Kidney Week

Abstract: TH-PO0626

Assessing the Protective Effects of the N264K Variant (M1) in APOL1-Mediated Kidney Disease in a Real-World CKD Population

Session Information

• Genetic Diseases of the Kidneys: Complex Kidney Traits
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Complex Kidney Traits

Authors

• Clark, Dinah, Natera, Inc., Austin, Texas, United States

Dinah Clark, MS

• Aushev, Vasily, Natera, Inc., Austin, Texas, United States

Vasily Aushev, PhD

• Bloom, Michelle, Natera, Inc., Austin, Texas, United States

Michelle Bloom, PhD

• Powerman, Bryce, Natera, Inc., Austin, Texas, United States

Bryce Powerman

• Antonopoulos, Alyssa, Natera, Inc., Austin, Texas, United States

Alyssa Antonopoulos, MS

• Andrews, Stephen, Natera, Inc., Austin, Texas, United States

Stephen Andrews, PhD

• Schneider, Ronen, Natera, Inc., Austin, Texas, United States

Ronen Schneider, MD

Background

APOL1-mediated kidney disease is associated with the presence of dual risk variants (DRV, G1/G1, G1/G2, G2/G2) in APOL1 and is believed to contribute to the high rate of chronic kidney disease (CKD) among African American individuals. Recently, the APOL1 p.N264K variant (M1), has been shown to confer protection against the development of CKD and FSGS when co-inherited with G2. Here we use real-world data to assess the effect of the M1 allele on CKD/ESKD progression

Methods

A retrospective analysis was performed utilizing Natera’s proprietary real-world database of patients tested by the Renasight^TM test and linked to claims data (Panalgo). CKD patients of African ancestry were identified and the presence of the M1 allele was assessed. Real-world progression-free and ESKD-free survival (rwPFS; rwEFS) was assessed in patients using events defined as progression in CKD stage or a dialysis event.

Results

Of 2604 individuals with DRV and linked claims data, 43.6% (n=1135) had G1/G1, 44.1% (n=1148) had G1/G2 and 12.3% (n=321) had G2/G2. Compared to those with no risk variants (NRV; n=4062), G1/G1 (HR=1.3, 95% CI: 1.1-1.5, p=0.01) and G1/G2 patients (HR=1.3, 95% CI: 1.0-1.5, p=0.02) were at significantly higher risk of progression to ESKD, while those with G2/G2 were not (HR=1.0; p=1.0). M1 prevalence was 3.3% (n=38) among G1/G2, 6.2% (n=20) among G2/G2, and 0.0% in G1/G1. While differences in rwPFS and rwEFS were not significant, 16.7% of G1/G2 individuals with M1 progressed to ESKD compared to 29.5% without M1 (OR=0.57). Among G2/G2 individuals with M1, 7.7% progressed to ESKD, compared to 26.6% without M1 (OR=0.29); those with M1 were at significantly lower risk of CKD progression (HR=0.2, 95% CI: 0.1-0.8, p=0.02).

Conclusion

A real-world analysis of individuals of African ancestry revealed that APOL1-DRV genotypes correlated with varying risks of ESKD progression. Furthermore, our data supports a protective role of the M1 variant against CKD progression in the subcohort of individuals with G2/G2 as well as a trend toward reduced progression among G1/G2. While further clinical and genetic characterization in this population is warranted, these findings add to the evolving role of APOL1 in CKD and associated genetic modifiers.

Funding

• Commercial Support – Natera, Inc.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20252w1mg8d1