APOL1 Genotype, Proteinuria, and the Risk of Kidney Failure: A Secondary Analysis of the AASK (African American Study of Kidney Disease and Hypertension) and CRIC (Chronic Renal Insufficiency Cohort) Studies

RATIONALE & OBJECTIVE: Patients with a high-risk Apolipoprotein L1 (APOL1) genotype are more likely to develop chronic kidney disease and kidney failure. It is unclear whether this increased risk is entirely mediated by the development of proteinuria. STUDY DESIGN: Retrospective observational study of the African American Study of Kidney Disease and Hypertension cohort and Chronic Renal Insufficiency Cohort. EXPOSURES & PREDICTORS: Self-identified race (Black/non-Black) and presence of high-risk APOL1 genotype. The primary model was adjusted for age, sex, diabetes, estimated glomerular filtration rate, and urinary protein-creatinine ratio. OUTCOMES: Time to kidney failure defined as time to dialysis or transplantation. ANALYTICAL APPROACH: We used Cox proportional hazard models to study how proteinuria mediates the association between APOL1 and kidney failure. We modeled proteinuria at baseline and as a time-varying covariate. RESULTS: A high-risk APOL1 genotype was associated with a significantly higher risk of kidney failure, even for patients with minimal proteinuria (HR, 1.87; 95% CI, 1.23-2.84). The association was not significant among patients with high proteinuria (HR, 1.22; 95% CI, 0.93-1.61). When modeling proteinuria as a time-varying covariate, a high-risk APOL1 genotype was associated with higher kidney failure risk even among patients who never developed proteinuria (HR, 2.04; 95% CI, 1.10-3.77). Compared to non-Black patients, Black patients without the high-risk genotype did not have higher risk of kidney failure (HR, 0.96; 95% CI, 0.85-1.10). LIMITATIONS: Two datasets were combined to increase statistical power. Limited generalizability beyond the study cohorts. Residual confounding common to observational studies. CONCLUSIONS: A high-risk APOL1 genotype is significantly associated with increased kidney failure risk, especially among patients without baseline proteinuria. Although our results suggest that the risk is partially mediated through proteinuria, higher kidney failure risk was present even among patients who never developed proteinuria. Providers should consider screening for the high-risk APOL1 genotype, especially among Black patients without proteinuria in populations with chronic kidney disease.