CHRONIC KIDNEY DISEASE AND PROGRESSION

Volume 14 • Number 4 • October 2015 NephSAP ® Nephrology Self-Assessment Program Chronic Kidney Disease and Progression Co-Editors: Michael J. Choi, MD Linda F. Fried, MD EDUCATION DIRECTOR, NephSAP Gerald A. Hladik, MD University of North Carolina at Chapel Hill Chapel Hill, NC DEPUTY EDUCATION DIRECTOR, NephSAP Jerry Yee, MD, FASN Henry Ford Hospital Detroit, MI MANAGING EDITOR Gisela Deuter, BSN, MSA Washington, DC ASSOCIATE EDITORS Michael J. Choi, MD Johns Hopkins University School of Medicine Baltimore, MD Debbie L. Cohen, MD University of Pennsylvania School of Medicine Philadelphia, PA Linda F. Fried, MD, MPH University of Pittsburgh Pittsburgh, PA Richard J. Glassock, MD Professor Emeritus, The David Geffen School of Medicine at the University of California Los Angeles, CA Stanley Goldfarb, MD University of Pennsylvania School of Medicine Philadelphia, PA Ruediger W. Lehrich, MD Duke University Durham, NC Kevin J. Martin, MBBCh St. Louis University School of Medicine St. Louis, MO John P. Middleton, MD Duke University Durham, NC Patrick T. Murray, MD University College Dublin Dublin, Ireland Aldo J. Peixoto, MD Yale University West Haven, CT Preface NephSAPÒ is one of the premiere educational activities of the American Society of Nephrology (ASN). Its primary goals are self-assessment, education, and the provision of Continuing Medical Education (CME) credits and Maintenance of Certification (MOC) points for individuals certified by the American Board of Internal Medicine. Members of the ASN receive NephSAP electronically through the ASN website by clicking on the NephSAP link under “Education and Meetings” tab. EDUCATION: Medical and nephrologic information continually accrues at a rapid pace. Bombarded from all sides with demands on their time, busy practitioners, academicians, and trainees at all levels are increasingly challenged to review and understand new and evolving evidence. Each bimonthly issue of NephSAP is dedicated to a specific theme, i.e., to a specific area of clinical nephrology, hypertension, dialysis, and transplantation, and consists of an editorial, a syllabus, and self-assessment questions, to serve as a self-study device. Over the course of 24 months, all clinically relevant and key elements of nephrology will be reviewed and updated. The authors of each issue digest, assimilate, and interpret key studies published since the release of the previous issues and integrate this new material with the body of existing information. Occasionally a special edition is produced to cover an area not ordinarily addressed by core issues of NephSAP. SELF-ASSESSMENT: Thirty, single-best-answer questions will follow the 80 to 100 pages of syllabus text. The examination is available online with immediate feedback. Those answering 75% correctly will receive MOC and CME credit, and receive the answers to all the questions along with brief discussions and an updated bibliography. Members will find a new area reviewed every 2 months, and they will be able to test their understanding with our quiz. This format will help readers stay up to date in developing areas of clinical nephrology, hypertension, dialysis, and transplantation, and the review and update will support those taking certification and recertification examinations. CONTINUING MEDICAL EDUCATION: Most state and local medical agencies as well as hospitals are demanding documentation of requisite CME credits for licensure and for staff appointments. A maximum of 48 credits annually can be obtained by successfully completing the NephSAP examinations. In addition, individuals enrolled in Maintenance of Certification (MOC) through the American Board of Internal Medicine may obtain points toward MOC by successfully completing the self-assessment examination of NephSAP. N This paper meets the requirements of ANSI/NISO Z39.48-1921 (Permanence of Paper), effective with July 2002, Vol. 1, No. 1. Asghar Rastegar, MD Yale University New Haven, CT Brad H. Rovin, MD Ohio State University Medical Center Columbus, OH Manoocher Soleimani, MD University of Cincinnati Cincinnati, OH Charuhas V. Thakar, MD University of Cincinnati Cincinnati, OH John P. Vella, MD Maine Medical Center Portland, ME Alexander C. Wiseman, MD University of Colorado at Denver Denver, CO FOUNDING EDITORS Richard J. Glassock, MD Editor-in-Chief Emeritus Robert G. Narins, MD CONTRIBUTING AUTHOR FOR THIS ISSUE Sumeska Thavarajah, MD Johns Hopkins University School of Medicine Baltimore, MD NephSAPÒ Ó2015 by The American Society of Nephrology Volume 14, Number 4, October 2015 283 Editorial 317 Volume Overload Obesity and Kidney Disease 317 Vascular Disease Holly Kramer, Karen Griffin 318 Pulsatility and Pulse Pressure 318 Retinopathy 318 Preexisting CVD 318 Hypoxemia 319 Hyperuricemia/Allopurinol 319 Pentoxifylline in Diabetes 320 Microbiome 320 Prediction Models 321 Conclusions Syllabus 294 NephSAP, Volume 14, Number 4, October 2015— CKD and Progression Michael Choi, Linda Fried, Sumeska Thavarajah 294 Learning Objectives 294 CKD Surveillance and Geographic Variability 294 CKD Prevalence and Lifetime Risk in the United States 295 CKD Screening and Monitoring in the United States 324 Diabetic Kidney Disease and Kidney Biopsy 298 Worldwide Surveillance 325 Renin-Angiotensin-Aldosterone System Blockers 298 Mesoamerican Nephropathy 329 Cardiovascular Disease 300 301 Issues in GFR and Albuminuria Estimation Specific Populations 301 Patients with Diabetes and High Normal GFR 302 Asian Populations 303 Pediatrics 303 Severe Obesity 304 Advanced CKD 304 Elderly 304 305 GFR and Albumin Excretion Variability Risk Factors for Progression of Kidney Disease 329 Coronary Plaque Characteristics in CKD 330 Association of Kidney Disease with CVD in Type 2 Diabetes 330 Interaction of Age and CKD on Mortality and Coronary Event 331 Lipid Guidelines 333 Cardiac Biomarkers 334 Inflammatory Markers and the Microbiome 335 Urine Biomarkers 337 Echocardiographic Changes in CKD 337 Percutaneous Cardiovascular Intervention and Drug-Eluting Stents 305 Biomarkers 306 Genetics 338 Atrial Fibrillation 306 Obesity 339 Cardioverter Defibrillator 310 Diet 341 Exercise in CKD 310 Fluid 343 Depression in CKD 310 Dietary Patterns 344 CKD and Safety 310 Protein Intake 348 Systems of Care and Effect on CKD 311 Sodium 348 Multidisciplinary Clinics 313 Bicarbonate 349 Economics 315 Rate of Decline of GFR and GFR Variability 349 Electronic Health Records Volume 14, Number 4, October 2015 350 351 CKD Education Disparities 351 Race and Sex 352 Access to Care Upcoming Issues Transplantation John P. Vella, MD and Alexander C. Wiseman, MD November 2015 Hypertension 353 Geriatric Nephrology Issues 353 Physical Function and Frailty Aldo J. Peixoto, MD and Debbie L. Cohen, MD March 2016 354 Cognitive Impairment Pregnancy and the Kidney 355 Palliative Care CME Self-Assessment Questions 358 NephSAP, Volume 14, Number 4, October 2015— Chronic Kidney Disease and Progression Belinda Jim, MD, Kate Bramham, MBBS, Sharon E. Maynard, MD, and Michelle A. Hladunewich, MD May 2016 Glomerular, Vascular, and Tubulointerstitial Diseases Richard J. Glassock, MD and Brad H. Rovin, MD July 2016 Volume 14, Number 4, October 2015 The Editorial Board of NephSAP extends its sincere appreciation to the following reviewers. Their efforts and insights have helped to improve the quality of this postgraduate education offering. NephSAP Review Panel Alok Agrawal, MD, FASN Wright State University Dayton, OH Mustafa Ahmad, MD, FASN King Fahad Medical City Riyadh, Saudi Arabia Kamal E. Ahmed, MD, FASN Yuma Nephrology Yuma, AZ Sadiq Ahmed, MD University of Kentucky Lexington, KY Nasimul Ahsan, MD, FASN North Florida/South Georgia VA Health System Gainesville, FL Jafar Al-Said, MD, FASN Bahrain Specialist Hospital Manama, Bahrain Christopher A. Dyer, MD University of Texas Health Science Center at San Antonio San Antonio, TX Mahmoud El-Khatib, MD University of Cincinnati Cincinnati, OH Lynda A. Frassetto, MD, FASN University of California at San Francisco San Francisco, CA Nitin V. Kolhe, MD, FASN Royal Derby Hospital Derby, Derbyshire, UK Claude Mabry Galphin, MD Nephrology Associates Chattanooga, TN Nicolae Leca, MD University of Washington Seattle, WA Mohammad Reza Ganji, MD Tehran University Tehran, Iran Paolo Lentini, MD, PhD San Bassiano Hospital Bassano del Grappa, Italy Naheed Ansari, MD, FASN Jacobi Medical Center/Albert Einstein College of Medicine Bronx, NY Duvuru Geetha, MD, FASN Johns Hopkins University Baltimore, MD Carl S. Goldstein, MD, FASN Robert Wood Johnson Medical School New Brunswick, NJ Gopal Basu, MD Christian Medical College Vellore, Tamil Nadu, India Steven M. Gorbatkin, MD, PhD Emory University, Atlanta, GA Mona B. Brake, MD, FASN Robert J. Dole VA Medical Center Wichita, KS Ashik Hayat, MD, FASN Taranaki Base Hospital Newplymouth, Taranaki, NZ Ruth C. Campbell, MD Medical University of South Carolina Charleston, SC Ekambaram Ilamathi, MD, FASN State University of New York Stony Brook, NY Chokchai Chareandee, MD, FASN University of Minnesota Minneapolis, MN Dalila B. Corry, MD, FASN UCLA School of Medicine Northridge, CA Bulent Cuhaci, MD, FASN American Hastanesi Istanbul, Turkey Kevin A. Curran, MD Fresenius Medical Care & US Renal Care Dialysis Facilities Canton, TX Rajiv Dhamija, MD Rancho Los Amigos National Rehabilitation Center Downey, CA Talha Hassan Imam, MD Kaiser Permanente Fontana, CA Pradeep V. Kadambi, MD University of Arizona Tucson, AZ Sharon L. Karp, MD Indiana University Indianapolis, IN Amir Kazory, MD, FASN University of Florida Gainesville, FL Rahul Koushik, MD University of Texas Health Science Center San Antonio, TX Lalathaksha Murthy Kumbar, MBBS Henry Ford Hospital Detroit, MI Edgar V. Lerma, MD, FASN University of Illinois at Chicago College of Medicine Chicago, IL Orfeas Liangos, MD, FASN Klinikum Coburg Coburg, Bayern, Germany Meyer Lifschitz, MD Shaare Zedek Medical Center Jerusalem, Israel Jolanta Malyszko, MD, PhD Medical University Bialystok, Poland Christopher Mariat, MD, PhD University Jean Monnet Saint-Etienne, France Naveed Masani, MD Winthrop University Hospital Mineola, NY Hanna W. Mawad, MD, FASN University of Kentucky Lexington, KY Kevin McConnell, MD Jefferson Nephrology, Ltd Charlottesville, VA Apurv Khanna, MD SUNY Upstate Medical University Syracuse, NY Pascal Meier, MD, FASN Centre Hospitalier du Valais Romand Sion, Switzerland Istvan Kiss, MD, PhD Semmelweis University Budapest, Hungary Ashraf Mikhail, MBBCh Morriston Hospital Swansea, Wales, UK Tanuja Mishra, MD Kaiser Permanente Mid-Atlantic Region Ellicott City, MD Wajeh Y. Qunibi, MD University of Texas Health Science Center San Antonio, TX Lawrence S. Moffatt, Jr., MD Carolinas Medical Center Charlotte, NC Pawan K. Rao, MD, FASN St. Joseph Hospital Syracuse, NY Sumit Mohan, MD Columbia University College of Physicians and Surgeons New York, NY Bharathi V. Reddy, MD University of Chicago Medical Center Chicago, IL Shahriar Moossavi, MD, PhD, FASN Wake Forest School of Medicine Winston-Salem, NC Joel C. Reynolds, MD, FASN Internal Medicine Clinic Meridian, MS Koosha Mortazavi, MD Vista Del Mar Medical Group Oxnard, CA Brian S. Rifkin, MD Hattiesburg Clinic Hattiesburg, MS Tariq Mubin, MD Kern Nephrology Medical Group Bakersfield, CA Helbert Rondon-Berrios, MD, FASN University of Pittsburgh School of Medicine Pittsburgh, PA Narayana S. Murali, MD Marshfield Clinic Marshfield, WI Thangamani Muthukumar, MD Cornell University New York, NY Mohanram Narayanan, MD, FASN Scott and White Healthcare Temple, TX Macaulay A. Onuigbo, MD, FASN Mayo Clinic Rochester, MN Kevin P. O'Reilly, MD Ohio State University Columbus, OH Carlos E. Palant, MD Washington DC VA Medical Center Washington, DC Malvinder Parmar, MB, MS, FASN Northern Ontario School of Medicine Timmins, ON, Canada Bijan Roshan, MD, FASN Kidney Associates of Colorado Denver, CO Mario F. Rubin, MD, FASN University of Arizona Tucson, AZ Ehab R. Saad, MD, FASN Medical College of Wisconsin Milwaukee, WI Bharat Sachdeva, MBBS Louisiana State University Health Sciences Center Shreveport, LA Mark C. Saddler, MBChB Durango Nephrology Associates Durango, CO Mohammad G. Saklayen, MBBS Wright State University Boonshoft School of Medicine Dayton, OH Pairach Pintavorn, MD, FASN East Georgia Kidney and Hypertension Augusta, GA Muwaffaq Salameh, MBBS St. Martha Regional Hospital Antigonish, NS, Canada James M. Pritsiolas, MD, FASN CarePoint Health Medical Group Bayonne and Chatham, NJ Mohammad N. Saqib, MD Lehigh Valley Hospital Orefield, PA Paul H. Pronovost, MD, FASN Yale University School of Medicine Waterbury, CT Henry L. Schairer, Jr., MD, FASN Lehigh Valley Health Network Allentown, PA Mohammad A. Quasem, MD Universal Health Services Hospitals Binghamton, NY Gaurang M. Shah, MD, FASN Long Beach VA Healthcare System Long Beach, CA Nita K. Shah, MD St. Barnabas Health Center Livingston, NJ Arif Showkat, MD, FASN University of Tennessee Memphis, TN Sandeep S. Soman, MD Henry Ford Hospital Detroit, MI Manish M. Sood, MD, FASN University of Manitoba Winnipeg, MB, Canada Susan P. Steigerwalt, MD St. John Providence Hospital Detroit, MI Ignatius Yun-Sang Tang, MD University of Illinois Hospital and Health Sciences System Chicago, IL Ahmad R. Tarakji, MD, FASN College of Medicine, King Saud University Riyadh, Saudi Arabia Hung-Bin Tsai, MD National Taiwan University Hospital Taipei, Taiwan Anthony M. Valeri, MD Columbia University New York, NY Allen W. Vander, MD, FASN Kidney Center of South Louisiana Thibodaux, LA Juan Carlos Q. Velez, MD Medical University of South Carolina Charleston, SC Anitha Vijayan, MD, FASN Washington University in St. Louis St. Louis, MO Shefali Vyas, MD St. Barnabas Health Center Livingston, NJ Nand K. Wadhwa, MD Stony Brook University Stony Brook, NY Sameer Yaseen, MD Nephrology PC Des Moines, IA Mario Javier Zarama, MD Kidney Specialists of Minnesota, PA Saint Paul, MN Volume 14, Number 4, October 2015 Program Mission and Objectives The Nephrology Self-Assessment Program (NephSAP) provides a learning vehicle for clinical nephrologists to renew and refresh their clinical knowledge, diagnostic, and therapeutic skills. This enduring material provides nephrologists challenging, clinically oriented questions based on case vignettes, a detailed syllabus that reviews recent publications, and an editorial on an important and evolving topic. This combination of materials enables clinicians to rigorously assess their strengths and weaknesses in the broad domain of nephrology. Accreditation Statement The American Society of Nephrology (ASN) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA Credit Designation Statement The ASN designates this enduring material for a maximum of 8.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Original Release Date October 2015 CME Credit Termination Date September 30, 2017 Examination Available Online On or before Thursday, October 15, 2015 Estimated Time for Completion 8 hours Answers with Explanations Provided with a passing score after the first and/or after the second attempt October 2017: posted on the ASN website when the issue is archived. • • Target Audience Nephrology certification and recertification candidates Practicing nephrologists Internists • • • Method of Participation Read the syllabus that is supplemented by original articles in the reference lists. Complete the online self-assessment examination. Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit. Upon completion, review your score and incorrect answers and print your certificate. Answers and explanations are provided with a passing score or after the second attempt. • • • • • Volume 14, Number 4, October 2015 Activity Evaluation and CME Credit Instructions Go to www.asn-online.org/cme, and enter your ASN login on the right. Click the ASN CME Center. Locate the activity name and click the corresponding ENTER ACTIVITY button. Read all front matter information. On the left-hand side, click and complete the Demographics & General Evaluations. Complete and pass the examination for CME credit. Upon completion, click Claim Your Credits, check the Attestation Statement box, and enter the number of CME credits commensurate with the extent of your participation in the activity. If you need a certificate, Print Your Certificate on the left. • • • • • • • • For your complete ASN transcript, click the ASN CME Center banner, and click View/Print Transcript on the left. Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria: Be certified by ABIM in internal medicine and/or nephrology and enrolled in the ABIM–MOC program Enroll for MOC via the ABIM website (www.abim.org). Enter your (ABIM) Candidate Number and Date of Birth prior to completing the examination. Take the self-assessment examination within the timeframe specified in this issue of NephSAP. Below your score select “Click here to post to ABIM.” • • • • • MOC points will be applied to only those ABIM candidates who have enrolled in the MOC program. It is your responsibility to complete the ABIM MOC enrollment process. System Requirements Compatible Browser and Software The ASN website (asn-online.org) has been formatted for cross-browser functionality, and should display correctly in all modern web browsers. To view the interactive version of NephSAP, your browser must have Adobe Flash Player installed or have HTML5 capabilities. NephSAP is also available in Portable Document Format (PDF), which requires Adobe Reader or comparable PDF viewing software. Monitor Settings The ASN website was designed to be viewed in a 1024 · 768 or higher resolution. Medium or Combination of Media Used The media used include an electronic syllabus and online evaluation and examination. Technical Support If you have difficulty viewing any of the pages, please refer to the ASN technical support page for possible solutions. If you continue having problems, contact ASN at email@asn-online.org. Volume 14, Number 4, October 2015 Disclosure Information The ASN is responsible for identifying and resolving all conflicts of interest prior to presenting any educational activity to learners to ensure that ASN CME activities promote quality and safety, are effective in improving medical practice, are based on valid content, and are independent of the control from commercial interests and free of bias. All faculty are instructed to provide balanced, scientifically rigorous and evidence-based presentations. In accordance with the disclosure policies of the Accreditation Council for Continuing Medical Education (ACCME), individuals who are in a position to control the content of an educational activity are required to disclose relationships with a commercial interest if (a) the relation is financial and occurred within the past 12 months; and (b) the individual had the opportunity to affect the content of continuing medical education with regard to that commercial interest. For this purpose, ASN consider the relationships of the person involved in the CME activity to include financial relationships of a spouse or partner. Peer reviewers are asked to abstain from reviewing topics if they have a conflict of interest. Disclosure information is made available to learners prior to the start of any ASN educational activity. EDITORIAL BOARD: Michael J. Choi, MD—Current Employer: Johns Hopkins University School of Medicine; Consultancy: GlaxoSmithKline-Data monitoring safety board, Relypsa-Advisory board; Scientific Advisor/Membership: Editorial Board: Clinical Journal of the American Society of Nephrology, Clinical Nephrology, National Kidney Foundation Board of Directors Linda F. Fried, MD, MPH, FASN—Current Employer: VA Pittsburgh Healthcare System; Research Funding: Site investigator in study: Abbvie, NephroGenex, Merck (study drug donation); Ownership Interest: Pfizer expert witness Gerald A. Hladik, MD—Current Employer: University of North Carolina at Chapel Hill; Scientific Advisor/Membership: Education Director for NephSAP, American Society of Nephrology John P. Middleton, MD—Current Employer: Duke University; Consultancy: Relypsa, AstraZeneca; Research Funding: Keryx, Bristol-Myers Squibb, Janssen, NephroGenex; Scientific Advisor/Membership: Editorial Board: Journal of Human Hypertension, Advances in CKD; Steering committee NIDDK CKD Consortium Asghar Rastegar, MD—Current Employer: Yale University School of Medicine Jerry Yee, MD, FASN—Current Employer: Henry Ford Hospital; Consultancy: Amgen, Vasc-Alert, Alexion, ZS Pharma; Ownership Interest: Merck, Gilead; Honoraria: Amgen, Alexion, Gerson, Drexel University, University of California at San Diego, ZS Pharma; Patents/Inventions: VascAlert; Scientific Advisor/Membership: NKF: Editor-In-Chief of Advances in CKD (journal); Editorial Board: CJASN, American Journal of Nephrology, Deputy Editor, NephSAP; Other Interests/Relationships: Chief Medical Director, Greenfield Health Systems CONTRIBUTING AUTHOR: Sumeska Thavarajah, MD—Current Employer: Johns Hopkins Bayview Medical Center; Scientific Advisor/Membership: Medical Advisory BoardNKF of Maryland, Current Chair EDITORIAL AUTHORS: Karen Griffin, MD, FASN—Current Employer: Loyola University Medical Center, Hines VA Hospital; Research Funding: Complexa; Scientific Advisor/Membership: Member, Editorial Board of Hypertension; Chair, Professional & Public Education Committee of the American Heart Association Hypertension Council Member, NIH PBKD Study Section; Other Interests/Relationships: Member of the Scientific Advisory Board of the National Kidney Foundation of Illinois Holly J. Kramer, MD—Current Employer: Loyola University Medical Center; Scientific Advisor/Membership: Editorial Board: American Journal of Kidney Disease, Advances in Chronic Kidney Disease, Clinical Journal of the American Society of Nephrology ASN STAFF: Gisela A. Deuter, BSN, MSA—Nothing to disclose Commercial Support There is no commercial support for this issue. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Editorial Obesity and Kidney Disease Holly Kramer, MD, MPH,*†‡ and Karen Griffin, MD†‡ *Departments of Public Health Sciences and †Medicine, Division of Nephrology and Hypertension, Loyola University Chicago, Maywood, Illinois; and Section of Nephrology, ‡Hines Veterans Affairs Medical Center, Hines, Illinois “No disease that can be treated by diet should be treated with any other means,” Mosheh ben Maimon (Maimonides, circa 1200 AD). activity” to manage a patient with moderate CKD and obesity (5). Similar to caloric restriction, specific aspects of nutritional management, which may deter the development and progression of CKD in the setting of obesity, are not widely used. These nutritional aspects include salt and protein restriction and increasing the fiber content of the diet. Behavioral change, however, is extremely difficult to initiate and sustain. The industrialization of food, gradual increases in portion sizes, and concomitant changes in the cost structure of foods over the past three decades have largely mediated the obesity epidemic and impeded public health efforts. Since the 1980s, healthier foods have become relatively more expensive compared with processed foods, and portion sizes for processed foods have increased disproportionately to those of healthy foods (6). Despite the ubiquity and quantity of calorically dense and palatable processed foods in the 21st century, marked interindividual differences in obesity risk remain. These interindividual differences in obesity risk have been attributed to genetic factors, with numerous variants across the genome, each contributing very small effects (7). However, such genetic effects cannot be operative if caloric intake does not exceed caloric expenditure. The answer to why some individuals consume food in great excess of caloric needs may be found in the vast array of neuroimaging studies that have been reported in obese and nonobese individuals. Overall, comparisons of brain imaging studies by obesity status have shown increased activity in the areas of the brain that modulate the neural circuits for somatosensory processes, memory, and mesolimbic pathways (8). A meta-analysis of neuroimaging studies in obese and nonobese individuals reported that obese individuals in general have increased Obesity Within the United States adult population, approximately one in three is overweight (body mass index [BMI] ¼25–29.9 kg/m2), one in three is obese (BMI$30 kg/m2), and approximately 1 in 20 is morbidly obese (BMI$40 kg/m2) (1,2). Thus, approximately only one in three United States adults has an ideal BMI (18.5–24.9 kg/m2). Estimates of the costs of obesity in the US health care system are staggering, with up to $150 billion spent on obesity-related comorbidities annually, including CKD (3). Currently, it is estimated that up to 24% of CKD can be attributed to obesity among industrialized countries (4). However, the majority of diabetes and hypertension incidence remains a function of excessive caloric intake combined with low physical activity. Thus, it stands to reason that the United States obesity epidemic contributed to the concurrent and rapid rise in ESRD over the past 25 years and that most ESRD in the United States originates directly or indirectly from obesity. Public health efforts to address the obesity epidemic have been extremely slow to respond. Even today, the overwhelming majority of physicians are not addressing obesity with their patients and/or providing nutrition and weight management counseling for management of chronic diseases, including CKD. Within the nephrology community, the role of obesity in CKD management remains contentious. Among 399 nephrologists (57% from Europe and 12% from Central and South America), only 65% stated that obesity per se is a risk factor for CKD, and only 32% said that they would “prescribe a calorically restricted diet and try to motivate the patient to increase his/her degree of physical 283 284 activation of certain prefrontal cortical regions after viewing images of food (9). The increased activation of these prefrontal cortical regions when viewing food images compared with that in nonobese individuals suggests that obese individuals are more likely to focus on the hedonic or reward aspects of the food (8,9). In other words, the amount of ingested food required to make an individual feel rewarded differs by obesity status. While viewing food images, obese individuals also have higher and more consistent activation of prefrontal cortical regions that modulate neural circuits involved with habit formation (mesolimbic pathways) but reduced activation of cortical areas that regulate feelings of satiety and cognitive control compared with nonobese individuals (8,9). However, it remains unclear whether differences in mesolimbic pathway activation between individuals are a function of genetic variants, diet, or gene-environment interactions. Consumption of energy-dense and highly palatable foods elicits neurologic responses very similar to neurologic responses elicited by illicit drug use. Repeated consumption of energy-dense foods and fast foods may alter mesolimbic pathways and lead to addictive behaviors. It has been hypothesized that consumption of salty processed foods activates areas in the brain that elicit a hedonic reward followed by cravings for more salty, processed foods, similar to responses of opiate use (10). The scientific community has not reached consensus that certain foods, such as fast food, are addictive (11); however, the cortical activation patterns after viewing food among obese individuals are similar to patterns seen in drug-addicted individuals (8). Is Obesity an Independent Risk Factor for CKD? Obesity, especially morbid obesity, seems to be a very strong risk factor for future risk of ESRD when obesity is present during young adulthood. Between 1964 and 1985, 320,252 adults ages 18–34 years old volunteered for screening health evaluations in a large health care system. When participants had been followed for 15–34 years and were 33–68 years old, morbid obesity (BMI$40 kg/m2) was associated with a 6-fold higher risk of ESRD compared with that in individuals with an ideal BMI (18.5–24.9 kg/m2). Among the young adults with baseline CKD, morbid obesity was associated with a 3-fold higher risk of ESRD compared with that in individuals with an ideal BMI (18.5–24.9 kg/m2) Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 and baseline CKD (12). Similar associations were noted between overweight and obesity during adolescence and risk for developing ESRD during midlife (13). Studies that used older cohorts with more recent follow-up time periods have found much weaker associations between obesity and ESRD risk (14–16) and suggested that the association between obesity and ESRD risk is limited to individuals with metabolic syndrome and/or elevated BP (14,16). Among 21,840 participants in the Reasons for Geographic and Racial Differences in Stroke Study, a cohort with a mean baseline age of approximately 65 years old followed for 6.361.3 years, 247 developed ESRD. Participants who were obese defined by a BMI$30 kg/m2 had an approximately 2-fold higher risk for ESRD compared with participants with an ideal BMI after adjustment for covariates, but this association was limited to individuals with metabolic syndrome (14). Measures of abdominal obesity, such as increased waist circumference or waist to hip ratio, are more consistently associated with ESRD risk compared with BMI (17–19). BMI reflects muscle mass and visceral and peripheral adipose tissue, whereas measures of abdominal adiposity reflect visceral fat, a strong risk factor for development of insulin resistance (20). However, regardless of the measurement methods, the presence of obesity among older adults (e.g., 60 years old and older) only modestly increases the risk of ESRD, and associations are largely caused by the confounding effects of hypertension and diabetes (14,15). In contrast, obesity, especially morbid obesity, during adolescence or young adulthood extrapolates to a prolonged period of exposure to obesity-related comorbidities that increase CKD risk (e.g., metabolic syndrome, diabetes, and hypertension). This prolonged effect of obesity takes place along with the potentially independent effects of obesity on kidney functional parameters as discussed below (Figure 1). Thus, public health efforts to curb the epidemic of CKD should include obesity prevention and treatment programs that target adolescents and young adults. Such programs that target young adults will not only help retard CKD incidence (21) but also, will reduce cardiovascular disease frequency and lengthen the life expectancy of young adults (22–24). Weight loss for older obese adults (age .60 years old) may also provide health benefits, but the overall public health benefits of obesity prevention are much larger for young individuals who have several decades of life ahead of them. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Figure 1. Hypothesized model for time of obesity onset and future risk for ESRD. Obesity during young adulthood versus older age translates to a longer cumulative exposure to obesity-related factors. On the basis of data from refs. 12–15. Obesity and Hyperfiltration The kidneys are remarkable organs that adapt readily to changes in caloric intake and metabolic rate (25,26). With weight gain, metabolic rate, glomerular diameter, GFR, and renal plasma flow (RPF) all increase (27) along with regional blood flow, arterial pressure, and cardiac output (28,29). The greater GFR frequently noted in obese individuals has been called hyperfiltration, a term previously described in association with diabetes and pregnancy, where GFR increases to a level higher than normal, generally two SDs above the normal for healthy individuals (30). Indexing GFR for body surface area usually eliminates the higher GFR noted in the obese state; therefore, the higher GFR noted with obesity is not a pathophysiologic state per se. However, nephron number is set at birth, and therefore the increase in total GFR with weight gain occurs at the expense of increasing single-nephron GFR (SNGFR). It is often suggested that obesity-related hyperfiltration is analogous to the 5/6th remnant kidney model, in which hyperfiltration is thought to be mediated by increases in both glomerular capillary RPF rate and mean glomerular capillary hydraulic pressure caused by adaptive reductions in preglomerular and postglomerular arteriolar resistances. The increase in glomerular capillary pressure (PGC) has been ascribed to a greater dilation of the afferent than the efferent arteriole that results in a relative efferent vasoconstriction, giving rise to glomerular hypertension (31–34). However, hyperfiltration can also be achieved through coordinated increases in glomerular filtration surface area (hypertrophy) and increases in single-nephron RPF through proportionate afferent and efferent vasodilation without significant glomerular 285 hypertension. Indeed, recent data suggest that glomerular hypertrophy along with increases in RPF are the dominant mechanisms by which hyperfiltration is achieved in normotensive states. In fact, glomerular hypertension may not even be effective in increasing SNGFR because of the inverse relationship between PGC and the ultrafiltration coefficient (Kf), the product of hydraulic conductivity and glomerular capillary surface area (35). The link between glomerular hypertrophy and hyperfiltration was recently addressed by Lenihan et al. (36). Using kidney donation as a model, the increased GFR in the remaining kidney after kidney donation was shown to be mainly a function of increasing Kf as determined by renal cortical volume measured pre- and postkidney donation by magnetic resonance imaging and an estimation of nephron number from a core biopsy specimen obtained from the donated kidney. Hence, the expected increase in Kf when accompanied by increased RPF facilitates the requisite increase in GFR without a pathologic increase in PGC. In other words, it is like growing glomeruli in situ. However, it should be noted that, in the obese state, increases in RPF tend to lag behind the increase in GFR. Kwakernaak et al. (37) previously summarized the numerous studies that examined GFR, effective renal plasma flow (ERPF), and the GFR to RPF ratio or filtration fraction (FF) by obesity status and found fairly consistent associations between obesity status and greater FF across studies. Increased FF reflects a disproportionate increase in GFR relative to RPF and has been considered a proxy for glomerular hypertension. The theory that increased FF equates with glomerular hypertension is on the basis of micropuncture data in certain colonies of Munich Wistar rats. In these animals, ultrafiltration concludes before the end of the glomerular capillaries when filtration pressure equilibrium has been achieved and net ultrafiltration pressure equals zero. In other words, these rats do not completely use the available glomerular capillary surface area for ultrafiltration. In contrast, humans, large animals (dogs), and other rat strains seem to use the entire glomerular capillary surface area for filtration, a state of filtration pressure disequilibrium. In filtration pressure disequilibrium states, any decrease in RPF, even if caused by proportional increases in afferent and efferent resistance, may increase FF without an increase in PGC. Additionally, assuming that greater FF in humans reflects glomerular hypertension is 286 problematic, because PGC correlates poorly with SNGFR because of the aforementioned inverse relationship with Kf (35). Susceptibility to Obesity-Mediated CKD The increase in SNGFR as a result of unilateral nephrectomy for kidney donation or during pregnancy exceeds the more modest increases in SNGFR as a result of the obese state. This modest increase in SNGFR in the obese state may explain the overall low risk of kidney disease among obese individuals given the absence of diabetes or hypertension. Similarly, PGC unlikely increases in most patients after kidney donation, and this may explain why the absolute risk of ESRD among kidney donors is low, albeit higher than in nonkidney donors, despite the presence of glomerular hyperfiltration in the nondonated kidney (36,38,39). Hence, obesity-associated hyperfiltration itself is likely not sufficient for development of CKD, and additional factors are required to induce susceptibility and injury, such as reduced nephron mass. Total GFR is the product of SNGFR, with total nephron number having a Gaussian distribution with a mean centered around 1,000,000 (40). After kidney donation, the remaining kidney hypertrophies and renocortical volumes increase, reflecting an increase in glomerular capillary surface area to augment filtration surface area and GFR. Similarly, as an individual gains weight, GFR must increase further to match metabolic demands. Consequentially, individuals at the low end of the spectrum of nephron number may be at particular risk for obesity-related nephropathy. Augmentation of SNGFR with weight gain in the setting of reduced nephron number may require a degree of vasodilation of the afferent arteriole that compromises the normal vasoconstrictive response to elevations in systemic BP. This impairment in renal autoregulatory capacity/efficiency results in enhanced transmission of systemic pressure to the glomerular capillaries, and glomerular hypertension results in obesity–related glomerular sclerosis (32,41). Similarly, the greater increases in glomerular hypertrophy require that terminally differentiated podocytes envelop a larger glomerular capillary surface area. It has been postulated that podocytes provide mechanical support against PGC. Accordingly, a reduction in podocyte density may compromise the ability to withstand mechanical stress, particularly during PGC elevations (42,43). In moderate glomerular hypertrophy, the increase in glomerular capillary surface area is usually accomplished by increases in glomerular Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 capillary length without an increase in diameter. However, with more extreme glomerular enlargement, increases in both glomerular capillary length and diameter occur. Thus, on the basis of the Law of LaPlace, in which wall tension increases as a function of glomerular diameter at constant PGC, there is increased susceptibility for the development of glomerulosclerosis (44). In addition, when the glomerular radius can increase no further in the face of increasing PGC, wall tension must increase with equivalent pathobiology. Management of Obese Patients with CKD Because obesity has been proposed as a high-risk state for glomerular hypertension, blockade of the renin-angiotensin-aldosterone system has been suggested as the primary treatment for obesity-associated hypertension. The relatively lower ERPF observed in the obese state may be more dependent on angiotensin, because changes in ERPF observed with use of angiotensin–converting enzyme inhibitors (ACEIs) are significantly higher among obese individuals compared with lean or overweight individuals (BMI,30 kg/m2) (45). Medications that block the renin-angiotensin-aldosterone system show renal protective effects for obese and nonobese adults with established proteinuria. However, superior benefits from ACEIs or angiotensin receptor blockers (ARBs) versus diuretics or calcium channel blockers have not been shown in large–scale clinical trials in populations not enriched with adults with CKD. Focusing solely on use of ACEI/ARB medications for BP management in obese adults has limitations. Obesity is a volume-expanded state, and obese individuals frequently have a high salt intake, which will attenuate the BP-lowering effects of drugs that block the reninangiotensin system, such as ACEIs or ARBs (46). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) included over 33,000 individuals 55 years of age and older with mean BMI ¼29.7 kg/m2 (47). ALLHAT showed no difference in the primary outcome of fatal coronary heart disease or nonfatal myocardial infarction by allocation status to chlorthalidone, lisinopril, or amlodipine, regardless of baseline GFR. Risks of ESRD and mortality also did not differ by allocation status to chlorthalidone, lisinopril, or amlodipine (48). However, the lisinopril arm had a 1.15-fold higher relative risk for stroke (95% confidence interval [95% CI], 1.05 to 1.16) and a 1.19fold higher relative risk for heart failure (95% CI, 1.07 to 1.31) compared with chlorthalidone (47). During all of Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 the years of the trial, mean systolic BP was lowest in the chlorthalidone arm. Study outcomes for the amlodipine arm were similar to the chlorthalidone arm, except for an increased risk of heart failure with amlodipine compared with chlorthalidone (relative risk, 1.38; 95% CI, 1.25 to 1.52). Because of impairment of autoregulation, use of calcium channel blockers can accelerate kidney damage in obese adults with hypertension by transmission of systemic pressures to the glomerular capillary, especially if the hypertension is inconsistently controlled (49,50). Salt Restriction The obesity epidemic has been fueled by the industrialization of our diet, and processed foods are not only calorically dense but also, high in salt. Obese individuals will, in general, have a higher salt intake compared with lean individuals (51,52). High salt intake will heighten BP and lead to volume expansion, making BP management more difficult. High salt intake may also accelerate kidney injury by amplifying glomerular hypertrophy with weight gain. Although no study has examined the effect of salt intake on glomerular volume in humans, animal models of renal mass reduction show that salt restriction reduces glomerular hypertrophy and susceptibility to hypertensive injury (53,54). Additionally, research suggests that high salt intake impairs renal autoregulatory responses (55–57), but this remains controversial (58,59). High salt intake may also affect kidney disease through nonhemodynamic pathways. High salt intake magnifies oxidative stress and contributes to renal injury through stimulation of renal cortical NADH– and NADPH–induced superoxide generation (60,61). High salt intake has also been shown to induce fibrogenic pathways through upregulation of TGF-b (62,63). The effect of a high-salt diet on GFR, RPF, and FF may be most operative in overweight or obese adults (44,64). Krikken et al. (64) showed that, when healthy young men transition from a low-sodium (50 mmol/d) to a high-sodium diet (200 mmol/d), GFR, ERPF, and FF increase only among men with BMI .25 kg/m2. It should be noted that only two men in this study had a BMI .30 kg/m2. Thus, dietary recommendations for both overweight and obese individuals with CKD should include salt restriction. Protein Restriction The typical United States diet contains about two times the protein intake recommended by the United States dietary guidelines (65). For patients with CKD, 287 managing proper protein intake remains an important modifiable factor for slowing the rate of CKD progression, but the role of dietary protein in CKD progression may be most operative in adults with obesity and CKD. The current recommended daily allowance for protein intake is 0.8 g/kg healthy body wt (not total body weight) (66). Among obese adults, mean protein intake exceeds 100 g protein per day. Assuming a healthy body weight of 70 kg, 100 g of protein intake per day equates to an obese individual consuming at least 1.43 g protein per 1 kg healthy body wt or approximately 80% more protein intake than the recommended daily allowance (67). The effect of animal protein intake on glomerular hemodynamics was shown several decades ago (68). Both ERPF and GFR increase by at least 30% when healthy persons transition from a low–animal protein diet to a high– animal protein diet (68). These hemodynamic effects are limited to animal protein, because increasing vegetable protein intake does not increase RPF (69). Friedman et al. (70) elegantly showed that hyperfiltration in obese patients is not mediated by protein intake. However, high–animal protein intake may heighten PGC through afferent dilation as a function of amino acids triggering multiple humoral and local mediators (69,71–73). Afferent vasodilation will enhance transmission of systemic pressures to the glomerular capillary in obese individuals who are frequently hypertensive. Among adults with established CKD, moderate protein restriction (approximately 0.7 g/kg per day) compared with a standard protein intake (approximately 1.0 g/kg per day) is associated with a 0.53-ml/min per year (95% CI, 0.08 to 0.98) lower GFR decline compared with a standard protein intake, but stronger effects are noted in adults with diabetes, a group with a high prevalence of obesity (74). High intake of animal protein combined with low intake of fruits and vegetables is the most common dietary pattern among United States adults (75), and it translates to high net endogenous acid production (76). Higher net endogenous acid production increases reninangiotensin system activity and the amount of hydrogen ions that individual nephrons must excrete to maintain acid-base balance (77). Sodium bicarbonate supplementation will help counteract higher net endogenous acid production. However, increasing fruit and vegetable intake will not only reduce net endogenous acid production but also increase the fiber content of the diet. Dietary fibers are generally the plant cell wall polysaccharides that remain undigested by gastrointestinal tract enzymes (78). High–fiber diet content reduces total 288 caloric intake without major disruptions in satiety, thereby facilitating weight loss and/or weight maintenance (79). High-fiber foods, such as whole grains, legumes, fruits, and vegetables, have the added benefit of reducing systemic inflammation (80,81), which may potentially affect CKD incidence and progression (82–85). It has been postulated that diets high in fiber reduce systemic inflammation by facilitating the growth of endosymbiotic bacteria colonizers of the gut, such as Bifidobacterium, which inhibit intestinal colonization by gram-negative pathogens and reduce the formation of endotoxins and end products of urease-producing bacteria (79,86,87). Reduction of bacterial end products leads to more junctional proteins at intestinal epithelial zonula occludens, thereby decreasing paracellular gut wall permeability and the likelihood of translocation of bacteria and endotoxins from intestinal lumen to the systemic circulation (88). Although no specific recommendations for dietary fiber intake exist for adults with CKD, the American Dietetic Association recommends 14 g dietary fiber per 1000 kcal per day (78). These reference intakes may confer benefits for patients with CKD, but serum potassium and phosphate levels should be monitored. Caloric Restriction Multiple studies have consistently shown a link between abdominal obesity and increased urine protein (mainly albumin) excretion across a wide range of patient populations (89–92). Higher urine protein excretion generally correlates with a faster rate of GFR decline for the majority of kidney diseases (93–95). Although intensive BP lowering reduces urine protein excretion (96,97), caloric restriction and weight loss are also effective interventions that lower urine protein excretion among adult patients, regardless of BP (98,99). For example, caloric intake during the first 6 months after bariatric surgery is markedly limited. Notably, although this weight loss does not reverse morbid obesity by 6 months, GFR, ERPF, and urine protein excretion decline significantly compared with prebariatric surgery levels (98,100). One pathway that mechanistically reconciles how caloric restriction reduces protein excretion is the Sirt1Foxo1 pathway (101). Sirt1 is an NAD1-dependent deacteylase (102) that is abundantly expressed in the renal inner medulla and activates the cell cycle protein Foxo1 (103). Activated Foxo1 forms a transcriptional complex with CCAAT/enhancer binding protein a Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 (C/EBP-a) the adiponectin gene promoter site, thereby upregulating gene expression of adiponectin (104). Adiponectin receptors reside on podocytes and likely play a role in podocyte morphology, function, and response to injury (105–107). In a study of 30 overweight and obese adults with proteinuria and proteinuric kidney diseases (both with and without diabetes), eliminating 500 kcal/d for 5 months decreased urine protein excretion by 30%, despite achieved weight loss of only 4% of baseline weight (108). Moreover, the decline in urine protein excretion occurred as early as 1 month after initiation of caloric restriction (108,109). Consistent caloric restriction combined with an increased or stable physical activity level will lead to weight loss. Drastic weight loss is not required to positively affect CKD, and in some patients, the detrimental effects of obesity, especially with morbid obesity, may be reversible. A systematic review that included 522 adults from clinical trials and cohort studies of dietary interventions and bariatric surgery disclosed that every 1 kg of intentional weight loss, regardless of intervention, led to a decrease in urine protein excretion of approximately 110 mg (95% CI, 60 to 160 mg) and a decrease in urine albumin excretion of 1.1 mg (95% CI, 0.5 to 2.4 mg) (110). Clinically meaningful changes in GFR measures are limited to individuals with baseline morbid obesity, hyperfiltration, and substantial weight loss with bariatric surgery (110). Interventions for Obese Patients with CKD It remains controversial whether persons with established CKD, especially advanced CKD and dialysisdependent CKD, will benefit from caloric restriction. The effect of obesity on CKD and mortality differs by age, presence of obesity-related comorbidities, such as hypertension and diabetes, and expected years of survival. Other factors, including patient preference and nutritional status, must also be considered when determining the risks and benefits of weight loss for an individual patient. In an older patient with limited years of remaining life, the benefits of weight loss will unlikely outweigh the risks. Several review articles have provided outlines for weight management strategies in obese patients with CKD and may help guide clinicians to initiate discussions with their patients (111–113). Certainly, weight management interventions should include approaches that increase physical activity levels. However, given the limited time for a clinic visit and the multiple aspects of CKD care that must be discussed, 289 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 most clinicians will struggle to adequately discuss nutritional interventions with their obese patients with CKD. Fortunately, the Affordable Care Act expanded preventive services, including medical nutritional therapies, for people receiving Medicare. These preventive services are now provided with no out-of-pocket expenses. Medicare will pay for three visits per year for medical nutritional counseling services with a registered dietician or nutritionist for Medicare Part B enrollees with diabetes, with CKD, or in persons who received a kidney transplant within 3 years of the clinic visit (114). During the first year, patients are eligible for 3 hours of either face-to-face counseling or counseling through an interactive telecommunications system. During subsequent years, patients are eligible for 2 hours of annual counseling. Unfortunately, younger patients with nondialysis CKD are not covered by Medicare. These individuals may benefit greatly from nutritional counseling services, but cost frequently precludes the acquisition of these services. Peer-to-peer support facilitates weight loss, and a multitude of online support systems exist and are relatively inexpensive. Weight Watchers and other weight loss programs that include peer support systems can be effective but may not be affordable for some patients. Weight Loss and Bariatric Surgery For morbidly obese individuals, dietary interventions fail and fail consistently. For morbidly obese patients with CKD, many clinicians are hesitant to pursue bariatric surgery for obesity management given the lack of large–scale clinical trials showing safety in this population. During years 2002–2011, in total, 1114 patients with dialysis-dependent CKD and 395 recipients of kidney transplants underwent bariatric surgery for obesity management in the United States. Most surgeries were done by open or laparoscopic bypass procedures. The mean BMI of these patients before surgery was 42.1 kg/m2, and the maximum weight loss was achieved at 18 months, with mean BMI plateauing around 35 kg/m2 (115). The 30-day postoperative mortality rate was 1.3%, similar to mortality rates among patients without CKD. After 3 years, survival rates were 92% among the recipients of transplants and 79% among patients receiving dialysis (115). Without clinical trial data, evaluating the long-term benefits versus risks of bariatric surgery for obesity management in adults with CKD remains extremely difficult. AKI may occur in up to 8% of patients who have undergone bariatric surgery, and hospital stay, postoperative complications, and kidney stones may be higher in patients with CKD than patients without CKD (116–118). However, bariatric surgery does lead to sustained weight loss (over 3 years) and facilitates kidney transplantation in obese patients otherwise excluded from transplantation because of body size (115). In a decision analysis of weight loss strategies comparing Roux-en-Y gastric bypass (RYGB) to diet and exercise in patients precluded from transplantation because of obesity, Choudhury et al. (119) determined that RYGB led to shorter transplantation wait times and longer survival compared with diet and exercise. Patients with RYGB and BMI$40 kg/m2 gained 5.4 years of life compared with only 2.8 years of life gained through sustained diet and exercise of at least 2 years. Data from the US Renal Data System showed that .70% of patients with ESRD who underwent bariatric surgery while on a transplant waiting list received a kidney transplant (120). Thus, bariatric surgery alone may facilitate kidney transplantation in a timely manner and improve survival for patients precluded from kidney transplantation because of obesity. Conclusions Obesity remains one of the most important modifiable risk factors for CKD, which is attributable to its tremendous effect on diabetes, hypertension, and multiple aspects of glomerular hemodynamics as well as podocyte function and the response to injury of these cells. At a minimum, patients with CKD should receive medical nutritional counseling with an individualized plan to optimize their diet and reduce intake of processed foods and salt. Diet and exercise frequently fail to enhance weight loss in morbidly obese patients, and bariatric surgery should be considered, especially if morbid obesity precludes kidney transplantation. Public policy efforts to address the obesity epidemic must include the nephrology community, because obesity effects CKD risks and outcomes, kidney transplantation rates, and incidence and prevalence of ESRD. Acknowledgments The authors thank Tom Mattix for his graphical expertise and contribution of a figure to this manuscript. Disclosures None. 290 References 1. Flegal KM, Carroll MD, Ogden CL, Curtin LR: Prevalence and trends in obesity among US adults, 1999-2008. JAMA 303: 235–241, 2010 PubMed 2. Sturm R: Increases in clinically severe obesity in the United States, 1986-2000. Arch Intern Med 163: 2146–2148, 2003 PubMed 3. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W: Annual medical spending attributable to obesity: Payer-and service-specific estimates. 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Transplantation 87: 1167–1173, 2009 PubMed Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Syllabus NephSAP, Volume 14, Number 4, October 2015—CKD and Progression Michael Choi, MD,* Linda Fried, MD, MPH, FASN,†‡ and Sumeska Thavarajah, MD* *Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Marland; † Renal Section, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania; and ‡ University of Pittsburgh Graduate School of Public Health, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania and Nutrition Examination Survey (NHANES III) in 1988–1994 and the NHANES in 1999–2002. By the CKD-EPI creatinine equation, the prevalence of reduced eGFR increased from 4.7% to 6.5% between these two periods. By CKD-EPI creatinine, the prevalence increased from 5.5% to 8.7%, and using CKD-EPI creatinine-cystatin C formula, prevalence increased from 4.4% to 7.1%. After adjustments for changes in the United States population, prevalence ratios for reduced eGFR in the latter versus former surveys were 1.24 (95% confidence interval [95% CI], 1.09 to 1.45), 1.34 (95% CI, 1.15 to 1.67), and 1.33 (95% CI, 1.17 to 1.65) by creatinine, cystatin C, and creatinine-cystatin C, respectively. The prevalence changes of CKD did not include changes in increased urine albumin excretion between time periods. Also, in an accompanying editorial, Hsu and Hsu (2) point out that, more recently, the prevalence of stages 3 and 4 CKD in the NHANES was stable (8.1% in 2001–2002 and 7.8% in 2009–2010). Grams et al. (3) examined the lifetime risks for CKD and ESRD using Markov Monte Carlo models to simulate kidney disease development. Mortality rates were obtained from the National Vitals Statistics Report, mortality risk was obtained from the 2 million person meta-analyses, CKD prevalence was obtained from the NHANES, and ESRD incidence, prevalence, and mortality were obtained from the US Renal Data System. Overall lifetime risks for stages 3a, 3b, 4, and ESRD were 59.1%, 33.6%, 11.5%, and 3.6%, respectively. Women had greater CKD risk but lower ESRD risk. One half of the patients with stage 3a CKD developed it over age 70. Lifetime risks of stages 4 and 5 CKD and ESRD were higher in blacks and developed 10–15 years earlier than in whites. ESRD lifetime risks for white women, white men, black women, and black men were 2.2%, 3.3%, 7.8%, and 8.5%, respectively Learning Objectives 1. To review new information on risk factors for development and progression of CKD 2. To examine new information on screening for CKD and approaches to care for patients with CKD 3. To discuss new research on clinical risk factors for and treatment of cardiovascular disease in CKD 4. To review and describe the new Kidney Disease: Improving Global Outcomes guidelines for lipid management in nondialysis CKD This issue of NephSAP presents an overview of the new information in nondialysis CKD from January of 2013 to October of 2014. The topic of CKD is broad, and one issue cannot cover all new research in CKD. This issue focuses on important areas of clinical relevance to nephrologists. Not covered in this issue of NephSAP are glomerular and tubulointerstitial diseases, transplantation, and divalent ion metabolism, because they have been recently reviewed in other issues of NephSAP. CKD Surveillance and Geographic Variability CKD Prevalence and Lifetime Risk in the United States It is unclear if the prevalence of reduced eGFR, defined as eGFR,60 ml/min per 1.73 m2, in the United State is increasing. Grams et al. (1) examined trends of prevalence of CKD by eGFR calculated using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine, CKD-EPI cystatin C, and CKD-EPI creatininecystatin C equations. CKD prevalence in adult participants was compared between the Third National Health 294 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 295 Figure 1. Lifetime risks for CKD from stage 3a to end- stage renal disease from Markov Monte Carlo models. Cumulative incidence from birth by race and sex of CKD stages (A) 3a1, (B) 3b1, and (C) 3b1 and (D) ESRD. Reprinted with permission from Grams ME, Chow EK, Segev DL, Coresh J: Lifetime incidence of CKD stages 3-5 in the United States. Am J Kidney Dis 62: 245–252, 2013. (Figure 1). Accompanying editorials to that study ask readers to consider CKD screening for blacks (4) and the elderly (5). For those .80 years old, an analysis of the NHANES data between 1988–1994 and 2005–2010 showed that prevalence of eGFR by CKD-EPI creatinine ,45 ml/min per 1.73 m2 increased from 14.3% to 21.7% (6). CKD Screening and Monitoring in the United States CKD is usually asymptomatic, and awareness of CKD is low among providers and patients with CKD (7). Komenda et al. (8) performed a systematic review of the cost-effectiveness of CKD screening in the general population as well as in hypertensive and diabetic populations. There were eight studies that evaluated the cost-effectiveness of proteinuria and two studies that evaluated screening with eGFR. In general, the threshold for an intervention considered as cost-effective is ,$50,000 per quality–adjusted life year (QALY) gained. Incremental cost–effectiveness ratios for proteinuria screening had ranges from $14,063 to $160,018 per QALY in the general population, from $5,298 to $54,943 per QALY in the diabetic population, and from $23,680 to $73,939 per QALY in the hypertensive population. In patients with diabetes, one study for eGFR screening reported a cost of $23,680 per QALY versus $100,253–$109,912 per QALY in two studies of the general population. The cost-effectiveness of screening various populations was determined by estimates of the incidence of CKD in the population studied, the estimated rate of progression in that population, and the effectiveness of drug therapy for slowing progression. Komenda et al. (8) concluded that CKD screening is cost-effective in patients with diabetes and hypertension. The US Preventive Task Force’s systematic review concluded that there was insufficient evidence to screen asymptomatic adults (9). The American College 296 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Table 1. American College of Physicians clinical practice guidelines for CKD Reprinted with permission from Qaseem A, Hopkins RH Jr., Sweet DE, Starkey M, Shekelle P; Clinical Guidelines Committee of the American College of Physicians: Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians. Ann Intern Med 159: 835–847, 2013. of Physicians (ACP) published clinical practice guidelines for screening, monitoring, and treatment of adults with stages 1–3 CKD on the basis of a systematic evidence review (Table 1) (10). The first guideline did not recommend screening for CKD in asymptomatic adults without risk factors for CKD. The major risk factors for CKD listed included diabetes, hypertension, and cardiovascular disease. Other risk factors listed were older age, obesity, family history, and black, NativeAmerican, or Hispanic ethnicity. The ACP guideline Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 statement was on the basis of the lack of randomized, controlled trials (RCTs) that compared the effect of systematic CKD screening versus no CKD screening on clinical outcomes, sources of variability for measuring single urinary albumin excretion, and lack of effectiveness of treatment on clinical outcomes of CKD identified through screening. There were no RCTs evaluating harms of systematic screening, but expert opinion– based harms included misclassification with false-positive tests, adverse effects of unnecessary testing, psychologic effects of being labeled with a diagnosis of CKD, potential adverse effects of pharmacologic treatment changes after diagnosis with CKD, and possible financial ramifications of CKD diagnosis. The second guideline opposed the recommendation of testing for proteinuria in adults with or without diabetes currently taking an angiotensin– converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB). As above, the guidelines found no trials that evaluated clinical outcomes for patients with stages 1 and 2 CKD who were systematically monitored for worsening kidney function versus no CKD monitoring, usual care, or an alternative CKD monitoring regimen. There were no RCTs that compared harm for those monitored versus no monitoring, usual care, or an alternative CKD monitoring regimen. Potential harms included incorrect reclassification with possibly increased financial costs attributable to a diagnosis of more advanced CKD, adverse effects of unnecessary testing, psychologic effects of being labeled as having CKD, and adverse events associated with medication changes. Other published guidelines agree on targeted screening for those at risk rather than general population screening. A letter to the editor of the ACP guidelines asked why the language for screening was written as a negative (who not to screen rather than a recommendation as a declarative statement as to who should be screened) (11). Perhaps this was because the ACP guideline statement found insufficient evidence to directly recommend screening for CKD in asymptomatic adults, even those with CKD risk factors, which Qassem et al. (12) reiterated in a separate article on CKD screening. However, the ACP guideline statement did not go so far as to suggest limiting screening to only symptomatic patients with CKD risk factors. The United States Preventive Services Task Force systematic review of the ACP guideline did acknowledge that most persons with CKD stages 1 to 3, even those with diabetes and hypertension, are not clinically recognized and do not have CKD testing in usual care. 297 Hellemons et al. (13) found low adherence by primary care providers to nationwide screening guidelines for annual albuminuria testing and treatment of albuminuria with renin-angiotensin-aldosterone system (RAAS) blockers. This issue was studied in a cohort of 14,210 patients with type 2 diabetes from The Netherlands. The urine albumin to creatinine ratio was measured in 56.8% of patients in 2009; ,25% had annual screening, and .20% were never screened. RAAS treatment was prescribed in 78% with prevalent microalbuminuria/macroalbuminuria, 66.5% with incident microalbuminuria/macroalbuminuria, 59.3% with normoalbuminuria, and 52.1% of those without albumin to creatinine ratio measurements. The second ACP guideline to forego monitoring proteinuria for those on RAAS blockade with or without diabetes contrasts with recommendations from other societies. The American Diabetes Association recommends annual screening for albuminuria in patients with diabetes and continued monitoring for albuminuria with treatment (14). The international Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for CKD also advocates for at least yearly monitoring for CKD progression (15). The KDIGO CKD guideline did not specifically address screening, but the national Kidney Disease Outcomes Quality Initiative (KDOQI) commentary on the KDIGO CKD clinical practice guideline specifically disagreed with the ACP recommendation to cease monitoring proteinuria after RAAS blockers had been initiated. The KDOQI group felt that monitoring proteinuria for prognosis and not just treatment was important (16). Editorials pointed out that monitoring proteinuria would allow for possibly increasing RAAS blockade if significant proteinuria persisted after the initial dose (17,18). Although hyperkalemia and AKI were acknowledged as potential harms of RAAS blockade, there was no formal ACP guideline statement about rechecking potassium and eGFR after patients had begun RAAS blockade. The prudence of rechecking these values in patients taking a combination of RAAS blockers, diuretics, and nonsteroidal anti– inflammatory drugs, the combination of which can increase the incidence of AKI, was also advocated in response to the ACP guideline (17,19). Qaseem et al. (12) did acknowledge that SCr levels should checked for adverse effects after RAAS blockade in a separate screening article. In addition, the ACP guideline recommends the use of ACEIs or ARBs in patients with hypertension and stages 1–3 CKD, regardless of the level of albumin excretion. The KDIGO guidelines differ in 298 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 recommending ACEIs or ARBs for adults with diabetes with urine albumin .30 mg/24 h or adults without diabetes with urine albumin .300 mg/24 h (15). The ACP guideline recommended initiating a statin if elevated LDL values are above goal. This contrasts with the KDIGO Work Group recommendations on lipid management of patients of CKD and will be reviewed in the cardiovascular section of this NephSAP (20). The ACP guidelines correctly emphasize the indirect costs of screening in those who have false-positive tests. However, the reliance on RCTs for judging the efficacy of CKD screening by changes in mortality and ESRD may be problematic in a population screened with early to moderate CKD, because CKD is generally a slowly progressive disease, in which rapid progression is often defined as loss of eGFR.3–5 ml/min per 1.73 m2 per year. Interventions in well established CKD require many years of follow-up to show changes in outcome. Recommending screening to primary care providers for asymptomatic patients at risk for CKD seems prudent as does the continued monitoring of proteinuria with or without RAAS blockade. countries. In Taiwan in 2003, with a budget of $15 million/yr, a campaign was initiated to ban herbs with aristolochic acid, increase public awareness, educate patients, and set up integrated care teams for patients with CKD. Annual incidence for ESRD decreased from 432 per million population in 2005 to 361 per million population in 2010 (25). The program resulted in a savings of $36 million annually with reduced dialysis costs and improved quality of life. In Uruguay and Chile, the initiation of prevention programs has resulted in dramatic decreases in the incidence and prevalence of ESRD. The details of the surveillance programs in developed countries, such as the United States, Europe, Australia, England, and Japan, are discussed in a review by Radhakrishnan et al. (24). An increase in patients referred for planned initiation of dialysis was observed after implementation of a CKD screening and intervention program in England in 2006. Other countries have demonstrated lower rates of ESRD after implementation of similar screening and intervention programs. Hopefully, these programs will reduce complications, deaths, disabilities, and economic burdens associated with CKD throughout the world. Worldwide Surveillance Mesoamerican Nephropathy The number of worldwide deaths between 1990 and 2010 from CKD has increased by 82%, the third largest increase behind HIV and diabetes according to the Global Burden of Disease study (21). This figure may be even higher, because Rao et al. (22) concluded that mortality from diabetic kidney disease was underestimated by 4- to 9-fold. Jha et al. (23) reviewed the global dimension of CKD. Prevalence, which is highest in developed countries, is estimated to be 8%–16% worldwide. CKD risk factors, such as hypertension, diabetes, and obesity, continue to grow in developing countries. It is projected that the number of patients with ESRD will increase disproportionally in the developing countries of India and China, where the number of elderly is increasing. Worldwide, diabetes is still the leading cause of CKD in developed and many developing countries. However, in many parts of the world, CKD affects younger people, 40% of who do not have diabetes or hypertension (24). GN and other causes, such as herbal and environmental toxins, are important causes of CKD in developing countries. The poorest populations are at the highest risk for CKD. Unfortunately, many of those who develop ESRD in these countries cannot afford RRT. Screening and intervention strategies have been implemented, resulting in reduction of incidence of ESRD in developing Unexplained kidney disease was first noted in the early 1990s in Costa Rican sugarcane workers. This epidemic of CKD has been named Mesoamerican Nephropathy, and findings of the First International Research Workshop on Mesoamerican Nephropathy were reported (26). In their extensive review of the literature, Correa-Rotter et al. (27) describe this disease, which affects young men who are agricultural workers, especially those working in sugarcane fields, and reside in communities along the Pacific coast of Central America. Working in extreme heat is a common condition, and the patients with this progressive form of CKD are often asymptomatic, with normal to slightly elevated BP and low-grade or non-nephrotic proteinuria. These patients often manifest hyperuricemia and/or surprisingly, hypokalemia. A series of eight patients with eGFR creatinine of 27–79 ml/min per 1.73 m2 underwent renal biopsy (28). There was extensive glomerulosclerosis (29%–78%) with signs of chronic glomerular ischemia, tubular atrophy, and interstitial fibrosis with vascular lesions. Podocytes showed glomerular injury, and six of eight specimens revealed the variable presence of podocyte vacuolization. These features are similar to a CKD epidemic in Sri Lanka (29). Also, Mesoamerican Nephropathy has more extensive glomerular involvement Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 compared with Balkan and Chinese Herb Nephropathy. Correa-Rotter et al. (27) concluded that the histologic patterns were consistent with glomerular ischemia. Potential causes for the epidemic include heat stress with volume depletion. In an animal model of CKD generated by repeated episodes of dehydration, increased serum osmolality–stimulated aldose reductase activity converted glucose to sorbitol and fructose for additional metabolism by fructokinase to oxidant mediators (30). Notably, sugar cane workers often take high fructose– containing beverages as well as nonsteroidal anti– inflammatory drugs. Arsenic in drinking water, pesticides, Leptopirosis, and genetic susceptibility were also possible mediators of the disease. References 1. Grams ME, Juraschek SP, Selvin E, Foster MC, Inker LA, Eckfeldt JH, Levey AS, Coresh J: Trends in the prevalence of reduced GFR in the United States: A comparison of creatinine- and cystatin C-based estimates. Am J Kidney Dis 62: 253–260, 2013 PubMed 2. Hsu RK, Hsu CY: Temporal trends in prevalence of CKD: The glass is half full and not half empty. Am J Kidney Dis 62: 214–216, 2013 PubMed 3. 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Fink HAIA, Ishani A, Taylor BC, Greer NL, MacDonald R, Rossini D, Sadiq S, Lankireddy S, Kane RL, Wilt TJ: Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: A systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 156: 570–581, 2012 PubMed 10. Qaseem A, Wilt T, Denberg TD: Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease. Ann Intern Med 161: 83–84, 2014 PubMed 11. Stefan N, Artunc F, Heyne N, Machann J, Schleicher ED, Häring HU: Obesity and renal disease: Not all fat is created equal and not all obesity is harmful to the kidneys [published online ahead of print April 20, 2014]. Nephrol Dial Transplant PubMed 12. Qaseem A, Wilt TJ, Cooke M, Denberg TD: The paucity of evidence supporting screening for stages 1-3 CKD in asymptomatic patients with or without risk factors. Clin J Am Soc Nephrol 9: 1993–1995, 2014 PubMed 13. Hellemons ME, Denig P, de Zeeuw D, Voorham J, Lambers Heerspink HJ: Is albuminuria screening and treatment optimal in patients with type 2 diabetes in primary care? Observational data of the GIANTT cohort. Nephrol Dial Transplant 28: 706–715, 2013 PubMed 14. American Diabetes Association: Executive Summary: Standards of Medical Care in Diabetes –2014 Diabetes Care 37: Supplement 1 S5– S13; 2014 PubMed 299 15. KDIGO CKD Work Group: KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 3: 1–150, 2013 16. Inker LAAB, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura M, Feldman HI: KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD. Am J Kidney Dis 63: 713–735, 2014 PubMed 17. Abdel-Kader K: Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease. Ann Intern Med 161: 83, 2014 PubMed 18. Lambers Heerspink HJ, Gaillard CJ, Gansevoort RT: Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease. Ann Intern Med 161: 82–83, 2014 PubMed 19. Lapi F, Azoulay L, Yin H, Nessim SJ, Suissa S: Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: Nested case-control study. BMJ 346: e8525, 2013 PubMed 20. KDIGO Lipid Work Group: KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Int Suppl 3: 259–305, 2013 21. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, Alvarado M, Anderson HR, Anderson LM, Andrews KG, Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D, Bhalla K, Bikbov B, Bin Abdulhak A, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C, Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD, Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, de Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD, Forouzanfar MH, Fowkes FG, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E, Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R, Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns N, Karthikeyan G, Kassebaum N, Keren A, Khoo JP, Knowlton LM, Kobusingye O, Koranteng A, Krishnamurthi R, Lipnick M, Lipshultz SE, Ohno SL, Mabweijano J, MacIntyre MF, Mallinger L, March L, Marks GB, Marks R, Matsumori A, Matzopoulos R, Mayosi BM, McAnulty JH, McDermott MM, McGrath J, Mensah GA, Merriman TR, Michaud C, Miller M, Miller TR, Mock C, Mocumbi AO, Mokdad AA, Moran A, Mulholland K, Nair MN, Naldi L, Narayan KM, Nasseri K, Norman P, O’Donnell M, Omer SB, Ortblad K, Osborne R, Ozgediz D, Pahari B, Pandian JD, Rivero AP, Padilla RP, Perez-Ruiz F, Perico N, Phillips D, Pierce K, Pope CA 3rd, Porrini E, Pourmalek F, Raju M, Ranganathan D, Rehm JT, Rein DB, Remuzzi G, Rivara FP, Roberts T, De León FR, Rosenfeld LC, Rushton L, Sacco RL, Salomon JA, Sampson U, Sanman E, Schwebel DC, Segui-Gomez M, Shepard DS, Singh D, Singleton J, Sliwa K, Smith E, Steer A, Taylor JA, Thomas B, Tleyjeh IM, Towbin JA, Truelsen T, Undurraga EA, Venketasubramanian N, Vijayakumar L, Vos T, Wagner GR, Wang M, Wang W, Watt K, Weinstock MA, Weintraub R, Wilkinson JD, Woolf AD, Wulf S, Yeh PH, Yip P, Zabetian A, Zheng ZJ, Lopez AD, Murray CJ, AlMazroa MA, Memish ZA: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet 380: 2095–2128, 2012 PubMed 22. Rao C, Adair T, Bain C, Doi SA: Mortality from diabetic renal disease: A hidden epidemic. Eur J Public Health 22: 280–284, 2012 PubMed 23. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW: Chronic kidney disease: Global dimension and perspectives. Lancet 382: 260–272, 2013 PubMed 24. Radhakrishnan J, Remuzzi G, Saran R, Williams DE, Rios-Burrows N, Powe N, Brück K, Wanner C, Stel VS, Venuthurupalli SK, Hoy WE, Healy HG, Salisbury A, Fassett RG, O’Donoghue D, Roderick P, Matsuo S, Hishida A, Imai E, Iimuro S; CDC-CKD Surveillance Team; 300 25. 26. 27. 28. 29. 30. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 European CKD Burden Consortium; CKD.QLD group: Taming the chronic kidney disease epidemic: A global view of surveillance efforts. Kidney Int 86: 246–250, 2014 PubMed Wei SYCY, Chang YY, Mau LW, Lin MY, Chiu HC, Tsai JC, Huang CJ, Chen HC, Hwang SJ: Chronic kidney disease care program improves quality of pre-end-stage renal disease care and reduces medical costs. Nephrology (Carlton) 15: 108–115, 2010 PubMed Wesseling C, Crowe J, Hogstedt C, Jakobsson K, Lucas R, Wegman DH; First International Research Workshop on the Mesoamerican Nephropathy: Resolving the enigma of the mesoamerican nephropathy: A research workshop summary. Am J Kidney Dis 63: 396–404, 2014 PubMed Correa-Rotter R, Wesseling C, Johnson RJ: CKD of unknown origin in Central America: The case for a Mesoamerican nephropathy. Am J Kidney Dis 63: 506–520, 2014 PubMed Wijkström J, Leiva R, Elinder CG, Leiva S, Trujillo Z, Trujillo L, Söderberg M, Hultenby K, Wernerson A: Clinical and pathological characterization of Mesoamerican nephropathy: A new kidney disease in Central America. Am J Kidney Dis 62: 908–918, 2013 PubMed Athuraliya NTAT, Abeysekera TD, Amerasinghe PH, Kumarasiri R, Bandara P, Karunaratne U, Milton AH, Jones AL: Uncertain etiologies of proteinuric-chronic kidney disease in rural Sri Lanka. Kidney Int 80: 1212–1221, 2011 PubMed Roncal Jimenez CAIT, Ishimoto T, Lanaspa MA, Rivard CJ, Nakagawa T, Ejaz AA, Cicerchi C, Inaba S, Le M, Miyazaki M, Glaser J, CorreaRotter R, González MA, Aragón A, Wesseling C, Sánchez-Lozada LG, Johnson RJ: Fructokinase activity mediates dehydration-induced renal injury. Kidney Int 86: 294–302, 2014 PubMed Issues in GFR and Albuminuria Estimation The exact role for cystatin C in GFR estimation is debated (1,2). As reviewed in the last NephSAP CKD issue, the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease recommended using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation instead of the four–variable Modification of Diet in Renal Disease (MDRD) equation. KDIGO also recommended the use of cystatin C alone or combined with creatinine in the 2012 CKD-EPI equations to avoid overdiagnosis of CKD in individuals with stage 3a CKD without other markers of kidney damage (3). An important goal for an eGFR equation using an endogenous filtration marker, such as creatinine or cystatin C, is how well an equation predicts clinical outcomes. An equally important but not necessarily parallel criterion is the formula’s accuracy compared with measured GFR with an exogenous marker. Risk prediction by eGFR with cystatin C seems superior to that by eGFR with creatinine. The Chronic Kidney Disease Prognosis Consortium included 90,750 participants from the general population and 2960 participants with CKD. Shlipak et al. (2) compared the association of eGFR using creatinine, cystatin C, or both with the outcomes of death, cardiovascular death, and ESRD as well as reclassification. Relative accuracy between these eGFR formulas could not be assessed, because measured GFR was not available. Cystatin C assay was calibrated to the international reference standard. Reclassification of eGFR to an improved GFR category by cystatin C compared with creatinine was associated with reduced risk in all outcomes, and similarly, reclassification to a worse eGFR category by cystatin C was associated with increased risk. The net reclassification improvement for combining all cohorts for cystatin C versus creatinine was impressively 21% (95% confidence interval [95% CI], 17% to 26%) for death but curiously, not significant for ESRD at 3% (95% CI, 23% to 8%, P¼0.46) and barely significant for predicting ESRD, thereby limiting analysis to general population cohorts at 10% (0%–21%, P¼0.05). Interestingly, the combined cystatin C and creatinine equation did not predict risk of death as well as the cystatin C alone formula, but the combined equation more accurately predicted ESRD. Cystatin C seems to be a better biomarker for mortality than ESRD (Figure 2). eGFR formulas may be superior for predicting adverse clinical outcomes in patients with CKD compared with measured GFR values. Factors other than GFR that alter SCr and cystatin C levels include generation, metabolism, and nonglomerular excretion. There are also surrogates for these determinants, which may track with outcomes better than measured GFR. For example, age is a variable in all eGFR formulas, with the CKD-EPI cystatin C equation having the largest contribution from age. Non-GFR determinants of cystatin C may be altered by factors such as inflammation, obesity, and atherosclerosis. Rule and Glassock (4) evaluated the degree to which risk factors interacted with different eGFR formulas relative to their interaction with measured GFR. There were 1150 participants with iothalamate clearance who had CKD-EPI eGFR calculated by creatinine, cystatin C, or both. One explanation for an improved risk prediction with certain eGFR formulas over measured GFR is that there is variability between measured GFR values compared with the relative stability of eGFR values. However, in the analysis by Rule and Glassock (4), the mean variation for measured GFR in 40 participants who had repeat measurements was similar to the variation in all of the eGFR formulas (8.2%, 6.4%, 8.2%, and 10.7% for measured GFR and CKD-EPI creatinine, creatinine-cystatin C, and cystatin C alone, respectively). Measured GFR was most accurately estimated by the CKD-EPI creatinine-cystatin C 301 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Figure 3. The association of chronic kidney disease risk factors with percentage decrease in glomerular filtration rate (Y GFR) by each method (measured GFR (mGFR), eGFRCr, eGFRCr-CysC, and eGFRCysC. The * identifies P,0.05 for eGFR compared with mGFR using model 1 (generalized estimating equations). Risk factor associations with mGFR were more similar to those with eGFRCr than with eGFRCr-CysC or eGFRCysC. The one exception was 24-h urine creatinine, for which eGFRCysC was more similar to the same association with mGFR. Alb., albumin; BMI, body mass index; Cr, creatinine; CRP, C-reactive protein; CysC, cystatin C; eGFR, estimated GFR. Reprinted with permission from Rule AD, Bailey KR, Lieske JC, Peyser PA, Turner ST: Estimating the glomerular filtration rate from serum creatinine is better than from cystatin C for evaluating risk factors associated with chronic kidney disease. Kidney Int 83: 1173, 2013. Figure 2. Risk prediction of death, cardiovascular death and endstage renal disease by eGFR from serum creatinine, cystatin C or combination. Adjusted hazard ratios for (A) all-cause mortality, (B) cardiovascular death, and (C) ESRD in the general population cohort studies. Reprinted with permission from Shlipak MG, Coresh J, Gansevoort RT: Cystatin C versus creatinine for kidney function-based risk. N Engl J Med 369: 2459, 2013. formula. Body mass index (BMI), albuminuria .30 mg/g, hypertension, diabetes, and C-reactive protein tracked with decreased CKD-EPI by cystatin C and creatinine-cystatin C to a significantly greater degree than their influence on decreased measured GFR. The association of risk factors to lower measured GFR was best approximated by the CKD-EPI creatinine formula (Figure 3). Rule and Glassock (4) maintain that an eGFR equation should be judged on how well its associations with CKD risk factors and outcomes approximate those measured GFR. Cystatin C–based eGFR formulas seem better at predicting CKD complications, perhaps because of nonGFR determinants of serum cystatin C levels. However, unless combined with SCr, eGFR formulas with cystatin C are not more accurate in estimating GFR. Specific Populations Patients with Diabetes and High Normal GFR. As discussed in the last NephSAP CKD issue, the creatinine–based CKD-EPI formula is less likely to misclassify an individual with CKD than the MDRD formula when measured GFR is close to 60 ml/min per 1.73 m2. However, it seems to overestimate GFR in older individuals. There are questions regarding this formula’s 302 accuracy in patients with diabetes on the basis of a small cross–sectional study (5,6). One study compared the performance of creatinine-based formulas with longitudinal iohexol clearance measurements in 600 Italian patients with type 2 diabetes over a median of 4 years (6). The participants followed in the Bergamo Nephrologic Diabetes Complications Trial B Study and the Delapril and Manidpine for Nephroprotection in Diabetic Nephropathy Study were .40 years old and had normo- or microalbuminuria. They underwent serial iohexol measurements every 6 months. Overall, there was weak agreement between measured GFR and eGFR by all of the creatinine-based formulas. The mean biases between eGFR and measured eGFR for the MDRD and CKD-EPI formulas were 216 and 212.5 ml/min per 1.73 m2, respectively. Detection of participants who were hyperfiltering (.120 ml/min per 1.73 m2) at baseline and change in short-term GFR was poor. At baseline, 90 of 600 participants had hyperfiltration by measured GFR, but only 9 were detected by MDRD and 0 were detected by CKD-EPI formulas. The underestimation by eGFR formulas at baseline was greatest with the highest measured GFR values. In addition, eGFR formulas could not predict short- or long-term declines in measured GFR over time. In general, the eGFR formulas underestimated the magnitude of declines in measured GFRs. In 1441 young participants with type 1 diabetes from the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Study, de Boer et al. (7) compared the accuracy of longitudinal changes between iothalamate–based measured GFRs and eGFRs by CKD-EPI creatinine, CKD-EPI cystatin C, and creatinine-cystatin C combined formulas. Mean baseline iothalamate GFR was 122.7621 ml/min per 1.73 m2. In cross-sectional analyses, CKD-EPI creatinine-cystatin C had the highest correlation, precision, and accuracy with measured GFR. In longitudinal analyses, the change in CKD-EPI creatinine-cystatin C correlated best with the change in measured GFR, but the differences between estimating formulas were small. Over a median of 32 years of follow-up, mean rates of change between CKD-EPI creatinine, cystatin, and creatinine-cystatin were 21.37, 21.11, and 21.29 ml/min per 1.73 m2 per year, respectively. de Boer et al. (7) concluded that adding cystatin C to creatinine had a modestly greater precision and accuracy versus eGFR on the basis of creatinine alone, but this difference was subtle and may not be meaningful in improving GFR tracking. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 The ability to predict progression to ESRD using 1/SCr, MDRD creatinine, CKD-EPI creatinine, 1/serum cystatin C, CKD-EPI cystatin C, CKD-EPI creatininecystatin, and measured GFR was assessed in 234 Pima Indians with type 2 diabetes. Mean baseline measured GFR was 156 ml/min, with hemoglobin A1C of 9.7, albumin to creatinine ratio (ACR) .30 mg/g, and age of 43 years old (8). During median follow-up of 10.7 years, 29% developed ESRD. After adjustment for age, sex, diabetes duration, weight, hemoglobin A1C, and ACR, the 1/serum cystatin C had the best ability to predict ESRD (receiver operating characteristic- area under the curve¼0.84510.026), whereas measured GFR and 1/SCr had significantly lower predictive abilities (0.81460.28 and 0.81560.28, respectively). After adjustment, CKD-EPI creatinine-cystatin C and cystatin alone formulas were also significantly better predictors than measured GFR. Given the risk with hyperfiltration, it is not surprising that measured GFR would show a J-shaped curve for association with ESRD. Pavkov et al. (8) concluded that increased risk prediction using cystatin C was related to non-GFR determinants, such as inflammation and vascular remodeling. In a study of 778 participants with diabetes in the National Health and Nutrition Examination Survey (NHANES), which compared CKD-EPI cystatin C with the CKD-EPI creatinine formula, the cystatin C equation classified more participants as having reduced kidney function (22.0% versus 16.5%) (9). For those with eGFR values of 15 to 30 ml/min per 1.73 m2 by the cystatin C equation, there was a significantly increased risk of cardiovascular mortality that was not detected by the creatinine equation for those in the same category. In patients with diabetes, the ability of cystatinbased formulas to predict CKD complications seems to be superior to those of creatinine–based eGFR formulas and measured GFR. As above, non-GFR determinants of cystatin C track with risk factors for progression. The CKD-EPI creatinine-cystatin C formula may best approximate measured GFR, but no formula seems to be ideal for detecting hyperfiltration and short-term changes. Asian Populations. The MDRD and CKD-EPI creatinine–based equations may not be as accurate in different populations because of differences in muscle mass from the cohorts used to develop the equations. There are modifications of the MDRD equation for Chinese, Japanese, Thai, and Korean populations (10– 13). The CKD-EPI four–variable ethnicity equation (black, Asian, Native American and Hispanic, white, and other) seemed to show increased accuracy in Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Asian populations, especially in those with eGFR values .60 ml/min per 1.73 m2 (14). In 977 Chinese participants, which included those with CKD as well as healthy volunteers, the 2009 CKD-EPI creatinine equation and modified MDRD creatinine equation for the Chinese population (10) showed less bias, more precision, and greater accuracy than the CKD-EPI four–variable or MDRD creatinine equation compared with measured 99mTc-diethylenetriamine pentaacetic acid clearance (15). It was unclear why the standard CKD-EPI equation outperformed the four–variable MDRD equation, although Kong et al. (15) point out that there were only 100 Asians in the four–level development dataset. There is also a Chinese modification of the CKDEPI creatinine formula (16) that was tested for risk prediction compared with the modified MDRD creatinine equation in Chinese patients who had a stroke. In a large cohort of 15,791 individuals with short follow-up, there was improved risk prediction for all-cause mortality, stroke recurrence, death, or stroke recurrence and disability with the CKD-EPI modified formula (17). There have been attempts to modify cystatin C eGFR equations in the Japanese population. The standard CKD-EPI cystatin C and CKD-EPI creatinine-cystatin C formulas as well as modifications for cystatin C–based formulas were compared with measured inulin clearance. Interestingly, in 763 Japanese individuals with a mean measured GFR of 58 ml/min per 1.73 m2, the standard CKD-EPI cystatin C formula without ethnic modification seemed to perform as well or better than the other formulas (18). In studies reviewed for this issue, population– modified, creatinine–based formulas seem to be better for accuracy of GFR and risk prediction. A modified cystatin C–based formula was not more accurate for GFR estimation compared with the standard CKD-EPI cystatin C formula. Pediatrics. The updated Schwartz equation developed in the Chronic Kidney Disease in Children (CKiD) Cohort of 349 children ages 1–16 years old with a median iohexol measured GFR of 41.3 ml/min per 1.73 m2 has been used to estimate GFR in children with a practical bedside formula of eGFR¼0.413·(height[cm]/SCr) (19). Hoste et al. (20) developed an eGFR formula that could be used in adolescents and young adults with a wider range of GFR values. The formula was validated in a European cohort of 750 individuals ages 10–25 years old with a mean inulin measured GFR of 95 ml/min per 1.73 m2. The formula was eGFR¼107.3/(Scr/(3.94·ht[m]1 303 17.6·ht[m]229.84·ht[m]312.04·ht[m]4 for boys and girls. The new eGFR equation outperformed other creatinine–based formulas, including the Schwartz formula, overall for the spectrum of measured GFR values from ,60 to .90 ml/min per 1.73 m2; however, the updated Schwartz equation performed better in the ,60 ml/min per 1.73 m2 range. Schwartz et al. (21) developed a different combined creatinine and cystatin C equation using the CKiD Cohort, and this new equation was touted to be more accurate than the modified Schwartz creatinine formula. This new formula performs well for GFRs from 15 to 75 ml/min per 1.73 m2 (21), with limitation at higher GFR levels. The combined Schwartz formula eGFR¼ 39.8·(ht[m]/Scr)0.456·(1.8/cystatin C)0.418·(30/BUN)0.0791/ 76male·(ht[m]/1.4)0.179 was compared with a combined serum creatinine-cystatin C formula in 238 children with a median GFR of 86 ml/min per 1.73 m2 measured by sinistrin clearance (22). The equations are 0.42 · (ht[m]/Scr)20.04 · (ht[m]/Scr) 2 214.5 · CysC10.69 · age118.25 for girls and 0.42 · (ht[m]/ Scr)20.04 · (ht[m]/Scr)2214.5 · CysC10.69 · age1 21.88 for boys. The new quadratic combined formula was felt to outperform the combined Schwartz formula, which had poor accuracy for sinistrin-based GFRs .91 ml/min per 1.73 m2. Severe Obesity. Although the KDIGO Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease advocate the use of the CKDEPI creatinine formula over the MDRD formula, it is unclear which formula is superior in obese patients with BMI levels predominantly in the 30- to 35-kg/m2 range (23,24). These two formulas were compared in 366 obese individuals from Europe (50 of African descent) with mean BMIs in the severely obese range of 36 kg/m2 and mean measured chromium-51 ethylenediamine tetraacetic acid GFR of 56 ml/min per 1.73 m2 (2,25). In the overall group, MDRD performed better with less mean bias (11.9614.3 versus 14.6614.7 ml/min per 1.73 m2 for the MDRD and CKD-EPI equations, respectively) and greater accuracy (within 30% of the measured value; 80% for MDRD versus 76% with CKD-EPI). In participants with measured GFR .60 ml/min per 1.73 m2, MDRD again was closer to measured GFR (bias of 14.6618.4 versus 9.3617.2 ml/min per 1.73 m2 and accuracy within 30% [81% versus 79% for MDRD and CKD-EPI, respectively]). This study was performed in a predominantly European cohort with more severe obesity than prior studies that had compared these two formulas. 304 Advanced CKD. The MDRD and CKD-EPI equations were derived from cohorts with mean GFRs of 40 and 69 ml/min per 1.73 m2, respectively. Using the Swedish Renal Registry, Evans et al. (26) examined the performance of various creatinine–based formulas, among them the Cockcroft–Gault, MDRD, and CKD-EPI equations, with measured GFRs in 2098 individuals with stages 4 and 5 CKD. There were 398 participants with measured GFRs ,10 ml/min per 1.73 m2 and 1974 participants with measured GFRs of 11–20 ml/min per 1.73 m2. For the entire cohort, median bias was 1.2, 1.6, and 4.6 ml/min per 1.73 m2 for the CKD-EPI, MDRD, and Cockcroft–Gault formulas, respectively. There was poor accuracy within 30% of measured GFR for all formulas (67%, 65%, and 54%, respectively). Elderly. The accuracy of estimating equations for the elderly is unclear, because cohorts used to develop and validate the MDRD and CKD-EPI formulas had few individuals .65 years old. In previous studies of the elderly, the CKD-EPI creatinine formula seemed to underestimate GFR, resulting in overdiagnosis of CKD. The accuracy of the MDRD, CKD-EPI creatinine, CKDEPI cystatin C, and CKD-EPI creatinine-cystatin C formulas was compared with measured GFR by iohexol clearance in 395 participants from Kent, England who were .74 years old (27). Mean measured GFR was 53.4 ml/min per 1.73 m2. All of the CKD-EPI formulas performed slightly better than the MDRD; however, there was not a tremendous difference. Accuracy within 30% was not optimal for any formula. Bias was slightly less with formulas that included cystatin (3.5 [1.9–4.8], 1.7 [0.3–3.2], 21.2 [22.2 to 0], and 0.8 [20.4 to 1.9] ml/min per 1.73 m2 for the MDRD, CKD-EPI creatinine, CKDEPI cystatin C, and CKD-EPI creatinine-cystatin C formulas, respectively, with corresponding accuracies within 30% of measured values of 81%, 83%, 86%, and 86%, respectively). All formulas overestimated GFR for measured values .60 ml/min per 1.73 m2 to a similar degree (3.4–5.5 ml/min per 1.73 m2). The differences in bias for those with measured GFRs ,60 ml/min per 1.73 m2 were smaller: 2 (95% CI, 0.8 to 3.9), 0.6 (95% CI, 20.7 to 2.3), 22.9 (95% CI, 23.7 to 1.9), and 21.6 (95% CI, 22.8 to 0.2) ml/min per 1.73 m2 for MDRD, CKD-EPI creatinine, CKD-EPI cystatin C, and CKD-EPI creatinine-cystatin C, respectively. Kilbride et al. (27) concluded that both creatininebased formulas worked fairly well. This was a European cohort, which limits application of these findings to other populations. Improved risk prediction Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 of clinical outcomes for different formulas was not ascertained. GFR and Albumin Excretion Variability The extent of day to day variability of markers for glomerular filtration and albumin excretion is not well described. Selvin et al. (28) examined the within-person variation of serum markers creatinine, cystatin C, b-trace protein, and b2-microglobulin and urine markers albumin, creatinine, and ACR in participants of the NHANES III. These values were separated about 18 days apart. Serum creatinine (SCr) and cystatin C had the lowest withinperson variability (7.6% and 6.8%, respectively), and although urine albumin alone had a variability of .30%, the ACR was only 11.3%. If repeat values of ,60 ml/min per 1.73 m2 were required to define CKD, CKD prevalence would decrease by nearly 20% (17.6% by CKD-EPI creatinine and 21.1% by CKD-EPI creatininecystatin C formulas). For increased albumin excretion .30 mg/g, requiring two tests to be above this threshold would decrease the prevalence for albuminuria by about 33% from having only one test above the threshold. The requirement for repeat eGFR values ,60 ml/min per 1.73 m2 .3 months apart to define CKD could also be applied to urine ACR values to define albuminuria. References 1. Rule AD, Glassock RJ: GFR estimating equations: Getting closer to the truth? Clin J Am Soc Nephrol 8: 1414–1420, 2013 PubMed 2. Shlipak MG, Coresh J, Gansevoort RT: Cystatin C versus creatinine for kidney function-based risk. N Engl J Med 369: 2459, 2013 PubMed 3. KDIGO CKD Work Group: KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 3: 1–150, 2013 4. Rule AD, Bailey KR, Lieske JC, Peyser PA, Turner ST: Estimating the glomerular filtration rate from serum creatinine is better than from cystatin C for evaluating risk factors associated with chronic kidney disease. Kidney Int 83: 1169–1176, 2013 PubMed 5. Silveiro SP, Araújo GN, Ferreira MN, Souza FD, Yamaguchi HM, Camargo EG: Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation pronouncedly underestimates glomerular filtration rate in type 2 diabetes. Diabetes Care 34: 2353–2355, 2011 PubMed 6. Gaspari F, Ruggenenti P, Porrini E, Motterlini N, Cannata A, Carrara F, Jiménez Sosa A, Cella C, Ferrari S, Stucchi N, Parvanova A, Iliev I, Trevisan R, Bossi A, Zaletel J, Remuzzi G; GFR Study Investigators: The GFR and GFR decline cannot be accurately estimated in type 2 diabetics. Kidney Int 84: 164–173, 2013 PubMed 7. de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, Zinman B, Steffes MW; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group: Longitudinal changes in estimated and measured GFR in type 1 diabetes. J Am Soc Nephrol 25: 810–818, 2014 PubMed 8. Pavkov ME, Knowler WC, Hanson RL, Williams DE, Lemley KV, Myers BD, Nelson RG: Comparison of serum cystatin C, serum 305 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. creatinine, measured GFR, and estimated GFR to assess the risk of kidney failure in American Indians with diabetic nephropathy. Am J Kidney Dis 62: 33–41, 2013 PubMed Tsai CW, Grams ME, Inker LA, Coresh J, Selvin E: Cystatin C- and creatinine-based estimated glomerular filtration rate, vascular disease, and mortality in persons with diabetes in the U.S. Diabetes Care 37: 1002–1008, 2014 PubMed Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, Xu JS, Huang SM, Wang LN, Huang W, Wang M, Xu GB, Wang HY: Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 17: 2937–2944, 2006 PubMed Imai E, Horio M, Nitta K, Yamagata K, Iseki K, Hara S, Ura N, Kiyohara Y, Hirakata H, Watanabe T, Moriyama T, Ando Y, Inaguma D, Narita I, Iso H, Wakai K, Yasuda Y, Tsukamoto Y, Ito S, Makino H, Hishida A, Matsuo S: Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease. Clin Exp Nephrol 11: 41–50, 2007 PubMed Praditpornsilpa K, Townamchai N, Chaiwatanarat T, Tiranathanagul K, Katawatin P, Susantitaphong P, Trakarnvanich T, Kanjanabuch T, Avihingsanon Y, Tungsanga K, Eiam-Ong S: The need for robust validation for MDRD-based glomerular filtration rate estimation in various CKD populations. Nephrol Dial Transplant 26: 2780–2785, 2011 PubMed Lee CS, Cha RH, Lim YH, Kim H, Song KH, Gu N, Yu KS, Lim CS, Han JS, Kim S, Kim YS: Ethnic coefficients for glomerular filtration rate estimation by the Modification of Diet in Renal Disease study equations in the Korean population. J Korean Med Sci 25: 1616–1625, 2010 PubMed Stevens LA, Claybon MA, Schmid CH, Chen J, Horio M, Imai E, Nelson RG, Van Deventer M, Wang HY, Zuo L, Zhang YL, Levey AS: Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating the glomerular filtration rate in multiple ethnicities. Kidney Int 79: 555–562, 2011 PubMed Kong X, Ma Y, Chen J, Luo Q, Yu X, Li Y, Xu J, Huang S, Wang L, Huang W, Wang M, Xu G, Zhang L, Zuo L, Wang H; Chinese eGFR Investigation Collaboration: Evaluation of the Chronic Kidney Disease Epidemiology Collaboration equation for estimating glomerular filtration rate in the Chinese population. Nephrol Dial Transplant 28: 641– 651, 2013 PubMed Teo BW, Xu H, Wang D, Li J, Sinha AK, Shuter B, Sethi S, Lee EJ: GFR estimating equations in a multiethnic Asian population. Am J Kidney Dis 58: 56–63, 2011 PubMed Wang X, Luo Y, Wang Y, Wang C, Zhao X, Wang D, Liu L, Liu G, Wang Y; China National Stroke Registry Investigators: Comparison of associations of outcomes after stroke with estimated GFR using Chinese modifications of the MDRD study and CKD-EPI creatinine equations: Results from the China National Stroke Registry. Am J Kidney Dis 63: 59–67, 2014 PubMed Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S; Collaborators Developing the Japanese Equation for Estimated GFR: GFR estimation using standardized serum cystatin C in Japan. Am J Kidney Dis 61: 197– 203, 2013 PubMed Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL: New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20: 629–637, 2009 PubMed Hoste L, Dubourg L, Selistre L, De Souza VC, Ranchin B, Hadj-Aïssa A, Cochat P, Martens F, Pottel H: A new equation to estimate the glomerular filtration rate in children, adolescents and young adults. Nephrol Dial Transplant 29: 1082–1091, 2014 PubMed Schwartz GJ, Schneider MF, Maier PS, Moxey-Mims M, Dharnidharka VR, Warady BA, Furth SL, Muñoz A: Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C. Kidney Int 82: 445–453, 2012 PubMed Chehade H, Cachat F, Jannot AS, Meyrat BJ, Mosig D, Bardy D, Parvex P, Girardin E: New combined serum creatinine and cystatin C quadratic 23. 24. 25. 26. 27. 28. formula for GFR assessment in children. Clin J Am Soc Nephrol 9: 54– 63, 2014 PubMed Stevens LA, Schmid CH, Greene T, Zhang YL, Beck GJ, Froissart M, Hamm LL, Lewis JB, Mauer M, Navis GJ, Steffes MW, Eggers PW, Coresh J, Levey AS: Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kidney Dis 56: 486–495, 2010 PubMed Nyman U, Grubb A, Sterner G, Björk J: The CKD-EPI and MDRD equations to estimate GFR. Validation in the Swedish Lund-Malmö Study cohort. Scand J Clin Lab Invest 71: 129–138, 2011 PubMed Bouquegneau A, Vidal-Petiot E, Vrtovsnik F, Cavalier E, Rorive M, Krzesinski JM, Delanaye P, Flamant M: Modification of Diet in Renal Disease versus Chronic Kidney Disease Epidemiology Collaboration equation to estimate glomerular filtration rate in obese patients. Nephrol Dial Transplant 28[Suppl 4]: iv122–iv130, 2013 PubMed Evans M, van Stralen KJ, Schön S, Prütz K-G, Stendahl M, Rippe B, Jager KJ; ERA-EDTA Registry; Swedish Renal Registry Collaboration: Glomerular filtration rate-estimating equations for patients with advanced chronic kidney disease. Nephrol Dial Transplant 28: 2518– 2526, 2013 PubMed Kilbride HS, Stevens PE, Eaglestone G, Knight S, Carter JL, Delaney MP, Farmer CK, Irving J, O’Riordan SE, Dalton RN, Lamb EJ: Accuracy of the MDRD (Modification of Diet in Renal Disease) study and CKD-EPI (CKD Epidemiology Collaboration) equations for estimation of GFR in the elderly. Am J Kidney Dis 61: 57–66, 2013 PubMed Selvin E, Juraschek SP, Eckfeldt J, Levey AS, Inker LA, Coresh J: Within-person variability in kidney measures. Am J Kidney Dis 61: 716–722, 2013 PubMed Risk Factors for Progression of Kidney Disease This NephSAP section reviews risk factors for CKD progression. The role of AKI and important studies in pediatrics were reviewed in prior NephSAP editions. Biomarkers Promising biomarkers that accurately predict CKD progression are not ready for clinical use at the time of this edition of NephSAP. An albumin to creatinine ratio (ACR) is routinely used to predict the onset of diabetic nephropathy. However, patients with type 1 diabetes can have severe glomerular lesions, and patients with type 2 diabetes can develop CKD with normal albumin excretion (1,2). Haptoglobin binds to hemoglobin, and its increased appearance in the urine may be caused by increased glomerular permeability, tubular damage, or a response to oxidative injury. Bhensdadia et al. (3) assessed if the baseline urine haptoglobin to creatinine ratio (HCR) would predict early renal functional decline in patients with type 2 diabetes more accurately than ACR. HCR was tested in 204 patients with type 2 diabetes enrolled in the Veterans Affairs Diabetes Trial with an average 306 follow-up of 3.7 years. Early renal functional decline was defined as $3.3% annual loss of GFR. Urine proteomic analysis showed that haptoglobin levels were markedly increased in preliminary screening of patients with type 2 diabetes with increasing SCr versus those who had a stable SCr. Comparing highest with lowest tertiles of HCR, there was an adjusted 2.7-fold increased risk (95% confidence interval [95% CI], 1.15 to 6.32) for predicting early functional decline versus a 2.5-fold risk (95% CI, 1.14 to 5.48) using ACR. The ability to predict ESRD was fair. Using both markers did not significantly improve performance. (receiver operating characteristic [ROC] area under the curves were 0.613, 0.621, and 0.664 for HCR, ACR, and both, respectively). HCR was equal to ACR in predicting other renal outcomes, such as a .50% increase in SCr. The HCR shows some promise as an additional marker to ACR in type 2 diabetes in predicting rapid progression, especially in those without increased albumin excretion, but it requires confirmation in future studies. It is unclear if this marker will predict less rapid disease progression in patients with diabetes compared with ACR. In addition, the threshold level for HCR to identify progression is not established. Genetics The increased risk of nondiabetic CKD and FSGS in blacks has been partially attributed to variants of the apolipoprotein L1 (APOL1) gene. The G1 and G2 variants appear with increased frequency in individuals of West African ancestry by virtue of their protective carrier state against Trypanosoma brucei rhodesiense. Parsa et al. (4) investigated the effects of having two copies of APOL1 gene variants (high risk) versus zero or one copy (low risk) on progression of CKD in two cohorts: the black Study of Kidney Disease and Hypertension (AASK) Trial and the Chronic Renal Insufficiency Cohort (CRIC) Study. AASK participants in this study included 693 blacks genotyped for APOL1 who had CKD attributed to hypertension without diabetes. The AASK end points were the composite of ESRD or doubling of SCr. In the CRIC Study, outcomes were slope in eGFR and the composite of ESRD or a 50% reduction of measured GFR from baseline. Of 2955 White and black individuals in the CRIC Study, 46% had diabetes. In the AASK, those with two gene variants had an adjusted 88% increased risk for ESRD or doubling of SCr (hazard ratio [HR], 1.88; 95% CI, 1.46 to 2.41; Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 P,0.001) (Figure 4). CRIC participants with two risk variants had a more rapid decline in eGFR and higher risk of the composite renal outcome versus White patients with or without diabetes. After adjustment, blacks with diabetes and high–risk APOL1 status had faster progression of CKD compared with Whites with diabetes and blacks with diabetes and low–risk APOL1 status. Patients with diabetes and high–risk APOL1 variants had a difference in eGFR slope of 21.32 ml/min per 1.73 m2 per year compared with Whites with diabetes and 21.07 ml/min per 1.73 m2 per year compared with blacks with diabetes and low–risk APOL1 status. In patients without diabetes, blacks with high–risk APOL1 status displayed faster loss by 21.05 and 21.21 ml/min per 1.73 m2 per year compared with Whites and blacks with low risk, respectively. After 4.4 years of follow-up, there was a 46% increased chance of reaching the composite end point in blacks with diabetes and high–risk APOL1 status versus blacks with diabetes and low–risk APOL1 status. In blacks without diabetes and with high–risk APOL1 status, there was a 61% increased risk of reaching the composite end point versus blacks without diabetes and with low–risk APOL1 status (Figure 4). The mechanism for progressive CKD in individuals with APOL1 high–risk variants is unclear. APOL1 variants may reduce podocyte autophagy, a process that eliminates toxic protein aggregates and damaged organelles from cells. In addition, only a minority of patients with two APOL1 risk alleles develop CKD. Other genes, inflammation, viral infection, or other environmental factors are hypothesized to act as a second hit to cause progressive CKD. Blacks both with and without diabetes with two APOL1 risk alleles developed more rapid CKD progression and increased chance of ESRD or .50% decrease in measured GFR. Other genes, inflammation, viral infection, or other environmental factors most likely act as a second hit to cause progressive CKD. Obesity The connection between obesity and CKD is complex and comprehensively reviewed by Stenvinkel Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 307 Figure 4. High risk APOL1 status increases risk for doubling of serum creatinine or ESRD independent of proteinuria, blood pressure goal, or ACE inhbitor use in the black Study of Kidney Disease and Hypertension. (A) Entire Cohort. (B) Level of proteinuria. Proteinuria defined as urine protein to creatinine ratio equal to or . 220 mg/g. (C) Blood pressure goal, standard defined as ,102-107 mmHg and intensive defined as , or equal to 92 mmHg. (D) Use of initial anti hypertensive medication. ACE inhibitor or other (metoprolol or amlodipine). Proportion of patients free from progression of CKD in the black Study of Kidney Disease and Hypertension. ACE, angiotensin-converting enzyme; APOL1, apolipoprotein L1. Reprinted with permission from Parsa A, Kao WH, Xie D, Astor BC, Li M, Hsu CY, Feldman HI, Parekh RS, Kusek JW, Greene TH, Fink JC, Anderson AH, Choi MJ, Wright JT Jr., Lash JP, Freedman BI, Ojo A, Winkler CA, Raj DS, Kopp JB, He J, Jensvold NG, Tao K, Lipkowitz MS, Appel LJ; AASK Study Investigators; CRIC Study Investigators: APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 369: 2183–2196, 2013. 308 et al. (5). Independent of hypertension and diabetes, the postulated mechanisms for how obesity and lipid accumulation in the kidney could directly cause CKD progression include hyperfiltration, cell maladaptation, albuminuria, inflammation, and tubulointerstitial injury and fibrosis. These mechanisms have been recently reviewed (6,7). In addition, the risk for CKD is less in the 10%–30% of patients who are obese but metabolically healthy (8). Increased body mass index (BMI), the metric used by the World Health Organization to define obesity, was reported to be linked to new-onset CKD in a large European cohort (9). In the Coronary Artery Risk Development in Young Adults (CARDIA) Longitudinal Cohort Study of 2839 participants with cystatin C eGFR values .90 ml/min per 1.73 m2 at baseline, Grubbs et al. (10) studied the association of BMI with the trajectory of kidney function decline, rapid decline (.3% loss of eGFR per year), and incident CKD (estimated glomerular filtration rate from serum cystatin C [eGFRcys],60 ml/min per 1.73 m2). For those .30 years old, higher BMI category was associated with increased odds of rapid decline. For BMI categories of 25.0–29.9, 30–39.9, and $40 kg/m2, adjusted odds ratios (ORs) were 1.50 (95% CI, 1.21 to 1.87), 2.01 (95% CI, 1.57 to 2.87), and 2.57 (95% CI, 1.67 to 3.94), respectively, compared with the reference BMI of 18.5–24.9 kg/m2. However, increasing BMI was not related to incident CKD. In participants of the CARDIA Study without albuminuria or decreased eGFR at baseline, obesity ($30 kg/m2) was found to be associated with incident albuminuria by ACR after adjustment (OR, 1.9; 95% CI, 1.1 to 3.3) (11). Although traditionally, BMI has been used to define obesity (.30 kg/m2), this may not be the optimal estimate of fat mass in patients with CKD (12). Central or visceral body fat distribution has been linked to CKD. Central deposition of body fat can be measured by waist-to-hip ratios (WHRs). Disease risk increases with high waist circumference and WHR (.102 cm and .0.9 in men and .88 cm and .0.8 in women, respectively) (5). Kwakernaak et al. (13) examined if WHR was related to kidney outcomes. This study had 315 participants with a baseline mean BMI of 24.9 kg/m2 and 125I-iothalamate GFR of 109 ml/min per 1.73 m2. After adjustment (including BMI), increasing WHR was associated with lower baseline measured GFR, lower effective renal plasma flow measured by 131I-hippurate, and higher filtration fraction (GFR/effective renal plasma flow), a marker for Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 glomerular hyperfiltration in both crude and BSAnormalized measurements. This cross-sectional study showed these associations with increasing WHR, independent of BMI. Of note, there was no association between increased WHR and albumin excretion. Accumulation of lipid in nonadipose tissue, such as the liver, could play an important role in the pathogenesis of obesity–related kidney disease. Nonalcoholic fatty liver disease (NAFLD) has been shown experimentally to release inflammatory, coagulant, oxidant, and fibrogenic meditators (14). Targher et al. (14) studied the relationship of NAFLD diagnosed by liver ultrasound and incident CKD in 261 patients with type 1 diabetes. These participants had a mean eGFR of 92 ml/min per 1.73 m2 without macroalbuminuria (10.3% had microalbuminuria). For those individuals with NAFLD, there was a doubling of risk for incident CKD (Modification of Diet in Renal Disease [MDRD] eGFR ,60 ml/min per 1.73 m2) or the occurrence of macroalbuminuria (adjusted HR, 2.03; 95% CI, 1.10 to 3.77). Liver ultrasound may be insensitive in determining NAFLD, although one-half of the cohort had NAFLD identified by ultrasound criteria. Self-reporting was used to determine the nonalcoholic state. The relationship between increasing BMI and kidney outcomes in those with prevalent rather than incident CKD is not straightforward. Lu et al. (15) examined renal outcomes in 453,946 veterans with eGFRs,60 ml/min per 1.73 m2 stratified by BMI (,20, 20–24.9, 25–29.9, 30–34.9, 35–39.9, 40–44.9, 45–49.9, and .50 kg/m2). Mean age was 74 years old, 87% were white, and 94% were men in this observational study. Obese patients were younger, had higher BP, had greater medication use, had greater prevalence of heart failure (HF) and diabetes, and had lower prevalence of malignancies and lung, liver, and rheumatologic diseases. After adjustment, BMI showed a U-shaped association with clinical outcomes for all-cause mortality and various measures of CKD progression, such as incidence of ESRD, doubling of SCr, and slope of eGFR. Kidney outcomes were worst for those with BMIs,25 kg/m2 and best for those in the 25–29.9- and 30–34.9-kg/m2 categories. Those with BMIs.35 kg/m2 had worse outcomes for progression of CKD if they had a baseline eGFR.30 ml/min per 1.73 m2, but worse outcomes were attenuated if baseline eGFR was ,30 ml/min per 1.73 m2 (Figure 5). This observational study of older men with prevalent CKD neither shows causality nor describes a relationship with incident CKD. Lu et al. (15) Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 309 Figure 5. All-cause mortality and CKD progression in veterans with baseline eGFR,60 ml/min per 1.73 m2 by BMI. Body mass index (BMI) categories showing a U-shaped association with progression of CKD in 453,946 United States veterans with eGFR,60 ml/min per 1.73 m2. Association of BMI categories with four different outcomes representing progression of CKD: (A) steeper slopes of eGFR versus time (defined as slopes ,24 ml/min per 1.73 m2 per year), (B) doubling of serum creatinine or ESRD, (C) projected eGFR ,10 ml/min per 1.73 m2 or ESRD, and (D) ESRD. Estimates were calculated from a logistic regression model (for steeper slopes) and Cox models (for all other outcomes) adjusted for age, race, comorbidities, medications, and baseline eGFR. Reprinted with permission from Lu JL, Kalantar-Zadeh K, Ma JZ, Quarles LD, Kovesdy CP: Association of body mass index with outcomes in patients with CKD. J Am Soc Nephrol 25: 2088–2096, 2014 provided explanations for the relative slowing of CKD progression in individuals with moderate to advanced CKD with BMIs in the 25- to 35-kg/m2 range. Those with greater BMIs may have increased nutritional reserves, which would be advantageous with advanced CKD, where there may be malnutrition. A higher BMI may be caused by increased muscle or bone mass rather than more adiposity. In addition, a normal BMI may not represent the metabolic effects of obesity caused by increased visceral adiposity as described above. Abou-Mrad et al. (16) reviewed weight reduction regimens and bariatric surgery in the obese with CKD. An earlier study by Navaneethan and Yehnert (17) reviewed here described the effects of both restrictive and 310 malabsorptive bariatric surgery in 25 severely obese participants (mean BMI ¼49.8 kg/m2) with stage 3 CKD. There was an improved eGFR from a mean of 47.9 ml/min per 1.73 m2 presurgery to 61.6 ml/min per 1.73 m2 2 years after surgery. However, Navaneethan and Yehnert (17) excluded those who developed AKI postbariatric surgery Diet Fluid. A high fluid intake has been postulated to lower CKD incidence by increasing solute clearance and preventing kidney stones, whereas a lower fluid intake may increase metabolic demand in the kidney from urinary concentration. Clark et al. (18) had previously shown that drinking larger volumes of fluid (24-hour urine volumes .3 L/d) was associated with a reduced incidence of CKD. Palmer et al. (19) also examined the relationship between fluid intake (evaluated by a food frequency questionnaire) and all-cause and cardiovascular mortality and eGFR. This longitudinal, elderly, Australian cohort had 3858 participants with a mean age of 70 years old. There were 1479 participants who had measurements of SCr at 10 years of follow-up. No relationship was found between higher fluid intake and mortality or changes in eGFR after adjustment. Dietary Patterns. Dietary patterns may be more important than specific macronutrients, such as protein, or micronutrients, such as sodium, in modifying CKD progression. In 3972 participants from the Reasons for Geographic and Racial Difference in Stroke (REGARDS) Study with eGFR,60 ml/min per 1.73 m2 or ACR$30 mg/g, Gutiérrez et al. (20) examined the effect of dietary patterns on incident ESRD over 6 years of follow-up. A participant’s dietary pattern was characterized by food type predominance on a food frequency questionnaire. Classifications were convenience (Chinese and Mexican foods, pizza, and frozen or take-out dishes), plant based (fruits, vegetables, and fish), sweets/fats (sugary foods and carbohydrate heavy), Southern (fried foods, organ meats, greens typical of Southern cuisines, and sweetened beverages), and alcohol/salads (alcohol, green leafy vegetables, and salad dressing). There was no association of any dietary pattern with incident ESRD in adjusted models. The Southern diet was associated with higher mortality, whereas the plant-based diet was associated with improved mortality. The lack of influence of various dietary patterns on incident ESRD may be because there were nearly six times as many deaths as Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 ESRD events, and the study may have been underpowered to detect CKD progression on the basis of the predominance of ESRD events. The accuracy of the food reporting questionnaires employed in this study is not clear. Tirosh et al. (21) examined the effects of three diets on eGFR and albumin excretion. The diets consisted of low fat, Mediterranean, or low carbohydrate/increased protein. This 2-year randomized, controlled trial (21) included 318 participants with or without type 2 diabetes with BMI.27 kg/m2 (mean 31 kg/m2) and eGFR.30 ml/min per 1.73 m2 (mean eGFR 70.5 ml/min per 1.73 m2). All diets resulted in significant improvements in 2-year eGFR. The low–carbohydrate/increased protein diet raised eGFR by 15.4% (95% CI, 2.1 to 8.5), the Mediterranean raised eGFR by 15.2% (range 3.0–7.4), and the low-fat diet raised eGFR by 14% (range 0.9– 7.1). The eGFR increased by the same magnitude for those with or without diabetes and for those with eGFR values above or below 60 ml/min per 1.73 m2. Urine albumin excretion among those with microalbuminuria did not decrease significantly in any diet group. The participants with eGFRs in the 30–60 ml/min per 1.73 m2 range on the low–carbohydrate/higher protein diet had a 10% increase in eGFR over 2 years. Interestingly, after 2 years, there was no significant change in weight, and 2-year weight loss was not associated with increased eGFR. Tirosh et al. (21) concluded that the low–carbohydrate/ increased protein diet was as safe as the other diets in moderately obese patients with or without diabetes with a SCr of ,2 mg/dl. The differences in protein intake between diets were not large (22% of energy from protein with the low-carbohydrate diet verse 19% in the other two diets). However, this was only a 2- year study, in which participants had relatively preserved GFRs. Protein Intake. Higher protein intake increases glomerular hyperfiltration and may eventually lead to incident CKD. In an ancillary study of the Optimal Macro-Nutrient Intake Trial, a randomized, cross-over trial of three separate diets emphasized carbohydrates, unsaturated fats, or protein during 6-week periods. The protein content varied from 15% in the carbohydrateand unsaturated fat–emphasized diets to 25% in the protein-emphasized diet. In 164 participants, mean cystatin C eGFR was 92.0 ml/min per 1.73 m2. This increased by 3.81 ml/min per 1.73 m2 in the higher protein diet independent of BP, with no change in the other diets in the short term (22). Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 A longer post hoc analysis over 5.5 years by Dunkler et al. (23) examined the association of the healthiness of a diet as well as protein content on incident CKD and progression. The latter was defined as newonset micro- or macroalbuminuria or eGFR decline of .5% per year (23). This cohort of 6213 patients with type 2 diabetes without macroalbuminuria ages 55 years old and older was enrolled in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Mean eGFR was about 72 ml/min per 1.73 m2. Diet was recorded from a food questionnaire at baseline, and the healthiness of diets was assessed using a standardized index. The healthiest tertile had a 27% lower adjusted risk of CKD (adjusted OR, 0.73; 95% CI, 0.64 to 0.84). Participants in the lowest tertile of total and animal protein intake surprisingly had a slightly increased risk of CKD compared with those in the highest tertile (OR, 1.167; 95% CI, 1.05 to 1.30); however, median total protein intake was only 0.58 g/kg per day (interquartile range 0.42–0.82). The majority of participants in this cohort had only mild CKD at baseline (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] eGFR of approximately 72 ml/min per 1.73 m2), and 21.1% manifested microalbuminuria. In those with more severe CKD, Piccoli et al. (24) reported the feasibility of using a low-protein diet supplemented with a-keto analogues of essential amino acids (LPD-KA) to slow CKD progression. This diet consisted of 0.6 g/kg per day supplemented with Ketsteril (1 pill per 10 kg), one to three free choice meals per week, and a list of allowed and forbidden foods. These keto analogues of amino acids do not have the nitrogen load of the essential amino acids. This was a vegan diet, except for the free choice meals. Patients had either stage 4 or nondialysis stage 5 CKD (n¼129), rapidly progressive stage 3 CKD (n¼29), and/or refractory proteinuria (n¼10) (24). This older cohort had severe CKD (mean age 70 years old; median GFR 17 ml/min per 1.73 m2 with median proteinuria of 1.4 g/d) and prevalent comorbidities comparable with patients on dialysis. Of those who started the LPD-KA, there was a low mortality rate (4.4% per year). The diet was discontinued for a variety of reasons: 40 participants started dialysis, 8 participants died, 7 participants discontinued the diet because of clinical reasons, 14 participants discontinued the diet because of personal preference (monotony of diet), and 8 participants discontinued the diet because of improvement in eGFR. Although this study was not sufficiently powered to show an effect on CKD progression rate, eGFR loss before this diet 311 was 28 ml/min per year, which improved to no reduction in eGFR after 6 months of the diet in 95 participants. This was not a uniform study population because of the inclusion of 10 subjects with severe proteinuria and more normal eGFR. In pregnant women with CKD, higher protein intake could exacerbate glomerular hypertension, but there also may be a requirement for higher protein intake for the fetus during pregnancy. Piccoli et al. (25) compared the LPD-KA diet (0.6–0.8 g/kg per day with keto supplementation and one to three protein–unrestricted meals per week) in 21 pregnant women with stages 3–5 CKD or nephrotic-range proteinuria with 16 pregnant women with CKD not on this diet. There was significantly less likelihood of small for gestational age babies (3 of 21) compared with that in the control diet group (7 of 16), but there were no other significant differences as far as maternal kidney function or proteinuria. Piccoli et al. (25) concluded that the diet was safe during pregnancy and reduced the likelihood of small for gestational age children, although it did not seem to affect long-term growth. Sodium. The effect of dietary sodium restriction on CKD progression is controversial, and studies reported here do not clarify our goal sodium intake for preventing CKD progression. Excess sodium intake could cause kidney vascular damage through volume retention with increased shear stress and nonhemodynamic oxidative stress and inflammation (26). However, there are concerns that a low-sodium diet could result in increased activity of the renin-angiotensin-aldosterone system (RAAS), increased activity of the sympathetic nervous system, or insulin resistance, which potentially would accelerate CKD progression. In patients with CKD, excess sodium intake has been associated with CKD progression that is not independent of proteinuria. McQuarrie et al. (27) studied the association between urinary sodium excretion and urine sodium to creatinine ratio, time to death, or requirement for RRT in 423 participants with mean GFR of 48 ml/min per 1.73 m2. There were 102 deaths and 99 patients who required RRT during follow-up. The overall cohort’s mean age was 51 years old, mean eGFR was 48625 ml/min per 1.73 m2, mean ACR was 97.3 mg/g, and mean sodium intake was 155 mmol/d (3.56 g/d). After adjustment, a high versus low dietary sodium intake measured by either 24-hour urine sodium or 24-hour urine sodium to creatinine ratio did not independently predict mortality or ESRD. However, the mean 312 24-hour urine sodium was 160 mmol/d (3.68 g/d) in the high–sodium diet group compared with 127 mmol/d (2.92 g/d) in the low-sodium group. This lack of effect between dietary sodium and CKD progression was supported by the findings by Dunkler et al. (23) in the previously reported study of patients with type 2 diabetes. Mean urinary sodium excretion was higher in this study at 4.89 g/d (212 mmol/d), with a wide range of dietary sodium intake that had little association with CKD progression (23). The mean eGFR was about 72 ml/min per 1.73 m2. Those with a urine sodium excretion ,3 g/d had slightly higher odds of CKD progression with increased odds of death. A complex relationship between sodium intake, proteinuria, and kidney failure was described by Fan et al. (28). The 840 participants in the MDRD Study had a mean measured GFR of 32.5 ml/min per 1.73 m2 with median urine protein excretion of 320 mg/d (0.07–1.510). This was a post hoc analysis of the association of unrestricted sodium intake with kidney failure, defined as onset of dialysis or transplant, which developed in 617 participants, and the composite outcome of kidney failure or death achieved in 723 participants over a median follow-up of 6 years. Mean baseline 24-hour urine sodium excretion was 3.46 g/d. After adjustment, there was no relation with either kidney failure (HR, 0.99; 95% CI, 0.91 to 1.08) or the composite of kidney failure and death (OR, 1.01; 95% CI, 0.93 to 1.09) for every 1-g/d greater urinary sodium excretion. On additional analysis, when urine sodium was .3 g/d, there was no association with kidney failure. In individuals with ,1 g/d proteinuria with urine sodium excretion ,3 g/d, dietary sodium restriction was related to protection against kidney failure (adjusted HR, 0.61; 95% CI, 0.42 to 0.89). However, there seemed to be a J-shaped relationship; if urine sodium was ,3 g/d in participants with .1 g/d proteinuria, the risk for kidney failure increased (adjusted HR, 1.72; 95% CI, 1.31 to 2.24). Similar results were found using baseline or time–dependent urine sodium measurements. Why dietary sodium restriction would increase the risk of kidney failure in patients with more proteinuria is unclear. It is possible that the observed lower dietary sodium intake resulted from decreased intake in sicker patients. Those with proteinuria may have been more susceptible to episodes of AKI with a lower sodium intake. This association contradicted findings by Vegter et al. (29) in the Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Ramipril Efficacy in Nephropathy Trial of patients who were highly proteinuric (median daily protein excretion 3 g/d), where increased time–averaged urine sodium excretion was associated with an increased risk for developing ESRD. A randomized, double–blinded, placebo, controlled trial was performed to assess dietary sodium intake on BP and proteinuria in 20 elderly participants with stages 3 or 4 CKD (30). Changes in ambulatory BP, 24-hour urine protein and albumin excretion, fluid status measured by a body composition monitor, renin and aldosterone levels, and arterial stiffness measured by pulse wave velocity (aPWV) and augmentation index were assessed on high- and low-sodium diets. Participants were counseled on a low-sodium diet of 60–80 mmol/d. The high-sodium diet consisted of the same diet plus 120 mmol/d sodium tablets for a goal of 180–200 mmol/d. Placebo tablets were given to participants ingesting the low-sodium diet. The mean 24hour urine sodium excretion values were 75 and 168 mmol/L for low- and high-sodium diets, respectively. The two diets lasted 6 weeks before participants crossed over to the other diet after a 1-week washout period. The low-sodium diet resulted in multiple beneficial effects. BP decreased by a mean of 10/4 mmHg (95% CI, 5 to 15/1 to 6 mmHg), extracellular fluid volume decreased (mean ¼0.8 L; 95% CI, 0.4 to 4.2), and albuminuria and proteinuria decreased by medians of 148 and 342 mg/d, respectively (Table 2). The large effect on BP may have been because these patients may have been especially salt sensitive, with a mean of 3.2 antihypertensive medications. Although promising, this small trial was of short duration. A possible detrimental effect was that plasma renin and aldosterone increased with the low-sodium diet. The change in the six participants on RAAS blockade was not reported. Taken together, the studies by McQuarrie et al. (27) and Fan et al. (28) question what the optimal sodium intake is for patients with CKD. These were post hoc analyses that did not target specific sodium intakes for outcomes. The sodium intake trial by McMahon et al. (30) confirms the influence of sodium restriction on lowering BP and proteinuria. Therefore, making adjustments for these variables to assess an independent effect of restricting sodium intake is questionable. Perhaps, in the study by Fan et al. (28), the worse outcomes with sodium restriction in patients who were proteinuric resulted in either increased AKI Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 313 Table 2. Values during low- and high-salt periods Reprinted with permission from McMahon EJ, Bauer JD, Hawley CM, Isbel NM, Stowasser M, Johnson DW, Campbell KL: A randomized trial of dietary sodium restriction in CKD. J Am Soc Nephrol 24: 2096-2103, 2013. events or excessive activation of the RAAS. In this study, the optimal sodium intake for patients with .1 g/d proteinuria seemed to be about 3 g sodium, with worsening with more restriction. For those with ,1 g/d proteinuria, the optimal sodium intake seemed to be ,3 g/d. Perhaps those with CKD who are not hypertensive may not benefit from limiting sodium intake. In practice, there will be a difference between advising and following sodium restriction. For now, aiming for a daily 2- to 3-g sodium intake seems reasonable. Bicarbonate Acidosis stimulates ammonia, aldosterone, and endothelin production to increase tubular acid excretion to ameliorate acidosis. However, these mediators may also increase tubulointerstitial damage and CKD progression. Low serum bicarbonate levels may represent a biomarker for those who will develop increased CKD progression. Driver et al. (31) examined the association between serum bicarbonate and rapid renal function decline (.5% per year) as well as incident CKD defined as ,60 ml/min per 1.73 m2 by CKD-EPI cystatin C-creatinine formula. Participants from the Multi-Ethnic Study of Atherosclerosis had a mean age of 61 years old, mean bicarbonate level of 23 mEq/L, and baseline eGFR of 84 ml/min per 1.73 m2 with median ACR of 5.2 mg/g. The median follow-up was 3.9 years. After adjustment, each 1.8-mEq/L decline in serum bicarbonate concentration was associated with a slightly higher odds of rapid kidney function decline (OR, 1.12; 95% CI, 1.06 to 1.20) and incident CKD (incidence rate ratio, 1.12; 95% CI, 1.03 to 1.20), although the relationship for incident disease seemed to dissipate at both lower and higher values for serum bicarbonate. Limitations of this study are that these findings are on the basis of a single serum bicarbonate value. It is also not known which patients had a concurrent primary respiratory acidbase disorder. In addition, bicarbonate was measured from frozen samples, which can significantly reduce serum bicarbonate levels. Goldenstein et al. (32) also examined the association between serum bicarbonate and GFR decline and incident CKD in an older cohort (mean age of 75.2 years old) followed for 7 years. These participants had a mean baseline eGFR of 84.2 ml/min per 1.73 m2 determined by the CKD-EPI cystatin C-creatinine formula. A serum bicarbonate ,23.0 mEq/L was associated with a 0.54 ml/min per year (95% CI, 20.97 to 20.12; P,0.01) faster annual decline as well as an 81% increased chance for incident CKD after adjustment compared with the reference group with serum bicarbonate levels of 23– 28 mEq/L. Small trials using sodium bicarbonate supplementation showed decreased CKD progression compared with control groups (33,34). Sodium citrate also slowed 314 Figure 6. Similar changes in eGFR in stage 4 CKD participants with serum bicarbonate ,22 mEq/L after one year of sodium bicarbonate or fruits and vegetables. Box plots of plasma cystatin C eGFR (cys GFR; left panel) and plasma creatinine eGFR (cr GFR; right panel) at baseline and 1-year follow-up. The bottom and top of the boxes span the 25th and 75th percentiles of data points. The dark bar within the box indicates the 50th percentile or median. The whiskers indicate 1.5 times the interquartile range from the lower and upper quartiles. F/U, follow-up; F1V, fruits and vegetables. *P,0.05 versus respective baseline. Reprinted with permission from Goraya N, Simoni J, Jo CH, Wesson DE: A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol 8: 371–381, 2013 the rate of decrease in eGFR in participants with stage 3b CKD (35). Although sodium bicarbonate may not increase volume to the same degree as sodium chloride, alkali supplementation with sodium could result in worsening hypertension or volume. Fruits and vegetables (F1V) represent an alternative source of citrate alkali, which may help delay CKD progression without sodium but with high potassium content. Goraya et al. (36) examined the use of F1V in participants with stage 4 CKD with total CO2 levels ,22 mEq/L over 1 year. Participants were excluded if they had edema, congestive heart failure (CHF), liver failure, nephrotic syndrome, diabetes, or serum potassium levels .4.6 mEq/L (36). Alkali therapy as 1 mEq/kg per day sodium bicarbonate was administered to 35 individuals, and F1V, approximately 0.4 mEq/kg per day, were provided to reduce dietary acid by one half in 36 individuals. Mean serum bicarbonate levels were higher at 1 year versus baseline in both groups (19.561.5 to 21.261.3 in the sodium Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 bicarbonate group and 19.361.9 to 19.961.7 in the F1V group). After 1 year, markers of tubulointerstitial damage (urinary N-acetyl-b-d-glucosaminidase [NAG] and urinary TGF-b) were lower compared with baseline in both groups. Decreases in systolic BP (approximately 4.5 mmHg) and weight (approximately 4.7 kg) occurred in the F1V group, with no change in the bicarbonate group. There were no differences between the alkali treatment groups as far as baseline or 1-year eGFR values by cystatin C or creatinine. In both treatment groups, eGFR decreased slightly over 1 year. The change in mean eGFR in the sodium bicarbonate group was 21.763.4 to 20.363.2 ml/min per 1.73 m2 for eGFRcys and 23.063.5 to 21.463.3 ml/min per 1.73 m2 for estimated GFR from serum creatinine (eGFRcr), whereas mean change in the F1V group was 21.664.6 to 20.764.7 ml/min per 1.73 m2 for eGFRcys and 22.864.9 to 21.965.1 ml/min per 1.73 m2 for eGFRcr (Figure 6). Plasma potassium did not change from baseline in either group. The same group examined whether treatment with alkali in those with stage 3 CKD who had serum bicarbonate levels between 22 and 24 mEq/L (above the threshold for treatment by Kidney Disease Outcomes Quality Initiative guidelines) might slow CKD progression in a 2-year trial (37). Individuals were divided into sodium bicarbonate (n¼36), F1V (n¼36), or usual care (n¼36) groups. The participants had metabolic acidosis by venous blood gas and moderate to severe albumin excretion (mean .300 mg/g) and were treated with RAAS blockers. Exclusion criteria were similar to those used in the trial above. The sodium bicarbonate group was treated with 0.3 mEq/kg per day bicarbonate to reduce acid excretion by 50%. Compared with baseline, serum bicarbonate increased in the alkali treatment groups, whereas it decreased in the usual care group. Urinary albumin decreased in all groups with RAAS blockade, but there were greater decreases in both alkali treatment groups. Markers of tubulointerstitial damage and kidney angiotensin levels (urinary angiotensinogen) decreased in the alkali groups but increased in the usual care group. Systolic BP was lower in all groups, with the largest decrease in the F1V group (approximately 35 mmHg), which corresponded to the largest weight loss (approximately 4 kg). Declines in eGFR by creatinine and cystatin C over 3 years were significantly less in both alkali treatment groups compared with the usual care group (eGFRcr from 42.667.6 to 28.867.3 ml/min per 315 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Figure 7. Changes in eGFR in stage 3 CKD participants with serum bicarbonate 22–24 mEq/L with ACR.300 mg/g after 3 years of sodium bicarbonate, fruits and vegetables or usual care. Plasma creatinine–based eGFR (cys GFR; left panel) and cystatin C eGFR (cr GFR; right panel) in the group treated with fruits and vegetables (F1V) versus usual care. *P,0.05 versus usual care at 2 years; 1P,0.05 versus usual care at 3 years. Reprinted with permission from Goraya N, Simoni J, Jo CH, Wesson DE: Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate. Kidney Int 86: 1031–1038, 2014 1.73 m2 in the usual care group, eGFRcr from 42.667.0 to 35.266.9 ml/min per 1.73 m2 in the sodium bicarbonate group, and eGFRcr from 42.367.1 to 36.966.7 ml/min per 1.73 m2 in the F1V group) (Figure 7). Plasma potassium was unchanged from baseline in all three groups. It is unclear what the optimal level of serum bicarbonate should be for patients with CKD. Experimental studies in cardiac myocytes show that alkalosis may modify proteins that regulate gene transcription and decrease cell survival. Dobre et al. (38) examined serum bicarbonate levels as a risk factor for renal outcomes, cardiovascular events (CVEs), and mortality in CKD. There were 3939 participants in the CRIC Study with a mean eGFR of 44.8 ml/min per 1.73 m2 and a median bicarbonate of 24 mEq/L (interquartile range 22–26 mEq/L) who were followed for 3.9 years on average. After adjustment, every 1-mEq/L increase in serum bicarbonate was associated with a 3% lower risk of developing a renal end point (50% decrease in eGFR or ESRD; HR, 0.97; 95% CI, 0.85 to 0.97; P¼0.04), which increased to 9% in those with an eGFR.45 ml/min per 1.73 m2 (HR, 0.91; 95% CI, 0.85 to 0.97). However, for every 1-mEq/L increase in serum bicarbonate over 24 mEq/L, there was a 14% higher adjusted risk of developing HF (adjusted HR, 1.14; 95% CI, 1.03 to 1.26). There were no increases in atherosclerotic events or all-cause mortality. These relationships were maintained after accounting for diuretic use and exclusion of the small minority of patients who were on alkali supplementation (n¼91). Again, it was not known which participants had respiratory acidosis. Alkali therapy, whether in the form of sodium alkali or F1V, seems to decrease CKD progression with moderate to severe CKD. This may benefit those with only mildly decreased serum bicarbonate levels, but the patients selected for therapy must be chosen carefully. Although the optimal upper limits are not clear, bicarbonate supplementation should be titrated so as not to greatly exceed the level of 24 mEq/L. Rate of Decline of GFR and GFR Variability Clinical trials in nephrology have traditionally used doubling of SCr, corresponding to a drop in GFR of 57%, or ESRD as the end point to determine if interventions slow CKD progression. Trials may have to have follow-up for 5 years for there to be a significant number of participants reaching these end points. Using meta-analysis of 1.7 million participants from the Chronic Kidney Disease Prognosis Consortium, Coresh et al. (39) explored whether a reduction in GFR,57% over a shorter timeframe would predict CKD progression to ESRD and mortality. For participants with an initial eGFR ,60 ml/min per 1.73 m2 who also suffered additional decrease of .30% in eGFR over 2 years, there was a 5.4-fold increased odds of ESRD (HR, 5.4; 95% CI, 4.5 to 6.4) after adjustment (39). For those participants with initial eGFR .60 ml/min per 1.73 m2, there was a 6.7-fold increase in odds of ESRD if there was an additional .30% decrease in eGFR (95% CI, 3.9 to 11.5). For the entire consortium, the 10-year risks of ESRD and death were 64% and 50%, respectively, for a 30% decrease in eGFR over 2 years. The odds of ESRD were markedly increased if the standard doubling of SCr, corresponding to the 57% decrease in eGFR, was used, but the prevalence of this larger change was much lower (cumulative prevalence of 0.79% versus 6.9% with 257% versus 230% change in eGFR over 2 years, respectively) (Figure 8). 316 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Figure 8. 30% decrease in eGFR over 2 years robustly predicts increased ESRD risk. ESRD associated with percentage change in eGFR during a 2-year baseline period. Values were trimmed at ,270% change (0.22% and 0.055% of the study population for eGFR,60 [A] and $60 ml/min per 1.73 m2 [B], respectively) and .40% change (5.9% and 0.51% of the population for eGFR,60 [A] and $60 ml/min per 1.73 m2 [B], respectively). In top panels, the diamonds indicate the reference point of 0% change in eGFR. Reprinted with permission from Coresh J, Turin TC, Matsushita K, Sang Y, Ballew SH, Appel LJ, Arima H, Chadban SJ, Cirillo M, Djurdjev O, Green JA, Heine GH, Inker LA, Irie F, Ishani A, Ix JH, Kovesdy CP, Marks A, Ohkubo T, Shalev V, Shankar A, Wen CP, de Jong PE, Iseki K, Stengel B, Gansevoort RT, Levey AS; CKD Prognosis Consortium: Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JAMA 311: 2518– 2531, 2014 It is assumed that increased proteinuria is correlated with increased CKD progression. Turin et al. (40) quantified the decrease in annual eGFR by baseline eGFR level and proteinuria divided into normal, mild, or heavy categories. There were 638,150 adults in the Alberta Canada registry with more than three creatinine measurements over $1 year with either dipstick proteinuria or ACR. Proteinuria was categorized as normal (urine dipstick negative), mild (urine dipstick trace or 11), or heavy (urine dipstick 21). In sensitivity analyses, ACR was used with proteinuria categories classified as normal (ACR,30 mg/g), mild (ACR¼30– 300 mg/g), or heavy (ACR.300 mg/g). The eGFR decrease could not be adjusted for BP control, smoking, 317 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 or lipid status. Notably, in those with stage 4 CKD with no or mild proteinuria, eGFR remained stable or actually increased. Changes smaller than a doubling of serum creatinine (57% reduction in eGFR) predict ESRD. The 10-year risks of ESRD and death were 64% and 50%, respectively, for a 30% decrease in eGFR over 2 years. Volume Overload Fluid overload may be a risk factor for progression of CKD independent of hypertension, because this may lead to vascular remodeling, diastolic dysfunction, and inflammation. Chen et al. (41) had previously reported that an enlarged left atrial diameter, a reflection of volume overload and diastolic dysfunction, was associated with faster decline in eGFR. Tsai et al. (42) enrolled 472 Taiwanese patients with stages 4 or 5 CKD in a prospective, observational study to discern whether fluid overload was independently related to initiation of RRT or rapid progression of CKD (.3 ml/min per 1.73 m2 per year). During a median follow-up of 17.3 months, RRT was initiated in 15%, and 39.6% had rapid CKD progression. Bioimpedance spectroscopy was used to determine the degree of fluid overload as the difference between measured and expected extracellular water. Those in the highest tertile of fluid overload, corresponding to .1.6 L, had an increased HR of 3.16 (95% CI, 1.33 to 7.50; P¼0.01) versus the lowest tertile (,0.6 L). The highest tertile of relative hydration status (fluid overload/extracellular water), corresponding to .11%, similarly showed a .3-fold increased adjusted HR (HR, 3.08; 95% CI, 1.33 to 7.16; P¼0.01) compared with the lowest tertile. The adjusted ORs for rapid progression in the highest tertiles of fluid overload and relative hydration status were both .4 compared with the lowest tertile (adjusted OR, 4.68; 95% CI, 2.30 to 9.52 and adjusted OR, 4.15; 95% CI, 2.06 to 8.36, respectively). Adjustments included systolic BP, cardiovascular disease (CVD), and diabetes. The study had limitations, because there was only baseline rather than time-varying measurements of fluid overload. Rapid progression may have been the cause rather than the result of fluid overload. Baseline characteristics associated with more fluid overload are related to CKD progression, thereby making adjustments complex. However, subsets of patients in the highest fluid overload tertile without CVD, diabetes, or serum albumin ,3.5 g/dl also had an increased adjusted HR for RRT compared with the lowest tertile (HR, 3.53; 95% CI, 1.43 to 8.69; HR, 6.38; 95% CI, 1.44 to 28.32; and HR, 2.77; 95% CI, 1.0 to 7.01 without CVD, diabetes, or serum albumin ,3.5 g/dl, respectively). The bioimpedance device has been validated for the general population and in ESRD but not in CKD. Tsai et al. (43) hypothesized that fluid overload may be even more important than diabetes for rapid progression and initiation of RRT in stages 4 and 5 CKD. Using this same cohort, with 44% of participants having diabetes and fluid overload (defined as relative hydration status .7%; 90th percentile in normal individuals), there were nearly 3- and .4-fold adjusted risks for initiating RRT in patients without and with diabetes, respectively, compared with those who had a hydration status ,7% (43). The adjusted OR for rapid progression was also higher. These results require verification in larger studies, but they are certainly intriguing. Vascular Disease Atherosclerotic vascular disease detected outside of the kidney may predict CKD progression. The anklebrachial index (ABI) is a marker of generalized atherosclerosis. Foster et al. (44) examined if low ABI ,0.9 was associated with the outcomes of rapid eGFR decline defined as decline .3 ml/min per 1.73 m2 per year, incident stage 3 CKD, and incident microalbuminuria. There were 2592 participants in the Framingham Offspring Cohort followed over an average of 9.5 years. Rapid eGFR decline and incident CKD stage 3 occurred in 9% and 11.1% of the cohort, respectively. A low ABI (,0.9) was associated with 3.6-fold increased adjusted odds of rapid eGFR decline. Low ABI was not associated with incident CKD and incident albuminuria in fully adjusted models. Hung et al. (45) examined the relationship between stroke and subsequent ESRD. In a retrospective cohort study of nationwide claims data of 442,355 Taiwanese patients with stroke, 1.8% developed ESRD in a mean follow-up of 4 years. The standardized incident ratio (observed ESRD/expected ESRD) was used as a measure of relative risk for ESRD. The relative risk for ESRD in patients with stroke was 2.78 (95% CI, 2.72 to 2.84). The relative risk for ESRD in young patients ages 25–44 years old with stroke was markedly increased to 22.73 (95% CI, 20.39 to 25.20). When patients with diabetes, hypertension, or prior CKD by claims data were excluded, the relative risks for the entire cohort and those ages 25–44 years 318 old were slightly attenuated (2.27; 95% CI, 2.22 to 2.33 and 17.72; 95% CI, 15.66 to 19.91, respectively). Those who suffered ischemic stroke had a higher standardized incident ratio. The younger age stroke group had a higher prevalence of small vessel disease than the older groups. Hung et al. (45) postulated that stroke in younger patients could be from vasculitis, which could cause renal disease as well, explaining the higher ESRD risk. Participant smoking history, alcohol use, and socioeconomic status adjustments could not be performed, because these data were not captured. Pulsatility and Pulse Pressure Vascular stiffness may cause kidney function decline through damage to small arteries, with pulsatile stress leading to glomerular hypertension. Madero et al. (46) explored the relationship between arterial stiffness and kidney damage in 2129 elderly participants (mean age 74 years old; mean eGFRcys of 79 ml/min per 1.73 m2). There was long follow-up (median follow-up 8.9 years) in this cohort of the Health, Aging, and Body Composition Study (46). Arterial rigidity was measured by aPWV and pulse pressure (PP). In multivariate analysis, aPWV was not associated with rapid decline of eGFR (.3 ml/min per 1.73 m2), but it was associated with a 42% increased chance of incident CKD (95% CI, 1.12 to 1.81), although this required doubling of aPWV. Increase in PP by 10 mmHg was associated with a 9% increased chance (95% CI, 1.02 to 1.16) of rapid decline as well as a 6% increased chance (95% CI, 1.01 to 1.12) of incident CKD. PP may have more accurately predicted renal outcomes than aPWV, because pulsatility is influenced by left ventricular contractility, pattern of left ventricular ejection, and aortic valve competence as well as aortic stiffness. Retinopathy Retinal abnormalities may be associated with renal vascular changes and could be a marker for disease progression. In 1852 participants from the CRIC Study, retinal images were compared with renal outcomes (47). No link was established between retinopathy grade, retinal arteriole diameter or retinal vein diameter, and renal outcomes of ESRD or eGFR decline. Only the highest quartile of retinal arteriole to vein diameter was associated with an increased risk of ESRD compared with the first quartile. Preexisting CVD CVD may increase CKD progression by altering renal hemodynamics with cardiorenal syndrome, increasing Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 susceptibility to AKI by hospitalization and intervention for coronary events, or generalized atherosclerosis with renovascular disease. Left ventricular hypertrophy is used as a surrogate end point for cardiovascular morbidity in patients with CKD. Peterson et al. (48) found no association of left ventricular hypertrophy for the outcome of doubling for SCr or ESRD in 578 participants in the AASK Cohort, although there was an association with CVEs causing hospitalization or death. Sud et al. (49) performed a retrospective cohort study examining the relationship between CVEs (HF, myocardial infarction, and stroke) after initial nephrology consultation and the outcomes of ESRD and all-cause mortality before ESRD. This cohort had 2964 participants with CKD with a mean eGFR of 35 ml/min per 1.73 m2 and a median ACR of 97 mg/g seen in an Ontario nephrology clinic. Data for ESRD and CVEs were obtained from electronic medical records and registry data. Having a CVE after initial nephrology consultation was associated with an adjusted .5-fold increased risk of subsequent ESRD (HR, 5.33; 95% CI, 3.73 to 7.58) and a .4-fold increase in all-cause mortality before ESRD (HR, 4.15; 95% CI, 3.30 to 5.23). Of those who died before ESRD, there was an almost 6-fold increase in cardiovascular-related deaths compared with noncardiovascular-related deaths. Hypoxemia Sleep disturbances and nocturnal hypoxemia could potentially contribute to CKD progression through systemic inflammation, oxidative stress, and RAAS activation with resulting tubulointerstitial injury. In patients with CKD, there may be few sleep–related symptoms in those with sleep apnea (50). Ahmed et al. (51) had previously linked nocturnal hypoxemia with accelerated loss of kidney function (.4 ml/min per 1.73 m2 per year) in an obese cohort (BMI¼32.8 kg/m) with relatively preserved kidney function (eGFR¼70.8 ml/min per 1.73 m2). It is difficult to determine whether CKD progression was attributable to obesity or sleep apnea. Sakaguchi et al. (52) examined the role of nocturnal hypoxemia and GFR loss in 161 Japanese patients who were with not obese and had stage 3 or 4 CKD. The mean BMI was 21.8 kg/m2 (95% CI, 20.1 to 23.1) in this elderly cohort, and the eGFR loss was measured over only 1 year. The mean eGFR of the cohort was 31 ml/min per 1.73 m2. The oxygen desaturation index (ODI) was the frequency of a .4% drop from the baseline oxygen saturation level. Nocturnal hypoxemia was defined as none if ODI was ,5 times per 319 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 hour, mild if ODI was 5–15 times per hour, and moderate to severe if ODI was .15 times per hour. A portable monitor also measured apnea and hypopnea. The moderate to severe nocturnal hypoxemia group had a faster eGFR decline of 28.59 ml/min per 1.73 m2 per year (22 to 15.2) compared with no and mild degrees of hypoxemia. The rates of eGFR loss were 22.13 ml/min per 1.73 m2 per year (21.06 to 23.21) and 23.02 ml/min per 1.73 m2 per year (21.31 to 24.74) in the no and mild hypoxemia groups, respectively. It is unclear if the relationship between hypoxemia and loss of GFR is maintained for the nonobese in other populations. Although the patients were not obese by BMI, visceral adiposity was not measured, and therefore, a contribution from adiposity cannot be ruled out. Hyperuricemia/Allopurinol The possible contribution of hyperuricemia to progression was reviewed in the last NephSAP CKD and progression issue. Proposed mechanisms for uric acid–induced kidney damage include hypertension with RAAS activation, renal afferent arteriolopathy, increased glomerular hypertension, and fibrosis. Allopurinol could be protective by reducing not only serum uric acid but also, oxidative stress by inhibition of xanthine oxidase. A meta-analysis assessing the role of allopurinol and CKD progression included eight heterogeneous trials with 476 participants (53). Median follow-up was only 11 months. The trials had varying entry criteria for GFR, indications (diabetic nephropathy and IgA nephropathy), and allopurinol doses (100–300 mg/d). In five trials that reported GFR, there was a higher GFR in allopurinol versus control groups of 3.1 ml/min per 1.73 m2, but this was not statistically significant (95% CI, 20.9 to 7.1 ml/min per 1.73 m2; P¼0.10). In three trials that reported change in SCr, there was a difference of a decrease of 0.4 mg/dl in the allopurinol-treated group, but this finding was not statistically significant (95% CI, 20.8 to 0.0; P¼0.22). Although serum uric acid was reduced, there was no change in proteinuria or BP in those studies that reported these results. With the potentially severe toxicities with this medication, there is not enough evidence to use allopurinol to slow CKD progression in asymptomatic patients with hyperuricemia and CKD at this time. There have been no trials that have reported the use of febuxostat on CKD progression, although one has completed recruitment (54). Pentoxifylline in Diabetes Figure 9. Pentoxifylline decreases eGFR in open label trial of type 2 diabetic participants. Evolution of the mean eGFR at randomization (basal) and during follow-up in the control and pentoxifylline (PTF) groups. Difference of the mean eGFR between groups shows statistical significance after 24 months of follow-up. Vertical bars represent the SDs. P values are for the comparison of the PTF group with the control group. Reprinted with permission from NavarroGonzález JF, Mora-Fernández C, Muros de Fuentes M, Chahin J, Méndez ML, Gallego E, Macía M, del Castillo N, Rivero A, Getino MA, García P, Jarque A, García J: Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: The PREDIAN trial. J Am Soc Nephrol 26: 220–229, 2015. Recent treatments for diabetic kidney disease have been disappointing. Pentoxifylline (PTF) has been used for peripheral vascular disease and has anti-inflammatory, antiproliferative, and antifibrotic actions. Goicoechea et al. (55) previously performed a 1-year-long trial using PTF, which showed not only a decrease in inflammatory measurements but also, a benefit on slowing progression (approximately 6.8 ml/min per 1.73 m2 between groups. Navarro-González et al. (56) performed a larger 2-year, open-label, controlled trial using PTF. The trial included 169 Whites with type 2 diabetes on RAAS blockers. The BP control, glucose control, and kidney parameters were well matched at baseline (eGFR: 37.6 versus 37.1 ml/min per 1.73 m2 by MDRD and urine albumin excretion: 1000 versus 1100 mg/d in the control versus PTF groups, respectively). The eGFR with PTF had slower progression, because eGFR decreased by 2.160.4 compared with 6.560.4 ml/min per 1.73 m2 in the control group at the end of 2 years (Figure 9). Urine albumin decreased by 14.9% (95% CI, 220.4% to 29.4%) with PTF, whereas it increased by 5.7% (95% CI, 20.3% to 11.1%) in the control group. ESRD was infrequent in both groups, occurring in 2 of 82 patients with PTF treatment compared 320 with 3 of 87 patients in the control group. There was no difference in hospitalization or CVEs between the two groups, but there were more side effects (transient digestive symptoms in 21.9% assigned to the PTF group versus 10.3% in control group). Urinary TNF-a also decreased with PTF. These preliminary results of this limited, single–center, open–label trial are exciting. This enthusiasm should be balanced by experience with prior trials aimed at slowing diabetic nephropathy that showed early promise but were not effective in larger studies. Microbiome The role of the gut microbiome will be discussed in more detail in the cardiovascular section. Briefly, the gut microbiota is altered with CKD. Increased fermentation by certain harmful bacteria leads to increased toxic metabolites, such as p-cresol and indoxyl sulfate. Short–chain fatty acids produced by certain bacteria may protect against kidney injury. A disrupted gut barrier leads to increased endotoxin translocation, which also contributes to the increased inflammatory state in CKD. There have been prior trials with prebiotics, nondigested food products that promote the growth of bacteria that are beneficial, and probiotics, which are reviewed by Ramezani and Raj (57). However, there was no demonstration of a decrease in progression. The phase 3 trial that evaluated the orally administered spherical carbon adsorbent AST-120 (note there is no abbreviation for AST-120) that binds gut indoxyl sulfate was reported in the last NephSAP CKD and progression issue. This trial showed no difference in CKD progression with treatment. Interventions aimed at restoring the gut microbiome in CKD will be an area of increased future research. Prediction Models The ability to accurately predict who will have rapidly progressive CKD would help providers focus on which patients need closer monitoring and earlier nephrology referral. In 2011, Tangri et al. (58) constructed prediction models for RRT that were developed and validated in Canadian patients with stages 3–5 CKD. The eight-variable model by Tangri et al. (58) used age, sex, eGFR, albuminuria, serum calcium, serum phosphate, serum bicarbonate, and serum albumin to predict dialysis or preemptive kidney transplant in individuals with stages 3–5 CKDs. The ROC curve C statistics were 0.92 and 0.84 for the prediction of progression to ESRD in their development and validation cohorts, respectively. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 The net classification improvement for outcome was superior to the other models with fewer variables by Tangri et al. (58). A meta-analysis of prediction models for patients with CKD determined the models by Tangri et al. (58) above to be the most clinically useful for predicting CKD progression (59). Elley et al. (60) aimed to develop a prediction model specifically for individuals with type 2 diabetes and less advanced CKD. This group used the New Zealand Diabetes Cohort Study, which included 25,736 individuals with median eGFR of 77 ml/min per 1.73 m2. The most complex model by Elley et al. (60) included sex, ethnicity in New Zealand, age, diabetes duration, albuminuria, SCr, systolic BP, hemoglobin A1C, smoking status, and history of CVD. This 10-variable model performed well in the derivation and validation cohorts for predicting the outcomes of ESRD or death with ESRD as a contributing cause (ROC curve C statistics: 0.89 and 0.92, respectively). This 10-variable model for individuals with type 2 diabetes and higher eGFR values outperformed the models by Tangri et al. (58) in predicting fatal and nonfatal ESRD outcomes. It is unclear if the model by Tangri et al. (58) was used as a comparator in the study. Death was not one of the outcomes tested for in the models by Tangri et al. (58). Elley et al. (60) felt that inclusion of ethnicity in New Zealand increased the accuracy of the model. For adults .65 years old, Drawz et al. (61) created a model for predicting ESRD at 1 year in those with baseline eGFR values ,30 ml/min per 1.73 m2. This was developed in 1866 veteran participants. The model used age, systolic BP, eGFR, potassium, serum albumin, and CHF. Interestingly, proteinuria was not helpful for improving prediction of ESRD in this model. In the validation cohort, the C statistic was 0.82 compared to 0.78 using the model by Tangri et al. (58). Rucci et al. (62) examined predictive factors that determined annual decline in eGFR before ESRD in the Prevention of Renal Insufficiency Progression Project. This study included 2265 participants in Italy who had four or more SCr measurements in 1 year. In general, this was an elderly cohort with mean age of 71 years old, and mean eGFR by the CKD-EPI equation was 28.8 ml/min per 1.73 m2. As expected, those with proteinuria (urine dipstick .20 mg/L or urine albumin .20 mg/L) had a greater annual rate of decline. Those with proteinuria and eGFR.33 ml/min per 1.73 m2 had the fastest progression of 23.66 ml/min per 1.73 m2 per year. Individuals who were proteinuric with eGFR,33 ml/min per 1.73 m2 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 and serum phosphorus .4.3 mg/dl had a decline of 22.83 ml/min per 1.73 m2 per year. If proteinuria was absent and age was ,67 years old, individuals with diabetes had a progression of 22.98 ml/min per 1.73 m2 per year. The inclusion of ethnicity and CVD may improve the performance of future prediction models for progression to ESRD. However, vascular disease, defined as cardiovascular and peripheral vascular, was not predictive in the models by Tangri et al. (58). Conclusions Blacks have an increased incidence of CKD. Those with two APOL1 risk variants were shown to have increased risk of CKD progression. Black participants without diabetes and with two high–risk APOL1 alleles in the AASK Study had a higher risk of doubling their SCr or developing ESRD. Blacks with or without diabetes and with two APOL1 risk alleles had faster CKD progression and higher chance of ESRD or .50% decrease in measured GFR. Additional genes, inflammation, infection, or environmental factors are required to cause progressive CKD in individuals with high–risk APOL1 variants. Adiposity is linked to CKD progression and most likely caused by associated hypertension, insulin resistance, and inflammation. Obesity is traditionally quantified by BMI, but this may not be the optimal measure for risk in patients with CKD. Studies showed that central adiposity as measured by WHR or visceral adiposity as measured by liver ultrasound or magnetic resonance imaging may prove more accurate in determining the risk of CKD progression. One large cohort study revealed that low BMIs may have attendant risks for progressive CKD as well. Nephrologists may counsel on alterations in food content, exercise, and finally, bariatric surgery for the severely obese in attempts to slow CKD progression, although there are no large therapeutic trials that validate these measures. Studies that assessed dietary interventions to slow CKD progression showed mixed results. Fluid intake did not seem to influence GFR in a large Australian cohort. Dietary patterns did not seem to alter incidence of ESRD in the REGARDS cohort, although plant-based diets were associated with improved mortality for patients with CKD, whereas Southern diets were associated with increased mortality. Because the competing risk of death was 6-fold higher than ESRD, a beneficial effect may have been masked. In the ONTARGET cohort of 321 individuals with diabetes, the healthiest tertile diet had a 27% lower risk of incident CKD. A pilot study using a low-protein diet supplemented with a-keto analogs of essential amino acids showed some initial promise in slowing eGFR loss in those with rapidly progressive stage 3, stage 4, or nondialysis stage 5 CKD and those with refractory proteinuria. In pregnant women with CKD, this diet seemed to decrease the likelihood of small for gestational age babies but did not show a significant improvement in longer–term infant growth or kidney maternal outcomes. Two cohort studies with varying sodium intakes did not seem to show an improvement in CKD progression. A post hoc analysis of dietary sodium intake in participants in the MDRD Study showed that urinary excretion of ,3 g/d was associated with protection against kidney failure in those with ,1 g/d proteinuria but increased risk with the same restriction for those with .1 g/d proteinuria. A placebo, controlled, cross–over trial of short duration confirmed the benefits of low-sodium intake of 60–80 mmol/d on reducing BP and proteinuria, although clinical results could not be assessed. Perhaps overadjustments for BP and albumin excretion in observational studies of sodium intake attenuate associations with improved kidney outcomes. However, there does not seem to be a benefit in restricting sodium intake to ,2–3 g/d in these observational studies. As mentioned previously, counseling or a goal for sodium restriction does not necessarily equate to actual intake for patients. Lower serum bicarbonate may be a biomarker of progressive CKD. In addition, in carefully selected patients without hyperkalemia, a diet high in F1V that provides alkali as potassium citrate seemed to stabilize GFR as well as sodium bicarbonate in trials of participants with acidotic stage 4 CKD as well as stage 3 CKD with normal serum bicarbonate but severely increased albuminuria. Optimal serum bicarbonate levels are unknown. Participants in the CRIC cohort who had higher serum bicarbonate over 24 mEq/L had an increased association with CHF. Excessive volume overload may be a risk factor independent of hypertension, diabetes, and CVD for CKD progression, because it can lead to vascular remodeling and inflammation. A Taiwanese cohort study of stages 4 and 5 CKD showed that those with volume overload measured by baseline bioimpedance spectroscopy had an increased risk for RRT and rapid progression. Tsai et al. (43) felt that fluid overload was more important than diabetes in CKD progression in a separate analysis. This 322 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 association is intriguing, although confirmation in other studies will be required. The presence of vascular disease is associated with CKD progression. Atherosclerosis detected by a low ABI and stroke was associated with markedly increased odds for RRT in observational studies. Increased PP was associated with small increased odds of a rapid eGFR decline and incident CKD. aPWV was associated with a 42% increase in incident CKD but required a doubling of this value. Retinal abnormalities in the CRIC Study were not associated with ESRD or eGFR decline. A CVE in those with CKD referred to nephrology predicted ESRD. It is unclear if sleep disorders play a role in CKD progression because of the difficulty in separating the independent effects of sleep disorders and obesity. In a Japanese cohort with moderate CKD and normal BMI, nocturnal hypoxemia was associated with more rapid GFR loss. End points for CKD progression have traditionally been selected as a doubling of SCr or ESRD. Data from the large Chronic Kidney Disease Prognosis Consortium suggest that a .30% decline in eGFR over 2 years is strongly associated with ESRD. 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Sakaguchi Y, Hatta T, Hayashi T, Shoji T, Suzuki A, Tomida K, Okada N, Rakugi H, Isaka Y, Tsubakihara Y: Association of nocturnal hypoxemia with progression of CKD. Clin J Am Soc Nephrol 8: 1502–1507, 2013 PubMed 53. Bose B, Badve SV, Hiremath SS, Boudville N, Brown FG, Cass A, de Zoysa JR, Fassett RG, Faull R, Harris DC, Hawley CM, Kanellis J, Palmer SC, Perkovic V, Pascoe EM, Rangan GK, Walker RJ, Walters G, Johnson DW: Effects of uric acid-lowering therapy on renal outcomes: A systematic review and meta-analysis. Nephrol Dial Transplant 29: 406–413, 2014 PubMed 54. Hosoya T, Kimura K, Itoh S, Inaba M, Uchida S, Tomino Y, Makino H, Matsuo S, Yamamoto T, Ohno I, Shibagaki Y, Iimuro S, Imai N, Kuwabara M, Hayakawa H: The effect of febuxostat to prevent a further reduction in renal function of patients with hyperuricemia who have never had gout and are complicated by chronic kidney disease stage 3: Study protocol for a multicenter randomized controlled study. Trials 15: 26, 2014 PubMed 55. Goicoechea M, García de Vinuesa S, Quiroga B, Verdalles U, Barraca D, Yuste C, Panizo N, Verde E, Muñoz MA, Luño J: Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: A randomized trial. J Nephrol 25: 969–975, 2012 PubMed 56. Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, Chahin J, Méndez ML, Gallego E, Macía M, del Castillo N, Rivero A, Getino MA, García P, Jarque A, García J: Effect of pentoxifylline on renal function and urinary albumin excretion in patients with diabetic kidney disease: The PREDIAN trial. J Am Soc Nephrol 26: 220–229, 2015 PubMed 57. Ramezani A, Raj DS: The gut microbiome, kidney disease, and targeted interventions. J Am Soc Nephrol 25: 657–670, 2014 PubMed 58. Tangri N, Stevens LA, Griffith J, Tighiouart H, Djurdjev O, Naimark D, Levin A, Levey AS: A predictive model for progression of chronic kidney disease to kidney failure. JAMA 305: 1553–1559, 2011 PubMed 59. Tangri N, Kitsios GD, Inker LA, Griffith J, Naimark DM, Walker S, Rigatto C, Uhlig K, Kent DM, Levey AS: Risk prediction models for patients with chronic kidney disease: A systematic review. Ann Intern Med 158: 596–603, 2013 PubMed 60. Elley CR, Robinson T, Moyes SA, Kenealy T, Collins J, Robinson E, Orr-Walker B, Drury PL: Derivation and validation of a renal risk score for people with type 2 diabetes. Diabetes Care 36: 3113–3120, 2013 PubMed 61. Drawz PE, Goswami P, Azem R, Babineau DC, Rahman M: A simple tool to predict end-stage renal disease within 1 year in elderly adults with advanced chronic kidney disease. J Am Geriatr Soc 61: 762–768, 2013 PubMed 62. Rucci P, Mandreoli M, Gibertoni D, Zuccalà A, Fantini MP, Lenzi J, Santoro A; Prevention of Renal Insufficiency Progression (PIRP) Project: A clinical stratification tool for chronic kidney disease progression rate based on classification tree analysis. Nephrol Dial Transplant 29: 603–610, 2014 PubMed Diabetic Kidney Disease and Kidney Biopsy The classic course of diabetic nephropathy is development of increasing albuminuria from microalbuminuria to overt proteinuria and then, decline in glomerular filtration, leading to ESRD. It has now been recognized that many individuals with diabetes develop kidney disease with a low eGFR but without overt Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 proteinuria. Recent studies have found that this heterogeneity in kidney disease is also reflected in a corresponding heterogeneity in kidney biopsies, particularly in those without overt albuminuria. Ekinci et al. (1) invited patients attending the Diabetes Clinics at Austin Health with type 2 diabetes, an eGFR ,60 ml/min per 1.73 m2, and an albuminuria ,200 mg/min (approximately 300 mg/d) to participate in a study that included a kidney biopsy; 14 participants (10 with normoalbuminuria and 4 with microalbuminuria, although 2 with normoalbuminuria had microalbuminuria after renin-angiotensin-aldosterone system blocking agents were held) were biopsied. The biopsy results from these research biopsies were compared with biopsies from individuals with diabetes and overt proteinuria who underwent biopsies for clinical indications (n¼17). Typical histologic changes consistent with diabetic nephropathy were seen in all patients with macroalbuminuria, five of six (83%) patients with microalbuminuria, and only three of eight patients with normoalbuminuria (mean eGFR ¼31 ml/min per 1.73 m2). In three of eight patients with normoalbuminuria, predominantly vascular or interstitial changes were seen. The mean mesangial area was greater, with greater degrees of albuminuria (Figure 10). Most kidney biopsies in individuals with diabetes are done because of atypical clinical factors that suggest a nondiabetic process. Sharma et al. (2) reviewed all consecutive native renal biopsies from 2011 that had been reviewed at the Columbia Renal Pathology Laboratory. Of 2642 biopsies during this time period, almost one quarter (23.5%) were performed in individuals with diabetes. Diabetic nephropathy alone was found in 37% of specimens, diabetic nephropathy plus nondiabetic kidney disease was found in 27% of specimens, and nondiabetic kidney disease alone was found in 36% of biopsies. Although the proportion with nondiabetic kidney disease is high, it is important to remember that this is a selected population that underwent biopsy for clinical reasons. The study also evaluated clinical predictors of finding diabetic kidney disease or nondiabetic kidney disease. The main predictor was duration of diabetes. A longer duration of diabetes was associated with a greater likelihood of finding diabetic nephropathy and a lower likelihood of finding nondiabetic kidney disease; each additional 1 year of diabetes decreased the odds of nondiabetic kidney disease by 5%. Using receiver operating characteristic curves, a duration of diabetes Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Figure 10. Increase in mean mesangial area with greater levels of albuminuria in type 2 diabetes. The figure shows mean mesangial area (micrometer2) across normal controls (normal C), patients with type 2 diabetes and normoalbuminuria (normo), patients with type 2 diabetes and microalbuminuria (micro), and patients with type 2 diabetes and macroalbuminuria (macro). P¼0.02 (one-way ANOVA for mean mesangial area across four groups). Reprinted with permission from Ekinci EI, Jerums G, Skene A, Crammer P, Power D, Cheong KY, Panagiotopoulos S, McNeil K, Baker ST, Fioretto P, Macisaac RJ: Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care 36: 3620–3626, 2013. $12 years was the best predictor of finding diabetic nephropathy alone (57.5% sensitivity, 73.3% specificity, 56.0% positive predictive value, and 74.5% negative predictive value). References 1. Ekinci EI, Jerums G, Skene A, Crammer P, Power D, Cheong KY, Panagiotopoulos S, McNeil K, Baker ST, Fioretto P, Macisaac RJ: Renal structure in normoalbuminuric and albuminuric patients with type 2 diabetes and impaired renal function. Diabetes Care 36: 3620–3626, 2013 PubMed 2. Sharma SG, Bomback AS, Radhakrishnan J, Herlitz LC, Stokes MB, Markowitz GS, D’Agati VD: The modern spectrum of renal biopsy findings in patients with diabetes. Clin J Am Soc Nephrol 8: 1718–1724, 2013 PubMed Renin-Angiotensin-Aldosterone System Blockers It is not uncommon that physicians are uncomfortable treating individuals with advanced kidney disease with an angiotensin–converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB). However, 325 the benefits and harms of continuing ACEI or ARB use have not been directly studied. Using the National Health Insurance Research Database in Taiwan, Hsu et al. (1) evaluated the association between use of ACEIs or ARBs and risk of ESRD in adult individuals with stage 5 CKD who had hypertension and were treated with erythropoiesisstimulating agents. Hsu et al. (1) identified 28,497 individuals with stage 5 CKD, approximately one half of which were on an ACEI, an ARB, or both. The mean age of the population was 65 years old. Users of ACEIs or ARBs were younger and more likely to have diabetes or cardiovascular disease. The majority of users and nonusers progressed to ESRD (70.7%), whereas 20% died before reaching ESRD. Users of ACEIs or ARBs were less likely to progress to dialysis (hazard ratio [HR], 0.94; 95% confidence interval [95% CI], 0.91 to 0.97) or the composite end point of dialysis or mortality (HR, 0.94; 95% CI, 0.92 to 0.97). Although the benefit was small, it is encouraging that the outcomes are not worse in those taking ACEIs or ARBs, which would counter the practitioner tendency to stop these medications in advanced CKD. Although analyses of outcomes of users versus nonusers of medications are potentially biased, it is important to note that there are also no randomized studies that suggest that we should stop ACEI or ARB use in patients with advanced kidney disease. The only randomized study in individuals with advanced kidney disease (SCr 3.1–5.0 mg/dl) and proteinuria showed that starting an ACEI or ARB slowed progression (doubling of SCr, ESRD, or death) (2). Thus, the weight of evidence supports continuing ACEIs or ARBs in patients with advanced kidney disease who are tolerating the medications, especially if they are proteinuric. Treatment with an ACEI or ARB decreases the progression of kidney disease in patients with proteinuria (3–6). The percentage reduction in proteinuria with these agents is a marker of response and correlates with benefit; residual proteinuria after use of ACEIs and ARBs predicts progression (7). Imai et al. (8), in a secondary analysis of the Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy (ORIENT) Study, evaluated the association of baseline proteinuria level, percentage reduction in proteinuria, and residual proteinuria with doubling of SCr, ESRD, or death. 326 The ORIENT Study was a double-blind study of olmesartan versus placebo added onto standard of care in patients with type 2 diabetes and an albumin to creatinine ratio (ACR) .300 mg/g. Standard of care could include an ACEI, and therefore, the olmesartan group was a mix of patients on dual therapy (73%) and monotherapy (27%), which was compared with a placebo group that was predominantly on an ACEI (9). The mean age was 59 years old, mean creatinine was 1.62 mg/dl, and median urine ACR was 1.7 g/g. For baseline proteinuria, compared with individuals with albuminuria ,1 g/g, the risk of progression was three times higher in individuals with an ACR of 1–3 g/g and nine times higher in those with an ACR.9 g/g. Percentage reduction in proteinuria and residual proteinuria (proteinuria at 24 weeks) were both associated with progression, with the lowest risk being for those individuals who had residual proteinuria ,1 g and ,30% reduction. However, the title of the paper labeling albuminuria as a therapeutic target implies that the percentage change was a response to treatment. The association of proteinuria and change in proteinuria with progression was seen in both placebo and olmesartan groups. The study overall was negative with regards to progression (HR, 0.97; 95% CI, 0.76 to 1.24) (9). Therefore, the association of albuminuria and change in albuminuria with outcomes indicates that it is a risk marker, and the study does not inform us regarding a benefit of adding olmesartan Because 73% of the individuals in the ORIENT Study were on an ACEI at baseline, the study was primarily a study of combination ARB plus ACEI versus monotherapy with ACEI alone. As reviewed in the prior CKD NephSAP issue, combination therapy has been shown to decrease proteinuria but has not been shown to improve outcomes. Makani et al. (10) performed a meta-analysis of studies of dual blockade of the renin-angiotensin system. Studies were included if they reported data on long-term efficacy ($1 year) or safety ($4 weeks) with a sample size of at least 50 individuals. Analysis was stratified by trials of heart failure (HF) versus nonHF studies; few studies were in patients with kidney disease. The studies included seven efficacy studies with 56,824 subjects, and five were HF studies. Dual therapy had no benefit on mortality overall. There seemed to be a difference in mortality outcomes when stratified by HF versus non-HF studies (P for interaction ¼0.02). Combining the two non-HF studies (the Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial and Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE)), dual therapy was associated with a small increase in mortality in those without HF (HR, 1.07; 95% CI, 1.0 to 1.14; P¼0.04). In contrast, there was not an increased risk in those without HF (HR, 0.96; 95% CI, 0.88 to 1.05). Dual therapy led to a decrease in admissions for HF overall (HR, 0.82; 95% CI, 0.74 to 0.92), in those with HF (HR, 0.77; 95% CI, 0.68 to 0.88), and in those without HF (HR, 0.91; 95% CI, 0.82 to 1.01). In studies with and without HF, dual therapy was associated with an increased risk of hyperkalemia, hypotension, and withdrawal caused by drug–related adverse events. Dual therapy was also associated with an increased risk of renal failure indicated as SCr .2.0 mg/dl or a doubling of SCr (HR, 1.41; 95% CI, 1.09 to 1.84), which was predominantly caused by an increased risk in the studies with HF (HR, 2.19; 95% CI, 1.82 to 2.65). Since publication of the meta-analysis, VA NEPHRON-D: Diabetes in Nephropathy Study was published (11). VA NEPHRON-D compared dual therapy with losartan and lisinopril with monotherapy with losartan (plus placebo) in individuals with type 2 diabetes, ACR.300 mg/g, and eGFR¼30–89.9 ml/min per 1.73 m2. The primary outcome was time for first event of all-cause mortality, ESRD, or progression of CKD (absolute reduction of eGFR by at least 30 ml/min per 1.73 m2 if baseline eGFR was between 60 and 89.9 ml/min per 1.73 m2 at enrollment and halving of eGFR if baseline eGFR was ,60 ml/min per 1.73 m2). The study was stopped early by the data monitoring safety committee; 1448 individuals were randomized, mean age was 65 years old, mean eGFR was 54 ml/min per 1.73 m2, and median urine ACR was 845 mg/g. There was no significant benefit on the primary end point (HR, 0.88; 95% CI, 0.70 to 1.12), renal progression (change in eGFR or ESRD; HR, 0.78; 95% CI, 0.58 to 1.05), or all-cause mortality (HR, 1.04; 95% CI, 0.73 to 1.49) (Figure 11). As anticipated, combination therapy decreased the ACR (baseline to 1 year: 786 to 517 mg/g in the combination group versus 829 to 701 mg/g in the monotherapy group). There was a significantly increased risk of hyperkalemia (serum potassium .6 mEq/L that required an ER visit, admission, or dialysis; HR, 2.8; 95% CI, 1.8 to 4.3) and AKI (HR, 1.7; 95% CI, 1.3 to 2.2). AKI events were considered serious adverse events that required or occurred during Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 327 Figure 11. Dual therapy versus monotherapy on primary end point, renal end point, and mortality in the VA NEPHRON-D Study (A) Primary endpoint (time for first event of all-cause mortality, ESRD, or progression of CKD (absolute reduction of eGFR by at least 30ml/min per 1.73 m2 if baseline eGFR was between 60 and 89.9 ml/min per 1.73 m2 at enrollment and halving of eGFR if baseline eGFR was, 60 ml/min per 1.73 m2); (B) secondary endpoint ESRD or progression of CKD; (C) all-cause mortality. CI, confidence interval. Reprinted with permission from Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O’Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D Investigators: Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 369: 1892–1903, 2013. 328 admission, but outpatient changes in creatinine were not considered AKI events. Combination ACEI plus ARB decreases albuminuria but does not significantly decrease progression of kidney disease and is associated with an increased risk of AKI and hyperkalemia. The addition of a mineralocorticoid receptor blocker to an ACEI or an ARB is another approach for dual therapy. The addition of spironolactone to full-dose ACEI lowers proteinuria more than dual ACEI plus ARB therapy (12,13). However, it is associated with a much higher risk of hyperkalemia, especially in individuals with reduced eGFR. Van Buren et al. (14) reported on hyperkalemia in a randomized study comparing the addition of placebo, losartan (100mg), or spironolactone (25mg) to lisinopril (80 mg) in patients with diabetes and proteinuria. Full details of the study results have been previously published (12). The study enrolled 81 individuals with a mean creatinine clearance of 64.5 ml/min and mean albuminuria of 1 g determined from 24-hour urine collections. Compared with placebo, spironolactone decreased albuminuria by 34%, and losartan decreased albuminuria by 17%. A potassium level .6.0 mEq/L occurred in 7.4%, 38.5%, and 51.9% in the placebo, losartan, and spironolactone groups, respectively. In addition to study medications, higher baseline potassium levels (.4.5 mEq/L) and lower 24-hour creatinine clearances were predictors of hyperkalemia. Esteghamati et al. (13) performed an 18-month open–label study of spironolactone added to an ARB in 136 individuals with diabetes and ACR.30 mg/g. At baseline, individuals were being treated with combination therapy with enalapril (30–40 mg/d) and losartan (50–100 mg/d) for at least 1 year. Then, participants were randomized to either a group that continued their ACEI and ARB combination or one that underwent enalapril washout with spironolactone substitution at 25 mg daily. The mean age was 58 years old, mean eGFR was approximately 70 ml/min per 1.73 m2, and the majority had microalbuminuria (72%). Spironolactone led to a greater reduction in BP (18% difference in systolic BP and 16% difference in diastolic BP) and albuminuria (8.4%) at 18 months. The change in SCr over time was similar in the two groups. The risk of discontinuation because of hyperkalemia was low. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 However, because the study enrolled individuals who had been tolerating dual ACEI and ARB therapy for over 1 year and did not have advanced kidney disease, the study may have enrolled a group at lower risk for hyperkalemia (mean serum K and the cutoff for hyperkalemia were not defined). At this time, hyperkalemia would be the limiting factor to studying whether a mineralocorticoid receptor antagonist decreases the risk of progression of CKD. Whether one of two new potassium–lowering medications currently under development, patiromer (15) and sodium zirconium cyclosilicate (16), would allow continuation of spironolactone as GFR declines, enabling an outcomes study to be conducted, deserves additional consideration. However, these medications have not been approved by the Food and Drug Administration at the time that this issue was composed. References 1. Hsu TW, Liu JS, Hung SC, Kuo KL, Chang YK, Chen YC, Hsu CC, Tarng DC: Renoprotective effect of renin-angiotensin-aldosterone system blockade in patients with predialysis advanced chronic kidney disease, hypertension, and anemia. JAMA Intern Med 174: 347–354, 2014 PubMed 2. Hou FF, Zhang X, Zhang GH, Xie D, Chen PY, Zhang WR, Jiang JP, Liang M, Wang GB, Liu ZR, Geng RW: Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 354: 131–140, 2006 PubMed 3. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345: 861–869, 2001 PubMed 4. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: 851–860, 2001 PubMed 5. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD; The Collaborative Study Group: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329: 1456–1462, 1993 PubMed 6. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P; The Angiotensin-ConvertingEnzyme Inhibition in Progressive Renal Insufficiency Study Group: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 334: 939–945, 1996 PubMed 7. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, Snapinn S, Cooper ME, Mitch WE, Brenner BM: Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: Lessons from RENAAL. Kidney Int 65: 2309–2320, 2004 PubMed 8. Imai E, Haneda M, Chan JCN, Yamasaki T, Kobayashi F, Ito S, Makino H: Reduction and residual proteinuria are therapeutic targets in type 2 diabetes with overt nephropathy: A post hoc analysis (ORIENT-proteinuria). Nephrol Dial Transplant 28: 2526–2534, 2013 PubMed Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 9. Imai E, Chan JC, Ito S, Yamasaki T, Kobayashi F, Haneda M, Makino H; ORIENT study investigators: Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: A multicentre, randomised, placebo-controlled study. Diabetologia 54: 2978–2986, 2011 PubMed 10. Makani H, Bangalore S, Desouza KA, Shah A, Messerli FH: Efficacy and safety of dual blockade of the renin-angiotensin system: Meta-analysis of randomised trials. BMJ 346: f360, 2013 PubMed 11. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O’Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D Investigators: Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 369: 1892–1903, 2013 PubMed 12. Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD: Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 20: 2641–2650, 2009 PubMed 13. Esteghamati A, Noshad S, Jarrah S, Mousavizadeh M, Khoee SH, Nakhjavani M: Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: A randomized clinical trial. Nephrol Dial Transplant 28: 2823–2833, 2013 PubMed 14. Van Buren PN, Adams-Huet B, Nguyen M, Molina C, Toto RD: Potassium handling with dual renin-angiotensin system inhibition in diabetic nephropathy. Clin J Am Soc Nephrol 9: 295–301, 2014 PubMed 15. Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, Wittes J, Christ-Schmidt H, Berman L, Pitt B; OPAL-HK Investigators: Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med 372: 211–221, 2015 PubMed 16. Packham DK, Rasmussen HS, Lavin PT, El-Shahawy MA, Roger SD, Block G, Qunibi W, Pergola P, Singh B: Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 372: 222–231, 2015 PubMed 329 images of plaque on the basis of the emission and reflection of near-infrared light (3–5). Using the Massachusetts General Hospital Optical Coherence Tomography Multicenter Registry, Kato et al. (6) evaluated the plaque characteristics in patients with and without CKD. Kato et al. (6) analyzed 61 plaques in 37 patients with CKD and 402 plaques in 250 patients without CKD. CKD was defined as an eGFR,60 ml/min per 1.73 m2, and the mean eGFR in individuals with CKD was 48 ml/min per 1.73 m2. The plaques in individuals with CKD had a higher prevalence of calcification, cholesterol crystal, and disruption, with a trend toward a greater prevalence of thrombus (Figure 12). These findings may indicate more vulnerable plaques (7). Nakano et al. (8) evaluated the relationship of CKD with neovascularization and intraplaque hemorrhage in coronary atherosclerosis in autopsies of elderly residents of Hisayama, Japan. The Hisayama study is a population-based study with autopsy verification of death in 75% of those who died. For the current analysis, Nakano et al. (8) randomly selected 126 subjects from 844 consecutive autopsies. In individuals with an eGFR,45 ml/min per 1.73 m2, there was a statistically Cardiovascular Disease Since the last issue of CKD NephSAP, there have been many articles on cardiovascular disease (CVD) in CKD. We cannot cover all of the interesting and relevant articles that address CVD and have primarily focused this section on subtopics that are most applicable to clinical practice or could become applicable in the near future. Coronary Plaque Characteristics in CKD In the last issue of NephSAP, we reviewed studies that showed that the characteristics of coronary plaques differ between those with and without CKD. One particular factor that may increase the risk of a cardiovascular event (CVE) is that individuals with CKD are more likely to have thin-cap fibroatheromas (1), which increases the likelihood of plaque rupture (2). Recent studies have further refined the information regarding coronary plaque. Intracoronary optical coherence tomography is an intravascular technique that produces high-resolution Figure 12. Qualitative optical coherence tomography findings. Compared with non-CKD plaques, plaques with CKD had a higher prevalence of calcification, cholesterol crystals, and disruption. Thrombus tended to be more frequently observed in the CKD group. TCFA, thin-cap fibroatheroma. Reprinted with permission from Kato K, Yonetsu T, Jia H, Abtahian F, Vergallo R, Hu S, Tian J, Kim SJ, Lee H, McNulty I, Lee S, Uemura S, Jang Y, Park SJ, Mizuno K, Yu B, Jang IK: Nonculprit coronary plaque characteristics of chronic kidney disease. Circ Cardiovasc Imaging 6: 448– 456, 2013. 330 greater degree of immunohistochemical identification of vascular endothelial growth factor and a higher number of new vessels; in those with an eGFR,30 ml/min per 1.73 m2, there was also greater staining for oxidized LDL. The odds of intraplaque hemorrhage increased with lower eGFR; in individuals with an eGFR,30 ml/ min per 1.73 m2, the adjusted odds ratio for intraplaque hemorrhage was 6.22 (95% confidence interval [95% CI], 1.10 to 35.04) compared with that in those with an eGFR$60 ml/min per 1.73 m2. These findings are also consistent with more vulnerable plaques in individuals with CKD. Association of Kidney Disease with CVD in Type 2 Diabetes Prior issues of the CKD NephSAP have discussed that individuals with CKD have a higher risk of CVD and mortality. One reason is the higher prevalence of diabetes among individuals with CKD. Recent studies have evaluated the association of CKD with cardiovascular risk and mortality within individuals with type 2 diabetes. Wang et al. (9) evaluated the association of eGFR with the development of coronary heart disease (CHD) and stroke in 28,391 individuals with type 2 diabetes receiving care in the Louisiana State University Health Care Services Division and compared whether the associations differed in black and white patients. Individuals with a prior history of CHD and stroke were excluded. There was no interaction of sex and eGFR with risk of CHD or stroke (i.e., the relationship of eGFR with events was similar in men and women). There was a statistical interaction of race with eGFR regarding the development of stroke, although the relationships seem similar with an increasing risk as GFR decreases in both racial groups. In white individuals, the rates of stroke per 1000 personyears were 11.9, 15.9, 18.2, 26.9, and 39.3 for eGFRs$90, 75–89, 60–74, 30–59, and 15–29 ml/min per 1.73 m2, respectively. In blacks, the stroke rates were 10.9, 12.6, 15.4, 21.4, and 24.8 events per 1000 personyears for eGFR$90, 75–89, 60–74, 30–59, and 15–29 ml/ min per 1.73 m2, respectively. In type 1 diabetes, two separate cohort studies have found that kidney disease explains much of the increased mortality rate seen in type 1 diabetes (10,11). In the absence of kidney disease, the age– and sex–adjusted mortality rates in individuals with type 1 diabetes were similar to those of the general population. Afkarian et al. (12) evaluated whether this was also true in type 2 diabetes Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 using the third National Health and Nutrition Examination Survey III (NHANES III). Of 15,762 individuals participating in NHANES III, 9.5% had type 2 diabetes; among those with diabetes, 42.3% had CKD, with the majority defined by the presence of albuminuria. Both diabetes and kidney disease were risk factors for mortality. The presence of both diabetes and kidney disease showed an additive interaction for the risk of mortality. In individuals with diabetes but without kidney disease, there was a small increased risk of mortality compared with the general population. However, most of the excess mortality risk was in those with both diabetes and kidney disease (Figure 13). Interaction of Age and CKD on Mortality and Coronary Event Recent studies have found that the cardiovascular risk associated with CKD varies across age groups. Choi et al. (13) analyzed the association of eGFR with 1-year mortality within age strata in individuals with myocardial infarction (MI) in the Korean Acute Myocardial Infarction Registry. Choi et al. (13) divided patients into four age groups: ,55, 55–64, 65–74 and $75 years old. There were 11,268 participants, and Figure 13. Increased ten-year mortality in type 2 diabetes with both albuminuria and impaired eGFR. Absolute differences in mortality risk were estimated using linear regression and adjusted for age, sex, and race. Standardized 10-year all– cause cumulative incidences were estimated for the mean levels of the covariates in the study population. The dashed line indicates mortality in persons without diabetes or kidney disease (the reference group). The numbers above bars indicate excess mortality above the reference group. Error bars indicate 95% confidence intervals. Reprinted with permission from Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, de Boer IH: Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol 24: 302– 308, 2013. 331 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Table 3. Cox proportional analysis for mortality by age Reprinted with permission from Choi JS, Kim MJ, Kang YU, Kim CS, Bae EH, Ma SK, Ahn YK, Jeong MH, Kim YJ, Cho MC, Kim CJ, Kim SW; Korea Acute Myocardial Infarction Registry Investigators: Association of age and CKD with prognosis of myocardial infarction. Clin J Am Soc Nephrol 8: 939–944, 2013. 26% had an eGFR,60 ml/min per 1.73 m2. Mortality increased as age increased and eGFR decreased. However, although the absolute mortality rate was higher in older age with low GFR, the relative mortality was lower in the older group (Table 3). As an example, 18% of individuals ages 55–74 years old with an eGFR of 30–44 ml/min per 1.73 m2 had died by 1 year versus 28.6% of those ages $75 years old. The relative risk of death compared with the same age group with an eGFR$60 ml/min per 1.73 m2 was 9.93 for those ages 55–64 years old but only 3.36 for those $75 years old. The difference in relative risk reflects the higher overall mortality in older individuals as well as competing risks of other diseases on mortality. From a prevention and care of an individual patient point of view, it is more important to use absolute risk rather than relative risk when considering interventions. An example is the lipid treatment guidelines that base treatment for primary prevention on a 10-year absolute risk of CHD events of .10% (10 per 1000 person-years). Tonelli et al. (14) analyzed the association of age and CKD with risk of hospitalization for MI or death caused by CHD in the Alberta Kidney Disease Network Database (n¼1,268,538). Not surprisingly, these investigators found that the risk of CHD events was greater in those with CKD versus without CKD (Table 4). None of the groups under age 40 years old had a risk of CHD events .10 per 1000 person-years. In those ages 40–49 years old, the only group with the risk .10 per 1000 person-years was that with an eGFR,60 ml/min per 1.73 m2 and an albumin to creatinine ratio (ACR) .30 mg/g. However, the risk is not .10 per 1000 person years if one excludes individuals with diabetes or a prior MI. Participants with CKD over the age 50 years old with an elevated ACR or a low eGFR had a high risk of CHD events. This supports the current Kidney Disease: Improving Global Outcomes (KDIGO) lipid guidelines to treat all individuals over age of 50 years old with nondialysis CKD with a statin and treat those over age 40 years old if they have a 10-year risk .10% (e.g., with diabetes). To illustrate where one might draw different conclusions on the relationship of age and risk in CKD using absolute and relative risks, we have calculated the relative risk (incident rate CKD group/incident rate no CKD group) (Table 4). Overall, one can see that there is a higher risk of CHD events in those with both lower eGFR and higher ACR in all age groups. However, from Table 4, you can see that the highest absolute risk is in individuals over age 50 years old, but the highest relative risk is in those younger than age 40 years old. Lipid Guidelines In November of 2013, KDIGO published a clinical practice guideline for lipid management in CKD (15). Also, in November of 2013, the American Heart Association/American College of Cardiology (AHA/ ACC) updated guideline was released (16). There is a paradigm shift in the recommendations in these guidelines. Both move away from LDL-based treatment, and now, treatment recommendations are on the basis of cardiovascular risk assessment instead of LDL levels and goals. A summary of the KDIGO recommendations for nondialysis, nontransplant CKD is shown in Table 5. A major change is that the guidelines recommend treating all individuals with CKD ages 50 years old and over with a statin, regardless of LDL levels. Individuals 332 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Table 4. Rate of coronary death or nonfatal myocardial infarction by age and CKD stage Primary Cohort Age ,40 yr No CKD Any CKD eGFR¼15–59.9, ACR.30 eGFR¼15–59.9, ACR,30 eGFR$60, ACR.30 Age 40–49 yr No CKD Any CKD eGFR¼15–59.9, ACR.30 eGFR¼15–59.9, ACR,30 eGFR$60, ACR.30 Age $50 yr No CKD Any CKD eGFR¼15–59.9, ACR.30 eGFR¼15–59.9, ACR,30 eGFR$60, ACR.30 Rate per 1000 person-years (95% Confidence Interval) 0.2 (0.2 to 0.2) 0.5 (0.4 to 0.6) 3.2 (1.6 to 6.4) — 0.4 (0.3 to 0.5) 1.1 3.2 10.3 2.6 2.9 (1.1 (2.8 (7.6 (1.7 (2.6 to to to to to 1.2) 3.5) 14.2) 3.8) 3.3) 5.0 17.3 33.2 16.2 12.8 (4.8 to 5.1) (16.9 to 17.1) (31.8 to 34.6) (15.7 to 16.7) (12.3 to 13.4) Subgroup without Diabetes or Prior Myocardial Infarction Relative Risk Rate per 1000 person-years (95% Confidence Interval) Relative Risk 1.0 (reference) 2.5 16 — 2 0.2 (0.1 to 0.2) 0.3 (0.2 to 0.4) — — 0.3 (0.2 to 0.4) 1.0 (reference) 1.5 — — 1.5 1.0 (reference) 2.9 9.3 2.3 2.6 1.0 2.1 5.2 1.9 2.0 1.0 (reference) 2.1 5.2 1.9 2.0 1.0 (reference) 3.46 6.6 3.24 2.6 4.2 13.4 25.9 13.3 9.3 (0.9 (1.8 (3.1 (1.2 (1.7 to to to to to 1.1) 2.4) 8.7) 3.1) 2.3) (4.1 to 4.3) (13.0 to 13.8) (24.3 to 27.5) (12.8 to 13.9) (8.7 to 9.8) 1.0 (reference) 3.1 6.2 3.2 2.2 Events that were so small that a reliable estimate could not be calculated are indicated by —. ACR, albumin to creatinine ratio. Modified with permission from Tonelli M, Muntner P, Lloyd A, Manns B, Klarenbach S, Pannu N, James M, Hemmelgarn B; Alberta Kidney Disease Network: Impact of age on the association between CKD and the risk of future coronary events. Am J Kidney Dis 64: 375–382, 2014. age ,50 years old should be treated if they have CVD or are at high risk for future events. The treatment recommendations are on the basis of the CKD subgroup analyses of large statin studies in mainly non-CKD populations and the Study of Heart and Renal Protection (SHARP) in CKD. These studies used a fixed dose of statins in individuals with CVD or who were at risk for CVD. Because the prior studies did not adjust statin doses on the basis of target, the new recommendations reflect the study design. The recommendations also reflect the high risk of CVD in individuals with CKD, especially in older individuals. The recommendations to move away from LDL targets in the AHA/ACC guidelines are controversial (in light of the recently presented Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). The results of the IMPROVE-IT were presented at the AHA meeting and are unpublished. From the presentation, the study found that the addition of ezetimibe to simvastatin in patients with acute coronary syndrome (ACS) reduced LDL further (54 versus 69 mg/dl) and reduced CVE (primary end point) by 6%. The findings suggest that lowering LDL further in highrisk individuals is beneficial, but the negative findings in other studies that included the addition of a fibrate or niacin to a statin indicate that it may matter how LDL is lowered. An argument could be made that the age cutoff in the KDIGO guidelines for treatment should be age 40 years old, because the SHARP Study enrolled individuals over the age of 40 years old(17); therefore, using this cutoff would put the guideline more in line with the trial evidence, and using age 40 years old would put the KDIGO guidelines more in line with the AHA/ACC guidelines. One difficulty that may arise with use of the KDIGO guidelines is that there are currently no risk calculators for individuals under the age of 40 years old with or without CKD. There is also a lack of treatment studies in younger individuals. This leaves us with clinical judgment for risk in individuals under the age of 40 years old (e.g., nephrotic-range proteinuria, multiple risk factors, and length of time with CKD) as well as potential benefits (e.g., life expectancy and transplant candidacy). Overall, the guidelines would recommend that most individuals with nondialysis CKD should receive 333 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Table 5. Kidney Disease: Improving Global Outcomes Lipid Guideline Recommendations for nondialysis, nontransplant CKD Assessment of lipid status In adults and children with newly identified CKD, evaluation with a lipid profile recommended In adults with CKD, follow-up measurement of lipid levels is not required for the majority of patients In children with CKD, annual follow-up of fasting lipid levels suggested Pharmacologic treatment In adults ages $50 years old with CKD and eGFR$60 ml/min per 1.73 m2, treatment with a statin recommended In adults ages $50 years old with eGFR,60 ml/min per 1.73 m2 not treated with chronic dialysis or kidney transplantation, treatment with a statin or statin/ezetimibe combination recommended In adults ages 18–49 years old with CKD not treated with chronic dialysis or kidney transplantation, treatment with a statin suggested for those with one or more of the following Known coronary disease (myocardial infarction or coronary revascularization) Diabetes mellitus Prior ischemic stroke Estimated 10-year incidence of coronary death or nonfatal myocardial infarction .10% In children with CKD, suggest not initiating statins or statin/ezetimibe combination Triglyceride lowering In adults and children with CKD and hypertriglyceridemia, therapeutic lifestyle changes should be advised Modified with permission from KDIGO Lipid Work Group: KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney Int Suppl 3: 259–305, 2013. lipid treatment with moderate–intensity statin treatment but that, in general, we no longer need to follow lipid levels or target a particular LDL level. Cardiac Biomarkers Cardiac biomarkers are often elevated in CKD, even without the presence of acute coronary syndrome (ACS) or congestive heart failure (CHF), and this can affect their clinical use. A recent systematic review evaluated the clinical use of troponin in patients with CKD and suspected ACS (18). It identified 23 relevant studies. However, there was significant heterogeneity among studies, and many of the studies were low quality; thus, no definitive conclusion could be drawn regarding the clinical use of troponin in ACS. A second systematic review addressed cardiac troponin’s prognostic value in patients with CKD in the absence of suspected ACS (19). The review identified 98 studies of patients with dialysis and nondialysis CKD that evaluated the use of troponin for risk stratification. In both groups, elevated troponin levels were associated with a 2- to 4-fold increased risk of all-cause mortality and major adverse cardiovascular events (CVE). In asymptomatic patients with CKD, an elevated troponin may indicate chronic structural heart disease rather than ACS, and this observation may explain the prognostic significance of the elevated echocardiographic findings in the Chronic Renal Insufficiency Cohort (CRIC) Study (20). Among 2735 participants, 84% had detectable cardiac troponin T by a highsensitive assay. Dividing the participants into five groups of undetectable troponin levels and quartiles of detectable levels, the prevalence of left ventricular hypertrophy (LVH), low ejection fraction (,45%), and diastolic dysfunction increased across the groups, although the relationship was strongest for LVH. With adjustment for demographics, cause of kidney disease, BP, and other cardiovascular risk factors, the relationship remained significant for LVH. The odds ratios for LVH compared with those with undetectable troponin were 1.26, 1.35, 1.91, and 2.43 for quartiles 1–4, respectively. When evaluated as a screening test for the diagnosis of LVH, only troponin T had an area under the curve (ROC) of 0.64, which is inadequate for a diagnostic test. Although not a cardiac biomarker, an analogous issue of altered clinical use of a biomarker in CKD is the use of D-dimer to rule out pulmonary embolus (PE). In evaluation for pulmonary embolism, the first step is to estimate the pretest probability of a PE with a score, such as the Wells score or the modified Geneva score. Individuals with intermediate to high pretest probability should undergo imaging. In individuals with low pretest probability, a D-dimer can be drawn. If the level is ,500 mg/L, additional testing is not necessary. This can save a patient from a test with iodinated radiographic contrast. However, there are issues with a one size fits all cutoff 334 for D-dimer; D-dimer levels rise with age, and recent studies have found that using an age-based cutoff led to a larger proportion of patients in whom a PE could be ruled out with a low risk of a false-negative result (,1%) (21). Lindner et al. (22) subsequently proposed that there should be renal function–adjusted D-dimer cutoffs. Lindner et al. (22) evaluated the data on individuals who presented to the emergency room and had data by computed tomography angiogram (CTA), D-dimer level, and kidney function. Overall, 12% had a D-dimer level ,500 mg/L; 13% of those with an eGFR.60 ml/min per 1.73 m2 had a D-dimer ,500 mg/L, whereas only 6% of individuals with an eGFR of 30–60 ml/min per 1.73 m2 and no individuals with an eGFR,30 ml/min per 1.73 m2 had a D-dimer level ,500 mg/L. By ROC curve analysis, Lindner et al. (22) found that the suggested cutoff levels for D-dimer would be ,594 mg/L for an eGFR of 30–60 ml/min per 1.73 m2 and ,1738 mg/L for an eGFR ,30 ml/min per 1.73 m2. There are a number of limitations that would need to be addressed before this could be used in daily practice. The number of individuals with kidney disease was relatively small, especially for eGFRs,30 ml/min per 1.73 m2. In addition, in this analysis, all participants had undergone CTA, which would have excluded a number of individuals at low risk of PE. In fact, the prevalence of D-dimer ,500 mg/L was one half that in a prospective study evaluating age-based cutoffs for dimer (28%), indicating that they had reviewed a higher-risk group (21). However, it does highlight the need for future studies to address this issue, which might help avoid unnecessary contrast administration to patients with CKD. Inflammatory Markers and the Microbiome CKD is associated with higher levels of inflammatory markers and markers of oxidative stress, which may be one of the mediators that increases the risk of CVD in CKD (23). In NHANES III, Stack et al. (24) found that higher levels of fibrinogen, an acute-phase reactant, were associated with an increased risk for mortality. The relationship with mortality was similar between those with and without kidney disease. The hazard ratios (HRs) per 1-mmol/L increase were 1.06 (95% CI, 1.02 to 1.10), 1.05 (95% CI, 1.10 to 1.09), and 1.07 (95% CI, 1.03 to 1.11) for eGFRs,60, 60–89, and $90 ml/min per 1.73 m2, respectively. However, individuals with CKD had higher levels of fibrinogen, and fibrinogen may be an additional CKD risk factor. Another acute-phase reactant that is associated with Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 cardiovascular risk in CKD is ceruloplasmin. Kennedy et al. (25) evaluated ceruloplasmin levels with major adverse CVEs in 654 individuals with CKD who were undergoing elective cardiovascular evaluation by either coronary angiography or CTA. A ceruloplasmin level .25.5 mg/dl was associated with an increased risk of CVE (adjusted HR, 1.69; 95% CI, 1.18 to 2.42). As inflammatory levels rise, there is also an increase in immunoregulatory cytokines that balance the response. Elevated immunoregulatory cytokine levels may reflect an ongoing inflammatory state. What may be important in predicting disease severity is the balance between proinflammatory and anti-inflammatory responses (26,27). Yilmaz et al. (28) evaluated the association of serum IL-10, a counter-regulatory cytokine, with CVD in 403 patients with stages 1–5 CKD (27). With worsening CKD stage, levels of C-reactive protein, pentraxin-3, IL-6, and IL-10 increased, although the IL-6 to IL-10 ratio decreased. Higher IL-10 levels were associated with an increased risk of CVEs, which persisted after adjustment for demographics, other cardiovascular risk factors, and comorbidities. IL-6 and pentraxin-3 were also associated with the risk of CVE. Whether the findings reflect harmful effects of IL-10, an issue of balance between proinflammatory and counterinflammatory responses, or that IL-10 levels reflect the overall inflammatory state is unknown and will require controlled treatment trials to sort out. Although there are not currently approved interventions that decrease inflammation and cardiovascular risk (except perhaps for statins), inflammation is a potentially remediable risk factor. An emerging approach would be to target the microbiome. The human gut microbiome is comprised of up to 100 trillion organisms that live in symbiosis with us (29). The predominant phyla are Bacteroidetes and Firmicutes, and others are present in smaller proportion (30). The microbiome has a number of physiologic beneficial effects (Table 6) (29). CKD alters the microbiome. Vaziri et al. (31) analyzed the microbial population in stool samples from 24 patients with ESRD and 12 controls. Microbial DNA was extracted and analyzed by phylogenetic microarray, classifying the bacteria into 190 operational taxonomic units (OTUs). The pattern of OTUs differed between patients with ESRD and controls. To determine whether the change in the microbiome could be caused by ESRD per se rather than differences in diet and medications, Vaziri et al. (31) examined the microbiome in rats after 335 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Table 6. Physiologic effect of gut microbiota (1) Integrity and function of gastrointestinal tract Restoration of tight junction protein structure Induction of epithelial heat–shock proteins Upregulation of mucin genes Competition with pathogenic bacteria for binding to intestinal epithelial cells Secretion of antimicrobial peptides Suppression of intestinal inflammation (2) Immunologic effects Maturation of intestinal immune system Reduction of allergic response to food and environmental antigens Promotion of immunomodulation and cell differentiation (3) Metabolic effects Breakdown of indigestible plant polysaccharides and resistant starch Facilitated absorption of complex carbohydrates Synthesis of vitamins (K and B groups) Synthesis of amino acids (threonine and lysine) Biotransformation of conjugated bile acids Degradation of dietary oxalates Modified with permission from Sabatino A, Regolisti G, Brusasco I, Cabassi A, Morabito S, Fiaccadori E: Alterations of intestinal barrier and microbiota in chronic kidney disease. Nephrol Dial Transplant 30: 924–933, 2015. 5/6th nephrectomy and control rats. Changes in microbiome OTUs were also seen in the rats after nephrectomy, indicating that uremia may lead to alterations of the microbiome. In addition to uremia affecting the microbiome, the microbiome could affect the health of the individual. There can be an imbalance in the microbiome with an increase in pathogenic bacteria and a decrease in commensal bacteria (30,32). This can lead to disruption in the epithelial barrier and an increase in inflammation. A number of the uremic toxins, such as p-cresol, are produced by microbiomes that, because of decreased renal clearance, accumulate in renal failure (30,32). These changes could promote atherosclerosis. One gut-derived toxin is trimethylamine-Noxide (TMAO), which is derived from gut microbiota metabolism of dietary phosphatidylcholine, choline, or L-carnitine (33). Tang et al. (33) evaluated the association of TMAO levels in 3687 individuals undergoing cardiac catheterization at the Cleveland Clinic, and 521 of those individuals had CKD. Individuals with CKD had higher TMAO levels (median of 7.9 versus 3.4 mM), and TMAO levels correlated with eGFR (r¼20.48). In CKD, the highest quartile was associated with increased risk of mortality at 5 years after controlling for cardiovascular risk factors, C-reactive protein, and kidney function by eGFR or cystatin C (HR, 1.45; 95% CI, 1.05 to 2.02). The negative changes in the microbiome with CKD might be amenable to dietary interventions. Patel et al. (34) found that, in healthy subjects, individuals who ate a vegetarian diet have a nearly 60% lower generation of p-cresol and indoxyl sulfate than individuals who eat an unrestricted diet with meat. The decreased production of these compounds was associated with a higher fiber intake and lower protein intake. The microbiome may also be affected by interventions with dietary supplements (Table 7 shows terms describing the types of supplements) (35). Guida et al. (36) performed a 30-day randomized study of a synbiotic supplement (Probinul-neutro) versus placebo in 30 patients with stages 3 or 4 CKD. Treatment with the synbiotic decreased p-cresol levels by 40%, whereas there was a nonstatistically significant increase in p-cresol levels in the control group. The main side effects were gastrointestinal, although all subjects completed the study. In patients on hemodialysis, treatment with probiotics (fiber) has been shown to decrease their levels of p-cresol and indoxyl sulfate (35,37). Future studies should be done to determine whether these interventions can decrease the risk of CVD. Urine Biomarkers Urinary biomarkers of acute tubular injury were developed for AKI. Recent studies have found that they predict mortality in the general population, even after controlling for eGFR. In an analysis from the Health, Aging and Body Composition (Health ABC) Study (a cohort study of older individuals), Sarnak et al. (38) evaluated the association of urine kidney injury molecule 1 (KIM-1), IL-18, and microalbuminuria with mortality and CVD in 3010 individuals; 17% of the participants had an eGFR,60 ml/min per 1.73 m2, and 19% had a urine ACR .30 mg/g. Urinary KIM-1/creatinine was modestly associated with urine ACR (r¼0.17) and weakly associated with eGFR (r¼20.08). Urinary IL-18/creatinine was weakly positively associated with eGFR (r¼0.10) and modestly associated with urine ACR (r¼0.17). An eGFR,60 ml/min per 1.73 m2 was significantly associated with higher KIM-1 and urine albumin levels but not with IL-18 levels. The patterns of association with mortality differed among the markers (Figure 14). Urine KIM-1 levels were associated with mortality. After adjustment for eGFR and albuminuria as well, the 336 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Table 7. Types of supplements affecting microbiome Term Definition Examples Prebiotic Nondigestible food ingredients that stimulate growth and/or activity of bacteria Living organisms that, on ingestion, can improve the health of the organism Combines prebiotics with probiotics Inulin (nondigestible fiber) present in foods, such as Jerusalem artichokes and chicory Bifidus regularis in some yogurts Probiotic Synbiotic Some yogurts and supplements Modified with permission from National Kidney Foundation: 2012 Update. Am J Kidney Dis 60: 850–886, 2012. relationship was attenuated, but the fourth quartile remained significantly associated with mortality (HR, 1.33; 95% CI, 1.12 to 1.57). KIM-1 was not associated with CVD, and IL-18 was not associated with either outcome. In contrast, urine albuminuria remained significantly associated with both mortality and CVD. In a separate Health ABC analysis, Driver et al. (39) found that urinary KIM-1 was associated with risk for heart failure, but the association with albuminuria was also stronger; IL-18 was not associated with risk of heart failure. Carlsson et al. (40) evaluated the association of urinary KIM-1 with total and cardiovascular mortality in 529 men participating in the Uppsala Longitudinal Study of Adult Men. KIM-1/creatinine was associated with a higher risk of cardiovascular and all-cause mortality. Comparing individuals with normal values of all three markers (eGFR, albuminuria, and KIM-1), individuals with one abnormal value had a 2-fold greater risk of cardiovascular mortality. The greatest risk was if all three were abnormal (low eGFR, high urine ACR, and high KIM-1), where the risk of all-cause mortality was 3-fold higher and the risk of cardiovascular mortality .6-fold higher, even after adjustment for other cardiovascular risk factors. Another urinary biomarker is urinary liver–type fatty acid–binding protein (L-FABP), which is an intracellular carrier protein of free fatty acids. It is produced by the liver and kidney (proximal tubule); circulating L-FABP is filtered at the glomerulus and taken up by the proximal tubules (41,42). Araki et al. (43) studied the association of L-FABP with the subsequent development of a renal and CVD composite (hemodialysis, MI, angina, stroke, cerebral hemorrhage, and peripheral vascular disease) in individuals with type 2 diabetes. Individuals at baseline had a SCr #1.0 mg/dl and either normoalbuminuria (n¼422) or microalbuminuria (n¼196). After a median of 12 years, higher tertiles of L-FABP were associated with a higher risk of the composite end point (HR, 1.64 and 1.93 for the second and third tertiles, respectively). The highest two tertiles had a 75% higher risk of developing CVD. Figure 14. Mortality and cardiovascular disease (CVD) by urinary injury markers. (A) Mortality rates by quartiles of kidney injury marker 1 (KIM-1), IL-18, and urinary albumin to creatinine ratio (UACR). (B) CVD by quartiles of KIM-1, IL-18, and UACR. CVD was defined by a coronary heart disease event and/or stroke. Q, quartile. Reprinted with permission from Sarnak MJ, Katz R, Newman A, Harris T, Peralta CA, Devarajan P, Bennett MR, Fried L, Ix JH, Satterfield S, Simonsick EM, Parikh CR, Shlipak MG; Health ABC Study: Association of urinary injury biomarkers with mortality and cardiovascular events. J Am Soc Nephrol 25: 1545–1553, 2014. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Echocardiographic Changes in CKD Echocardiographic changes, such as LVH, diastolic dysfunction, and increased left atrial volume, are common in CKD and associated with an increased risk of CVEs and development of HF (44–46). Peterson et al. (46) evaluated the relationship of baseline echocardiographic findings with outcomes in the black Study of Kidney Disease and Hypertension Trial. The average left ventricular mass index (LVMI) was 70.6 g/m2 in patients with CVE versus 59.2 g/m2 in patients without CVE; for HF events, LVMI was 75.6 g/m2 in patients with HF events (hospitalization for CHF or death caused by CHF) versus 59.7 g/m2 in patients without events. The presence of LVH was associated with higher average systolic BP, greater prevalence of albuminuria, and greater prevalence of baseline CVD. After adjustment for other covariates, LVMI remained a significant predictor of CVEs and HF events. In addition, measures of diastolic dysfunction were predictors of HF. An E/A ratio #0.75 was associated with a 2-fold higher risk of HF compared with E/A ratios between 0.75 and 1.5 (adjusted HR, 2.05; 95% CI, 1.03 to 4.06). What has been less well studied in CKD are the longitudinal changes in echocardiographic findings over time. Cai et al. (47) performed a longitudinal study in 300 individuals with stages 3–5 CKD. Of 300 individuals, 278 had baseline and 1-year echocardiograms. Over the 1-year period, LVMI increased (105632 to 112634 g/m2), left ventricular volume index increased (42.8611.1 to 43.9611.8 ml/m2), and multiple parameters of diastolic dysfunction worsened. There was also a small but statistically significant decrease in left ventricular ejection fraction (LVEF; from 70% to 69%). The echocardiographic changes were greater in CKD stages 4 or 5 than in stages 3A or 3B. Bansal et al. (48) evaluated change in echocardiographic findings before and after the transition to ESRD in the CRIC Study. For this analysis, Bansal et al. (48) analyzed 190 individuals who had an echocardiogram at advanced CKD and after ESRD was established, excluding those who received a preemptive transplant. At the first echocardiogram, the mean eGFR was 16.9 ml/min per 1.73 m2, and median proteinuria was 2.75 g per day. After transitioning to ESRD, there was a decrease in BP and body mass index, an increase in hemoglobin, and an increase in the prevalence of reported CVD. The LVMI did not change, but LVEF decreased. The lack of change in LVMI contrasts with 337 the work by Cai et al. (46). The reasons for the difference could reflect the wider eGFR range in the study by Cai et al. (47) or perhaps, better volume and BP control after transition to ESRD. Additional studies would need to determine whether the decline in ejection fraction seen in both studies could be prevented with interventions, such as anti–renin-angiotensin-aldosterone system treatment, and whether this could decrease the risk of mortality. Percutaneous Cardiovascular Intervention and Drug-Eluting Stents Over the past 25 years, there have been major changes in the care of patients with acute MI. Nauta et al. (49) evaluated time trends in care received and outcomes in 12,087 adult patients who were admitted with an ST elevation MI or non-ST elevation MI to the intensive care unit of the Erasmus University Medical Center between June of 1985 and December of 2008. Patients were divided into three groups according to the year of hospitalization: 1985–1990, 1990–2000, and 2000–2008. Of the patients in the study, 29% had no kidney disease, 46% had stage 2 CKD, 21% had stage 3 CKD, and 4% had stage 4 or 5 CKD. The use of reperfusion therapy (thrombolytics or percutaneous coronary intervention [PCI]) increased over time during all CKD stages but remained lower in those with advanced CKD compared with those with normal kidney function (Figure 15). Not surprisingly, mortality was higher in individuals with CKD, with the risk for 30-day mortality 4 times higher in those with stage 3 CKD and 8.5 times higher in those with stage 4 or 5 CKD compared with the normal population. Over 20 years, there was improved 30-day mortality after MI in all CKD stages, although there was no significant change in 5-year mortality. The increased use of indicated medications for CKD is encouraging as is the decline in 30-day mortality; however, the results still reveal that such medications are underused and that additional interventions are vital for better longer–term outcomes. The use of a drug-eluting stent (DES) rather than a bare metal stent (BMS) might decrease adverse outcomes after PCI. Wang et al. (50) performed a meta-analysis of DESs versus BMSs in individuals with eGFRs,60 ml/min per 1.73 m2. These studies were primarily observational, because there are few randomized studies of PCI that include individuals with CKD, and some were post hoc subgroup analyses of trials. Altogether, Wang et al. (50) compiled 26 studies with 66,840 individuals. DESs were associated with 338 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Figure 15. Treatment of patients with cardiovascular treatments after myocardial infarction over time (A) Use of PCI; (B) Use of aspirin; (C) Use of statin. ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; ASA, aspirin; ICCU, intensive coronary care unit; PCI, percutaneous coronary intervention; ThT, thrombolytic therapy. Reprinted with permission from Nauta ST, van Domburg RT, Nuis RJ, Akkerhuis M, Deckers JW: Decline in 20-year mortality after myocardial infarction in patients with chronic kidney disease: Evolution from the prethrombolysis to the percutaneous coronary intervention era. Kidney Int 84: 353–358, 2013. a lower mortality (odds ratio, 0.77; 95% CI, 0.65 to 0.90). It is notable that this result was not seen in the subgroup analysis of randomized trials. There was a significantly decreased risk of revascularization (odds ratio, 0.61; 95% CI, 0.50 to 0.74) that was seen in randomized and observational studies. Since the meta-analysis was published, there has been a randomized study that focused on CKD. The Randomized Comparison of Xience V and Multilink Vision Coronary Stents in the Same Multivessel Patient with Chronic Kidney Disease Study compared an everolimus-eluting stent with a BMS in individuals with a creatinine clearance between 30 and 59 ml/min with two significant lesions in two major epicardial vessels (51). The stents were randomized by coronary vessel (so each patient received both). The primary outcome was ischemia–driven target vessel revascularization as detected by myocardial scintigraphy at 12 months (a positive stress test indicating ischemia in area supplied by vessel); 215 individuals were randomized. The incidence of ischemia– driven target level revascularization was lower for the DES group (11.4% versus 2.4%; P,0.001). The benefit seemed greater with more advanced CKD (moderate CKD, 7.3% versus 2.6% and stages 4 and 5 CKD, 24.2% versus 3.1% for BMS and DES, respectively). However, because the study randomized vessels rather than patients, mortality cannot be assessed. The use of a DES improved revascularization of blood vessels compared with a BMS in patients with stage 3 CKD. Atrial Fibrillation CKD is a risk factor for the development of atrial fibrillation (AF) (52,53). Warfarin use in CKD is associated with a decreased risk of thromboembolic events but also, an increased risk of bleeding. What is not clear is the balance between risk and benefit. Bonde et al. (54) used nationwide registries to identify Danish individuals who had nonvalvular AF, and this information was linked to laboratory data and medication data. Of 154,259 individuals with nonvalvular AF, 11,128 had nondialysis CKD, and 1728 had ESRD. In those with CKD and a CHA2DS2-VASc score $2 (high risk), which includes a score for prior stroke or thromboembolism, individuals who were not treated with warfarin had a higher risk of stroke than individuals who were treated with warfarin. Net clinical benefit was evaluated using a composite that combined efficacy and safety (stroke and fatal bleeding) plus cardiovascular death, all-cause mortality, and fatal bleeding. In high–risk nondialysis CKD, treatment with warfarin was associated with decreased risk in all three outcomes: fatal stroke/fatal bleeding (HR, 0.71; 95% CI, 0.57 to 0.88), cardiovascular death (HR, 0.80; 95% CI, 0.74 to 0.88), and all-cause mortality (HR, 0.64; 95% CI, 0.60 to 0.69). Using a nationwide Swedish registry of subjects admitted to a coronary care unit with symptoms suggestive of ACS, Carrero et al. (55) analyzed the association of warfarin treatment with cardiovascular outcomes and bleeding in patients with AF. There were 24,317 individuals included in the analysis: 41.7% had stage 3 CKD, 8.1% had stage 4 CKD, and 2.0% had 339 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 stage 5 CKD. Most individuals had a CHAD2 score $2. Warfarin was prescribed in 22.0% of individuals with no CKD, 22.4% of individuals with stage 3 CKD, 18.9% of individuals with stage 4 CKD, and 13.8% of individuals with stage 5 CKD. The risk of the composite end point of mortality, stroke, and MI increased across all CKD stages. Within each CKD stratum, those treated with warfarin had an approximately 25% lower risk. Overall, the risk of bleeding was greater in those with CKD. However, within CKD strata, warfarin use was not associated with increased bleeding risk, indicating that individuals with CKD have a higher bleeding risk overall and not just with anticoagulants. These two studies were not randomized, and therefore, the characteristics of patients who were treated are likely to differ significantly from those of patients who were not treated, which could lead to bias. Overall, however, it suggests that treatment with anticoagulation is warranted in high-risk patients with CKD. Cardioverter Defibrillator Individuals with CKD have an increased risk of sudden cardiac death (SCD). Implanted cardioverter defibrillators (ICDs) decrease SCD in the non-CKD population, raising the question of whether they would be beneficial in patients with CKD. Hess et al. (56) studied the association of CKD with mortality after placement of an ICD for primary prevention using the National Cardiovascular Data Registry’s ICD Registry. ICDs were placed in individuals with a history of MI and LVEF#30% or a history of HF with an LVEF#35%. Among 47,282 patients, 21,226 had CKD. CKD was associated with a higher mortality risk (13.5%, 26.2%, 44.7%, and 49.0% at 3 years for no CKD, stages 3 or 4/5 CKD not on dialysis, and ESRD, respectively). The very high mortality, especially for individuals with an eGFR,30 ml/min per 1.73 m2, raises the question of whether one can change the natural history of the disease in those with advanced CKD. Pun et al. (57) performed a patient–level metaanalysis of randomized studies of ICD placement for primary prevention of SCD. There were seven studies with 2867 patients; 1040 had an eGFR,60 ml/min per 1.73 m2. Because these were randomized studies, the majority of patients with CKD had stage 3 CKD (only 3.6% had an eGFR,30 ml/min per 1.73 m2). Individuals with CKD were older and had more comorbidities. There was a significant interaction between eGFR and benefit of ICD. The survival benefit with ICDs steadily declined with lower eGFR, although it was not possible to determine where the threshold should be (where benefit disappears), because there were few individuals with advanced CKD. This metaanalysis, however, supports the conduct of a randomized intervention study in advanced CKD, because there would now be equipoise (i.e., ethical to randomize to no ICD for primary prevention in advanced CKD). References 1. Wada M, Ueda Y, Higo T, Matsuo K, Nishio M, Hirata A, Asai M, Nemoto T, Kashiyama T, Murakami A, Kashiwase K, Kodama K: Chronic kidney disease and coronary artery vulnerable plaques. Clin J Am Soc Nephrol 6: 2792–2798, 2011 PubMed 2. Schaar JA, Muller JE, Falk E, Virmani R, Fuster V, Serruys PW, Colombo A, Stefanadis C, Ward Casscells S, Moreno PR, Maseri A, van der Steen AF: Terminology for high-risk and vulnerable coronary artery plaques. Report of a meeting on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece. 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TNF-alpha: Central factors in the altered cytokine network of uremia–the good, the bad, and the ugly. Kidney Int 67: 1216–1233, 2005 PubMed Stack AG, Donigiewicz U, Abdalla AA, Weiland A, Casserly LF, Cronin CJ, Nguyen HT, Hannigan A: Plasma fibrinogen associates independently with total and cardiovascular mortality among subjects with normal and reduced kidney function in the general population. QJM 107: 701–713, 2014 PubMed Kennedy DJ, Fan Y, Wu Y, Pepoy M, Hazen SL, Tang WH: Plasma ceruloplasmin, a regulator of nitric oxide activity, and incident cardiovascular risk in patients with CKD. Clin J Am Soc Nephrol 9: 462–467, 2014 Bone RC: Immunologic dissonance: A continuing evolution in our understanding of the systemic inflammatory response syndrome (SIRS) and the multiple organ dysfunction syndrome (MODS). Ann Intern Med 125: 680–687, 1996 PubMed Gigante A, Gasperini ML, Afeltra A, Barbano B, Margiotta D, Cianci R, De Francesco I, Amoroso A: Cytokines expression in SLE nephritis. Eur Rev Med Pharmacol Sci 15: 15–24, 2011 PubMed Yilmaz MI, Solak Y, Saglam M, Cayci T, Acikel C, Unal HU, Eyileten T, Oguz Y, Sari S, Carrero JJ, Stenvinkel P, Covic A, Kanbay M: The relationship between IL-10 levels and cardiovascular events in patients with CKD. Clin J Am Soc Nephrol 9: 1207–1216, 2014 PubMed Sabatino A, Regolisti G, Brusasco I, Cabassi A, Morabito S, Fiaccadori E: Alterations of intestinal barrier and microbiota in chronic kidney disease. Nephrol Dial Transplant 30: 924–933, 2015 PubMed Ramezani A, Raj DS: The gut microbiome, kidney disease, and targeted interventions. J Am Soc Nephrol 25: 657–670, 2014 PubMed Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, Ni Z, Nguyen TH, Andersen GL: Chronic kidney disease alters intestinal microbial flora. Kidney Int 83: 308–315, 2013 PubMed Mafra D, Lobo JC, Barros AF, Koppe L, Vaziri ND, Fouque D: Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol 9: 399–410, 2014 PubMed Tang WH, Wang Z, Kennedy DJ, Wu Y, Buffa JA, Agatisa-Boyle B, Li XS, Levison BS, Hazen SL: Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116: 448–455, 2015 PubMed Patel KP, Luo FJ, Plummer NS, Hostetter TH, Meyer TW: The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores. Clin J Am Soc Nephrol 7: 982–988, 2012 PubMed Vitetta L, Gobe G: Uremia and chronic kidney disease: The role of the gut microflora and therapies with pro- and prebiotics. Mol Nutr Food Res 57: 824–832, 2013 PubMed Guida B, Germanò R, Trio R, Russo D, Memoli B, Grumetto L, Barbato F, Cataldi M: Effect of short-term synbiotic treatment on plasma p-cresol levels in patients with chronic renal failure: A randomized clinical trial. Nutr Metab Cardiovasc Dis 24: 1043–1049, 2014 PubMed Sirich TL, Plummer NS, Gardner CD, Hostetter TH, Meyer TW: Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. Clin J Am Soc Nephrol 9: 1603–1610, 2014 PubMed Sarnak MJ, Katz R, Newman A, Harris T, Peralta CA, Devarajan P, Bennett MR, Fried L, Ix JH, Satterfield S, Simonsick EM, Parikh CR, Shlipak MG; Health ABC Study: Association of urinary injury biomarkers with mortality and cardiovascular events. J Am Soc Nephrol 25: 1545–1553, 2014 PubMed Driver TH, Katz R, Ix JH, Magnani JW, Peralta CA, Parikh CR, Fried L, Newman AB, Kritchevsky SB, Sarnak MJ, Shlipak MG; Health ABC Study: Urinary kidney injury molecule 1 (KIM-1) and interleukin 18 (IL-18) as risk markers for heart failure in older adults: The Health, Aging, and Body Composition (Health ABC) Study. 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Clin Chim Acta 374: 1–7, 2006 PubMed Araki S, Haneda M, Koya D, Sugaya T, Isshiki K, Kume S, Kashiwagi A, Uzu T, Maegawa H: Predictive effects of urinary liver-type fatty acid-binding protein for deteriorating renal function and incidence of cardiovascular disease in type 2 diabetic patients without advanced nephropathy. Diabetes Care 36: 1248–1253, 2013 PubMed Hee L, Nguyen T, Whatmough M, Descallar J, Chen J, Kapila S, French JK, Thomas L: Left atrial volume and adverse cardiovascular outcomes in unselected patients with and without CKD. Clin J Am Soc Nephrol 9: 1369–1376, 2014 PubMed Park M, Hsu CY, Li Y, Mishra RK, Keane M, Rosas SE, Dries D, Xie D, Chen J, He J, Anderson A, Go AS, Shlipak MG; Chronic Renal Insufficiency Cohort (CRIC) Study Group: Associations between kidney function and subclinical cardiac abnormalities in CKD. J Am Soc Nephrol 23: 1725–1734, 2012 PubMed Peterson GE, de Backer T, Contreras G, Wang X, Kendrick C, Greene T, Appel LJ, Randall OS, Lea J, Smogorzewski M, Vagaonescu T, Phillips RA; African American Study of Kidney Disease Investigators: Relationship of left ventricular hypertrophy and diastolic function with cardiovascular and renal outcomes in African Americans with hypertensive chronic kidney disease. Hypertension 62: 518–525, 2013 PubMed Cai QZ, Lu XZ, Lu Y, Wang AY: Longitudinal changes of cardiac structure and function in CKD (CASCADE study). J Am Soc Nephrol 25: 1599–1608, 2014 PubMed Bansal N, Keane M, Delafontaine P, Dries D, Foster E, Gadegbeku CA, Go AS, Hamm LL, Kusek JW, Ojo AO, Rahman M, Tao K, Wright JT, Xie D, Hsu CY; CRIC Study Investigators: A longitudinal study of left ventricular function and structure from CKD to ESRD: The CRIC study. Clin J Am Soc Nephrol 8: 355–362, 2013 PubMed Nauta ST, van Domburg RT, Nuis RJ, Akkerhuis M, Deckers JW: Decline in 20-year mortality after myocardial infarction in patients with chronic kidney disease: Evolution from the prethrombolysis to the percutaneous coronary intervention era. Kidney Int 84: 353–358, 2013 PubMed Wang ZJ, Harjai KJ, Shenoy C, Gao F, Shi DM, Liu YY, Zhao YX, Zhou YJ: Drug-eluting stents versus bare-metal stents in patients with decreased GFR: A meta-analysis. Am J Kidney Dis 62: 711–721, 2013 PubMed Tomai F, Ribichini F, De Luca L, Petrolini A, Ghini AS, Weltert L, Spaccarotella C, Proietti I, Trani C, Nudi F, Pighi M, Vassanelli C: Randomized Comparison of Xience V and Multi-Link Vision Coronary Stents in the Same Multivessel Patient With Chronic Kidney Disease (RENAL-DES) Study. Circulation 129: 1104–1112, 2014 PubMed Myrvang H: Cardiovascular disease: CKD increases the risk of atrial fibrillation. Nat Rev Nephrol 7: 426, 2011 PubMed Xu D, Murakoshi N, Sairenchi T, Irie F, Igarashi M, Nogami A, Tomizawa T, Yamaguchi I, Yamagishi K, Iso H, Ota H, Aonuma K: Anemia and reduced kidney function as risk factors for new onset of atrial fibrillation (from the Ibaraki prefectural health study). Am J Cardiol 115: 328–333, 2015 PubMed Bonde AN, Lip GY, Kamper AL, Hansen PR, Lamberts M, Hommel K, Hansen ML, Gislason GH, Torp-Pedersen C, Olesen JB: Net clinical benefit of antithrombotic therapy in patients with atrial fibrillation and chronic kidney disease: A nationwide observational cohort study. J Am Coll Cardiol 64: 2471–2482, 2014 PubMed Carrero JJ, Evans M, Szummer K, Spaak J, Lindhagen L, Edfors R, Stenvinkel P, Jacobson SH, Jernberg T: Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation. JAMA 311: 919–928, 2014 PubMed 56. Hess PL, Hellkamp AS, Peterson ED, Sanders GD, Al-Khalidi HR, Curtis LH, Hammill BG, Pun PH, Curtis JP, Anstrom KJ, Hammill SC, Al-Khatib SM: Survival after primary prevention implantable cardioverter-defibrillator placement among patients with chronic kidney disease. Circ Arrhythm Electrophysiol 7: 793–799, 2014 PubMed 57. Pun PH, Al-Khatib SM, Han JY, Edwards R, Bardy GH, Bigger JT, Buxton AE, Moss AJ, Lee KL, Steinman R, Dorian P, Hallstrom A, Cappato R, Kadish AH, Kudenchuk PJ, Mark DB, Hess PL, Inoue LY, Sanders GD: Implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in CKD: A meta-analysis of patient-level data from 3 randomized trials. Am J Kidney Dis 64: 32–39, 2014 PubMed Exercise in CKD Individuals with CKD have decreased physical activity, which may contribute to the high risk of cardiovascular disease as well as frailty. Chen et al. (1), in a cohort study of 6363 patients with stages 3–5 CKD at the China Medical University Hospital, found that 65.7%, 73.1%, and 77.5% of individuals with stages 3, 4, and 5 CKD, respectively, never exercised. In individuals who did exercise, the most common form of exercise was walking. Overall, 21% of the cohort walked for exercise. Walking was associated with a decreased risk of mortality (hazard ratio, 0.67; 95% confidence interval, 0.53 to 0.84) and progression to ESRD (hazard ratio, 0.79; 95% confidence interval, 0.73 to 0.85), even after adjusting for eGFR, age, body mass index, and comorbidity. Robinson-Cohen et al. (2) also found that higher physical activity was associated with a slower change in kidney function. Robinson-Cohen et al. (2) evaluated the association of physical activity as assessed by the Four-Week Physical Activity History Questionnaire with a change in kidney function in 256 individuals with stage 3 or 4 CKD who were participating in the Seattle Kidney Study. The overall change in eGFR was 27.6% per year. The percentage change in kidney function was slower in those with greater physical activity: 29.65%, 28.25%, 26.85%, and 26.2% for 0, 1–59, 60–150, and $150 minutes leisure time physical activity minutes per week, respectively. In adjusted analysis, each 60-minute higher level of weekly physical activity was associated with a 0.5% slower decline in eGFR annually (2). However, observational studies of exercise are potentially confounded, because sicker people are less likely to exercise. In addition, it may not be exercise per se that leads to a slower decline, but rather other factors that associate with exercise (e.g., individuals who exercise may be less likely to smoke). 342 Heiwe and Jacobson (3) performed a meta-analysis of randomized studies of exercise training in CKD. Heiwe and Jacobson (3) found 41 studies with 928 participants. Most of the studies were in individuals on dialysis or after transplantation. Confining the outcomes to those with nondialysis, nontransplant CKD, exercise increased aerobic capacity, lowered systolic BP, and increased thigh muscle mass and muscle strength. Although the importance of exercise is generally appreciated, how to increase patient participation in exercise is not clear and has not been adequately studied. Watson et al. (4) performed a randomized study of an 8-week progressive resistance exercise program versus usual care in individuals ages $40 years old with stage 3b or 4 CKD who were receiving care at the Leicester General Hospital Nephrology Outpatient Clinic. Exclusion criteria included myocardial infarction within the past 6 months, an unstable chronic condition, physical impairment preventing ability to undertake intervention, hemoglobin A1C $9%, insufficient command of English, or inability to provide informed consent. Similar to the findings of the meta-analysis by Heiwe and Jacobson (3), the resistance program increased muscle mass, lower extremity muscle strength, and exercise capacity. What is notable from the study is how small a proportion of individuals was eligible and willing to participate in the study. Over a 16-month period, Watson et al. (4) screened 2349 individuals, and 403 were found to be eligible and were approached for recruitment (17%). Of 403 eligible, only 38 consented to participate (9.4% of those eligible and 1.6% of those screened in clinic). A randomized study in patients with CKD in Brazil highlights that how exercise is delivered might influence the effectiveness of the intervention. Baria et al. (5) randomized 27 sedentary men with stage 3 or 4 CKD and a body mass index .25 kg/m2 (mean ¼30.4 kg/m2) to an aerobic exercise group (n¼19) or a control group (n¼9). Those in the exercise group could participate in either a center-based program (n¼10) or a home-based program (n¼9) for 12 weeks. An exercise stress test was done before randomization to ensure that individuals did not have active coronary artery disease and determine the ventilatory threshold (VT), the point where metabolism switches from aerobic to anaerobic metabolism (6,7). At this point, the minute ventilation increases faster than the VO2 (oxygen consumption) to compensate for the metabolic acidosis. The prescribed exercise program in the study was on the basis of VT and heart rate at VT and used to guide exercise intensity. In both groups, there was Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 an improvement in VO2 peak and the sit to stand test. In the center-based group, visceral fat and waist circumference decreased, but these increased in the control group. In addition, leg lean mass increased in the in-center group. In the home-based group, there was no change in body composition. In both groups, there was an improvement in the 6-minute walk and sit to stand tests, but there were no changes in the control group. Exercise was effective, and the in-center approach was more effective than the home-based program. An effective home–based program would be more feasible to widely implement than in-center programs. One reason that the home program seemed less effective might be lower adherence. A non–CKD meta-analysis of studies of home exercise programs to prevent falls showed that the components of the home program seemed to affect adherence in older adults (8). Programs with greater adherence included home visit support or telephone support and used a physiotherapist rather than a trained instructor to deliver the program. A factor that might relate to why the participants chose to participate was that higher adherence was found for programs that included balance exercises, which the participants might be able to more directly relate to fall prevention. The factors that might affect patient acceptance and adherence to exercise studies in CKD have not, to our knowledge, been previously studied. This would be an important area of future research. References 1. Chen IR, Wang SM, Liang CC, Kuo HL, Chang CT, Liu JH, Lin HH, Wang IK, Yang YF, Chou CY, Huang CC: Association of walking with survival and RRT among patients with CKD stages 3-5. Clin J Am Soc Nephrol 9: 1183–1189, 2014 PubMed 2. Robinson-Cohen C, Littman AJ, Duncan GE, Weiss NS, Sachs MC, Ruzinski J, Kundzins J, Rock D, de Boer IH, Ikizler TA, Himmelfarb J, Kestenbaum BR: Physical activity and change in estimated GFR among persons with CKD. J Am Soc Nephrol 25: 399–406, 2014 PubMed 3. Heiwe S, Jacobson SH: Exercise training in adults with CKD: A systematic review and meta-analysis. Am J Kidney Dis 64: 383–393, 2014 PubMed 4. Watson EL, Greening NJ, Viana JL, Aulakh J, Bodicoat DH, Barratt J, Feehally J, Smith AC: Progressive resistance exercise training in CKD: A feasibility study [published online ahead of print December 17, 2014]. Am J Kidney Dis doi:10.1053/j.ajkd.2014.10.019 PubMed 5. Baria F, Kamimura MA, Aoike DT, Ammirati A, Rocha ML, de Mello MT, Cuppari L: Randomized controlled trial to evaluate the impact of aerobic exercise on visceral fat in overweight chronic kidney disease patients. Nephrol Dial Transplant 29: 857–864, 2014 PubMed 6. Kaminsky DA, Knyazhitskiy A, Sadeghi A, Irvin CG: Assessing maximal exercise capacity: Peak work or peak oxygen consumption? Respir Care 59: 90–96, 2014 PubMed 7. Loe H, Steinshamn S, Wisløff U: Cardio-respiratory reference data in 4631 healthy men and women 20-90 years: The HUNT 3 fitness study. PLoS One 9: e113884, 2014 PubMed Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 8. Simek EM, McPhate L, Haines TP: Adherence to and efficacy of home exercise programs to prevent falls: A systematic review and metaanalysis of the impact of exercise program characteristics. Prev Med 55: 262–275, 2012 PubMed Depression in CKD As reviewed in the last issue of NephSAP, depression is common in patients with CKD and associated with decreased quality of life and worse outcomes. A recent meta-analysis evaluated the prevalence of depression in CKD. The meta-analysis included 216 studies of 55,982 individuals with various levels of CKD (1). The largest group was individuals undergoing dialysis. When questionnaires were used to diagnoses depressive symptoms, the prevalence was 39.3% in patients on dialysis versus 26.5% in patients with CKD stages 1–5 not on dialysis and 26.6% in patients with transplants. The prevalence in patients on dialysis was lower if interview-based assessments of depression were used. In fact, the rates of depression were similar across all stages of CKD (22.8% for patients on dialysis, 21.4% for patients with stages 1–5 CKD, and 25.7% for patients with transplants) when using interview-based assessment, which is the gold standard for diagnosis of depression. The high prevalence of depressive symptoms using questionnaire-based measures may be because of the overlap between somatic symptoms of depression and common symptoms of renal failure (e.g., fatigue and poor sleep). These findings suggest that depression instruments might be more useful as a screening test, but this may be mainly an issue for patients on dialysis, because there was a greater disparity between the interview- and questionnaire-based measures in this population. It is notable that, even with the gold standard clinical interview, approximately one fourth of patients with CKD are clinically depressed. One of the commonly used instruments for depressive symptoms is the Patient Health Questionnaire-9 (PHQ-9), which is composed of nine questions regarding symptoms that the patient has experienced during the past 2 weeks. Questions are graded on a zero (not at all) to three (nearly every day) scale, and the scores across questions are summed. Scores of 15 or greater are consistent with moderately severe or severe depression. Yu et al. (2) evaluated the PHQ-9 in 3886 adults with diabetes enrolled in primary care in Group Health, a health maintenance organization in Washington and Idaho. In this study, Yu et al. (2) classified major and minor depressive 343 symptoms on the basis of the number of symptoms rather than the score (five or more symptoms .50% of the time for major and two to four symptoms for minor). The mean scores using the traditional scoring method were 17.263.8 and 9.662.2 for major and minor depressive symptoms, respectively. Participants with major depressive symptoms tended to be younger, black, and women, were more likely to smoke, and had lower socioeconomic status (lower education and income). Hemoglobin A1C was higher in individuals with depressive symptoms (7.7%, 7.9%, and 8.1% for no, minor, and major depressive symptoms, respectively). Adherence to aspects of diabetes self-care (e.g., glucose testing, diet, and exercise) was lower in individuals with major depressive symptoms. More significantly, the risk of ESRD was higher in those with depressive symptoms (incident rates: 2.78, 4.30, and 6.65 per 1000 patient-years for those with no, mild, and severe depressive symptoms, respectively). The association of severe but not mild depressive symptoms with ESRD risk persisted after adjustment. Depressive symptoms have also been shown to be associated with an increased risk of mortality, but most of the studies have been performed in patients on dialysis (3). In addition to depressive symptoms, health–related quality of life is associated with adverse outcomes. Porter et al. (4) analyzed the association of quality of life with the 36 Item Short Form Health Survey (SF-36) in the black Study of Kidney Disease and Hypertension Trial and cohort with outcomes. At baseline, the mean age was 55 years old, and mean eGFR was 48 ml/min per 1.73 m2. The median mental health composite score was 50, and the median physical composite score was 47. Both scores were associated with an increased risk of cardiovascular event/cardiovascular death, which persisted after adjustment for other factors. What is not clear from these studies is the mechanism of association between worse depressive symptoms or quality of life and adverse events. Furthermore, it is not known whether treatment of depression would decrease adverse events or patient-reported outcomes. In the study by Yu et al. (2) discussed above, 52% of individuals with severe depression were prescribed antidepressant medications. Although this may be relatively low, it suggests that we need additional studies to determine the best approach to deliver care for individuals with depression. 344 References 1. Palmer S, Vecchio M, Craig JC, Tonelli M, Johnson DW, Nicolucci A, Pellegrini F, Saglimbene V, Logroscino G, Fishbane S, Strippoli GF: Prevalence of depression in chronic kidney disease: Systematic review and meta-analysis of observational studies. Kidney Int 84: 179–191, 2013 PubMed 2. Yu MK, Weiss NS, Ding X, Katon WJ, Zhou XH, Young BA: Associations between depressive symptoms and incident ESRD in a diabetic cohort. Clin J Am Soc Nephrol 9: 920–928, 2014 PubMed 3. Palmer SC, Vecchio M, Craig JC, Tonelli M, Johnson DW, Nicolucci A, Pellegrini F, Saglimbene V, Logroscino G, Hedayati SS, Strippoli GF: Association between depression and death in people with CKD: A meta-analysis of cohort studies. Am J Kidney Dis 62: 493–505, 2013 PubMed 4. Porter A, Fischer MJ, Wang X, Brooks D, Bruce M, Charleston J, Cleveland WH, Dowie D, Faulkner M, Gassman J, Hiremath L, Kendrick C, Kusek JW, Norris KC, Thornley-Brown D, Greene T, Lash JP; AASK Study Group: Quality of life and outcomes in African Americans with CKD. J Am Soc Nephrol 25: 1849–1855, 2014 PubMed CKD and Safety The multiple complications of CKD and coexistent comorbid conditions often lead to complex medication regimens. This can increase the risk of adverse events from side effects, drug interactions, and medication errors. Farag et al. (1) evaluated outpatient antibiotic dosing in patients over age 65 years old with stages 4 and 5 CKD in southwest Ontario. The study from 2003 to 2010 was divided into monthly intervals. Ambulatory laboratories began reporting eGFR in January of 2006. The average number of patients was 667 per month. For antibiotics that require adjustment for the degree of Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 kidney function, the prescribed dose was too high in two thirds of prescriptions (970 of 1464). This was true for the time periods before and after automated eGFR reporting. In addition, nitrofurantoin, contraindicated in individuals with low levels of kidney function, was prescribed 169 times. This indicated a need for greater attention to drug dosing in kidney disease and that automatic reporting, by itself, will not be sufficient. The Safe Kidney Care Study is an observational cohort study in adults with nondialysis CKD and an eGFR,60 ml/min per 1.73 m2 designed to track the frequency of disease–specific adverse safety events. The events included patient-reported events (class 1) and abnormal laboratory results (class 2) (2). Ginsberg et al. (2) fount that, of 267 participants in the cohort, 185 (69%) had at least one safety event, and 102 (38%) had more than one event. The most common adverse safety event was hypoglycemia, occurring in 34% of subjects overall, with 58% in those on a medication that lowers glucose. Hypoglycemia was followed by severe falling or dizziness (24%). This study did not define the severity of the hypoglycemic episodes. With regard to abnormal laboratory results that might relate to medications, the most common was hyperkalemia (serum potassium .5.5 mEq/L), with 19% of participants taking a medication that could raise potassium levels. Individuals with diabetes were more likely to have more than one event (e.g., hypoglycemia and falling). Table 8. Glycemic targets in Kidney Disease Outcomes Quality Initiative and American Diabetes Association guidelines Kidney Disease Outcomes Quality Initiative (2.1) We recommend a target hemoglobin A1C of approximately 7.0% to prevent or delay progression of microvascular complications of diabetes, including CKD (2.2) We recommend not treating to a target ,7% in patients at risk of hypoglycemia (2.3) We suggest that the target hemoglobin A1C be extended above 7% in individuals with comorbidities or limited life expectancy and risk of hypoglycemia American Diabetes Association (targets 1 and 3 most applicable to patients with CKD) (1) Lowering hemoglobin A1C to approximately 7% or less has been shown to reduce microvascular complications of diabetes, and if implemented soon after the diagnosis of diabetes, it is associated with long-term reduction in macrovascular disease; therefore, a reasonable hemoglobin A1C goal for many nonpregnant adults is ,7% (2) Providers might reasonably suggest more stringent hemoglobin A1C goals (such as ,6.5%) for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment; appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease (3) Less stringent hemoglobin A1C goals (such as ,8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes, in whom the general goal is difficult to attain, despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose–lowering agents, including insulin Modified with permission from National Kidney Foundation: 2012 Update. Am J Kidney Dis 60: 850–886, 2012 and American Diabetes Association: Standards of medical care in diabetes, 2015. Diabetes Care 38[Suppl]: S1–S93, 2015. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 345 Figure 16. Patient and disease factors used to determine optimal hemoglobin A1C targets. Characteristics and predicaments toward the left justify more stringent efforts to lower hemoglobin A1C targets; those toward the right suggest less stringent efforts. Reprinted with permission from American Diabetes Association: Standards of medical care in diabetes, 2015. Diabetes Care 38(Suppl): S1–S93, 2015. Yun et al. (3) evaluated the incidence of severe hypoglycemia, defined as an episode requiring the assistance of another person, in a cohort of 1217 individuals with type 2 diabetes and preserved kidney function (eGFR$60 ml/min per 1.73 m2). Over a median 10 years of follow-up, there were 140 episodes in 111 patients. Severe hypoglycemia was more common in individuals with overt albuminuria, even after accounting for age, duration of diabetes, mean hemoglobin A1C, insulin and sulfonylureas, and eGFR (3). The risk was 2.5 times higher compared with that in those without albuminuria. Individuals with microalbuminuria did not have an increased risk. Other independent risk factors included older age and longer duration of diabetes. Because eGFR was not lower, decreased clearance of medications would not explain the finding, and the mechanism is not clear. However, the results of studies by Ginsberg et al. (2) and Yun et al. (3) reinforce the recommendation that tight glycemic control in the older, diabetic patient with advanced microvascular complications is not advisable. The current recommendations for hemoglobin A1C targets from Kidney Disease Outcomes Quality Initiative (4) and the American Diabetes Association (ADA) (5) are shown in Table 8. A useful figure that can be a guide for when to be less stringent in hemoglobin A1C goals is depicted in Figure 16 from the 2015 ADA Practice Guidelines (5). Complex regimens can also affect medication adherence. The Chronic Kidney Disease in Children Study is a prospective cohort study in North America of children with CKD (6). In this study of 558 children, the median age was 11 years old, and median GFR was 44 ml/min per 1.73 m2. Not unexpectedly, more medications were required with worse levels of GFR. Self-reported 346 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 nonadherence with medications was associated with older age, White race, and increased dosing frequency. Nonadherence was 70% more likely for medications dose greater than two times per day compared with that one time per day. A larger number of comorbidities was not associated with nonadherence or the number of different medication classes prescribed. This suggests that, if the medications can be taken all together, the number of medications taken is not as important as a regimen that requires medications to be spaced apart or taken at multiple times during the day. Other common medication issues include the use of nonsteroidal anti–inflammatory drugs and the Table 9. National Kidney Foundation list of 37 unique herbs potentially harmful in the setting of CKD (http:// www.kidney.org/atoz/herbalsupp) as listed by Grubbs et al. Potentially Toxic to the Kidneys Artemisia absinthium (wormwood plant)a Autumn crocus Chuifong tuokuwan (black pearl) Horse chestnut Periwinkle Sassafrasb Tung shueh Vandelia cordifolia Potentially Harmful in CKD Known to Be Unsafe for All People Alfalfaa Chapparal Aloea Bayberrya Comfrey Ephedra (ma huang)a Lobelia Mandrake Pennyroyal Pokeroota Sassafrasb Sennaa,b Yohimbea Blue cohosh Brooma Buckthorna Capsicuma Cascaraa Coltsfoot Dandeliona Gingera Ginsenga Horsetaila Licoricea Mate Nettlea Noni juicea Panaxa Rhubarba Sennaa,b Vervain Modified with permission from Grubbs V, Plantinga LC, Tuot DS, Hedgeman E, Saran R, Saydah S, Rolka D, Powe NR; Centers for Disease Control and Prevention CKD Surveillance Team: Americans’ use of dietary supplements that are potentially harmful in CKD. Am J Kidney Dis 61: 739–747, 2013. a Identified in dietary supplements reportedly taken in the study population. b Herb listed in more than one category but only counted one time as a unique herb. relatively frequent use of herbal supplements that may be harmful in patients with CKD. Some of these herbs are nephrotoxic, whereas others can interfere with medications or aggravate other CKD complications or risk factors. Grubbs et al. (7) evaluated the use of dietary supplements that might be harmful in CKD in the National Health and Nutrition Examination Survey. Grubbs et al. (7) used the list compiled by the National Kidney Foundation of 37 supplements/herbs that are harmful in CKD (Table 9). Over 50% of participants took some form of herbal supplement. Approximately 8.5% of individuals without CKD versus 6% of those with CKD used a supplement that was potentially harmful. Although the proportion using a harmful supplement was slightly lower in those with CKD, individuals with CKD were more likely to be taking the supplement for .3 years, increasing the risk of cumulative harm. The most commonly used potentially harmful supplement was ginseng or supplements that contained ginseng. Individuals who used supplements were more likely to be non-Hispanic white, have higher education levels, have higher income, and have a higher number of health care visits. This suggests that more attention needs to be paid to supplement use among patients with CKD. The higher number of visits among those who did use supplements indicates that there are opportunities for education to decrease risk. The pharmacokinetics and safety of a number of diabetic medications are changed by CKD. The half-life of insulin and a number of sulfonylureas are increased in CKD, increasing the risk of hypoglycemia. Metformin, typically the first-choice medication for diabetes, is contraindicated in advanced CKD. The use of metformin in CKD was discussed in one of the medication safety recommendations from the 2012 Kidney Disease: Improving Global Outcomes Guideline 4.4.6: “We recommend that metformin be continued in people with GFR $45 ml/min per 1.73 m2 (GFR categories G1–G3a); its use should be reviewed in those with GFR 30–44 ml/min per 1.73 m2 (GFR category G3b); and it should be discontinued in people with GFR ,30 ml/min per 1.73 m2 (GFR categories G4–G5)” (4). After lower GFR levels are reached, other agents are needed, although they may be associated with an increased risk of hypoglycemia. There are a number of new diabetic medications that patients with CKD may be using. One class is the dipeptidyl peptidase-4 (DPP-4) inhibitors. 347 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Table 10. Dose adjustment of Food and Drug Administration–approved dipeptidyl peptidase 4 inhibitors in CKD Medication Creatinine Clearance .50 ml/min Creatinine Clearance ¼30–50 ml/min Sitagliptin (mg/d) Saxagliptin (mg/d) Linagliptin (mg/d) Alogliptin (mg/d) 100 2.5–5 5 25a 50 (1/2 dose) 2.5 (1/2 dose) 5 (no adjustment) 12.5a (1/2 dose) Creatinine Clearance ,30 ml/min 25 2.5 5 6.25 (1/4 dose) (1/2 dose) (no adjustment) (1/4 dose) Modified with permission from Ioannidis I: Diabetes treatment in patients with renal disease: Is the landscape clear enough? World J Diabetes 5: 651–658, 2014. a Alogliptin creatinine clearance categories are $60 and 30 to ,60. The inhibition of DPP-4 blocks breakdown of glucagon-like peptide-1, which enhances insulin secretion in response to a meal, reduces gastric emptying time, and reduces appetite (8). Except for linagliptin, the DPP-4 inhibitors must be dose adjusted in kidney disease (Table 10) (9). A recent metaanalysis evaluated the safety and efficacy of DPP-4 inhibitors in CKD in 10 studies (4). Compared with placebo, DPP-4 medications lowered hemoglobin A1C, on average, by 0.5%. In two studies that compared a DPP-4 inhibitor with glipizide, the degree of hemoglobin A1C lowering was similar. DPP-4 inhibitors had a lower risk of hypoglycemia than glipizide and a similar rate to placebo (Figure 17) (10). Thus, these medications may be safer alternatives in kidney disease; however, we do not have large, long–term safety studies. Individuals with CKD are at increased risk for hypoglycemia, with at least one episode occurring in more than one half of patients with CKD. This observation should reinforce the need to adjust hypoglycemic agents and avoid targeting a hemoglobin A1C of ,7% in individuals at risk for hypoglycemia. References 1. Farag A, Garg AX, Li L, Jain AK: Dosing errors in prescribed antibiotics for older persons with CKD: A retrospective time series analysis. Am J Kidney Dis 63: 422–428, 2014 PubMed 2. Ginsberg JS, Zhan M, Diamantidis CJ, Woods C, Chen J, Fink JC: Patient-reported and actionable safety events in CKD. J Am Soc Nephrol 25: 1564–1573, 2014 PubMed 3. Yun JS, Ko SH, Ko SH, Song KH, Ahn YB, Yoon KH, Park YM, Ko SH: Presence of macroalbuminuria predicts severe hypoglycemia in Figure 17. Meta-analysis for the risk of hypoglycemia. (A) DPP-4 inhibitor vs. placebo or no treatment. (B) DPP-4 inhibitor versus glipizide 95% CI, 95% confidence interval; DPP4i, dipeptidyl pepdidase-4; M-H. Reprinted with permission from Cheng D, Fei Y, Liu Y, Li J, Chen Y, Wang X, Wang N: Efficacy and safety of dipeptidyl pepdidase-4 in type 2 diabetes mellitus patients with moderate to severe renal impairment: A systematic review and meta-analysis. PLoS One 9: e111543, 2014. 348 4. 5. 6. 7. 8. 9. 10. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 patients with type 2 diabetes: A 10-year follow-up study. Diabetes Care 36: 1283–1289, 2013 PubMed National Kidney Foundation: 2012 Update. Am J Kidney Dis 60: 850– 886, 2012 PubMed American Diabetes Association: Standards of medical care in diabetes, 2015. Diabetes Care 38[Suppl]: S1–S93, 2015 PubMed Blydt-Hansen TD, Pierce CB, Cai Y, Samsonov D, Massengill S, Moxey-Mims M, Warady BA, Furth SL: Medication treatment complexity and adherence in children with CKD. Clin J Am Soc Nephrol 9: 247–254, 2014 PubMed Grubbs V, Plantinga LC, Tuot DS, Hedgeman E, Saran R, Saydah S, Rolka D, Powe NR; Centers for Disease Control and Prevention CKD Surveillance Team: Americans’ use of dietary supplements that are potentially harmful in CKD. Am J Kidney Dis 61: 739–747, 2013 PubMed Garber AJ: Incretin therapy–present and future. Rev Diabet Stud 8: 307– 322, 2011 PubMed Ioannidis I: Diabetes treatment in patients with renal disease: Is the landscape clear enough? World J Diabetes 5: 651–658, 2014 PubMed Cheng D, Fei Y, Liu Y, Li J, Chen Y, Wang X, Wang N: Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with moderate to severe renal impairment: A systematic review and meta-analysis. PLoS One 9: e111543, 2014 PubMed Systems of Care and Effect on CKD There has been increasing emphasis on the understanding the effect of the education programs and care delivery on the recognition and progression of CKD. With the financial costs associated with CKD, assessing the effectiveness of the interventions to slow the progression of kidney disease has been the focus of several studies. Multidisciplinary Clinics A multidisciplinary care (MDC) approach to CKD management has been promoted on the basis of the potential to affect the decline of renal function. Chen et al. (1) studied the effect of MDC versus usual care in a prospective cohort study involving 1056 Taiwanese subjects over a 3-year period. Primary end points were progression to ESRD (initiation of dialysis) and mortality. The rate of renal functional decline, BP control, anemia management, and metabolic bone disease parameters were studied as well. The rates of decline for CKD stages 4 and 5 were slower in the MDC group (25.1% versus 27.3% ml/min). The MDC group spent more time with RRT planning/education, which was reflected by the greater percentage of participants who opted for peritoneal dialysis, fewer individuals beginning dialysis with a temporary catheter, and a 51% decrease in mortality but an anticipated increase in dialysis initiation of 68%. The latter finding may be attributed to lower mortality, because there was no difference in the combined end point of death or dialysis initiation (adjusted hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.50). There was an increased use of medications for reduction of proteinuria, phosphate binding, and anemia treatment with erythropoiesisstimulating agents in the MDC group. The predialysis education and team management approach helped delay progression of renal disease and facilitated RRT preparation. The addition of nephrology nurses or nurse practitioners to usual care has not consistently shown positive results as reviewed in the last NephSAP CKD edition. The Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse Practitioners Study involved 788 individuals with moderate to severe CKD randomized to additional care by a nurse practitioner (intervention group) or usual care by a physician group (control) (2). Over a median follow-up of 5–7 years, there was a 20% reduction in the composite renal end point of death, ESRD, and a 50% increase in the SCr (99.6 versus 118.7 events per 100 person-years). The intervention group had a 0.45-ml/min less decline in GFR per year and better achievement of clinical targets, such as BP control, thereby showing the value of a team approach to CKD. Although prior trials showed inconsistent results, in a recent randomized trial comparing additional care by a nurse practitioner with usual care, there was a 20% reduction in progression of kidney disease. Preparation for RRT is one of the key steps in management of CKD. The ability to influence the choice of RRT modality through a combination of education, MDC, and patient engagement was highlighted in a prospective study by Rayner et al. (3). Changes in the incidence and treatment modality were followed in 10,522 patients with CKD and 8509 patients with diabetes but no CKD between 2003 and 2006. Patient engagement strategies, such as education, financial incentives, and personalized reports after each clinical visit, and the incorporation of practice changes of automated GFR reporting and multidisciplinary pre–RRT care were used on the cohort of patients. After 2 years, the incident rate of RRT declined from 23.9% to 19.6%%. A 63% increase in the combined end points of transplantation, choice of peritoneal dialysis, and arteriovenous fistula use was noted by 2012. Of those who opted not to pursue dialysis, 52% were able to make the arrangements to die at home. The lack of having a multidisciplinary team approach can result in gaps in care. Identifying these issues can be turned into opportunities for collaboration. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Reviewing the records of 196 adolescents with CKD, ESRD, or transplantation who were transitioning from pediatric to adult care providers, Hooper et al. (4) determined that only 58% had the recommended cardiovascular risk assessment. Recommended therapy for modifiable risk factors was documented just 57% of the time. The identification of the gap in care for these adolescents in terms of adequate cardiovascular risk management shows an opportunity for developing collaborative teams to help transition them from pediatric practitioners to adult nephrologists. Ovbiagele et al. (5) reviewed the records of 236,662 patients with ischemic stroke and CKD hospitalized between 2009 and 2012. Those with severe renal dysfunction or failure were less likely to receive the therapy-based guidelines, such as anticoagulation, smoking cessation intervention, or lipid reduction. Inpatient mortality was higher in patients with CKD. Economics Using National Health and Nutrition Examination Survey data and Medicare claims, Honeycutt et al. (6) analyzed medical costs associated with different stages of CKD. Medicare costs ranged from $1700 per year for stage 2 CKD and $3500 per year for stage 3 CKD to $12,700 per year for stage 4 CKD. The financial burdens of CKD and ESRD are significant and make the case for interventions that slow progression of CKD. The cost of care and lack of coverage influence the outcomes and management decisions. The effect of broadened Medicaid coverage was examined in 408,535 adults ages 20–65 years old with variable levels of Medicaid coverage (7). With every 10% increase in the population covered by Medicaid, there was a 1.8% decrease in ESRD incidence. There were also concomitant reductions in the access gap to transplantation and peritoneal dialysis (Figure 18). Electronic Health Records The use of electronic health records has the ability to influence practice patterns and trigger management strategies for aspects of CKD. The influence of eGFR reporting on decisions in dialysis initiation, referral patterns to nephrology, recognition of CKD stage, and effects on medication prescription has been studied recently. A retrospective review of patients with CKD followed in a rural primary care practice showed the effect of eGFR reporting on recognition of CKD (8). Of those with CKD on the basis of laboratory values, 52% had no documentation of a CKD diagnosis. Patients 349 Figure 18. Effects of insurance status on various aspects of renal replacement therapy preparation. Rates of access to care among privately insured, Medicaid, and uninsured nonelderly adults between 2001 and 2008. AVF, arteriovenous fistula. Reprinted with permission from Kurella-Tamura M, Goldstein BA, Hall YN, Mitani AA, Winkelmayer WC: State medicaid coverage, ESRD incidence, and access to care. J Am Soc Nephrol 25: 1321–1329, 2014. formally diagnosed with CKD by primary care practitioners had more antihypertensive medication changes and increased comanagement with nephrologists. Some data suggest greater recognition of CKD but not necessarily with changes in management. In a survey of nephrologists regarding their likelihood of initiating dialysis in four different clinical scenarios, Brimble et al. (9) examined the effect that eGFR had on decision making. For each scenario, the respondent was asked to rank his or her likelihood of recommending dialysis initiation on a modified eight-point Likert scale ranging from one (definitely would not) to eight (definitely would). Dialysis initiation recommendations increased by 0.55 points when eGFR was reported. A subgroup analysis showed that physicians in practice for .13 years were more influenced (P¼0.03). eGFR reporting was also shown to effect the timing of referrals to nephrology. A study of 25,000 patients who initiated RRT between January 1, 1999 and December 31, 2010 from the Australia and New Zealand Dialysis Transplant Registry showed an absolute reduction of 3.7% (P,0.001) in late referrals comparing the pre–GFR reporting period with its post-GFR counterpart (10). However, this small reduction in late referrals did not extend to improvements in preparation for RRT, such as arteriovenous fistula creation. Another example of where eGFR reporting facilitated recognition and documentation of CKD but did not 350 translate to meaningful changes in outcomes is found in the study of two Veterans Administration cohorts before and after introduction of laboratory–automated eGFR reporting (11). Wang et al. (11) detected an increased recognition and documentation of CKD stage, but there no change in nephrology referral rate. Wei et al. (12) looked at the effect of reporting eGFR on prescribing of nonsteroidal anti–inflammatory drugs (NSAIDs). NSAID prescriptions decreased from 39,459 to 35,415 after implementation of eGFR reporting. Those patients who stopped NSAIDs experienced improvements in eGFR. In patients with stage 4 CKD, eGFR increased slightly from 23.9 to 27.1 ml/min per 1.73 m2; however, the increase was from 12.4 to 26.4 ml/min per 1.73 m2 among patients with stage 5 CKD. There are several guidelines for CKD management, but incorporation into routine practice has been difficult to achieve. In a prospective study of an academic primary care clinic, the implementation of a checklist for laboratory testing and interventions for each stage of CKD was evaluated (13). The patients assigned to primary care providers using the checklist were more routinely tested for albuminuria, hyperparathyroidism by parathyroid hormone, and phosphorus. The same group displayed superior rates of diabetes control, anti–renin-angiotensin-aldosterone system drug use, appropriate immunizations, and avoidance of NSAIDs. CKD Education The importance of education regarding CKD and RRT options has been established. However, the ability to provide this during a routine physician visit is limited. Verhave et al. (14) assessed awareness of CKD and cardiovascular risk factors among 20,004 patients who had free access to medical care in Quebec. Self-awareness of CKD, diabetes, hypertension, or hyperlipidemia was low, despite the regular physician checkups. Thus, there is a need for interventions to increase awareness of the disease processes and subsequently, improve achievement of guideline targets. Attempts to incorporate a teaching tool that could be used during a routine nephrology visit was assessed by Wright Nunes et al. (15). A one–page education worksheet was used during routine visits for patients with stages 1–5 CKD. Of 155 patients who received this teaching tool, there were higher rates of CKD awareness and acknowledgment of kidney function level and stage. Kurella Tamura et al. (16) compared 595 patients with ESRD who had participated in the National Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Kidney Foundation Kidney Early Evaluation Program (KEEP) with a group of matched patients not in the KEEP. Those who had gone through the KEEP had significantly higher rates of pre–ESRD nephrology care, choice of peritoneal dialysis as renal replacement modality, preemptive transplant listing, and transplantation over participants not in the KEEP (76.0% versus 69.3%, 10.3% versus 6.4%, 24.1% versus 17.2%, and 9.7% versus 6.4% in KEEP versus non-KEEP, respectively). There was no statistically significant difference in mortality. References 1. Chen Y-R, Yang Y, Wang S-C, Chiu P-F, Chou W-Y, Lin C-Y, Chang J-M, Chen T-W, Ferng S-H, Lin C-L: Effectiveness of multidisciplinary care for chronic kidney disease in Taiwan: A 3-year prospective cohort study. Nephrol Dial Transplant 28: 671–682, 2013 PubMed 2. Peeters MJ, van Zuilen AD, van den Brand JA, Bots ML, van Buren M, Ten Dam MA, Kaasjager KA, Ligtenberg G, Sijpkens YW, Sluiter HE, van de Ven PJ, Vervoort G, Vleming LJ, Blankestijn PJ, Wetzels JF: Nurse practitioner care improves renal outcome in patients with CKD. J Am Soc Nephrol 25: 390–398, 2014 PubMed 3. Rayner HC, Baharani J, Dasgupta I, Suresh V, Temple RM, Thomas ME, Smith SA: Does community-wide chronic kidney disease management improve patient outcomes? Nephrol Dial Transplant 29: 644– 649, 2014 PubMed 4. Hooper DK, Williams JC, Carle AC, Amaral S, Chand DH, Ferris ME, Patel HP, Licht C, Barletta GM, Zitterman V, Mitsnefes M, Patel UD: The quality of cardiovascular disease care for adolescents with kidney disease: A Midwest Pediatric Nephrology Consortium study. Pediatr Nephrol 28: 939–949, 2013 PubMed 5. Ovbiagele B, Schwamm LH, Smith EE, Grau-Sepulveda MV, Saver JL, Bhatt DL, Hernandez AF, Peterson ED, Fonarow GC: Patterns of care quality and prognosis among hospitalized ischemic stroke patients with chronic kidney disease. J Am Heart Assoc 3: e000905, 2014 PubMed 6. Honeycutt AA, Segel JE, Zhuo X, Hoerger TJ, Imai K, Williams D: Medical costs of CKD in the Medicare population. J Am Soc Nephrol 24: 1478–1483, 2013 PubMed 7. Kurella-Tamura M, Goldstein BA, Hall YN, Mitani AA, Winkelmayer WC: State medicaid coverage, ESRD incidence, and access to care. J Am Soc Nephrol 25: 1321–1329, 2014 PubMed 8. Rao MK, Morris CD, O’Malley JP, Davis MM, Mori M, Anderson S: Documentation and management of CKD in rural primary care. Clin J Am Soc Nephrol 8: 739–748, 2013 PubMed 9. Brimble KS, Mehrotra R, Tonelli M, Hawley CM, Castledine C, McDonald SP, Levidiotis V, Gangji AS, Treleaven DJ, Margetts PJ, Walsh M: Estimated GFR reporting influences recommendations for dialysis initiation. J Am Soc Nephrol 24: 1737–1742, 2013 PubMed 10. Foote C, Clayton PA, Johnson DW, Jardine M, Snelling P, Cass A: Impact of estimated GFR reporting on late referral rates and practice patterns for end-stage kidney disease patients: A multilevel logistic regression analysis using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). Am J Kidney Dis 64: 359– 366, 2014 PubMed 11. Wang V, Maciejewski ML, Hammill BG, Hall RK, Van Scoyoc L, Garg AX, Jain AK, Patel UD: Recognition of CKD after the introduction of automated reporting of estimated GFR in the Veterans Health Administration. Clin J Am Soc Nephrol 9: 29–36, 2014 PubMed 12. Wei L, MacDonald TM, Jennings C, Sheng X, Flynn RW, Murphy MJ: Estimated GFR reporting is associated with decreased nonsteroidal antiinflammatory drug prescribing and increased renal function. Kidney Int 84: 174–178, 2013 PubMed Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 13. Mendu ML, Schneider LI, Aizer AA, Singh K, Leaf DE, Lee TH, Waikar SS: Implementation of a CKD checklist for primary care providers. Clin J Am Soc Nephrol 9: 1526–1535, 2014 PubMed 14. Verhave JC, Troyanov S, Mongeau F, Fradette L, Bouchard J, Awadalla P, Madore F: Prevalence, awareness, and management of CKD and cardiovascular risk factors in publicly funded health care. Clin J Am Soc Nephrol 9: 713–719, 2014 PubMed 15. Wright Nunes J, Greene JH, Wallston K, Eden S, Shintani A, Elasy T, Rothman RL, Ikizler TA, Cavanaugh KL: Pilot study of a physiciandelivered education tool to increase patient knowledge about CKD. Am J Kidney Dis 62: 23–32, 2013 PubMed 16. Kurella Tamura M, Li S, Chen SC, Cavanaugh KL, Whaley-Connell AT, McCullough PA, Mehrotra RL: Educational programs improve the preparation for dialysis and survival of patients with chronic kidney disease. Kidney Int 85: 686–692, 2014 PubMed Disparities Risk for development of CKD, rate of progression of kidney disease, and outcomes can be influenced by different factors, such as sex, race, socioeconomic status, and health literacy. Having a better understanding of these factors will guide more targeted management strategies. Race and Sex The effect of race on incidence, rate of progression, and mortality continues to be an area of focus. Derose et al. (1) analyzed a retrospective cohort from the Kaiser Permanente Database from 2003 to 2009 and documented racial differences in projected kidney failure and mortality. Black patients had more extreme rates of eGFR decline. The first percentile of 136,923 black patients decreased by 223.6 ml/min per year compared with the first percentile of 350,917 Hispanic patients (220.9-ml/min per year decline), the first percentile of 526,498 white patients (220.1-ml/min per year decline), and the first percentile of 105,476 Asian patients (217.6-ml/min per year decline). However, these greater rates of decline in black patients did not result in greater rates of mortality. The highest rate of mortality was among white patients. The difference in survival, despite slower rates of GFR decline, was noted again in the historical cohort of 518,406 white men and 52,402 black men in the United Stated veterans studies by Kovesdy et al. (2). Over a median follow-up of 4.7 years, 172,093 patients died. Black race was associated with lower crude mortality rates, especially in the setting of more advanced CKD (hazard ratio, 0.95; 95% confidence interval, 0.94 to 0.97); the effect persisted with full adjustment (hazard ratio, 0.72; 95% confidence interval, 0.70 to 0.73). The difference in mortality may be attributable to the different etiologies of CKD. The varying rates of GFR decline were further illustrated in the longitudinal study of 3348 351 black and white adults who were enrolled in the Coronary Artery Risk Development in Young Adults Study (3). Renal functional assessment by cystatin C–based eGFR was completed during routine study visits. Among blacks, there was a more rapid decline in GFR at earlier ages. During period 1 of the study (10–15 years postbaseline examination), the rate of decline in GFR was 0.13 ml/min faster. In period 2 (.15 years postbaseline), the rate of decline was 0.32 ml/min faster. Some of the difference in GFR decline could be related to creatinine differences. The identification of different genes associated with renal disorders has been implicated in the racial differences in prevalence and progression of CKD. Case-control studies have noted that blacks with variants of apolipoprotein L1 (APOL1) are more likely to have FSGS, HIV-associated nephropathy, and ESRD. The importance of APOL1 variants in terms of susceptibility was examined in blacks with nondiabetic nephropathy (4). Both related and unrelated blacks with nondiabetic nephropathy were assessed for the interaction between JC virus, BK polyomavirus, human herpesvirus 6, or cytomegalovirus and APOL1 risk alleles. Given the rare incidence of human herpesvirus 6 and cytomegalovirus within the study, conclusions about the interaction of these viruses with APOL1 could not be made; however, BK virus did not cause nephropathy. Blacks at risk for APOL1-associated nephropathy who had concomitant JC viruria had a lower risk of kidney disease. The effect of APOL1 G1 and G2 risk alleles on the development of CKD and progression to ESRD was assessed in 3607 blacks in the Atherosclerosis Risk in Communities (ARIC) Study (5). Carrying two risk alleles was associated with a 1.49-fold increased risk of CKD and a 1.58-fold increased risk of ESRD compared with those with zero or one allele. The association of APOL1 risk variants on progression of CKD in black patients compared with white patients was assessed in the black Study of Kidney Disease and Hypertension (AASK) Trial and the Chronic Renal Insufficiency Cohort (CRIC) Study (6) as previously reviewed in this issue of NephSAP in the section on Genetics. The effect of having two risk alleles of APOL1 (high risk) versus zero or one copy (low risk) was analyzed using data from 693 black patients enrolled in the AASK Trial and 2955 black and white patients enrolled in the CRIC Study, in which 45% of the population had diabetes. In the AASK Trial, the primary outcome of ESRD or doubling of the SCr was achieved in 58.1% of the APOL1 high–risk group and 36.6% of the APOL1 low–risk group. In the CRIC Study, 352 the APOL1 high–risk group had a more rapid decline in GFR and higher risk of worse renal outcomes. The presence of albuminuria is a known risk factor for renal disease, and it is a marker of vascular injury. The effect of albumin to creatinine ratio (ACR) and eGFR on risk of stroke, heart failure, and coronary artery disease was assessed in the ARIC Study observational cohort of 11,060 white and black individuals who were 52–75 years old (7). An eGFR,70 ml/min per 1.73 m2 and the log ACR were linearly associated with risk of cardiovascular disease (CVD). In this study, associations of eGFR and ACR with CVD were generally similar among subgroups of age, sex, and race. However, it remains unclear if albuminuria has a different effect on CVD on the basis of sex or race. A meta-analysis of 46 cohorts from Europe, North and South America, Asia, and Australia focused on the interaction of sex on GFR and albuminuria with all-cause mortality, cardiovascular mortality, and ESRD (8). Risks of all-cause mortality and cardiovascular mortality were higher in men at all levels of eGFR and ACR. The slope of the risk relation was steeper in women. There was no difference between sexes in terms of ESRD risk. There were a few studies addressing the role of albuminuria as a risk factor for racial differences in the outcomes. Extrapolating on the increased rate of incident stroke in black individuals with excess urinary albumin excretion, Gutiérrez et al. (9) looked at the risk of incident coronary heart disease (CHD) related to albuminuria in a prospective cohort study of subjects enrolled in the Reasons for Geographic and Racial Difference in Stroke Study between 2003 and 2007. Among those who, at baseline, had no CHD (n¼23,373), rates of incident events occurred at a 1.5-fold greater rate than in black participants. Higher rates of albuminuria were associated with greater risk of incident CHD among black participants. Those with recurrent CHD had similar degrees of albuminuria. The prevalence of diabetes and ESRD was greater in blacks and Hispanics. Using the National Health and Nutrition Examination Survey (NHANES) data, a survey of 2310 patients with diabetes over the age of 20 years old was performed to assess the effect of albuminuria (10). The prevalence of early CKD was greater among Hispanics and blacks and associated with urinary albumin excretion and C–reactive protein levels. Access to Care Access to care, specifically education, has an effect on modality choice of RRT, pursuit of preemptive Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 transplantation, and rate of progression of CKD. Whether this can be generalized to different racial groups, economic groups, or geographic areas was addressed by a few studies. On the basis of 2009–2011 data from The Netherlands Predialysis Patient Record Study of patients with CKD within a universal health care system, blacks have faster disease progression than whites (11). At baseline, black patients were younger, more likely diabetic, had greater proteinuria, and had greater eGFRs. There was more rapid decline in renal function of 0.18 ml/min per month in blacks compared with white patients. van den Beukel et al. (11) drew the conclusion that the health care system factors have a less influential role in explaining black and white differences in progression to ESRD. Vart et al. (12) studied the effect of education in two cohorts: one from the United States (NHANES) and one from The Netherlands (Prevention of Renal and Vascular Endstage Disease Study). In the United States, where access to care is income dependent, low income was a predictor of CKD. In The Netherlands, lower education levels had an association with CKD. Racial variations in pre-ESRD care were noted in the analysis of the US Renal Data System data regarding 404,622 non–Hispanic white and black patients starting dialysis between 2005 and 2010 (13). Yan et al. (13) consistently noted patterns, in which black patients received less pre–ESRD care, defined as having an arteriovenous access at the start of dialysis, nephrology care at 6–12 months, and use of erythropoietin-stimulating agents. Larger metropolitan and small rural areas had lower rates of pre-ESRD care. The importance of education and health literacy is difficult to assess given that a lack of access to care has a more overwhelming effect. References 1. Derose SF, Rutkowski MP, Crooks PW, Shi JM, Wang JQ, KalantarZadeh K, Kovesdy CP, Levin NW, Jacobsen SJ: Racial differences in estimated GFR decline, ESRD, and mortality in an integrated health system. Am J Kidney Dis 62: 236–244, 2013 PubMed 2. Kovesdy CP, Quarles LD, Lott EH, Lu JL, Ma JZ, Molnar MZ, Kalantar-Zadeh K: Survival advantage in black versus white men with CKD: Effect of estimated GFR and case mix. Am J Kidney Dis 62: 228– 235, 2013 PubMed 3. Peralta CA, Vittinghoff E, Bansal N, Jacobs D Jr., Muntner P, Kestenbaum B, Lewis C, Siscovick D, Kramer H, Shlipak M, Bibbins-Domingo K: Trajectories of kidney function decline in young black and white adults with preserved GFR: Results from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Am J Kidney Dis 62: 261–266, 2013 PubMed 4. Divers J, Núñez M, High KP, Murea M, Rocco MV, Ma L, Bowden DW, Hicks PJ, Spainhour M, Ornelles DA, Kleiboeker SB, Duncan K, Langefeld CD, Turner J, Freedman BI: JC polyoma virus interacts with APOL1 in African Americans with nondiabetic nephropathy. Kidney Int 84: 1207–1213, 2013 PubMed Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 5. Foster MC, Coresh J, Fornage M, Astor BC, Grams M, Franceschini N, Boerwinkle E, Parekh RS, Kao WH: APOL1 variants associate with increased risk of CKD among African Americans. J Am Soc Nephrol 24: 1484–1491, 2013 PubMed 6. Parsa A, Kao WH, Xie D, Astor BC, Li M, Hsu CY, Feldman HI, Parekh RS, Kusek JW, Greene TH, Fink JC, Anderson AH, Choi MJ, Wright JT Jr., Lash JP, Freedman BI, Ojo A, Winkler CA, Raj DS, Kopp JB, He J, Jensvold NG, Tao K, Lipkowitz MS, Appel LJ; AASK Study Investigators; CRIC Study Investigators: APOL1 risk variants, race, and progression of chronic kidney disease. N Engl J Med 369: 2183–2196, 2013 PubMed 7. Hui X, Matsushita K, Sang Y, Ballew SH, Fülöp T, Coresh J: CKD and cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study: Interactions with age, sex, and race. Am J Kidney Dis 62: 691–702, 2013 PubMed 8. Nitsch D, Grams M, Sang Y, Black C, Cirillo M, Djurdjev O, Iseki K, Jassal SK, Kimm H, Kronenberg F, Oien CM, Levey AS, Levin A, Woodward M, Hemmelgarn BR; Chronic Kidney Disease Prognosis Consortium: Associations of estimated glomerular filtration rate and albuminuria with mortality and renal failure by sex: A meta-analysis. BMJ 346: f324, 2013 PubMed 9. Gutiérrez OM, Khodneva YA, Muntner P, Rizk DV, McClellan WM, Cushman M, Warnock DG, Safford MM; REGARDS Investigators: Association between urinary albumin excretion and coronary heart disease in black vs white adults. JAMA 310: 706–714, 2013 PubMed 10. Sinha SK, Shaheen M, Rajavashisth TB, Pan D, Norris KC, Nicholas SB: Association of race/ethnicity, inflammation, and albuminuria in patients with diabetes and early chronic kidney disease. Diabetes Care 37: 1060–1068, 2014 PubMed 11. van den Beukel TO, de Goeij MC, Dekker FW, Siegert CE, Halbesma N; PREPARE Study Group: Differences in progression to ESRD between black and white patients receiving predialysis care in a universal health care system. Clin J Am Soc Nephrol 8: 1540–1547, 2013 PubMed 12. Vart P, Gansevoort RT, Coresh J, Reijneveld SA, Bültmann U: Socioeconomic measures and CKD in the United States and The Netherlands. Clin J Am Soc Nephrol 8: 1685–1693, 2013 PubMed 13. Yan G, Cheung AK, Ma JZ, Yu AJ, Greene T, Oliver MN, Yu W, Norris KC: The associations between race and geographic area and quality-of-care indicators in patients approaching ESRD. Clin J Am Soc Nephrol 8: 610–618, 2013 PubMed Geriatric Nephrology Issues Many of the relevant topic areas have been covered by the geriatrics NephSAP issue. Here, we highlight some more recent studies. We refer the reader to the geriatrics NephSAP for a more complete overview. Physical Function and Frailty Individuals with CKD have decreased physical function, which increases the risk of developing disability. This section reviews some recent studies related to function. In a cross-sectional study of 120 patients with stages 2–5 CKD in Japan with a mean age of 66.5 years, the correlation of eGFR with grip and knee strength, single–leg stance time, and gait speed was 353 approximately 0.45 for all measures, and these correlations persisted in adjusted models (1). One concern with using creatinine–based eGFR measures in studies of physical function is that creatinine itself is a function of muscle mass. Decreases in muscle mass might mask the association of reduced kidney function with decline in physical function. Liu et al. (2) evaluated the association of cystatin C–based eGFR and creatinine-based eGFR with the development of mobility impairment (inability to walk 0.5 mile and/or climb a flight of stairs) in 1226 individuals over age 60 years old participating in the Framingham Offspring Study. CKD as defined by cystatin C was associated with the development of mobility impairment (adjusted hazard ratio, 1.55; 95% confidence interval, 1.05 to 2.31), but CKD defined by creatinine was not (adjusted hazard ratio, 1.03; 95% confidence interval, 0.64 to 1.62). Dalrymple et al. (3) evaluated eGFR by cystatin C and creatinine with prevalent and incident frailty in the Cardiovascular Health Study, a community-based study of adults ages $65 years old. Frailty is a state of decreased physiologic function. In research studies, frailty is commonly operationalized as the presence of three of five criteria: (1) shrinking (unintentional weight loss $10 lb or 5% in the past year), (2) poor endurance and energy as assessed by two questions from the Centers for Epidemiologic Studies Depression Scale, (3) weakness (grip strength in the lowest 20% adjusted for sex and body mass index), (4) slowness (lowest gait speed adjusted for sex and height), and (5) low physical activity (lowest quintile for each sex). The prevalence of frailty increased with lower eGFR by cystatin C and was greater in women than in men. Individuals with an eGFR,45 ml/min per 1.73 m2 had a 2-fold higher risk for incident frailty (assessed 4 years later). In contrast, CKD as assessed by creatinine was not associated with a higher prevalence or incidence of frailty. In the general population, lower physical performance is associated with increased risk of disability, nursing home placement, and mortality (4). Roshanravan et al. (5) analyzed the association of physical performance measures with mortality in individuals with CKD participating in the Seattle Kidney Study and the Baltimore University of Maryland Study. There were 385 participants with mean eGFR of 41619 ml/min per 1.73 m2. At baseline, gait speed, timed up and go test, and the 6-minute walk test were 30%–39% lower than predicted. 354 Similar to the findings for prevalence of frailty by Dalrymple et al. (3), the decrements in physical function were worse in women. Handgrip strength was not lower than normal older adult controls. The median follow-up was 3 years; 13% died. In unadjusted analyses, lower performance in all four measures was associated with a greater risk of mortality. However, with adjustment, handgrip strength was no longer associated with mortality. Another way to look at mobility is the life-space approach that considers mobility in the context of a person’s environment (6). A person’s life space is the area through which one routinely and purposefully moves (Figure 19). Assessment by this concept may allow earlier detection of problems before decrements in instrumental activities of daily living or activities of daily living recognize that chronic conditions may lead to greater isolation and inactivity. Functional assessment can be evaluated by a questionnaire using the different levels multiplied by frequency over a 4-week period (scores range from 0 to 120) (6). Bowling et al. (7) applied this concept to individuals with CKD in the University of Alabama Study of Aging, a population–based longitudinal study of mobility among community–dwelling older adults. Bowling et al. (7) evaluated whether kidney function was associated with the trajectories of life-space levels over time. Of 390 participants, 49.7% had an eGFR$60 ml/min per 1.73 m2, 30% had an eGFR between 45 and 59 ml/min per 1.73 m2, and 20.2% had an eGFR,45 ml/min per 1.73 m2. At baseline, the mean life–space scores were lower (more limited) with lower eGFRs, and those with lower eGFRs had a greater decline over time. More information is needed on the implications Figure 19. Functional mobility status by questionnaire of life space area. Life-space assessment is on the basis of a distribution range, which is divided among six different categories. Reprinted with permission from Parker M, Baker PS, Allman RM: A life-space approach to functional assessment of mobility in the elderly. J Gerontol Soc Work 35: 35–55, 2002. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 of the decline in life space and whether interventions would improve function and independence. Cognitive Impairment In a prior issue of NephSAP, we reviewed studies that found that lower eGFR and higher albuminuria were associated with cognitive impairment, with albuminuria being the stronger marker in CKD. Recent studies have further refined this risk (8–12). CKD is associated with an increased risk of cognitive impairment. Potential causes of cognitive impairment include small vessel vascular disease, higher levels of inflammatory markers, and other potential risk factors for neurotoxicity (13). These issues were recently discussed in a review by Bugnicourt et al. (13). A recent study lends support to the association of small vessel vascular disease with cognitive impairment in CKD. Yaffe et al. (11) evaluated the association of retinopathy with cognitive impairment in the Chronic Renal Insufficiency Cohort (CRIC) Study; 30% of participants in the CRIC Study had retinopathy. Those with retinopathy were older, were less likely to be white, had higher systolic BP, and were more likely to have diabetes, a history of coronary artery disease, stroke, and proteinuria. In unadjusted analyses, individuals with retinopathy were more likely to have cognitive impairment. After adjustment, participants with retinopathy had worse scores in trials A and B of testing, measures of attention and executive function, and the Boston Naming Test, a measure of language function. In addition, the scores on these three tests were worse with more severe retinopathy. Davey et al. (9) evaluated the association of kidney function with longitudinal change in cognitive function in 590 participants in the Main-Syracuse Longitudinal Study, a community-based study of cardiovascular risk factors and cognition. Individuals completed a complete battery of cognitive tests covering visual-spatial organization and memory, scanning, tracking (including executive function), verbal memory, working memory, and abstract reasoning. Baseline eGFR was not associated with change in cognitive function; however, a greater decline in kidney function (.3 ml/min per 1.73 m2) was associated with a greater decline in verbal memory and abstract reasoning. Individuals with diabetes have an increased risk for cognitive impairment. Barzilay et al. (8) evaluated the association of albuminuria with cognitive decline in individuals with diabetes and preserved eGFR in the Action to Control Cardiovascular Risk in Diabetes 355 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Memory in Diabetes Follow-Up Study (ACCORD MIND). The ACCORD MIND was an ancillary study that aimed to evaluate whether the interventions studied in the Action to Control Cardiovascular Risk in Diabetes Study slowed the deterioration of cognitive function over 40 months of follow-up. The primary test of cognitive function was the Digit Symbol Substitution Test (measure of psychomotor speed and performance); other cognitive tests were the Rey Auditory Verbal Learning Test (verbal memory) and the modified Stroop test (executive function). Albuminuria was measured at baseline and three follow–up visits. Individuals with albumin to creatinine ratios (ACRs) ,30 mg/g on all visits were classified as no albuminuria (n¼1689), individuals with an ACR$30 mg/g on all three visits were classified as persistent albuminuria (n¼469), individuals without albuminuria at baseline but with an ACR.30 mg/g on one follow–up measurement were classified as progressors (n¼429), and individuals who had albuminuria at baseline but not at the follow-up visits were classified as remitters (n¼370). The mean eGFR in all of the groups was approximately 90 ml/min per 1.73 m2. After adjustment, both persistent albuminuria and progression were associated with a $5% decline in the Dantes Subject Standardized Test. None of the albuminuria groups were associated to a .5% decline in verbal memory or executive function. Palliative Care Individuals .65 years of age have accounted for the largest proportion of the incident ESRD population recently, and decisions regarding whether to start dialysis or continue therapy are being discussed with greater frequency. Having an understanding about the outcomes of older patients on dialysis with multiple comorbidities and the perceptions of individuals on dialysis are key for practitioners to help guide decision making. Tonge et al. (14) performed a systematic review of 26 studies involving 711 patients to identify common themes of attitudes toward dialysis therapy. The majority of patients studied were on hemodialysis (n¼544), and a small proportion of patients were treated with conservative management (n¼86). Common themes of pervasive suffering (loss of freedom and independence), personal vulnerability (imminence of death and medical abandonment), relational responsibility (burden to family), and negotiating existential tensions (preparing for death) were noted among patients. Patients were experiencing both physical and psychosocial stress, but because of concerns of upsetting their families or their physicians, they did not pursue palliative care. Caregivers often would like treatment to focus on relief of pain but were unsure how to go about discontinuation of dialysis support. This highlights that palliative care options need to be part of routine CKD management. Additional support for palliative care comes from data that show that older patients with CKD and other comorbidities do not have improvement in morbidity or mortality from dialysis compared with those treated conservatively. The review by Luckett et al. (15) raised the importance of advance care planning for older individuals on dialysis who may become unwell and unable to speak for themselves. Because cognitive decline is an issue among older patients on dialysis, the need for providers and family members to determine whether to continue dialysis treatments is becoming an increasing and regular issue. The review highlighted different interventions to achieve better advance care planning, including involvement of families in decision making, ensuring that the patient’s wishes will be carried out, education for the patient and family regarding conservative therapy, and separating decisions about RRT from other life–sustaining measures. One of the limitations to offering appropriate end of life care counseling is the lack of comfort among providers. Combs et al. (16) surveyed 104 of the nephrology fellowship programs in the United States in 2013 regarding the perceptions of end-of-life care. Compared with a similar survey of fellowship programs, there was an increase in the sense of importance of the ability to provide end-of-life care (95% in 2013 versus 54% in 2003). Fellows surveyed felt that training in this area was still lacking and that they were unprepared to provide end-of-life care counseling. References 1. Hiraki K, Yasuda T, Hotta C, Izawa KP, Morio Y, Watanabe S, Sakurada T, Shibagaki Y, Kimura K: Decreased physical function in pre-dialysis patients with chronic kidney disease. Clin Exp Nephrol 17: 225–231, 2013 PubMed 2. Liu CK, Lyass A, Massaro JM, D’Agostino RB Sr., Fox CS, Murabito JM: Chronic kidney disease defined by cystatin C predicts mobility disability and changes in gait speed: The Framingham Offspring Study. J Gerontol A Biol Sci Med Sci 69: 301–307, 2014 PubMed 3. Dalrymple LS, Katz R, Rifkin DE, Siscovick D, Newman AB, Fried LF, Sarnak MJ, Odden MC, Shlipak MG: Kidney function and prevalent and incident frailty. Clin J Am Soc Nephrol 8: 2091–2099, 2013 PubMed 4. Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, Scherr PA, Wallace RB: A short physical performance battery assessing lower extremity function: Association with selfreported disability and prediction of mortality and nursing home admission. J Gerontol 49: M85–M94, 1994 PubMed 356 5. Roshanravan B, Robinson-Cohen C, Patel KV, Ayers E, Littman AJ, de Boer IH, Ikizler TA, Himmelfarb J, Katzel LI, Kestenbaum B, Seliger S: Association between physical performance and all-cause mortality in CKD. J Am Soc Nephrol 24: 822–830, 2013 PubMed 6. Parker M, Baker PS, Allman RM: A life-space approach to functional assessment of mobility in the elderly. J Gerontol Soc Work 35: 35–55, 2002 7. Bowling CB, Muntner P, Sawyer P, Sanders PW, Kutner N, Kennedy R, Allman RM: Community mobility among older adults with reduced kidney function: A study of life-space. Am J Kidney Dis 63: 429–436, 2014 PubMed 8. Barzilay JI, Lovato JF, Murray AM, Williamson J, Ismail-Beigi F, Karl D, Papademetriou V, Launer LJ: Albuminuria and cognitive decline in people with diabetes and normal renal function. Clin J Am Soc Nephrol 8: 1907–1914, 2013 PubMed 9. Davey A, Elias MF, Robbins MA, Seliger SL, Dore GA: Decline in renal functioning is associated with longitudinal decline in global cognitive functioning, abstract reasoning and verbal memory. Nephrol Dial Transplant 28: 1810–1819, 2013 PubMed 10. Seidel UK, Gronewold J, Volsek M, Todica O, Kribben A, Bruck H, Hermann DM: The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease. Kidney Int 85: 693–702, 2014 PubMed 11. Yaffe K, Ackerson L, Hoang TD, Go AS, Maguire MG, Ying GS, Daniel E, Bazzano LA, Coleman M, Cohen DL, Kusek JW, Ojo A, Seliger S, Xie D, Grunwald JE; CRIC Study Investigators: Retinopathy Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 12. 13. 14. 15. 16. and cognitive impairment in adults with CKD. Am J Kidney Dis 61: 219–227, 2013 PubMed Yaffe K, Kurella-Tamura M, Ackerson L, Hoang TD, Anderson AH, Duckworth M, Go AS, Krousel-Wood M, Kusek JW, Lash JP, Ojo A, Robinson N, Sehgal AR, Sondheimer JH, Steigerwalt S, Townsend RR; CRIC Study Investigators: Higher levels of cystatin C are associated with worse cognitive function in older adults with chronic kidney disease: The chronic renal insufficiency cohort cognitive study. J Am Geriatr Soc 62: 1623–1629, 2014 PubMed Bugnicourt JM, Godefroy O, Chillon JM, Choukroun G, Massy ZA: Cognitive disorders and dementia in CKD: The neglected kidney-brain axis. J Am Soc Nephrol 24: 353–363, 2013 PubMed Tong A, Cheung KL, Nair SS, Kurella Tamura M, Craig JC, Winkelmayer WC: Thematic synthesis of qualitative studies on patient and caregiver perspectives on end-of-life care in CKD. Am J Kidney Dis 63: 913–927, 2014 PubMed Luckett T, Sellars M, Tieman J, Pollock CA, Silvester W, Butow PN, Detering KM, Brennan F, Clayton JM: Advance care planning for adults with CKD: A systematic integrative review. Am J Kidney Dis 63: 761– 770, 2014 PubMed Combs SA, Culp S, Matlock DD, Kutner JS, Holley JL, Moss AH: Update on end-of-life care training during nephrology fellowship: A cross-sectional national survey of fellows. Am J Kidney Dis 65: 233– 239, 2015 PubMed Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Chronic Kidney Disease and Progression Claiming Credits and Evaluation Process Accreditation Statement The American Society of Nephrology (ASN) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA Credit Designation Statement The ASN designates this enduring material for a maximum of 8.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Original Release Date: October 2015 CME Credit Termination Date: September 30, 2017 Examination Available Online: On or before Thursday, October 15, 2015 Estimated Time for Completion: 8 hours Answers with Explanations Provided with a passing score after the first and/or after the second attempt October 2017: posted on the ASN website when the issue is archived. • • Method of Participation Read the syllabus that is supplemented by original articles in the reference lists. Complete the online self-assessment examination. Each participant is allowed two attempts to pass the examination (.75% correct) for CME credit. Upon completion, review your score and incorrect answers and print your certificate. Answers and explanations are provided with a passing score or after the second attempt. • • • • • Activity Evaluation and CME Credit Instructions Go to www.asn-online.org/cme, and enter your ASN login on the right. Click the ASN CME Center. Locate the activity name and click the corresponding ENTER ACTIVITY button. Read all front matter information. On the left-hand side, click and complete the Demographics & General Evaluations. Complete and pass the examination for CME credit. Upon completion, click Claim Your Credits, check the Attestation Statement box, and enter the number of CME credits commensurate with the extent of your participation in the activity. If you need a certificate, Print Your Certificate on the left. • • • • • • • • For your complete ASN transcript, click the ASN CME Center banner, and click View/Print Transcript on the left. Instructions to obtain American Board of Internal Medicine (ABIM) Maintenance of Certification (MOC) Points Each issue of NephSAP provides 10 MOC points. Respondents must meet the following criteria: Be certified by ABIM in internal medicine and/or nephrology and enrolled in the ABIM–MOC program Enroll for MOC via the ABIM website (www.abim.org). Enter your (ABIM) Candidate Number and Date of Birth prior to completing the examination. Take the self-assessment examination within the timeframe specified in this issue of NephSAP. Below your score select “Click here to post to ABIM.” • • • • • MOC points will be applied to only those ABIM candidates who have enrolled in the MOC program. It is your responsibility to complete the ABIM MOC enrollment process. 358 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 NephSAP, Volume 14, Number 4, October 2015—Chronic Kidney Disease and Progression 3. You are seeing a 65-year-old woman in follow-up for advanced kidney disease. Her disease has progressed slowly. Her weight has been stable, and her appetite is preserved. Medications are lisinopril, amlodipine, furosemide, metoprolol, calcitriol, darbepoetin, and atorvastatin. Her BP is 139/85 mmHg, and her pulse is 65 per minute. She has no edema. Laboratory studies show sodium 139 mEq/L, potassium 4.2 mEq/L, total CO2 23 mmol/L, BUN 65 mg/dl, SCr 4.5 mg/dl (eGFR 10 ml/min per 1.73 m2), calcium 9.5 mg/dl, phosphorus 4.5 mg/dl, parathyroid hormone (PTH) 115 pg/ml (normal 10–65 pg/ml) unchanged from 3 months ago, and Hb 10.0 g/dl. Which ONE of the following is the MOST appropriate management? A. Discontinue lisinopril B. Increase darbepoetin C. Increase calcitriol D. No change in management 1. A 51-year-old woman with stage 4 CKD secondary to polycystic kidney disease is evaluated during a routine clinic visit. She has hypertension that is controlled on lisinopril and amlodipine. She does not smoke. The physical examination is notable for a body mass index (BMI) of 32 kg/m2, a BP of 132/70 mmHg, and enlarged kidneys. The remainder of the examination is normal. Laboratory studies show normal serum electrolytes, eGFR 29 ml/min per 1.73 m2, hemoglobin (Hb) 12 g/dl, total cholesterol 186 mg/dl, HDL-cholesterol 35 mg/dl, LDL-cholesterol 95 mg/dl, and triglycerides 300 mg/dl. Which ONE of the following is the MOST appropriate management? A. Start fenofibrate B. Start pravastatin C. No change in management D. You should use a risk calculator to determine whether she should receive pharmacologic treatment for her lipid values 4. You are asked to evaluate a 65-year-old man with diabetes mellitus in consultation for management of CKD. His medications are losartan 100 mg daily, lisinopril 20 mg daily, sodium bicarbonate 650 mg two times per day, and furosemide 40 mg daily. His BP is 145/80 mmHg. He has trace edema. Laboratory studies show potassium 4.9 mEq/L, total CO2 23 mmol/L, and SCr 2.5 mg/dl. Continuation of the current medication regimen places him at increased risk for which ONE of the following complications? A. Congestive heart failure B. Mortality C. AKI D. ESRD 2. A 65-year-old man with type 2 diabetes mellitus and stage 3b CKD is evaluated in follow-up. His medications include losartan 100 mg daily, furosemide 20 mg daily, simvastatin 20 mg daily, metoprolol succinate 50 mg daily, amlodipine 5 mg daily, and aspirin 81 mg daily. His BP is 129/79 mmHg. The remainder of the examination is normal. Laboratory studies show sodium 138 mEq/L, potassium 4.9 mEq/L, total CO2 22 mmol/L, BUN 40 mg/dl, serum creatinine (SCr) 1.9 mg/dl (eGFR 42 ml/min per 1.73 m2), LDL-cholesterol 105 mg/dl, and HDL-cholesterol 35 mg/dl. The urine albumin-to-creatinine ratio (UACR) is 800 mg/g. Which ONE of the following is the MOST appropriate management to delay progression of CKD? A. Add lisinopril B. Double the losartan dose C. Add ezetimibe D. Double the furosemide dose E. No change in management 5. A 45-year-old man with stage 4 CKD secondary to IgA nephropathy is evaluated during a routine clinic visit. He smokes one pack of cigarettes daily. He has hypertension but does not have diabetes. There is no family history of kidney disease or heart disease. His medications include valsartan, fish oil, amlodipine, and furosemide. The physical examination is notable for a BP of 140/70 mmHg. The 359 360 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 remainder of the examination is normal. Laboratory studies show eGFR 29 ml/min per 1.73 m2, HDLcholesterol 35 mg/dl, LDL-cholesterol 125 mg/dl, and triglycerides 300 mg/dl. According to the most recent Kidney Disease Improving Global Outcomes lipid guidelines (November of 2013), which ONE of the following is the recommended treatment strategy? A. He should start a fibrate B. He should start a statin C. He should start a bile acid sequestrant D. You should use a risk calculator to determine whether he should be treated 6. Which ONE of the following regarding blockade of the renin-angiotensin-aldosterone system is correct? A. Combination angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blocker therapy reduces proteinuria more than the addition of spironolactone to an ACEI B. Combination of spironolactone and lisinopril has a lower risk of hyperkalemia than losartan and lisinopril C. Because combination ACEI and angiotensin receptor blocker therapy decreases proteinuria, it will decrease progression of kidney disease (doubling SCr, ESRD, or death) D. Combination therapy is associated with an increased risk of mortality in heart failure E. A high normal serum potassium level (4.5–4.9 mEq/L) is a risk factor for hyperkalemia on renin-angiotensin blockade 7. You are seeing a 75-year-old man with type 2 diabetes and hypertension. His current medications include metformin and glyburide. His wife reports that he recently had an episode of severe hypoglycemia requiring the intervention of emergency services. His BP is 140/70 mmHg. The physical examination is otherwise normal. His SCr is 0.8 mg/dl (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] eGFR¼87 ml/min per 1.73 m2). The UACR is 200 mg/g. The HbA1c is 7.2%. Which ONE of the following places him at increased risk for serious hypoglycemia? A. His age B. His clearance of glyburide C. His level of albuminuria D. His use of metformin 8. A 17-year-old young man with CKD caused by FSGS is evaluated in follow-up. His current medications include lisinopril (40 mg daily), bumetanide (1 mg two times per day), clonidine (0.1 mg three times per day), iron sulfate (325 mg two times per day), sodium bicarbonate (650 mg three times per day), and tacrolimus (2 mg two times per day). He reports difficulty taking all of his medications, and he misses doses on a regular basis. Which ONE of the following would be the MOST effective intervention to improve medication adherence for this young man? A. Change three times per day–dosed medications to two times per day B. Decrease the number of classes of medications taken per day C. Discontinue iron sulfate D. Provision of an educational intervention 9. A 65-year-old woman with type 2 diabetes mellitus is evaluated for ongoing follow-up of advanced CKD. She has recently moved to the area to be near her daughter and grandchildren. She has coronary artery disease, hypertension, and atrial fibrillation. She does not have symptoms of uremia and remains active. Her medications are losartan 100 mg daily, diltiazem (extended release formulation) 120 mg daily, atorvastatin 20 mg daily, warfarin 4 mg daily, bumetanide 1 mg two times per day, glipizide 5 mg two times per day, and sitagliptin 50 mg one time per day. Her BP is 130/70 mmHg, and her pulse is irregularly irregular, with an average rate of 85 per minute. There is trace lower extremity edema. Laboratory studies show sodium 139 mEq/L, potassium 4.2 mEq/L, chloride 102 mEq/L, total CO2 23 mmol/L, BUN 60 mg/dl, SCr 5.0 mg/dl (Modification of Diet in Renal Disease eGFR 9 ml/min per 1.73 m2), international normalized ratio of 2.0, and HbA1c of 7.2%. The UACR is 350 mg/g. Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Which ONE of the following is the MOST appropriate treatment intervention for this patient? A. Change glipizide to glyburide B. Decrease the dose of sitagliptin C. Change warfarin to aspirin D. Discontinue the losartan 10. A 55-year-old woman with stage 3b CKD caused by autosomal dominant polycystic kidney disease is hospitalized for evaluation of right–sided chest pain and shortness of breath. On physical examination, she is in mild distress from the chest discomfort. Her respirations are nonlabored with a rate of 16 per minute. The oxygen saturation on ambient air is 96%. The BP is 140/80 mmHg, and the pulse is 106 per minute. The chest examination shows tenderness on palpation of the right anterior chest wall. The lung fields show faint end–expiratory wheezes bilaterally. There is no leg edema or calf tenderness. Her eGFR is stable at 29 ml/min per 1.73 m2. An arterial blood gas on ambient air shows pH 7.44, PaCO2 of 38 mmHg, and PaO2 of 88 mmHg. The D-dimer level is 0.7 mg/ml (reference range ,0.5 mg/ml). A chest radiograph is normal. The Wells score for pulmonary embolism (PE) is 1, consistent with a low probability for PE. Which ONE of the following regarding the interpretation of this woman’s D-dimer level is correct? A. The D-dimer level is diagnostic of a thrombus (deep venous thrombosis or pulmonary embolus) B. The elevated D-dimer level is atypical of patients with CKD C. The specificity of D-dimer is lower in CKD D. The positive predictive value of this woman’s D-dimer level is equivalent to that of persons with a normal GFR 11. A 60-year-old man with stage 3b CKD secondary to membranous glomerulopathy is hospitalized for evaluation of atypical chest pain. He noted onset of intermittent sharp left–sided chest pain that was not consistently associated with exertion on the day of admission. On physical examination, he is in mild respiratory distress, with a respiratory rate of 18 per minute. The BP is 150/84 mmHg, and the pulse is regular, with a rate of 84 per minute. 361 The jugular venous pressure is 10 cm H2O. The lungs show basilar crackles. There is 21 leg edema. His eGFR is 35 ml/min per 1.73 m2. The highly sensitive serum troponin T level on admission is 0.06 mg/L (reference value #0.014 mg/L), and a follow-up level the following morning is unchanged. The electrocardiogram shows a right bundle branch block and no ST-T wave changes, and it is unchanged from his electrocardiogram performed 7 months ago. Which ONE of the following is correct regarding the significance of the elevated serum troponin T levels in this patient? A. The increased highly sensitive serum troponin T level on admission is highly specific for acute myocardial infarction (MI) B. The lack of a dynamic change in the serum troponin level excludes acute MI C. The increased levels are most strongly associated with left ventricular hypertrophy on echocardiography D. The increased levels are not of clinical significance at his level of GFR 12. A 65-year-old man with stage 3 CKD is admitted for management of acute coronary syndrome. After a rapid prehydration protocol to decrease the risk of contrast nephropathy, he undergoes coronary angiography. This reveals a 90% stenosis in the left circumflex artery. Which ONE of the following interventions has the greatest likelihood of decreasing the need for repeat coronary interventions at 1 year? A. Coronary angioplasty with placement of a bare metal stent B. Coronary angioplasty with placement of a drug-eluting stent C. Coronary angioplasty without placement of a stent D. Coronary angioplasty without a stent plus clopidogrel 13. A 70-year-old woman with stage 5 CKD is diagnosed with new–onset atrial fibrillation. She is preparing for but has not yet started dialysis. She has hypertension and type 2 diabetes mellitus. Her CHA2DS2-VASC score is 4. Her eGFR is 14 ml/min per 1.73 m2. Her heart rate is controlled with diltiazem. 362 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 Which ONE of the following is the MOST appropriate treatment? A. Aspirin 325 mg daily B. Warfarin to a target international normalized ratio of 2–3 C. Rivaroxaban 20 mg daily D. Clopidogrel 75 mg daily E. No additional medication 14. A 70-year-old woman with CKD secondary to diabetes mellitus is evaluated in follow-up. She has a history of coronary artery disease and hypertension. She is concerned because her laboratory reports show that her HbA1c is above the reference range. Her current medications for diabetes include linagliptin (5 mg daily) and insulin glargine (25 units at bedtime). Laboratory values show an SCr of 1.6 (eGFR 37 ml/min per 1.73 m2), a UACR of 100 mg/g, and a HbA1c of 7.2%. Which ONE of the following is the MOST appropriate management? A. Add glipizide B. Increase insulin glargine to 30 units daily C. Add insulin aspartate before meals D. Increase linagliptin to 10 mg daily E. Make no changes to the current regimen 15. A 67-year-old man has an eGFR of 25 ml/min per 1.73 m2 and a BMI of 32 kg/m2. He has hypertension and type 2 diabetes mellitus. His BP is 130/80 mmHg on losartan 100 mg daily, furosemide 40 mg daily, and metoprolol succinate 100 mg daily. The UACR is 400 mg/g. He has been advised to lose weight in preparation for transplantation. He asks about the effect of obesity on CKD progression. Which ONE of the following statements is MOST accurate regarding CKD progression and obesity in this patient? A. Lowering the BMI to 20–25 kg/m2 would decrease his CKD progression B. This patient’s BMI is not associated with faster progression to dialysis compared with other BMI categories C. The patient’s BMI is associated with the highest rate of CKD progression D. The patient should undergo bariatric surgery to decrease CKD progression 16. A 55-year-old woman with diabetes mellitus is referred for evaluation of CKD. Her eGFR has ranged from 48 to 53 ml/min per 1.73 m2, and the UACR has been persistently elevated in the 40 to 80 mg/g range over a period of 6 months. The LDL-cholesterol is 136 mg/dl. Therapy with losartan was initiated 6 months ago, and subsequent home BP monitoring shows average BPs of approximately 132/78 mmHg. On physical examination, her BP is 138/80 mmHg. The remainder of the examination is normal. According to the American College of Physicians guidelines for CKD screening and management, which ONE of the following is the MOST appropriate management? A. Serial measurements of UACR B. Initiate statin therapy C. Add a thiazide diuretic D. Begin a low-protein diet E. No change in management 17. Which ONE of the following is correct regarding the effect of dietary sodium restriction and CKD progression on the basis of recent prospective trials and studies? A. It slowed CKD progression B. It hastened CKD progression C. It increased serum renin and aldosterone levels D. It had no effect on BP 18. A 64-year-old woman with stage 4 CKD is evaluated in follow-up. Medications are low-dose aspirin, pravastatin, metoprolol, and bumetanide. Her eGFR is 29 ml/min per 1.73 m2, and it decreased from 32 ml/min per 1.73 m2 last year. Her physical examination shows a BP of 138/88 mmHg. She has no edema. Other laboratory studies show serum potassium of 4.4 mEq/L, total CO2 of 18 mmol/L, and a normal anion gap. She has not tolerated sodium bicarbonate or sodium citrate because of gastrointestinal side effects. Which ONE of the following is the MOST likely to correct this patient’s metabolic acidosis? A. An endothelin antagonist B. A diet enriched in fruits and vegetables C. Lisinopril D. Spironolactone 19. A 47-year-old African-American man with stage 4 CKD caused by diabetic kidney disease is evaluated in follow-up. He has a family history Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 of diabetes, hypertension, and CKD. The BP is 134/82 mmHg, and there is no edema. Laboratory tests reveal an eGFR of 17 ml/min per 1.73 m2, and it decreased from 21 ml/min per 1.73 m2 last year. He recently read a report about APOL1 and the risk of CKD on the internet and asks for more information about the effect of the risk allele on CKD progression. Which ONE of the following would you tell him regarding APOL1 risk status and CKD? A. APOL1 risk status does not affect the risk of CKD progression in patients with diabetes B. APOL1 high–risk compared with low–risk status is associated with a 4-fold increase in the composite risk of ESRD plus doubling of SCr C. The majority of individuals with two APOL1 risk alleles will develop CKD D. Individuals with two APOL1 risk alleles are at risk for developing CKD 20. A 48-year-old man with type 2 diabetes mellitus and stage 3a CKD is evaluated for intermittent right upper quadrant abdominal pain. An abdominal ultrasound shows fatty infiltration of the liver and a single stage I Bosniak right–sided kidney cyst. He does not smoke and has never consumed excess alcohol. On physical examination, the BP is 130/78 mmHg, and there is no edema. The BMI is 26.9 kg/m2. He has a waist-to-hip ratio of 0.8. Which ONE of the following findings in this patient has been shown to be associated with an increased incidence of CKD? A. His waist-to-hip ratio B. Nonalcoholic fatty liver disease C. His BMI D. The renal cyst 21. A 22-year-old man is evaluated in the emergency department for a several week history of progressive fatigue. He had recently moved from Costa Rica, where he was an agricultural worker in a sugar cane field, frequently working in a hot and humid environment. He does not take prescribed or over the counter medications and has not used illicit drugs. There is no family history of kidney disease. His BP is 145/78 mmHg, and his pulse is 76 per minute. The remainder of the 363 examination is normal. His laboratory studies show an SCr of 1.8 mg/dl. The urine protein-tocreatinine ratio is 500 mg/g. Which ONE of the following would you MOST likely expect to find in this patient? A. Hypokalemia B. Hypertriglyceridemia C. Hypouricemia D. Hematuria 22. You are asked to participate in a focus group to develop a clinical trial that studies the efficacy of screening for CKD. Information is given to you about current United States position statements as well as worldwide screening and intervention programs. Which ONE of the following statements is correct regarding CKD epidemiology and CKD screening/intervention programs? A. Death attributed to CKD worldwide has remained relatively constant for the past 2 decades B. Diabetes is no longer the leading cause of ESRD worldwide C. Implementation of a CKD screening and intervention program in England has been associated with an increase in planned initiation of dialysis D. It is projected that ESRD incidence in developing countries will decrease relative to developed countries 23. A 56-year-old man has type 2 diabetes, stage 3b CKD, hypertension, and hyperlipidemia. His medications are valsartan, chlorthalidone, metformin, atorvastatin, and low-dose aspirin. He has claudication and was recently prescribed pentoxifylline by his primary care provider, because cilostazol caused diarrhea. His BP is 130/76 mmHg, and he has no edema. His eGFR is 39 ml/min per 1.73 m2 compared with an eGFR of 43 ml/min per 1.73 m2 3 years ago. The UACR is 280 mg/g. Other laboratory studies are HbA1c 7%, uric acid 7.4 mg/dl, calcium 9.5 mg/dl, phosphorous 4.5 mg/dl, intact PTH 50 pg/ml, total cholesterol 190 mg/dl, and LDL-cholesterol 90 mg/dl. Which ONE of the following is the MOST appropriate management? A. Discontinue metformin and start sitagliptin B. Discontinue pentoxifylline 364 Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 C. Discontinue atorvastatin D. Start paricalcitol E. No change in management 24. A 57-year-old man with type 2 diabetes mellitus is referred for evaluation and management of stage 4 CKD. He has hypertension and hyperlipidemia. He is on glipizide 2.5 mg daily, furosemide 40 mg daily, linagliptin, enalapril, amlodipine, metoprolol tartrate, and atorvastatin. He does not have chest pain, shortness of breath, or joint pain. On physical examination, the BP is 138/78 mmHg, and the pulse is 62 per minute. The jugular venous pressure is 10 cm, and there is 11 leg edema. Laboratory studies show an eGFR of 19 ml/min per 1.73 m2, which is decreased from 24 ml/min per 1.73 m2 last year. The potassium is 5.6 mEq/L, the total CO2 is 24 mEq/L, the uric acid is 7 mg/dl, the Hb is 10.6 g/dl, the HbA1c is 7%, and the UACR is 220 mg/g. Which ONE of the following is the MOST appropriate management? A. Discontinue enalapril B. Increase the dose of glipizide C. Increase the dose of furosemide D. Start sodium bicarbonate 25. A 53-year-old man is seen for ongoing management of hypertension. His BP is 144/88 mmHg. The BMI is 24 kg/m2. The remainder of the physical examination is normal. The eGFR by the CKD-EPI creatinine equation is 59 ml/min per 1.73 m2. His UACR is 56 mg/g. Which ONE of the following statements is MOST accurate regarding risk prediction by various eGFR estimating methods for this patient? A. Cystatin C–based eGFR reclassification to a category with lower eGFR is associated with an increased risk of death B. Cystatin C–based eGFR reclassification to a category with lower eGFR improves risk prediction for ESRD but not mortality C. Associations of albuminuria .30 mg/g and hypertension with lower measured GFR are best approximated by CKD-EPI cystatin C–based but not creatinine–based eGFR estimations D. Measured GFR is accurately predicted by the CKD-EPI creatinine equation 26. A 51-year-old man returns for follow-up after an initial evaluation of stage 3 CKD one year ago. His initial evaluation was significant for the presence of moderate hypertensive retinopathy and left ventricular hypertrophy. Three months ago, he suffered an MI and underwent percutaneous coronary intervention requiring the placement of two drug–eluting stents. His eGFR decreased from 42 to 38 ml/min per 1.73 m2 after the procedure. On physical examination, the BP is 150/50 mmHg. Cardiac auscultation reveals an S4 gallop. Funduscopic examination shows unchanged moderate hypertensive retinopathy with cotton wool spots and hard exudates bilaterally. The remainder of the examination is normal. Which ONE of the following clinical findings in this patient has been found to be MOST strongly associated with risk for progression to ESRD? A. Hypertensive retinopathy B. Recent MI C. Increased pulse pressure D. Left ventricular hypertrophy 27. Which ONE of the following is correct about CKD progression in African Americans? A. Higher 24-hour ambulatory systolic BP levels are not associated with increased risk of progression B. CKD progresses more rapidly but is not associated with a higher level of mortality compared with white individuals C. The presence of two APOL1 alleles has a greater role in the progression of diabetic compared with nondiabetic CKD D. The degree of albuminuria has little effect on the risk of CKD progression 28. Which ONE of the following outcomes has been shown in recent trials of individuals treated in CKD clinics that use physician extenders? A. A decreased rate in the decline of GFR B. No difference in the use of erythropoiesisstimulating agents C. No difference in the use of phosphate binders D. A decreased rate of initiation of dialysis Nephrology Self-Assessment Program - Vol 14, No 4, October 2015 29. Which ONE of the following is the MOST likely reason that older adults with stage 5 CKD are often not provided or offered conservative management? A. Lack of provider comfort or training in discussing end-of-life options B. Providers’ unwillingness to have discussions regarding end-of-life care C. Improved outcomes for older individuals on dialysis D. Frequent use of limited trials of dialysis 30. A clinic associated with a local hospital laboratory is about to incorporate a new electronic medical record with automatic eGFR reporting. A recent quality improvement project showed that an excessive number of patients were not 365 meeting targets for Hb and intact PTH. Stakeholders expect automatic eGFR reporting to improve the number of patients in the target range for these laboratory parameters. You are asked to provide an opinion of the effects of automatic eGFR reporting as an initial intervention. Which ONE of the following is an expected outcome from implementation of automated eGFR reporting? A. No effect on the decision to initiate dialysis B. Increased recognition and documentation of CKD C. Increased number of patients with Hb and intact PTH levels in the target range D. An improvement in the timely placement of dialysis access

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