Kidney Week 2025 Annual Meeting-APOL1-Mediated Kidney Disease: A Blueprint for Precision Nephrology?

Video Transcription

Video Summary

The session reviews APOL1 as a model for precision medicine in kidney disease, spanning mechanisms, African population genetics, transplantation, and emerging therapies.<br /><br />Dr. Martin Pollak explains why APOL1 kidney disease is unusual: common, positively selected risk alleles (G1, G2) in people of recent African ancestry; recessive-like inheritance despite apparent gain-of-function; wide phenotypic range; and incomplete penetrance. The kidney does not require APOL1 (loss-of-function can occur without kidney disease). Using isogenic transgenic mice, his group shows no baseline phenotype but severe collapsing glomerulopathy after interferon exposure in G1/G2—highlighting “second hits,” thresholds, and feedback loops. Risk is modified by haplotype background (e.g., N264K can neutralize G2 toxicity), copy number, and regulation at transcription/translation (interferon responses, ADAR RNA editing, microRNAs, proteostasis). At the protein level, APOL1 behaves as a cation channel; risk variants alter conductance/gating and may promote aggregation and ER stress.<br /><br />Prof. Ifeoma Ulasi presents H3Africa data (8,355 participants in Nigeria/Ghana). High-risk (two-allele) genotypes are ~30% overall, with major ethnolinguistic variation (e.g., Igbo ~50% vs Hausa-Fulani ~9–11%). Both two-risk and, notably, one-risk allele states show increased CKD/FSGS risk, with G2 appearing stronger than G1 in this cohort. Effect sizes are lower than in African Americans, suggesting environmental/social modifiers and CKD heterogeneity.<br /><br />Dr. Krista Lentine updates APOLLO (deceased donor/recipient genotyping; >2,700 paired samples) and LITO (long-term living donor outcomes pre-genotyping era). These studies aim to replace race-based risk with genotype-informed transplant counseling and policy.<br /><br />Dr. Opeyemi Olabisi summarizes therapeutic strategies: JAK-STAT inhibition (e.g., baricitinib), APOL1 mRNA suppression (antisense), and APOL1 channel/pore blockers (Vertex inaxaplin and others). He emphasizes equitable trial participation and access if therapies succeed.

Asset Subtitle

Moderator(s): Marva Moxey-Mims, Simone Sanna-Cherchi

Presentation(s):

Mechanisms of APOL1-Mediated Kidney Disease - Martin Pollak
APOL1 in West Africa: Updates from the H3Africa Study - Ifeoma Ulasi
APOL1 and Kidney Transplantation: Impact on Donors and Recipients - Krista Lentine
Therapeutic Targeting of APOL1-Mediated Kidney Disease - Opeyemi Olabisi

Meta Tag

Date 11/8/2025

Pathway 1 Genetic Diseases and Development

Session ID 507332

Keywords

APOL1

precision medicine

kidney disease

G1 and G2 risk alleles

African population genetics

collapsing glomerulopathy

FSGS

interferon second hit

incomplete penetrance

haplotype modifiers (N264K)

cation channel function

ER stress and protein aggregation

H3Africa cohort (Nigeria and Ghana)

APOLLO and LITO transplant studies

APOL1-targeted therapies (baricitinib, antisense, inaxaplin)