Evidence-Based Nephrology


John Wiley & Sons

Copyright © 2009 Blackwell Publishing
All right reserved.

ISBN: 978-1-4051-3975-5


Chapter One

Epidemiology of Chronic Kidney Disease

William M. McClellan & Friedrich K. Port

Introduction

End-stage renal disease (ESRD) is defined by the cessation of effective kidney function and the substitution of renal replacement therapy (RRT), such as hemodialysis, peritoneal dialysis, or kidney transplantation, for native kidney function to sustain life. During the last 3 decades, an epidemic of ESRD has occurred in both industrialized and developing countries. The epidemic increase in ESRD was initially attributed to the dissemination and adoption of RRT with the attendant extension of productive life. Although there is evidence that the rate of increase in ESRD incidence has abated in the USA, continuing increases in ESRD incidence rates after access to RRT becomes available to an entire population of a particular country have been documented by registries throughout the world.

The public health impact of the epidemic of ESRD is substantial. In the USA, it is estimated that the lifetime risk of being treated for ESRD is 2.5% for white men, 1.8% for white women, 7.3% for blackmen, and 7.8% for black women. Life expectancy among individuals treated for ESRD is substantially shortened, and treatment is punctuated by frequent hospitalizations and progressive disability. The economic costs of the epidemic are substantial as well, and the per-patient cost of care can exceed by severalfold the costs incurred by age-, gender-, and ethnicity-matched individuals in the general population. Furthermore, these costs only partially capture the full economic burden of ESRD, which includes the costs of chronic disability, premature mortality, and diminished quality of life.

Given the population cost burden of this epidemic of ESRD, it is increasingly recognized that strategies must be designed to increase the early detection and care of the antecedent diseases that contribute to this epidemic of end-organ failure. There are multiple causes of kidney injury that result in ESRD, and the evidence-based diagnosis and management of these conditions are discussed in detail in subsequent chapters of this textbook. Common to each, however, is a continuum of progressive decline in kidney function that leads to a syndrome of chronic kidney disease (CKD), which is characterized by hypertension, anemia, renal/metabolic bone disease, nutritional impairment, neuropathy, impaired quality of life, and reduced life expectancy and which culminates in ESRD. The purpose of this chapter is to describe the definition of CKD and the measurement of the population-based health burden of CKD across the continuum of disease, from mild impairment to ESRD, as an essential foundation for the evidence-based management of kidney disease. Problems inherent in using biomarkers and prediction equations to define kidney function and detect CKD are discussed in chapter 2. The epidemiology of CKDis discussed in chapter 4, and risk factors associatedwith progressive loss of kidney function can befoundin chapter3. Chapter2 examines howsurveillance systems have been used to measure and improve the care of patients receiving RRT.

Definition of chronic kidney disease

CKD can be defined as the persistence for 3 or more months of structural and/or functional abnormalities of the kidney. This definition replaces previous case definitions that described variable degrees of impaired kidney function. The rationale for adopting a uniform case definition of CKD includes the need for 1) improved comparability across observational and clinical studies, 2) an improved capability for uniform comparisons of kidney disease incidence and prevalence, and 3) improved communications about diagnosis and treatment of kidney disease. The most important anticipated benefit of a common terminology is more effective communication with patients and the public.

The "structural" abnormalities used to define CKD are 1) microalbuminuria or overt proteinuria; 2) an abnormal urinary sediment as evidenced by the presence of red blood cells (RBCs), RBC casts, white blood cells (WBCs), WBC casts, tubular cells, cellular casts, granular casts, oval fat bodies, fatty casts, or free fat; and 3) abnormal findings on imaging tests, including ultrasound, intravenous pyelogram, computer tomography, magnetic resonance imaging, and nuclear scans. Overt proteinuria is defined as an increased urinary concentration of albumin and other proteins detected by routine laboratory measures (e.g. urine dipstick test for protein), and microalbuminuria is an increased albumin excretion that can be detected only by laboratory methods more sensitive than the standard protein assay that uses the urine dipstick.

The functional component of the definition of CKD uses creatinine-based estimates of clearance derived from the Modification of Diet in Renal Disease (MDRD) glomerular filtration rate (GFR) estimating equation or the Cockcroft-Gault creatinine clearance equation. The derivation and use of these multivariate prediction equations are discussed in chapter 5. At present, no single method of GFR estimation is strongly recommended. Clinicians should choose a method that is appropriate for their population to determine the estimated GFR (eGFR) and assign a stage of kidney disease, always cognizant that failing to account for the modification of the complex association between serum creatinine and GFR by age, gender, and race is likely to lead to misclassification of kidney function and attendant errors in clinical decision making.

The available estimating equations are imprecise at higher levels of GFR, and there is great interest in revising them or identifying better filtration markers that will improve our ability to measure kidney function across the continuum of kidney performance from normal to ESRD. The inherent imprecision of all methods of estimating GFR led to the decision to rank the degree of impaired kidney function into more global stages (levels) by the eGFR in the following manner:

Stage 1: eGFR>90 mL/min/1.73 [m.sup.2] (with structural abnormalities)

Stage 2: 60-90 mL/min/1.73 [m.sup.2] (with structural abnormalities)

Stage 3: 30-59 mL/min/1.73 [m.sup.2]

Stage 4: 15-29 mL/min/1.73 [m.sup.2]

Stage 5: <15 mL/min/1.73 [m.sup.2]

In addition to these eGFR ranges, the persistence of structural abnormalities for at least 3 months is necessary to assigning CKD stages 1 and 2, and stages 3-5 of CKD are defined by persistent impairments for greater than 3 months in the eGFR alone.

This staging algorithm is illustrated by using data from the US population aged 20 years and older (Table 1.1). The prevalence of CKD based on eGFR and presence and degree of proteinuria CKD is estimated to be 11% of the US population. Over 50% of the prevalent disease is due to the presence of proteinuria among individuals with stage 1 (3.3%) and stage 2 (3.0%) CKD, and this proteinuria is largely due to microalbuminuria. Among individuals with stages 3-5 CKD, which are defined by eGFR alone, 85% of individuals have stage 3 disease (4.3%).

Kidney disease: improving global outcomes

The definition of CKD was reviewed at the 2004 "Kidney Disease: Improving Global Outcomes (KDIGO)" Controversies Conference. Two further modifications were proposed to better adapt the staging algorithm for international use: 1) clinical judgment should be used to decide the relevance of nonproteinuric markers of kidney damage prior to diagnosing CKD in individuals without either proteinuria or reduced GFR; 2) individuals with a transplanted kidney should be considered as having CKD irrespective of other structural or functional markers. The KDIGO modified the CKD risk stratification by adding the letter T to denote CKD in a transplanted kidney and recommended that stage 5 CKD be modified by the letter D to denote RRT by dialysis.

International Classification of Diseases and kidney diseases

The International Classification of Diseases (ICD) classifies each condition that has given rise to the chain of events leading to death (underlying cause of death) as recorded on death certificates. The ICD is used by national vital statistics registries. At present, it provides the only uniform population-based case definition for international comparisons of the burden of disease attributable to earlier stages ofCKDand, as such, is an important actuarial tool in defining the health burden of CKD across populations and, with certain limitations described below, temporally. The Ninth Revision of the ICD (ICD-9), used between January 1, 1979 and December 31, 1998, was replaced by ICD-10 on January 1, 1999.

Revisions of the ICD reflect the evolution of disease classification and emergence of new diseases, and they resolve administrative issues that have stemmed from a particular version of the codes. Clinicians should be aware that ICD revisions often introduce changes in the classification of an underlying cause of death. Comparisons of death rates due to specific causes, such as kidney disease, across different ICD revisions can be facilitated by using comparability ratios that relate rates from different time periods. The comparability ratio relating rate computed from ICD-9 (ICD-9 codes 580-589) and ICD-10 (ICD-10 codes N00-N07, N17-N19, and N25-N27) data is estimated to be 1.23, indicating that the new ICD-10 coding will result in a 23% increase in classification of deaths due to kidney disease compared with the ICD-9 codes. This version-to-version difference is due, in part, to a change in the classification of ESRD from an unspecified disorder of the kidney in ICD-9 to ESRD (N18.0), a subcategory of kidney failure (N17-N19) in ICD-10.

Secular trends in kidney disease as an underlying cause of death need to be interpreted with these changes in mind. This can be illustrated by trends in kidney disease as a cause of death in the USA (Figure 1.1), which declined between 1958 and 1978 and then increased substantially until the end of the century. The transition fromICD-9 to ICD-10 in 1998 is represented by the discontinuity in the trend line for deaths due to nephritis, nephrotic syndrome, and nephrosis.

The Clinical Modification of ICD-9 (ICD-9-CM) is used administratively in the USA and was modified in 2005 to reflect the new nomenclature for CKD. ICD-9-CM code 585, "Chronic renal failure," was dropped, and seven new four-digit codes were introduced to code for the presenceofCKD. Thesenewcodes reflect the National Kidney Foundation (NKF) CKD staging definitions:

585.1: Chronic kidney disease, stage 1

585.2: Chronic kidney disease, stage 2 (mild)

585.3: Chronic kidney disease, stage 3 (moderate)

585.4: Chronic kidney disease, stage 4 (severe)

585.5: Chronic kidney disease, stage 5

585.6: End-stage renal disease

585.9: Chronic kidney disease, unspecified

Furthermore, in 2006, the ICD-9-CM nomenclature for codes 403 and 404, denoting kidney complications of hypertension, were changed from "renal disease" to "kidney disease" and from "renal failure" to "chronic kidney disease." A revision of the clinical modification of ICD-9 to reflect the ICD-10 coding conventions is currently being developed.

The standardized ICD nomenclature provides some uniformity of data that allows descriptions of population-to-population differences in death rates attributed to kidney disease. This standard nomenclature stands in contrast to the information reported by national ESRD registries that collect and report information on the occurrence of stage 5D CKD (see chapter 2). A report by Maison-neuve et al. found substantial variability in the definition and classification of primary causes of ESRD throughout the world. Comparisons of the burden of CKD based on ICD-related mortality statistics also avoid the skewing of prevalence rates based on ESRD rates that would be introduced by the variable coverage of ESRD registries in economically developing countries.

The use of international comparisons of kidney disease burden can be illustrated by considering the proportionate mortality attributed to kidney disease throughout the world. Kidney disease is the 9th leading cause of death in the USA and the 12th leading cause of death worldwide. The burden of mortality due to kidney disease in different world regions was recently reported by the Global Burden of Disease Report. Age- and gender-adjusted proportionate death rates for genito-urinary diseases, which include nephritis and nephrosis, benign prostatic hypertrophy, and other genito-urinary system diseases, vary from less than half of to 50% greater than those observed in high-income regions of the world (Figure 1.2).

There are multiple potential explanations for this region-to-region variability in the overall mortality burden due to kidney disease. Regional differences in the prevalence of risk factors for kidney injury and progressive loss of kidney function, access to health care, detection and treatment of kidney disease, and diagnostic convention could contribute to the observed variability. The main point of international comparisons is that a better understanding of the source of variation is essential for better control of CKD and its risk factors through public health measures and may lead to important generalizable insights into the reasons for the occurrence and progression of CKD.

Functional and etiologic diagnoses for CKD

CKD is a nonspecific diagnosis that describes the presence and degree of structural and functional abnormalities of the kidney. CKD does not identify the cause for the injury and/or impaired kidney function. Thus, the stage of CKD is an incomplete clinical description of the underlying disease process, and identification of CKD should also lead to a clinical diagnosis that includes a cause (etiology) for the kidney disease and the stage of CKD. For example, a diagnosis for CKD might be stated as "stage 3 CKD due to diabetes," "immunoglobulin A nephropathy with stage 4 CKD," or "stage 2 CKD of unknown etiology."

At present, the best estimates for the relative contributions of specific etiologies to the total burden of CKD within populations are derived from the proportionate, cause-specific incidence of ESRD within a population (see below). These estimates, however, have a number of limitations. Most important is the possibility that variations in survival and progression to stage 5 CKD among individuals with kidney disease due to different causes might alter the patterns of disease and the proportionate health burden over the course of CKD. It is also likely that there are substantial regional and ethnic variations within and between groups with respect to specific causes of initial kidney injury. It is likely that many individuals with prevalent kidney disease will have a number of competing risk factors associated with the initiation and progression of kidney disease, and the precise temporal relationship between these and the etiology of the initial kidney injury remains obscure. Finally, systematic studies to estimate the risk of kidney injury among individuals with less common forms of stage 5 CKD remain to be conducted.

Prognostic importance of the stage of CKD

As discussed in chapter 2, the classification of CKD using the NKF stages provides substantial prognostic and diagnostic information concerning 1) outcomes (progression to ESRD and mortality) and 2) ocurrence of intercurrent morbidity (ischemic heart disease, stroke, and peripheral vascular disease). Further, the stage of CKD is predictive of the prevalence of complications associated with impaired kidney function (anemia, bone disease, and nutritional and functional status) (Table 1.2).

Complications of CKD and CKD stages

Complications that develop in CKD are listed in Table 1.2. The diagnosis and management of these complications are discussed in greater detail in the sections Prognostic importance of the stage of CKD and Complications of CKD and CKD stage of this text. Some of the important CKD-specific associations between the development of comorbidities and CKD stage that have emerged from epidemiologic studies are described in brief below.

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