Pooled cohort analysis of renin-angiotensin system inhibition and the risk of kidney outcomes in APOL1-mediated chronic kidney disease in the CRIC and SPRINT studies

INTRODUCTION: Apolipoprotein L1 (APOL1) variants are common in individuals of African descent and increase risk of chronic kidney disease (CKD). Renin-angiotensin system inhibitors (RASis) are a mainstay of therapy for hypertension and proteinuric CKD but were not historically recommended as first-line anti-hypertensive therapy in Black individuals. Here, we evaluated RASis versus other antihypertensive therapy on kidney outcomes in Black individuals by APOL1 genotype. METHODS: We included Black participants with APOL1 genotyping on first-line anti-hypertensive therapy from the Chronic Renal Insufficiency Cohort (CRIC) and Systolic Blood Pressure Intervention Trial (SPRINT). We evaluated whether the impact of RASi-prescription on kidney outcomes was modified by APOL1 risk allele number or baseline albuminuria, using Cox models with inverse probability of treatment weighting and marginal structural models. RESULTS: A total of 3418 participants (62% from SPRINT), 40%, 44% and 16% carrying zero, one and two APOL1 risk alleles, respectively, were included. RASi-use compared to other first-line antihypertensive therapy was associated with a comparably lower risk of the kidney outcome in individuals with zero (hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.44-0.87]), one (HR 0.68 [95% CI 0.49-0.94]) or two risk alleles (HR 0.59 [95% CI 0.40-0.86]). This benefit was driven by albuminuric participants, but estimates were similarly low for RASi-use compared to other antihypertensive therapy in albuminuric (HR 0.62, 95% CI [0.41-0.93]) and non-albuminuric (HR 0.37, 95% CI [0.13-1.08]) participants with two APOL1 risk alleles, although the estimate was imprecise in non-albuminuric participants. CONCLUSIONS: RASi-based therapy, addressed as a time-updated pooled treatment, provided similar benefit across APOL1 genotypes, driven by albuminuric participants. Among individuals with two APOL1 risk alleles, outcomes were similar regardless of baseline albuminuria. However, further studies are needed due to small sample sizes and the inability of statistical methods to capture clinical variables that may have affected prescription changes.