Recipient APOL1 Genotype Effects on Outcomes After Kidney Transplantation

Abstract

Commentary on Zhang Z, Sun Z, Fu J, et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J Clin Invest. Published online September 9, 2021. https://doi.org/10.1172/JCI146643 Commentary on Zhang Z, Sun Z, Fu J, et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J Clin Invest. Published online September 9, 2021. https://doi.org/10.1172/JCI146643 Compared to other populations, individuals with recent African ancestry have markedly higher incidence rates of kidney failure and faster progression of chronic kidney disease (CKD).1Peralta C.A. Katz R. DeBoer I. et al.Racial and ethnic differences in kidney function decline among persons without chronic kidney disease.J Am Soc Nephrol. 2011; 22: 1327-1334Crossref PubMed Scopus (77) Google Scholar Transplanted kidneys from deceased donors with recent African ancestry fail more rapidly and African American living kidney donors more often develop kidney failure.2Reeves-Daniel A.M. Depalma J.A. Bleyer A.J. et al.The APOL1 gene and allograft survival after kidney transplantation.Am J Transplant. 2011; 11: 1025-1030Crossref PubMed Scopus (236) Google Scholar, 3Freedman B.I. Julian B.A. Pastan S.O. et al.Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.Am J Transplant. 2015; 15: 1615-1622Crossref PubMed Scopus (121) Google Scholar, 4Freedman B.I. Pastan S.O. Israni A.K. et al.APOL1 genotype and kidney transplantation outcomes from deceased African American donors.Transplantation. 2016; 100: 194-202Crossref PubMed Scopus (116) Google Scholar, 5Doshi M.D. Ortigosa-Goggins M. Garg A.X. et al.APOL1 genotype and renal function of black living donors.J Am Soc Nephrol. 2018; 29: 1309-1316Crossref PubMed Scopus (76) Google Scholar Two coding variants in the apolipoprotein L1 gene (APOL1) contribute to these disparities with autosomal recessive inheritance.6Freedman B.I. Limou S. Ma L. Kopp J.B. APOL1-associated nephropathy: a key contributor to racial disparities in CKD.Am J Kidney Dis. 2018; 72: S8-S16Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Inherited forms of nephropathy are typically cured by kidney transplantation. They do not recur in allografts because functional variants in the transplant replace causative host variants.7Mason A.E. Saleem M.A. Bierzynska A. A critical re-analysis of cases of post-transplantation recurrence in genetic nephrotic syndrome.Pediatr Nephrol. 2021; 36: 3757-3769Crossref PubMed Scopus (1) Google Scholar In this fashion, the pathogenesis of APOL1-associated nephropathy is believed to primarily result from increased gene expression in kidney cells, producing high intracellular levels of the APOL1 risk variant protein. Circulating liver-synthesized APOL1 protein does not appear to play a role.8Freedman B.I. Kopp J.B. Sampson M.G. Susztak K. APOL1 at 10 years: progress and next steps.Kidney Int. 2021; 99: 1296-1302Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Additional evidence supporting kidney APOL1 expression as causing nephropathy came from studies of APOL1 transgenic mice.9Beckerman P. Bi-Karchin J. Park A.S. et al.Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.Nat Med. 2017; 23: 429-438Crossref PubMed Scopus (187) Google Scholar Given this background, Zhang et al report intriguing data suggesting recipient APOL1 genotypes impact kidney transplant outcomes and the immune response.10Zhang Z, Sun Z, Fu J, et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J Clin Invest. Published online September 9, 2021. https://doi.org/10.1172/JCI146643Google Scholar In 356 transplants with donor and recipient APOL1 genotypes from the Genomics of Chronic Allograft Rejection (GOCAR), the number of recipient APOL1 risk variants was additively associated with graft losses unrelated to recipient death with a functioning transplant, and T cell–mediated rejection. Similar results were observed in 120 transplants from Clinical Trials in Organ Transplantation (CTOT1/17). As mechanistic support, Zhang et al reported peripheral blood mononuclear cells from healthy individuals showed enrichment for differentially expressed genes in pathways involved in immune activation, with activated CD4 and cytotoxic CD56dim cells from those with 1 or 2 APOL1 risk variants (versus zero). Of note, APOL1 high-risk genotypes were enriched in the 73 African Americans with kidney failure who received kidneys in GOCAR and CTOT; 31.5% (23/73) had APOL1 high-risk genotypes. This shows powerful effects of APOL1 on risk for nephropathy. If validated, findings would support a previously unappreciated role of recipient APOL1 genotype and risk variant protein on kidney allograft failure. Effects in recipients could relate to circulating, immune cell, or vascular cell APOL1 protein content. Circulating APOL1 protein protects from trypanosomal infection; however, recipient APOL1 genotype effects on kidney transplant outcomes would be novel. Given the major implications of this work, it is important to consider the study design and populations analyzed.10Zhang Z, Sun Z, Fu J, et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J Clin Invest. Published online September 9, 2021. https://doi.org/10.1172/JCI146643Google Scholar The number of kidney transplants in the combined GOCAR and CTOT studies was 476. Of these, only 13.9% (66/476) of recipients had an APOL1 risk variant (37 had 1 copy, 29 had 2 copies). Approximately 52% of the general African American population has APOL1 risk variants; 13% possess 2 copies (comprising APOL1 high-risk genotypes) and 39% have 1.11Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1316) Google Scholar The reason that so few study recipients had APOL1 risk variants is that European and Asian recipients made up 67.6% (322/476) of the study sample. As expected, all 322 European and Asian recipients lacked APOL1 risk variants. To account for genetic heterogeneity among recipients and low numbers with recent African ancestry, the investigators performed genome-wide single-nucleotide polymorphism genotyping and adjusted analyses for recipient ancestry. In addition, a total of 50 graft losses were recorded in the 476 kidney recipients. Of these, just 18 occurred in the 66 recipients possessing 1 or 2 APOL1 risk variants (14 in GOCAR and 4 in CTOT).10Zhang Z, Sun Z, Fu J, et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J Clin Invest. Published online September 9, 2021. https://doi.org/10.1172/JCI146643Google Scholar Low numbers of graft losses (events) impact study power. Finally, the majority of transplanted kidneys in GOCAR and CTOT were from living donors. Transplants from living kidney donors function longer than those from deceased donors. The majority of published data on donor and recipient APOL1 genotype effects in transplantation came from deceased donor kidney transplantation (DDKT). The new findings are provocative and will serve as the basis for future research. However, the limited sample size, low frequency of APOL1 risk variants in transplant recipients, and relatively few graft failures limit reproducibility and generalizability of results. It is also puzzling that recipient-based APOL1 risk variant effects on transplant outcomes and mechanistic models were additive and dominant, respectively, whereas native CKD and donor-based outcomes are consistently recessive. One year after the landmark 2010 report of APOL1 association with nondiabetic CKD,11Genovese G. Friedman D.J. Ross M.D. et al.Association of trypanolytic ApoL1 variants with kidney disease in African Americans.Science. 2010; 329: 841-845Crossref PubMed Scopus (1316) Google Scholar Reeves-Daniel et al2Reeves-Daniel A.M. Depalma J.A. Bleyer A.J. et al.The APOL1 gene and allograft survival after kidney transplantation.Am J Transplant. 2011; 11: 1025-1030Crossref PubMed Scopus (236) Google Scholar reported that DDKT from African American APOL1 high-risk genotype deceased donors failed more rapidly than those from African American APOL1 low-risk genotype donors. This suggested donor APOL1 genotypes, not donor race/ethnicity as in the Kidney Donor Risk Index (KDRI), contribute to more rapid graft failure in African-ancestry deceased donors. Histology was available from all transplanted kidneys that failed in this single-center report of 136 DDKT from 106 African American donors. In the 8 graft failures from APOL1 high-risk genotype donors, 6 (75%) revealed lesions compatible with APOL1-associated nephropathy, 1 had hyperacute rejection (day 5), and 1 had multiple infarcts; cell-mediated rejection was not observed. Importantly, 67 of the 136 recipients were non–African American and likely lacked APOL1 risk variants.12Cooke J.N. Bostrom M.A. Hicks P.J. et al.Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans.Nephrol Dial Transplant. 2012; 27: 1505-1511Crossref PubMed Scopus (70) Google Scholar Nonetheless, in unpublished observations (B.I.F.) shorter allograft survivals were seen in non–African American recipients of African American kidneys, compared to African American recipients. This suggested recipient APOL1 genotypes were less likely critical determinants of DDKT outcomes. Larger multicenter series supported the importance of donor APOL1 genotypes on DDKT outcomes.3Freedman B.I. Julian B.A. Pastan S.O. et al.Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.Am J Transplant. 2015; 15: 1615-1622Crossref PubMed Scopus (121) Google Scholar,4Freedman B.I. Pastan S.O. Israni A.K. et al.APOL1 genotype and kidney transplantation outcomes from deceased African American donors.Transplantation. 2016; 100: 194-202Crossref PubMed Scopus (116) Google Scholar Lee et al13Lee B.T. Kumar V. Williams T.A. et al.The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival.Am J Transplant. 2012; 12: 1924-1928Crossref PubMed Scopus (132) Google Scholar subsequently reported results from 119 DDKT in African American recipients with APOL1 genotypes. Recipient APOL1 genotypes did not increase the risk of allograft loss after transplant and recipients with 2 risk variants were not felt to be an impediment to transplantation. Weaknesses of these reports were their retrospective nature and lack of APOL1 genotype data in matched donor-recipient pairs. Two studies further support the importance of donor APOL1 genotypes on outcomes after kidney transplantation. Santoriello et al14Santoriello D. Husain S.A. De Serres S.A. et al.Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts.Kidney Int. 2018; 94: 1189-1198Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar assessed de novo collapsing focal segmental glomerulosclerosis (FSGS) after transplantation. Predisposing factors were African American donor race, acute rejection, viral infection, and acute vaso-occlusion. Recipient race did not associate with risk and the authors concluded donor APOL1 high-risk genotype kidneys associated with a higher incidence of de novo collapsing FSGS after transplant and shorter allograft survival. Recently, Chen et al15Chen D.P. Zaky Z.S. Schold J.D. et al.Podocyte density is reduced in kidney allografts with high-risk APOL1 genotypes at transplantation.Clin Transplant. 2021; 35e14234Crossref PubMed Scopus (4) Google Scholar assessed podocyte density in kidneys from 107 live and deceased African American donors based on APOL1 genotypes. Despite normal kidney function and renal histology at procurement, APOL1 high-risk genotype kidneys had 15% lower podocyte density compared to APOL1 low-risk genotype kidneys. Recipients of APOL1 high-risk genotype donor kidneys had more rapid declines in kidney function, likely related to the lower podocyte density (subclinical kidney disease). APOL1 genotypes were available in 87 recipients, 64% African American and 36% European American. The authors stated they lacked sufficient power to determine effects of transplanting APOL1 high-risk donor kidneys to APOL1 high-risk recipients. As such, recipient genotype effects could not be adequately assessed. Table 1 summarizes existing reports on donor and recipient APOL1 genotype effects after kidney transplantation.Table 1Donor and Recipient APOL1 Genotype Effects on Kidney TransplantationSample GenotypedPrimary ResultsCommentsReferenceDeceased donorsFaster graft failure in recipients of APOL1 2-KRV kidneysRetrospective, single-center study, lack of recipient genotypesReeves-Daniel et al2Reeves-Daniel A.M. Depalma J.A. Bleyer A.J. et al.The APOL1 gene and allograft survival after kidney transplantation.Am J Transplant. 2011; 11: 1025-1030Crossref PubMed Scopus (236) Google ScholarDeceased donorsFaster graft failure in recipients of APOL1 2-KRV kidneysRetrospective, lack of recipient genotypesFreedman et al3Freedman B.I. Julian B.A. Pastan S.O. et al.Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.Am J Transplant. 2015; 15: 1615-1622Crossref PubMed Scopus (121) Google ScholarDeceased donorsFaster graft failure in recipients of APOL1 2-KRV kidneysRetrospective, lack of recipient genotypesFreedman et al4Freedman B.I. Pastan S.O. Israni A.K. et al.APOL1 genotype and kidney transplantation outcomes from deceased African American donors.Transplantation. 2016; 100: 194-202Crossref PubMed Scopus (116) Google ScholarDDKT recipientsRecipient genotype did not impact outcomesRetrospective, lack of donor genotypesLee et al13Lee B.T. Kumar V. Williams T.A. et al.The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival.Am J Transplant. 2012; 12: 1924-1928Crossref PubMed Scopus (132) Google ScholarDonors & recipientsDonor (but not recipient) genotypes increased risk of de novo collapsing FSGSBeyond collapsing FSGS, graft failures not assessedSantoriello et al14Santoriello D. Husain S.A. De Serres S.A. et al.Donor APOL1 high-risk genotypes are associated with increased risk and inferior prognosis of de novo collapsing glomerulopathy in renal allografts.Kidney Int. 2018; 94: 1189-1198Abstract Full Text Full Text PDF PubMed Scopus (20) Google ScholarDonors & recipientsAPOL1 2-KRV donor kidneys had 15% lower podocyte density and more rapid kidney function decline in recipientsUnderpowered to assess recipient genotype effectsChen et al15Chen D.P. Zaky Z.S. Schold J.D. et al.Podocyte density is reduced in kidney allografts with high-risk APOL1 genotypes at transplantation.Clin Transplant. 2021; 35e14234Crossref PubMed Scopus (4) Google ScholarDonors & recipientsRecipients with 1 and 2 APOL1 KRVs had more graft failures and T cell–mediated acute rejection (additive model)Limited sample size, low frequency of recipient APOL1 KRVs, few allograft failuresZhang et al10Zhang Z, Sun Z, Fu J, et al. Recipient APOL1 risk alleles associate with death-censored renal allograft survival and rejection episodes. J Clin Invest. Published online September 9, 2021. https://doi.org/10.1172/JCI146643Google ScholarAbbreviations: DDKT, deceased donor kidney transplantation; FSGS, focal segmental glomerulosclerosis; KRV, kidney risk variant. Open table in a new tab Abbreviations: DDKT, deceased donor kidney transplantation; FSGS, focal segmental glomerulosclerosis; KRV, kidney risk variant. The role of APOL1 in native kidney disease and transplantation is widely appreciated, and novel therapies are under development.16Aghajan M. Booten S.L. Althage M. et al.Antisense oligonucleotide treatment ameliorates IFN-γ-induced proteinuria in APOL1-transgenic mice.JCI Insight. 2019; 4e126124Crossref PubMed Scopus (36) Google Scholar The importance of donor APOL1 genotypes on kidney transplant outcomes is firmly established. These new data suggest a potential role for recipient APOL1 genotype, as well. Results from large, prospective, well-powered studies of kidney transplants with matched donor and recipient APOL1 genotypes will clarify the issue. The prospective National Institutes of Health–sponsored APOL1 Long-term Kidney Transplant Outcomes (APOLLO) Consortium is working toward this goal.17Freedman B.I. Moxey-Mims M.M. Alexander A.A. et al.APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): design and rationale.Kidney Int Rep. 2020; 5: 278-288Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar APOLLO is recruiting kidney donors with recent African ancestry and the recipients of their kidneys. APOLLO is now following more than 3,600 DDKT with donor DNA, and DNA has been collected from nearly 1,600 recipients. Prospective studies such as APOLLO will provide answers to the relative importance of kidney donor and recipient APOL1 genotypes on DDKT outcomes. At present, recipient APOL1 genotypes should not limit receipt of a kidney transplant. We believe that the initial clinical utility of APOL1 genotyping will be to more precisely define deceased donor kidney quality in the KDRI. Julian et al18Julian B.A. Gaston R.S. Brown W.M. et al.Effect of replacing race with apolipoprotein L1 genotype in calculation of kidney donor risk index.Am J Transplant. 2017; 17: 1540-1548Crossref PubMed Scopus (40) Google Scholar reported that replacing donor race with APOL1 genotypes in the KDRI would dramatically improve kidney quality in more than 85% of African American deceased donors. This change should result in fewer discarded kidneys; more transplants; better matching of donors and recipients, yielding longer graft survival; and lower costs. APOL1 genotyping can be performed in hours; therefore, donor genotypes can be considered in organ allocation. If results from Zhang et al are replicated, the field will need to reconsider the pathogenesis of APOL1-associated kidney diseases beyond a role for kidney-synthesized APOL1 risk variant protein.19Heymann J. Winkler C.A. Hoek M. Susztak K. Kopp J.B. Therapeutics for APOL1 nephropathies: putting out the fire in the podocyte.Nephrol Dial Transplant. 2017; 32: i65-i70Crossref PubMed Scopus (25) Google Scholar Circulating, vascular, and immune cell APOL1 risk variant proteins will need to be reassessed for roles in early allograft failure and potentially native CKD.20Weckerle A. Snipes J.A. Cheng D. et al.Characterization of circulating APOL1 protein complexes in African Americans.J Lipid Res. 2016; 57: 120-130Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Kidney donor APOL1 genotypes play a critical role in transplant outcomes.2Reeves-Daniel A.M. Depalma J.A. Bleyer A.J. et al.The APOL1 gene and allograft survival after kidney transplantation.Am J Transplant. 2011; 11: 1025-1030Crossref PubMed Scopus (236) Google Scholar, 3Freedman B.I. Julian B.A. Pastan S.O. et al.Apolipoprotein L1 gene variants in deceased organ donors are associated with renal allograft failure.Am J Transplant. 2015; 15: 1615-1622Crossref PubMed Scopus (121) Google Scholar, 4Freedman B.I. Pastan S.O. Israni A.K. et al.APOL1 genotype and kidney transplantation outcomes from deceased African American donors.Transplantation. 2016; 100: 194-202Crossref PubMed Scopus (116) Google Scholar,15Chen D.P. Zaky Z.S. Schold J.D. et al.Podocyte density is reduced in kidney allografts with high-risk APOL1 genotypes at transplantation.Clin Transplant. 2021; 35e14234Crossref PubMed Scopus (4) Google Scholar We eagerly await new data to determine the role recipient APOL1 genotypes may play in kidney transplantation. Barry I. Freedman, MD, Alejandra M. Mena-Gutierrez, MD, and Lijun Ma, MD, PhD. Wake Forest University Health Sciences receives funding via NIH grants U01 DK116040 and U01 DK116041. Wake Forest University Health Sciences and Barry Freedman have rights to an issued US patent related to APOL1 genetic testing (www.apol1genetest.com). Dr Freedman is a consultant for and receives research funding from AstraZeneca and Renalytix AI. The other authors declare that they have no relevant financial interests. The authors wish to thank Dr Amber M. Reeves-Daniel for her expert review of this manuscript. Received October 25, 2021 in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form November 4, 2021.