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Chronic Kidney Disease, Dialysis, and Transplantation Chronic Kidney Disease, Dialysis, and Transplantation Companion to Brenner & Rector’s The Kidney Third Edition Jonathan Himmelfarb, MD Professor of Medicine Joseph W. Eschbach Endowed Chair for Kidney Research Director, Kidney Research Institute Department of Medicine, Division of Nephrology University of Washington Seattle, WA Mohamed H. Sayegh, MD, FAHA, FASN, ASCI, AAP Raja N. Khuri Dean, Faculty of Medicine, American University of Beirut Director, Schuster Family Transplantation Research Center Brigham Women’s Hospital & Children’s Hospital, Boston Visiting Professor of Medicine and Pediatrics, Harvard Medical School Boston, MA 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 Chronic Kidney Disease, Dialysis, and Transplantation ISBN: 978-1-4377-0987-2 Third Edition Copyright # 2010 by Saunders, an imprint of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they sh; ould be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Previous editions copyrighted 2005, 2000. Library of Congress Cataloging-in-Publication Data Chronic kidney disease, dialysis, and transplantation : companion to Brenner & Rector’s the kidney / [edited by] Jonathan Himmelfarb, Mohamed H. Sayegh. – 3rd ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4377-0987-2 1. Hemodialysis. 2. Kidneys–Transplantation. I. Himmelfarb, Jonathan. II. Sayegh, Mohamed H. III. Brenner & Rector’s the kidney. [DNLM: 1. Renal Dialysis. 2. Kidney Failure, Chronic–complications. 3. Kidney Failure, Chronic–therapy. 4. Kidney Transplantation. WJ 378 C55675 2011] RC901.7.H45D5226 2011 616.6’1–dc22 2009050616 Acquisitions Editor: Kate Dimock Developmental Editor: Taylor Ball Publishing Services Manager: Hemamalini Rajendrababu Project Manager: Nayagi Athmanathan Design Direction: Steven Stave Illustrations Manager: Lesley Frazier Marketing Manager: Abigail Swartz Printed in United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1 To my wonderful wife, Deborah, and children, Sarah, Rachel, and Joshua, for their love, support, and guidance. —JH To my precious daughter, Layal, and my amazing son, Malek. —MHS PREFACE Chronic Kidney Disease, Dialysis in Transplantation is a companion to Brenner and Rector’s The Kidney. This 3rd edition is designed to provide a comprehensive and systematic review of the latest available information concerning patho-biology, clinical consequences and therapeutics over a wide spectrum of clinically important kidney diseases. The pace of acquisition of new knowledge in kidney disease is fast and furious, and our goal is to bring a thoughtful, well organized exposition of this burgeoning knowledge base to the readers. To accomplish this we are pleased to have been able to assemble a leading panel of expert contributors who have been challenged to summarize state of the art knowledge in each chapter of the book. Compared to previous editions, the number of chapters in each section has been expanded and every chapter in this edition has been thoroughly revised and updated. New chapters have been created to cover topics of emerging importance such as chronic kidney disease in the elderly, pharmacoepidemiology in kidney disease, utilization and outcomes of peritoneal dialysis, and biomarkers in acute kidney injury. It is our hope that the reader of these and other chapters will become acquainted with the latest thinking in some of the most important topics in kidney disease. Thus the book is designed to be both a reference source and a practical guide to the clinical management of most major kidney diseases. The text should prove useful and valuable to clinicians, educators and investigators alike. We wish to thank Barry M. Brenner for his confidence in allowing us to edit this companion volume to the comprehensive accounting of kidney disease found in Brenner and Rector’s The Kidney. We also wish to acknowledge the logistical and practical support we received from Ms. Adrianne Brigido and Taylor Ball, who played major roles in the preparation of this new edition for publication. We would particularly like to thank the section editors (Ann O’Hare, Katherine Tuttle, John Stivelman, Rajnish Mehrotra, John Vella, Anil Chandraker, and Sushrut Waikar) for their tremendous contribution in the editing of each chapter, and for working in close conjunction with the chapter authors. Their intellectual rigor and enthusiasm have dramatically influenced the content of this book. We also wish to thank each author for taking considerable time and effort to ensure that each chapter provides state of the art information. We hope that readers achieve the same level of acquisition of new knowledge and enjoyment as we have attained by editing this book. SECTION EDITORS Anil Chandraker, MD, FRCP Assistant Professor of Medicine, Harvard Medical School; Medical Director of Kidney Transplantation, Renal Division, Brigham and Women’s Hospital, Brigham and Women’s Hospital, Boston, MA Section V: Transplantation Rajnish Mehrotra, MD, FACP, FASN Associate Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles; Director, Peritoneal Dialysis Program, Harbor-UCLA Medical Center, Torrance, CA Section IV: Peritoneal Dialysis Ann M. O’Hare, MA, MD Associate Professor, Division of Nephrology, Department of Medicine, University of Washington; Staff Physician, VA Puget Sound Healthcare System, Seattle, WA Section I: Chronic Kidney Disease John C. Stivelman, MD Chief Medical Officer, Northwest Kidney Centers, Professor of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, WA Section III: Hemodialysis Katherine R. Tuttle, MD, FASN, FACP Medical and Scientific Director, Providence Medical Research, Center Sacred Heart Medical Center, Spokane, WA; Clinical Professor of Medicine, Division of Nephrology, University of Washington School of Medicine, Spokane and Seattle, WA Section II: Complications and Management of Chronic Kidney Disease John P. Vella, MD, FRCP, FACP, FASN Associate Professor, Department of Medicine, Tufts University School of Medicine; Director of Transplantation, Department of Medicine/Nephrology/Transplant, Maine Medical Center, Portland, ME Section V: Transplantation Sushrut S. Waikar, MD, MPH Assistant Professor of Medicine, Harvard Medical School; Associate Physician, Renal Division, Brigham and Women’s Hospital, Boston, MA Section VI: Acute Kidney Injury LIST OF CONTRIBUTORS Matthew K. Abramowitz, MD, MS Assistant Professor of Medicine and Epidemiology & Population Health, Department of Medicine, Epidemiology & Population Health, Albert Einstein College of Medicine; Attending Physician, Department of Medicine, Montefiore Medical Center, Bronx, NY The Pathophysiology of Uremia Stuart Abramson, MD, MPH Clinical Assistant Professor, Tufts University School of Medicine, Boston, MA; Medical Director, Center for Dialysis & Hemotherapeutics, Department of Medicine, Division of Nephrology, Maine Medical Center, Portland, ME Extracorporeal Treatment of Poisonings M. Javeed Ansari, MD Assistant Professor of Medicine, Medicine, Division of Nephrology, Comprehensive Transplant Center, Northwestern University, Feinberg School of Medicine, Chicago, IL Novel Diagnostics in Transplantation Matthew J. Arduino, MS, Dr PH Research Microbiologist, Acting Chief Clinical and Environmental Microbiology Branch, Div Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, GA Hemodialysis-associated Infections Monica C. Beaulieu, MD, FRCPC, MHA Clinical Assistant Professor, Department of Nephrology and Internal Medicine, University of British Columbia, Vancouver, BC, Canada The Role of the Chronic Kidney Disease Clinic Jeffrey S. Berns, MD Professor of Medicine and Pediatrics, Department of Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, PA Anemia in Chronic Kidney Disease Peter G. Blake, MB, FRCPC, FRCPI Professor of Medicine, University of Western Ontario, Chair of Nephrology, London Health Sciences Center, London, Ontario, Canada Peritoneal Dialysis Prescription and Adequacy Joseph V. Bonventre, MD, PhD Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA Acute Kidney Injury: Biomarkers from Bench to Bedside Steven M. Brunelli, MD, MSCE Assistant Professor, Harvard Medical School; Renal Division, Brigham and Women’s Hospital, Boston, MA Anemia in Chronic Kidney Disease George L. Bakris, MD Professor Medicine, Director, Hypertensive Diseases Unit, Department of Medicine, University of Chicago, Pritzker School of Medicine, Chicago, IL Hypertensive Kidney Disease Marilia Cascalho, MD, PhD Professor of Surgery and Professor of Microbiology and Immunology, Transplantation Biology; Associate Professor of Surgery and Associate Professor of Microbiology & Immunology, Transplantation Biology, University of Michigan, Ann Arbor, MI Emerging Strategies in Kidney Transplantation Rasheed Abiodun Balogun, MD Associate Professor of Medicine, Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA Pharmacological Interventions in Acute Kidney Injury Vimal Chadha, MD Assistant Professor of Pediatrics, Chair, Section of Nephrology, Virginia Commonwealth University Medical Center, Richmond, VA The Pediatric Patient with Chronic Kidney Disease Joanne M. Bargman, MD, FRCPC Professor of Medicine, Faculty of Medicine, University of Toronto; Staff Nephrologist, Department of Medicine, University Health Network, Toronto, Ontario, Canada Non-infectious Complications of Peritoneal Dialysis Glenn M. Chertow, MD, MPH Professor of Nephrology, Stanford School of Medicine, Stanford, CA Dialytic Management for Acute Renal Failure xii List of Contributors Alfred K. Cheung, MD Professor of Medicine, Department of Medicine, University of Utah; Staff Physician, Department of Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, UT Hemodialysis Adequacy Yi-Wen Chiu, MD Assistant Professor, Department of Renal Care; Attending Physician, Department of Nephrology, Kaohsiung Medical University, Kaohsiung, Taiwan The Utilization and Outcome of Peritoneal Dialysis Szeto Cheuk Chun, MD, FRCP Professor, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China Peritoneal Dialysis-related Infections Josef Coresh, MD, MHS, PhD Professor, Department of Epidemiology, Biostatistics and Medicine, Johns Hopkins University; Faculty, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD Chronic Kidney Disease: Definition, Epidemiology, Cost and Outcomes Daniel Cukor, PhD Assistant Professor of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY Depression and Neurocognitive Function in Chronic Kidney Disease Bruce F. Culleton, MD, FRCPC Adjunct Associate Professor, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; Senior Medical Director, Renal Division, Baxter Healthcare Corporation, McGaw Park, IL Hemodialysis Adequacy Bryan M. Curtis, MD, FRCPC Memorial University of Newfoundland, St. John’s, NL, Canada The Role of the Chronic Kidney Disease Clinic Gabriel Danovitch, MD Professor of Medicine, Department of Medicine, Division of Nephrology, David Geffen School of Medicine at UCLA; Ronald Reagan Medical Center at UCLA, Kidney and Pancreas Transplant Program, Los Angeles, CA Diagnosis and Therapy of Graft Dysfunction Simon J. Davies, MD Professor of Nephrology and Dialysis Medicine, Institute of Science and Technology in Medicine, Keele University; Consultant Nephrologist, Department of Nephrology, University Hospital of North Staffordshire, Stoke-on-Trent, UK Peritoneal Dialysis Solutions Ian H. de Boer, MD, MS Assistant Professor of Medicine, Division of Nephrology, University of Washington, Seattle, WA Vitamin D Deficiency Laura M. Dember, MD Associate Professor of Medicine, Boston University School of Medicine, Boston, MA Vascular Access Thomas A. Depner, MD Professor of Medicine, Division of Nephrology, Department of Medicine, University of California, Davis, Sacramento, CA Principles Of Hemodialysis Bradley S. Dixon, MD Associate Professor, Department of Internal Medicine, University of Iowa; Staff Physician, Internal Medicine, University of Iowa Hospitals and Clinics; Staff Physician, Department of Medicine, Veterans Affairs Medical Center, Iowa City, IA Vascular Access Martin S. Favero, PhD Director of Scientific Affairs, Advanced Sterilization Products, Irvine, CA Hemodialysis-associated Infections John S. Gill, MD, FRCPC, MS Associate Professor of Medicine and Transplant Fellowship Director, Division of Nephrology, Department of Medicine; Associate Professor of Medicine and Transplant Nephrologist, Division of Nephrology, Department of Medicine, St. Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada Chronic Kidney Disease and the Kidney Transplant Recipient Mónica Grafals, MD Medical Director Pancreas Transplant, Lahey Clinic Medical Center Assistant Professor, Tufts University Noninfectious Complications in Transplantation After Kidney Simin Goral, MD Associate Professor of Medicine, Department of Medicine: Renal, Electrolyte, and Hypertension Division, University of Pennsylvania, Philadelphia, PA Current and Emerging Maintenance Immunosuppressive Therapy Ziv Harel, MD, FRCPC Department of Medicine, Division of Nephrology, University of Toronto; University Health Network, Toronto, Ontario, Canada Non-infectious Complications of Peritoneal Dialysis List of Contributors William E. Harmon, MD Harvard Medical School, Children’s Hospital Boston, Division of Nephrology, Boston, MA Pediatric Renal Transplantation Olof Heimbürger, MD, PhD Associate Professor, Division of Renal Medicine, Department of Clinical Science, Intervention and Technology, Karolinska Institutet; Senior Consultant, Department of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden Peritoneal Physiology J. Harold Helderman, MD Professor of Medicine, Microbiology & Immunology, Department of Internal Medicine; Medical Director Vanderbilt Transplant Center; Chief, Renal Transplant Medicine, Vanderbilt University School of Medicine, Nashville, TN Current and Emerging Maintenance Immunosuppressive Therapy Thomas H. Hostetter, MD Professor, Department of Medicine; Director, Division of Nephrology, Albert Einstein College of Medicine; Director, Division of Nephrology, Montefiore Medical Center, Bronx, NY The Pathophysiology of Uremia Cindy Huang, MD, PhD Instructor, Department of Medicine, Tufts University School of Medicine; Research Fellow, William B. Schwartz Division of Nephrology, Tufts Medical Center, Boston, MA Measurement and Estimation of Kidney Function Edmund Huang, MD Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD Biological Agents in Kidney Transplantation Alp Ikizler, MD Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN Nutrition and Metabolism in Kidney Disease Betrand L. Jaber, MD, MS, FASN Associate Professor of Medicine, Department of Medicine, Tufts University School of Medicine; Vice Chair of Clinical Affairs, Department of Medicine; Director, Kidney & Dialysis Research Laboratory, St. Elizabeth’s Medical Center, Boston, MA Acute Complications Associated with Hemodialysis xiii Olwyn Johnston, MB, MRCPI, MD, MHSc Clinical Assistant Professor of Medicine, Division of Nephrology, Department of Medicine; Clinical Assistant Professor of Medicine and Transplant Nephrologist, Division of Nephrology, Department of Medicine, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada Chronic Kidney Disease and the Kidney Transplant Recipient Rigas Kalaitzidis, MD Postdoctoral Fellow in Hypertension, Department of Medicine, University of Chicago, Pritzker School of Medicine, Chicago, IL Hypertensive Kidney Disease Kamyar Kalantar-Zadeh, MD, MPH, PhD Associate Professor-in-Residence of Medicine, Pediatrics & Epidemiology Medicine, UCLA, Los Angeles, CA; Director of Dialysis Expansion & Epidemiology, Harbor-UCLA, Torrance, CA Inflammation in Chronic Kidney Disease Nitin Khosla, MD Senior Fellow in Nephrology, Department of Medicine, University of California at San Diego, San Diego, CA Hypertensive Kidney Disease Paul L. Kimmel, MD George Washington University, Department of Medicine, Washington, DC Depression and Neurocognitive Function in Chronic Kidney Disease Alan S. Kliger, MD Clinical Professor of Medicine, Department of Internal Medicine, Yale University School of Medicine; Chief Medical Officer, Chief Quality Officer, Hospital of Saint Raphael, New Haven, CT Frequent Hemodialysis: Physiological, Epidemiological, and Practical Aspects Camille Nelson Kotton, MD Clinical Director, Transplant and Immunocompromised Host, Infectious Diseases, Division of Infectious Diseases, Massachusetts General Hospital; Assistant Professor, Department of Medicine, Harvard Medical School, Boston, MA infection in renal transplant recipients Csaba P. Kovesdy, MD, FASN Associate Professor of Clinical Internal Medicine, Department of Medicine, University of Virginia, Charlottesville, VA; Chief of Nephrology, Salem Veterans Affairs Medical Center, Salem, VA; Associate Professor of Medicine, Department of Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA Inflammation in Chronic Kidney Disease xiv List of Contributors Andrew S. Levey, MD Dr Gerald J. and Dorothy R. Friedman Professor of Medicine, Department of Medicine, Tufts University School of Medicine; Chief, William B. Schwartz Division of Nephrology, Attending Physician, William B. Schwartz Division of Nephrology, Tufts Medical Center, Boston, MA Measurement and Estimation of Kidney Function Sharon M. Moe, MD Professor of Medicine and Anatomy and Cell Biology, Vice-Chair for Research, Department of Medicine, Indiana University School of Medicine; Staff Physician, Roudebush VAMC and Clarian Health Partners, Indianapolis, IN Chronic Kidney Disease-mineral Bone Disorder Adeera Levin, MD, FRCPC University of British Columbia, St. Paul’s Hospital, British Columbia Provincial Renal Agency, Vancouver, British Columbia, Canada The Role of the Chronic Kidney Disease Clinic Nader Najafian, MD Assistant Professor of Medicine, Renal Division, Transplantation Research Center, Brigham and Women’s Hospital, Children’s Hospital, Boston, Harvard Medical School, Boston, MA Transplantation Immunobiology John K. Leypoldt, PhD Senior Director, Renal Division, Baxter Healthcare Corporation, McGaw Park, IL Hemodialysis Adequacy Cynthia C. Nast, MD Professor of Pathology, Cedars-Sinai Medical Center and UCLA School of Medicine, Los Angeles, CA Diagnosis and Therapy of Graft Dysfunction Philip Kam-Tao Li, MD, FRCP, FACP Chief of Nephrology & Consultant Physician, Honorary Professor of Medicine, Department of Medicine & Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong Peritoneal Dialysis-related Infections Akinlolu O. Ojo, MD, PhD Professor of Medicine and Attending Transplant Nephrologist, University of Michigan Medical School, Ann Arbor, MI Chronic Kidney Disease in Nonkidney Transplant Recipients: Hematopoetic Cell and Solid Organ Transplantation Orfeas Liangos, MD, FACP, FASN Adjunct Assistant Professor of Medicine, Department of Medicine, Tufts University School of Medicine, Boston, MA; Physician, III. Med. Klinik (Nephrology), Klinikum Coburg, Coburg, BY, Germany Acute Complications Associated with Hemodialysis Mark Douglas Okusa, MD John C. Buchanan Distinguished Professor of Medicine, Department of Medicine, University of Virginia; Attending Physician, Department of Medicine, University Health of Virginia Health System, Charlottesville, VA Pharmacological Interventions in Acute Kidney Injury Etienne Macedo, MD Postdoctorate Fellow, School of Medicine, University of California San Diego, San Diego, CA Dialytic Management for Acute Renal Failure Yvonne M. O’Meara, MD, FRCPI Senior Lecturer in Medicine, Department of Medicine, University College Dublin; Consultant Nephrologist, Department of Renal Medicine, Mater Misericordiae University Hospital, Dublin, Ireland Recurrent and De Novo Renal Diseases After Kidney Transplantation Colm C. Magee, MD, MPH, FRCPI Clinical Lecturer, Royal College of Surgeons in Ireland; Consultant Nephrologist, Beaumont Hospital, Dublin, Ireland Evaluation of Donors and Recipients Sayeed K. Malek, MD, FACS Clinical Director of Transplant Surgery, Brigham & Women’s Hospital, Instructor in Surgery, Harvard Medical School, Boston, MA Surgical Management of the Renal Transplant Recipient Ravindra L. Mehta, MD Clinical Professor, School of Medicine, University of California San Diego, San Diego, CA Dialytic Management for Acute Renal Failure Timothy W. Meyer, MD Professor, Department of Medicine, Stanford University, Stanford, CA; Staff Physician, Department of Medicine, VA Palo Alto HCS, Palo Alto, CA The Pathophysiology of Uremia Priti R. Patel, MD, MPH Medical Epidemiologist, Prevention and Response Branch, Div Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, GA Hemodialysis-associated Infections Phuong-Chi T. Pham, MD Professor of Clinical Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles; Professor of Clinical Medicine, Department of Medicine, Nephrology Division, Olive View-UCLA Medical Center, Sylmar, CA Diagnosis and Therapy of Graft Dysfunction List of Contributors Phuong-Thu T. Pham, MD Associate Clinical Professor of Medicine, Director of Outpatient Services, Department of Medicine, Nephrology Division, David Geffen School of Medicine at UCLA; Associate Clinical Professor of Medicine, Director of Outpatient Services, Kidney and Pancreas Transplant Program, Ronald Reagan Medical Center at UCLA, Los Angeles, CA Diagnosis and Therapy of Graft Dysfunction Jeffrey L. Platt, MD Professor of Surgery and Professor of Microbiology and Immunology, Transplantation Biology; Associate Professor of Surgery and Associate Professor of Microbiology & Immunology, Transplantation Biology, University of Michigan, Ann Arbor, MI Emerging Strategies in Kidney Transplantation Lara B. Pupim, MD, MSCI Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN; Mitsubishi Pharma America, Inc., Warren, NJ Nutrition and Metabolism in Kidney Disease Emilio Ramos, MD Clinical Professor of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD Infection in Renal Transplant Recipients Deborah S. Rosenthal, MA Ferkauf Graduate, School of Psychology Yeshiva University, New York, NY Depression and Neurocognitive Function in Chronic Kidney Disease Maria-Eleni Roumelioti, MD Postdoctoral Associate, Department of Medicine, Renal and Electrolyte Division, University of Pittsburgh, Pittsburgh, PA Sleep Disorders Venkata Sabbisetti, PhD Research Fellow in Medicine, Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA Acute Kidney Injury: Biomarkers from Bench to Bedside Denise M. Sadlier, MB, PhD, FRCPI Senior Lecturer in Medicine, Department of Medicine, University College Dublin; Consultant Nephrologist, Department of Renal Medicine, Mater Misericordiae University Hospital, Dublin, Ireland Recurrent and De Novo Renal Diseases after Kidney Transplantation Mark J. Sarnak, MD, MS Professor of Medicine, Tufts University School of Medicine, Nephrologist, Tufts Medical Center, Boston, MA Cardiovascular Disease in Patients with Chronic Kidney Disease xv Tariq Shafi, MBBS, MHS Assistant Professor of Medicine, Department of Medicine/ Nephrology, Johns Hopkins University; Associate Faculty, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD Chronic Kidney Disease: Definition, Epidemiology, Cost and Outcomes Edward D. Siew, MD, MSCI Clinical Instructor of Medicine, Vanderbilt University Medical Center, Department of Medicine, Division of Nephrology, Nashville, TN Metabolic and Nutritional Complications of Acute Kidney Injury Robert C. Stanton, MD Principal Investigator, Chief of the Nephrology Section, Joslin Diabetes Center, Associate Professor of Medicine, Harvard Medical School, Boston, MA Diabetic Kidney Disease: Current Challenges Lesley A. Stevens, MD, MS Assistant Professor of Medicine, Department of Medicine, Tufts University School of Medicine; Attending Physician, William B. Schwartz Division of Nephrology, Tufts Medical Center, Boston, MA Measurement and Estimation of Kidney Function Patrick J. Strollo, Jr., MD, FACCP, FAASM Associate Professor of Medicine and Clinical and Translational Science, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA Sleep Disorders Terry B. Strom, MD Professor of Medicine, Department of Medicine, Harvard Medical School; Scientific Co-Director, The Transplant Institute, Beth Israel Deaconess Medical Center, Boston, MA Novel Diagnostics in Transplantation Rita S. Suri, MD Assistant Professor, Department of Nephrology, University of Western Ontario; Clinical Nephrologist, Department of Nephrology, London Health Sciences Center, London, Ontario, Canada Frequent Hemodialysis: Physiological, Epidemiological, and Practical Aspects Peritoneal Dialysis Prescription and Adequacy Nicola D. Thompson, PhD Epidemiologist, Surveillance Branch, Division of Healthcare Quality Promotion, Centers for Disease Control and Prevention, Atlanta, GA Hemodialysis-associated Infections xvi List of Contributors Stefan G. Tullius, MD, PhD, FACS Chief, Division of Transplant Surgery, Brigham & Women’s Hospital, Associate Professor of Surgery, Harvard Medical School, Boston, MA Surgical Management of the Renal Transplant Recipient Wolfgang C. Winkelmayer, MD, ScD Associate Professor of Medicine and Director of Clinical Research, Division of Nephrology, Stanford University School of Medicine, Palo Alto, CA Kidney Disease and Medications Mark Unruh, MD, MSc Assistant Professor of Medicine, Department of Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA Sleep Disorders Karl L. Womer, MD Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD Biological Agents in Kidney Transplantation Flavio Vincenti, MD Kidney Transplant Service, University of California, San Francisco School of Medicine, San Francisco, CA Biological Agents in Kidney Transplantation Bradley A. Warady, MD Professor of Pediatrics, Department of Pediatrics, University of Missouri-Kansas City School of Medicine; Interim Chairman, Department of Pediatrics, Chief, Section of Nephrology, Director, Dialysis and Transplantation, The Children’s Mercy Hospital, Kansas City, MO The Pediatric Patient with Chronic Kidney Disease Daniel E. Weiner, MD, MS Assistant Professor of Medicine, Tufts University School of Medicine; Nephrologist, Tufts Medical Center, Boston, MA Cardiovascular Disease in Patients with Chronic Kidney Disease Mark E. Williams, MD, FACP, FASN Associate Professor of Medicine, Harvard Medical School, Co-Director of Dialysis, Beth Israel Deaconess Medical Center; Senior Staff Physician, Joslin Diabetes Center, Boston, MA Diabetic Kidney Disease: Current Challenges Jane Y. Yeun, MD Professor of Clinical Medicine, Division of Nephrology, Department of Medicine, University of California, Davis; Staff Nephrologist, Nephrology Section, Medical Service, Veterans Administration Northern California Healthcare System, Sacramento, CA Principles of Hemodialysis Bessie Ann Young, MD, MPH Associate Professor, Department of Medicine, Division of Nephrology, University of Washington; Staff Nephrologist, Primary and Specialty Care, Division of Nephrology, Veterans Affairs Puget Sound Health Care System, Seattle, WA Timing and Initiation and Modality Options for Renal Replacement Therapy CHRONIC KIDNEY DISEASE: DEFINITION, EPIDEMIOLOGY, COST, AND OUTCOMES Chapter 1 Tariq Shafi, M.B.B.S., M.H.S., F.A.C.P. and Josef Coresh, M.D., M.H.S., Ph.D. DEFINITION OF CHRONIC KIDNEY DISEASE 3 Strengths and Limitations of the Current Chronic Kidney Disease Classification System 5 Future Directions 6 EPIDEMIOLOGY OF CHRONIC KIDNEY DISEASE 6 Etiology of Chronic Kidney Disease 7 Incidence of Chronic Kidney Disease 8 Prevalence of Chronic Kidney Disease 9 Incidence of End-Stage Renal Disease 11 Prevalence of End-Stage Renal Disease 13 COSTS OF CHRONIC KIDNEY DISEASE 14 Chronic Kidney Disease (Not on Dialysis) Costs 15 Costs during Transition from Chronic Kidney Disease to End-Stage Renal Disease 15 End-Stage Renal Disease Costs 16 Chronic kidney disease (CKD) is a global public health problem with a rising prevalence. Glomerular filtration rate (GFR) is considered the best overall index of kidney function, and low GFR is associated with higher risk of kidney failure requiring dialysis and cardiovascular disease, hypertension, anemia, and other metabolic complications. The last decade has seen significant improvement in recognition of the incidence, prevalence, and complications of CKD due in major part to the development of definitions of CKD by the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (K/DOQI). The wide dissemination and adoption of K/DOQI classification, with its emphasis on routine and automated estimation of GFR from serum creatinine (eGFR), has improved recognition of CKD in many populations where it was previously under recognized, such as the elderly and women. Increased awareness of CKD and uniform classification criteria have led to a better understanding of the burden of illnesses that accompany CKD and have increased focus on developing methods to slow CKD progression and increased emphasis on early recognition and prevention of complications associated with decline in GFR. While much progress has been made, the number of therapies and clinical trials on which to base recommendations is still very limited. OUTCOMES OF CHRONIC KIDNEY DISEASE 16 Glomerular Filtration Rate and its Association with Outcomes in Chronic Kidney Disease 17 Albuminuria and its Association with Outcomes in Chronic Kidney Disease 18 End-Stage Renal Disease Outcomes 20 CONCLUSION 20 DEFINITION OF CHRONIC KIDNEY DISEASE Renal parenchymal disease is the result of a variety of acute and chronic insults that can lead to nephron loss followed by adaptive hyperfiltration in the remaining nephrons. This adaptive hyperfiltration results in long-term glomerular damage leading to proteinuria and progressive loss of renal function. The initial decline of renal function is asymptomatic, and clinical manifestations of kidney failure occur late in the course of the disease. Loss of renal function, however, is variable and can be relentless even despite optimal medical therapy. Definitions of kidney disease have therefore focused on measures of function (GFR) and measures of damage (proteinuria, anatomical abnormalities). Prior to the K/DOQI guidelines in 2002, there were numerous definitions of CKD in use. Many of these definitions were not well understood by patients and the lay public due to the use of word “renal” and its Latin and Greek roots. Hsu and Chertow enumerated the different names used for CKD from abstracts submitted to the American Society of Nephrology meetings in 1998 and 1999 and in articles indexed in Medline.1 They noted 23 different terms used to describe states of reduced GFR along with a number of 3 4 Section I Chronic Kidney Disease different and overlapping definitions of kidney failure using serum creatinine, creatinine clearance, or GFR. The use of serum creatinine, in isolation, for defining CKD is especially problematic.2 Mild elevations of serum creatinine can often be dismissed as clinically insignificant, and even when recognized as abnormal, the emphasis on creatinine alone may underestimate the severity of underlying kidney disease. Serum creatinine is dependent not only on creatinine clearance by the kidney but also on creatinine generation and dietary animal protein intake. Creatinine generation in turn is strongly dependent on age, gender, race, and muscle mass.3 Many individuals including women and elderly may have decreased muscle mass and therefore lower creatinine.4 These individuals can have moderately or severely reduced kidney function with creatinine values that may be within the distribution of “normal” population ranges. Reliance on serum creatinine alone will therefore result in a systematic underestimation of kidney disease prevalence and severity in these groups. Considering these factors, the K/DOQI working group decided to use the word “kidney” instead of “renal” and developed an operational definition of CKD (Table 1-1).3 CKD is defined as the presence of kidney damage for at least 3 months. Kidney damage could be either: (1) Pathological abnormalities of the kidney such as the presence of polycystic kidney disease TABLE 1-1 Definition of Chronic Kidney Disease CRITERIA 1. Kidney damage for 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either: • Pathological abnormalities • Markers of kidney damage, including abnormalities in the composition of the blood or urine or abnormalities in imaging tests 2. GFR < 60 ml/min/1.73 m2 for 3 months, with or without kidney damage GFR, glomerular filtration rate. Adapted from National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification, Am. J. Kidney Dis. 39 (2 Suppl 1) (2002) S1-S266. (2) Presence of markers of kidney damage such as proteinuria (3) GFR less than 60 ml/min/1.73 m2 without any other evidence of kidney damage The guidelines also defined a five-stage system for classification of CKD (Table 1-2). Stages 1 and 2 are defined by the presence of markers of kidney damage and distinguished from each other by the absence (stage 1) or presence (stage 2) of mildly reduced GFR. Stages 3 to 5 are based solely on the level of GFR. The staging system represents the increasing azotemic burden as GFR declines and recognizes the common manifestations of reduced kidney function such as anemia and hyperparathyroidism that can occur independent of the etiology of the underlying kidney disease (such as glomerulonephritis or hypertensive nephrosclerosis). At each stage of CKD, an action plan was proposed with the goal of improving outcomes in patients and reducing mortality based on the best, but often limited, available evidence. The K/DOQI classification system complements the traditional classification systems that are based on clinical features (such as nephrotic syndrome) or pathophysiological mechanisms (such as immunoglobulin A (IgA) nephropathy on kidney biopsy). A major contribution of the K/DOQI guidelines is the emphasis on defining CKD based on estimated GFR (eGFR). GFR remains the best overall index of kidney function, but actual measurement of GFR is cumbersome and is reserved for special situations. K/DOQI recommended the use of equations to estimate GFR from serum creatinine using the Cockcroft-Gault equation or Modification of Diet in Renal Disease (MDRD) Study equation in adults and the Schwartz and Counahan-Barratt equations in children. The Cockcroft-Gault equation estimates GFR by calculating the unadjusted creatinine clearance.5 The equation was developed in a sample of 249 men. It is used for creatinine clearance calculation in women by using a theoretical adjustment factor for lower muscle mass in women. Creatinine is actively secreted by the proximal tubule, and the secretion increases as the GFR declines. As a result, creatinine clearance overestimates the GFR, especially in the lower range of GFR in patients with advanced CKD. The CockcroftGault equation also tends to underestimate the GFR in the TABLE 1-2 Chronic Kidney Disease Stages: K/DOQI Classification and Updates K/DOQI CLASSIFICATION STAGE DESCRIPTION UPDATES GFR 1 Kidney damage with normal or increased GFR 90 2 Kidney damage with mild decrease in GFR 60-89 3 Moderate decrease in GFR 30-59 KDIGO CARI NICE “P” if proteinuria Identify rate of progression. “T” if kidney transplant “D” if on dialysis “P” if proteinuria 3a (eGFR 45-59) 3b (eGFR 30-44) 4 Severe decrease in GFR 15-29 5 Kidney failure <15 CARI, Caring for Australians with Renal Impairment; GFR, glomerular filtration rate in ml/min/1.73 m2; K/DOQI, National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative; KDIGO, Kidney Disease: Improving Global Outcomes; NICE, National Health Service–National Institute for Health and Clinical Excellence. Chapter 1 Chronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes elderly and overestimate it in edematous or obese patients. Finally, the calibration of serum creatinine for the equation is uncertain, and standardization for body surface area requires a separate step. The MDRD Study equation was developed in a sample of 1,628 patients with CKD that were screened for enrollment in the MDRD Study.6 The equation estimates GFR adjusted to body surface area and accounts for creatinine generation by adjusting for age, gender, and race. Although the calculation of estimated GFR by the MDRD equation is mathematically complex, it has been greatly simplified by the nearly universal availability of various “calculators” in healthcare settings and by the K/DOQI initiative to have eGFR reported by the laboratory measuring serum creatinine. The MDRD equation has been widely used and independently validated in several populations, including transplant recipients.7,8 The MDRD equation, however, underestimates GFR at higher levels of GFR. The equation has recently been updated by a new equation developed by the Chronic Kidney Disease Epidemiology Collaboration, a National Institutes of Health (NIH) sponsored initiative. This new equation, the CKD-EPI creatinine equation, was derived using pooled data from 26 studies where GFR measurement was performed.9 Ten studies including 8254 patients served as the development dataset for the equation and 16 studies with 3896 people as the validation dataset. This new equation is at least as accurate as the MDRD equation in predicting measured GFR in patients with eGFR less than 60 ml/min/1.73 m2, but is substantially more accurate than the MDRD study equation in individuals with eGFR above 60 ml/min/1.73 m2. The median difference (interquartile range) between measured GFR and eGFR (bias) in the group with eGFR greater than or equal to 60 ml/min/1.73 m2 was 3.5 (2.6, 4.5) ml/min/ 1.73 m2 using the CKD-EPI equation compared with 10.6 (9.8, 11.3) ml/min/1.73 m2 using the MDRD equation. The equation also has improved accuracy at the higher GFR level. In the group with estimated eGFR greater than or equal to 60 ml/min/1.73 m2, using the CKD-EPI equation, 88.3% (95% Confidence Interval [CI], 86.9-89.7) of the GFR estimates were within 30% of the measured GFR (P30) compared with 84.7% (95% CI, 83.0-86.3) for the MDRD equation. The equation was developed on a population that included a larger number of African Americans and older individuals compared to the MDRD equation. The CKD-EPI 2009 creatinine equation is most easily expressed separately for each gender, race, and creatinine group. This improved equation will enhance clinical decision making in individuals with CKD stages 1 to 3 and will reduce misclassification while improving prevalence estimates of the disease burden of CKD. The K/DOQI classification system for CKD has been endorsed by many international societies and groups including: • Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO accepted the K/DOQI guidelines with the following additional recommendations:10 • Infer chronicity based on documentation of kidney disease for 3 months or longer. • Consider all patients with kidney transplant to have CKD and indicate that by “T”. • Designate “D” for CKD stage 5 patients on peritoneal dialysis or hemodialysis. 5 • Consider threshold for microalbuminuria as greater than 30 mg of albumin per gram of creatinine (greater than 30 mg/g) • The Canadian Society of Nephrology (CSN) endorsed the K/DOQI classification system with the modifications proposed by KDIGO.11 • The Caring For Australians with Renal Impairment (CARI) Guidelines—Australia/New Zealand: The CARI guidelines also endorsed the K/DOQI guidelines with KDIGO modifications and recommended addition of suffix “P” for proteinuria.12 • The National Health Service—National Institute for Health and Clinical Excellence (NICE) Chronic Kidney Disease Guidelines.13 The United Kingdom guidelines for CKD also endorsed the K/DOQI classification. The guidelines recommend: • Subdividing stage 3 CKD into 3a (eGFR 45 to 59 ml/ min/1.73 m2) and 3b (eGFR 30 to 44 ml/min/1.73 m2) • Use of suffix “P” for proteinuria (greater than 0.5 g/24 hours or protein:creatinine ratio greater than or equal to 50 mg/mmol) or albuminuria (greater than or equal to 30 mg/mmol) • Identifying progressive disease (eGFR decline greater than 5 ml/min/1.73 m2 in 1 year or greater than 10 ml/min/1.73 m2 within 5 years) It is noteworthy that all guidelines suggest that only a subset of CKD patients be referred.The K/DOQI hypertension guidelines suggest referral to a nephrologist for CKD patients with advance disease (stages 4 and 5) proteinuria (adding microalbuminuria and retinopathy in diabetic patients), rapid progression of CKD, or uncontrolled complications (hyperkalemia and resistant hypertension). These criteria suggest only 19% of U.S. patients with stage 3 CKD should be referred to a nephrologist.14 Thus, the current definition of CKD addresses the full spectrum of disease, including milder cases that do not require specialty care. This shift in emphasis suggests a partnership with general practitioners in caring for the full spectrum of disease. Strengths and Limitations of the Current Chronic Kidney Disease Classification System Strengths The K/DOQI classification system for CKD has led to reporting of eGFR with serum creatinine. Reporting of eGFR is important and “the only reason to measure serum creatinine is to assess GFR.”15 Determination of the severity of kidney disease with serum creatinine is difficult due to the log-linear relationship between serum creatinine levels and measured GFR and multiple non-GFR determinants of serum creatinine concentration. Less than 50% of individuals with eGFR below 30 ml/min/1.73 m2, the group with the highest risk of progression to end-stage renal disease (ESRD), recall ever being told about weak or failing kidneys.16 Even physicians fail to recognize the presence of CKD with low levels of eGFR when relying on serum creatinine measurement alone.17 As discussed in the next section, over 100,000 persons reach ESRD every year and require renal replacement therapy. Therefore, early diagnosis is important to prevent progression and to prepare for 6 Section I Chronic Kidney Disease renal replacement therapy. Early detection of CKD, by automated reporting of eGFR, may allow early referral of the highest risk subset of CKD patients to nephrologists. Early referral is associated with improved survival with and without dialysis and with reduction in the number of hospitalizations.18–21 There is widespread agreement that CKD classification has raised awareness of the full spectrum of CKD and its wide range of complications. The challenge and controversy is that increased awareness also points a brighter spotlight on gaps in the knowledge base, particularly with regard to efficacy, cost effectiveness, and thresholds for interventions. Changing the practice from excluding severe CKD patients from trials to including CKD patients and focusing on testing efficacy in this high risk population may be one of the most important outcomes of a clear and simple classification system centered on uniform reporting of the key markers of kidney damage (albuminuria) and function (eGFR). Limitations The current classification system also has its limitations, and these have been actively debated.22–25 There is inherent error and variability in the measurement of GFR, and there are limitations in the accuracy and precision of the estimating equations used to predict GFR. As discussed previously, the MDRD equation performs best at GFR levels below 60 ml/min/1.73 m2. The creatinine estimating equations suffer the limitations imposed by serum creatinine as an endogenous marker of GFR and are not reliable at extremes of body weight or when a patient’s creatinine metabolism is not in steady state such as in acute kidney injury. Therefore, there has been criticism of estimating GFR using the MDRD Study equation in general population samples, defining CKD based on a single eGFR cutoff rather than age specific cutoff, and defining CKD stages 1 and 2 based on persistent microalbuminuria without significant proteinuria as having a “disease.”23 Application of the CKD definitions to the population provides a useful indicator of the implications of the definition. However, it also clearly points out the large number of individuals meeting the CKD definition, particularly among many older individuals who will never progress to ESRD. Some fear that these individuals may undergo unnecessary diagnostic testing23 while others suggest the potential benefit of alerting physicians to optimize existing therapies and avoid nephrotoxic medications.22 General screening for CKD using eGFR is unlikely to be cost-effective. The National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) uses a targeted screening protocol based on the presence of hypertension, diabetes, cardiovascular disease, and first-degree relatives with ESRD.26,27 Finally, the presence of CKD has been misinterpreted as indicating a need for referral to a nephrologist despite guidelines suggesting that only a subset of patients require specialty care. The 2002 K/DOQI guidelines recommend nephrology referral for patients with eGFR less than 30 ml/min/1.73 m2, and a similar threshold for referral was endorsed by the CARI guidelines.3,12 The NICE guidelines also recommend nephrology referral for patients with eGFR less than 30 ml/min/1.73 m2 with added emphasis on patients with significant proteinuria and those with rapid declining GFR.13 Future Directions The concept of classifying CKD based on eGFR has greatly improved our understanding of the epidemiology of CKD. The focus is now shifting toward risk stratification and identification of the individuals at the highest risk of progression that may benefit from early referral and evaluation. Another challenge is to recognize the full range of preventable complications of CKD. The early focus was on cardiovascular disease and mortality as the most common cause of death and kidney failure as the end-stage kidney outcome. However, a wide-spectrum acute kidney injury is likely more common in the presence of underlying CKD, as are suboptimal medical care, including inappropriate medication dosing, and nonkidney outcomes such as infection and pneumonia. In this context, a KDIGO Controversies Conference on “Chronic Kidney Disease: Definition, Classification and Prognosis” was held in October 2009. The conference gathered data and focused on prognosis of CKD as well as discussed revision to the present CKD stages. Some of these results have been recently published and quantitatively demonstrate that eGFR <60 ml/min/1.73 m2 is an independent predictor of mortality in the general population.28 EPIDEMIOLOGY OF CHRONIC KIDNEY DISEASE In this section, we will discuss the distribution and determinants of the occurrence of CKD. We will review the available epidemiological evidence of some of the common causes of CKD. We define “incidence” as the occurrence or diagnosis of CKD in an individual who was disease-free at an earlier time. We define “prevalence” as the distribution of the individuals with CKD in the population at any given time. Incidence refers to occurrence of new disease, whereas prevalence is a “snapshot” of disease distribution in a population at a particular time. Incidence of a disease is dependent on the presence of a susceptible population with etiological factors for development of disease whereas prevalence depends on the incidence of the disease, and duration of the disease. Incidence of CKD, for example, depends on the population distribution of diabetes, hypertension, and other etiological risk factors for CKD. Prevalence of CKD will depend on the incidence of CKD and the life span of individuals and outcomes of other causes of illness and death, with atherosclerotic cardiovascular heart disease being the leading cause of death in CKD. Increasing population burden of obesity, diabetes, and hypertension will increase incidence. Improved treatment of cardiovascular heart disease is likely to prolong the life span and lead to increase in prevalence of CKD. Most epidemiological descriptions of CKD (for patients not on dialysis) are limited to prevalence estimates because documentation of occurrence of CKD requires establishing an earlier disease-free state followed by a long period of observation with repeated assessment of kidney function. More data are available on the incidence and prevalence of kidney failure treated with renal replacement therapy due to availability of registries in most developed countries. The United States Renal Data System (USRDS) provides comprehensive description of CKD and ESRD incidence and prevalence. In addition, the system has expanded to cover treatment and Chapter 1 Chronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes outcomes in the administrative data and more recently has included detailed information on CKD.29 The Centers for Disease Control (CDC) has also developed a project to provide surveillance for CKD using a wide range of parameters and data sources that will be tracked continuously.30 in CKD prevalence to follow. Diabetic nephropathy occurs in both type I and type II diabetes. Type I Diabetes The incidence of type I diabetes has progressively increased.35 The clear cut clinical onset of type I diabetes allows better estimation of the time to development of diabetic nephropathy compared to type II diabetes. Most studies reporting the incidence of diabetic nephropathy rely on urine albumin excretion as a surrogate marker for the presence of diabetic nephropathy. It is, however, important to note that morphological changes of diabetic glomerulosclerosis precede the occurrence of albuminuria, although albuminuria itself is a risk factor for progression of diabetic nephropathy.36 The occurrence of diabetic nephropathy in type I diabetes has changed with focus on improved glycemic and blood pressure control. Prior to the modern day intensive treatment strategies, diabetic nephropathy, as detected by microalbuminuria, was described in 20% to 30% of the patients after 15 years of follow-up, and ESRD was described in 4% to 17% of the patients at 20 years.37,38,39 More recently, a study from Sweden noted a much lower incidence of diabetic nephropathy (8.9% at 25 years), and another from Finland reported a much lower incidence of ESRD (2.2% at 20 years), which may reflect the protective effects of intensive blood pressure and glucose control.40,41 Type II Diabetes Sedentary lifestyle and obesity are contributing to a rising prevalence of type II diabetes.42 Recent data from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 demonstrated that among adults aged 20 to 39 years, 28.5% were obese; among those 40 to 59 years, 36.8% were obese; and among those aged 60 years or older, 31% were obese.43 Obesity was defined as a body mass index of 30 kg/m2 or higher. The prevalence of diabetes was 2.4% among normal weight individuals but rose to 14.2% among those with body mass index of 40 kg/m2 or higher.44 In the United States, age, gender, and race adjusted incidence rates of ESRD attributed to diabetes has doubled in the last decade.32 In the United Kingdom Prospective Diabetes Study, among 5097 patients with type II diabetes enrolled in the study, at 10 years, the prevalence of microalbuminuria was 24.9%, macroalbuminuria was 5.3%, and serum creatinine greater than 2 mg/dl or the need for renal replacement therapy was 0.8%.45 The progression to microalbuminuria was 2% per year, from microalbuminuria to macroalbuminuria was 2.8% per year, and from macroalbuminuria to serum creatinine greater than 2 mg/dl or renal replacement therapy was 2.3% per year. Etiology of Chronic Kidney Disease CKD can result from any underlying kidney disease that results from either acute kidney injury or a slowly progressive kidney disease. Discussion of all the causes of kidney disease is beyond the scope of this chapter. Instead, we will focus on available epidemiological data of a few common causes of CKD. From an epidemiological perspective, it is important to recognize that etiologies of CKD, as determined by ESRD registries, are limited by a number of factors. ESRD patients are disease “survivors” who initiate renal replacement therapy (dialysis and kidney transplantation) and thus reflect the progressive forms of CKD. Initiation of renal replacement therapies is also determined by physician practice characteristics, availability of resources, and societal and cultural norms. Finally, registry data are dependent on completion of regulatory forms that may or may not be accurate. The importance of established risk factors for ESRD was recently highlighted in a report of 177,570 Kaiser Permanente of Northern California members who participated in the Multiphasic Health Testing Services Program in Oakland and San Francisco between June 1, 1964 and August 31, 1973.31 Initiation of ESRD treatment was ascertained via linking with the USRDS database and identifying 842 cases of ESRD. Higher risk of ESRD was seen with male gender, older age, proteinuria, diabetes mellitus, lower educational attainment, African American race, higher blood pressure, body mass index, and serum creatinine level. These data are in agreement with the USRDS 2008 Annual Data Report (ADR) demonstrating diabetes and hypertension as the leading primary reported diagnoses for ESRD (Figure 1-1) with the highest rates of ESRD in African Americans and Native Americans as well as seminal reports from the Multiple Risk Factor Intervention Trial screenees and population based case-control studies.32–34 Diabetes Diabetes is the leading cause of CKD and ESRD worldwide. There has been a global increase in prevalence of diabetes over the last 2 decades, raising concerns about a rise Rates 50 160 Diabetes Hypertension GN Cystic kidney 40 Rate per million population Number of patients (in thousands) Counts FIGURE 1-1 Adjusted U.S. Incidence of ESRD by Primary Diagnosis. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 1: Fig 2.8. Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/ adr.htm. Last accessed 6/24/2010.) 7 30 20 10 120 80 40 0 0 80 84 88 92 96 00 04 80 84 88 92 96 00 04 8 Section I Chronic Kidney Disease Hypertension Hypertension is the second most commonly reported etiology of ESRD in the United States.32 The overall prevalence of hypertension in the United States determined using the NHANES data is 29.3%.46 The prevalence rates of hypertension in the United States have remained stable between 1999 to 2000 and 2003 to 2004. High prevalence rates have also been described in other populations. In the 2002 China National Nutrition and Health Survey, about 153 million or one in six Chinese adults were hypertensive. Similar to diabetes, the rising prevalence of hypertension also reflects the increasing obesity in the population. Hypertension precedes the development of ESRD with progressively higher risk at higher blood pressure.33,47–49 In 1091 participants of the African American Study of Kidney Disease, with optimal blood pressure control and use of angiotensin-converting enzyme inhibitors, the 10-year cumulative incidence of doubling of serum creatinine, ESRD, or death was 53.9%. The study showed that excellent control of hypertension among African Americans with CKD is possible and that in this setting, average loss of kidney function was still approximately 2 ml/min/1.73 m2 per year, but one third of participants showed slow to no decline in GFR (< 1ml/min/1.73 m2 per year).50 However, randomization to low blood pressure versus conventional (mean arterial pressure less than 92 mm Hg vs. 102–107 mm Hg) did not show the expected benefit. This suggests there is more to learn about optimizing therapy and the difficulties of studying progression when the control group does not have proteinuria and achieves conventional blood pressure targets. Hypertension is also associated with rapid progression to ESRD in patients with other forms of kidney disease. Finally, recent genetic studies implicate the myosin heavy chain 9 (MYH9) genetic variation as a major contributor to the excess risk of nondiabetic ESRD among African Americans and indicate a shared etiology with focal segmental glomerulosclerosis.33,47,49,51,52 Glomerulonephritis Glomerulonephritis is the third most common cause of ESRD.32 The diagnosis of glomerulonephritis requires a kidney biopsy. Advances in percutaneous kidney biopsy techniques are probably responsible for an increasing diagnosis of glomerulonephritis rather than a rising incidence rate. There remains a large variation in the biopsy practices of nephrologists worldwide; patients with isolated hematuria are more likely to undergo kidney biopsy in Asia than in the United States or Europe.53 IgA nephropathy is the most common glomerulonephritis in the world, especially among Caucasians and Asians. It is relatively rare in blacks. In a report of 13,519 kidney biopsies performed from 1979 to 2002 in China, IgA nephropathy accounted for 45% of the primary glomerulonephritis.54 Idiopathic focal segmental glomerulosclerosis is the most common cause of ESRD caused by primary glomerular disease in the United States.55 Analysis of the USRDS data suggests that the proportion of ESRD attributed to focal segmental glomerulosclerosis in the non-HIV population has increased elevenfold; from 0.2% in 1980 to 2.3% in 2000 with a fourfold higher risk in African Americans compared to Caucasians and Asians. Whether this risk represents a true increase in the incidence of focal segmental glomerulosclerosis (FSGS) or is a reflection of newer classification and biopsy practices remains to be determined, but a similar trend has also been noted in the results of kidney biopsies performed in the Unites States for diagnosis of nephrotic syndrome in adults. In a kidney biopsy series reported by Haas and colleagues, data from 1000 kidney biopsies performed between 1976 and 1979 was compared to 1000 kidney biopsies performed between 1995 and 1997.56 During the 1976 to 1979 period, the relative frequencies of membranous (36%) and minimal-change (23%) nephropathies and of focal segmental glomerulosclerosis (15%) as causes of unexplained nephrotic syndrome were similar to those observed in previous studies during the 1970s and early 1980s. In contrast, from 1995 to 1997, focal segmental glomerulosclerosis was the most common cause of this syndrome, accounting for 35% of cases compared with 33% for membranous nephropathy. During the 1995 to 1997 period, focal segmental glomerulosclerosis accounted for more than 50% of cases of unexplained nephrotic syndrome in black adults and for 67% of such cases in black adults younger than 45 years. Although the relative frequency of nephrotic syndrome due to focal segmental glomerulosclerosis was two to three times higher in black than in white patients during both study periods, the frequency of focal segmental glomerulosclerosis increased similarly among both racial groups from the earlier to the later period. In 2008, two groups found that a common genetic variation in the MYH9, a nonmuscle myosin found in more than one third of African Americans but less than 1% of European Americans increases the risk of focal segmental glomerulosclerosis and nondiabetic ESRD, providing a major breakthrough in our understanding of the biology of focal sclerosis in African Americans.51,52 Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease is a common disorder occurring in approximately 1 per 800 live births. It affects 500,000 persons in the United States and is responsible for 7% to 10% of ESRD cases.57 Autosomal dominant polycystic kidney disease can lead to ESRD in childhood, but usually progression to kidney failure occurs after the fourth decade of life. The risk of progression to ESRD is less than 2% below age 40 years, 20% to 25% by age 50, 35% to 45% by age 60, and 50% to 75% by age 70.58 Incidence of Chronic Kidney Disease Incidence of CKD is difficult to ascertain as it requires establishment of a cohort with normal kidney function at baseline with serial measurements of kidney function over a long period. As a result, few studies report the incidence of CKD. Furthermore, most studies are unable to apply the requirement for chronicity (more than 3 months duration). Incidence of CKD was examined in the 2585 participants of the Framingham cohort who attended both a baseline examination in 1978 to 1982 and a follow-up examination in 1998 to 2001 and who were free of kidney disease at baseline. CKD was defined as eGFR (by MDRD equation) in the fifth or lower percentile ( 59.25 ml/min/1.73 m2 Chapter 1 Chronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes in women, 64.25 ml/min/1.73 m2 in men). CKD developed in 9.4% of participants over the follow-up period and was associated with baseline GFR, diabetes, hypertension, and smoking.59 Incident CKD was examined in the Atherosclerosis Risk in Communities Study participants, including 3859 African American and 10,661 white adults, aged 45 to 64 years without severe kidney dysfunction at baseline in 1987 to 1989. Incident CKD was defined as hospitalization or death with kidney disease or increase in serum creatinine level of 0.4 mg/dl. During median follow-up of 14 years, CKD developed in 1060 individuals (incidence per 1000 person-years: 5.5 overall; 8.8 in African Americans and 4.4 in whites).60 Incidence of new-onset proteinuria may also reflect incident CKD. This was assessed in a 10-year prospective cohort study of 104,523 Korean men and 52,854 women, aged 35 to 59 years, who attended Korea Medical Insurance Corporation health examinations and who did not have proteinuria at baseline. Incident proteinuria developed in 3951 men (3.8%) and 1527 women (2.9%), and the associated risk factors were diabetes, male gender, and obesity.61 There is no accepted definition of CKD incidence. A recent comparison of different definitions included several alternatives. Incidence among 14,873 middle-age adults with eGFR greater than 60 ml/min/1.73 m2 at baseline was defined as: (1) low eGFR (< 60 ml/min/1.73 m2), (2) low and declining ( 25%) eGFR, (3) increase in serum creatinine ( 0.4 mg/dl) at 3 or 9 year follow-ups, and (4) CKD-related hospitalization or death. These definitions identified progressively fewer cases (1086, 677, 457, and 163 cases, respectively). There was relatively good agreement among definitions 1 to 3, but definition 4 identified mostly different cases. Risk factor associations were consistent across definitions for hypertension and lipids. Diabetes showed a stronger association with hospitalization, and gender differed in direction and magnitude across definitions.62 A complementary approach to incidence is to examine the rate of decline in eGFR. This is particularly effective in high risk populations but has been applied to general population studies as well.63,64 Prevalence of Chronic Kidney Disease Prevalence of CKD can be inferred from registries of patients with advanced kidney failure requiring dialysis. Not all patients, however, progress to ESRD. Many patients experience a slow decline in GFR and can avoid dialysis for a long period. Many others will succumb to complications of CKD and cardiovascular disease without ever starting dialysis. In a study of 220 consecutive patients at a Veterans Administration Medical Center renal clinic who met the definition of CKD (eGFR < 60 ml/min/ 1.73 m2 or urine protein/creatinine ratio of > 0.22 g/g), the cumulative incidence of mortality over 7 years was 18.5%, and that for ESRD was 17.6%.65 Prevalence estimates in ESRD registries reflect not only incidence and survival but also acceptance criteria into the dialysis programs, which vary over time and place. In the next two sections, we will first present information on the prevalence of CKD not on dialysis followed by the prevalence of ESRD. 9 Prevalence of Chronic Kidney Disease (Not on Dialysis) The most rigorous prevalence estimates for CKD in the United States are based on the analysis of the NHANES. The NHANES are cross-sectional, multistage, stratified, clustered probability samples of the U.S. civilian noninstitutionalized population conducted by the National Center of Health Statistics, which is a branch of the CDC. The NHANES were conducted from 1988 to 1994 in two phases (from 1988 to 1991 and from 1991 to 1994) and starting from 1999 to 2000 in 2-year phases. Prevalence estimates from NHANES are based on participants that were older than 20 years and did not have a missing serum creatinine concentration. Serum creatinine in NHANES was measured using the kinetic rate Jaffe method, and the creatinine values were calibrated to the Cleveland Clinic Research Laboratory. Albuminuria was assessed using a spot urine sample and calculation of urine albumin-to-creatinine ratios. Estimates of persistence of albuminuria were based on a sample of 1241 patients in NHANES from 1988 to 1994 that underwent repeat measurements. The number of people with albuminuria is limited and contributes to imprecision, but trends over time assume constant persistence based on these data. The CKD stages are based on the K/DOQI classification system. The prevalence estimates for the U.S. population have recently been revised using the CKD-EPI creatinine equation.9 The study population for these estimates included 16,032 participants that were older than 20 years, completed examination in the mobile center, were not pregnant or menstruating, and were not missing serum creatinine measurements. GFR was not measured in NHANES, but is estimated using serum standardized serum creatinine measurements. Estimated GFR was calculated using the CKDEPI creatinine MDRD Study equations. Individuals with eGFR less than 15 ml/min/1.73 m2 were excluded and those with eGFR greater than 200 ml/min/1.73 m2 were truncated at that level. The mean GFR (standard error) in the U.S. population using the CKD-EPI equation was 93.2 (0.39) ml/min/1.73 m2 compared with 86.3 (0.40) ml/min/1.73 m2 for the MDRD equation. The revised equation results in a shift to the right in GFR values at estimated GFR greater than or equal to 45 ml/min/1.73 m2; below that level the GFR distribution remains unchanged (Figure 1-2). The overall prevalence of CKD in adults in the United States is 11.5% (95% CI, 10.6 to 12.4), which translates to 23.2 (95% CI, 21.3 to 25.0) million people in the United States with CKD (Table 1-3). This estimate is lower than the estimated 13.1% based on the MDRD Study equation. The prevalence of CKD stages 1 through 4 based on NHANES 1996 to 2006 are: 2.24% (stage 1), 2.56% (stage 2), 6.32% (stage 3), and 0.4% (stage 4). Compared to the prevalence estimates based on MDRD equation, the CKD-EPI equation eGFR leads to a lower prevalence of CKD estimates in women (compared to men) and in whites (compared to blacks). As a result, the prevalence of CKD stages 3 and 4 are not statistically higher in women versus men and in whites versus blacks as was the case using prevalence estimates based on MDRD Study eGFR. Using the CKD-EPI equation, the prevalence estimates of CKD for those older than 70 years are similar to the MDRD equation. 10 Section I MDRD CKD-EPI Chronic Kidney Disease 15-29 30-59 0.4% 7.8% 0.4% 6.3% 60-89 52.2% 35.4% 90-119 120-149 150-179 33.8% 0.5% 5.2% 0% 9.5% 48.3% 180+ 0.1% 0% 12 Percent 10 8 6 4 2 <1 5 25 -2 9 40 -4 4 55 -5 9 70 -7 4 85 -8 10 9 01 11 04 51 13 19 013 14 4 51 16 49 016 17 4 51 19 79 019 4 0 Estimated GFR (ml/min/1.73 m2) FIGURE 1-2 Comparison of distribution of estimated glomerular filtration rate (GFR) and chronic kidney disease (CKD) prevalence by age in the United States. (NHANES 1999-2004). (Adapted from A.S. Levey, L.A. Stevens, C.H. Schmid, et al., A new equation to estimate glomerular filtration rate, Ann. Intern. Med. 150  604-612.) CKD prevalence information in the United States is also available through claims data for services provided to healthcare beneficiaries. Lack of a universal healthcare system in the United States limits the ability to obtain these data. Although prevalence estimates from populations based samples, such as NHANES, are more standardized and representative for estimating disease prevalence, review of claims-based data allows for an estimation of provider assessment of CKD, estimation of costs associated with CKD care, and a larger sample size. The 2008 USRDS ADR provides prevalence estimates of CKD based on claims data from Medicare (65 years and older), Ingenix i3 dataset, and Thomson Healthcare MarketScan Data. The Ingenix i3 database is a commercial and noncapitated health plan database covering employees from multiple employers within a single insurer. It includes claims data and laboratory-based data, allowing linking of CKD claims with lab-based definitions of CKD. The Thomson Healthcare MarketScan Data includes specific health services records for employees and their dependents in a selection of large employers, health plans, and government and public organizations. The Thomson database includes health claims data for about 10.5 million people but does not include laboratory data. Figure 1-3 shows the distribution of claims data using these three databases. CKD claims are much more frequent in the Medicare population. There also appears to be a marked discrepancy between CKD defined by lab data in Ingenix i3 and claims for CKD; only 0.13% of subjects have claims for CKD stages 3 to 5 compared to 10.5% based on laboratory estimates. These data indicate that CKD remains largely unrecognized, and consequently, metabolic complications of CKD are unlikely to be identified and treated. The widespread acceptance of the K/DOQI classification system has allowed estimation of CKD prevalence using eGFR. Table 1-4 presents a summary of literature on CKD prevalence reported in large population samples. The TABLE 1-3 Prevalence of Chronic Kidney Disease in the US based on NHANES 1996-2006 and the CKD-EPI 2009 Creatinine Equation for Estimating GFR STAGE DESCRIPTION eGFR Stages (1-5) PREVALENCE % (95% CI) N (1000s) (95% CI) 11.52 (10.62-12.43) 26,247 (24,264-28,223) 1 Kidney damage with normal or increased GFR 90 2.24 (1.74-2.77) 3412 (2624-4255) 2 Kidney damage with mild decrease in GFR 60-89 2.56 (2.05-3.07) 6443 (5212-7650) 3 Moderate decrease in GFR 30-59 6.32 (5.79-6.86) 15687 (14,364-16,992) 4 Severe decrease in GFR 15-29 0.4 (0.29-0.5) 705 (519-892) 5 Kidney failure 15 NA NA eGFR, estimated glomerular filtration rate in ml/min/1.73 m2; NHANES, National Health and Nutrition Examination Surveys. CKD Defined by Diagnosis Codes 7 Medicare Medstat Ingenix i3 6 Percent of population CKD Defined by Lab Data (Ingenix i3) 12 5 10 8 4 6 3 4 2 2 1 0 0 CKD 585 585.1 585.2 585.3 585.4 585.5 585.9 Stage 3-5 Stage 3 Stage 4 Stage 5 FIGURE 1-3 Chronic kidney disease (CKD) prevalence in the United States by CKD stage and dataset. (Data from U.S. Renal Data System, USRDS 2008 Annual Data report: volume 1: Fig 2.7. atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) Chapter 1 Chronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes 11 TABLE 1-4 Prevalence Studies of Chronic Kidney Disease STUDY SOURCE POPULATION COUNTRY OR REGION (AGE, YR) PROTEINURIA/ ALBUMINURIA (CUTOFF) (%) N HEMATURIA (%) GFR £ 60 ml/min/ 1.73 m2 AGE OVERALL DEPEND(%) ENCE (%) NHANES9 GP (PS) U.S. 1999-2006 (20þ) 16,032 9.3 (>30 mg/g) Persistent albuminuria estimate - 6.8 (4.8 with eGFR>60) NA CKD-EPI 6.7C MDRD 8.2C CKD-EPI 0.18-37.8 MDRD 0.55-37.4 REGARDS125 GP (PS) Southeastern U.S. (45þ) 20,667 NA NA 43.3C 19.3-71 NA 17.5C Strong Kaiser82 Clinical U.S. Northern California (20þ) KEEP126 High-risk U.S. 11,246 32.5 3 14.9 Strong NEOERICA127 Clinical U.K. region (0-90þ) 28,862 NA NA 4.9 0.2-33.4 Salford128 Diabetes U.K., Salford region (adult) 7596 9 NA 27.5 Strong SAPALDIA129 GP (PS) Swiss 1991 (adult) 6317 NA NA NA 0-35 HUNT II130 GP (Cohort) Norway, Nord-Trndelag 1995-1997 (20þ) 65,181 5.9 (>30 mg/g) NA 4.4C 0.2-18.6 Ausdiab131 GP (PS) Australia (25þ) 11,247 2.4 (>200 mg/g) 4.6 11.2 0-54.8 Aboriginies132 High-risk (V) Australia, Tiwi (18þ) 237 44 - 12 Strong 0.7-8.1 1120 NA InterAsia133 GP (PS) China (35-74) 15,540 NA NA 2.5C Beijing134 GP (V) China, Beijing (40þ) 2310 8.4 (S) 0.7 4.9C 0.3-11.5 Okinawa135 GP (V) Japan, Okinawa (30-79) 6980 NA NA NA NA Okinawa Screening95 GP (V) Japan, Okinawa GHMA (20þ) 95,255 47.4 (1¼) NA 42.6 Strong Karachi136 GP (V) Pakistan, Karachi (40þ) 1166 NA NA 10 6-21.2 Thailand EGA137 Workplace Thailand, Nonthaburi 1985 (35-55) 3499 2.64 (1þ) NA 1.7 Strong Saarland138 GP Germany, Saarland 2002 (50þ) 9806 11.9% (>20 mg/L) NA 17.4% 13.2-23.9 TLGS139 PS Tehran, Iran 2000 (20þ) 10,063 NA NA 18.9 1.8-76.6 Polnef140 PS Starogard Gdanski, Poland (18þ) 2471 15.6 % ( 1þ) NA 8.8 Strong PDMRA141 PS Kinshasa, Democratic Republic of Congo (20þ) 503 5% (>300 mg/d) NA 8.0 Strong Gubbio142 PS Gubbio, Italy (18þ) 4574 NA NA 6.4% 0.4-31.6 Reykjavik Heart Study143 CS Reykjavik, Iceland 1996 (34þ) 19,381 NA NA 7.2% Strong c Some calibration of serum creatinine to the MDRD research laboratory. Age dependence shows the prevalence from the youngest to the oldest age group studied. Source population: cohort, existing clinical or workplace population without specific criteria noted; GP, general population; PS, probability sample; V, volunteer sample. populations for these estimates are varied, and some include probability sampling (allowing for generalization to a larger population), screening of high-risk population groups, or cohorts of people in clinics or in workplace. The surveys using probability sampling methods, such as the NHANES, the InterAsia Study, and AusDiab offer many advantages over the other sampling designs. Volunteer populations inherently suffer from selection biases that are reduced, though not eliminated, using probability sampling. Use of probability samples also allows generation of population estimates using appropriately applied weights. The disadvantages of cross-sectional estimates include the selection of diseases with a slow onset and prolonged duration as those with the most rapidly progressing disease may be too sick or die prior to be included in the survey. Prevalence estimates in the reported studies are quite varied reflecting the nature of the study population. Presence of albuminuria or proteinuria as a marker of kidney damage is in the range of 5% to 10% in these varied populations. Incidence of End-Stage Renal Disease Patients with advanced CKD, typically stage 5 (eGFR less than 15 ml/min/1.73 m2), that start renal replacement therapy are referred to as having reached ESRD. Renal replacement therapy includes hemodialysis, peritoneal dialysis, and kidney transplantation. It is important to recognize Section I Chronic Kidney Disease Bars: Rate per million population that kidney transplantation can be performed once the eGFR is less than 20 ml/min/1.73 m2 and before dialysis is started if there is an available kidney donor or a matched deceased donor kidney becomes available (preemptive transplantation). The use of the term ESRD in the United States dates back to 1972 when the U.S. Congress passed legislation authorizing the End Stage Renal Disease (ESRD) program under Medicare (section 299I of Public Law 92-603). Coverage for ESRD, considered a “rare” disease at the time, was authorized for all individuals regardless of their age if they would otherwise be eligible for social security benefits. In the United States, the USRDS collects, analyzes, and distributes information about ESRD. The USRDS is funded by the National Institute of Diabetes and Digestive and Kidney Diseases in conjunction with the Centers for Medicare & Medicaid Services. The USRDS has become an excellent resource for providing precise data on ESRD and publishes an ADR summarizing its findings. The 2008 ADR includes data up until 2006 with projections up to the year 2020. The most up-to-date data are available at www.usrds.org, and for the overall incidence and prevalence data, the 2-year lag period may be reduced in the future. In 2006, 110,854 persons reached ESRD reflecting an age, race, and gender adjusted incidence of 360 per million population (Figure 1-4). Growth in the incident counts was 3.4% and for the incidence rate was 2.1% over the 2005 rate. This represents an increase in incidence after 4 years where the yearly incidence rates were less than 1%. The incidence rates of ESRD have changed substantially since the program’s inception. From 1980, the incidence rate increased by 155% to 1990 (217 per million population) and 295% by 2000 (337.5 per million population). Similar trends were noted in a cohort of 320,252 members of the Kaiser Permanente Cohort in Northern California where the likelihood of ESRD increased by 8% per year from 1973 to 2000.66 Several factors play a role in the rising incidence of ESRD, but perhaps the most important reason is liberal criteria for accepting patients for renal replacement therapy.32 With aging and increased population burden of diabetes, hypertension, and obesity, the absolute numbers of patients initiating renal replacement therapy continues to increase. The median age of incident ESRD patients was 64.4 years in 2006. Adjusted for age, sex, and race, the incidence of ESRD has largely stabilized for all but the oldest age groups. For those older than 75 years, ESRD incidence increased by 11% to 1744 per million population (Figure 1-5). Between 1996 and 2003, the rates of dialysis initiation among octogenarians and nonagenarians increased by 57%.67 Rising prevalence of CKD is also a possible contributing factor to increasing incidence of ESRD. The number of patients with diabetes listed as the primary cause of ESRD continues to increase. In addition, diabetes is associated with a higher rate of ESRD ascribed to other causes.29 In 2006, 48,157 persons (159 per million population) with incident ESRD were diabetic, representing a 4.6% increase compared to 2005 and a 17.2% increase compared to 2000. In contrast, the incidence 400 15 300 10 200 5 100 0 Symbols: 1-year % change 12 ⫺5 0 80 82 84 86 88 90 92 94 96 98 00 02 04 06 Rates Counts 2,000 40 0-19 20-44 45-64 65-74 75+ 30 Rate per million population Number of patients (in thousands) FIGURE 1-4 Adjusted U.S. incidence rates of ESRD and annual percent change. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 2.3. Atlas of EndStage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds. org/adr.htm. Last accessed 6/24/2010.) 20 10 0 0-19 20-44 45-64 65-74 75+ All 1,500 1,000 500 0 80 84 88 92 96 00 04 80 84 88 92 96 00 04 FIGURE 1-5 Incident counts and adjusted rates for ESRD in the United States, by age. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 2.5. atlas of end-stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) Chronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes of ESRD due to glomerulonephritis continues to fall and was 26 per million population in 2006. Racial and ethnic disparities in the incidence of ESRD persist. In 2006, the incidence for African Americans was 3.6 times higher (1010 per million population) and for Native Americans was 1.8 times higher (489 per million population) compared to whites. Similarly, among Hispanics the incidence of ESRD (520 per million population) was 1.5 times greater than the non-Hispanic population. Median age (in years) 60 Prevalence of End-Stage Renal Disease White (2006: 60) Af Am (56.9) 55 50 N Am (57.8) Asian (59.1) Hispanic (57.2) All (58.8) 45 40 78 At its inception, ESRD was expected to plateau at 40,000 prevalent patients, a number that was reached over 20 years ago. In 2006, 506,256 persons received renal replacement therapy, reflecting an age, gender, and race adjusted prevalence of 1626 per million population (Figure 1-6). This prevalence represents a 2.3% increase since 2005 and a 15% increase since 2000. This rise in prevalence has stabilized in the past 5 years. The median age of the prevalent ESRD persons continues to increase and was 58.8 years in 2006 (Figure 1-7). The gender and race adjusted prevalence of ESRD has increased the greatest among persons aged 65 to 74 years reaching 5700 per million population, reflecting a 20% increase since 2000 and a 48% increase since 1996. Numerically the largest single age group receiving renal replacement therapy is those aged 45 to 64 years. For persons aged 75 and older, the prevalence is 5000 per million population, and this prevalence is 23.6% higher than in 2000. Prevalent ESRD rates continue to reflect the race and ethnic disparities observed with incident ESRD. In 2006, prevalence of ESRD was 5004 per million population in African Americans, 2691 per million population in Native Americans, 1831 per million population among Asians, and 1194 per million population among whites. Diabetic ESRD continues to be the leading cause for prevalent ESRD patients (604 per million population) followed by hypertension and glomerulonephritis. Global Perspectives on the Incidence and Prevalence of End-Stage Renal Disease The USRDS 2008 ADR includes data on incidence and prevalence of ESRD from 44 countries and regions that voluntarily provide registry data to the USRDS. ESRD Bars: Rate per million population 13 82 86 90 94 98 02 06 FIGURE 1-7 Median age of prevalent ESRD patients in the United States. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 2.17. Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) incidence and prevalence varies widely between countries (Figures 1-8 and 1-9). Incidence for reported ESRD is the highest in Taiwan at 418 per million population, followed by the United States. Incidences below 100 per million population are reported from a number of countries including Bangladesh, Pakistan, Russia, Philippines, Finland, and Norway. The highest prevalence of ESRD is also reported by Taiwan at 2226 per million population, followed by the United States and Japan. Clearly, factors beyond progression to advanced kidney failure play an important role in these estimates. There are differences in completeness and accuracy of data across regions and differences in resources and access to care. As a result, these comparisons must be performed with caution. Perspective on the global trends in ESRD care is also provided by survey data reported by Fresenius Medical Care, a worldwide dialysis company. Grassmann and colleagues reported the results of survey data from 122 countries with established dialysis programs.68 These countries represented 92% of the world population, and the report focused on treated ESRD patients at the end of 2004. Globally, 1.783 million persons received treatment for ESRD in 2004, reflecting an overall prevalence of 280 per million people worldwide. The prevalence was reported to be the highest in Japan (2045 per million population), followed by the United States. The lowest prevalence (70 per million population) 1600 16 1200 12 800 8 400 4 0 Symbols: 1-year % change Chapter 1 0 80 82 84 86 88 90 92 94 96 98 00 02 04 06 FIGURE 1-6 Adjusted U.S. prevalent rates of ESRD and annual percent change. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 2.11. Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) Section I Chronic Kidney Disease Taiwan Japan United States Germany Belgium, French sp. Belgium, Dutch sp. Hong Kong Spain Greece France Rep. of Korea Chile Jalisco (Mexico) Uruguay Austria Sweden Denmark New Zealand Australia Scotland Netherlands Norway Finland Hungary UK Israel Malaysia Argentina Turkey Bosnia/Herzegov. Luxembourg Iceland Czech Republic Shanghai Romania Thailand Russia Bangladesh Philippines Taiwan United States Jalisco (Mexico) Shanghai Japan Luxembourg Germany Israel Greece Turkey Belgium, Dutch sp. Belgium, French sp. Rep. of Korea Czech Republic Canada Hungary Austria Croatia Uruguay Argentina Chile Hong Kong France Thailand Bosnia/Herzegov. Spain Sweden Italy Malaysia New Zealand Australia Scotland Denmark Netherlands UK Norway Finland Philippines Romania Iran Iceland Pakistan Russia Bangledesh 0 150 300 450 FIGURE 1-8 International comparison of ESRD incidence rates. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 12.2. Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) was reported from Africa and rest of Asia, excluding Japan. The global prevalence numbers were 20% higher than an earlier survey using similar methodology performed in 2001. National economic strength appeared to be correlated with ESRD prevalence especially in countries with a Gross Domestic Product (GDP) per capita per annum below $10,000 (U.S. GDP for 2004 was $37,800 per capita), where access to dialysis is often limited. At higher GDPs, there did not appear to be a correlation suggesting factors other than economy may be playing a role in the prevalence of treated ESRD (Figure 1-10). COSTS OF CHRONIC KIDNEY DISEASE The K/DOQI classification has allowed better description of the costs associated with care of CKD patients not on dialysis. The new CKD diagnostic billing codes introduced in FIGURE 1-9 International comparison of ESRD prevalence rates. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 12.4. Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/ adr.htm. Last accessed 6/24/2010.) ESRD prevalence p.m.p. 14 2000 1800 1600 1400 1200 1000 800 600 400 200 0 0 10,000 20,000 30,000 40,000 GDP per capita in US $ FIGURE 1-10 Prevalence of ESRD in 2004 versus economic welfare in the 75 countries with the largest ESRD populations. (From A. Grassmann, S. Gioberge, S. Moeller, G. Brown, ESRD patients in 2004: global overview of patient numbers, treatment modalities and associated trends, Nephrol. Dial. Transplant. 20   2587-2593.) 2006 have allowed improved enumeration of costs using healthcare databases. Costs for CKD care can be divided into costs for CKD patients not on renal replacement therapy, costs during transition to renal replacement therapy, and ESRD costs. Chronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes PPPM expeditures ($, in thousands) Chapter 1 Chronic Kidney Disease (Not on Dialysis) Costs CKD is highly associated with diabetes, hypertension, obesity, cardiovascular disease, and stroke. In addition, patients with CKD are at higher risk of renal and nonrenal complications due to treatment of these disorders. As a result, the cost of care of patients with CKD is expected to be high. In an analysis of healthcare costs and resource use for 13,796 Kaiser Permanente Northwest Region health maintenance organization members and their age- and gender-matched controls followed for up to 5.5 years ( June 2001), patients with CKD and no comorbidities had medical costs averaging $18,000 compared to $9800 among nonCKD patients without comorbidities.69 The increment in costs for a patient with comorbidities was greater in those with than without CKD. The 2008 USRDS ADR also reports the economic impact of CKD using the Medicare and Employee Group Health Plan (EGHP) data. In general, the EGHP costs are higher, reflecting cost shifting from Medicare and the lower ability of the private payors to set fees compared to Medicare. In 2006, CKD costs for Medicare patients exceeded $49 billion and represented 24.5% of the general Medicare costs. These costs have increased fivefold since 1993. The overall per patient per month costs are $2289 for dually-enrolled (Medicare and a secondary insurance) patients compared to 1,889 for Medicare enrollees and $2274 for the younger EGHP patients. These costs are several fold higher than the per patient per month cost of care for non-CKD patients with Medicare ($697 in 2006). CKD also has a multiplier impact on healthcare costs (Figure 1-11). The per patient per month costs in persons with CKD, diabetes, and congestive heart failure were $2973; twofold higher than in those with CKD alone ($1232). Costs during Transition from Chronic Kidney Disease to End-Stage Renal Disease The period of transition of care from CKD to ESRD is associated with high morbidity and mortality, which is reflective in the cost of care of these patients. The per PPPM expenditures ($, in thousands) Medicare (65+) 15 30 Medicare (67+) Medstat (<65) 20 10 0 ⫺6 ⫺5 ⫺4 ⫺3 ⫺2 ⫺1 1 2 3 4 Months pre- and postinitiation 5 6 FIGURE 1-12 Total per patient per month costs in the transition to ESRD. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 11.9. Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) patient per month costs rise dramatically during this transition period (Figure 1-12). The overall transition costs for Medicare patients increase from $6701 in the month prior to initiation of dialysis to $14,461 following initiation. Of this first month cost, $9588 (66.3%) is due to inpatient hospitalization; cardiovascular ($3478) and vascular ($1509) hospitalizations account for 52.7% of the total inpatient costs. The hospital use for ESRD patients is significantly higher in the first 3 months, and the presence of ischemic heart disease, late nephrologist referral, and use of temporary vascular access for dialysis are risk factors for increased hospital days.70 Similar trends have been reported in other studies. In a study of ESRD in France, the mean duration of hospitalization at dialysis initiation was 30 days in late referred patients compared to 8 days for those referred at least 6 months prior to initiation, resulting in an excess cost of approximately 30,000 Euros per patient.71 Similar findings were reported in a Scandinavian study; the duration of hospitalization was 31 days in the late referral population compared to 7 days in those referred early.72 These data strongly support an advantage for early referral, but the ability to control for all factors that differ between the groups is limited. For example, acute kidney injury in the setting of Dually-Enrolled (65+) Medstat (50-64) 6 All CKD CKD (NDM, non-CHF) CKD + DM CKD + CHF CKD + DM + CHF 5 4 3 2 1 0 93 95 97 99 01 03 05 93 95 97 99 01 03 05 00 01 02 03 04 05 06 FIGURE 1-11 Per person per month CKD expenditures in the United States, by diagnosis and dataset. For comparison, the cost for Medicare enrollees without CKD is $697 per patient per month. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 1: Figure 5.4. Atlas of EndStage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) Section I Chronic Kidney Disease CKD may lead to initiation of dialysis without the opportunity for early referral. Additional cost-effective analyses and, if possible, clinical trials of programs incorporating early referral and improved CKD care are needed. End-Stage Renal Disease Costs Total expeditures ($, in billions) Costs of renal replacement therapy include expenses of the dialysis treatment (peritoneal or hemodialysis); creation of access for dialysis treatment; hospitalizations due to cardiovascular, infectious, and access-related complications; transplant related costs including costs of organ procurement, surgery, and immunosuppression; and costs of medications used for treatment of anemia (erythropoietin supplementation agents [ESAs] and iron) and hyperparathyroidism (vitamin D analogues). The high disease burden of this population contributes to the high healthcare resource use. In 2006, ESRD costs as determined by Medicare spending were $23 billion or 6.4% of the Medicare budget. Although the ESRD costs continue to increase, they have remained at a stable 6.3% to 6.5% of the Medicare budget. Of the total Medicare costs (Figure 1-13), three-quarters are spent on inpatient (38.5%) and outpatient care (34.6%). Per patient per year costs for hemodialysis were $71,889 in 2006, compared to $53,327 for peritoneal dialysis and $24,951 for kidney transplantation. Among dialysis patients, those with catheters and grafts have the highest per person per year costs, at $77,093 and $71,616, respectively, whereas $59,347 and $53,470 are spent annually on those with arteriovenous (AV) fistulas and peritoneal dialysis catheters, respectively. These costs were much higher for non-Medicare providers. The effect of comorbidities in contributing to these high costs is illustrated by the costs for inpatient and outpatient services for diabetics versus nondiabetics; the costs for diabetics ($54,936 per year) was 25% greater than the $43,920 per year costs incurred by nondiabetic patients. ESAs account for approximately 10% of the Medicare spending, but the rise in ESA costs has plateaued. Per patient per year costs for injectable vitamin D therapy was approximately $2000, and the cost for intravenous iron was approximately $700. The costs for vascular access infections were the highest for those with catheters at $2500 compared to $775 for those with an arteriovenous graft and $240 for those with a fistula. 25 20 15 Hospice Home health Skilled nursing Physician/supplier Outpatient Inpatient 10 5 0 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 FIGURE 1-13 Total medicare dollars spent on ESRD, by type of service. (Data from U.S. Renal Data System, USRDS 2008 Annual Data Report: Volume 2: Fig 11.6. Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2008. Available online at: http://www.usrds.org/adr.htm. Last accessed 6/24/2010.) International comparison of ESRD costs is more problematic due to the vastly different healthcare systems, funding sources, accounting methods, access to care, costs of hospitalization and medications, and societal norms.73 The economic burden of ESRD in Canada in 2000 was estimated to be $1.9 billion with a per patient per year cost of $51,099.74 United Kingdom hemodialysis costs for 2005 were estimated to be approximately $18,000 per person per year but did not include the cost of medications.75 In Sweden in 2002, the cost of hemodialysis was $70,796 per person per year.76 In Spain during 2003, the cost of hemodialysis per patient per year was estimated to be $46,327.77 The annual expenditure per ESRD patient in Japan was estimated to be $41,681.78 In New Zealand, where ESRD care has always been “rationed,” the 2003 ESRD expenditures were $23,372 per person per year.79 In Australia, the total annual expenditure per ESRD patient per year in 2006 was estimated to be $36,917.80 A comparative review of healthcare systems and ESRD costs in 12 countries was performed as part of the International Study of Health Care Organization and Financing, a substudy within the Dialysis Outcomes and Practice Patterns Study (DOPPS).81 A moderate correlation (p ¼ 0.70) was noted between the annual healthcare expenditures per capita and the annual expenditure per ESRD patient but appears to be significantly influenced by the U.S. healthcare spending (Figure 1-14). OUTCOMES OF CHRONIC KIDNEY DISEASE CKD is progressive disorder associated with a myriad of complications. Some of these complications are direct consequences of loss of kidney function such as volume overload, hyperkalemia, hyperphosphatemia, metabolic acidosis, secondary hyperparathyroidism, anemia, and hypertension. Many complications are also the results of treatment of causes of CKD as in the case of chemotherapy for glomerulonephritis. Ultimately, CKD progression to ESRD is an important outcome. Table 1-5 provides a conceptual overview of some of the most common outcomes whose risk is elevated by Annual health expenditure per capita* ($, in thousands, PPP) 16 6 r = 0.70 p = 0.01 5 US 4 AU SW 3 NZ 2 CA FR GE BE IT JP UK SP 1 0 0 10 20 30 40 50 60 Annual expenditure per ESRD patient ($, in thousands, PPP) 70 FIGURE 1-14 Annual expenditure per ESRD patient and general population health expenditure per capita. (From A. Dor, M.V. Pauly, M.A. Eichleay, P.J. Held, End-stage renal disease and economic incentives: the International Study of Health Care Organization and Financing [ISHCOF], Int. J. Health Care Finance Econ. 7 [2-3]  73-111.) Chapter 1 Chronic Kidney Disease: Definition, Epidemiology, Cost, and Outcomes TABLE 1-5 Risk Factors for Progression of Chronic Kidney Disease (CKD), Cardiovascular Disease (CVD), and Death OUTCOME IMPORTANCE FOR DIFFERENT OUTCOMES CKD STAGE TYPE OF KIDNEY DISEASE (DIAGNOS