Andrew S. Levey

A More Accurate Method To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation

The glomerular filtration rate (GFR) is traditionally considered the best overall index of renal function in health and disease (1). Because GFR is difficult to measure in clinical practice, most clinicians estimate the GFR from the serum creatinine concentration. However, the accuracy of this estimate is limited because the serum creatinine concentration is affected by factors other than creatinine filtration (2, 3). To circumvent these limitations, several formulas have been developed to estimate creatinine clearance from serum creatinine concentration, age, sex, and body size (4-12). Despite more recent studies that have related serum creatinine concentration to GFR (13-24), no formula is more widely used to predict creatinine clearance than that proposed by Cockcroft and Gault (4). This formula is used to detect the onset of renal insufficiency, to adjust the dose of drugs excreted by the kidney, and to evaluate the effectiveness of therapy for progressive renal disease. More recently, it has been used to document eligibility for reimbursement from the Medicare End Stage Renal Disease Program (25) and for accrual of points for patients on the waiting list for cadaveric renal transplantation (26). Major clinical decisions in general medicine, geriatrics, and oncology (as well as nephrology) are made by using the Cockcroft-Gault formula and other formulas to predict the level of renal function. Therefore, these formulas must predict GFR as accurately as possible. The Modification of Diet in Renal Disease (MDRD) Study, a multicenter, controlled trial, evaluated the effect of dietary protein restriction and strict blood pressure control on the progression of renal disease (27-30). During the baseline period, GFR, serum creatinine, and several variables that affect the relation between them were measured in patients with chronic renal disease. The purpose of our study was to develop an equation from MDRD Study data that could improve the prediction of GFR from serum creatinine concentration. Methods Baseline Cohort and Measurement Methods in the Modification of Diet in Renal Disease Study The overall study design and methods of recruitment for the MDRD Study have been described elsewhere (31, 32). A total of 1785 patients entered the baseline period. Of these patients, 1628 (91%) also underwent measurement of GFR and the other variables described below; these patients constitute the study group for these analyses. Glomerular filtration rate was measured as the renal clearance of 125I-iothalamate (33, 34). Creatinine clearance was computed from creatinine excretion in a 24-hour urine collection and a single measurement of serum creatinine. Serum and urine creatinine were measured by using a kinetic alkaline picrate assay with a normal range in serum of 62 to 124 mol/L (0.7 to 1.4 mg/dL) (35). Glomerular filtration rate and creatinine clearance were expressed per 1.73 m2 of body surface area by multiplying measured values by 1.73/body surface area (36). The serum and urine specimens were also used for other measurements, including serum albumin (bromcresol green method [35]), serum urea nitrogen (urease method [35]), and urine urea nitrogen (urease method [35]). Protein intake (g/d) was estimated as 6.25 [UUN (g/d) + 0.031 (g/kg per day) SBW (kg)], where UUN is urine urea nitrogen, SBW is standard body weight, and 0.031 g/kg per day is a constant reflecting the rate of excretion of nitrogen in compounds other than urine urea (37, 38). The diagnosis of diabetes and the cause of renal disease were assigned on the basis of chart review at the clinical center (39). Statistical Analysis Descriptive Statistics The relation of renal function measurements to other baseline characteristics was assessed by using contingency tables, t-tests, analysis of variance, and linear regression, as appropriate. Nonparametric tests (Wilcoxon rank-sum tests and Kruskal-Wallis tests) gave consistent results. A P value less than 0.01 was considered statistically significant. Multivariable Analysis of Glomerular Filtration Rate We used stepwise multiple regression to determine a set of variables that jointly predicted GFR. The stepwise regression models were developed by using a training sample consisting of a random sample of 1070 of the 1628 patients. We found that the variability of the difference between the observed and predicted GFR values was greater for higher GFR values. This increase was eliminated by performing multiple regressions on log-transformed data. To facilitate clinical interpretation, the results were re-expressed in terms of the original units. Consequently, the prediction equation is a multiplicative model; regression coefficients refer to the change in geometric mean GFR associated with unit changes in the independent variable. Predicted GFR is expressed in mL/min per 1.73 m2. The following variables were considered for possible inclusion in the regression model: weight, height, sex, ethnicity, age, diagnosis of diabetes, serum creatinine concentration, serum urea nitrogen level, serum albumin level, serum phosphorus level, serum calcium level, mean arterial pressure, urine creatinine level, urine urea nitrogen level, urine protein level, and urine phosphorus level. The cause of renal disease was not included because in clinical practice, the cause may be unknown or clinicians may not use the same classification method as the investigators in the MDRD Study. A P value less than 0.001 was used as the criterion for entry of a variable into the model. Because of the difficulty in collecting complete 24-hour urine samples in clinical practice, an additional stepwise regression was performed to develop a prediction model that did not include urine biochemistry variables. Finally, because of the interest in developing a prediction equation to assess eligibility for Medicare reimbursement and listing for cadaveric renal transplantation, we repeated the analysis restricting the population to the subgroup of patients with higher serum creatinine concentrations (>221 mol/L [2.5 mg/dL]; n=509 in the training sample). Methods for Comparing Equations To Predict Glomerular Filtration Rate We first developed coefficients for each prediction equation (including the selection of the predictor variables for the stepwise regressions) using the data from the training sample to predict log GFR. Each prediction equation also included a multiplicative constant to account for any consistent bias in the application of that equation in the MDRD Study Group. This was particularly important for equations that are intended to estimate creatinine clearance, which is known to be higher than GFR. The regression coefficients determined in the training sample were then applied to obtain predicted GFRs in a separate validation sample consisting of the remaining 558 patients (172 patients with serum creatinine concentration>221 mol/L [2.5 mg/dL]). These predicted GFR values were compared with the actual GFRs in the validation sample to evaluate the performance of each prediction equation. In this way, separate data sets were used to construct the equations and assess their accuracy after removal of systematic bias. For each equation, we computed overall R 2 (percentage of variability in log GFR explained by the regression model) and the 50th, 75th, and 90th percentiles of the distribution of the percentage absolute difference between measured and predicted GFRs in the validation sample. The 50th percentiles indicate the typical size of the errors in prediction of GFR, and the 75th and 90th percentiles assess the sizes of the larger errors that occurred for each model. Development of Final Prediction Equations To improve the accuracy of the final MDRD Study prediction equations, the regression coefficients derived from the training sample were updated on the basis of data from all 1628 patients. As a result, the standard errors of the regression coefficients in the final MDRD Study prediction equations are slightly smaller than those derived from the training sample; thus, the accuracy of the final prediction equations may be slightly better (by about 0.1% to 0.2%) than their accuracy as assessed in the validation sample. Results Demographic and Clinical Characteristics The mean age ( SD) of the cohort was 50.6 12.7 years. Sixty percent of patients were male, 88% were white, and 6% were diabetic. Causes of renal disease were glomerular disease (32%), polycystic kidney disease (22%), tubulointerstitial disease (7%), and other or unknown renal diseases (40%). Mean protein intake was 0.99 0.24 g/kg of body weight per day and mean arterial pressure was 99.4 12.2 mm Hg. Mean weight was 79.6 16.8 kg, body surface area was 1.91 0.23 m2, serum urea nitrogen concentration was 11.4 5.7 mmol/L [32 16 mg/dL], and serum albumin concentration was 40.0 4.0 g/L [4.0 0.4 g/dL], respectively. Glomerular Filtration Rate, Creatinine Clearance, and Serum Creatinine Concentration Renal function measurements for the study group and for various subgroups are shown in Table 1. Mean GFR for the population was 0.38 mL s 2 m 2 (39.8 mL/min per 1.73 m2), with lower values in patients with lower protein intake, white patients compared with black patients, and older patients ( 55 years) compared with younger patients (P<0.01). The mean value of creatinine clearance was 0.81 mL s 2 m 2 (48.6 mL/min per 1.73 m2) and was lower in older patients and patients with lower protein intake (P 0.01). The mean serum creatinine concentration was 203 mol/L (2.3 mg/dL) and was higher in men, patients with lower protein intake, and patients with higher mean arterial pressure (P 0.01). Figure 1 shows the well-known reciprocal relation of serum creatinine concentration to GFR for subgroups based on sex and ethnicity. At any given GFR, the serum creatinine concentration is significantly higher in men than in women and in black persons than in white persons (P<0.001). Table 1. Association of Renal Fu

Using Standardized Serum Creatinine Values in the Modification of Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate

Context Guidelines recommend that laboratories estimate glomerular filtration rate (GFR) with equations that use serum creatinine level, age, sex, and ethnicity. Standardizing creatinine measurements across clinical laboratories should reduce variability in estimated GFR. Contribution Using standardized creatinine assays, the authors calibrated serum creatinine levels in 1628 patients whose GFR had been measured by urinary clearance of 125I-iothalamate. They used these data to derive new equations for estimating GFR and to measure their accuracy. The equations were inaccurate only when kidney function was near-normal. Cautions There was no independent sample of patients for measuring accuracy. Implications By using this equation and a standardized creatinine assay, different laboratories can report estimated GFR more uniformly and accurately. The Editors Chronic kidney disease is a recently recognized public health problem. Current guidelines define chronic kidney disease as kidney damage or a glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m2 for 3 months or more, regardless of cause (13). Kidney damage is usually ascertained from markers, such as albuminuria. The GFR can be estimated from serum creatinine concentration and demographic and clinical variables, such as age, sex, ethnicity, and body size. The normal mean value for GFR in healthy young men and women is approximately 130 mL/min per 1.73 m2 and 120 mL/min per 1.73 m2, respectively, and declines by approximately 1 mL/min per 1.73 m2 per year after 40 years of age (4). To facilitate detection of chronic kidney disease, guidelines recommend that clinical laboratories compute and report estimated GFR by using estimating equations, such as equations derived from the Modification of Diet in Renal Disease (MDRD) Study (13, 510). The original MDRD Study equation was developed by using 1628 patients with predominantly nondiabetic kidney disease. It was based on 6 variables: age; sex; ethnicity; and serum levels of creatinine, urea, and albumin (11). Subsequently, a 4-variable equation consisting of age, sex, ethnicity, and serum creatinine levels was proposed to simplify clinical use (3, 12). This equation is now widely accepted, and many clinical laboratories are using it to report GFR estimates. Extensive evaluation of the MDRD Study equation shows good performance in populations with lower levels of GFR but variable performance in those with higher levels (1332). Variability among clinical laboratories in calibration of serum creatinine assays (33, 34) introduces error in GFR estimates, especially at high levels of GFR (35), and may account in part for the poorer performance in this range (13, 14, 16, 1821, 27, 30). The National Kidney Disease Education Program (NKDEP) has initiated a creatinine standardization program to improve and normalize serum creatinine results used in estimating equations (36). The MDRD Study equation has now been reexpressed for use with a standardized serum creatinine assay (37), allowing GFR estimates to be reported in clinical practice by using standardized serum creatinine and overcoming this limitation to the current use of GFR estimating equations. The purpose of this report is to describe the performance of the reexpressed 4-variable MDRD Study equation and compare it with the performance of the reexpressed 6-variable MDRD equation and the CockcroftGault equation (38), with particular attention to the level of GFR. This information should facilitate implementation of reporting and interpreting estimated GFR in clinical practice. Methods Laboratory Methods Urinary clearances of 125I-iothalamate after subcutaneous infusion were determined at clinical centers participating in the MDRD Study. Serum and urine 125I-iothalamate were assayed in a central laboratory. All serum creatinine values reported in this study are traceable to primary reference material at the National Institute of Standards and Technology (NIST), with assigned values based on isotope-dilution mass spectrometry. The serum creatinine samples from the MDRD Study were originally assayed from 1988 to 1994 in a central laboratory with the Beckman Synchron CX3 (Global Medical Instrumentation, Inc., Ramsey, Minnesota) by using a kinetic alkaline picrate method. Samples were reassayed in 2004 with the same instrument. The Beckman assay was calibrated to the Roche/Hitachi P module Creatinase Plus enzymatic assay (Roche Diagnostics, Basel, Switzerland), traceable to an isotope-dilution mass spectrometry assay at NIST (37, 39). On the basis of these results, the 4-variable and 6-variable MDRD Study equations were reexpressed for use with standardized serum creatinine assay. The CockcroftGault equation was not reexpressed because the original serum creatinine samples were not available for calibration to standardized serum creatinine assay. Derivation and Validation of the MDRD Study Equation The MDRD Study was a multicenter, randomized clinical trial of the effects of reduced dietary protein intake and strict blood pressure control on the progression of chronic kidney disease (40). The derivation of the MDRD Study equation has been described previously (11). Briefly, the equation was developed from data from 1628 patients enrolled during the baseline period. The GFR was computed as urinary clearance of 125I-iothalamate. Creatinine clearance was computed from creatinine excretion in a 24-hour urine collection and a single measurement of serum creatinine. Glomerular filtration rate and creatinine clearance were expressed per 1.73 m2 of body surface area. Ethnicity was assigned by study personnel, without explicit criteria, probably by examination of skin color. The MDRD Study equation was developed by using multiple linear regression to determine a set of variables that jointly estimated GFR in a random sample of 1070 patients (development data set). The regressions were performed on log-transformed data to reduce variability in differences between estimated and measured GFR at higher levels. Several equations were developed, and the performance of these equations was compared in the remaining sample of 558 patients (validation data set). To improve the accuracy of the final equations, the regression coefficients derived from the development data set were updated on the basis of data from all 1628 patients (11). Estimation of GFR Glomerular filtration rate was estimated by using the following 4 equations: the reexpressed 4-variable MDRD Study equation (GFR= 175standardized Scr 1.154age0.2031.212 [if black]0.742 [if female]), the reexpressed 6-variable MDRD Study equation (GFR= 161.5standardized Scr 0.999age0.176SUN0.17albumin0.3181.18 [if black]0.762 [if female]), the CockcroftGault equation adjusted for body surface area (Ccr= [140age]weight0.85 [if female]1.73/72 standardized ScrBSA), and the CockcroftGault equation adjusted for body surface area and corrected for the bias in the MDRD Study sample (Ccr= 0.8[140age]weight0.85 [if female]1.73/72 standardized ScrBSA). In these equations, GFR and creatinine clearance (Ccr) are expressed as mL/min per 1.73 m2, serum creatinine and urea nitrogen (SUN) are expressed as mg/dL, albumin is expressed as g/dL, weight is expressed as kg, age is expressed as years, and body surface area (BSA) is expressed as m2. Correction for bias improves performance of the CockcroftGault equation because it adjusts for systematic differences between studies, such as differences in the measures of kidney function (GFR in the MDRD Study and creatinine clearance in the study by Cockcroft and Gault), the serum creatinine assays, and the study samples. Hence, the bias correction for the CockcroftGault equation provided here reexpresses that equation for the estimation of GFR for use with standardized creatinine in study samples similar to that in the MDRD Study. Measures of Performance Measures of performance include bias (median difference of measured minus estimated GFR and measured GFR) and percentage bias (percentage of bias divided by measured GFR), precision (interquartile range of the difference between estimated and measured GFR, and percentage of variance in log-measured GFR explained by the regression model [R2 values]), and accuracy (percentage of estimates within 30% of the measured values). In the overall data set, bias is expected to be close to 0 for equations derived in the MDRD Study database, including the 4-variable and 6-variable equations and the CockcroftGault equation adjusted for bias. The bootstrap method (based on percentiles, with 2000 bootstrap samples) was used to estimate 95% CIs for interquartile ranges and R2 values. Confidence intervals for the percentage of estimates within 30% of measured values were computed by using the normal approximation to the binomial or exact binomial probabilities, as appropriate. We also computed sensitivity, specificity, positive and negative predictive value of estimated GFR less than 60 mL/min per 1.73 m2, and receiver-operating characteristic (ROC) curves by using measured GFR less than 60 mL/min per 1.73 m2 as the criterion standard. Areas under the ROC curves were compared by using the method of DeLong and colleagues (41). R, version 2 (Free Software Foundation, Inc., Boston, Massachusetts), and SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina), were used for statistical analysis. We used the lowess function in R to plot smoothed functions in the figures. Role of the Funding Source The study was funded by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as part of a cooperative agreement that gives the NIDDK substantial involvement in the design of the study and in the collection, analysis, and interpretation of the data. The NIDDK was not required to approve publication of the finished manuscript. The institutional review boards of all participating institutions approved the study. Results Clinical characteristics of

Kidney Disease as a Risk Factor for Development of Cardiovascular Disease A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention

Chronic kidney disease1 (CKD) is a worldwide public health problem. In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost. The number of individuals with kidney failure treated by dialysis and transplantation exceeded 320 000 in 1998 and is expected to surpass 650 000 by 2010.1,2 There is an even higher prevalence of earlier stages of CKD (Table 1).1,3 Kidney failure requiring treatment with dialysis or transplantation is the most visible outcome of CKD. However, cardiovascular disease (CVD) is also frequently associated with CKD, which is important because individuals with CKD are more likely to die of CVD than to develop kidney failure,4 CVD in CKD is treatable and potentially preventable, and CKD appears to be a risk factor for CVD. In 1998, the National Kidney Foundation (NKF) Task Force on Cardiovascular Disease in Chronic Renal Disease issued a report emphasizing the high risk of CVD in CKD.5 This report showed that there was a high prevalence of CVD in CKD and that mortality due to CVD was 10 to 30 times higher in dialysis patients than in the general population (Figure 1 and Table 2).6–18 The task force recommended that patients with CKD be considered in the “highest risk group” for subsequent CVD events and that treatment recommendations based on CVD risk stratification should take into account the highest-risk status of patients with CKD. View this table: TABLE 1. Stages of CKD Figure 1. Cardiovascular mortality defined by death due to arrhythmias, cardiomyopathy, cardiac arrest, myocardial infarction, atherosclerotic heart disease, and pulmonary edema in general population (GP; National Center for Health Statistics [NCHS] multiple cause of mortality data files International Classification of Diseases, 9th Revision [ICD 9] codes 402, 404, 410 to 414, and …

National Kidney Foundation Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification

Chronic kidney disease is a worldwide public health problem. In the United States, the incidence and prevalence of kidney failure are rising, the outcomes are poor, and the costs are high. The number of persons with kidney failure who are treated with dialysis and transplantation is projected to increase from 340 000 in 1999 to 651 000 in 2010 (1). The major outcomes of chronic kidney disease, regardless of cause, include progression to kidney failure, complications of decreased kidney function, and cardiovascular disease (CVD). Increasing evidence indicates that some of these adverse outcomes can be prevented or delayed by early detection and treatment (2). Unfortunately, chronic kidney disease is underdiagnosed and undertreated, resulting in lost opportunities for prevention (3-5), in part because of a lack of agreement on a definition and classification of stages in the progression of chronic kidney disease (6) and a lack of uniform application of simple tests for detection and evaluation. In February 2002, the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation (NKF) published 15 clinical practice guidelines on chronic kidney disease [7]. The goals of the guidelines are to 1) define chronic kidney disease and classify its stages, regardless of underlying cause; 2) evaluate laboratory measurements for the clinical assessment of kidney disease; 3) associate the level of kidney function with complications of chronic kidney disease; and 4) stratify the risk for loss of kidney function and development of CVD. Our goal is to disseminate the simple definition and five-stage classification system of chronic kidney disease, to summarize the major recommendations on early detection of chronic kidney disease in adults (Table 1), and to consider some of the issues associated with these recommendations. Because of the high prevalence of early stages of chronic kidney disease in the general population, this information is particularly important for general internists and specialists. Table 1. Guidelines, Recommendations, Ratings, and Key References Methods The guidelines of the K/DOQI are based on a systematic review of the literature. The approach used for the review was outlined by the Agency for Healthcare Research and Quality (formerly the Agency for Health Care Policy and Research) (46), with modifications appropriate to the available evidence and the goals of the K/DOQI Work Group. The Work Group considered diverse topics, which would have been too large for a comprehensive review of the literature. Instead, a selective review of published evidence was used to focus on specific questions: a summary of reviews for established concepts and a review of original articles and data for new concepts. The strength of recommendations is graded according to a new classification (Table 2) recently adopted by the K/DOQI Advisory Board (see Appendix 1). Table 2. National Kidney Foundation Kidney Disease Outcomes Quality Initiative Rating of the Strength of Recommendations Framework The Work Group defined two principal outcomes of chronic kidney disease: the progressive loss of kidney function over time (Figure 1) and the development and progression of CVD. Figure 1, which defines stages of chronic kidney disease, as well as antecedent conditions, outcomes, risk factors for adverse outcomes, and actions to improve outcomes, is a model of the course of chronic kidney disease. This diagram provides a framework that has previously been lacking for the development of a public health approach to chronic kidney disease. Figure 1. Evidence model for stages in the initiation and progression of chronic kidney disease ( CKD ) and therapeutic interventions. black dark gray light gray white GFR Table 3. Risk Factors for Chronic Kidney Disease and Its Outcomes Risk factors for chronic kidney disease are defined as attributes associated with increased risk for adverse outcomes of chronic kidney disease (Table 3). The guidelines focus primarily on identifying susceptibility factors and initiation factors (to define persons at increased risk for developing chronic kidney disease) and progression factors (to define persons at high risk for worsening kidney damage and subsequent loss of kidney function). Because kidney disease usually begins late in life and progresses slowly, most persons in the stage of decreased glomerular filtration rate (GFR) die of CVD before they develop kidney failure. However, decreased GFR is associated with a wide range of complications, such as hypertension, anemia, malnutrition, bone disease, neuropathy, and decreased quality of life, which can be prevented or ameliorated by treatment at earlier stages. Treatment can also slow the progression to kidney failure. Thus, measures to prevent, detect, and treat chronic kidney disease in its earlier stages could reduce the adverse outcomes of chronic kidney disease. Cardiovascular disease deserves special consideration as a complication of chronic kidney disease because 1) CVD events are more common than kidney failure in patients with chronic kidney disease, 2) chronic kidney disease seems to be a risk factor for CVD, and 3) CVD in patients with chronic kidney disease is treatable and potentially preventable (48-50). The 1998 Report of the NKF Task Force on Cardiovascular Disease in Chronic Renal Disease recommended that patients with chronic kidney disease be considered in the highest risk group for subsequent CVD events and that most interventions that are effective in the general population should also be applied to patients with chronic kidney disease (49). Definition and Classification of Stages of Chronic Kidney Disease Guideline 1. Definition and Stages of Chronic Kidney Disease Adverse outcomes can often be prevented or delayed through early detection and treatment of chronic kidney disease. Earlier stages of chronic kidney disease can be detected through routine laboratory measurements. Chronic kidney disease is defined as either kidney damage or decreased kidney function (decreased GFR) for 3 or more months (level A recommendation). Kidney disease can be diagnosed without knowledge of its cause. Kidney damage is usually ascertained by markers rather than by kidney biopsy. According to the Work Group, persistent proteinuria is the principal marker of kidney damage (8, 9). An albumincreatinine ratio greater than 30 mg/g in untimed (spot) urine samples is usually considered abnormal; proposed sex-specific cut points are greater than 17 mg/g in men and greater than 25 mg/g in women (10, 11). Other markers of damage include abnormalities in urine sediment, abnormalities in blood and urine chemistry measurements, and abnormal findings on imaging studies. Persons with normal GFR but with markers of kidney damage are at increased risk for adverse outcomes of chronic kidney disease. Glomerular filtration rate is the best measure of overall kidney function in health and disease (12). The normal level of GFR varies according to age, sex, and body size. Normal GFR in young adults is approximately 120 to 130 mL/min per 1.73 m2 and declines with age (12-15). A GFR level less than 60 mL/min per 1.73 m2 represents loss of half or more of the adult level of normal kidney function. Below this level, the prevalence of complications of chronic kidney disease increases. Although the age-related decline in GFR has been considered part of normal aging, decreased GFR in the elderly is an independent predictor of adverse outcomes, such as death and CVD (51-53). In addition, decreased GFR in the elderly requires adjustment in drug dosages, as in other patients with chronic kidney disease (54). Therefore, the definition of chronic kidney disease is the same, regardless of age. Because GFR declines with age, the prevalence of chronic kidney disease increases with age; approximately 17% of persons older than 60 years of age have an estimated GFR less than 60 mL/min per 1.73 m2 (16). The guidelines define kidney failure as either 1) GFR less than 15 mL/min per 1.73 m2, which is accompanied in most cases by signs and symptoms of uremia, or 2) a need to start kidney replacement therapy (dialysis or transplantation). Approximately 98% of patients with kidney failure in the United States begin dialysis when their GFR is less than 15 mL/min per 1.73 m2 (17). Kidney failure is not synonymous with end-stage renal disease (ESRD). End-stage renal disease is an administrative term in the United States. It indicates that a patient is treated with dialysis or transplantation, which is the condition for payment for health care by the Medicare ESRD Program. The classification of ESRD does not include patients with kidney failure who are not treated with dialysis and transplantation. Thus, although the term ESRD provides a simple operational classification of patients according to treatment, it does not precisely define a specific level of kidney function. The level of kidney function, regardless of diagnosis, determines the stage of chronic kidney disease according to the K/DOQI chronic kidney disease classification (level A recommendation). Data from the Third National Health and Nutrition Examination Survey (NHANES III) show the increasing prevalence of complications of chronic kidney disease at lower levels of GFR (7). These data and other studies provide a strong basis for using GFR to classify the stage of severity of chronic kidney disease. Table 4 shows the classification of stages of chronic kidney disease and the prevalence of each stage, estimated by using data from NHANES III (16). Approximately 11% of the U.S. adult population (20 million persons from 1988 to 1994) have chronic kidney disease. The prevalence of early stages of disease (stages 1 to 4; 10.8%) is more than 100 times greater than the prevalence of kidney failure (stage 5; 0.1%). The burden of illness associated with earlier stages of chronic kidney disease has not been systematically studied (55,

Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

BACKGROUND Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. METHODS In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. FINDINGS The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. INTERPRETATION eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. FUNDING Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation.Background A comprehensive evaluation of the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality is required for assessment of the impact of kidney function on risk in the general population, with implications for improving the definition and staging of chronic kidney disease (CKD).

The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease

Background Restricting protein intake and controlling hypertension delay the progression of renal disease in animals. We tested these interventions in 840 patients with various chronic renal diseases. Methods In study 1, 585 patients with glomerular filtration rates of 25 to 55 ml per minute per 1.73 m2 of body-surface area were randomly assigned to a usual-protein diet or a low-protein diet (1.3 or 0.58 g of protein per kilogram of body weight per day) and to a usual- or a low-blood-pressure group (mean arterial pressure, 107 or 92 mm Hg). In study 2, 255 patients with glomerular filtration rates of 13 to 24 ml per minute per 1.73 m2 were randomly assigned to the low-protein diet (0.58 g per kilogram per day) or a very-low-protein diet (0.28 g per kilogram per day) with a keto acid-amino acid supplement, and a usual- or a low-blood-pressure group (same values as those in study 1). An 18-to-45-month follow-up was planned, with monthly evaluations of the patients. Results The mean follow-up was 2.2 years. ...

Estimating Glomerular Filtration Rate from Serum Creatinine and Cystatin C

BACKGROUND Estimates of glomerular filtration rate (GFR) that are based on serum creatinine are routinely used; however, they are imprecise, potentially leading to the overdiagnosis of chronic kidney disease. Cystatin C is an alternative filtration marker for estimating GFR. METHODS Using cross-sectional analyses, we developed estimating equations based on cystatin C alone and in combination with creatinine in diverse populations totaling 5352 participants from 13 studies. These equations were then validated in 1119 participants from 5 different studies in which GFR had been measured. Cystatin and creatinine assays were traceable to primary reference materials. RESULTS Mean measured GFRs were 68 and 70 ml per minute per 1.73 m(2) of body-surface area in the development and validation data sets, respectively. In the validation data set, the creatinine-cystatin C equation performed better than equations that used creatinine or cystatin C alone. Bias was similar among the three equations, with a median difference between measured and estimated GFR of 3.9 ml per minute per 1.73 m(2) with the combined equation, as compared with 3.7 and 3.4 ml per minute per 1.73 m(2) with the creatinine equation and the cystatin C equation (P=0.07 and P=0.05), respectively. Precision was improved with the combined equation (interquartile range of the difference, 13.4 vs. 15.4 and 16.4 ml per minute per 1.73 m(2), respectively [P=0.001 and P<0.001]), and the results were more accurate (percentage of estimates that were >30% of measured GFR, 8.5 vs. 12.8 and 14.1, respectively [P<0.001 for both comparisons]). In participants whose estimated GFR based on creatinine was 45 to 74 ml per minute per 1.73 m(2), the combined equation improved the classification of measured GFR as either less than 60 ml per minute per 1.73 m(2) or greater than or equal to 60 ml per minute per 1.73 m(2) (net reclassification index, 19.4% [P<0.001]) and correctly reclassified 16.9% of those with an estimated GFR of 45 to 59 ml per minute per 1.73 m(2) as having a GFR of 60 ml or higher per minute per 1.73 m(2). CONCLUSIONS The combined creatinine-cystatin C equation performed better than equations based on either of these markers alone and may be useful as a confirmatory test for chronic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

BACKGROUND Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. METHODS In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. RESULTS Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. CONCLUSIONS The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study

BACKGROUND Chronic kidney disease is a graded and independent risk factor for substantial comorbidity and death. We aimed to examine new onset of chronic kidney disease in patients with small, renal cortical tumours undergoing radical or partial nephrectomy. METHODS We did a retrospective cohort study of 662 patients with a normal concentration of serum creatinine and two healthy kidneys undergoing elective partial or radical nephrectomy for a solitary, renal cortical tumour (</=4 cm) between 1989 and 2005 at a referral cancer centre. Glomerular filtration rate (GFR) was estimated with the abbreviated Modification in Diet and Renal Disease Study equation. Separate analysis was undertaken, with chronic kidney disease defined as GFR lower than 60 mL/min per 1.73 m(2) and GFR lower than 45 mL/min per 1.73 m(2). FINDINGS 171 (26%) patients had pre-existing chronic kidney disease before surgery. After surgery, the 3-year probability of freedom from new onset of GFR lower than 60 mL/min per 1.73 m(2) was 80% (95% CI 73-85) after partial nephrectomy and 35% (28-43; p<0.0001) after radical nephrectomy; corresponding values for GFRs lower than 45 mL/min per 1.73 m(2) were 95% (91-98) and 64% (56-70; p<0.0001), respectively. Multivariable analysis showed that radical nephrectomy remained an independent risk factor for patients developing new onset of GFR lower than 60 mL/min per 1.73 m(2) (hazard ratio 3.82 [95% CI 2.75-5.32]) and 45 mL/min per 1.73 m(2) (11.8 [6.24-22.4]; both p<0.0001). INTERPRETATION Because the baseline kidney function of patients with renal cortical tumours is lower than previously thought, accurate assessment of kidney function is essential before surgery. Radical nephrectomy is a significant risk factor for the development of chronic kidney disease and might no longer be regarded as the gold standard treatment for small, renal cortical tumours.

Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease and All-Cause Mortality: A Pooled Analysis of Community-Based Studies

Chronic kidney disease (CKD) is a major public health problem. Conflicting evidence exists among community-based studies as to whether CKD is an independent risk factor for adverse cardiovascular outcomes. After subjects with a baseline history of cardiovascular disease were excluded, data from four publicly available, community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were indirectly calibrated across studies. CKD was defined by a GFR between 15 and 60 ml/min per 1.73 m(2). A composite of myocardial infarction, fatal coronary heart disease, stroke, and death was the primary study outcome. Cox proportional hazards models were used to adjust for study, demographic variables, educational status, and other cardiovascular risk factors. The total population included 22,634 subjects; 18.4% of the population was black, and 7.4% had CKD. There were 3262 events. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.32), and there was a significant interaction between kidney function and race. Black individuals with CKD had an adjusted HR of 1.76 (95% CI, 1.35-2.31), whereas whites had an adjusted HR of 1.13 (95% CI, 1.02-1.26). CKD is a risk factor for the composite outcome of all-cause mortality and cardiovascular disease in the general population and a more pronounced risk factor in blacks than in whites. It is hypothesized that this effect may be due to more frequent or more severe subclinical vascular disease secondary to hypertension or diabetes in black individuals.