Should kidney donors be genotyped for APOL1 risk alleles?

Abstract

Clinical nephrology has advanced rapidly as a result of recent breakthroughs in genomic medicine. Several forms of nephropathy heretofore labeled ‘idiopathic’ now have a well-defined genetic basis; more will follow. Whereas it was once taboo to suggest that population ancestry-based genetic variation contributes to ethnic-specific risk for end-stage kidney disease, the identification of impressive genetic association between two coding variants in the apolipoprotein L1 gene (APOL1) and a spectrum of nondiabetic nephropathies in individuals with recent African ancestry unequivocally proves this to be the case.1 This finding is a striking and unusual example where variation in a single gene associates with pronounced risk for a complex disease. The two nephropathy-risk variants include G1, a non-synonymous coding variant, and G2, a 6-base pair deletion. Each chromosome 22 typically possesses only a G1 or a G2 APOL1 allele (alleles are mutually exclusive on a single chromosome). About 13% of African Americans have two APOL1 nephropathy-risk variants, and 49% lack a risk variant.1 Possession of two APOL1 nephropathy-risk variants (G1/G1, G1/G2, or G2/G2) is associated with markedly increased risk for progressive chronic kidney disease due to focal segmental glomerulosclerosis (FSGS), focal global glomerulosclerosis, primary and secondary forms of FSGS-collapsing variant (notably HIV-associated nephropathy), sickle-cell nephropathy, and severe lupus nephritis.2 Although these disorders are primarily classified on the basis of glomerular pathology, they manifest pronounced interstitial and vascular changes that potentially relate to APOL1. The mechanism(s) by which an APOL1 variant may cause this renal injury remains undefined. Individuals of European, Asian, and Hispanic descent virtually lack APOL1 G1 and G2 nephropathy-risk alleles. Selection for nephropathy-associated risk variants likely occurred about 10,000 years ago in sub-Saharan Africa due to protection from infection with Trypanosoma brucei rhodesiense, a cause of African sleeping sickness. This benefit requires the presence of only one APOL1 variant. Possession of two variants (versus zero or one variant; autosomal recessive inheritance) in APOL1 fully explains the majority of the excess risk of nondiabetic chronic kidney disease in African Americans relative to European Americans. These same APOL1 variants in deceased African-American organ donors predispose to shortened allograft survival after kidney transplantation. Translating the APOL1 molecular breakthrough in the clinic will ultimately improve risk prediction and lead to novel therapies to prevent kidney failure. This Editorial makes the case that considering APOL1 risk variants in kidney transplantation will likely be an important clinical application that transforms current practice.