Should kidney donors be genotyped for APOL1 risk alleles?

Clinical nephrology has advanced rapidly due to 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 (ESKD), the identification of impressive genetic association between two coding variants in the apolipoprotein L1 gene (APOL1) and a spectrum of non-diabetic 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 six-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 (CKD) due to focal segmental glomerulosclerosis (FSGS), focal global glomerulosclerosis (FGGS), 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 based on glomerular pathology, they manifest pronounced interstitial and vascular changes potentially relating 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 nephropathyassociated risk variants likely occurred about 10,000 years ago in sub-Saharan Africa due to protection from infection with Trypanosma brucei rhodesiense, a cause of African sleeping