Short-Term Kidney Function Decline in Patients with Nondiabetic Kidney Disease and Albuminuria with and without APOL1 High-Risk Variants

Background: Having two APOL1 high-risk kidney variants has been associated with higher risk of developing end-stage kidney disease (ESKD). Less is known about short-term kidney outcomes in patients with decreased kidney function and albuminuria. Methods: The study population included participants of recent African Ancestry with CKD, urine protein-creatinine ratios (UPCR) >=0.2 g/g, and no diabetes who were genotyped for APOL1 kidney risk variants in the African American Study of Kidney Disease and Hypertension (AASK) and the Chronic Renal Insufficiency Cohort (CRIC). Unadjusted GFR slopes were estimated using linear mixed effect models with random intercept and random slope, and change in albuminuria estimated as percent change in UPCR. Outcomes were estimated over the total study follow-up as well as three years. Results: There were 223 and 273 participants included in AASK and CRIC, respectively, with 35.9% and 33.7% having the high-risk genotype (G1/G1, G1/G2, or G2/G2). In AASK, baseline measured GFR was 39 ml/min/1.73 m2 and similar by risk status; UPCR was higher among those with the high-risk genotype (median 0.7 g/g vs. 0.5 g/g, p=0.02). Over 12 years, risk of ESKD was higher in high-risk individuals compared with low-risk individuals (77.5% vs. 56.6%, p=0.002), as was eGFR slope (-4.3 vs. -3.7 ml/min/1.73 m2 per year, p=0.05). Shorter-term eGFR slope and percent change in UPCR were not different by genotype. In CRIC, baseline eGFR was 40 ml/min/1.73 m2 and similar by genotype; UPCR was also similar between genotypes (median 0.7 g/g vs. 0.6 g/g, p=0.7). Patients in the high-risk genotype were younger and had a lower proportion of cardiovascular disease than patients in the low-risk genotype. Over 18 years, there was a non-significant trend toward higher risk of ESKD in individuals with the high-risk genotype (65% vs. 59%, p=0.3), similar to that for eGFR slope (-3.1 vs. -2.8 ml/min/1.73 m2 per year, p=0.16). Shorter-term eGFR slope and percent change in UPCR were not different by genotype. Conclusion: When conditioned on established CKD, UPCR ≥0.2 g/g, as well as the absence of diabetes in two prospective cohorts, short-term eGFR slope and change in UPCR were not meaningfully different by APOL1 genotype, although long-term ESKD risk appeared to be higher in the high-risk genotype. Funding: Private Foundation Support