Chronic Kidney Disease
The Basics
Kevin Harley, M.D.
Assistant Clinical Professor
Department of Medicine
Division of Nephrology & Hypertension
UC Irvine Medical Center
Objectives
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Review Definition of CKD and its classification
Discuss Hypertension in CKD
Anemia in CKD
Mineral Bone Disorders in CKD
Nutrition in CKD
Renal replacement therapy prep
A Case
76 y/o white female visits clinic. She is distraught.
Another MD told her she has stage 3 CKD. She looked it
up on the internet and she is afraid she will need dialysis.
Has 20 year history of hypertension, on amlodipine. BP
138/72, UA no protein, Cr 1.3 mg/dl
Which of following is the next best step?
a)
b)
c)
d)
e)
Repeat blood test to confirm CR and MDRD eGFR
Repeat blood test for cystatin C level and eGFR
Repeat labs for CKD-epi CR+cystatin C eGFR
24 Hr urine Cr Clearance
Encourage her to get another doctor
Chronic Kidney Disease
How big a problem?
• 10-15% of US population have
non-dialysis dependent CKD
• In 2011, there were over
620,000 people receiving ESRD
Medicare benefits
Chronic Kidney Disease
The Basics
• CKD is defined as either of the following
present for 3 months:
– Markers of kidney damage
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Pathologic albuminuria
Abnormal urine sediment
Anatomic defect detected by imaging
Histopathologic abnormality
OR
– Decline in GFR < 60ml/min/1.73m2
Chronic Kidney Disease
(…Its not good for your health)
Over 1.1 million pts followed > 3 years
New Engl J Med 351:1296, 2004
Classifying CKD: Cause
Type of Disease
Examples of systemic
diseases affecting the
kidney
Examples of Primary
kidney disease
Glomerular
diseases
DM, Autoimmune Disease (eg SLE),
infections, neoplasia
FSGS, Primary Membranous,
Minimal Change, Proliferative or
crescentic GNs
Tubulointerstitial
diseases
Infections, Sarcoid, Drugs, Urate,
myeloma, environmental toxins
UTIs, Stones, Obstruction
Vascular Disease
Atherosclerosis, HTN, ischemia,
cholesterol emboli, systemic
vasculitis, TMAs, scleroderma
ANCA-associated renal limited
vasculitides, fibromuscular
dysplasia
Cystic &
Congenital
Disease
PKD, Alports, Fabrys
Renal dysplasia, medullary cystic
kidney disease
Classifying CKD: eGFR
Classifying CKD: Albuminuria
Category
Albumin/CR
(mg/g)
Terms
A1
<30
Normal
A2
30-300
Moderately
Increased
A3
>300
Severely Increased
Albuminuria:
Outcomes by eGFR
Pink = ACR > 300 mg/g
Green = ACR 30 – 299 mg/g
Blue = ACR < 30 mg/g
Levey, et al, Kidney International (2011) 80, 17–28
Glomerular Filtration
Clearance
Glomerular Filtration Rate (GFR): 120-130 ml/min
Estimating Kidney Function
•
If 24 hr urine can be collected:
CrCl = (Ucr x Volume) / Pcr
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Time averaged urine urea and Creatinine
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Cockroft-Gault (0.85 for women) – use serum Creatinine
CrCl = 0.85 * ( Wt x [140-age] ) / Scr x 72
• MDRD Equation:
eGFR = 170 * Scr-0.999 * age-0.176 * sex * race *
(Female: 0.762)
• CKD-EPI Equation:
GFR = 141 X min(Scr/κ,1)α X max(Scr/κ,1)-1.209 X 0.993Age X 1.018 [if female] X
1.159 [if black]
Plasma Creatinine
• Creatinine is derived from the metabolism of
creatine in skeletal muscle and from dietary
meat intake.
Kidney Handling of Creatinine
• 10-40% Urine Cr is from tubular secretion by
the PCT
• IF GFR, tubular creatinine secretion, dietary
intake, and muscle mass all remain constant,
then the serum [Cr] should remain constant
Every Creatinine is Not the Same
• Patient 1 : 22y/o African American male
– Cr = 1.2 mg/dl, MDRD eGFR = 98 ml/min
= normal kidney function, or stage 1 if history of problem
• Patient 2: 50 y/o white male
– Cr = 1.2 mg/dl, MDRD eGFR = 68 ml/min
= stage 2 chronic kidney disease
• Patient 3: 80 y/o white female
– Cr = 1.2 mg/dl, MDRD eGFR = 46 ml/min
= stage 3 chronic kidney disease
From National Kidney Foundation
Creatinine Caveats
• Decreased Cr secretion (sCr can rise 0.5mg/dl)
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Trimethoprim
Dronedarone
Cimetidine
Tenofovir
• Increased Cr production
– Large meat intake
• Interference with Cr assay (alkaline picrate method)
– Flucytosine, cefoxitin, acetoacetate
Creatinine
Normal Values
Category
Male
Female
U.S. (all)
1.13
0.93
Mexican-Americans
1.07
0.86
Non-Hispanic Black
1.25
1.01
White (non-Hispanic)
1.16
0.92
NHANES III
Cystatin C
(0.53-0.95 mg/L)
• 13 kDa protein produced by all nucleated cells
– Freely filtered at glomerulus
– 99% reabsorbed at PCT and catabolized
• cant be used to measure clearance
– …its not perfect
• Level rises with age
• And w/ inflammation/CRP
Cystatin C to Predict CV Death
Shlipak, NEJM 2005;352:2049-60
CR+Cys C eGFR
Inker, NEJM 2012;367:20-9
Combined creatinine-cystatin C e-GFR performed better than
equations based on either of these alone and may be useful as a
confirmatory test for CKD.
A Case
76 y/o white female visits clinic. She is distraught.
Another MD told her she has stage 3 CKD. She looked it
up on the internet and she is afraid she will need dialysis.
Has 20 year history of hypertension, on amlodipine. BP
138/72, UA no protein, Cr 1.3 mg/dl
Which of following is the next best step?
a)
b)
c)
d)
e)
Repeat blood test to confirm CR and MDRD eGFR
Repeat blood test for cystatin C level and eGFR
Repeat labs for CKD-epi CR+cystatin C eGFR
24 Hr urine Cr Clearance
Encourage her to get another doctor
Predictable Progression of CKD
GFR
Time
Loss of nephrons  compensatory hyperfiltration
 glomerular HTN  further loss of nephrons.
Primary Diagnoses for
ALL Patients Who Start Dialysis
Diabetes
45%
Other
17%
Cystic Disease
3%
Glomerulonephritis
7%
Hypertension
28%
USRDS 2010 Annual Data Report
Management of CKD
Nephrology. A Photographic History
Role of the Nephrologist
• Mortality rate is lower in 1st 3 months of
ESRD in CKD pts who were established with
a nephrologist prior to reaching ESRD status
– Adjusted HR for Death: 1.60-1.75
– Survival increased with # nephrology encounters
Kessler et al (EPIREL Study); Am J Kidney Dis 2003; 42: 474-485
Winkelmayer et al. J Am Soc Nephrol 2003; 14: 486-492
Avorn et al. Arch Intern Med 2002; 162: 2002-2006
Stack et al. Am J Kidney Dis 2003; 41: 310-318
Kinchen et al. Ann Intern Med 2002; 137: 479-486
CKD Associated Conditions
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Hypertension
Anemia
Secondary Hyperparathyroidism
Metabolic Acidosis
Hyperkalemia
Malnutrition
Uremia
Question
60 y/o White Male with PMH of DM2 >20 yrs, HTN,
Dyslipidemia comes to clinic.
Meds = insulin
BP 152/90, CR 2.1, urine spot PCR = 1.5g
Which is the next step in managing BP?
A) Start HCTZ
B) Start Losartan
C) Start Lisinopril AND Losartan
D) Counsel on low NaCl diet, no meds needed
E) Start amlodipine
Hypertension in CKD
• 85% CKD patients have hypertension
• Prevalence of HTN increases linearly as GFR falls
• Treating HTN can slow the progression of CKD and reduce
the rate of CV complications
What Causes Hypertension in CKD?
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Tend to retain Na+
Increased activity of the RAS
Enhanced sympathetic activity
Impaired nitric oxide synthesis
Secondary hyperparathyroidism
Loss of normal nighttime decline in BP
ESA agents
Hypertension in CKD
ACEI or ARB use
Placebo or captopril in DM1 with proteinuria and a sCR >= 1.5
Losartan effect on doubling of the sCR and rate of proteinuria in
NEJM 1993; 329:1456
DM2
RENAAL, NEJM 2001;345:861-9
Hypertension in CKD
• Ramipril Efficacy In Nephropathy, (No DM)
– Ramipril slowed GFR decline (and proteinuria)
• REIN 2
– ACEi+/- CCB: no additional benefit
• AASK: ACEi benefit extends to Blacks
Hypertension in CKD
Is combined ACEi+ARB the way to go?
• ONTARGET trial enrolled 25,620 pts with PVD or DM
to evaluate the effects of ramipril, telmisartan, or
both on CV endpoints over 4 yrs
• Of the 5623 patients who had baseline CKD…
– ACEi+ARB was associated with significantly
increased composit outcome (ESRD or 50% increase CR)
– Higher rates of hyperkalemia
Hypertension in CKD
JNC 8
• Expect to use 3+ agents
Question
60 y/o White Male with PMH of DM2 >20 yrs, HTN,
Dyslipidemia comes to clinic.
Meds = insulin, lisinopril
BP 138/79, CR 2.2, urine spot PCR = 0.7g,
Hemoglobin 8.9, T Sat 18%, ferritin is 100
Which is the true regarding anemia management in this CKD
pt?
A) Colonoscopy is unnecessary – this is Anemia due to CKD
B) He is a candidate for darbepoetin with goal Hg 10-11.5
C) He is a candidate for darbepoetin with goal Hg 12-14
D) He should start oral ferrous sulfate
Etiology of Anemia of CKD
• Erythropoietin deficiency
• Suppression of RBC synthesis by uremic toxins
• Short RBC survival
• Iron deficiency
–Blood loss: GI tract, GU tract, etc
• Folate or B12 deficiency
• Hyperparathyroidism
• Chronic inflammation
• Infection
Anemia of CKD
• 2006 K/DOQI guidelines suggest administering Fe to:
– ≥20% saturation,
– serum ferritin > 100 ng/mL
• Erythropoeitin Stimulating Agents considered in pts
with Hg < 10, & with repleted Fe stores
– *** Target Hg is 10-12g
– *** Do not exceed Hg > 12. (More MIs and Strokes!!)
(CREATE, CHOIR, Normal HCT trials)
– *** Beware of pro-malignant effect
Question
60 y/o White Male with PMH of DM2 >20 yrs, HTN,
Dyslipidemia comes to clinic. Recent negative
colonoscopy
Meds = insulin, Lisinopril, occasional ESA and IV Iron
BP 138/79, CR 2.2, urine spot PCR = 2g, Hg = 10.5
CO2 = 19, Phos 4.5, iPTH 130, Albumin 2.7
Which of the following is TRUE?
A) Normalization of his CO2 level might delay ESRD onset
B) Persistent metabolic acidosis may lead to malnutrition
C) He does not yet need to start phosphorus binders
D) He is a candidate for active vitamin D
Chronic Metabolic Acidosis in CKD
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Increase skeletal muscle breakdown
Decreased albumin synthesis
Muscle weakness
Release of Ca++ and PO4 from bone, which can
worsen bone health
• Activation of complement pathway  promote
tubulo-interstitial injury
• **HCO3 supplementation may slow progression
Chronic Metabolic Acidosis
Alkali Supplementation Slows CKD Progression
in Diabetics and Non-Diabetics
Brito-Ashurst, et al, JASN, 20: 2075–2084, 2009
Hyperphosphatemia in CKD
• In CKD there is reduction in the filtered PO4 load.
• Hyperphosphatemia becomes manifest usually as GFR
falls < 30 ml/min
• Eventual development of secondary
hyperparathyroidism  renal bone disease:
– osteitis fibrosa, osteomalacia, and adynamic bone disease
Secondary Hyperparathyroidism in CKD
Decreased Vitamin D Receptors
and Ca-Sensing Receptors
 PTH
 PTH
 Ca++
Bone Disease
Fractures
 Serum P
Bone pain
Marrow fibrosis
Erythropoietin resistance
FGF-23
1,25D
Calcitriol
Systemic Toxicity
CVD
Hypertension
Inflammation
Calcification
Immunological
25D
Renal Failure
Mineral Done Disease in CKD
Uncontrolled 2nd HPT and HyperPhos
At time of ESRD diagnosis
3 years later
Hyperphosphatemia & Bone Disease
• CKD 3 (30-60 ml/min)
– Measure Ca and Phos yearly
– Measure iPTH yearly - goal is 35-70
– Use active vitamin D if needed
• CKD 4 (15-30 ml/min)
– Measure Ca and Phos every 3 months
– Measure iPTH every 3 months – goal is 70-120
– Use active vitamin D if needed
Malnutrition in CKD
Associated with incremental mortality risk
Relative mortality risk in new starts on chronic HD.
Data from 1980s
Am J Kidney Dis 1992; 20(Suppl 2):32
Modification of Protein Intake in CKD
• Recommended: 0.6-0.8 g protein/kg/day
• Measure 24-hr urine urea nitrogen:
Estimated protein intake =
= 6.25 * (UUN + 3%(Wt in kg))
(add urine protein if >5 g/d)
Kopple et al. Kidney Int. 2000
Maroni et al. Kidney Int. 1985
Question
60 y/o White Male with PMH of DM2 >20 yrs, HTN,
Dyslipidemia comes to clinic.
Wt = 100kg, 24 hr urine urea = 8, Urine PCR 2
Est protein intake = 6.25 * (UUN + 3%(Wt in kg))
Estimated dietary protein intake = 6.25 + 0.03(90)
= 8.95g/day
In a 90kg male, 0.8g/kg/day would be 7.2g
His goal is less than 7.2 g/day, he is taking ~9/day
….he needs nutritional counseling
Hyperkalemia in CKD
• Reduced nephron mass  reduced K+ excretion
• Hyporenin, Hypoaldosterone state
• Excessive dietary K+ intake
• Medication effects (ACEi/ARB)
Medications and CKD
• NSAIDs (including COX2 inhibitors)
• Iodinated contrast
• Aminoglycosides
• ***...always do a complete inventory
of unprescribed meds and
herbal/supplement intake
Question
5 years later…
Cr 4.2, BUN 58, K 5.1, Phos 5.6, Urine PCR 4g
eGFR 20
Hg 10 on regular ESA use
BP 160/70 on 4 BP meds +Diuretic
1+ leg edema
How do we manage CKD pts as they approach
ESRD?
Renal Replacement Therapy
• Hemodialysis
– Most common RRT
– Requires planning for AV fistula once eGFR < 20
• Peritoneal Dialysis
– Requires education, dedicated RN- pt training
– Requires planning for PD catheter placement
• Kidney Transplant
– **the best option
– Patients can be listed when GFR < 20
– Wait time for deceased donor kidney in Southern California
is 8-10 years
Monitoring for Uremia
and Indication to Start RRT
Signs and symptoms + eGFR:
– Loss of appetite, nausea, vomiting, fetor
– MS, ↓ concentration, seizure, coma
– Cramps, pruritus
– Uremic pericarditis (rub)
– Uremic bleeding tendency, ecchymoses
– Volume overload, Anasarca
– Acute Neuropathies
Natural Progression of CKD
Reduce Albuminuria
Cardiac Risk Modification
GFR
HTN control
Treat 2nd HPT
DM control
Alkali Rx
50
80
Age (years)
The rate of progression of GFR is usually predictable...
…but can be slowed = longer life and longer time to ESRD.
Accurate diagnosis is key.
Managing CKD involves
multidisciplinary approach to patient
care and education
Thank You