Management of chronic kidney disease

Mustafa Arici
Editor

Management of
Chronic Kidney Disease
A Clinician’s Guide

123


Management of Chronic Kidney Disease



Mustafa Arici
Editor

Management of Chronic
Kidney Disease
A Clinician’s Guide


Editor
Mustafa Arici, MD
Department of Nephrology
Faculty of Medicine
Hacettepe University
Ankara
Turkey

ISBN 978-3-642-54636-5

ISBN 978-3-642-54637-2
DOI 10.1007/978-3-642-54637-2
Springer Heidelberg New York Dordrecht London

(eBook)

Library of Congress Control Number: 2014941922
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To my admirable wife Esra, and my lovely daughters Ayse and
Zeynep, for their love, support, time and patience, but above
all, for them being “all my reasons” for life
To my parents and brothers, for their continuous love,
encouragement and wisdom



Preface

To study the phenomena of disease without books is to sail an uncharted sea, while
to study books without patients is not to go to sea at all.
William Osler

I am very pleased to offer the first edition of Management of Chronic Kidney
Disease: A Clinician’s Guide. Actually, there are many textbooks devoted to general nephrology or books that are particularly focused on dialysis or renal transplantation. However, there is a real deficiency of books devoted particularly to the
care of chronic kidney disease (CKD) patients. This book attempts to fulfill this
gap by providing a comprehensive, guideline-based, practice-oriented management plan for physicians who continuously take care of adult CKD patients.
Chronic kidney disease is now a significant public health problem worldwide. CKD globally affects almost 10 % of general population. Incidence and
prevalence of CKD figures are still rising especially in developing countries.
The rise in CKD figures are fuelled by aging of the populations and growing
problems of obesity, diabetes, high blood pressure and cardiovascular diseases.
Today, the number of CKD patients from stage 1 to 5 not on dialysis exceeds
the number of patients with end-stage renal disease (ESRD) by a factor of
50–100. Practicing nephrologists come across much more CKD patients than
dialysis or renal transplantation cases. CKD management is, therefore, a major
item in the agenda of nephrology practice, and its pressure will increase more
in the following years. Physicians in the other disciplines will also see more
CKD patients in their daily practice due to increasing prevalence of CKD. This

book covers adult CKD patients, starting from “at risk” for CKD to CKD stage
5 not on renal replacement therapies. The book’s major target audience is
nephrologists and residents/fellows and attending physicians in nephrology.
The book, however, may also serve as a multidisciplinary resource for many
doctors, including family physicians, internists, endocrinologists, cardiologists,
and geriatrists, who frequently encounter many CKD patients at earlier stages.
The book is intended to cover the whole journey of a CKD patient as:
• Defining and diagnosing CKD
• Assessing and controlling risk factors of CKD
• Stopping/slowing progression in CKD
• Assessing and managing complications of CKD
• Caring for CKD patients under special conditions
• Caring for CKD patients just before initiating renal replacement
therapies
vii


Preface

viii

In the book, diagnostic and therapeutic approaches were presented according to
latest staging system of CKD, from earlier to late stages. The book have some
novel chapters such as “Quality of Life in CKD”, “Pain Management in CKD”,
“CKD in Intensive Care Unit”, “CKD and Cancer”, “CKD Management Programs
and Patient Education” and “Conservative/Palliative Treatment and End-of-Life
Care in CKD”. These chapters aim to complement some neglected but substantial
steps in CKD care. In this book, many special chapters were written by nonnephrologists but specialists of that particular field like radiologists, cardiologists,
neurologists, surgeons, obstetricians, dermatologists, psychiatrists, etc. As CKD
care needs a multidisciplinary action, this book intends to increase communication

between different disciplines while looking after the same CKD patient.
All chapters start and end with boxes titled as “Before You Start: Facts You
Need to Know” and “Before You Finish: Practice Pearls for the Clinician”. Most
chapters have also “What the Guidelines Say You Should Do?” and “Relevant
Guidelines” boxes for easy access to guidelines and guideline recommendations. These boxes will suffice to distill “practical practice pearls” from the
bulky volumes of guidelines and other sources of information with a “5-min
attention” of busy clinicians. Each chapter has a very selective list of references
restricted to 15–20 in maximum. I encourage all who use this book to send their
suggestions and comments both for the content and the design of the book.
The book is intended for a global coverage of CKD problem. The contributing authors are world-known experts in their fields and act as executive
members of many national and international associations in nephrology.
Most authors have participated in writing guidelines on CKD.
This book will not be possible were it not for so many people. Firstly, I have
been fortunate that many distinguished authors, colleagues and friends have
kindly accepted to contribute to this book. I would like to take this opportunity
to thank them all very warmly. They have generously spent their most valuable
hours to produce high-quality and up-to-date chapters. They were very considerate and rigorous during the review processes. Secondly, I would like to express
my sincere gratitude to Portia Levasseur, the Developmental Editor for the book.
Without her excellent support and enthusiasm, it will be impossible to hold this
book in your hands. Last but not least, I thank all the staff of Springer, but particularly Sandra Lesny who gave me the opportunity to edit this book.
I also would like to acknowledge my mentors, colleagues, my residents/
fellows and my students in Hacettepe University. I have learned many things
from them and they helped me to be who I am. My major inspiration in
nephrology practice is seeing the joy in the faces of patients when their CKD
progression were slowed down or halted completely. It is a privilege for me
to care for them and they have been the powerful source of my motivation,
dynamism and knowledge.
Increasing the awareness of CKD, mounting the chances for early recognition and definition of CKD and managing better for preventing or delaying/
halting progression of CKD and its complications were major aims of this
book. If the readers will apply at least some of those to their clinical practice,

the editor and the authors will feel rewarded for their efforts.
Ankara, Turkey

Mustafa Arici


Contents

Part I

Chronic Kidney Disease: Basics and Clinical Assessment

1

What Is Chronic Kidney Disease? . . . . . . . . . . . . . . . . . . . . . . . . .
Rajeev Raghavan and Garabed Eknoyan

2

Clinical Assessment of a Patient with Chronic
Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mustafa Arici

3

Imaging in Chronic Kidney Disease. . . . . . . . . . . . . . . . . . . . . . .
Yousef W. Nielsen, Peter Marckmann, and Henrik S. Thomsen

Part II

3

15
29

Chronic Kidney Disease Risk Factors:
Assessment and Management

4

Diabetes and Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . .
Meryem Tuncel Kara, Moshe Levi, and Devasmita Choudhury

43

5

Hypertension and Chronic Kidney Disease. . . . . . . . . . . . . . . . .
Stephanie Riggen and Rajiv Agarwal

57

6

Dyslipidemia and Chronic Kidney Disease . . . . . . . . . . . . . . . . .
Kosaku Nitta

71

7

Metabolic Acidosis and Chronic Kidney Disease . . . . . . . . . . . .
Richard M. Treger and Jeffrey A. Kraut

83

8

Acute Kidney Injury in Chronic Kidney Disease . . . . . . . . . . . .
Sharidan K. Parr and Edward D. Siew

93

9

Preventing Progression of Chronic Kidney Disease:
Diet and Lifestyle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Merlin C. Thomas

10

Preventing Progression of Chronic Kidney Disease:
Renin–Angiotensin–Aldosterone System Blockade
Beyond Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Merlin C. Thomas

113

123

ix


Contents

x

Part III

Chronic Kidney Disease and Cardiovascular Diseases

11

Chronic Kidney Disease and the Cardiovascular Connection. . . .
Peter A. McCullough and Mohammad Nasser

12

Screening and Diagnosing Cardiovascular Disease
in Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Peter A. McCullough and Mohammad Nasser

145

Management of Cardiovascular Disease
in Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Mohammad Nasser and Peter A. McCullough

157

13

14

Cerebrovascular Disease and Chronic Kidney Disease . . . . . .
Semih Giray and Zülfikar Arlier

Part IV

15

137

183

Chronic Kidney Disease Complications:
Assessment and Management

Anemia and Disorders of Hemostasis in Chronic
Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Joshua S. Hundert and Ajay K. Singh

205

16

Mineral and Bone Disorders in Chronic Kidney Disease. . . . .
Jorge B. Cannata-Andía, Natalia Carrillo-López,
Minerva Rodriguez-García, and José-Vicente Torregrosa

17

Protein–Energy Wasting and Nutritional Interventions
in Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
T. Alp Ikizler

241

Infectious Complications and Vaccination in Chronic
Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Vivek Kumar and Vivekanand Jha

255

18

223

19

Endocrine Disorders in Chronic Kidney Disease . . . . . . . . . . .
Marcin Adamczak and Andrzej Więcek

20

Liver and Gastrointestinal Tract Problems in Chronic
Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Michel Jadoul

279

Pruritus and Other Dermatological Problems in Chronic
Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Jenna Lester and Leslie Robinson-Bostom

287

21

22

Pain Management in Chronic Kidney Disease . . . . . . . . . . . . .
Edwina A. Brown and Sara N. Davison

23

Depression and Other Psychological Issues in Chronic
Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nishank Jain and S. Susan Hedayati

24

Sexual Dysfunction in Chronic Kidney Disease . . . . . . . . . . . .
Domenico Santoro, Ersilia Satta, and Guido Bellinghieri

267

297

305

319


Contents

xi

25

Sleep Disorders in Chronic Kidney Disease . . . . . . . . . . . . . . .
Rosa Maria De Santo

26

Neuropathy and Other Neurological Problems
in Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ria Arnold and Arun V. Krishnan

Part V

329

343

Chronic Kidney Disease: Special Conditions

27

Drug Prescription in Chronic Kidney Disease . . . . . . . . . . . . .
Jan T. Kielstein

355

28

Pregnancy and Chronic Kidney Disease . . . . . . . . . . . . . . . . . .
Sarah Winfield and John M. Davison

363

29

Surgery and Chronic Kidney Disease . . . . . . . . . . . . . . . . . . . .
Caroline West and Andrew Ferguson

381

30

Chronic Kidney Disease in the Elderly . . . . . . . . . . . . . . . . . . .
Kai Ming Chow and Philip Kam-tao Li

397

31

Chronic Kidney Disease and Cancer . . . . . . . . . . . . . . . . . . . . .
Vincent Launay-Vacher

407

32

Chronic Kidney Disease in the Intensive Care Unit . . . . . . . . .
Pedro Fidalgo and Sean M. Bagshaw

417

Part VI

33

34

35

36

37

Chronic Kidney Disease: Final Path to Renal
Replacement Therapy

Chronic Kidney Disease Management Programmes
and Patient Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Kevin Harris, Coral Graham, and Susan Sharman

441

Conservative/Palliative Treatment and End-of-Life

Care in Chronic Kidney Disease. . . . . . . . . . . . . . . . . . . . . . . . .
Jean L. Holley and Rebecca J. Schmidt

451

How to Prepare a Chronic Kidney Disease Patient
for Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Rahmi Yilmaz and Mustafa Arici

463

How to Prepare a Chronic Kidney Disease Patient
for Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ricardo Correa-Rotter and Juan C. Ramírez-Sandoval

475

Quality of Life in Chronic Kidney Disease . . . . . . . . . . . . . . . .
Rachael L. Morton and Angela C. Webster

487

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

501



Contributors

Marcin Adamczak, MD, PhD Department of Nephrology,
Endocrinology and Metabolic Diseases, Medical University of Silesia,
Katowice, Poland
Rajiv Agarwal, MD, FASN, FAHA, FASH Department of Medicine,
Indiana University School of Medicine, Indianapolis, IN, USA
Mustafa Arici, MD Department of Nephrology, Faculty of Medicine,
Hacettepe University, Ankara, Turkey
Zülfikar Arlier, MD Neurology Department, Baskent University
Medical Faculty, Adana Teaching and Research Hospital, Adana, Turkey
Ria Arnold, BS Department of Neurological Sciences,
Prince of Wales Hospital, Sydney, NSW, Australia
Sean M. Bagshaw, MD, MSc, FRCPC Department of Critical
Care Medicine, Faculty of Medicine and Dentistry, University of Alberta,
Clinical Sciences Building, Edmonton, AB, Canada
Guido Bellinghieri, MD Department Clinical and Experimental Medicine,
University of Messina, Messina, Italy
Edwina A. Brown, DM (Oxon), FRCP Imperial College Kidney and
Transplant Centre, Hammersmith Hospital, London, UK
Jorge B. Cannata-Andía, MD, PhD Bone and Mineral Research Unit,
Hospital Universitario Central de Asturias, Instituto Reina Sofía de
Investigación (REDinREN-ISCIII), Oviedo, Asturias, Spain
Natalia Carrillo-López, PhD Bone and Mineral Research Unit, Hospital
Universitario Central de Asturias, Instituto Reina Sofía de Investigación
(REDinREN-ISCIII), Postdoctoral Fellow Hospital Universitario Central de
Asturias, Oviedo, Asturias, Spain
Devasmita Choudhury, MD Department of Medicine,
University of Virginia, Salem VA Medical Center, Salem, VA, USA
Kai Ming Chow, MBChB, FRCP Division of Nephrology,
Department of Medicine and Therapeutics, Prince of Wales Hospital,
Chinese University of Hong Kong, Hong Kong, China

xiii


xiv

Ricardo Correa-Rotter, MD Department of Nephrology
and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y
Nutrición Salvador Zubirán, Mexico City, DF, Mexico
John M. Davison, MD, FRCPE, FRCOG Institute of Cellular Medicine,
Royal Victoria Infirmary and Newcastle University, Newcastle upon Tyne,
Tyne and Wear, UK
Sara N. Davison, MD, MSc Department of Medicine and Dentistry,
University of Alberta Hospital, Edmonton, AB, Canada
Rosa Maria De Santo Italian Institute for Philosophical Studies,
Naples, Italy
Garabed Eknoyan, MD Department of Medicine, Baylor College
of Medicine, Houston, TX, USA
Andrew Ferguson, MB, BCh, BAO, Med, FRCA, FFICM Department
of Anaesthetics, Craigavon Area Hospital, Portadown, Co. Armagh, UK
Pedro Fidalgo, MD Division of Critical Care Medicine,
Faculty of Medicine and Dentistry, University of Alberta, Clinical Sciences
Building, Edmonton, AB, Canada
Semih Giray, MD Neurology Department, Baskent University Medical
FacultyAdana Teaching and Research Hospital, Adana, Turkey
Coral Graham, MSc School of Nursing and Midwifery, De Montfort
University, Leicester, UK
Kevin Harris, MD, MB, BS, FRCP John Walls Renal Unit,
Leicester General Hospital, University Hospitals of Leicester,
Leicester, UK

S. Susan Hedayati, MD, MHSc Division of Nephrology, Department
of Internal Medicine, University of Texas Southwestern Medical Center
and Veterans Affairs North Texas Health Care System, Dallas, TX, USA
Jean L. Holley, MD Department of Internal Medicine and Nephrology,
University of Illinois, Urbana-Champaign and Carle Physician Group,
Urbana, IL, USA
Joshua S. Hundert, MD Renal Division, Department of Medicine,
Brigham and Women’s Hospital, Boston, MA, USA
T. Alp Ikizler, MD Division of Nephrology, Department of Medicine,
Vanderbilt University School of Medicine, Nashville, TN, USA
Michel Jadoul, MD Department of Nephrology, Cliniques Universitaires
Saint-Luc, Université catholique de Louvain, Brussels, Belgium
Nishank Jain, MD, MPH Division of Nephrology,
Department of Internal Medicine, University of Texas Southwestern
Medical, Dallas, TX, USA

Contributors


Contributors

xv

Vivekanand Jha, MD, DM, FRCP Department of Nephrology,
Postgraduate Institute of Medical Education and Research,
Chandigarh, India
Jan T. Kielstein, MD Department of Nephrology and Hypertension,
Hannover Medical School, Hannover, Germany
Jeffrey A. Kraut, MD Division of Nephrology,
VHAGLA Healthcare System, Los Angeles, CA, USA

UCLA Membrane Biology Laboratory, David Geffen UCLA School
of Medicine, Los Angeles, CA, USA
Arun V. Krishnan, MBBS, PhD, FRACP Department of Neurology,
Prince of Wales Hospital, Sydney, NSW, Australia
Vivek Kumar, MBBS, MD, DM Department of Nephrology,
Postgraduate Institute of Medical Education and Research,
Chandigarh, India
Vincent Launay-Vacher, PharmD Service ICAR – Department
of Nephrology, Pitié-Salpetrière University Hospital, Paris, France
Jenna Lester, BA Department of Dermatology, Warren Alpert Medical
School of Brown University, Providence, RI, USA
Moshe Levi, MD Department of Internal Medicine/Division of Renal
Diseases and Hypertension, University of Colorado Denver AMC, Aurora,
CO, USA
Philip Kam-tao Li, MD, FRCP, FACP Department of Medicine and
Therapeutics, Princes of Wales Hospital, Chinese University of Hong Kong,
Hong Kong, China
Peter Marckmann, MD, DMSc Department of Nephrology,
Roskilde Hospital, Roskilde, Denmark
Peter A. McCullough, MD, MPH Department of Cardiovascular
Medicine, Baylor Heart and Vascular Institute, Baylor University Medical
Center, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas,
TX, USA
The Heart Hospital, Plano
Rachael L. Morton, MScMed(Clin Epi)(Hons), PhD Sydney School
of Public Health, University of Sydney, Sydney, NSW, Australia
Nuffield Department of Population Health, Health Economics
Research Centre, University of Oxford, Headington, Oxfordshire, UK
Mohammad Nasser, MD Department of Internal Medicine,
Providence Hospitals and Medical Centers, Southfield, MI, USA

Yousef W. Nielsen, MD, PhD Department of Diagnostic Radiology,
Copenhagen University Hospital, Herlev, Denmark
Kosaku Nitta, MD, PhD Department of Medicine, Kidney Center,
Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan


xvi

Sharidan K. Parr, MD Division of Nephrology and Hypertension,
Department of Medicine, Vanderbilt University Medical Center, Nashville,
TN, USA
Rajeev Raghavan, BS, MD Department of Medicine, Department
of Medicine, Baylor College of Medicine, Houston, TX, USA
Juan C. Ramírez-Sandoval, MD Department of Nephrology and Mineral
Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador
Zubirán, Mexico City, DF, Mexico
Stephanie Riggen, MD Department of Medicine, Indiana University
School of Medicine, Indianapolis, IN, USA
Leslie Robinson-Bostom, MD Division of Dermatopathology,
Warren Alpert Medical School of Brown University, Providence, RI, USA
Department of Dermatology, Rhode Island Hospital, Providence, RI, USA
Minerva Rodríguez-García, MD, PhD Department of Nephrology,
Hospital Universitario Central de Asturias REDinREN, Oviedo, Spain
Domenico Santoro, MD Department Clinical and Experimental Medicine,
University of Messina, Messina, Italy
Ersilia Satta, MD Department Clinical and Experimental Medicine,
University of Messina, Messina, Italy
Rebecca J. Schmidt, DO Department of Medicine, Nephrology Section,
West Virginia University School of Medicine, Morgantown, WV, USA
Susan Sharman, DiPHE, BA John Walls Renal Unit – Renal

Community Team, Leicester General Hospital, Leicester, UK
Edward D. Siew, MD, MSCI Division of Nephrology and Hypertension,
Department of Medicine, Vanderbilt University Medical Center, Nashville,
TN, USA
Ajay K. Singh, MBBS, MBA Renal Division, Brigham and Women’s
Hospital, Boston, MA, USA
Merlin C. Thomas, MBChB, PhD, FRACP Department of Biochemistry
of Diabetes Complications, Baker IDI Heart and Diabetes Institute,
Melbourne, VIC, Australia
Henrik S. Thomsen, MD, DMSc Department of Diagnostic Radiology,
Copenhagen University Hospital, Herlev, Denmark
Faculty of Medical and Health Sciences, University of Copenhagen,
Copenhagen, Denmark
José-Vicente Torregrosa, MD Department of Nephrology and Renal
Transplant, Hospital Clinic REDinREN, University of Barcelona,
Barcelona, Spain

Contributors


Contributors

xvii

Richard M. Treger, MD Division of Nephrology, Department of Internal
Medicine, VHAGLA Healthcare System, Los Angeles, CA, USA
David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
Meryem Tuncel Kara, MD Department of Internal Medicine,
University of Connecticut School of Medicine/John Dempsey Hospital,
Internal Medicine/Calhoun Cardiology Center, University of Connecticut

Health Center, Farmington, CT, USA
Angela C. Webster, MBBS MM (Clin Epid) PhD Sydney School
of Public Health, University of Sydney, Sydney, NSW, Australia
Centre for Transplant and Renal Research, Westmead Hospital, Sydney,
NSW, Australia
Caroline West, MBChB, MRCP, FCARCSI Department of Anaethetics,
Craigavon Area Hospital, Portadown, Co.Armagh, UK
Andrzej Więcek, MD, PhD, FRCP (Edin), FERA Department
of Nephrology, Endocrinology and Metabolic Diseases,
Medical University of Silesia, Katowice, Poland
Sarah Winfield, MBBS, MRCOG Department of Obstetrics
and Gynaecology, Leeds Teaching Hospitals NHS Trust,
Leeds General Infirmary, Leeds, West Yorkshire, UK
Rahmi Yilmaz, MD Department of Nephrology,
Hacettepe University Hospital, Medical Faculty of Hacettepe University,
Ankara, Turkey


Part I
Chronic Kidney Disease: Basics and Clinical
Assessment


1

What Is Chronic Kidney Disease?
Rajeev Raghavan and Garabed Eknoyan

Before You Start: Facts You Need to Know

• Chronic kidney disease (CKD) is defined
as having abnormalities of kidney structure
or function for at least 3 months with
implications for the health of the
individual.
• CKD is classified based on cause (C), GFR
category (G; G1 to G5), and albuminuria
(A; A1 to A3).
• CKD is common (1 in 10 adults, 500 million persons worldwide), harmful, treatable, and a major public health problem
worldwide.

1.1

Introduction

Diseases of the kidney have afflicted humans
from time immemorial. Medical interest in the
detection and treatment of kidney disease can be
traced to antiquity, but all past efforts have been

R. Raghavan, BS, MD (*)
Division of Nephrology, Department of Medicine,
Baylor College of Medicine,
1709 Dryden ST, Ste 900, Houston, TX 77030, USA
e-mail:
G. Eknoyan, MD
Department of Medicine, Baylor College of Medicine,
One Baylor Plaza, Houston, TX 77030, USA
e-mail:

• CKD is easily diagnosed from urinalysis
and the estimated GFR (eGFR) calculated
from serum creatinine.
• There is a strong graded and consistent
relationship between the severity of the
two hallmarks of CKD: reduced eGFR and
increased albuminuria.
• CKD is more common in the elderly, males,
and individuals of African or Latino descent.
• Detection of CKD is best accomplished
with serial measurements of blood pressure,
serum creatinine, and urinalysis in select
populations at a higher risk of disease.

fragmentary and almost entirely focused on its
symptomatic manifestations as a change in urine
color (hematuria) and flow (obstruction) or pain
due to stones or obstruction. It is only in the past
decade that the actual burden of kidney disease
has been documented and identified as a global
public health problem [1, 2].
The traditional lineage of detecting and defining kidney disease is traced to Richard Bright
(1789–1858), who in 1827 described the autopsy
findings of the kidneys in 24 albuminuric, dropsical patients who had died of kidney failure.
Bright considered his disease an inflammatrory
lesion (nephritis) that was rather rare as reflected
in his statement that “Inflammation of one or
both kidneys, as a primary idiopathic disease, is

M. Arici (ed.), Management of Chronic Kidney Disease,

DOI 10.1007/978-3-642-54637-2_1, © Springer-Verlag Berlin Heidelberg 2014

3


R. Raghavan and G. Eknoyan

4

less frequently met than most other forms of
phlegmasiae.” In his textbook on the practice
of medicine published in 1839, he devotes most
of the discussion of nephritis to calculous or
obstructive diseases rather than the rare disease
he had identified. In the century that followed,
the acute and chronic forms of Bright’s disease
were defined, their diagnosis from urinalysis was
refined, and their microscopic renal lesions were
described; but its therapy remained symptomatic
and outcome fatal much as it had been in 1827
when Bright described his eponymous disease. It
was the conceptual and technical advances in
medicine during and after the Second World War
that were to change it all, most notably that of the
introduction of the artificial kidney that was to
transform the fatal disease of Bright into a treatable one, a milestone achievement that catapulted
the growth of nephrology in the closing decades
of the past century [1].
Ironically, it was the treatment of Bright’s endstage renal disease (ESRD) with dialysis that
focused attention on the broader and more serious

issue of chronic kidney disease (CKD). Dialysis
started as an exploratory effort to sustain the life
of acute renal failure patients in the years that followed the Second World War; it evolved in the
1970s into a lifesaving therapy for patients whose
CKD had progressed to kidney failure necessitating renal replacement therapy (RRT) with dialysis. For most of the years thereafter, the problem
of kidney disease came to be viewed in the context of ESRD, which affects about 0.1 % of the
population. As administrative data from national
dialysis registries accrued in the 1980s, it became
evident that the care of patients with ESRD should
have been started well before they presented for
dialysis having sustained already the ravaging
consequences of progressive loss of kidney function. It was this concern that at the turn of the century prompted the first efforts at the definition,
classification, and evaluation of CKD [1, 2].

1.2

Definition of CKD

In 2002, the Kidney Disease Outcomes Quality
Initiative (KDOQI) developed guidelines for a
working definition of CKD, independent of the

cause of the disease, based on the presence of
either kidney damage (proteinuria, abnormal kidney biopsy, or imaging studies) or a glomerular
filtration rate (GFR) of less than 60 ml/
min/1.73 m2 for more than 3 months [3]. The
guidelines also proposed a classification of CKD
based on severity determined by the level of kidney function calculated from the serum creatinine and expressed as the estimated GFR (eGFR).
They proposed the classification of CKD into 5
stages: with stages 1 and 2 as covert disease

requiring the presence of kidney damage (proteinuria, abnormal urinalysis, biopsy, or imaging
studies) and stages 3, 4, and 5 as overt diseases
(i.e., when the eGFR was less than 60 ml/
min/1.73 m2) with eGFR of 30–59, 29–15, and
<15 ml/min/1.73 m2, respectively. The conceptual model of CKD used in proposing this classification is shown in Fig. 1.1. The five stages of
CKD classification do not appear in this cartoon.
Rather, stages 1 and 2 are grouped together and
implicitly represented in the ellipse-labeled
“injury” and flagged for albuminuria and stages 3
and 4 in the ellipse-labeled “decreased GFR” and
flagged <60 ml/min/1.73 m2. These guidelines
were a major step forward in the evolution of our
understanding of kidney disease as they provided
a uniform definition of CKD that replaced the
inchoate, ambiguous, and descriptive terms that
had been used theretofore such as pre-end-stage
renal disease, pre-dialysis, renal insufficiency,
azotemia, uremia, and chronic renal failure. The
proposed common terminology of CKD and its
standardized classification provided new tools
whereby kidney disease could be explored and
the results compared across different studies,
regions, and countries.
Methodological issues associated with the initial definition of CKD were addressed in the following years and to some extent resolved. Serum
creatinine measurements have now been standardized, the equation to calculate eGFR refined,
and many clinical laboratories have integrated
the reporting of eGFR in their laboratory results.
Recently, the cystatin C level has been added to
that of creatinine and integrated in the formula
used to calculate the eGFR. This new CKD-EPI

equation based on serum creatinine alone is more
reliable in predicting the morbidity and mortality


1

What Is Chronic Kidney Disease?

5

CKD complications

Normal

Increased
risk

Albuminuria

<60 ml/min/1.73 m2

Injury

Decreased
GFR

Kidney
failure

Death

Co-morbidity
complications

Fig. 1.1 A conceptual model of the course, complications,
and outcomes of chronic kidney disease. The ellipses represent the progressive stages and consequences of progressive chronic kidney disease (CKD). The first two ellipses
are antecedent stages representing cohorts at increased risk
of developing CKD. The next two ellipses are flagged for
the two hallmarks used in the definition and staging of
CKD: albuminuria (stages 1 and 2) and a glomerular filtration rate of <60 ml/min/1.73 m2 (stages 3 and 4). The gradually increasing thickness of the arrows connecting the
ellipses reflects the increasing risk of progressing from one
stage to the next stage of CKD as the disease progresses.

The dotted arrows connecting the ellipses indicate the
potential for improvement from one stage to its preceding
stage due to treatment or variable natural history of the
primary kidney disease. The rectangle at the top indicates
the complications of CKD (anemia, mineral and bone disorders, hypertension, hyperparathyroidism). The rectangle
at the bottom indicates the risk multiplier effect of CKD of
coexistent comorbidities, principally that of cardiovascular
disease. The gradually increasing thickness of the arrows
connecting the ellipses to the upper and lower rectangle
represents the increased risk of the complications as the
CKD progresses from one stage to the next

outcomes of CKD [4] and is further improved
when the serum cystatin level is incorporated in
the equation [5]. The standardization and reporting of urinary albumin measurements are under
active investigation but remain to be refined.
In defining CKD as kidney damage for at least

3 months, the guidelines also set the stage for the
identification of another form of kidney disease,
the potentially reversible form of acute kidney
injury (AKI) of less than 3 months duration that
is now the subject of its own guideline. A discussion of AKI is beyond the scope of this chapter,
but familiarity with its guideline is essential for
the care of CKD patients who are the subjects
most susceptible to AKI and sustain its poorest
outcomes of morbidity, mortality, the additional
loss of residual kidney function, and accelerated
progression to ESRD [6].
Importantly, based on available evidence then,
the KDOQI guidelines documented the increased
number of systemic complications (anemia,
hypertension, mineral and bone disorders), morbidity, and mortality associated with declining

eGFR and described the greater risk of death of
CKD patients from cardiovascular disease than
from their progression to kidney failure and
ESRD [3, 4]. During the decade that followed the
issue of these guidelines, epidemiologic data has
validated, refined, and provided convincing
evidence that CKD is common, harmful, treatable, and a major public health problem worldwide [7, 8]. CKD is definitely much more
common than had been appreciated theretofore.
The prevalence of CKD is over 10 % of the general population and increases in high-risk populations (diabetic, hypertensive, obese, elderly),
some ethnic groups (Latin Americans, African
Americans, Pima Indians), and those with predisposing genetic composition. Importantly, there is
now persuasive evidence that the presence and
severity of CKD adversely affects the outcome of
not only cardiovascular disease but also other

prevalent diseases such as that of diabetes, hypertension, and obesity [9]. The reciprocity of these
major chronic diseases is shown in Fig. 1.2, in
which the overall interaction of chronic diseases


R. Raghavan and G. Eknoyan

6

Hypertension

Cardiac

Diabetes

CKD
Cerebrovascular

Obesity

Metabolic
syndrome

Fig. 1.2 The cluster of comorbidities associated with and
aggravated by chronic kidney disease (CKD). Where there
is clinical intersection of the circle representing a given
comorbidity with that of CKD, the presence of CKD
emerges as a risk multiplier of the outcome of that disease,
and conversely the severity and course of CKD are aggravated by that of the disorder with which it overlaps. In
areas where there is overlap of more than one circle, the

risks are further magnified

can be viewed as an overlap phenomenon
whereby the presence of CKD emerges as a risk
multiplier of the morbidity and mortality of the
other major chronic diseases. The risk of each
disease increases in the areas of their overlap
with CKD, and the magnitude of this detrimental
effect is related to the severity of CKD [9, 10].
Thus, both detection of CKD in these conditions
and evaluation of the severity of CKD are essential to appropriately estimate its impact on
outcomes.

1.3

Staging of CKD

By any criteria, the paradigm shift created by the
2002 KDOQI guidelines for the definition and
the classification of CKD is a milestone in the
evolution of nephrology, but was not without its
limitations. Despite the effort that went into
developing the evidence base of the proposed

classification, a major limiting factor was the
quality and quantity of evidence then available.
Fortunately, one of the most fruitful derivatives
of that initial step forward has been the stimulus
it provided for new research and hence the subsequent incremental accrual of new evidence for
their support as well as their refinement. Apart

from information on the epidemiology and outcomes of CKD, the new evidence revealed a
strong, graded, and consistent relationship
between the severity of the two hallmarks of
CKD: reduced eGFR and increased albuminuria
[10]. As a result, the Kidney Disease Improving
Global Outcomes (KDIGO) released a new
guideline for the staging of CKD that integrates
albuminuria as a determinant of severity of the
disease. The new guideline refines the definition
of CKD as abnormalities of kidney structure or
function, present for >3 months, with implications for health of the individual, and classifies
CKD based on cause (C), GFR (G), and albuminuria (A) category (CGA) [11]. The classification
of CKD by the level of eGFR and albuminuria
(the GA of CGA) and their impact on prognosis
is shown in Fig. 1.3. That of the cause (C) is
based on the presence and absence of systemic
diseases and the location of the disease within the
kidney (glomerulus, tubule, vasculature, cystic,
or genetic). The principal systemic diseases that
overlap with CKD and are affected by and in turn
affect the severity of CKD are shown in Fig. 1.2.
The importance of considering the cause (the
C of CGA) of CKD, now part of the new definition, is highlighted in the conceptual model of
CKD shown in Fig. 1.1. The dotted arrows in the
figure reflect the potential for reversibility at each
stage of CKD. This improvement may be part of
the natural course of the cause of some diseases
but is also and to a greater extent the result of
detection and proper treatment of individual
cases. Thus, a patient with malignant hypertension who presents in ESRD requiring dialysis can

recover sufficient kidney function after control of
the blood pressure to cease requiring maintenance
dialysis and revert to a stage 3 or 4 CKD patient.
Similarly, a patient with congestive cardiomyopathy, who requires dialysis at presentation in


1

What Is Chronic Kidney Disease?

7

Persistent albuminuria categories
description and range

GFR categories (ml/min/ 1.73 m2)
Description and range

Prognosis of CKD by GFR
and albuminuria categories:
KDIGO 2012

A1

A2

A3

Normal to
mildly

increased

Moderately
increased

Severely
increased

<30mg/g
<3mg/mmol

30−300mg/g
3−30mg/mmol

>300mg/g
>30mg/mmol

≥90

G1

Normal or high

G2

Mildly decreased

60−89

G3a

Mildly to mederately
decreased

45−59

G3b

Mederately to
severely decreased

30−44

G4

severely decreased

15−29

G5

Kidney failure

<15

Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately incresed risk;
Orange: high risk; Red, very high risk.

Fig. 1.3 Staging and prognosis of chronic kidney disease (CKD) by glomerular filtration rate and albuminuria
(Reproduced with permission from Kidney Disease: Improving Global Outcomes (KDIGO) [11])

ESRD, can recover sufficient kidney function following treatment of the heart failure to perfuse the
kidneys well enough to move to an earlier stage of
CKD. The same argument can be made for all
CKD patients whose kidney function is aggravated by poor management of the comorbid conditions with which it overlaps (Fig. 1.2). By the
same token, improvement of kidney function with
regression to an earlier stage can be achieved by
the proper therapy (steroids, immunosuppression)
of the cause of the kidney disease in selected
cases (lupus nephritis, IgA nephropathy, etc.) or
the reduction of the magnitude of their albuminuria with angiotensin-converting enzyme inhibitors (ACEIs) and antihypertensive agents. In those
whose CKD continues to progress, their outcomes
can be improved by preventing the complications

of continued loss of kidney function (anemia,
mineral and bone disorders) to forestall the otherwise serious systemic ravages of CKD. This
underscores the vital importance of detecting kidney disease in its earliest stages before the onset
of serious and irreversible complications.
Whereas albuminuria is used in the grading of
CKD, the evaluation of the individual patient
with CKD should include all abnormalities
detected on urinalysis that are usually equally
important in diagnosis and affect CKD outcomes,
especially that of hematuria. As with its predecessor, the new 2012 KDIGO staging is not an
end but a beginning for the accrual of new information that could further refine the definition and
grading of CKD in future iterations of the
guideline.


R. Raghavan and G. Eknoyan

8

1.4

Epidemiology of CKD

The recognition of the global burden of CKD
prompted by the epidemiologic studies launched
after the definition and stratification of CKD in
2002 is attributable to several factors, notable
among which are (1) the facility of diagnosing
CKD from albuminuria and the eGFR calculated
from a serum creatinine measurement; (2) substantial epidemiologic data indicating that overt
kidney disease (stages 3–5) is the tip of an iceberg
of covert disease (stages 1 and 2); (3) the near
exponential increase in the prevalence of two
major causes of kidney disease, diabetes, and obesity (Fig. 1.2); (4) attempts to control the cost and
improve the outcomes of renal replacement therapy of ESRD by the early detection of overt CKD
for the amelioration of its course and prevention
or treatment of its complications; (5) compelling
evidence of the major role of CKD in increasing
the risk of cardiovascular disease as well as that of
other chronic diseases that has prompted active
interest in the detection of CKD by non-nephrologists; and (6) the availability of effective measures
to prevent the progression of CKD, reduce its
complications, and ameliorate its outcomes
(Fig. 1.1). While these factors render control of
CKD an achievable goal of healthcare planning in
the developed world, the problems they delineate

in the developing world are challenging and
remain to be adequately addressed.
Aggregate estimates suggest that CKD affects
as many as 1 in 10 adults (10 %) or over 500 million people worldwide [8]. However, concrete
data regarding the true incidence and prevalence
of CKD is hampered by the paucity of proper
record keeping and national renal registries, particularly in poorer countries (Table 1.1). In 2010,
approximately 13.1 % of US adults age 20 or
older, or 70,000 per million persons, had CKD –
defined as an estimated GFR less than 60 ml/
min/1.73 m2 or a urine albumin-to-creatinine
ratio (ACR) of ≥30 mg/g [12]. Because of the
high mortality from cardiovascular disease in
patients with CKD, for every patient who progresses to end-stage renal disease (ESRD), there
are more than 200 with overt chronic kidney
disease (stage 3 or 4) and almost 5,000 with
covert disease (stage 1 or 2) who succumb to

Table 1.1 Prevalence of CKD and ESRD in different
parts of the world

Global
estimates
Europe
United
Kingdom
Germany
Spain
Russia
Italy

Turkey
Australia
North America
Canada
United
States
Mexico
Asia
India
Japan
China
South America
Brazil
Africa
Nigeria

Prevalence of CKD
(percentage per
adult population)
10 %

Prevalence rate of
ESRD (number of
adults per million)
400

9%

659

5.4 %
5.1 %
N/A
6.4 %
15.7 %
11 %

1,020
991
130
755
756
778

9.5 %
13 %

1,007
1,641

8.1 %

929

N/A
10 %
10.8 %

15
1,956

150

N/A

520

1.6–12 %

N/A

All reported data was collected and published between
2005 and 2012. The definition of CKD includes persons
with estimated glomerular filtration rate (eGFR <60 ml/
min/1.73 m2) or albuminuria. Prevalence rate of ESRD is
defined as the number of persons sustained on dialysis

cardiovascular disease without ever progressing
to ESRD [8, 11, 12]. Those who progress to
ESRD present a challenge of their own. Nearly
two million people in the world have ESRD and
receive maintenance dialysis [3, 8]. The average
worldwide incidence of ESRD is estimated at
150 per million persons [8]. In the United States,
this number is 350 per million persons. Both the
incidence and prevalence of ESRD are higher in
developed countries, driven largely by healthcare
agenda for its treatment (availability of dialysis
and transplantation) [12]. Hence, it is not surprising that most of the world’s dialysis patients are
located in high-income countries, with 52 % of
the patients residing in just four countries: the

United States, Japan, Brazil, and Germany, which