Kidney disease in patients with two APOL1 risk variants

Nephrologists often order genetic testing panels to clarify diagnoses in patients with diverse presentations of kidney disease. This was not the case 10 years ago, prior to the current era of precision medicine. In the past, elevated blood sugars and blood pressures were felt to be the primary factors that initiated diabetic and mislabeled "hypertensive" nephropathy. In addition, the markedly higher incidence rates of kidney failure in African Americans relative to European, Asian, and Hispanic Americans were poorly understood. This changed with recognition of marked familial aggregation of kidney failure, particularly in the African American population. The 2010 discovery of the apolipoprotein L1 gene (APOL1) association with chronic kidney disease demonstrated that two coding variants in a single gene caused more than 35% of kidney failure in African Americans. APOL1 explained ancestry-based disparities in incidence rates of nephropathy, as well as outcomes after kidney transplantation and live kidney donation. This manuscript reviews the APOL1 discovery and its resultant changes in our understanding of kidney disease susceptibility. Mechanisms of APOL1 injury in kidney cells and novel therapies are reviewed with an emphasis on gaps in existing knowledge and future directions.