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Epidemiology and Outcomes |
,¶
* General Internal Medicine Section, Veterans Affairs Medical Center, San Francisco, California; Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, California; Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland; J. Paul Sticht Center on Aging and Rehabilitation, Wake Forest Bowman Gray School of Medicine, Winston-Salem, North Carolina; || Department of Preventive Medicine, University of Tennessee, Memphis, Tennessee; ¶ California Pacific Medical Center Research Institute, San Francisco, California; # Department of Epidemiology, University of Pittsburgh Graduate School of Public Health and the Division of Geriatric Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ** The Renal-Electrolyte Division, University of Pittsburgh School of Medicine, and the Renal Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania
Address correspondence to: Dr. Michael G. Shlipak, University of San Francisco, General Internal Medicine Section, VA Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121. Phone: 415-750-2093; Fax: 415-379-5573; shlip{at}itsa.ucsf.edu
Received for publication May 24, 2005. Accepted for publication September 27, 2005.
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Abstract |
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), each quintile of cystatin C was significantly associated with increased mortality risk compared with the lowest: Hazard ratios (HR; 95% confidence intervals) quintile 1, –1.0 (referent); quintile 2, –1.74 (1.21 to 2.50); quintile 3, –1.51 (1.05 to 2.18); quintile 4, –1.49 (1.04 to 2.13); and quintile 5, –2.18 (1.53 to 3.10). These associations did not differ by gender or race. Results were consistent for cardiovascular and other-cause mortality, but not cancer mortality. Creatinine quintiles were not associated with mortality after multivariate adjustment (HR: 1.0 [referent], 1.00 [0.72 to 1.39], 0.95 [0.68 to 1.32], 1.11 [0.79 to 1.57], 1.16 [0.86 to 1.58]). Cystatin C is a strong, independent risk factor for mortality in the elderly. Future studies should investigate whether cystatin C has a role in clinical medicine. |
Introduction |
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Cystatin C is a promising new measure of kidney function that has been found to better predict GFR than creatinine. Cystatin C may have particular advantage in the elderly, as the concentrations do not seem to be influenced by age, gender, or muscle mass (10–12). Investigators from the Cardiovascular Health Study found that cystatin C had a much stronger and more linear association with mortality risk than creatinine or creatinine-based estimates of GFR (13); however, the study did not have adequate numbers of black participants to evaluate whether the association of cystatin C with mortality differed by race.
The Health, Aging, and Body Composition Study (Health ABC) is a cohort of well-functioning elderly people, aged 70 to 79 yr, that includes a large number of black men and women. In Health ABC, we measured serum cystatin C at baseline to determine whether cystatin C concentrations were associated with mortality risk. The specific objectives of these inquiries were (1) to determine the association of cystatin C concentrations with mortality risk and to contrast this association with that of serum creatinine concentrations, (2) to evaluate whether the association differed by race and gender, and (3) to investigate whether inflammatory factors were potential mediators for the association between cystatin C and mortality.
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Materials and Methods |
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Kidney Function
Cystatin C was measured at the Health ABC core laboratory (University of Vermont, Burlington, VT) using a BNII nephelometer (Dade Behring Inc., Deerfield, IL) that used a particle-enhanced immunonepholometric assay (N Latex Cystatin C) (14). Among 61 healthy individuals with three cystatin C measurements over a 6-mo period, the intraindividual coefficient of variation was 7.7%, reflecting long-term stability of the measurement. The assay range is 0.195 to 7.330 mg/L, with the reference range for young, healthy individuals reported as 0.53 to 0.95 mg/L. The assay remained stable over five cycles of freeze/thaw without change in the measurement.
Before measuring cystatin C, we compared cystatin C concentrations in serum and EDTA-citrated plasma specimens from other individuals and found a linear slope of 0.977 and R2 of 0.958 using linear regression; compared with the serum measures, the plasma measures were slightly lower on average (mean difference 0.03 ± 0.02 mg/L; absolute range of differences 0.00 to 0.07 mg/L). We chose to use the plasma specimens, which had been stored at –70°C, for the measurement of cystatin C in the Health ABC cohort. Creatinine was used as a comparative measurement of kidney function, assayed by a colorimetric technique on a Johnson & Johnson Vitros 950 analyzer (New Brunswick, NJ); the intraindividual coefficient of variation approximately 2%.
For our primary analyses, we categorized cystatin C into quintiles. We also repeated our analyses with cystatin C concentrations grouped into low (quintile 1, <0.84 mg/L), medium (quintiles 2 to 4, 0.84 to 1.18 mg/L), and high (quintile 5, >1.18 mg/L). These categories were presented to reflect better the association of cystatin C with mortality risk and to facilitate comparisons with other studies (13).
Secondary Predictors
Other characteristics were used in these analyses as adjustment variables to determine the independence of the association of serum cystatin C with mortality. These included sociodemographic factors (age, gender, race, clinical site, education level); lifestyle factors (current smoking defined by current versus former or never; alcohol use defined by 
1 drink per week, with no use defined as <1 drink per week; body mass index); comorbid conditions (diabetes defined by use of hypoglycemic agents, self-report, fasting plasma glucose 126 mg/dl or an oral glucose tolerance test 200 mg/dl; hypertension by either self-report plus use of antihypertensive medications, or measured systolic BP 140 mmHg or diastolic BP 90 mmHg; chronic heart failure, coronary heart disease, myocardial infarction, angina, coronary artery bypass, chronic obstructive pulmonary disease, and cerebrovascular disease, which all were by self-report in this study); serum chemistries (glucose, total cholesterol, HDL cholesterol, triglycerides, and albumin, all measured by a colorimetric technique on a Johnson & Johnson Vitros 950 analyzer). LDL was calculated using the Friedewald equation (15). Baseline blood draws were taken after an 8-h fast. Samples then were aliquotted and stored at –80°C until analysis; all transportation was conducted using dry ice. Medications were brought in by the participant and recorded. We were particularly interested in use of aspirin, 
blockers, angiotensin-converting enzyme inhibitors, calcium antagonists, statins, and diuretics as predictors of survival.
Measures of IL-6, TNF-, and C-reactive protein (CRP) were performed using ELISA kits from R&D Systems (Minneapolis, MN). Detectable limits were 0.10 pg/ml for IL-6, 0.18 pg/ml for TNF-, and 0.007 mg/L for CRP. Interassay coefficients of variation were determined by duplicate analyses of 150 specimens; 10.3, 8.0, and 15.8% for IL-6, CRP, and TNF-, respectively.
Outcomes
Follow-up occurred every 6 mo either by telephone or by annual visits to clinical centers. Deaths were ascertained by review of local obituaries, by reports to the clinical centers by family members, or by means of the semiannual contacts. Immediate and underlying causes of death were determined by a central adjudication committee on the basis of review of the death certificate, all recent hospital records, and interview with the next of kin. Causes of death in this analysis were categorized as cardiovascular, cancer, and infection/other, on the basis of the underlying cause adjudicated by committee according to specific prestated protocols. One death was attributable to unknown causes, and this individual was grouped with infection/other. These analyses include all deaths that had occurred through August 30, 2004.
Statistical Analyses
We used ANOVA to compare the mean (± SD) serum cystatin C concentrations by gender, by race, and across the four race/gender subgroups. We compared the distribution of each secondary predictor variable across quintiles of cystatin C, using the 
2 test for categorical variables and ANOVA for continuous variables. Certain measures were log-transformed because of their rightward skew (glucose, triglycerides, CRP, IL-6, TNF-, and creatinine). Mortality rates (%/yr) were determined by quintile of cystatin C
Staged multivariable proportional hazards models were used to evaluate the adjusted association of cystatin C quintiles with subsequent mortality risk. Following an unadjusted model, adjustments for sociodemographic characteristics, lifestyle factors, comorbid conditions, and serum chemistry measurements were made with variables that were selected on the basis of their having an unadjusted association with mortality at P < 0.05. Once we had defined the optimal adjusted model, we then tested the effects of the three inflammatory biomarkers IL-6, CRP, and TNF-. We repeated these analyses modeling cystatin C as a continuous variable.
To quantify the potential mediating effect of the inflammatory factors, we compared the parameter estimate ( coefficient) from the multivariable model before and after adjustment for each inflammatory factor. We considered the percentage change in the parameter estimate as a metric for the extent to which each biomarker mediated the association between cystatin C and mortality.
We checked the linearity of the relationship between cystatin C and all-cause mortality by the addition of a quadratic term to an unadjusted proportional hazards model. A nonlinear relationship was initially detected, but upon further examination, 12 (0.50%) cystatin C outliers were responsible for the significance of the quadratic term. The quadratic term was not significant in adjusted analyses or when the 12 outliers were excluded. These 12 individuals were included in all subsequent analyses. After determining the relation between cystatin C and all-cause mortality, we proceeded with analyses of cause-specific mortality. In these analyses, we modeled cystatin C as a continuous variable and determined the relative hazard associated with a per-SD increase in cystatin C.
We determined the mortality rates across the four gender/race subgroups. We evaluated whether gender and race modified the association of cystatin C with mortality risk. First we constructed Kaplan Meier curves plotting the mortality risk of low (quintile 1), medium (quintiles 2 to 4), and high (quintile 5) cystatin C concentrations among white women, white men, black women, and black men. We separately tested for the presence of an interaction of cystatin C quintiles with race and with gender. In addition, we tested for an interaction of cystatin C and race within each gender and of cystatin C and gender within each race.
To compare creatinine as a predictor of mortality, we categorized creatinine into gender-specific quintiles, meaning that each quintile had roughly equal numbers of men and women. We repeated the staged, multivariate analyses as described above for cystatin C for the entire cohort. We tested for creatinine interactions with gender and race, separately.
Analyses were conducted using SAS v.8 (SAS Institute, Cary, NC). Testing of the proportional hazards assumption was performed using S-Plus V6.1 (Insightful Corp., Seattle, WA). The proportional hazards assumption was met for all models. Two-sided P < 0.05 were considered statistically significant.
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Results |
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Table 1 displays baseline characteristics by quintile of cystatin C. Higher concentrations of cystatin C were associated with older age, male gender, white race, and higher body mass index (Table 1). The prevalence of diabetes, hypertension, coronary heart disease, cerebrovascular disease, and heart failure increased with ascending quintiles of cystatin C, as did higher levels of triglycerides and lower levels of LDL and HDL. Levels of the inflammatory factors CRP, IL-6, and TNF- all increased with rising quintiles of cystatin C.
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) seemed to attenuate the association of each of the upper three quintiles with mortality risk, but all quintiles remained at significantly greater risk compared with the lowest quintile. We next adjusted for the inflammatory makers individually to test for which had the greatest mediating effect. Without adjustment for inflammation, the parameter estimate ( coefficient) for the high cystatin C quintile was 1.00 ± 0.18. Adjustment for each of the biomarkers individually had the following effects on the parameter estimate: TNF- 0.82 ± 0.17, IL-6 0.93 ± 0.17, and CRP 0.95 ± 0.16. Adjustment by all three biomarkers attenuated the parameter estimate to 0.79 ± 0.18. Thus, the modest attenuation of risk related to adjustment for inflammatory markers was largely attributable to TNF- rather than IL-6 or CRP. We repeated these analyses with cystatin C modeled as a continuous variable per SD (0.34 mg/L). In the unadjusted model, each 0.34 m/L of cystatin C was associated with a 1.24-fold (95% confidence interval [CI], 1.20 to 1.28) risk for death. This result was unchanged by adjustment for sociodemographic characteristics, lifestyle factors, comorbid conditions, and serum chemistry measurements (hazard ratio [HR], 1.24; 95% CI, 1.19 to 1.30). However, adjustment for the inflammatory markers did moderately attenuate the association of cystatin C with all-cause mortality (HR, 1.16; 95% CI, 1.09 to 1.24).
Stratification by Race
The associations (HR; 95% CI) of ascending quintiles of cystatin C with mortality risk in white individuals were 1.0 (referent), 1.74 (1.01 to 3.01), 1.32 (0.75 to 2.32), 1.63 (0.96 to 2.76), and 1.93 (1.13 to 3.31) after adjustment for sociodemographic characteristics, lifestyle factors, comorbid conditions, serum chemistry, and inflammatory markers. These adjusted HR (95% CI) in black individuals were 1.0 (referent), 1.64 (1.00 to 2.70), 1.72 (1.06 to 2.81), 1.50 (0.90 to 2.50), and 2.39 (1.47 to 3.88). Increasing quintiles of creatinine were not associated with mortality risk in white or black individuals. The adjusted HR (95% CI) in white individuals were 1.0 (referent), 1.13 (0.74 to 1.70), 0.86 (0.55 to 1.34), 1.02 (0.64 to 1.64), and 1.10 (0.71 to 1.70). These adjusted HR (95% CI) in black individuals were 1.0 (referent), 0.78 (0.44 to 1.39), 1.02 (0.61 to 1.71), 1.12 (0.67 to 1.88), and 1.15 (0.72 to 1.84).
Reclassification of Risk Groups
We repeated the analyses after classifying participants as low (quintile 1), medium (quintiles 2 to 4), or high (quintile 5) risk on the basis of cystatin C concentrations (Table 3). The absolute mortality risk ranged three-fold from the low- to high-risk categories. After full adjustment for all covariates, the medium-risk group had a 57% increase in risk, and the high-risk group had a 120% increase in risk compared with low-risk participants (Table 3).
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Creatinine Quintiles and Mortality
For comparison with cystatin C, we also evaluated gender-specific quintiles of creatinine as predictors of mortality (Table 4). In unadjusted analysis, the fifth quintile had a significantly higher mortality risk compared with the first quintile, but quintiles 2 to 4 had similar risk as quintile 1. After adjustment for sociodemographic factors, prevalent diseases, and laboratory measurements, the fifth quintile remained associated with a 40% higher mortality risk in both black and white participants. Further adjustment for inflammatory biomarkers substantially attenuated this association and rendered it nonsignificant. Tests for interaction in adjusted models were not significant for race (P = 0.37) and only marginally significant for gender (P = 0.07).
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Discussion |
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The results of this study confirm the findings from the Cardiovascular Health Study (CHS) that previously compared the associations of cystatin C and creatinine with mortality risk (13). The CHS investigators similarly found that quintiles of cystatin C could define low, medium, and high mortality risk. Some differences in the cutpoints of cystatin C to define low, medium, and high risk were noted between the two studies. In CHS, the low-risk group was defined as the lower two quintiles (<1.0 mg/L), whereas in this study, the lowest risk was in participants in quintile 1 (<0.84 mg/L). Both CHS and Health ABC found the fifth quintile to be at markedly increased mortality risk, although the cutpoint for quintile 5 was 1.19 mg/L in Health ABC and 1.28 mg/L in CHS. The lower distribution of cystatin C concentrations in this study is probably due to Health ABC participants’ having been selected on the basis of preserved physical function, whereas CHS recruitment was population based. As kidney disease is associated with frailty (16), participants with kidney dysfunction would be less likely to qualify for the Health ABC study. In addition, Health ABC has a greater proportion of black participants, who seem to have lower cystatin C concentrations.
A somewhat surprising finding from this study was the absence of association across creatinine quintiles and mortality risk, as risk was elevated only in the highest quintile. Because Health ABC participants were selected for their preserved functionality, we had hypothesized that elevated creatinine concentrations would be a strong and independent prognostic factor. However, unlike the results for cystatin C, creatinine concentrations in the highest quintile were no longer associated with increased risk for death after adjustment for inflammation. Furthermore, the uniform mortality risk across the lower four quintiles contrasts sharply with the three distinct levels of risk defined by cystatin C. These observations suggest that the multiple determinants of creatinine generation in the elderly limit its utility as a prognostic marker and perhaps as a diagnostic test. The reliance on serum creatinine in clinical research up to this time may have obscured the pathophysiologic importance of kidney function in the elderly.
An important and novel aspect of this study is its ability to compare creatinine and cystatin C as mortality predictors in black and white individuals. The association of higher cystatin C concentrations with higher mortality risk was roughly uniform among black and white participants. However, we found that cystatin C was a much stronger predictor of mortality than creatinine in black and white participants. The observation that cystatin C concentrations were lower in black than in white individuals is puzzling, however, particularly as the same was found in the CHS. A possible explanation is that the black participants had better kidney function than the white participants, but this seems unlikely as the prevalences of diabetes and elevated inflammatory markers were higher in black participants overall, and black men had higher levels of systolic BP than white men (17,18). Another explanation could be that cystatin C concentrations approximate GFR differently in black and white individuals. A comparison of cystatin C and creatinine-based estimated GFR as determinants of directly measured GFR in elderly black individuals would be an important topic for future study.
Inflammatory biomarkers are known to be elevated in people with chronic kidney disease (19,20) and to be independent predictors of mortality risk in the elderly (21). This study also suggests that inflammation may modify somewhat the strength of the association between cystatin C and mortality, as inflammatory cytokines were increased in Health ABC patients in the highest quintile of cystatin C, and the point estimate for the fifth quintile was attenuated after adjustment for CRP, IL-6, and TNF-. Despite adjustment for CRP, IL-6, and TNF-, however, the association of cystatin C with mortality risk remained strong and independent. This finding argues against the hypothesis that cystatin C is primarily a reflection of systemic inflammation rather than kidney function, as has been suggested (22). Furthermore, a recent study by Perkins et al. (23) found that cystatin C correlated tightly with serial measurements of GFR by iothalamate clearance, whereas creatinine-based Modification of Diet in Renal Disease was a much weaker reflection of GFR.
The potential role of cystatin C in clinical care warrants investigation, now that two studies have shown that cystatin C more accurately predicts mortality risk than serum creatinine in older people. In addition to predicting death, cystatin C was an independent predictor of congestive heart failure, stroke, and myocardial infarction in the CHS (13,24). Two cohort studies of patients with acute coronary syndrome have found that cystatin C predicted subsequent cardiovascular events better than creatinine (25,26). To demonstrate clinical utility, however, studies will need to determine whether diagnostic or screening strategies that are based on cystatin C can change clinical practice compared with strategies that are based on creatinine or estimated GFR and thus lead to improvement in clinical outcomes.
Four limitations of this study should be considered. Because the Health ABC study was composed solely of ambulatory elderly people, the described associations of cystatin C with mortality in younger populations or among elderly with significant functional disability cannot necessarily be extrapolated. Second, we cannot be certain that the association of cystatin C with adverse outcomes is solely due to its approximation of kidney function. Although a study suggested that cystatin C was influenced by factors other than GFR, the study measured creatinine clearance rather than GFR, so its conclusions remain speculative (27). However, we are unaware of any direct toxic role of cystatin C or of a mediator activated by cystatin C or secreted temporally in association with cystatin C that would account for these findings. Third, as with any observational study, there is likely to be residual confounding. Severity differences in measured factors (e.g., hypertension, diabetes) and a variety of unmeasured factors, such as homocysteine, lipoprotein (a), oxidative stress, and asymmetric dimethyl arginine, might modify the association between higher cystatin C concentrations and mortality. However, residual confounding is unlikely to extinguish the relatively large relative risks associated with the highest quintile of cystatin C concentration. Fourth, although we believe that the cause of death classification was rigorous, we cannot exclude the possibility of misclassification. In particular, among deaths that were classified as infection/other, we cannot exclude the possibility that cardiovascular disease was also a contributor.
In summary, we found that cystatin C was a strong and independent risk factor for all-cause and cause-specific mortality in a cohort of ambulatory elderly. Quintiles of cystatin C effectively delineated participants at low, medium, and high risk regardless of race or gender, whereas creatinine quintiles were unassociated with mortality after similar adjustment. We hypothesize that the sensitivity of cystatin C relative to creatinine for small declines in kidney function is the likely explanation for the difference in risk profiles. Future studies that measure both serum cystatin C and creatinine concentrations should address the potential clinical role for cystatin C in the diagnosis and management of kidney disease and its associated complications.
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Acknowledgments |
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