Kidney Function and Cardiovascular Events in Postmenopausal Women: The Impact of Race and Ethnicity in the Women's Health Initiative

Abstract

Background: Kidney disease disproportionately affects minority populations, including African Americans and Hispanics; therefore, understanding the relationship of kidney function to cardiovascular (CV) outcomes within different racial/ethnic groups is of considerable interest. We investigated the relationship between kidney function and CV events and assessed effect modification by race/ethnicity in the Women's Health Initiative.

Study design: Prospective cohort study.

Setting & participants: Baseline serum creatinine concentrations (assay traceable to isotope-dilution mass spectrometry standard) of 19,411 postmenopausal women aged 50 to 79 years who self-identified as either non-Hispanic white (n=8,921), African American (n=7,436), or Hispanic (n=3,054) were used to calculate estimated glomerular filtration rates (eGFRs).

Predictors: Categories of eGFR (exposure); race/ethnicity (effect modifier).

Outcomes: The primary outcome was the composite of 3 physician-adjudicated CV events: myocardial infarction, stroke, or CV-related death.

Measurements: We evaluated the multivariable-adjusted associations between categories of eGFR and CV events using proportional hazards regression and formally tested for effect modification by race/ethnicity.

Results: During a mean follow-up of 7.6 years, 1,424 CV events (653 myocardial infarctions, 627 strokes, and 297 CV-related deaths) were observed. The association between eGFR and CV events was curvilinear; however, the association of eGFR with CV outcomes differed by race (P=0.006). In stratified analyses, we observed that the U-shaped association was present in non-Hispanic whites, whereas African American participants had a rather curvilinear relationship, with lower eGFR being associated with higher CV risk, and higher eGFR, with reduced CV risk. Analyses among Hispanic women were inconclusive owing to few Hispanic women having very low or high eGFRs and very few events occurring in these categories.

Limitations: Lack of urinary albumin measurements; residual confounding by unmeasured or imprecisely measured characteristics.

Conclusions: In postmenopausal women, the patterns of association between eGFR and CV risk differed between non-Hispanic whites and African American women.

Keywords: African American; CV death; CV events; CV risk; Cardiovascular disease (CVD); Hispanic; Women’s Health Initiative (WHI); estimated glomerular filtration rate (eGFR); kidney disease; myocardial infarction (MI); race/ethnicity; renal function; serum creatinine; stroke.

Figure 1. Flow Diagram of WHI CVD Biomarker Study Cohort

Our analysis was restricted to a subset of WHI participants who participated in the WHI Core Biomarker Studies, including 8,505 African American and 3,503 Hispanic participants who comprised the WHI Single Nucleotide Polymorphism (SNP) Health Association Resource (SHARe) cohort and 10,300 participants of European ancestry who had participated in the WHI Memory Study or whose samples were analyzed in another WHI ancillary study, the Genomic and Randomized Trials Network (GARNET) study.(17) The African American and Hispanic participants in the SHARe cohort were drawn from the observational study and the clinical trial components. The participants of European ancestry were drawn from the hormone therapy components. The participants in these trials provided baseline data on various cardiovascular disease biomarkers including creatinine. After excluding participants whose serum creatinine measurements were not available (n=197) and/or those with missing data on covariates of interest (n=2,700), the final cohort included 19,411 participants. Abbreviations: SHARe, WHI SNP Health Association Resource; GWAS, Genome-Wide Association Study; WHIMS, WHI Memory study; GARNET, Genomic and Randomized Trials Network; CVD, cardiovascular disease.

Figure 2. Distribution of Estimated Glomerular Filtration Rate by Racial/Ethnic Group

This figure shows the distribution of eGFR, stratified by self-reported race and ethnicity. Racial and ethnic groups were in mutually exclusive categories: African American, Hispanic, and non-Hispanic white. Women self-identifying as Hispanic had a higher median eGFR (93.9 [IQR, 82.5–100.5] ml/min/1.73m²) compared to non-Hispanic whites (85.7 [IQR, 74.4–92.6] ml/min/1.73m²) and eGFR comparable to African American (93.7 [IQR, 79.3–107.5] ml/min/1.73m²) participants. The range for eGFR values was widest for the African American participants and most narrow for the non-Hispanic white participants. Abbreviations: eGFR, estimated glomerular filtration rate (in mL/min/1.73m²).

Figure 3. Associations between Estimated Glomerular Filtration Rate and Time to Cardiovascular Events (Myocardial Infarction, Stroke, Cardiovascular Death); Overall and by Racial/Ethnic Group

In the overall cohort, the association between eGFR and CV events curvilinear; effect modification by race and ethnicity was present in an omnibus test (P=0.006) as well as in a stratum-specific test for interaction by non-Hispanic white versus African American racial/ethnic group membership (P=0.001). Stratum-specific interaction was not found between Hispanic versus non-Hispanic white racial/ethnic group membership (P=0.4). In stratified analyses, we observed that the U-shaped association was present in non-Hispanic whites, whereas black participants had a rather curvilinear relationship with lower eGFR being associated with reduced (CV risk) and higher eGFR with increased CV risk. Analyses among Hispanic women were inconclusive owing to few Hispanic women having very low or high eGFR and very few events occurring in these categories. Multivariable adjustment for HRs included age, presence of diabetes, history of stroke, history of myocardial infarction, body mass index, physical activity, physical function, history of smoking, history of alcohol use, C- reactive protein, blood pressure, use of antihypertensives, and LDL and HDL. Reference group was defined as eGFR 75–90 ml/min/1.73m². Abbreviations: eGFR, estimated glomerular filtration rate (in mL/min/1.73m²).