Non-Podocyte Roles of APOL1 Variants: an Evolving Paradigm.

Since the seminal discovery of the trypanolytic, exonic variants in APOL1 and their association with kidney disease in persons of recent African ancestry, a wide body of research has emerged offering key insights into mechanisms of disease. Importantly, the podocyte has become a focal point for our understanding of how risk genotype leads to disease, with activation of putative signaling pathways within the podocyte identified as playing a causal role in podocytopathy, FSGS and progressive renal failure. However, the complete mechanism of "genotype-to-phenotype" progression remains incompletely understood in APOL1-risk individuals. An emerging body of evidence reports more than podocyte-intrinsic expression of APOL1 risk variants is needed for disease to manifest. This article reviews the seminal data and reports which placed the podocyte at the center of our understanding of APOL1-FSGS, as well as the evident shortcomings of this "podocentric" paradigm. We examine existing evidence for environmental and genetic factors that may influence disease, drawing from both clinical data and APOL1's fundamental role as an immune response gene. We also review the current body of data for APOL1's impact on non-podocyte cells, including endothelial cells, the placenta, and immune cells in both a transplant and native setting. Finally, we discuss the implications of this emerging data and how the paradigm of disease might evolve as a result.