Kidney Function and Aortic Valve and Mitral Annular Calcification in the Multi-Ethnic Study of Atherosclerosis (MESA)

Kidney Function and Aortic Valve and Mitral Annular Calcification in the Multi-Ethnic Study of Atherosclerosis (MESA) Joachim H. Ix, MD, MAS,1,2 Michael G. Shlipak, MD, MPH,1,3,4 Ronit Katz, PhD,5 Matthew J. Budoff, MD,6 David M. Shavelle, MD,6 Jeffrey L. Probstfield, MD,7 Junichiro Takasu, MD,6 Robert Detrano, MD,6 and Kevin D. O’Brien, MD7 Background: Aortic valve calcification (AVC) and mitral annular calcification (MAC) are highly prevalent and predictive of mortality in end-stage renal disease populations. Whether less severe kidney dysfunction is associated with AVC and MAC is uncertain. Study Design: Cross-sectional study. Setting & Participants: Ethnically diverse middle-aged adults without clinically apparent cardiovascular disease who participated in the Multi-Ethnic Study of Atherosclerosis. Predictor: Estimated glomerular filtration rate (eGFR), cystatin C, and microalbuminuria. Outcomes & Measurements: AVC and MAC were determined by means of computed tomography. Multivariable logistic regression evaluated the association of kidney function with AVC and MAC. Results: Of 6,785 participants, 10% had an eGFR less than 60 mL/min/1.73 m2 (⬍1.0 mL/s/1.73 m2), mean cystatin C level was 0.9 ⫾ 0.2 mg/L, 7% had microalbuminuria (albumin ⱖ 30 mg/g), 15% had diabetes, 13% had AVC, and 9% had MAC. In adjusted analyses for AVC, eGFR less than 60 mL/min/1.73 m2 (adjusted odds ratio, 1.23; 95% confidence interval, 0.99 to 1.14) and greater cystatin C concentrations (per SD increase; adjusted odds ratio, 1.06; 95% confidence interval, 0.99 to 1.14) had modest associations. Microalbuminuria was not associated independently with AVC (adjusted odds ratio, 1.11; 95% confidence interval, 0.89 to 1.40). For the MAC end point, associations of eGFR less than 60 mL/min/1.73 m2 and greater cystatin C level differed by diabetes status (P for interaction ⫽ 0.1 and 0.02, respectively). In persons with diabetes, eGFR less than 60 mL/min/1.73 m2 (adjusted odds ratio, 2.03; 95% confidence interval, 1.26 to 3.25) and greater cystatin C level (adjusted odds ratio, 1.38; 95% confidence interval, 1.14 to 1.68) were associated strongly, whereas no association was observed in subjects without diabetes (eGFR ⬍ 60 mL/min/1.73 m2: adjusted odds ratio, 1.13; 95% confidence interval, 0.86 to 1.49; cystatin C: adjusted odds ratio, 1.03; 95% confidence interval, 0.93 to 1.13). The association of microalbuminuria with MAC (adjusted odds ratio, 1.37; 95% confidence interval, 1.06 to 1.76) did not differ by diabetes status (P for interaction ⫽ 0.2). Limitations: There were few participants with severe kidney disease. Conclusions: Impaired kidney function had only a modest association with AVC, whereas its association with MAC was observed only in persons with diabetes. Future studies should evaluate whether associations of kidney impairment with dystrophic calcification differ by diabetes status in other clinical settings and vascular beds. Am J Kidney Dis 50:412-420. © 2007 by the National Kidney Foundation, Inc. INDEX WORDS: Calcium; kidney disease; heart valve; computed tomography; cystatin C; albuminuria.

ersons with end-stage renal disease have high rates of aortic valve calcification (AVC) and mitral annular calcification (MAC).1-5 Both AVC and MAC independently predict cardiovascular disease events4,6 and all-cause mor-

P

tality4,5 in end-stage renal disease populations, as well as in the general population.7 Several studies showed an association between moderate kidney disease and coronary artery calcification.8-10 Conversely, only 1 study examined the

From the Departments of 1Medicine (2Nephrology) and Epidemiology and Biostatistics, University of California, San Francisco; 4VA Medical Center, San Francisco, CA; 5Department of Biostatistics, Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA; 6Department of Medicine (Cardiology), Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA; and 7Department of Medicine (Cardiology), University of Washington, Seattle, WA.

Received January 29, 2007. Accepted in revised form May 29, 2007. Originally published online as doi: 10.1053/j.ajkd.2007.05.020 on July 24, 2007. Address correspondence to Joachim H. Ix, MD, Division of Nephrology, Department of Medicine, Box 0532, HSE 672, University of California, San Francisco, San Francisco, CA 94143-0532. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/5003-0011$32.00/0 doi:10.1053/j.ajkd.2007.05.020

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association of moderate kidney disease with AVC or MAC,11 and no study examined potential associations of early decreases in kidney function with valvular calcification. Prior studies evaluating the association of chronic kidney disease with measures of dystrophic calcification may have been limited by the use of serum creatinine and associated estimating equations as the measure of kidney function.8-11 These measures are not sensitive to changes in kidney function in the normal or near-normal range. For example, kidney function may decrease by as much as 50% before serum creatinine levels are greater than the normal laboratory range.12,13 Similarly, the Modification of Diet and Renal Disease (MDRD) Study equation for estimated glomerular filtration rate (eGFR) is inaccurate for persons with eGFR of 60 mL/min/1.73 m2 or greater (ⱖ1.0 mL/s/1.73 m2).14,15 Cystatin C is a novel endogenous marker of kidney function that is more sensitive for detecting decreases in kidney function in this range.14,16-19 Because coronary artery and valvular calcification share many similar risk factors20-22 and pathological features,21,23,24 we hypothesized that mild to moderate decreases in kidney function would be associated with AVC and MAC independent of traditional cardiovascular risk factors. We evaluated the associations of kidney disease with MAC and AVC in a large and ethnically diverse cohort, the Multi-Ethnic Study of Atherosclerosis (MESA). To more fully capture the associations, we used 3 measures of kidney function; eGFR by means of the MDRD Study equation, serum cystatin C level, and urinary albumincreatinine ratio.

of residents, dwellings, and telephone exchanges. In the last several months of the recruitment period, supplemental sources (lists of Medicare beneficiaries from the Centers for Medicare & Medicaid Services and referrals by participants) were used to ensure adequate numbers of minorities and elderly subjects. Institutional review boards at each participating center approved the study, and all participants provided written informed consent. Participants for whom serum creatinine (n ⫽ 25), AVC (n ⫽ 2), or MAC (n ⫽ 2) measurements were missing were excluded from analysis, resulting in an analytic sample of 6,785 individuals.

METHODS Participants MESA was initiated to investigate the prevalence and progression of subclinical cardiovascular disease. Details about the study design were published previously.25 In brief, between July 2000 and August 2002, a total of 6,814 men and women aged 45 to 84 years who identified themselves as Caucasian, African American, Hispanic, or Chinese and were free of clinically apparent cardiovascular disease were recruited from portions of 6 US communities: Baltimore City and Baltimore County, MD; Chicago, IL; Forsyth County, NC; Los Angeles County, CA; northern Manhattan and the Bronx, NY; and St Paul, MN. Each field site recruited from locally available sources, which included lists

Measurements

Kidney Function Both serum creatinine and cystatin C were measured from venous samples obtained after a 12-hour overnight fast. Serum creatinine concentrations were determined by using the amidinohydrolase method26 and were normalized to a reference standard at the Cleveland Clinic Foundation laboratory. Coefficient of variation was 2.2%. eGFR was calculated using the 4-variable MDRD study equation: eGFR ⫽ 186 * (serum creatinine⫺1.154) * (age⫺0.203) * (0.742 if female) * (1.21 if black).27 Urinary albumin and creatinine were measured by means of nephelometry and the rate Jaffé reaction as previously described, respectively.28 Spot urine albumin-creatinine ratios were calculated, and microalbuminuria was defined as a ratio of 30 mg/g or greater.29 Cystatin C was measured using a BNII nephelometer (Dade Behring Inc, Deerfield, IL) with a particle-enhanced immunonephelometric assay (N Latex Cystatin C; Dade Behring Inc).30 Monoclonal antibodies to cystatin C were coated on polystyrene particles that agglutinate to increase the intensity of scattered light in proportion to cystatin C concentration. The assay range is 0.195 to 7.330 mg/L. Intra-assay coefficients of variation range from 2.0% to 2.8%, and interassay coefficients of variation range from 2.3% to 3.1%.

Valvular Calcification AVC and MAC were evaluated by means of electronbeam computed tomography at 3 centers and by means of 4-slice mechanical computed tomography at 3 centers. The scanning method used in MESA was reported previously.31,32 Calcium within the mitral valve annulus (MAC) was differentiated from calcium within the left circumflex system by following the course of the left circumflex artery and differentiating it from the anatomic location of the mitral valve annulus. Scans were read centrally by experienced readers who were blinded to all clinical results at the Harbor-University of California Los Angeles Research and Education Institute. The calcium score of each lesion was calculated by multiplying lesion area by a density factor derived from maximal Hounsfield units within this area, as described by Agatston et al.33 We also used measured volume of calcium in cubic millimeters as volumetric score.34 Total calcium score was determined by summing the Agatston and volumetric scores of all individual lesions. Detailed descriptions of methods used to categorize AVC and MAC in

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MESA and their respective reproducibility were reported previously.31,35

Other Measurements Standardized questionnaires were used to obtain information for medical history, race/ethnicity, and medication use. Smoking is defined as current, former, or never. Height and weight were measured with participants wearing light clothing and no shoes. Body mass index was calculated (in kilograms per square meter). Resting blood pressure was measured 3 times with participants in the seated position by using a Dinamap model Pro 100 automated oscillometric sphygmomanometer (Critikon; General Electric, Madison, WI). The average of the last 2 measurements was used in analyses. Hypertension is defined as a systolic blood pressure of 140 mm Hg or greater, diastolic blood pressure of 90 mm Hg or greater, or current use of antihypertensive medication. Total and high-density lipoprotein cholesterol, triglycerides, and glucose were measured from venous samples obtained after a 12-hour overnight fast. Low-density lipoprotein was calculated using the Friedewald equation.36 Diabetes mellitus is defined as fasting glucose level of 126 mg/dL or greater (ⱖ6.99 mmol/L) or use of hypoglycemic medications.37

Statistical Analyses We began our analysis by using spline functions to evaluate parametric nonlinear functions for eGFR, cystatin C, and albumin-creatinine ratios. Natural piecewise cubic splines were used with the specified sequence of interior knots placed at the quartiles of the distributions of each kidney function measure. Because we observed nonlinear relationships for albumin-creatinine ratio and eGFR with each valvular outcome and prior studies showed that eGFR was inaccurate at levels of 60 mL/min/1.73 m2 or greater (ⱖ1.0 mL/s/1.73 m2),15 we categorized participants into groups on the basis of these variables by using clinically established cutoff values (eGFR ⱖ60 versus ⬍60 mL/min/1.73 m2 [ⱖ1.0 versus ⬍1.0 mL/s/1.73 m2]; albumin-creatinine ratio ⬍30 versus ⱖ30 mg/g, respectively).29,38 There were too few participants with eGFR less than 45 mL/min/1.73 m2 (⬍0.75 mL/s/1.73 m2; n ⫽ 102; 2%) to further categorize severity. Spline functions showed linear associations of cystatin C levels with each outcome; therefore, cystatin C was evaluated as a continuous predictor variable (per SD increase). Distributions of demographics and cardiovascular risk factors were compared across eGFR groups. Differences in baseline characteristics were compared using t-test for continuous variables (or Mann-Whitney rank-sum test for nonparametric variables) and chi-square test (or Fisher exact

Table 1. Baseline Characteristics of Multi-Ethnic Study of Atherosclerosis Participants by eGFR eGFR (mL/min/1.73 m2)

No. of patients Age (y) Women Ethnicity Caucasian African American Hispanic Chinese Body mass index (kg/m2) Medical history Diabetes mellitus Hypertension Current smoker Former smoker Laboratory measurements Cystatin C (mg/L) Albumin-creatinine ratio (mg/g) Total cholesterol (mg/dL) Low-density lipoprotein cholesterol (mg/dL) High-density lipoprotein cholesterol (mg/dL) Triglycerides (mg/dL) C-reactive protein (mg/dL) Cardiac valve calcification Aortic valve calcification Mitral annular calcification

ⱖ60

⬍60

P

6,132 (90) 62 ⫾ 10 3,184 (52)

653 (10) 70 ⫾ 9 400 (61)

⬍0.001 ⬍0.001

2,277 (37) 1,753 (29) 1,379 (23) 723 (12) 28.3 ⫾ 5.5

330 (51) 132 (20) 113 (17) 78 (12) 28.5 ⫾ 5.4

⬍0.001 ⬍0.001 ⬍0.01 0.9 0.5

894 (15) 2,556 (42) 827 (14) 2,214 (36)

133 (20) 450 (69) 50 (8) 244 (38)

⬍0.001 ⬍0.001 ⬍0.001 0.5

0.9 ⫾ 0.2 5.20 (3.3-10.4) 194 ⫾ 35 117 ⫾ 31 51 ⫾ 15 130 ⫾ 87 1.87 (0.82-4.22)

1.2 ⫾ 0.5 7.60 (3.8-24.1) 197 ⫾ 39 117 ⫾ 34 51 ⫾ 15 146 ⫾ 100 2.26 (1.02-4.65)

⬍0.001 ⬍0.001 0.01 0.9 0.4 ⬍0.001 ⬍0.01

165 (25) 135 (20)

⬍0.01 ⬍0.001

740 (12) 503 (8)

Note: Values expressed as mean ⫾ SD, number (percent), or median (interquartile range). Abbreviation: eGFR, estimated glomerular filtration rate.

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equivalent) for categorical variables. MAC and AVC were categorized as present (calcium score ⬎ 0) or absent. Logistic regression evaluated the association of each measure of kidney function with the presence or absence of MAC and AVC. An initial model was adjusted for age, sex, and race/ethnicity, and subsequent multivariable regression models were further adjusted for demographic and laboratory covariates. All variables listed in Table 1 were considered candidate covariates for adjustment. We retained important confounders if their inclusion led to a change greater than 5% in the association of eGFR with each outcome. Microalbuminuria and cystatin C models were adjusted for covariates identical to those retained in final eGFR models. Multiplicative interaction terms were created to evaluate for effect modification in the association of kidney function and valvular calcification by ethnicity and diabetes mellitus. Tests for interaction were limited to these variables, which were selected a priori because of hypotheses generated from prior published research.9,39 Statistical analyses were performed using SPSS 13.0.1 software for Windows (SPSS Inc, Chicago, IL) and STATA 8.0 for Windows (Stata Co, College Station, TX).

The association of microalbuminuria was no longer associated significantly with AVC (P ⫽ 0.4). We evaluated for interactions of associations between each kidney function measure with both diabetes and race/ethnicity for the outcome of AVC. We did not observe evidence for effect modification with either variable (all P for interactions ⬎0.1 for diabetes and ⬎0.2 for race/ ethnicity).

RESULTS

Participant Characteristics

Mean age of the 6,785 study participants was 63 years, and 53% were women. Caucasian, AfricanAmerican, Hispanic, and Chinese participants represented 38%, 28%, 22%, and 12% of the study sample, respectively. A total of 667 subjects (10%) had eGFR less than 60 mL/min/1.73 m2 (⬍1.0 mL/s/1.73 m2). Mean cystatin C concentration was 0.9 ⫾ 0.2 (SD) mg/L, 501 subjects (7%) had microalbuminuria, 905 participants (13%) hadAVC, and 638 (9%) had MAC. Table 1 lists baseline characteristics by eGFR groups. Persons with eGFR less than 60 mL/min/1.73 m2 were older, more frequently were women and Caucasian, had more prevalent diabetes and hypertension, and were less likely to smoke. Persons with low eGFR also had greater cystatin C levels, albumin-creatinine ratios, and total cholesterol, triglyceride, and C-reactive protein levels. Aortic Valve Calcification

In demographic-adjusted models (adjusted for age, sex, and race/ethnicity), each measure of kidney function was associated strongly with AVC (Table 2). However, after multivariable adjustment, each association was markedly attenuated, such that associations of eGFR less than 60 mL/min/1.73 m2 and greater cystatin C level with AVC were of modest strength and had only marginal statistical significance (P ⫽ 0.06).

Mitral Annular Calcification

Each measure of kidney function was associated with MAC in demographic-adjusted models (Table 3). In multivariable-adjusted models, associations were moderately attenuated, but each measure remained significantly associated with MAC. Associations of high cystatin C level with MAC differed by diabetes status (P for interactions ⫽ 0.02; Fig 1). After stratification by diabetes, there was no association of cystatin C level with MAC for subjects without diabetes. However, for subjects with diabetes, each SD increase Table 2. Association of Kidney Function With Aortic Valve Calcification

Predictor Variable

eGFR ⬍ 60 mL/min/1.73m2* Demographic adjusted† Fully adjusted‡ Cystatin C (/SD increase)§ Demographic adjusted† Fully adjusted‡ Microalbuminuria (ⱖ30 mg/g)储 Demographic adjusted† Fully adjusted‡

Odds Ratio

95% Confidence Interval

P

1.37 1.23

1.10-1.69 0.99-1.53

⬍0.01 0.06

1.11 1.06

1.04-1.19 0.99-1.14

⬍0.01 0.06

1.37 1.11

1.10-1.71 0.89-1.40

⬍0.01 0.4

Note: To convert GFR in mL/min/1.73 m2 to mL/s/1.73 m , multiply by 0.01667. Abbreviation: eGFR, estimated glomerular filtration rate. *Prevalences of aortic valve calcification were 740 of 6,118 subjects with eGFR of 60 mL/min/1.73 m2 or greater (12%) and 165 of 667 subjects with eGFR less than 60 mL/min/1.73 m2 (25%). †Age, sex, and race/ethnicity. ‡Age, sex, race/ethnicity, diabetes, hypertension, smoking status, body mass index, C-reactive protein level, high-density lipoprotein cholesterol level, and low-density lipoprotein cholesterol level. §Per 0.24 mg/L increase. 储Prevalences of aortic valve calcification were 756 of 6,109 subjects without microalbuminuria (12%) and 143 of 647 subjects with microalbuminuria (22%). 2

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Figure 1. Associations of estimated glomerular filtration rate (eGFR) and cystatin C concentration with mitral annular calcification stratified by the presence or absence of diabetes, with odds ratios (solid line) and 95% confidence intervals (dotted line). Figures show eGFR and serum cystatin C concentrations as natural cubic spline functions with knots at quartiles of each measure, adjusted for age, sex, race/ethnicity, diabetes, hypertension, smoking status, body mass index, C-reactive protein level, and high-density and low-density lipoprotein levels. P for interaction by diabetes ⫽ 0.1 for eGFR and 0.02 for cystatin C.

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Table 3. Association of Kidney Function With Mitral Annular Calcification Predictor Variable

Odds Ratio

95% Confidence Interval

1.37 1.29

1.08-1.72 1.02-1.63

⬍0.01 0.02

1.14 1.11

1.06-1.23 1.03-1.20

⬍0.001 0.01

1.56 1.37

1.22-1.99 1.06-1.76

⬍0.001 0.02

eGFR ⬍ 60 mL/min/1.73 m2* Demographic adjusted† Fully adjusted‡ Cystatin C (/SD increase)§ Demographic adjusted† Fully adjusted‡ Microalbuminuria (ⱖ30 mg/g)储 Demographic adjusted† Fully adjusted‡

P

Note: To convert GFR in mL/min/1.73 m2 to mL/s/1.73 m2, multiply by 0.01667. Abbreviation: eGFR, estimated glomerular filtration rate. *Prevalences of mitral annular calcification were 503 of 6,118 subjects with eGFR of 60 mL/min/1.73 m2 or greater (8%) and 135 of 667 subjects with eGFR less than 60 mL/min/1.73 m2 (20%). †Age, sex, and race/ethnicity. ‡Age, sex, race/ethnicity, diabetes, hypertension, smoking status, body mass index, C-reactive protein level, high-density lipoprotein cholesterol level, and low-density lipoprotein cholesterol level. §Per 0.24 mg/L increase. 储Prevalences of mitral annular calcification were 517 of 6,109 subjects without microalbuminuria (8%) and 113 of 647 subjects with microalbuminuria (17%).

in cystatin C level was associated with a 40% increased odds of MAC (Table 4, Fig 1). Results were similar with eGFR less than 60 mL/min/ 1.73 m2, but P did not reach statistical significance (P for interaction ⫽ 0.1; Fig 1; Table 4).

Microalbuminuria was associated strongly with MAC, an association that did not differ significantly by diabetes status (P for interaction ⫽ 0.2; Table 3). In the analyses with MAC end points, no effect modification was observed between

Table 4. Association of Kidney Function With Mitral Annular Calcification Stratified by Diabetes Predictor Variable

eGFR ⬍ 60 mL/min/1.73 m2 Diabetes* Demographic adjusted† Fully adjusted‡ No diabetes§ Demographic adjusted† Fully adjusted‡ Cystatin C (/SD increase)储 Diabetes Demographic adjusted† Fully adjusted‡ No diabetes Demographic adjusted† Fully adjusted‡

Odds Ratio

95% Confidence Interval

P

P for Interaction

0.1 2.11 2.03

1.33-3.34 1.26-3.25

⬍0.01 ⬍0.01

1.18 1.13

0.90-1.54 0.86-1.49

0.3 0.4 0.02

1.47 1.38

1.19-1.81 1.14-1.68

⬍0.001 ⬍0.01

1.07 1.03

0.98-1.17 0.93-1.13

0.1 0.6

Note: A total of 149 of 1,027 subjects with diabetes (15%) and 489 of 5,758 subjects without diabetes (8%) had mitral annular calcification. To convert GFR in mL/min/1.73 m2 to mL/s/1.73 m2, multiply by 0.01667. Abbreviation: eGFR, estimated glomerular filtration rate. *In the diabetic strata, 108 of 893 subjects with eGFR of 60 mL/min/1.73 m2 or greater (12%) and 41 of 134 subjects with eGFR less than 60 mL/min/1.73 m2 (31%) had mitral annular calcification. †Age, sex, and race/ethnicity. ‡Age, sex, race/ethnicity, diabetes, hypertension, smoking status, body mass index, C-reactive protein level, high-density lipoprotein cholesterol level, and low-density lipoprotein cholesterol level. §In the nondiabetic strata, 395 of 5,225 subjects with eGFR of 60 mL/min/1.73 m2 or greater (8%) and 94 of 533 subjects with eGFR less than 60 mL/min/1.73 m2 (18%) had mitral annular calcification. 储Per 0.24 mg/L increase.

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race/ethnicity and any kidney function measure (all P for interactions ⬎ 0.3). DISCUSSION

Because persons with moderate kidney dysfunction have alterations in mineral metabolism,40,41 have a greater prevalence of CAC,8-10 and are at increased risk of cardiovascular events,42 we hypothesized that kidney dysfunction would be associated independently with increased prevalences of AVC and MAC. However, in the present study, we show that lower eGFR and higher cystatin C level had only modest associations with AVC in adjusted models, whereas no association was observed with microalbuminuria. Moreover, associations of lower eGFR and higher cystatin C level with MAC were limited to persons with concomitant diabetes. These observations in part confirm findings from the Framingham Offspring Study, in which investigators observed no association of moderate kidney disease (defined as eGFR ⬍ 60 mL/ min/1.73 m2 [⬍1 mL/s/1.73 m2]) with AVC, but a modest association with MAC. However, the present report extends these observations in several important ways. First, we show that associations of lower eGFR or higher cystatin C level were limited to persons with concomitant diabetes. Second, the present report evaluated associations of cystatin C level and microalbuminuria with each valvular outcome, thereby investigating associations across a wider spectrum of kidney function. Last, the MESA cohort is larger and ethnically and geographically diverse, thereby extending the generalizability of the observations. In the MESA cohort, the association of lower eGFR and higher cystatin C level with MAC differed by diabetes status. This finding is of particular interest because a previous study showed that associations of moderate kidney disease and coronary artery calcification, a disease with similar risk factors and pathological characteristics, also was restricted to persons with diabetes.9 Diabetes is a strong independent risk factor for dystrophic calcification independent of kidney function35,43 and the leading cause of end-stage renal disease in the United States.44 Therefore, the increased prevalence of valvular calcification in persons with mild to moderate

decreases in kidney function and diabetes could reflect longer duration or increased severity of diabetes. Alternatively, factors associated with the diabetic state may accelerate dystrophic calcification at a lower threshold of kidney disease. In contrast to our observations, severe kidney dysfunction appears sufficient to promote dystrophic vascular and valvular calcification in the absence of diabetes.6,45-48 This study has several limitations. Because there were few participants with eGFR of 45 mL/min/1.73 m2 or less (ⱕ0.75 mL/s/1.73 m2), findings cannot be extrapolated to persons with more severe kidney disease. The study is crosssectional and therefore cannot determine the direction of observed associations. The association of moderate kidney disease with MAC differed qualitatively in persons with and without diabetes mellitus, but P for interaction was 0.10 and we therefore cannot exclude a chance association. However, effect modification was similar with cystatin C level, which also measures kidney clearance. Because the association of cystatin C level with each outcome was linear, we were able to evaluate the predictor as a continuous variable, thereby increasing statistical power. Nonetheless, this observation should be confirmed in future studies. Similarly, we cannot exclude that we missed modest effect modification by diabetes status in the associations of kidney function with AVC. Estimating kidney function by means of either eGFR or cystatin C in nonwhite Hispanic and Chinese subjects has not been validated in these ethnic groups. Finally, because calcium, phosphate, parathyroid hormone, and vitamin D were not measured in the MESA cohort, we could not evaluate their potential mediating effects. In conclusion, in a large and ethnically diverse cohort of persons without clinical cardiovascular disease, associations of mild to moderate decreases in kidney function with aortic valvular calcification were at most modest. Associations of mild to moderate decreases in kidney function were stronger for MAC, yet limited to persons with diabetes. Future studies should evaluate whether associations of kidney disease and dystrophic calcification differ by diabetes status in other clinical settings and in other vascular tissues and, if confirmed, evaluate the mechanisms responsible.

Kidney Function and Valvular Calcification in MESA ACKNOWLEDGEMENTS Cystatin-C assays were donated to the National Heart, Lung, and Blood Institute for measurement in the MESA cohort by Dade Behring Inc. Support: This study was supported by an American Heart Association Fellow to Faculty Transition Award (J.H.I.), a grant from the National Heart, Lung, and Blood Institute (RO1 HL63963-01A1; M.B. and J.T.), and contracts N01HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. Financial Disclosure: None.

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