APOL1 Kidney Risk Variants and Long-Term Kidney Function in Healthy Middle-Aged Black Individuals: The Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Rationale & Objective

The effect of apolipoprotein L1(APOL1) genotype on future risk of kidney disease among middle-aged individuals with good kidney function is not well established.

Study Design

Longitudinal cohort study.

Setting & Participants

In total, 5,886 healthy individuals (45-64 years old) enrolled in the Atherosclerosis Risk in Communities study with creatinine-based estimated glomerular filtration rate ≥ 80 mL/min who would be suitable kidney donors.

Exposures

Race and APOL1 genotype.

Outcomes

Creatinine- and cystatin C-based estimated glomerular filtration rate (eGFRcr-cys) using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2021 equation, urinary albumin-creatinine ratio (UACR), proportion with chronic kidney disease (CKD) 3a or worse, end-stage kidney disease (ESKD), and death.

Analytical Approach

Participants grouped based on race and APOL1 genotype. Compared eGFRcr-cys and UACR across groups. Multinomial logistic regression models were used compare odds of CKD. Kaplan–Meier survival curves were created to compare rates of ESKD and death at last follow-up.

Results

There were 5,075 Whites (86%), 701 Blacks carrying the low-risk APOL1 genotype (12%), and 110 Blacks carrying the high-risk APOL1 genotype (2%). The mean age at baseline was 53 ± 6 years. At 10 years, White participants had lower eGFRcr-cys than low-risk and high-risk groups (89 ± 16 vs 91 ± 16 and 92 ± 15 mL/min/1.73 m², respectively; P < 0.001). At 25 years, White participants continued to have lower eGFRcr-cys than the low-risk group (70 ± 18 vs 72 ± 19 mL/min/1.73 m²; P < 0.001) but not compared with the high-risk APOL1 genotype (67±23 mL/min/1.73 m²). There was no difference in UACR among groups at 10 and 25 years (P = 0.87 and 0.91, respectively). The odds of developing CKD stage 3a or worse were not different between low-risk and high-risk APOL1 group in both unadjusted and adjusted models (P = 0.26 and P = 0.39, respectively). At last follow-up, <5% developed ESKD, and 45% of individuals either died or reached ESKD with no difference in outcomes between the groups.

Limitations

Low ascertainment because of death and long follow-up.

Conclusions

Among middle-aged individuals, APOL1 genotype does not appear to be a major driver of future risk of kidney disease.

Plain-Language Summary

Black patients with kidney disease carrying 2 variants of the apolipoprotein L1 (APOL1) gene, referred to as the high-risk genotype, experience an accelerated decline in kidney function than those with 0 or 1 risk variant. It is unknown whether the high-risk genotype negatively affects kidney function of healthy middle-aged individuals. We evaluated the effect of APOL1 genotype on kidney function of the Atherosclerosis Risk in Communities study participants (mean age 53 years) who had normal kidney function and blood pressure at baseline. At 25 years of follow-up, the APOL1 high-risk genotype did not appear to be a major driver of future risk of kidney disease. Our study findings are relevant for counseling older living donor candidates as well as family members of patients with APOL1-associated kidney disease.