APOL1 Risk Alleles and Outcomes in Kidney Transplantation: Enter the Recipient

Kidney transplantation in African American recipients is associated with inferior outcomes compared with other racial groups, which include lower allograft survival and higher rates of delayed graft function.1 Additionally, receiving a kidney from an African American donor is associated with lower rates of graft survival.2 Although the presence of apoliprotein1 (APOL1) high-risk genotype (G1/G1, G1/G2, or G2/G2) in donors provides a pathophysiologic basis for reduced kidney transplant survival, its effect on the graft when the genotype is present in recipients is less clear. Roy et al3 explored this pertinent question by ascertaining graft outcomes in kidney transplant recipients grouped by APOL1 risk alleles in the Renal Transplant Outcome Study study.3 In this multicenter observational prospective study, 221 incident African American kidney transplant recipients (both deceased and living donors) were recruited at 3 transplant centers in Philadelphia, PA, between 1999 and 2004. For patients who received 2 kidney transplants within this 5-y period, only outcomes of the first transplant were included, whereas patients with multiorgan transplants were excluded. Genotype analysis was performed for 6 variants that define the G1 and G2 haplotypes. The primary outcome of the study was graft failure, with participants followed until development of this outcome, death, or up to 2000 d. Competing risk models were used to determine risk for graft failure stratified by APOL1 risk allele status, with Kaplan-Meier survival curves and log-rank tests used for comparisons of graft survival between these groups. Additionally, risk of rejection was also assessed as an outcome. Over 40% of kidney transplant recipients had the high-risk APOL1 genotype, with these patients receiving a transplant at a younger age in comparison with those with heterozygous status. The presence of a high-risk genotype in the recipient was associated with an increased risk of graft failure during the first posttransplant year; however, no difference was noted at 3 y among the APOL1 risk allele groups. This study adds to the data that APOL1 risk alleles in the recipients may influence graft outcomes in addition to having an immunomodulatory role. Genome-wide single-nucleotide polymorphism genotyping data on donors and recipients from 2 cohorts (Genomics of Chronic Allograft Rejection and Clinical Trials in Organ Transplantation 01/17) have demonstrated a correlation between number of recipient APOL1 G1/G2 alleles and increased risk of allograft loss and T cell–mediated rejection.4 Interestingly, ex vivo studies of peripheral blood mononuclear cells showed high expression levels of APOL1 in activated CD4+/CD8+ T cells and natural killer cells. The current study by Roy et al did show a trend for higher rate of rejection in the first transplant year (albeit not statistically significant); however, data regarding immunologic risk such as HLA mismatches, donor-specific antibodies, and type of rejection were not available. This study does not report if rejection was contributory to graft failure in the first year posttransplantation; the co-occurrence of both graft failure and rejection in this time frame requires further investigation, especially with the aforementioned association of APOL1 risk alleles with T cell–mediated rejection. One of the major limitations of the current study is that donor APOL1 genotype status was not available. These data would be essential to elucidate the interplay between varying combinations of APOL1 risk alleles in donors and recipients and their influence on graft outcomes. The ongoing APOL1 Long-term Kidney Transplantation Outcomes Network will be assessing these outcomes by genotyping donors and recipients.5 Additionally, the reported rates of rejection and allograft survival in the study are from the period of 1999–2004 and do not correspond to current improved rates of these pertinent outcomes. Also, the presence of a small sample size may explain why no difference was detected in outcomes at 3 y. Further studies are needed to elucidate the effect of donor factors (including APOL1 status) and immunologic risk (HLA mismatches, donor-specific antibodies, and type of rejection) on graft outcomes in the setting of high-risk APOL genotype in the recipient. To conclude, this was the largest prospective study of high-risk genotype kidney transplant recipients, providing more evidence that APOL1 risk alleles in recipients may influence graft outcomes and risk of rejection. Although these findings require validation in larger studies, these data represent an important step in understanding the influence of APOL1 risk alleles in an already high-risk population.