The APOL1 Gene and Allograft Survival after Kidney Transplantation

Abstract

Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox proportional-hazard models tested for association between time to graft failure and donor APOL1 genotypes. Mean follow-up was 26.4 ± 21.8 months. Twenty-two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT, and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p=0.008) and higher HLA mismatch (HR 1.52; p=0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long term renal allograft survival.

APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults

“…This scenario is proposed for renal disease associated with sickle cell disease, with collapsing nephropathy associated with lupus or HIV and with compromised graft survival after transplantation. [4][5][6][7][8][9] APOL1 risk variants are associated with earlier age of onset and progression to renal failure of subjects with FSGS, and prospective studies in the African American Study of Kidney Disease and Chronic Renal Insufficiency cohorts show that carriage of two APOL1 risk variants is associated with more rapid progression to clinical endpoints in persons with renal insufficiency at study entry. 2,3,5,7,8 Moreover, African-American participants without renal disease on enrolment in the ARIC study were more likely to develop CKD and to progress to renal failure if they had two APOL1 risk alleles, compared with those with no alleles or one allele.…”

Gene–Gene and Gene–Environment Interactions in Apolipoprotein L1 Gene-Associated Nephropathy

“…Disease etiologies include focal global glomerulosclerosis (FGGS) historically ascribed to hypertension, nonmonogenic forms of FSGS, HIV-associated nephropathy (HIVAN), sickle cell kidney disease, and severe lupus nephritis (LN) (7,8,(22)(23)(24)(25). The APOL1 risk variants also account for younger age of onset of ESRD and may also be associated with poorer outcome of kidney grafts from African-ancestry donors (26)(27)(28).…”

APOL1 Genotyping of African American Deceased Organ Donors: Not Just Yet

“…In a small study involving 119 African American kidney transplant recipients, Lee et al found no difference in graft survival in highrisk APOL1 (two alleles) compared to low-risk (zero or one allele) recipients (HR 0.96; 95% CI 0.61-1.49; p ¼ 0.84) (3). In a single center study from North Carolina, Reeves-Daniel et al examined outcomes from 106 African American deceased donors, of whom 22 (21%) had two APOL1 copies, and found that two APOL1 variants in a deceased donor was independently associated with a greater risk of graft failure (HR 3.84; p ¼ 0.0.84) (4). In this issue of AJT, Freedman et al follow-up on this original report from North Carolina by including new deceased donors from their state as well as from Alabama (5).…”