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Articles
15 August 2006

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

Publication: Annals of Internal Medicine
Volume 145, Number 4

Abstract

Background:

Cystatin C is an alternative measure of kidney function that may have prognostic importance among elderly persons who do not meet standard criteria for chronic kidney disease (estimated glomerular filtration rate [GFR] ≥60 mL/min per 1.73 m2).

Objective:

To evaluate cystatin C as a prognostic biomarker for death, cardiovascular disease, and incident chronic kidney disease among elderly persons without chronic kidney disease.

Design:

Cohort study.

Setting:

The Cardiovascular Health Study, a population-based cohort recruited from 4 communities in the United States.

Participants:

4663 elderly persons.

Measurements:

Measures of kidney function were creatinine-based estimated GFR by using the Modification of Diet in Renal Disease equation and cystatin C concentration. Outcomes were death, cardiovascular death, noncardiovascular death, heart failure, stroke, myocardial infarction, and incident chronic kidney disease during follow-up (median, 9.3 years).

Results:

At baseline, 78% of participants did not have chronic kidney disease (estimated GFR ≥60 mL/min per 1.73 m2) and mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.0 mg/L, 79.6 µmol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. Cystatin C concentrations (per SD, 0.18 mg/L) had strong associations with death (hazard ratio, 1.33 [95% CI, 1.25 to 1.40]), cardiovascular death (hazard ratio, 1.42 [CI, 1.30 to 1.54]), noncardiovascular death (hazard ratio, 1.26 [CI, 1.17 to 1.36]), incident heart failure (hazard ratio, 1.28 [CI, 1.17 to 1.40]), stroke (hazard ratio, 1.22 [CI, 1.08 to 1.38]), and myocardial infarction (hazard ratio, 1.20 [CI, 1.06 to 1.36]) among these participants. Serum creatinine concentrations had much weaker associations with each outcome and only predicted cardiovascular death. Participants without chronic kidney disease who had elevated cystatin C concentrations (≥1.0 mg/L) had a 4-fold risk for progressing to chronic kidney disease after 4 years of follow-up compared with those with cystatin C concentrations less than 1.0 mg/L.

Limitations:

Because this study did not directly measure GFR or albuminuria, the extent to which cystatin C may be influenced by nonrenal factors was not determined and participants with albuminuria might have been misclassified as having no kidney disease.

Conclusions:

Among elderly persons without chronic kidney disease, cystatin C is a prognostic biomarker of risk for death, cardiovascular disease, and chronic kidney disease. In this setting, cystatin C seems to identify a “preclinical” state of kidney dysfunction that is not detected with serum creatinine or estimated GFR.

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 effect—that milder reductions of actual GFR are clinically inconsequential—or may be due to inherent limitations of serum creatinine for estimating GFR (3–5).
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 (6–8). Cystatin C is a 122–amino 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 1992–1993 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 −70 °C. 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 µmol/L [1.16 mg/dL] to 344.8 µmol/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 laboratory—the core laboratory of the MDRD trial—as 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 (17–19).
We also compared the rate of progression to incident chronic kidney disease at the 1996–1997 examination among participants with estimated GFR greater than 60 mL/min per 1.73 m2 at baseline (1992–1993). 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 1996–1997 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 1992–1993 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 Kaplan–Meier 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 graphs based on Schoenfeld residuals, that is, we tested for a non-zero slope in a generalized linear regression of the scaled Schoenfeld residuals on a function of time. A non-zero slope would indicate that the proportional hazards assumption is violated.
To evaluate the clinical importance of elevated cystatin C concentrations in elderly persons without chronic kidney disease, we dichotomized cystatin C concentrations at 1.0 mg/L and defined an elevated cystatin C concentration to be 1.0 mg/L or greater. We chose this cut-point on the basis of 1) the proximity to the upper limit of the normal reference range (0.53 mg/L to 0.95 mg/L) in both young and middle-aged blood donors (12) and 2) the increased risk for death and cardiovascular events in our study and previous studies (21, 22). We categorized participants into 3 groups: 1) chronic kidney disease (estimated GFR < 60 mL/min per 1.73 m2), 2) no chronic kidney disease and high cystatin C concentration (estimated GFR ≥ 60 mL/min per 1.73 m2 and cystatin C level ≥ 1.0 mg/L), and 3) no chronic kidney disease and low cystatin C (estimated GFR ≥ 60 mL/min per 1.73 m2 and cystatin C level <1.0 mg/L).
We compared the incidence rates (events per 1000 person-years) of each outcome among these 3 groups. We used unadjusted and adjusted proportional hazards models to estimate the relative hazard of each outcome of interest among participants with chronic kidney disease and participants with no chronic kidney disease and high cystatin C levels compared with participants with no chronic kidney disease and low cystatin C levels. Multivariate models adjusted for the secondary predictors listed earlier. We performed formal hypothesis tests and graphical diagnostics to test the proportional hazards assumption.
For the outcome of incident chronic kidney disease, we used logistic regression to compare the proportions of participants with no chronic kidney disease and high cystatin C levels and participants with no chronic kidney disease and low cystatin C levels who progressed to subsequent chronic kidney disease at the 1996–1997 visit. Multivariate logistic regression models were adjusted for the secondary predictors listed earlier. Among participants with no chronic kidney disease and high cystatin C levels, we compared mortality rates and cardiovascular risk subsequent to the 1996–1997 visit among those who did progress or did not progress to chronic kidney disease. We conducted these analyses with multivariable proportional hazards models. We updated all secondary predictors, including prevalent cardiovascular disease, to the 1996–1997 visit.
We used S-PLUS, release 6.1 (Insightful Corp., Seattle, Washington), and SPSS statistical software, release 13.0.1 (SPSS Inc., Chicago, Illinois), for the analyses. We considered a P value less than 0.050 to be statistically significant.

Role of the Funding Source

This study was funded through contracts with the National Heart, Lung, and Blood Institute (NHLBI). The funding source had a role in the data collection, analysis, and interpretation of the study and in the manuscript preparation. Drs. Katz and Siscovick at the CHS Coordinating Center at the University of Washington, Seattle, Washington, had full access to all the data files.

Results

Among the 4663 participants in our study, 1004 (22%) had chronic kidney disease and 3659 (78%) had no chronic kidney disease. Among participants with chronic kidney disease, the mean cystatin C concentration, creatinine concentration, and estimated GFR were 1.5 mg/L, 123.8 µmol/L (1.4 mg/dL), and 50 mL/min per 1.73 m2, respectively. Among those without chronic kidney disease, the mean values were 1.0 mg/L, 79.6 µmol/L (0.9 mg/dL), and 83 mL/min per 1.73 m2, respectively. The Pearson correlations (r) of cystatin C with creatinine and with estimated GFR were 0.81 and −0.75 (both P < 0.001), respectively, among persons with chronic kidney disease and 0.38 and −0.46 (both P < 0.001), respectively, among persons without chronic kidney disease. These correlations with cystatin C were significantly stronger among the subgroup with chronic kidney disease than among the subgroup without chronic kidney disease (P < 0.001 for both correlations by the Fisher exact test). Figure 1 shows the distributions of creatinine and cystatin C concentrations among CHS participants without chronic kidney disease.
Figure 1. Distribution of creatinine concentration ( top ) and cystatin C concentration ( bottom ) in elderly participants without chronic kidney disease.  To convert creatinine values from mg/dL to µmol/L, multiply by 88.4.
Figure 1. Distribution of creatinine concentration (
top ) and cystatin C concentration ( bottom ) in elderly participants without chronic kidney disease.
To convert creatinine values from mg/dL to µmol/L, multiply by 88.4.
We compared the ability of creatinine, estimated GFR, and cystatin C to distinguish mortality risk among persons without chronic kidney disease. For each measure of kidney function, our models used P-splines adjusted for age, sex, and race. As shown in Figure 2 (top and middle), we observed essentially no gradient of risk across the distributions of creatinine and estimated GFR. However, elevated cystatin C concentrations were associated with incrementally increasing mortality risk, particularly those more than 1.0 mg/L (Figure 2, bottom).
Figure 2. Spline plots displaying association of creatinine concentration ( top ), estimated glomerular filtration rate ( GFR ) ( middle ), and cystatin C concentration ( bottom ) with risk for death across the full range in the subcohort of participants without chronic kidney disease.  To convert creatinine values from mg/dL to µmol/L, multiply by 88.4. MDRD = Modification of Diet in Renal Disease.
Figure 2. Spline plots displaying association of creatinine concentration (
top ), estimated glomerular filtration rate ( GFR ) ( middle ), and cystatin C concentration ( bottom ) with risk for death across the full range in the subcohort of participants without chronic kidney disease.
To convert creatinine values from mg/dL to µmol/L, multiply by 88.4. MDRD = Modification of Diet in Renal Disease.
We confirmed the appearance of the spline plots for death in multivariate proportional hazards models that evaluated cystatin C and creatinine as continuous variable predictors of death and cardiovascular risk (Table 1). Each SD (0.18 mg/L) increase in cystatin C concentration was statistically significantly associated with a 20% to 40% increased risk for each outcome. In contrast, creatinine concentrations had associations with each outcome that were much weaker and were statistically significant only for cardiovascular death.
Table 1. Comparison of Cystatin C and Creatinine Concentrations as Predictors of Cardiovascular Events and Death among Participants with an Estimated Glomerular Filtration Rate of 60 mL/min per 1.73 m2 or Greater
Table 1. Comparison of Cystatin C and Creatinine Concentrations as Predictors of Cardiovascular Events and Death among Participants with an Estimated Glomerular Filtration Rate of 60 mL/min per 1.73 m2 or Greater
Among the participants without chronic kidney disease, we dichotomized cystatin C concentrations as low (<1.0 mg/L [n = 1798]) and high (≥1.0 mg/L [n = 1861]). We compared death and cardiovascular risk among participants who were categorized as having chronic kidney disease, no chronic kidney disease and high cystatin C levels, and no chronic kidney disease and low cystatin C levels. For each outcome, persons with no chronic kidney disease and high cystatin C levels had higher rates of adverse events than persons with no chronic kidney disease and low cystatin C levels. These increased event rates (per 1000 years of follow-up) were 23 deaths, 13 cardiovascular deaths, 10 noncardiovascular deaths, 14 incident cases of heart failure, 6 myocardial infarctions, and 4 cases of stroke (all P < 0.001) (Figure 3). For each of these outcomes, except myocardial infarction (P = 0.95), chronic kidney disease was significantly associated with additional risk compared with the persons with no chronic kidney disease and high cystatin C levels (P < 0.001 for death, cardiovascular death, and noncardiovascular death; P = 0.005 for heart failure; P = 0.015 for stroke) (Figure 3).
Figure 3. Cardiovascular events and deaths per 1000 years.
Figure 3. Cardiovascular events and deaths per 1000 years.
After adjustment for traditional risk factors, prevalent stroke, heart failure, coronary heart disease, and C-reactive protein levels, the persons with no chronic kidney disease and high cystatin C levels had statistically significantly increased risk for each outcome compared with the persons with no chronic kidney disease and low cystatin C levels. These individuals were about 50% more likely to die, were nearly twice as likely to have a cardiovascular death, and were 30% more likely to have a noncardiovascular death; in addition, they had increased risks of 40% for heart failure, 20% for stroke, and 30% for myocardial infarction (Table 2). Participants with chronic kidney disease had larger magnitudes of increased risk for death, cardiovascular death, and heart failure but had similarly increased risks for myocardial infarction and stroke. We found no differences when we repeated these analyses after stratification by race or by age (older or younger than 75 years of age) (P > 0.20 for all interaction tests).
Table 2. Mortality and Cardiovascular Risk among Elderly Persons with Chronic Kidney Disease and Elderly Persons with No Chronic Kidney Disease and High Cystatin C Concentration*
Table 2. Mortality and Cardiovascular Risk among Elderly Persons with Chronic Kidney Disease and Elderly Persons with No Chronic Kidney Disease and High Cystatin C Concentration*
Finally, we compared the proportion of participants with no chronic kidney disease and low cystatin C levels who progressed to chronic kidney disease with the proportion of participants with no chronic kidney disease and high cystatin C levels who progressed to chronic kidney disease at the 1996–1997 follow-up visit. In this analysis, we could not include participants who died (n = 571) between the 1992–1993 visit (baseline of our analysis) and the 1996–1997 visit, those who did not return for a clinical follow-up visit (n = 194), and those without creatinine measures at the 1992–1993 clinical visit (n = 705). Among 1261 participants with no chronic kidney disease and high cystatin C levels who were eligible for this analysis, 345 (27%) developed chronic kidney disease, compared with 101 (7.5%) of 1347 eligible participants with no chronic kidney disease and low cystatin C levels (unadjusted odds ratio, 4.53 [95% CI, 3.56 to 5.77]). This association was only modestly attenuated by multivariate adjustment for secondary predictors (adjusted odds ratio, 4.18 [CI, 3.25 to 5.38]), although adjustment for baseline creatinine concentration markedly attenuated the association (adjusted odds ratio, 1.96 [CI, 1.49 to 2.59]).
To determine the clinical importance of progression to chronic kidney disease among participants with no chronic kidney disease and high cystatin C levels, we compared mortality and cardiovascular risk between those who did progress and those who did not progress to incident chronic kidney disease (Table 3). Participants who had developed chronic kidney disease by the 1996–1997 visit were at substantially greater risk for death and cardiovascular events subsequent to the 1996–1997 visit compared with those who did not develop chronic kidney disease (Table 3). The magnitudes of increased risk ranged from 35% for stroke to 80% for cardiovascular death across outcomes but were statistically significant only for death, cardiovascular death, and heart failure. Compared with participants with low cystatin C levels at baseline, participants with elevated cystatin C levels who progressed to chronic kidney disease had even greater adjusted risk increases for death (hazard ratio, 2.13 [CI, 1.66 to 2.73]), cardiovascular death (hazard ratio, 3.08 [CI, 2.08 to 4.55]), heart failure (hazard ratio, 2.00 [CI, 1.38 to 2.89]), and myocardial infarction (hazard ratio, 1.86 [CI, 1.05 to 3.28]). The participants with high cystatin C levels who did not progress to incident chronic kidney disease had increased risks for death (hazard ratio, 1.54 [CI, 1.25 to 1.89]) and cardiovascular death (hazard ratio, 1.77 [CI, 1.25 to 2.52]) after the 1996–1997 visit, compared with those with low cystatin C levels.
Table 3. Mortality and Cardiovascular Risk Subsequent to the 1996–1997 Clinical Visit among Elderly Persons with Elevated Cystatin C Concentrations in 1992–1993, Stratified by Progression to Estimated Glomerular Filtration Rate Less than 60 mL/min per 1.73 m2*
Table 3. Mortality and Cardiovascular Risk Subsequent to the 1996–1997 Clinical Visit among Elderly Persons with Elevated Cystatin C Concentrations in 1992–1993, Stratified by Progression to Estimated Glomerular Filtration Rate Less than 60 mL/min per 1.73 m2*

Discussion

In our study, we evaluated serum cystatin C and creatinine concentrations as predictors of death and cardiovascular events in elderly persons without chronic kidney disease, defined by an estimated GFR of 60 mL/min per 1.73 m2 or greater. Whereas serum creatinine levels had almost no statistically significant associations with the outcomes examined in our study, cystatin C concentrations were strongly associated with risk for death, heart failure, myocardial infarction, and stroke. We defined a large group of the cohort (39% of CHS participants) who had elevated cystatin C concentrations (≥1.0 mg/L) but did not have chronic kidney disease. Not only did these participants have increased mortality and cardiovascular risk compared with those with cystatin C levels less than 1.0 mg/L, but they were also at substantially increased risk for progression to chronic kidney disease after 4 years of follow-up. Furthermore, participants with elevated cystatin C concentrations who progressed to subsequent chronic kidney disease had statistically significantly increased mortality and cardiovascular risk compared with participants with elevated cystatin C levels who did not progress to chronic kidney disease.
Taken together, the findings suggest that elevated cystatin C concentrations capture a state of preclinical kidney disease that is highly prevalent among community-dwelling elderly persons. The term preclinical has been used to describe conditions that predate the development of clinical disease and are directly associated with adverse health consequences (23–27). By suggesting that elderly persons with an estimated GFR of 60 mL/min per 1.73 m2 or greater and cystatin C levels of 1.0 mg/L or greater have preclinical kidney disease, we make a direct analogy to “prehypertension” and “prediabetes.” The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) (23) described the importance of prehypertension on the basis of the association of systolic blood pressure between 120 mm Hg and 140 mm Hg with progression to clinical hypertension and with increased risk for subsequent cardiovascular events compared with systolic blood pressure less than 120 mm Hg (23, 24). Similarly, the American Diabetes Association has defined prediabetes on the basis of fasting glucose levels between 6.11 mmol/L (110 mg/dL) and 6.94 mmol/L (125 mg/dL). Persons with prediabetes are at greater risk for progression to clinical diabetes (25) and adverse cardiovascular outcomes than persons with normal glucose tolerance (glucose level<6.11 mmol/L [<110 mg/dL]) (26, 27). Similarly, participants in our study with elevated cystatin C levels and preserved estimated GFR were at substantially increased risk for progression to adverse kidney events, cardiovascular events, and death during follow-up.
The conception that elderly persons without chronic kidney disease who have abnormal cystatin C concentrations have preclinical kidney disease rests on the assumption that cystatin C concentrations are predominantly determined by GFR. In a meta-analysis of studies that compared creatinine and cystatin C concentrations with direct measures of GFR, Dharnidharka and colleagues (7) found that immunonephelometric measures of cystatin C—as used in our study—had a mean area under the receiver-operating characteristic curve of 0.93 (CI, 0.89 to 0.96) for predicting GFR, compared with 0.84 (CI, 0.80 to 0.88) for creatinine (6, 7). A recent study also found that the association of cystatin C with GFR was independent of age and sex, which is in contrast to creatinine (28). Furthermore, a recent study by Perkins and colleagues (8) found that cystatin C correlated tightly with serial measurements of GFR by iothalamate clearance, whereas the creatinine-based MDRD was a much weaker reflection of GFR. Thus, cystatin C concentrations seem primarily to reflect GFR and to do so better than serum creatinine concentrations. However, only a few studies with relatively small sample sizes have compared the 2 filtration markers as predictors of GFR in elderly persons (29–32). In addition, few studies comparing creatinine and cystatin C as predictors of GFR have included participants with advanced comorbid conditions who would also have reduced muscle mass.
Despite its promise as a measure of kidney function, cystatin C concentration may be altered by factors other than GFR. Cystatin C concentrations seem to be inappropriately elevated in the hyperthyroid state, and they may be biased downward relative to GFR in individuals with hypothyroidism (33, 34). This influence may be an effect of thyroid hormone on cystatin C production. Similarly, use of glucocorticoids has been found to cause dose-dependent increases in cystatin C concentrations (35), which have been attributed to a promoter-mediated effect of glucocorticoids on cystatin C production (36). In addition, a study from a large Dutch cohort suggested that cystatin C concentrations may be influenced by age, sex, body mass index, tobacco use, and C-reactive protein levels independent of kidney function (22). However, because the study used creatinine clearance as the index of kidney function rather than the criterion standard of GFR, its conclusions require confirmation. Despite these potential nonrenal influences, cystatin C represents kidney function better than creatinine.
The CHS investigators have previously published several papers that compared the abilities of cystatin C and creatinine to predict cardiovascular outcomes and death across their full range of values (21, 37–40). We aimed to evaluate elevated cystatin C concentrations as a prognostic biomarker among elderly persons without chronic kidney disease, to evaluate the association of cystatin C with development of chronic kidney disease, and to classify kidney function by using a combination of estimated GFR and cystatin C. Whether kidney disease is labeled as preclinical, subclinical, or undetected, elevated cystatin C concentrations were a robust predictor of death and of cardiovascular and kidney end points among persons without chronic kidney disease. Because an estimated GFR less than 60 mL/min per 1.73 m2 seems specific for defining abnormal kidney function in elderly persons, we believe it remains the appropriate initial screening measure for kidney dysfunction. However, among persons with estimated GFR greater than 60 mL/min per 1.73 m2, measuring cystatin C concentration may be a useful test for further defining kidney function and for distinguishing levels of risk for the consequences of kidney disease.
Our study has several important limitations. Most important, we did not have direct measures of GFR, so we cannot determine the extent to which either cystatin C or creatinine concentration reflects kidney function. We cannot determine whether thyroid dysfunction could have influenced our study, because measures of thyroid-stimulating hormone were available only in about half the cohort and at the 1989–1990 visit. In addition, we lacked measures of urinary albumin excretion, so we cannot compare albuminuria and cystatin C as markers of preclinical kidney disease. The absence of albuminuria measures may have led us to misclassify an unknown fraction of participants with no chronic kidney disease and low cystatin C concentrations as having no kidney disease.
Albuminuria is without question an important predictor of cardiovascular and renal outcomes, but only 23% of persons with chronic kidney disease (estimated GFR, 30 to 60 mL/min per 1.73 m2) in the Third National Health and Nutrition Examination Survey (NHANES III) had detectable albuminuria, suggesting that albuminuria measurement may capture only one dimension of preclinical kidney disease (41). Our analyses of incident chronic kidney disease could not include persons who died or who were lost to follow-up between the 1992–1993 and 1996–1997 clinical visits, so we cannot be sure whether the loss of these participants might have biased our results. Finally, our study used an automated particle-enhanced nephelometric assay. Cystatin C concentrations measured by particle-enhanced turbidimetric immunoassay are 20% to 30% higher, so different cut-points for elevated cystatin C would be required for users of this method.
Among elderly CHS participants without chronic kidney disease, we found that cystatin C concentrations were strongly predictive of death and cardiovascular and chronic kidney disease risk, whereas creatinine levels were, at best, weakly associated with longitudinal outcomes. In this setting, we believe that elevated cystatin C concentrations of 1.0 mg/L or greater represent preclinical kidney disease, which portends increased cardiovascular and renal risk. Future studies should compare cystatin C and albuminuria as prognostic biomarkers for cardiovascular and kidney risk among elderly persons without chronic kidney disease and should determine whether cystatin C measurement will have a useful clinical role.

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Information & Authors

Information

Published In

cover image Annals of Internal Medicine
Annals of Internal Medicine
Volume 145Number 415 August 2006
Pages: 237 - 246

History

Published online: 15 August 2006
Published in issue: 15 August 2006

Keywords

Authors

Affiliations

Michael G. Shlipak, MD, MPH
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Ronit Katz, PhD
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Mark J. Sarnak, MD
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Linda F. Fried, MD, MPH
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Anne B. Newman, MD, MPH
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Catherine Stehman-Breen, MD, MS
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Stephen L. Seliger, MD
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Brian Kestenbaum, MD
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Bruce Psaty, MD, PhD
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Russell P. Tracy, PhD
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
David S. Siscovick, MD, MPH
From the San Francisco Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California; University of Washington, Seattle, Washington; Tufts-New England Medical Center, Boston, Massachusetts; Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Pittsburgh, Pennsylvania; Amgen Inc., Thousand Oaks, California; and University of Vermont College of Medicine, Burlington, Vermont.
Grant Support: Drs. Shlipak, Fried, and Katz are funded by R01 HL073208-01. Dr. Shlipak is also supported by the American Federation for Aging Research and National Institute on Aging (Paul Beeson Scholars Program), by the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program), and by R01 DK066488. Drs. Sarnak, Fried, Shlipak, Siscovick, and Newman are also supported by R01 AG027002. Dr. Fried is supported by an Advanced Research Career Development award from the Office of Research and Development, Clinical Science Research and Development, U.S. Department of Veterans Affairs. The Cardiovascular Health Study (CHS) is supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01-HC-15103 from the National Heart, Lung, and Blood Institute (NHLBI). A full list of participating CHS investigators and institutions can be found at www.chs-nhlbi.org.
Disclosures: Employment: C. Stehman-Breen (Amgen); Stock ownership or options (other than mutual funds): C. Stehman-Breen (Amgen).
Corresponding Author: Michael G. Shlipak, MD, MPH, General Internal Medicine Section, Veterans Affairs Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121; e-mail, [email protected].
Current Author Addresses: Dr. Shlipak: General Internal Medicine Section, Veterans Affairs Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121.
Dr. Katz: Collaborative Health Studies Coordinating Center, University of Washington, Box 354922, Building 29, Suite 310, 6200 NE 74th Street, Seattle, WA 98115.
Dr. Sarnak: Tufts-New England Medical Center, 750 Washington Street, Box 391, Boston, MA 02111.
Dr. Fried: Veterans Affairs Pittsburgh Healthcare System, University Drive, 111F-U, Pittsburgh, PA 15240.
Dr. Newman: Healthy Aging Research Program, Bellefield Professional Building, 130 North Bellefield Avenue, Room 532, Pittsburgh, PA 15213.
Dr. Stehman-Breen: Amgen, One Amgen Center Drive, Mailstop 38-3-C, Thousand Oaks, CA 91320.
Dr. Seliger: University of Maryland, N3W143, 22 South Greene Street, Baltimore, MD 21201.
Dr. Kestenbaum: Department of Medicine, Division of Nephrology, University of Washington, Veterans Affairs Puget Sound Health Care System, Mail Stop 111A, 1660 South Columbian Way, Seattle, WA 98108.
Drs. Psaty and Siscovick: Cardiovascular Health Research Unit, University of Washington, 1730 Minor Avenue, Suite 1360, Seattle, WA 98101-1448.
Dr. Tracy: University of Vermont College of Medicine, Colchester Research Facility, 208 South Park Drive, Suite 2, Colchester, VT 05446.
Author Contributions: Conception and design: M.G. Shlipak, M.J. Sarnak, A.B. Newman, C. Stehman-Breen, B. Kestenbaum, B. Psaty, R.P. Tracy, D.S. Siscovick.
Analysis and interpretation of the data: M.G. Shlipak, R. Katz, M.J. Sarnak, L.F. Fried, C. Stehman-Breen, S.L. Seliger, B. Psaty, D.S. Siscovick.
Drafting of the article: M.G. Shlipak, R. Katz, D.S. Siscovick.
Critical revision of the article for important intellectual content: M.G. Shlipak, R. Katz, M.J. Sarnak, L.F. Fried, A.B. Newman, C. Stehman-Breen, S.L. Seliger, B. Kestenbaum, B. Psaty, R.P. Tracy, D.S. Siscovick.
Final approval of the article: M.G. Shlipak, R. Katz, M.J. Sarnak, L.F. Fried, A.B. Newman, C. Stehman-Breen, S.L. Seliger, B. Kestenbaum, B. Psaty, R.P. Tracy, D.S. Siscovick.
Provision of study materials or patients: B. Psaty, R.P. Tracy, D.S. Siscovick.
Statistical expertise: R. Katz.
Obtaining of funding: M.G. Shlipak, R.P. Tracy.
Administrative, technical, or logistic support: M.G. Shlipak, R.P. Tracy.
Collection and assembly of data: R. Katz, B. Psaty, R.P. Tracy.

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Michael G. Shlipak, Ronit Katz, Mark J. Sarnak, et al. Cystatin C and Prognosis for Cardiovascular and Kidney Outcomes in Elderly Persons without Chronic Kidney Disease. Ann Intern Med.2006;145:237-246. [Epub 15 August 2006]. doi:10.7326/0003-4819-145-4-200608150-00003

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