APOL1 risk variants, race, and progression of chronic kidney disease

Abstract

Background: Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.

Methods: In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.

Results: In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).

Conclusions: Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Figure 1. Proportion of Patients Free from Progression of Chronic Kidney Disease in AASK

In the African American Study of Kidney Disease and Hypertension (AASK), the primary outcome was defined as a doubling of the serum creatinine level or incident end-stage renal disease (the analyses shown in Panels A and B). In analyses of the interaction between APOL1 variants and trial interventions, the composite outcome was a reduction of 50% in the glomerular filtration rate (as measured by iothalamate clearance) or incident end-stage renal disease (the analyses shown in Panels C and D). Panel A shows the proportion of patients, among all 693 patients who were included in the study, who were free from progression of chronic kidney disease, according to the number of copies of the high-risk APOL1 variants (0, 1, or 2 copies). In Panels B, C, and D, patients who had 2 copies of high-risk APOL1 variants were classified as being in the APOL1 high-risk group; those with 0 or 1 copy were categorized as being in the APOL1 low-risk group. Panel B shows the results with stratification of the patients according to the proteinuria status at baseline and APOL1 risk status. Proteinuria was defined as a ratio of urinary protein to creatinine of at least 220 (with urinary protein measured in milligrams and creatinine in grams) or 0.22 (with both measured in grams). Panel C shows the results with stratification of the patients according to the randomized level of blood-pressure control (intensive vs. standard) and APOL1 risk status. Panel D shows the results with stratification of the patients according to whether they were assigned to receive an angiotensin-converting–enzyme (ACE) inhibitor or other antihypertensive medication and APOL1 risk status.

Figure 2. Between-Group Comparisons of the Estimated Glomerular Filtration Rate (eGFR) Slope and Proportion of Patients Free from a Primary Outcome Event in the CRIC Study

In the Chronic Renal Insufficiency Cohort (CRIC) study, the primary outcomes were the eGFR slope and a composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. Shown are mean differences in the eGFR slope for black patients in the APOL1 high-risk group versus white patients, black patients in the APOL1 low-risk group versus white patients, and black patients in the APOL1 high-risk group versus black patients in the APOL1 low-risk group, among patients with diabetes (Panel A) and among those without diabetes (Panel B). In Panels A and B, the I bars indicate 95% confidence intervals. I bars that cross above the horizontal black line indicate that the difference in eGFR is not significant. Also shown are the proportions of white patients and black patients in the APOL1 high-risk and low-risk groups who were free from the primary outcome of end-stage renal disease or a reduction of 50% in the eGFR from baseline, among patients with diabetes (Panel C) and among those without diabetes (Panel D).