Mechanism of Action of APOL1 in Renal Allograft Survival (and Native CKD) Remains Unclear

Field: Medicine (Health Sciences)

To the Editor: I read with great interest the article by Reeves-Daniel et al. “The APOL1 Gene and Allograft Survival after Kidney Transplantation,”(1Reeves-Daniel AM Depalma JA Bleyer AJ et al.The APOL1 gene and allograft survival after kidney transplantation.Am J Transplant. 2011; 11: 1025-1030Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar) in which the authors demonstrated that “risk variant” alleles of APOL1 in donor allografts negatively correlate with allograft outcome, with an adjusted Hazard Ratio of 3.84 for renal allografts with 2 APOL1 risk variant alleles versus 0/1 APOL1 risk variant alleles. These APOL1“risk variant” alleles are the African-Ancestral G1 and G2 alleles of APOL1, which were demonstrated by GWAS to correlate with chronic kidney diseases among African Americans, particularly FSGS and HIVAN (2Genovese G Friedman DJ Ross MD et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1413) Google Scholar,3Tzur S Rosset S Shemer R et al.Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene.Hum Genet. 2010; 128: 345-350Crossref PubMed Scopus (460) Google Scholar). These studies of native kidney disease offered the compelling hypothesis that, at the population level, G1 and G2 alleles of APOL1 are beneficial when heterozygous due to increased resistance to Human African Trypanosomiasis, but when homozygous result in increased susceptibility to kidney disease. Combining data for G1 and G2 APOL1 alleles demonstrated an odds ratio for FSGS in native kidneys for 2 alleles versus 0/1 alleles of 5.8 (CI, 4.5–7.5). The magnitude of this effect on disease susceptibility was much more impressive than the OR of 1.3–1.5 found for a given locus in most GWAS studies. Nevertheless, these data for APOL1 are correlative, not causal. There are no published data on a mechanism by which APOL1 alleles might cause or predispose to kidney disease. In their discussion, Reeves-Daniel et al. offer several possibilities for such a mechanism. APOL1 protein is principally synthesized in the liver and secreted into the serum, where it circulates as a constituent of circulating lipoprotein particles. However, the authors state that “nephrotoxicity relating to circulating APOL1 proteins in transplant recipients is unlikely. APOL1 is synthesized in the liver and would not be impacted by the genotype of the donor kidney.” As an alternative, Reeves-Daniel et al. cite unpublished data that APOL1 transcripts can be detected in podocytes, in which case APOL1 protein may be damaging the very cells in which it is expressed. However, while Reeves-Daniel et al. tested for APOL1 risk variant alleles in donor allografts they did not test for APOL1 risk variant alleles among transplant recipients. It remains possible that donor kidneys with G1 and G2 alleles were predominantly transplanted into recipients who carry G1 and G2 alleles. In this case, their analysis of APOL1 donor haplotype could be a surrogate for the APOL1 haplotype of transplant recipients. Deceased donor kidneys with APOL1 risk variant alleles would predominantly come from donors of West-African descent, and likely may be selected through haplotype matching for recipients of West-African descent, who would similarly be enriched for G1 and G2 risk alleles. In comparison with deceased donors, living donor allografts carrying G1 or G2 risk alleles are even more likely to go to recipients with G1 or G2 risk alleles because, among African-Americans, living-related donation is more likely than living-unrelated donation, as Reeves-Daniel and colleagues recently demonstrated in a separate study (4Reeves-Daniel A Bailey A Assimos D et al.Donor-recipient relationships in African American vs. Caucasian live kidney donors.Clin Transplant. 2011; (Apr 19. Epub ahead of print.)Crossref Scopus (18) Google Scholar). To play Devil’s advocate, I hypothesize that the APOL1 protein is synthesized in the liver, secreted into the circulation, and somehow causes subacute/chronic nephropathy in both native kidneys and renal allografts. If we assume this hypothesis is true (and we have no mechanistic data yet to favor or disfavor any hypothesis), then one would still find a correlation of allograft outcome with donor genotype, even though the site of action is from the circulation of the transplant recipient. The analysis by Reves-Daniel et al. is an excellent opportunity for the authors to extend their analysis of allograft outcome with respect to both donor and recipient APOL1 risk variant alleles. This would be similar to NIH clinical trial NCT 01143532, “Role of Donor Genetics and Recipient Genetics in Kidney Transplant Outcomes.” If one could demonstrate, hypothetically, that allograft outcome is related to the donor but NOT the recipient APOL1 haplotype, this would be an exciting step forward in understanding the mechanism by which this locus predisposes persons of African heritage to chronic kidney disease or allograft failure. The author is supported by KO8 award DK82616 from the NIH/NIDDK. The author of this manuscript has no conflicts of interest to disclose as described by the American Journal of Transplantation.