APOL1 Mediated Kidney Disease: A Review and Look Toward the Future

Individuals of recent African ancestry are disproportionately affected by kidney disease. The discovery of the Apolipoprotein L1 (APOL1) gene and, subsequently, the G1 and G2 risk alleles has helped to understand some of these disparities. The APOL1 gene does not appear to be necessary for normal kidney function, and the high-risk alleles appear to be gain of function mutations offering protection against Trypanosoma species. In the United States, ∼6 million African Americans have a high-risk genotype. However, not all patients with high-risk genotypes will develop kidney disease, leading to the idea of a second hit hypothesis by certain genetic, environmental, and inflammatory triggers. Recent clinical trials have focused on the different postulated mechanisms of cellular toxicity, and one promising candidate, inaxaplin, has advanced to a phase 3 study. This mini-review discusses the development of APOL1 risk alleles, clinical implications of a high-risk genotype, and a suggested framework for nephrologists to pursue genetic testing in countries where it is easily accessible.