APOL1-Mediated Kidney Disease and the Emerging Era of Precision Therapy

renal risk genetic variants (G1 and G2) account for a substantial portion of the excess burden of nondiabetic kidney disease among individuals with recent African ancestry (within the past 10,000 years). Apolipoprotein L1 (APOL1)-mediated kidney disease is characterized by incomplete penetrance and appears to require inflammatory or environmental "second hits" that increase APOL1 expression, activating toxic function in kidney cells. Mechanistic studies support a model in which APOL1 channel activity, intracellular trafficking stress, mitochondrial dysfunction, and inflammasome signaling contribute to podocyte and glomerular injury. These insights have made APOL1 an ideal target for precision nephrology. Emerging therapeutic strategies include direct APOL1 channel blockade, inhibition of Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT)-dependent APOL1 induction, antisense oligonucleotides that lower APOL1 expression, and downstream anti-inflammatory approaches. The major translational questions are who should be tested, who should be treated, and how to balance kidney benefit with host-defense, equity, and implementation challenges.