214 Diabetic ketoacidosis. 47, 941 Diabetic kidney disease (DKD). 9 3 9 -9 4 1 Diabetic nephropathy 940 Diabetic retinopathy (DR). 970 Dialysate. 102 Dialysis catheter thrombosis. 1010 Dialysis central venous catheter (CVC). 1019 Dialysis disequilibrium syndrome. 959. 1 0 1 4 -1 0 1 5 Druginduced encephalopathy. in CKD. 960 Drug reactions with eosinophilia and systemic symptoms (DRESS). 969 Drugs of abuse. 331 Drusen. 971 Dry weight (DW). 115 Dual energy xray absorpdometry (DXA) Tscore. 946 Duloxetine. 956 Duplex Doppler ultrasound. 28. 811 DSW 427 Dysproneinemiarelated renal diseases. 2.1 s Dysuria. 110 Dialysis. in hyperkalemia. 418 Dialysis membrane reaction, E 10 14-101 S Diarrheainduced NAGMA. 49 Diarrhea. in transplant recipients. 1119 Diethylene glycol. 336. 337 Early goalOirected therapy (EGDT). 1 17 Diffuse alveolar hemorrhage (DAH). 710. 99 Ecstasy. 331 Diffuse infiltrative Iymphocytosis syndrome (DILS). 938 Disusion. 101. 1026 Dihydropyridine (DHP). 85 Dimercaptosuccinic acid (DMSA), 62 Dipstick test, 11 Dipyridamole. 433 Directacting antiviral therapies (DAAs). 918 Direct renin inhibitor (DRI). 311 Direct sequencing. 512 Directtoconsumer (DTC) genetic testing. 219 Distal renal tubular acidosis (dRTA). 49-410. 54 Distal tubule EASTISeSAME syndrome, 42 ECG abnormalities. in hyperkalemia. 417 Eculizumab. 327 for C3 glomerulopathy. 720 for complementmediated HUS. 729 for hemolytic uremic syndrome. 728 Edema. 120 Electrolytefree water clearance. 26. 427 Electron microscopy (EM). 212 Emphysematous pyelonephritis. 63 ENaC antagonists. 314 Encapsulating peritoneal sclerosis. 911. 1032 Endocapillary proliferative glomerulonephritis. 213 Endothelial tubuloreticular inclusion. 215 EAST/$e$AME syndrome. 42 Gitelman syndrome. 42 Gordon syndrome.42 Endstage renal disease (ESRD), 131-132 physiology of. 42 Environmental substance. 332 Diuretics. 312 resistance. 314-315 syndrome. 3 15 Diureticsinduced hyponatremia. 425 Dlacdc acidosis, 46. 937 Dnaj heat shock protein family B member 9 (DNA]B9). 724 Enteric hyperoxaluria. 53 Epacadostat. 933 Epinephrine. 118 Epstein-Barr virus (EBV) infection. 1117 Equilibrated urea clearance. 1011 Erythrocytosis. 923 posttransplantation. 923 DNA sequencing. 217 Erythropoiesis, 920 Dobutamine. 118 Erythropoiesis stimulating agents (ESA). 921-922 Erythropoietin (EPO), 920 Dolutegravin 938 DonnaiBarrow/faciooculoacoustico renal syndromes. 12 Dopamine, 118 excess production. 924 Estimated dry weight (EDW). 108 DPP4 inhibitors. 941 Ethacrynic acid. 313 Droxidopa. 119 D~s(5) Ethanol. 48 dosage adjustments. 38 metabolizing mechanisms. 37 pharmacokinetics. 36-38 proximal tubule drug transporters. 37-38 Ethylene glycol ingestion. 336. 337. 47-48 Euvolemic hypematremia, 112 Everolimus, 320. 513 Exerciseassociated hyponatremia (EAH). 332 ; o Q Exerciseinduced AKl. in familial renal hypouricemia. 951 Exerciseinduced hematuria. 14 Extracapillary proliferative glomerulonephrinis. 213 Extracellular fluid (ECF). 111, 113 Extracorporeal membrane oxygenazion (ECMO). 99-910 Extracorporeal therapy of inroxicatian. 3 3 4 -3 3 5 Gastroparesis. 910 Gemcitabine. 932 Genetic counseling, 217 Generic diagnosis. 217 Generic diseases. features of. 217 Genetic hypophosphatemk rickets. 433 Genetic research, 219 Generic testing. 217-218 Genomic rearrangements, 218 Gentamicin. 936 Geriatrics. 971-973 F Fabry disease. 725-726. 970 Familial dysautonomia. 119 Familial hypocalciuric hypercalcemia (FHH). 949 Familial renal hypouricemia. 952 Fanconi syndrome, 433. 938. 952 Fasting ketoacidosis, 47 Far pad aspiration. 953 Febuxostac S14. 951 Fenoldopam. 87 Fentanyl, 9,55 Ferric carboxymaltose. 921 Ferric citrate.432 Ferric pyrophosphate citrate. 921 Ferumoxytol. 921 Fibrillary glomerulonephritis. 215. 724 Fibromuscular dysplasia (FMD).810. 812 Fibronectin GR 724 Fibrosis of skin. 952 Flow crossmatch (FXM). 1115 Fludrocortisone. 119 Fluid imbalance. 111-116 Fluid theapy. 32-36 Fluoxetine. 957 Flux. 101 Focal segmental glomerulosclerosis (FSGS), 213-2 14. 72-74 Fomepizole. 336. 48 Fractional excretion (FE), 25 Fractional excretion of sodium (FEM). 25 Fractional excretion of uric acid (FEud). 25, 422 Fracture Risk Assessment Tool (FRAX). 946 Free water clearance (Ciao). 26. 427 Free water deficit. 427 Fungal injections. in transplant recipients. 1118 Furosemide. 313 renal scan, 29 stress test. 128 Gabapenzin. 955 Gadoliniumbased contrast agents (GBCA). 29 Gadoliniuminduced nephrogenic systemic fibrosis (NSF), 29 Galaccosedeficient IgA1 . 711 Gallium nitrate. in hypercalcemia, 430 Gastric bypass surgery. 944 I Gascroincescinal bleeding. 910-911 Gestational diabetes insipidus. 15. 17 Gestational hypertension. 962 Giant cell arteritis. 953 GI cations exchangers. in hyperkalemia. 41a Gitelman syndrome, 42 Globotriaosylceramide (Gb3). 72S. 728 Glomerular basement membrane (GBM). 710 Glomerular disease.914 with organized deposits. 2 15 Glornerular injury. 212 Glomerular proteinuria. 12 Glomerulonephrids (GN). 122-123. 911 GLP1 agonists,941 Glucocorticoidinduced fracture risks. 318 GIucocorticoidinduced osteoporosis. 947 Glucocorticoid remediable aldosteronism (GRA). 814 Glucocorticoids in acute interstitial nephritis, 58 in lgG4RD. 510 in minimal change disease. 71 in MN. 76 Glucose disarray. in patients on dialysis, 941 Glucose. in urine. 23 Glue sniffing. 48 Goodpasture disease. 710 Goodpasture syndrome. 710 Gordon syndrome. 42 Gout. 951 Grasbeck-lmerslund disease. 12 H Hand ischemia. 1023 Hansel stain. 23 H2 antagonists. 960 HBV prophylaxis. 329 HCTZ. 313 Hernaropoietic stem cell zransplanurion (HSCT). 92B-929 Hemazuria, 13-1S. 121 Hemodiafiltradon (HDF). 102 Hemodialysis (HD). 334-335, 965. 101 adequate. 1011~1013 cathecen 1024 complication. 1 0 1 4 -1 0 1 8 dialysis catheter thrombosis, 1010 dialyzers. 108 Hemodlalysis (HD) (continued) and drug therapy, 38 estimated dry weight, 108 heparin anticoagulation, 109 Hyperchloremic normalgap metabolic acidosis. 9 16 Hyperkalemia. 416418. 1017-1018 urine laboratory tests in. 27 heparinfree dialysis. 109-1010 Hyperlactatemia, 46 inadequate. 1013 indications. 108 Hyperlipidemia. 121, 943 Hypermagnesemia, 433-434 Hypemazremia. 112. 426427 initiation. 108 prescription. 109 solute clearance. 1011-1013 in toxic alcohol ingestion. 336-337. 48 vascular access, 1019-1025 water treatment, 1013-1014 Hemodialysis catheter. 972 Hemofiltration (HF). 10 1 Hemoglobin (Hb). 919-920 Hemoglobinuria, 13 Hemoiysis. 1018 Hemolytic transfusion reaction. 922 Hemolytic uremic syndrome (HUS). 728 Hemoperitoneum. 1032 Hemosiderinuria, 13 Henderson-Hasselbalch equation. 43 Henoch-Schénlein Purpura (HSP), 712 Heparininduced thrombocytopenia. 1018 Hepatitis B virus (HBV). 916-917 Hepatitis C virus (HCV), 917-918 Hepatorenal syndrome (HRS). 913 He

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