Real-World Assessment of CKD/ESKD Risk Among Individuals with APOL1 Dual- and Single-Risk Variants

Background: Individuals of African ancestry are at increased risk for kidney failure, partially due to the presence of high-risk G1 and G2 alleles in APOL1. Presence of APOL1-dual risk variants (DRV) confers a 15-20% lifetime risk of developing chronic kidney disease (CKD). Recent evidence suggests the presence of a single APOL1 risk variant (SRV) among West Africans is associated with an 18% higher odds of developing CKD/ESKD than those with no risk variants (NRV). Here we used real-world data to characterize and assess CKD progression stratified by APOL1 genotypes. Methods: A retrospective analysis was performed utilizing Natera’s proprietary real-world database of patients tested by the RenasightTM test and linked to claims data (Panalgo). Patients of African ancestry across all forms of CKD were classified by APOL1 status: DRV (G1/G1, G1/G2, or G2/G2), SRV (G1 or G2), and NRV (G0). Individuals with positive findings in other genes were excluded. Real-world progression-free and ESKD-free survival (rwPFS; rwEFS) were assessed using events defined as progression in CKD stage or to ESKD (ICD-10 N18.5, N18.6, or dialysis event). Results: Of 11,139 patients, 23.4% (n=2604) had DRV, 40.2% (n=4473) had SRV and 36.5% (n=4062) were NRV. ESKD was present in 28.5%, 17.4%, and 16.0% of the DRV, SRV, and NRV groups, respectively. Compared to NRV, the DRV cohort was at significantly higher risk of CKD (HR=1.1; 95% CI: 1.0-1.2, p=0.035) and ESKD progression (HR=1.2, 95% CI: 1.1-1.4, p=0.0073), while those with SRV were not (p=0.9). Likewise, the DRV cohort had significantly higher rates of FSGS (14.8% vs 4.0%), proteinuria (34.1% vs 27.2%), hypertensive nephropathy (HN; 46.9% vs 34.6%), and transplants (9.8% vs 4.6%) (p<10-9). The rate of FSGS in SRV (4.9%) was nominally higher than NRV (p=0.04), while proteinuria (26.3%), HN (36.4%), and transplant (4.5%) differences were not significant (p>0.05). Conclusion: In a real-world analysis of individuals of African ancestry with CKD, the presence of APOL1-SRV was not associated with increased risk of CKD progression or ESKD. The clinical course of individuals with APOL1-SRV appeared more similar to those with NRV compared to those with DRV, adding further evidence that SRV may not contribute to the clinical features and disease progression of CKD. Funding: Commercial Support - Natera, Inc.