Mark J. Sarnak

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 …

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.

Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction

OBJECTIVES We sought to evaluate the relationship between the level of kidney function, level of hematocrit and their interaction on all-cause mortality in patients with left ventricular (LV) dysfunction. BACKGROUND Anemia and reduced kidney function occur frequently in patients with heart failure. The level of hematocrit and its relationship with renal function have not been evaluated as risk factors for mortality in patients with LV dysfunction. METHODS We retrospectively examined the Studies Of LV Dysfunction (SOLVD) database. Glomerular filtration rate (GFR) was predicted using a recently validated formula. Kaplan-Meier survival analyses were used to compare survival times between groups stratified by level of kidney function (predicted GFR) and hematocrit. Cox proportional-hazards regression was used to explore the relationship of survival time to level of kidney function, hematocrit and their interaction. RESULTS Lower GFR and hematocrit were associated with a higher prevalence of traditional cardiovascular risk factors. In univariate analysis, reduced kidney function and lower hematocrit, in men and in women, were risk factors for all-cause mortality (p < 0.001 for both). After adjustment for other factors significant in univariate analysis, a 10 ml/min/1.73 m(2) lower GFR and a 1% lower hematocrit were associated with a 1.064 (95% CI: 1.033, 1.096) and 1.027 (95% CI: 1.015, 1.038) higher risk for mortality, respectively. At lower GFR and lower hematocrit, the risk was higher (p = 0.022 for the interaction) than that predicted by both factors independently. CONCLUSIONS Decreased kidney function and anemia are risk factors for all-cause mortality in patients with LV dysfunction, especially when both are present. These relationships need to be confirmed in additional studies.

Cardiovascular Disease and Chronic Renal Disease: A New Paradigm

Cardiovascular disease (CVD) is a major cause of morbidity and mortality among patients with chronic renal disease (CRD). Despite Improvement in treatment for CVD over the past 30 years, CVD mortality is approximately 15 times higher in dialysis patients than in the general population. The high prevalence of CVD among Incident dialysis patients suggests that CVD begins in earlier stages of CRD, and that implementation of risk factor reduction strategies earlier in the course of CRD may provide an opportunity to prevent CVD in CRD. Based on parallels between CVD and renal disease progression, we have proposed a paradigm that CVD and CRD are outcomes of the same underlying disorders. We propose that risk factor reduction strategies used to prevent CVD in the general population also be applied to patients with CRD, with the hope of preventing progression of renal disease, as well as preventing CVD.

Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease

Context Cystatin C concentration approximates glomerular filtration rate (GFR) more precisely than creatinine concentration. Can it identify people without known kidney disease who have increased risks for cardiovascular disease? Contribution In this longitudinal study involving 3659 elderly persons without known kidney disease (estimated GFR 60 mL/min per 1.73 m2), increasing cystatin C concentration was associated with increased risks for death, stroke, myocardial infarction, heart failure, and progression to chronic kidney disease. Associations were much stronger for cystatin C than for creatinine. Cautions Albuminuria was not measured; some patients may have been misclassified as having no kidney disease. Implications Among elderly persons, cystatin C concentration may be a better biomarker for adverse outcomes than serum creatinine concentration. The Editors Chronic kidney disease is a worldwide health problem that carries a substantial risk for cardiovascular morbidity and death. Chronic kidney disease has been defined as a creatinine-based estimated glomerular filtration rate (GFR) less than 60 mL/min per 1.73 m2 (1), which represents a loss of more than half of normal kidney function. An estimated GFR less than 60 mL/min per 1.73 m2 has been strongly associated with cardiovascular risk and death (2). However, surprisingly little evidence supports an association of kidney function with adverse clinical events at GFR levels of 60 mL/min per 1.73 m2 or greater (1). The absence of risk associated with an estimated GFR of 60 mL/min per 1.73 m2 or greater may reflect a biological threshold effectthat milder reductions of actual GFR are clinically inconsequentialor may be due to inherent limitations of serum creatinine for estimating GFR (35). Cystatin C is an alternative serum measure of kidney function that approximates direct measures of GFR (for example, iothalamate clearance) more precisely than creatinine, because its serum concentrations are independent of muscle mass and do not seem to be affected by age or sex (68). Cystatin C is a 122amino acid, 13-kDa protein that is a member of a family of competitive inhibitors of lysosomal cysteine proteinases. Its functions include involvement in extracellular proteolysis, modulation of the immune system, and antibacterial and antiviral activities. Cystatin C has several properties that make it a good candidate marker of GFR, including a constant production rate regulated by a housekeeping gene expressed in all nucleated cells, free filtration at the glomerulus, complete reabsorption and catabolism by the proximal tubules with no reabsorption into the bloodstream, and no renal tubular secretion (6). Among elderly persons who do not meet standard criteria for chronic kidney disease (estimated GFR 60 mL/min per 1.73 m2), many participants in the Cardiovascular Health Study (CHS) have elevated cystatin C concentrations (1.0 mg/L). We hypothesized that cystatin C would be an important prognostic factor for risk for death, cardiovascular disease, and incident chronic kidney disease, whereas estimated GFR and creatinine would be unable to distinguish levels of risk. Our goal was to determine whether elevated cystatin C concentrations in patients with normal estimated GFR could define a state of preclinical kidney disease. Methods Description of the Cohort The Cardiovascular Health Study (CHS) is a community-based, longitudinal study of adults 65 years of age and older at baseline (9). Enrollment began in 1989, with annual visits thereafter. The study recruited persons from Medicare eligibility lists in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania, with the following inclusion criteria: 1) older than 65 years of age, 2) not institutionalized, 3) expected to remain in the current community for 3 years or longer, 4) not receiving active treatment for cancer, and 5) gave written informed consent without requiring a proxy respondent. The study design, quality control procedures, laboratory methods, and blood pressure measurement procedures have been published previously (9, 10). Our analysis includes 4663 CHS participants who attended the 19921993 annual visit and who had measurements of creatinine and cystatin C concentrations. We excluded 274 participants because creatinine concentration was not available or cystatin C concentration could not be measured due to inadequate serum specimens. Follow-up for events continued until 30 June 2002 with a median of 9.3 years (maximum of 10.1 years). Kidney Function Measurements We measured all assays on fasting plasma specimens that were stored at 70C. We measured cystatin C concentration by using a BNII nephelometer (Dade Behring Inc., Deerfield, Illinois) that utilized a particle-enhanced immunonephelometric assay (N Latex Cystatin C, Dade Behring Inc.) (11). The assay range is 0.195 mg/L to 7.330 mg/L. The reference ranges for young, healthy individuals and healthy persons older than 50 years of age are reported to be 0.53 mg/L to 0.92 mg/L and 0.58 mg/L to 1.02 mg/L, respectively (12). We measured serum creatinine concentration by using the Kodak Ektachem 700 Analyzer (Eastman Kodak, Rochester, New York), a colorimetric method. The mean coefficient of variation was 1.94% (creatinine level range, 102.5 mol/L [1.16 mg/dL] to 344.8 mol/L [3.90 mg/dL]). We calculated the estimated GFR from serum creatinine by using the modified 4-variable version of the Modification of Diet in Renal Disease (MDRD) formula (13). We indirectly calibrated the creatinine levels in our study with those from the Cleveland Clinic laboratorythe core laboratory of the MDRD trialas previously described (14, 15). As recommended by the Kidney Disease: Improving Global Outcomes (KDIGO) group, we defined chronic kidney disease on the basis of an estimated GFR less than 60 mL/min per 1.73 m2 (1). Secondary Predictors We chose demographic characteristics (age, sex, and race); traditional cardiovascular risk factors (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol levels, presence of diabetes and hypertension, current smoking, height, weight, and physical activity); C-reactive protein level; and prevalent heart failure, myocardial infarction, or stroke as adjustment variables for all analyses. We defined hypertension by a seated blood pressure average of 140/90 mm Hg or greater or a history of treated hypertension. We determined the presence of diabetes by clinical history of diabetes, use of hypoglycemic agent or insulin, or fasting glucose level of 7.0 mmol/L or greater (126 mg/dL). We adjudicated the self-report of prevalent myocardial infarction, stroke, and heart failure as previously described (16). Outcomes Follow-up visits occurred by telephone every 6 months and in person annually. The primary outcomes included in our study were all-cause death, cardiovascular death, noncardiovascular death, incident heart failure, stroke, and myocardial infarction. A CHS outcome assessment committee adjudicated these events. We identified deaths by review of obituaries, medical records, death certificates, the Centers for Medicare & Medicaid Services health care utilization database for hospitalizations, and household contacts. We have actively followed all persons through clinical visits, telephone calls, or surveillance of death registries. We defined cardiovascular death as death caused by coronary heart disease, heart failure, peripheral vascular disease, or cerebrovascular disease (16). Methods used to diagnose incident heart failure, stroke, and myocardial infarction have been previously described (1719). We also compared the rate of progression to incident chronic kidney disease at the 19961997 examination among participants with estimated GFR greater than 60 mL/min per 1.73 m2 at baseline (19921993). Unlike the primary outcomes that occurred on specific dates during follow-up, incident chronic kidney disease was a discrete outcome that could only occur at the time of the 19961997 examination when we measured follow-up creatinine concentration. Statistical Analysis Our analysis began by separating the cohort into persons with and without estimated GFR less than 60 mL/min per 1.73 m2 at the 19921993 clinical visit. We compared the mean cystatin C concentration, creatinine concentration, and estimated GFR within each stratum and Pearson correlations among the 3 measures. We used a Fisher 2-sample Z-test for correlations to determine whether the correlations of cystatin C with estimated GFR and creatinine differed between persons with and persons without chronic kidney disease. We limited our next analyses to participants without chronic kidney disease (estimated GFR 60 mL/min per 1.73 m2). We compared the distributions of creatinine and cystatin C concentrations graphically. We used penalized smoothing splines (P-splines) to depict the association of each measure with mortality risk across the full range in the subcohort without chronic kidney disease (20). Results are similar to smoothing splines with a knot at each data point but are computationally simpler. We used multivariate Cox proportional hazards models to compare the association of cystatin C and creatinine concentrations as linear variables (per SD) with each outcome. Evaluations of incident heart failure, stroke, and myocardial infarction excluded participants with prevalent disease. We tested for a nonlinear association by adding a quadratic term to each model, but these were not statistically significant. We verified the proportional hazards assumption by using graphical methods, as well as formal hypothesis testing. To test for proportionality of hazards, we used KaplanMeier curves. The graph of the survival function versus the survival time resulted in parallel curves. Similarly, the graph of the log(log(survival)) versus log(survival time) also resulted in parallel lines. We also used tests and

Multiple loci associated with indices of renal function and chronic kidney disease

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m2) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10−8) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts

We studied here the independent associations of estimated glomerular filtration rate (eGFR) and albuminuria with mortality and end-stage renal disease (ESRD) in individuals with chronic kidney disease (CKD). We performed a collaborative meta-analysis of 13 studies totaling 21,688 patients selected for CKD of diverse etiology. After adjustment for potential confounders and albuminuria, we found that a 15 ml/min per 1.73 m² lower eGFR below a threshold of 45 ml/min per 1.73 m² was significantly associated with mortality and ESRD (pooled hazard ratios (HRs) of 1.47 and 6.24, respectively). There was significant heterogeneity between studies for both HR estimates. After adjustment for risk factors and eGFR, an eightfold higher albumin- or protein-to-creatinine ratio was significantly associated with mortality (pooled HR 1.40) without evidence of significant heterogeneity and with ESRD (pooled HR 3.04), with significant heterogeneity between HR estimates. Lower eGFR and more severe albuminuria independently predict mortality and ESRD among individuals selected for CKD, with the associations stronger for ESRD than for mortality. Thus, these relationships are consistent with CKD stage classifications based on eGFR and suggest that albuminuria provides additional prognostic information among individuals with CKD.

Cystatin C versus Creatinine in Determining Risk Based on Kidney Function

BACKGROUND Adding the measurement of cystatin C to that of serum creatinine to determine the estimated glomerular filtration rate (eGFR) improves accuracy, but the effect on detection, staging, and risk classification of chronic kidney disease across diverse populations has not been determined. METHODS We performed a meta-analysis of 11 general-population studies (with 90,750 participants) and 5 studies of cohorts with chronic kidney disease (2960 participants) for whom standardized measurements of serum creatinine and cystatin C were available. We compared the association of the eGFR, as calculated by the measurement of creatinine or cystatin C alone or in combination with creatinine, with the rates of death (13,202 deaths in 15 cohorts), death from cardiovascular causes (3471 in 12 cohorts), and end-stage renal disease (1654 cases in 7 cohorts) and assessed improvement in reclassification with the use of cystatin C. RESULTS In the general-population cohorts, the prevalence of an eGFR of less than 60 ml per minute per 1.73 m(2) of body-surface area was higher with the cystatin C-based eGFR than with the creatinine-based eGFR (13.7% vs. 9.7%). Across all eGFR categories, the reclassification of the eGFR to a higher value with the measurement of cystatin C, as compared with creatinine, was associated with a reduced risk of all three study outcomes, and reclassification to a lower eGFR was associated with an increased risk. The net reclassification improvement with the measurement of cystatin C, as compared with creatinine, was 0.23 (95% confidence interval [CI], 0.18 to 0.28) for death and 0.10 (95% CI, 0.00 to 0.21) for end-stage renal disease. Results were generally similar for the five cohorts with chronic kidney disease and when both creatinine and cystatin C were used to calculate the eGFR. CONCLUSIONS The use of cystatin C alone or in combination with creatinine strengthens the association between the eGFR and the risks of death and end-stage renal disease across diverse populations. (Funded by the National Kidney Foundation and others.).

Anemia as a Risk factor for cardiovascular disease in the atherosclerosis Risk in communities (ARIC) study

OBJECTIVES We investigated whether the presence of anemia is a risk factor for cardiovascular disease (CVD) outcomes in the general population. BACKGROUND Chronic anemia is a risk factor for CVD outcomes in patients with kidney disease and in patients with heart failure, but has not been evaluated as a risk factor in the general population. METHODS The Atherosclerosis Risk in Communities (ARIC) study was used to evaluate the relationship of anemia, defined by hemoglobin <13 g/dl in men and <12 g/dl in women, to CVD. Cox proportional hazards regression was used to adjust the relationship between anemia and CVD outcomes for other covariates in the entire study cohort, as well as in subgroups of men, women, African Americans and whites. RESULTS A total of 14,410 subjects (6,267 men and 8,143 women) without CVD at baseline had hemoglobin levels measured. Three hundred men (4.8%) and 1,058 women (13.0%) were anemic. During an average follow-up of 6.1 years there was a total of 549 (3.8%) CVD events. The presence of anemia was independently associated with an increased risk of CVD (hazard ratio [95% confidence interval] of 1.41 [1.01, 1.95]) in the entire study cohort. In subgroup analyses the hazard ratios were in the same direction, although not statistically significant in all cases. CONCLUSIONS Anemia is an independent risk factor for CVD outcomes in the ARIC cohort, a community cohort of subjects between the ages of 45 and 64 years.

Cystatin C concentration as a risk factor for heart failure in older adults

Context Is cystatin-C, a novel marker of kidney function, an independent risk factor for heart failure? Contribution This 9-year observational study of 4384 older adults from 4 communities in the United States found that higher cystatin-C levels were independently associated with a stepwise increased risk for heart failure. Higher creatinine levels were not associated with increased risk for heart failure independent of other known risk factors. Implications These pioneering findings merit replication in other studies: Cystatin-C may be a better measure of renal function than serum creatinine and may better predict some cardiovascular diseases. The Editors Several recent studies suggest that chronic kidney disease is an independent risk factor for ischemic heart disease (1-4), particularly among participants with established cardiovascular disease (1, 2) or those who are at increased cardiovascular risk (3, 5-7). Few studies, however, have evaluated the effect of kidney function on risk for heart failure. Gottdiener and colleagues performed a comprehensive evaluation of risk factors for heart failure in the Cardiovascular Health Study and found that a serum creatinine concentration of 123.2 mol/L or greater (1.4 mg/dL) (present in 8% of the cohort) was an independent predictor of heart failure in older adults (8). Similarly, a recent study in women with coronary artery disease noted that a creatinine clearance less than 0.668 mL/s (<40 mL/min) (present in 10% of the cohort) was associated with an increased risk for heart failure (9). Finally, a recent analysis of the Established Populations for Epidemiologic Studies of the Elderly demonstrated that persons with creatinine clearance less than 0.616 mL/s (<36.9 mL/min) (lowest quartile of the sample) had an increased risk for heart failure compared with persons with creatinine clearance greater than 0.952 mL/s (>57 mL/min) (highest quartile of the sample) (10). All 3 studies, however, may underestimate the importance of kidney function as a risk factor for heart failure because creatinine concentration (or estimated glomerular filtration rate [GFR]) is insensitive in detecting reductions in kidney function. Creatinine concentration is a limited measure of kidney function because creatinine is a breakdown product of muscle and its serum levels are influenced not only by kidney function but also by age, sex, ethnicity, and body mass (11). Cystatin C concentration is a novel measure of kidney function that overcomes many of the limitations of the serum creatinine concentration. Cystatin C is a cysteine proteinase inhibitor that is produced by nearly all human cells and released into the bloodstream, from which it is freely filtered by the kidney glomerulus and metabolized by the proximal tubule (12). Several, but not all (13, 14), studies demonstrate that the cystatin C concentration may be a more sensitive indicator of mild kidney dysfunction and may better estimate GFR than serum creatinine concentration (15-17) and that the association of cystatin C concentration with GFR does not differ by age, sex, or muscle mass (15-20). We hypothesized that the cystatin C concentration would be associated with risk for heart failure and would be a better predictor than the serum creatinine concentration. Methods Participants The Cardiovascular Heath Study is a community-based longitudinal study of adults who were 65 years of age or older at baseline. The objective of the study was to evaluate risk factors for development and progression of cardiovascular disease (21). A main cohort of 5201 participants was recruited between 1989 and 1990 from 4 U.S. communities (Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Allegheny County, Pennsylvania) (22). An additional 687 African-American persons were recruited in 1992 and 1993 (Figure 1). Eligible participants were sampled from Medicare eligibility lists in each area. Follow-up interviews for events were done semi-annually at annual examinations and through interim 6-month telephone calls. Figure 1. Selection of patients. Cystatin C was measured from frozen samples that were collected at the 19921993 visit of the Cardiovascular Health Study. Because our goal was to assess the risk for incident heart failure, we excluded participants with prevalent heart failure at baseline and those who developed heart failure before the 19921993 visit (Figure 1). To compare the risk associated with cystatin C concentration with that indicated by serum creatinine concentration, only participants who were alive and had had both measurements at the 19921993 visit (n= 4384) were included in this analysis. The investigational review boards of the 4 clinical sites and the Data Coordinating Center (University of Washington) approved the data collection procedures of the Cardiovascular Health Study. In addition, we obtained investigational review board approval for our study from the University of California, San Francisco. Measurement of Markers All assays were performed on serum that was drawn in the morning and stored at 70 C. Cystatin C was measured by using a BNII nephelometer (Dade Behring, Inc., Deerfield, Illinois) with a particle-enhanced immunonepholometric assay (N Latex Cystatin C, Dade-Behring, Inc.) (23). Polystyrene particles were coated with monoclonal antibodies to cystatin C that agglutinate in the presence of antigen (cystatin C) to increase the intensity of scattered light. The increase in scattered light is proportional to the amount of cystatin C in the sample. The assay range is 14.6 to 549.0 nmol/L (0.195 to 7.330 mg/L); the reference range for young, healthy persons is reported to be 40 to 71 nmol/L (0.53 to 0.95 mg/L). The intra-assay coefficient of variation ranges from 2.0% to 2.8%, and the interassay coefficient of variation ranges from 2.3% to 3.1%. Serum creatinine was measured by using the Kodak Ektachem 700 Analyzer (Eastman Kodak, Rochester, New York), which is a colorimetric method. Clinical Assessments and Measurements Information on baseline risk factors for heart failure that may confound the association of kidney function with heart failure was obtained from the 19921993 visit (8). These included demographic characteristics (age, sex, and race); traditional cardiovascular risk factors, such as body mass index, smoking (current versus past or never), diabetes (defined by use of a hypoglycemic agent or insulin or a fasting glucose level 6.99 mmol/L [126 mg/dL]), systolic blood pressure (as measured by using a Hawksley random-zero sphygmomanometer), and fasting levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol; novel risk factors (C-reactive protein, hemoglobin, albumin, fibrinogen, and factor VII); noninvasive tests of the extent of disease (anklearm index, common carotid intimamedia thickness, internal carotid intimamedia thickness, and left ventricular hypertrophy and atrial fibrillation on electrocardiography); clinical disease (previous coronary heart disease or stroke, which were adjudicated by a combination of self-report of physician diagnosis and review of medical records); and use of blood pressure medications (diuretics, -blockers, angiotensin-converting enzyme inhibitors, or calcium-channel blockers) (24-26). Echocardiography was not done at the 19921993 visit. Adjudication of Heart Failure For the diagnosis of prevalent heart failure, self-reports were confirmed by components of the physical examination or, if necessary, by a validation protocol that included surveys of treating physicians or review of medical records (24). For the diagnosis of incident heart failure, a physicians diagnosis of heart failure was followed by review of the participants medical records. The Cardiovascular Health Study Cardiovascular Events Committee then determined the incidence of heart failure on the basis of diagnosis from a physician and consideration of symptoms, signs, chest radiographic findings, and treatment of heart failure (current prescription for a diuretic agent and either digitalis or a vasodilator) (8, 26). We examine heart failure events through 30 June 2001. Statistical Analysis We compared the distribution of demographic characteristics, traditional cardiovascular risk factors, novel risk factors, clinical disease, and noninvasive assessment of extent of disease across quintiles of cystatin C concentration. P values for linear trend across the quintiles were calculated. Incidence rates were calculated per 100 person-years and are reported as percentage per year. The association of kidney function and risk for heart failure was compared by using 3 measures of kidney function: serum cystatin C concentration, serum creatinine concentration, and GFR, as estimated by using the 4-variable version of the Modification of Diet in Renal Disease formula. This formula is as follows: GFR = 186.3 (serum creatinine concentration1.154) (age0.203) 1.212 (if black) 0.742 (if female) (27, 28). Each measure of kidney function was then divided into quintiles; for serum creatinine concentration, the quintile cut-offs were sex-specific because the distribution of serum creatinine concentration differed substantially between men and women in the Cardiovascular Health Study (29, 30). We used Cox proportional hazards models to examine the relationship of cystatin C and other known risk factors to incident heart failure in multivariable models. To evaluate the contribution of cystatin C as a marker of risk, models were generated in stages: unadjusted; adjusted for demographic characteristics; adjusted for demographic characteristics, traditional cardiovascular risk factors, and use of blood pressure medications; and adjusted for risk factors from the preceding model, other novel risk factors, measurements of clinical cardiovascular disease, and noninvasive measurements of the extent of the disease. We also included a term to adjust for clustering wi