Late Reoccurrence of Collapsing FSGS After Transplantation of a Living-Related Kidney Bearing APOL 1 Risk Variants Without Disease Evident in Donor Supports the Second Hit Hypothesis

Recent studies indicate that living kidney donors have higher rate of end-stage renal disease (ESRD) over their lifetime after donation compared with well-matched controls, with a much higher risk in African Americans (AA).1-3 Over the past decade, our understanding of the genetic underpinnings of chronic kidney disease (CKD) in the AA population has been enhanced by the discovery of common variants G1 and G2 in the apolipoprotein L1 gene (APOL1) that are associated both with higher rates of CKD and faster progression to ESRD.4 The G1 allele consists of missense variants in linkage disequilibrium, Ser342Gly and Ile384Met, and the G2 allele is a 2-amino acid deletion, delAsn388/Tyr389. 13% of the AA population carries 2 risk alleles (G1/G1, G1/G2, or G2/G2) and the inheritance of 2 risk alleles increases risk of hypertension-associated renal disease 7- to 10-fold and the risk of focal segmental glomerulosclerosis (FSGS) 10- to 17-fold. These risk alleles also appear to adversely affect renal allograft outcomes with deceased donor kidneys carrying 2 risk alleles having an approximately twofold increased risk of graft failure, whereas recipient genotype has no impact.5-