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American Journal of Epidemiology Advance Access originally published online on October 11, 2006
American Journal of Epidemiology 2006 164(12):1180-1189; doi:10.1093/aje/kwj333
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

Cystatin C and Measures of Physical Function in Elderly Adults

The Health, Aging, and Body Composition (HABC) Study

Michelle C. Odden1, Glenn M. Chertow2, Linda F. Fried3,4, Anne B. Newman3, Stephanie Connelly5, Sara Angleman5, Tamara B. Harris5, Eleanor M. Simonsick5, Michael G. Shlipak1,6 and for the HABC Study

1 General Internal Medicine Section, San Francisco VA Medical Center, San Francisco, CA
2 Department of Nephrology, University of California, San Francisco, San Francisco, CA
3 Department of Epidemiology, University of Pittsburgh School of Medicine, Pittsburgh, PA
4 Renal Section, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA
5 National Institute on Aging, National Institutes of Health, Bethesda, MD
6 Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, CA

Correspondence to Dr. Michael G. Shlipak, General Internal Medicine Section, VA Medical Center (111A1), 4150 Clement Street, San Francisco, CA 94121 (e-mail: shlip{at}itsa.ucsf.edu).

Received for publication March 10, 2006. Accepted for publication May 2, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Most studies of the relation between kidney function and physical function have been conducted in persons with advanced kidney disease and have used creatinine-based measures of kidney function. Cystatin C concentration is a measure of kidney function that is independent of muscle mass, unlike creatinine. Using baseline data on 3,043 elderly adults from the Health, Aging, and Body Composition Study (Blacks and Whites recruited from Pittsburgh, Pennsylvania, and Memphis, Tennessee, in 1997–1998), the authors examined the cross-sectional association between cystatin C level and performance on several tests of physical function. After adjustment for demographic and lifestyle variables, chronic health conditions, and inflammation, each standard-deviation (0.34 mg/liter) increase in cystatin C concentration was associated with 1.32 odds (95% confidence interval (CI): 1.20, 1.46) of not completing a 400-m walk, a 10.9-second (95% CI: 8.1, 13.8) slower 400-m walk time, a 0.11-point (95% CI: 0.09, 0.13) reduction in lower extremity performance score, a 1.12-kg (95% CI: 0.83, 1.40) lower grip strength, and a 4.7-nm (95% CI: 3.5, 5.9) lower knee extension strength. In contrast, when kidney function was measured by estimated glomerular filtration rate, the association of kidney function with physical function was only evident below 60 ml/minute/1.73 m2. In these older adults, mild decrements in kidney function, as measured by cystatin C concentration, were associated with poorer physical function.

aging; cystatin C; exercise tolerance; kidney diseases; muscle weakness; walking

Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; Health ABC, Health, Aging, and Body Composition; MDRD, Modification of Diet in Renal Disease


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Poor physical function in persons with severe chronic kidney disease has been well-documented (1–7). In recent studies, investigators have observed an association between poor health status and more modest decrements in kidney function. Mild-to-moderate chronic kidney disease has been associated with a lower quality of life and self-reported physical limitations (8–10). Odden et al. (11) reported a significant association of creatinine clearance with exercise capacity measured on a treadmill test, particularly among persons with creatinine clearance less than 60 ml/minute. These studies suggest that declines in physical function associated with chronic kidney disease may occur earlier in the disease process than has been previously recognized.

We hypothesized that modest decrements in kidney function would be associated with multiple dimensions of physical function in elderly adults, even in those with kidney function that was nearly normal by conventional measures. To test this hypothesis, we examined the association between cystatin C concentration and four measures of physical function: a 400-m endurance walk, lower extremity performance, grip strength, and knee extension strength. Cystatin C is a cysteine proteinase inhibitor that is produced by all nucleated cells and is freely filtered by the glomerulus; because of these properties, cystatin C is a measure of kidney function that is independent of muscle mass (12, 13). Because creatinine is a by-product of muscle and its levels are related to both kidney function and muscle mass, creatinine-based measures may have limited utility in studies of physical function. We hypothesized that cystatin C concentrations would be directly and independently associated with a diminished capacity to complete the 400-m walk, slower walking time among persons completing the walk, worse lower extremity performance, and lower strength. In addition, we hypothesized that cystatin C would be more strongly associated with each of these measures than a creatinine-based measure of kidney function.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study design and participants
The Health, Aging, and Body Composition (Health ABC) Study is an ongoing prospective study designed to determine the relation of age-related changes in health and body composition with incident functional limitations in initially well-functioning elderly adults. At baseline, the cohort included 3,075 persons aged 70–79 years; 42 percent were Black and 52 percent were female. At each of the two study sites—Pittsburgh, Pennsylvania, and Memphis, Tennessee—participants were recruited from a list of Medicare beneficiaries between April 1997 and June 1998. Inclusion criteria were 1) reported ability to walk one quarter mile (0.4 km), climb 10 steps, and perform basic activities of daily living without difficulty; 2) absence of life-threatening illness; and 3) intention to remain in the current geographic area for at least 3 years. Adequate baseline plasma specimens for analysis of cystatin C and creatinine were available for 3,043 persons (99 percent), the sample size for this analysis. All participants gave informed written consent; the protocol was approved by the institutional review boards of the clinical sites and the Data Coordinating Center (University of California, San Francisco).

Measures of physical function
Long-distance corridor walk.
The long-distance corridor walk was administered over a course 20 m in length, marked by traffic cones at both ends. Participants completed a 2-minute warm-up before completing the 400-m walk. Within 30 seconds of completion of the 2-minute warm-up, participants were brought back to the start for the 400-m walk and instructed to complete 10 laps "as quickly as possible." At the end of each lap, standard encouragement was given, and participants were told the number of laps remaining. A detailed description of the 400-m walk has been published previously (14, 15). The 400-m walk has been shown to provide a valid estimate of exercise tolerance (14).

Lower extremity performance score.
A summary lower extremity performance score was derived for the Health ABC Study from a modified version of the lower extremity performance test used in the Established Populations for Epidemiologic Studies of the Elderly (16). It consisted of five repeated chair stands, semi-tandem, full tandem, and single-leg standing balance tests, a 6-m walk test to determine usual gait speed, and a narrow walk test of balance. Performance on each test was given a score on a continuous scale ranging from 0 to 1, based on performance relative to the highest attained performance in an older population. The composite score including all four tests is a continuous variable with a range of 0 to 4 points (17). The expanded battery of tests in the Health ABC score was developed to differentiate ability at the upper end of physical function (to avoid ceiling effects) and to obtain a greater dispersion of scores on each measure.

Grip and knee extension strength.
Hand grip strength was measured using a handheld isometric dynamometer (Jaymar; JLW Instruments, Chicago, Illinois), and knee extension was measured using an isokinetic dynamometer (Kin-Com 125 AP; Chattanooga Group, Inc., Chattanooga, Tennessee). Grip strength was determined as the maximum performance in four trials, two using the left hand and two using the right. Participants with severe hand pain or recent surgery were excluded. For knee extension, the right leg was used unless this was contraindicated by pain or history of joint replacement. Maximum voluntary concentric isokinetic torque was assessed at 60 percent angular velocity. Participants were allowed to make at least three maximal efforts, but no more than six, in order to produce three overlying curves, and the mean maximal torque production was recorded. Participants were excluded if they had a history of uncontrolled hypertension, stroke, bilateral knee replacement, or severe bilateral knee pain.

Measures of kidney function
Cystatin C was measured in plasma specimens at the Health ABC core laboratory (University of Vermont, Burlington, Vermont) using a BNII nephelometer (Dade Behring, Inc., Deerfield, Illinois) that utilized a particle-enhanced immunonephelometric assay (N Latex Cystatin C) (18). The plasma specimens were citrated with ethylenediaminetetraacetic acid and stored at –70°C. The coefficient of variation for between-run imprecision was less than 2 percent for cystatin C (18). Additional characteristics of the assay have been reported previously (19).

Creatinine concentration was used as a comparative measure of kidney function and was assayed by means of a colorimetric technique on a Johnson & Johnson VITROS 950 Chemistry Analyzer (Johnson & Johnson, New Brunswick, New Jersey) using the enzymatic method. The intraindividual coefficient of variation was approximately 2 percent. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated (four-variable) equation from the Modification of Diet in Renal Disease (MDRD) Study (20), as recommended by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (21). eGFR based on the MDRD equation is hereafter referred to as MDRD-eGFR. Chronic kidney disease was defined as MDRD-eGFR <60 ml/minute/1.73 m2 (22).

Potential confounders
Other characteristics included as potential confounders were as follows: sociodemographic factors (age, sex, race, clinical site, educational level, annual family income); lifestyle factors (smoking history, alcohol drinking, body mass index (weight (kg)/height (m)2)); and chronic health conditions (hypertension, diabetes, coronary heart disease, heart failure, cerebrovascular disease, peripheral arterial disease, and osteoarthritis). Hypertension, coronary heart disease, heart failure, cerebrovascular disease, peripheral arterial disease, and osteoarthritis were assessed by self-report and medication use. Diabetes was assessed by self-report, medication use, or a positive diagnosis by fasting blood glucose level or oral glucose tolerance test. Serum albumin level was measured by a colorimetric technique on a Johnson & Johnson VITROS 950 Chemistry Analyzer. Levels of C-reactive protein, interleukin 6, and tumor necrosis factor {alpha} were measured by enzyme-linked immunosorbent assay (C-reactive protein: Calbiochem, San Diego, California; interleukin 6 and tumor necrosis factor {alpha}: R&D Systems, Minneapolis, Minnesota). Detectable limits were 0.08 µg/ml for C-reactive protein (using the World Health Organization's First International Reference Standard), 0.18 pg/ml for tumor necrosis factor {alpha} (using the HSTA50 kit; R&D Systems), and 0.10 pg/ml for interleukin 6 (using the HS600 Quantikine kit; R&D Systems). Physical activity was measured as kilocalories per week of walking and exercise, assessed by means of a detailed activity questionnaire based on that of Paffenbarger et al. (23).

Statistical analysis
Cystatin C was modeled both as a continuous variable (per standard-deviation change) and as a categorical variable (categorized as low (≤0.84 mg/liter), medium (0.85–1.18 mg/liter), or high (≥1.19 mg/liter)) on the basis of previous analyses correlating these levels with mortality risk in the Health ABC Study (19). Baseline characteristics were compared across cystatin C levels (low, medium, and high) and tested for significant differences using a linear test for trend (for continuous variables) or a chi-squared test for trend (for categorical variables).

Linear regression was used to evaluate the association of cystatin C and MDRD-eGFR with each outcome measure (400-m walk time, lower extremity performance score, grip strength, and knee extension strength). Persons who did not complete the 400-m walk were excluded from the analyses evaluating 400-m walk time. Adjusted mean scores for the physical function measures were calculated for persons with low, medium, and high cystatin C levels using parameter estimates from the regression models. For comparison, we also calculated adjusted mean scores for the physical function measures in subjects with low (<60 ml/minute/1.73 m2), medium (60–87 ml/minute/1.73 m2), and high (>87 ml/minute/1.73 m2) MDRD-eGFR, corresponding to the same proportions of persons with high (21 percent), medium (58 percent), and low (21 percent) cystatin C. These models were initially adjusted for sociodemographic characteristics (age, sex, race, clinical site, education, family income). All strength models were additionally adjusted for body mass to account for body-size differences in strength. In models adjusting for sociodemographic factors, data were also stratified by MDRD-eGFR (<60 ml/minute/1.73 m2 and ≥60 ml/minute/1.73 m2) on the basis of prior research that has shown a U-shaped association between MDRD-eGFR and mortality, myocardial infarction, and stroke (19, 24).

To explore potential confounders and mediators of the associations between cystatin C and the physical function measures, we used linear regression models for 400-m walk time, lower extremity performance score, grip strength, and knee strength. We used logistic regression models for completion of the 400-m walk. Model 1 included only sociodemographic characteristics (age, sex, race, clinical site, education, family income). In model 2, we added potential confounders, including lifestyle factors (smoking history, alcohol use, body mass index, body mass index squared) and chronic health conditions (hypertension, diabetes, coronary heart disease, heart failure, cerebrovascular disease, peripheral arterial disease, and osteoarthritis); and in model 3, we added inflammatory markers (albumin, C-reactive protein, interleukin 6, tumor necrosis factor {alpha}). We performed an exploratory analysis to see whether adjustment for physical activity attenuated the relation between cystatin C and physical function. Finally, we investigated the addition of knee extension strength to the models of cystatin C and completion of the 400-m walk, time to completion of the 400-m walk, and lower extremity performance. Since four outcomes were evaluated, a p value less than 0.0125 (0.05/4) was considered statistically significant (Bonferroni correction). All statistical tests were two-sided.

We tested for interactions between cystatin C and sex and race in the fully adjusted analyses, to determine whether the associations were uniform across these groups. All analyses were conducted using Stata 8.0 (Stata Corporation, College Station, Texas).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Health ABC participants with higher cystatin C concentrations were older and more often White and male (table 1). Cystatin C was also associated with more pack-years of smoking, higher body mass index, and higher prevalences of diabetes, hypertension, coronary heart disease, cerebrovascular disease, congestive heart failure, and peripheral vascular disease. Cystatin C was also associated with higher levels of C-reactive protein, interleukin 6, and tumor necrosis factor {alpha}.


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  		TABLE 1 Baseline characteristics of participants in the Health, Aging, and Body Composition Study, 1997–1998*

 
Higher concentrations of cystatin C (per standard deviation) were significantly associated with poorer physical function, as measured by a 10.9-second (95 percent confidence interval (CI): 8.1, 13.8) slower 400-m walk time, a 0.11-point (95 percent CI: 0.09, 0.13) reduction in lower extremity performance score, a 1.12-kg (95 percent CI: 0.83, 1.40) lower grip strength, and a 4.7-nm (95 percent CI: 3.5, 5.9) lower knee extension strength, independently of sociodemographic characteristics (p < 0.001 for all). The effect sizes (differences per standard deviation of cystatin C) were consistently 10–20 percent of the standard deviation across all outcome measures. Higher levels of MDRD-eGFR (better kidney function) were not associated with poorer performance on physical function measures. For example, a one-standard-deviation lower MDRD-eGFR (worse kidney function) was associated with a 1.9-second (95 percent CI:–0.6, 4.4) faster walk time (p = 0.14).

We next stratified the linear regression models by the presence or absence of chronic kidney disease, defined as MDRD-eGFR <60 ml/minute/1.73 m2 (table 2). Higher cystatin C concentrations remained significantly associated with poorer physical function in both persons with MDRD-eGFR <60 ml/minute/1.73 m2 and persons with MDRD-eGFR ≥60 ml/minute/1.73 m2. The associations of cystatin C with the measures of physical function were slightly more prominent in persons with MDRD-eGFR ≥60 ml/minute/1.73 m2. In contrast, the relation between MDRD-eGFR and physical function was not consistent. For persons with MDRD-eGFR <60 ml/minute/1.73 m2, the expected association between MDRD-eGFR and physical function was evident, whereas for persons with MDRD-eGFR ≥60 ml/minute/1.73 m2, we observed an inverse association between MDRD-eGFR and physical function. Addition of lean body mass to the models did not alter the inverted associations of MDRD-eGFR with measures of physical function.


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  		TABLE 2 Associations of kidney function with measures of physical function in participants with and without chronic kidney disease (defined as MDRD-eGFR* <60 ml/minute/1.73 m2), Health, Aging, and Body Composition Study, 1997–1998{dagger}

 
We also compared the adjusted mean physical function parameters among persons with low, medium, and high levels of cystatin C and MDRD-eGFR after adjustment for sociodemographic characteristics (figure 1). We observed a stepwise, statistically significant increase in physical function per category of cystatin C for 400-m walk time, lower extremity performance, and grip strength. Knee extension strength was similar among persons with low or medium cystatin C levels but was significantly lower in those with high cystatin C. In multivariable regression models, adjustment for lifestyle variables and chronic health conditions modestly attenuated the association between cystatin C and the odds of completing the 400-m walk, the time to completion of the 400-m walk, and lower extremity performance (table 3). Further adjustment for inflammation attenuated the magnitude of the association with the 400-m walk measures, but all remained significant. For comparison, the longer 400-m walk time associated with a one-standard-deviation higher concentration of cystatin C, 9.0 seconds (95 percent CI: 5.1, 12.8), was greater than the time associated with the presence of osteoarthritis, 6.4 seconds (95 percent CI: –0.2, 13.1), but less than that associated with the presence of peripheral arterial disease, 12.6 seconds (95 percent CI: –0.2, 25.3). The associations of cystatin C with grip and knee extension strength were attenuated after multivariate adjustment but remained significant in the fully adjusted models (table 4).


Figure 1
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  		FIGURE 1 Mean performance on measures of physical function by level of kidney function, using baseline data on 3,043 elderly adults enrolled in the Health, Aging, and Body Composition Study in 1997–1998. The physical function measures were adjusted for age, race, sex, clinical site, education, family income, and body mass (strength measures only) using linear regression models. All comparisons were significant at p < 0.0125, except for the following: knee extension strength in persons with low levels of cystatin C versus medium levels (p = 0.24); 400-m walk time and lower extremity performance in persons with a high estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation (MDRD-eGFR) (19) versus medium MDRD-eGFR (p = 0.19 and p = 0.10, respectively); and grip strength and knee extension strength in persons with medium MDRD-eGFR versus low MDRD-eGFR (p = 0.23 and p = 0.15, respectively). Lower extremity performance score is a continuous variable with a range of 0 to 4 points (see text for details).

 

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  		TABLE 3 Associations between cystatin C level and lower-body exercise performance measures, Health, Aging, and Body Composition Study, 1997–1998

 

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  		TABLE 4 Associations between cystatin C level and strength measures, Health, Aging, and Body Composition Study, 1997–1998

 
Adjustment for physical activity did not greatly alter any of the associations between kidney function and physical function. After adjustment for physical activity, the odds ratio for completing the 400-m walk was 1.15 (95 percent CI: 1.01, 1.30; p = 0.03), and the regression coefficients for the measures of physical function per standard deviation of cystatin C were as follows: time to completion of the 400-m walk, 8.7 seconds (95 percent CI: 4.9, 12.5); lower extremity performance, –0.09 points (95 percent CI: –0.12, –0.07); grip strength, –0.90 kg (95 percent CI: –1.27, –0.53); and knee extension strength, –4.0 nm (95 percent CI: –5.6, –2.5) (p < 0.001 for all measures).

In a final series of models, adjustment for knee extension strength did not materially affect the association of cystatin C with completion of the 400-m walk (odds ratio = 1.15, 95 percent CI: 1.00, 1.32; p = 0.05), but it reduced the association with 400-m walk time by 37 percent (5.7 seconds, 95 percent CI: 1.9, 9.4; p = 0.003) and reduced the association with lower extremity performance by 30 percent (–0.07 points, 95 percent CI: –0.10, –0.05; p < 0.001).

The interactions of cystatin C with race and sex were not significant in any of the models examined. However, the association of cystatin C with strength measures appeared to be modestly stronger in Blacks as compared with Whites. Higher cystatin C was associated with a 0.68-kg (95 percent CI: 0.20, 1.17) lower grip strength in Whites, whereas in Blacks, higher cystatin C was associated with a 1.13-kg (95 percent CI: 0.55, 1.72) lower grip strength (p for interaction = 0.06). We found similar results for knee extension strength; the coefficient was –2.9 nm (95 percent CI: –4.9, –1.0) in Whites and –5.5 nm (95 percent CI: –8.0, –2.9) in Blacks (p for interaction = 0.12).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this study, higher plasma concentrations of cystatin C were consistently associated with poorer performance on four measures of physical function, and these associations persisted after adjustment for sociodemographic factors, lifestyle, chronic health conditions, inflammation, and physical activity. Worse kidney function, as estimated by a creatinine-based measure (MDRD-eGFR), was associated with a slower 400-m walk time, a reduction in lower extremity performance, and lower strength among persons with MDRD-eGFR <60 ml/minute/1.73 m2. Paradoxically, among persons with MDRD-eGFR ≥60 ml/minute/1.73 m2, higher MDRD-eGFR (better estimated kidney function) was associated with worse physical function. The observed U-shaped association between MDRD-eGFR and physical function probably represents the misclassification of subjects with low creatinine levels as having normal kidney function, whereas low creatinine levels in many elderly persons are probably indicative of reduced muscle mass and frailty. Therefore, when evaluating the associations of estimates of kidney function with physical function, body composition, and nutrition- and inflammation-related conditions, cystatin C may provide a particular advantage over creatinine-based estimates of kidney function, especially in subjects with kidney function that is presumed to be nearly normal.

These findings expand upon prior research on physical performance among persons with severe chronic kidney disease. Numerous studies have shown that end-stage renal disease patients on dialysis have a reduced peak oxygen consumption when compared with healthy controls (5–7, 25–28), and a similar decrement in exercise capacity has been observed among persons with advanced (stages 4 and 5) chronic kidney disease (2, 3, 5). A study of 20 patients with severe (stage 5) chronic kidney disease, not on dialysis, who were undergoing bicycle exercise testing found that they retained only 74 percent of normal working capacity (3). In a study of 58 patients with inulin-clearance measured glomerular filtration rates ranging from 3 ml/minute/1.73 m2 to 32 ml/minute/1.73 m2, Clyne et al. (2) also reported that glomerular filtration rate was correlated with reduced exercise capacity. In addition, studies of dialysis patients have shown reduced muscle strength in comparison with healthy controls (29–34). One study of exercise training in 25 patients with severe (stage 5) chronic kidney disease who were not on dialysis reported reduced baseline muscle function and mobility in comparison with healthy controls (35). Together, these studies show consistent evidence of reduced exercise capacity and muscle strength among persons with severe chronic kidney disease.

Less research has been conducted on physical function among persons with mild-to-moderate chronic kidney disease. One study of physical capacity found mild-to-moderate chronic kidney disease to be associated with reduced exercise capacity and self-assessed physical function in the setting of coronary artery disease (11). However, this study was conducted in a predominantly White, male cohort and included only exercise capacity as a measure of function. We believe the present findings expand upon this study by including a biracial sample of healthy elderly men and women and by using multiple objective measures of physical function. In addition, the current study uses cystatin C as a measure of kidney function, which appears to be more sensitive for capturing small changes in kidney function, particularly among persons with mild decrements in kidney function (36).

Although the reasons for poor physical function in persons with kidney disease have been explored extensively, the exact mechanism remains elusive. Previous studies have demonstrated that levels of inflammatory variables are elevated in kidney disease (37–39), but there has been conflicting evidence regarding the role of inflammation as a potential mediator of reduced physical function in persons with kidney disease (40, 41). The large size of the Health ABC cohort allowed for identification of a small mediating effect of inflammation on the association between kidney function and physical function. Anemia clearly plays a role in the poor physical capacity of these subjects, but a prior study of subjects with mild-to-moderate kidney disease found reduced exercise capacity to be independent of anemia (11). Uremic myopathy and the resulting poor oxygen utilization has also been suggested as a potential mechanism for the reduced physical capacity of dialysis patients (4). Our study indicates that lifestyle, chronic health conditions, inflammation, and physical inactivity only moderately attenuate the relation between cystatin C and physical function. In contrast, adjustment for quadriceps strength attenuated the association between kidney function and 400-m walk time by almost 40 percent and attenuated the association between kidney function and lower extremity performance by 30 percent. These findings suggest that reduced muscle function may mediate the association of kidney function with lower body performance and exercise tolerance.

While the associations of kidney dysfunction, measured by cystatin C, with reduced physical function were somewhat modest, they were consistent across all outcome measures. In fully adjusted models, the slower 400-m walk time associated with a one-standard-deviation higher concentration of cystatin C was greater than the time associated with the presence of osteoarthritis but less than that associated with the presence of peripheral arterial disease. Kidney function appears to be an underrecognized correlate of physical function in the elderly. In addition, these findings underscore the importance of small decrements in kidney function as a potential correlate of adverse outcomes. Further understanding of the determinants of the progression of kidney disease may allow for a better understanding of functional decline and the aging process.

This study had several limitations that should be considered. It was a cross-sectional study, which limited our ability to determine the direction of the association or causality. We cannot exclude the possibility that some residual confounding due to unmeasured factors remained. For example, hemoglobin level was not recorded, so we could not assess whether anemia was a mediating factor in the relations among kidney function and physical performance measures in this cohort. Finally, cystatin C may have effects other than its indirect association with glomerular filtration rate (42).

In conclusion, impaired kidney function as measured by plasma cystatin C concentration was significantly associated with poorer performance on a 400-m walk, which is highly indicative of diminished exercise tolerance, and with a reduction in lower extremity performance and lower strength, independently of demographic characteristics, lifestyle variables, chronic health conditions, inflammation, and physical activity. These findings suggest that physical function is reduced among patients in the early stages of chronic kidney disease. This loss of function may lead to reduced quality of life or subsequent development of mobility limitations or disability. Longitudinal studies of kidney function, physical function, and potential mediators of functional decline are needed in order to better understand the mechanisms underlying the associations described herein. This may enable the development of prevention and treatment strategies for maintaining physical function in populations with kidney dysfunction.


   ACKNOWLEDGMENTS
 
This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106). Dr. Michael G. Shlipak was supported by the National Heart, Lung, and Blood Institute (grant R01 HL073208-01); the National Institute for Diabetes and Digestive and Kidney Diseases (grant R01 DK 066488); the American Federation for Aging Research and the National Institute on Aging (Paul Beeson Scholars Program); and the Robert Wood Johnson Foundation (Generalist Faculty Scholars Program).

Conflict of interest: none declared.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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