Modification of Association of Cystatin C With Kidney and Cardiovascular Outcomes by Obesity

Rationale & objective: Cystatin C-based estimated glomerular filtration rate (eGFR_cys) has stronger associations with adverse clinical outcomes than creatinine-based eGFR (eGFR_cr). Obesity may be associated with higher cystatin C levels, independent of kidney function, but it is unknown whether obesity modifies associations of eGFR_cys with kidney and cardiovascular outcomes.

Study design: Cohort study.

Setting & participants: 27,249 US adults in the Reasons for Geographic and Racial Differences in Stroke Study.

Predictors: eGFR_cys, eGFR_cr, waist circumference, and body mass index (BMI).

Outcome: All-cause mortality, kidney failure, incident atherosclerotic cardiovascular disease (ASCVD), and incident heart failure (HF).

Analytical approach: Multivariable Cox and Fine-Gray models with multiplicative interaction terms were constructed to investigate whether waist circumference quartiles or BMI categories modified associations of eGFR_cys with risks of 4 clinical outcomes.

Results: Participants had a mean age of 65 years; 54% were women, 41% were Black, and 21% had an eGFR_cys<60mL/min/1.73m². The baseline prevalence of abdominal obesity (waist circumference≥88cm for women or≥102cm for men) was 48% and obesity was 38%. In multivariable adjusted analyses, each 15mL/min/1.73m² lower eGFR_cys was associated with higher HR and 95% CI of mortality in each waist circumference quartile (first quartile, 1.19 [1.15-1.24]; second quartile, 1.22 [1.18-1.26]; third quartile, 1.20 [1.16-1.24]; fourth quartile, 1.19 [1.15-1.23]) as well as within each BMI category (BMI<24.9: 1.21 [1.17-1.25]; BMI 25.0-29.9: 1.21 [1.18-1.25]; BMI 30.0-34.9: 1.20 [1.16-1.25]; BMI≥35: 1.17, [1.12-1.22]). Neither waist circumference nor BMI modified the association of eGFR_cys with mortality, kidney failure, incident ASCVD, or incident HF (all P_interaction>0.05).

Limitations: Included only Black and White persons in the United States.

Conclusion: Obesity did not modify the association of eGFR_cys with all-cause mortality, kidney failure, incident ASCVD, or incident HF. Among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.

Plain-language summary: Cystatin C is increasingly used in clinical practice to estimate kidney function, and cystatin C-based eGFR (eGFR_cys) may be used to determine risk for adverse clinical outcomes. Adiposity may increase serum levels of cystatin C, independent of kidney function. This cohort study investigated whether associations of eGFR_cys with adverse kidney and cardiovascular outcomes are modified by measures of obesity, waist circumference, and body mass index. We found that obesity does not modify associations of eGFR_cys with 4 clinical outcomes and conclude that among individuals with obesity, cystatin C may be used to provide eGFR-based risk prognostication for adverse outcomes.