Cystatin C and the Risk of Death and Cardiovascular Events among Elderly Persons
Michael G. Shlipak, M.D., M.P.H., Mark J. Sarnak, M.D., Ronit Katz, Ph.D., Linda F. Fried, M.D., M.P.H., Stephen L. Seliger, M.D., Anne B. Newman, M.D., M.P.H., David S. Siscovick, M.D., M.P.H., and Catherine Stehman-Breen, M.D.
Background Cystatin C is a serum measure of renal function thatappears to be independent of age, sex, and lean muscle mass.We compared creatinine and cystatin C levels as predictors ofmortality from cardiovascular causes and from all causes inthe Cardiovascular Health Study, a cohort study of elderly personsliving in the community.
Methods Creatinine and cystatin C were measured in serum samplescollected from 4637 participants at the study visit in 1992or 1993; follow-up continued until June 30, 2001. For each measure,the study population was divided into quintiles, with the fifthquintile subdivided into thirds (designated 5a, 5b, and 5c).
Results Higher cystatin C levels were directly associated, ina dose–response manner, with a higher risk of death fromall causes. As compared with the first quintile, the hazardratios (and 95 percent confidence intervals) for death wereas follows: second quintile, 1.08 (0.86 to 1.35); third quintile,1.23 (1.00 to 1.53); fourth quintile, 1.34 (1.09 to 1.66); quintile5a, 1.77 (1.34 to 2.26); 5b, 2.18 (1.72 to 2.78); and 5c, 2.58(2.03 to 3.27). In contrast, the association of creatinine categorieswith mortality from all causes appeared to be J-shaped. As comparedwith the two lowest quintiles combined (cystatin C level, 0.99mg per liter), the highest quintile of cystatin C (1.29 mg perliter) was associated with a significantly elevated risk ofdeath from cardiovascular causes (hazard ratio, 2.27 [1.73 to2.97]), myocardial infarction (hazard ratio, 1.48 [1.08 to 2.02]),and stroke (hazard ratio, 1.47 [ 1.09 to 1.96]) after multivariateadjustment. The fifth quintile of creatinine, as compared withthe first quintile, was not independently associated with anyof these three outcomes.
Conclusions Cystatin C, a serum measure of renal function, isa stronger predictor of the risk of death and cardiovascularevents in elderly persons than is creatinine.
The presence of renal dysfunction in elderly persons has beenassociated with an increased risk of death among healthy personsin outpatient care1,2 and among those with several clinicalfactors, including heart failure,3 acute hospitalization,4 inpatientsurgery,5,6 and acute myocardial infarction.7,8 However, theprimary clinical tool for measuring renal function, the serumcreatinine level, is insensitive for the detection of moderatereductions in renal function and is affected by factors unrelatedto renal function, such as age, sex, race, and lean muscle mass.Creatinine-based equations to estimate the glomerular filtrationrate (GFR) have been derived to compensate for these nonrenalinfluences on the relationship between creatinine and GFR, buttheir precision when applied to elderly patients is unclear.9,10,11
Cystatin C is a cysteine protease inhibitor produced by nearlyall human cells and excreted into the bloodstream. At a molecularweight of 13 kD, the protein is freely filtered by the renalglomerulus and then metabolized by the proximal tubule.12,13Given its reported superiority over creatinine as a proxy forGFR, we hypothesized that cystatin C would be a stronger andmore linear predictor of the risk of illness and death amongelderly persons than either the serum creatinine level or theestimated GFR.14 To that end, we compared the associations ofcystatin C, creatinine, and the estimated GFR with the riskof cardiovascular events and death in a population-based cohortstudy of elderly adults.
Methods
Study Design
The Cardiovascular Heath Study (CHS) is a community-based, longitudinalstudy of adults who were 65 years of age or older at the study'sinception. Its main purpose is to evaluate risk factors forthe development and progression of cardiovascular disease inelderly persons.15 The study recruited participants from Medicareeligibility lists in Forsyth County, North Carolina; SacramentoCounty, California; Washington County, Maryland; and the cityof Pittsburgh. To be eligible, persons had to be at least 65years of age, not institutionalized (i.e., living in the community),expected to remain in the current community for three yearsor longer, and not under active treatment for cancer, and beable to provide written informed consent without the need fora proxy respondent. The initial 5201 participants were enrolledfrom January 1989 to June 1990; an additional 687 black participants(with race self-reported) were recruited and enrolled by June1993. The study design, quality-control procedures, laboratorymethods, and procedures for blood-pressure measurement havebeen published previously.15,16
This analysis includes all 4637 participants who attended theannual study visit in 1992 or 1993 and for whom serum was availablefor measurement of creatinine and cystatin C. Creatinine measurementswere performed in proximity to the 1992–1993 visit, whereascystatin C was measured in 2003 using frozen serum. Follow-upfor events continued until June 30, 2001 (median follow-up,7.4 years; maximum, 8.1).
Renal-Function Assays
All assays were performed in serum specimens that had been obtainedfrom participants after a fast and were stored at –70°C.Cystatin C was measured by means of a particle-enhanced immunonephelometricassay (N Latex Cystatin C, Dade Behring) with a nephelometer(BNII, Dade Behring).17 Among 61 healthy persons with threecystatin C measurements during a six-month period, the intraindividualcoefficient of variation was 7.7 percent, reflecting the long-termstability of the cystatin C level. The range of detection ofthe assay is 0.195 to 7.330 mg per liter, with the referencerange for young, healthy persons reported as 0.53 to 0.95 mgper liter. The assay remained stable, with no change in thevalues measured, over five cycles of freezing and thawing.
Serum creatinine was measured by a colorimetric method (Ektachem700, Eastman Kodak). The mean coefficient of variation for monthlycontrols was 1.94 percent (range, 1.16 to 3.90). We estimatedthe GFR with the use of the four-variable version of the Modificationof Diet in Renal Disease (MDRD) equation.9,18
Multivariate Adjustment
Information on characteristics that might confound the associationof renal function with the risk of cardiovascular events anddeath was obtained from the records of the 1992–1993 visit.These included the demographic factors age, sex, and race (self-reported);the cardiovascular risk factors body-mass index (BMI, the weightin kilograms divided by the square of the height in meters),smoking status (current smoker vs. former smoker or never smoked),presence or absence of diabetes (defined by a history of diabetes,use of a hypoglycemic agent or insulin, or a fasting glucoselevel of 126 mg per deciliter [6.99 mmol per liter] or higher),presence or absence of hypertension (defined by an average systolicblood pressure, measured with the participant seated, of 140/90mm Hg or higher or a history of treated hypertension), low-densitylipoprotein (LDL) and high-density lipoprotein (HDL) cholesterollevels, and left ventricular hypertrophy as detected on electrocardiography;the inflammatory factors C-reactive protein level, fibrinogenlevel, leukocyte count, and albumin level; the hemoglobin level;the presence or absence of clinical disease (a history of myocardialinfarction, heart failure, stroke, chronic obstructive pulmonarydisease, or cancer); and self-reported health status (fair orpoor vs. good, very good, or excellent).
Outcomes
Follow-up visits were conducted by telephone every six monthsand in person annually. All events were adjudicated by a CHSoutcome-assessment committee. Participants with a history ofmyocardial infarction or stroke were excluded from the analysesof the incidence of events. Myocardial infarction was ascertainedfrom hospital records and was indicated by a clinical historyof cardiac symptoms, elevated cardiac enzyme levels, and serialelectrocardiographic changes.19 Cases of possible stroke wereadjudicated by a committee of neurologists, neuroradiologists,and internists on the basis of interviews with patients, medicalrecords, and brain imaging studies.20 Deaths were identifiedby a review of obituaries, medical records, death certificates,and the Centers for Medicare and Medicaid Services health care–utilizationdatabase for hospitalizations and from household contacts; 100percent complete follow-up for ascertainment of mortality statuswas achieved. Death from cardiovascular causes was defined asdeath caused by coronary heart disease, heart failure, peripheralvascular disease, or cerebrovascular disease.21
Statistical Analysis
To evaluate the association of each renal measurement with theoutcomes, we initially created quintiles of the study populationaccording to cystatin C and creatinine levels and estimatedGFR. Because creatinine levels differ substantially betweenmen and women, we used sex-specific quintiles for creatinineso as to equalize the distribution of men and women.1 A previousstudy from the CHS found substantial increases in the risk ofdeath only for persons with creatinine levels greater than 1.5mg per deciliter (133 µmol per liter) — which correspondsto the highest 6 percent of the cohort1; therefore, we subdividedthe fifth quintile of each measure into thirds. These subdivisionsof the fifth quintile for each measurement were designated 5a(the lowest third), 5b (the middle third), and 5c (the highestthird). For cystatin C and creatinine, the fifth quintile wasmade up of the participants with the highest values. For estimatedGFR, because lower values are associated with worse renal function,the fifth quintile comprised the participants with the lowestvalues.
We began our analysis by examining the distribution of the adjustmentvariables, listed above, according to the quintile of cystatinC. The annual risk for each outcome was determined for eachof the seven levels of the measures of renal function. To evaluatethe joint effects of cystatin C and creatinine on mortality,we also cross-tabulated quintiles of both measures and determinedthe annual risk within each of the 25 resulting categories.
We used Cox proportional-hazards models to evaluate the associationof each measure of renal function, categorized in the sevensubgroups, with each outcome. Covariates were identified withuse of a model that included cystatin C as a continuous predictorof each outcome; each candidate variable was entered separately,and variables that changed the parameter estimate (beta coefficient)of cystatin C by 5 percent or more were retained in the finalmodel. For each outcome, the same covariates were entered intothe models for the categories of cystatin C, creatinine, andestimated GFR. For the outcome of death, we determined the populationattributable risk for cystatin C and compared it with thosefor the other significant predictors in the final model. Predictorsthat were on a continuous scale were dichotomized by using thefifth quintile as a cutoff point. S-Plus software (version 6.1,Insightful) and SPSS statistical software (version 12.0.0) wereused for the analyses.
This study was designed by Drs. Shlipak, Katz, Fried, Siscovick,and Stehman-Breen. Drs. Shlipak, Katz, and Siscovick vouch forthe data and the analysis. The manuscript was written solelyby the listed authors. The CHS was approved by the institutionalreview boards of the University of Washington and the affiliatedclinical centers; these analyses were approved by the Committeeon Human Research of the University of California, San Francisco.All participants gave written informed consent for enrollmentand follow-up in CHS and for the future use of biologic specimens.
Results
Characteristics Associated with Cystatin C
Participants with the highest cystatin C levels were older andmore likely to be male, but less likely to be black, than participantswith lower cystatin C levels (Table 1). Nearly all of the coexistingconditions we assessed were more prevalent among those withelevated levels of cystatin C, who also had a greater waist-to-hipratio, higher leukocyte count, and higher C-reactive proteinlevels and lower levels of HDL cholesterol and hemoglobin (Table 1).In contrast, the prevalence of current smoking did not varysignificantly among the quintiles of cystatin C; in addition,among current smokers the mean number of cigarettes smoked perday was similar among the cystatin C quintiles, ranging from12 to 15 (P for trend = 0.09).
Table 1. Baseline Characteristics of Elderly Participants in the Cardiovascular Health Study, According to Quintiles of Cystatin C.
Correlation among Measures of Renal Function
Overall, the cystatin C level had a strong, direct correlationwith the creatinine level (r=0.79, P<0.001) and an inversecorrelation with the estimated GFR (r=–0.63, P<0.001).However, correlations stratified according to the quintile ofcreatinine were somewhat weak, except in the fifth quintile(correlation coefficients: first quintile, 0.18; second quintile,0.23; third quintile, 0.29; fourth quintile, 0.23; and fifthquintile, 0.80 [P<0.001 for all quintiles]). Correlationsof estimated GFR values and cystatin C levels also varied markedly,with stratification according to the quintile of estimated GFR(first through fifth quintiles, –0.31 [P<0.001], –0.09[P=0.006], –0.06 [P=0.08], –0.13 [P<0.001], and–0.75 [P<0.001]).
Risk of Death from All Causes
The incidence of death from all causes was determined for eachof the seven categories of cystatin C, creatinine, and estimatedGFR, revealing substantive differences (Figure 1). The cystatinC categories were nearly linearly associated with the risk ofdeath. In contrast, creatinine and estimated GFR appeared tohave J-shaped associations with the risk of death. We foundno interactions of cystatin C levels with age, sex, race, orBMI; in contrast, creatinine levels had significant interactionswith each of these covariates (P<0.001).
Figure 1. Mortality from All Causes According to Quintile of Measures of Renal Function.
For cystatin C, creatinine, and estimated glomerular filtration rate (GFR), the fifth quintile was subdivided into three roughly equal groups, labeled 5a, 5b, and 5c.
To explore the joint effects of cystatin C and creatinine inpredicting mortality, we determined the incidence of death withineach of the 25 subgroups defined by quintiles of cystatin Cand creatinine (Figure 2). Within each quintile of creatinine,increasing levels of cystatin C were associated with increasedmortality.
Figure 2. Mortality from All Causes According to Quintile of Both Cystatin C and Creatinine.
Participants in the Cardiovascular Health Study were divided into 25 subgroups defined according to quintiles of both creatinine and cystatin C. Within each quintile of creatinine, higher quintiles of cystatin C appeared to be associated with increased mortality. Conversely, within each quintile of cystatin C, the lowest creatinine quintile appeared to have the greatest risk of death.
After multivariate analysis, the first and second quintilesof cystatin C had a similar mortality rate, the third and fourthquintiles were associated with significantly, albeit moderately,increased risk, and all three subgroups of the fifth quintilewere associated with roughly a doubling of mortality (Table 2).Among the predictors of mortality that were retained inthe final model, the highest quintile of cystatin C was associatedwith the greatest population attributable risk (12.7 percent),followed by fair or poor self-reported health status (10.6 percent)and the presence of diabetes (7.4 percent).
Table 2. Risk of Adverse Outcomes According to Measures of Renal Function among Elderly Participants in the Cardiovascular Health Study.
For creatinine, the J-shaped association with mortality persistedin the multivariate analyses, and only the highest creatininesubgroup (5c, accounting for 7 percent of the cohort) had asignificantly increased risk of death as compared with the riskin the lowest quintile. Only the two subgroups with the lowestestimated GFR levels (5b and 5c) had a significantly increasedrisk of death in adjusted analyses.
Risk of Cardiovascular Events
The association of cystatin C with mortality from cardiovascularcauses was even stronger than its association with mortalityfrom all causes (Table 2). As compared with the first quintilein the adjusted analysis, the second quintile had a similarrisk, quintiles 3 and 4 had approximately a doubled risk, andthe subgroups of the fifth quintile had nearly a tripled risk.None of the creatinine subgroups were at significantly increasedrisk in the adjusted analysis, and only the subgroup with thelowest estimated GFR values was at increased risk.
The associations of cystatin C with newly diagnosed myocardialinfarction and stroke were less strong than was the case forthe mortality outcomes. In unadjusted analysis, a significantincrease in the risk of myocardial infarction was observed forall subgroups of cystatin C above the second quintile. However,in adjusted analysis, only the subgroup with the highest values(5c) was at significantly increased risk for myocardial infarction.Creatinine and estimated GFR subgroups had no significant associationwith myocardial infarction in either unadjusted or adjustedanalyses. In an unadjusted analysis of newly diagnosed stroke,the fifth cystatin C quintile had twice the risk of the lowestquintile. After multivariate adjustment, the highest two subgroupsof the fifth quintile remained at significantly increased risk.In unadjusted analysis, the one or two subgroups of creatinineand estimated GFR that indicated the worst renal function wereassociated with the risk of stroke; however, no significantassociations remained after multivariate adjustment.
Low, Intermediate, and High Cystatin C Levels
On the basis of the findings presented in Table 2, we combinedsubgroups into categories designated low-risk (quintiles 1 and2), intermediate-risk (quintiles 3 and 4), and high-risk (quintile5), corresponding to cystatin C levels of less than 1.00 mgper liter, 1.00 to 1.28 mg per liter, and 1.29 mg per literor more (Table 3). The intermediate-risk group had an annualrisk of death of 3.9 percent, which was similar to the averagerisk of 4.3 percent for the entire cohort. As compared withthe low-risk group, the intermediate-risk group had a moderatelyelevated risk of death from all causes and death from cardiovascularcauses; the high-risk group had a substantially greater riskof both outcomes than did either the intermediate-risk or thelow-risk group (Table 3). For newly diagnosed myocardial infarctionand stroke, being in the intermediate-risk group was not independentlyassociated with greater risk. The high-risk group had a doublingof the risk of myocardial infarction and stroke in the unadjustedanalysis and an increase in risk of roughly 50 percent for eachoutcome after multivariate adjustment.
Table 3. Risk of Death and Cardiovascular Events According to Cystatin C Risk Categories among Elderly Participants in the Cardiovascular Health Study.
Discussion
In this study, we found cystatin C to be a strong and independentpredictor of overall mortality and mortality from cardiovascularcauses in a population-based cohort of ambulatory elderly persons.Using cutoff points at the 40th and 80th percentiles of cystatinC, we defined groups at low, intermediate, and high risk withrespect to death from all causes and from cardiovascular causes(cystatin C levels: <1.00, 1.00 to 1.28, and 1.29 mg perliter, respectively). High cystatin C levels were also independentlyassociated with the risk for newly diagnosed myocardial infarctionand stroke. In contrast, only the participants in the highest7 percent of the cohort with respect to creatinine levels hada significantly increased risk of death from all causes in theadjusted analysis, and we found no independent association ofthis creatinine category with the risk of death from cardiovascularcauses, myocardial infarction, or stroke. The estimated GFRvalue, derived with use of the MDRD equation, was only a slightlybetter predictor of mortality than was the creatinine level.Thus, the cystatin C level appears to provide a stronger estimateof the risk of cardiovascular events and death among elderlypersons than either the creatinine level or the estimated GFR.
In part, these results are consistent with previous studiesdemonstrating that renal dysfunction predicts adverse cardiovascularoutcomes and death in a variety of clinical settings. However,the insensitivity of creatinine levels and estimated GFR valuesfor detecting renal dysfunction has limited their value as prognosticfactors. We previously reported that elevated creatinine levelshad a linear association with the rates of cardiovascular eventsand with mortality.22 In fact, this linear increase in riskwas observed only among participants with creatinine levelsof 1.3 mg per deciliter (115 µmol per liter) or more —the upper 14 percent of the cohort.
Not only did cystatin C levels define a subgroup (the top 20percent) of elderly persons in the CHS cohort who had a substantiallyelevated risk of death, but they also defined a large subgroup(the lowest 40 percent) at below-average risk of death. Thisobservation is intriguing and provocative, since earlier studiesin which creatinine or estimated GFR was used had found onlya high-risk group associated with high creatinine levels orlow estimated GFR values; renal function had appeared to affectthe risk of death only when it dropped below a certain threshold,such as a GFR of 60 ml per minute per 1.73 m2 of body-surfacearea.1,2,3 The linear association of cystatin C with the riskof death among participants with predominantly "normal" renalfunction may indicate that differences in renal function wellwithin the normal range have clinical significance. Future researchshould evaluate distinctions between persons with low, intermediate,and high cystatin C levels to evaluate other potential consequencesof declining renal function. In addition, though we observedno interactions with race or sex in our study, this absenceof association should be confirmed in other cohorts, since ourstudy may have had inadequate statistical power to detect suchinteractions.
An additional task for future studies will be to determine whethercystatin C could have value in clinical medicine as an improvedmeasure of renal function in elderly patients. Our findingsindicate that cystatin C is a better marker of the risk of deaththan creatinine or the estimated GFR. However, to establishthat cystatin C has clinical value, studies would have to demonstratethat knowledge of cystatin C levels could improve clinical decisionmaking — as in the evaluation of the risk–benefittrade-offs in prescribing medication, administration of intravenouscontrast material, or surgical procedures — over thatbased on creatinine levels. Although its clinical role has notyet been delineated, measurement of cystatin C is approved bythe Food and Drug Administration as a diagnostic test for kidneydysfunction.
Cystatin C may have important limitations as a marker of kidneyfunction in certain disease states. In particular, cystatinC levels appear to be elevated in patients with hypothyroidismand depressed in those with hyperthyroidism23,24,25; yet theeffect of thyroid function on cystatin C levels could reflectactual changes in GFR, which appears to vary directly with basalmetabolic rate.26 Knight and colleagues from the Preventionof Renal and Vascular End-Stage Disease (PREVEND) study reportedthat the association of cystatin C with kidney function wasinfluenced by multiple factors; however, their findings mayhave been biased by their use of creatinine clearance as thegold standard for kidney function, so it is unclear whetherthese influences are independent of kidney function.27 In contrastto the findings from PREVEND, we found no significant associationbetween cystatin C levels and the prevalence of current smokingor the number of cigarettes smoked per day. Future researchshould clarify the effects of tobacco use and clinical diseasestatus on the capacity of cystatin C levels to predict the GFR.
Our study does have certain limitations. Most important, wecannot be certain whether the strong association of cystatinC with the outcomes we studied is due solely to its correlationwith kidney function. Cystatin C may have unforeseen toxic effectsthat also contribute to the strength of its association withmortality and cardiovascular risk. We also cannot exclude thepossibility of confounding due to potential associations ofcystatin C with diseases that are independent of its correlationwith kidney function. Since the adjusted hazard ratios are substantiallydifferent from the unadjusted estimates, we may have overlookedadditional, residual confounding. In addition, CHS enrolledonly elderly persons, so we do not know whether cystatin C wouldbe a stronger predictor of mortality than creatinine for youngerpersons, in whom lean muscle makes up a greater proportion ofbody mass. We also did not calibrate serum creatinine to themethods of the Cleveland Clinic for estimating GFR, as has beenrecommended.28 However, since we grouped participants accordingto quintiles of creatinine and estimated GFR, any arithmeticconversion of the creatinine levels would have no impact onour findings, because their distribution would be unchanged.
In summary, we found that cystatin C, an alternative measureof kidney function, was a stronger predictor of the risk ofcardiovascular events and death than either creatinine or theestimated GFR. If this result is confirmed in other studies,cystatin C could be a useful prognostic tool in the evaluationof elderly patients.
Supported by a grant (R01 HL073208-01, to Drs. Shlipak, Fried,and Katz) from the National Heart, Lung, and Blood Institute.Dr. Shlipak is also supported by the American Federation forAging Research and National Institute on Aging Paul Beeson ScholarsProgram and by the Robert Wood Johnson Foundation GeneralistFaculty Scholars Program. Drs. Sarnak and Seliger are supportedby K23 awards from the National Institute of Diabetes and Digestiveand Kidney Diseases. Dr. Fried is supported by an Advanced ResearchCareer Development award from the Office of Research and Development,Medical Service, Department of Veterans Affairs. The CardiovascularHealth Study is supported by contracts (N01-HC-85079 throughN01-HC-85086, N01-HC-35129, and N01 HC-15103) with the NationalHeart, Lung, and Blood Institute.
A full list of participating CHS investigators and institutionscan be found at http://www.chs-nhlbi.org.
Source Information
From the General Internal Medicine Section, Veterans Affairs Medical Center, and the Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco — both in San Francisco (M.G.S.); the Division of Nephrology, Department of Medicine, Tufts–New England Medical Center, Boston (M.J.S.); the Collaborative Health Studies Coordinating Center, Seattle (R.K.); the Renal Section, Medical Service, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh (L.F.F.); the Division of Nephrology, University of Maryland School of Medicine, Baltimore (S.L.S.); the Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, and the Division of Geriatric Medicine, University of Pittsburgh School of Medicine, Pittsburgh (A.B.N.); the Departments of Medicine and Epidemiology, University of Washington, Seattle (D.S.S.); and Amgen, Thousand Oaks, Calif. (C.S.-B.).
Address reprint requests to Dr. Shlipak at the General Internal Medicine Section, Veterans Affairs Medical Center (111A1), 4150 Clement St., San Francisco, CA 94121 or at shlip{at}itsa.ucsf.edu.
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Cystatin C and the Risk of Death
Berghout A., Wulkan R. W., den Hollander J. G., Risch L., Drexel H., Huber A. R., Perkins B. A., Nelson R. G., Krolewski A. S., Shlipak M. G., Sarnak M. J., Fried L. F.
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0.99 mg per liter), the highest quintile of cystatin C (
1.29 mg per liter) was associated with a significantly elevated risk of death from cardiovascular causes (hazard ratio, 2.27 [1.73 to 2.97]), myocardial infarction (hazard ratio, 1.48 [1.08 to 2.02]), and stroke (hazard ratio, 1.47 [ 1.09 to 1.96]) after multivariate adjustment. The fifth quintile of creatinine, as compared with the first quintile, was not independently associated with any of these three outcomes. 
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