CKD and cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study: interactions with age, sex, and race

Abstract

Background: Estimated glomerular filtration rate (eGFR) and albuminuria are central for diagnosis, staging, and risk evaluation in chronic kidney disease (CKD). Universal thresholds regardless of age, sex, and race are recommended, but relatively little is known about how these demographic factors alter the relationship of eGFR and albuminuria to cardiovascular outcomes.

Study design: Observational cohort study.

Setting & participants: 11,060 whites and blacks aged 52-75 years in the Atherosclerosis Risk in Communities (ARIC) Study with median follow-up of 11.2 years.

Predictors: eGFR by the CKD-EPI (CKD Epidemiology Collaboration) creatinine equation (reference, 95 mL/min/1.73 m(2)) and urinary albumin-creatinine ratio (ACR; reference, 5 mg/g).

Outcomes: Cardiovascular events (coronary disease, stroke, and heart failure) and all-cause mortality.

Measurements: Adjusted HRs associated with eGFR and ACR in subgroups according to age, sex, and race.

Results: Cardiovascular risk significantly increased at eGFR <70 mL/min/1.73 m(2) in all subgroups according to age (<65 vs ≥65 years), sex, and race (P for interaction >0.2 for these subgroups; eg, at eGFR of 30 mL/min/1.73 m(2), the adjusted HR was 2.19 [95% CI, 1.10-4.35] at age 52-64 years vs 2.23 [95% CI, 1.33-3.72] at age 65-75 years). Results were similar for mortality. Log(ACR) was associated linearly with cardiovascular risk without threshold effects in all subgroups, with some quantitative interactions. HRs according to ACR tended to be lower in men versus women (eg, at ACR of 40 mg/g, 1.18 [95% CI, 0.98-1.41] vs 1.77 [95% CI, 1.45-2.15]) and in the older versus younger population (1.24 [95% CI, 1.04-1.49] vs 1.73 [95% CI, 1.42-2.12]; P for interaction <0.01 for sex and age). Less evident interactions were observed for mortality.

Limitations: Single measurement of eGFR with creatinine and ACR and relatively narrow age range.

Conclusions: The associations of eGFR and ACR with cardiovascular events were largely similar, with some quantitative interactions, in age, sex, and racial subgroups, generally supporting universal thresholds of GFR and ACR for CKD definition/staging.

Keywords: Chronic kidney disease; all-cause mortality; cardiovascular disease; estimated glomerular filtration rate (eGFR); urinary albumin-creatinine ratio (ACR).

Figure 1

Adjusted hazard ratios (left panels) and adjusted incidence rates (right panels) and 95% CIs (shaded areas or whisker plots) of cardiovascular disease according to eGFR with 95 ml/min/1.73 m² as a reference (diamond) in each subgroup (left panels) and in the reference subgroup (right panels) of age (A–B), sex (C–D), and race (E–F). Dots on each plotted line represent statistical significance (P<0.05). Stars placed just above the y axis represent significant point-wise interactions (P<0.05) between two subgroups in multiplicative (left panels) and additive (right panels) scale (absence of stars indicates no significant point-wise interaction). Adjustments were for age, sex, race, smoking, history of cardiovascular disease, systolic blood pressure, diabetes, total cholesterol oncentration, bo index, and log-ACR.

Figure 2

Adjusted hazard ratios (left panels) and adjusted incidence rates (right panels) and 95% CIs (shaded areas or whisker plots) of cardiovascular disease according to ACR with 5 mg/g as a reference (diamond) in each subgroup (left panels) and in the reference subgroup (right panels) of age (A–B), sex (C–D), and race (E–F). Dots on each plotted line represent statistical significance (P<0.05). Stars placed just above the y axis represent significant point-wise interactions (P<0.05) between two subgroups in multiplicative (left panels) and additive (right panels) scale (absence of stars indicates no significant point-wise interaction). Adjustments were for age, sex, race, smoking, history of cardiovascular disease, systolic blood pressure, diabetes, total cholesterol concentration, body mass index, and eGFR splines.