The Real World Impact of APOL1 Variants on Kidney Transplantation

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It is well recognized that the risk of kidney failure among African Americans is higher than non-African Americans for both native kidneys and allografts. The estimate for cumulative lifetime risk of kidney failure amongst African Americans is 8% compared with 2% in whites.1 Although some of the excess risk in African Americans is associated with the traditional risk factors that disproportionately affect African Americans, such as obesity, smoking, socioeconomic position and diabetes, an additional genetic component has long been suspected. In a landmark article in 2010 using a case-control approach and data from the 1000 Genomes Project, individuals with high-risk variants of the APOL1 gene were first identified as having a significantly higher risk of renal failure. Subjects with 2 alleles of the high-risk APOL1 gene variants G1 or G2 were associated with a more than 7-fold risk of ESRD compared with zero-risk alleles.2 Although individuals with APOL1 high-risk variants are associated with a higher risk of renal failure, causality between these variants and renal disease has not been established.Although some data from animal models have indicated that the APOL1 gene itself may play a role in kidney development, the presence of the high-risk variants does not universally cause renal failure, but rather significantly increase the lifetime risk of kidney disease.3 This has lead some to speculate that in addition to genetic susceptibility, a “second hit” is also required to develop kidney injury. For example in a recently reported study conducted over a 20-year period, increased levels of the hemostatic factors VIIc, VIIIc, fibrinogen, von Willebrand factor, and protein C were associated with ESRD risk, with a significantly stronger association of factor VIIIc and protein C in African Americans with 2 APOL1 high-risk alleles.4Even though there seems to be no difference in mRNA expression of APOL1 in the kidneys of affected individuals, the risk seems to be associated with the kidney itself rather than a circulating factor as it has been shown that there is no difference in allograft survival in the medium term for kidney transplant recipients transplanted with kidneys that have the high-risk APOL1 genotypes.5As with native kidneys, renal transplantation donor kidneys carrying the high-risk variants of APOL1 are associated with worse outcomes. In this issue of Transplantation, Freedman et al6 analyzed a large group of renal transplant recipients and confirmed findings from previous studies, indicating that patients with 2 high-risk alleles of the APOL1 gene have shorter allograft survival and are more likely to have higher serum creatinine levels than recipients with 0/1 APOL1-renal-risk variant kidney. Although donor age is by itself associated with poorer outcomes the authors found no association between donor age and APOL1 genotype on renal allograft survival, and as in other studies, the high-risk APOL1 gene variant had no discernible effect on recipient survival. Based on their finding, the authors mulled whether rapid testing of the APOL1 status may help stratify deceased donor allocation.7Introduction of the Kidney Donor Profile Index scoring system for allocation of deceased donor organs in the United States has helped place “better” organs into those most likely to benefit from transplantation, but by giving every deceased donor kidney a score, the KDPI score may also have had a negative effect on the discard rate of deceased donor kidneys.

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