APOL1 genotype and patient outcomes in US and South African transplant recipients with HIV who received kidneys from donors with HIV

APOL1 genotype and patient outcomes in US and South African transplant recipients with HIV who received kidneys from donors with HIV | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search APOL1 genotype and patient outcomes in US and South African transplant recipients with HIV who received kidneys from donors with HIV View ORCID Profile Robert Freercks , Moreno Rodrigues , View ORCID Profile Kathryn Manning , View ORCID Profile Jurgen Heymann , View ORCID Profile Jeffrey B. Kopp , View ORCID Profile Savania Nagiah , Meenakshi Rana , View ORCID Profile Sander Florman , Rachel Friedman-Moraco , Peter Stock , Alexander Gilbert , Shikha Mehta , View ORCID Profile Valentina Stosor , Marcus R Pereira , View ORCID Profile Michele I Morris , Jonathan Hand , Ghady Haidar , Maricar Malinis , Carlos A. Q. Santos , View ORCID Profile Joanna Schaenman , View ORCID Profile Emily A. Blumberg , David Wojciechowski , Jonah Odim , Allan Massie , Miruthula Tamil Selvan , Serena Bagnasco , Dorry Segev , Aaron AR Tobian , View ORCID Profile Elmi Muller , View ORCID Profile Christine M Durand , Andrew D Redd doi: https://doi.org/10.1101/2025.04.15.25325856 Robert Freercks 1 Faculty of Health Sciences, Department of Medicine, Nelson Mandela University , Gqeberha, South Africa MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Robert Freercks Moreno Rodrigues 2 Department of Medicine, Johns Hopkins University , Baltimore MD, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kathryn Manning 3 Department of Surgery, University of Cape Town , Cape Town, South Africa MPH Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Kathryn Manning Jurgen Heymann 4 Division of Intramural Research , NIDDK, NIH, Bethesda MD, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jurgen Heymann Jeffrey B. Kopp 4 Division of Intramural Research , NIDDK, NIH, Bethesda MD, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jeffrey B. Kopp Savania Nagiah 1 Faculty of Health Sciences, Department of Medicine, Nelson Mandela University , Gqeberha, South Africa PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Savania Nagiah Meenakshi Rana 5 Department of Surgery, Mount Sinai School of Medicine , New York NY, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sander Florman 5 Department of Surgery, Mount Sinai School of Medicine , New York NY, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sander Florman Rachel Friedman-Moraco 6 Department of Medicine, Emory University , Atlanta GA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter Stock 7 Department of Surgery, University of California San Francisco , San Francisco CA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alexander Gilbert 8 Department of Surgery, Georgetown University , Washington DC, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shikha Mehta 9 Department of Surgery, University of Alabama Birmingham , Birmingham AL, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Valentina Stosor 10 Department of Surgery, Northwestern University , Chicago IL, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Valentina Stosor Marcus R Pereira 11 Department of Medicine, Columbia University , New York NY, USA MD MPH Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michele I Morris 12 Department of Medicine, University of Miami , Miami FL, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michele I Morris Jonathan Hand 13 Department of Surgery, Ochsner Medical Center , New Orleans LA, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ghady Haidar 14 Department of Medicine, University of Pittsburgh , Pittsburgh PA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maricar Malinis 15 Department of Internal Medicine, Yale University School of Medicine , New Haven, CT, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Carlos A. Q. Santos 16 Department of Internal Medicine, Rush University , Chicago IL, USA MD MPHS Find this author on Google Scholar Find this author on PubMed Search for this author on this site Joanna Schaenman 17 Department of Surgery, University of California Los Angeles , Los Angeles CA, US MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Joanna Schaenman Emily A. Blumberg 18 Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia PA, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Emily A. Blumberg David Wojciechowski 19 Department of Medicine, UT Southwestern Medical Center DO Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jonah Odim 20 Transplantation Branch , NIAID, NIH, Bethesda MD, USA MD PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Allan Massie 21 Department of Surgery, New York University , New York City, New York, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Miruthula Tamil Selvan 22 Department of Pathology, Johns Hopkins University , Baltimore MD, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Serena Bagnasco 22 Department of Pathology, Johns Hopkins University , Baltimore MD, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dorry Segev 21 Department of Surgery, New York University , New York City, New York, USA MD PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Aaron AR Tobian 22 Department of Pathology, Johns Hopkins University , Baltimore MD, USA MD PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site Elmi Muller 3 Department of Surgery, University of Cape Town , Cape Town, South Africa 23 Faculty of Medicine, Stellenbosch University , Cape Town South Africa MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Elmi Muller Christine M Durand 2 Department of Medicine, Johns Hopkins University , Baltimore MD, USA MD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Christine M Durand Andrew D Redd 2 Department of Medicine, Johns Hopkins University , Baltimore MD, USA 24 Division of Intramural Research , NIAID, NIH, Baltimore MD, USA 25 Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: reddandrew{at}niaid.nih.gov Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF ABSTRACT Importance Lower kidney allograft survival has been demonstrated in kidney transplant recipients (KTR) without HIV whose donors have two apolipoprotein L1 ( APOL1 ) renal risk variants (RRV). The effects of APOL1 RRV on kidney transplant outcomes in people with HIV (PWH) have not been fully assessed. Objective To determine whether APOL1 renal risk variants (G1/G2) in donors or recipients are associated with outcomes of kidney transplantation in people with HIV (PWH)? Design Comparative analysis of kidney allograft outcomes in two of the largest longitudinal clinical studies examining transplantation outcomes in PWH. Setting and participants Two cohorts of HIV-positive KTR (R+) and their respective HIV-negative (D-) or HIV-positive (D+) kidney donors from the South African (SA) HIV+ to HIV+ transplantation clinical study and the United States of America (US) HOPE in Action Kidney transplantation clinical trial. All patients with genomic DNA available for APOL1 genotyping were included. APOL1 Genotype was determined using a probe-based assay. Main outcomes measured Time to first rejection, HIV-associated nephropathy, graft failure or death were compared by both donor and recipient APOL1 RRV status. Results Genomic DNA was available for 21 donors with HIV and 38 HIV D+/R+ recipients in the SA cohort, and 57 donors (40 D+ and 17 D-) and 119 recipients (49 HIV D+/R+ and 70 D-/R+) in the US cohort. Recipient outcomes were not associated with recipient APOL1 genotype. However, recipients whose donor carried one versus zero APOL1 RRV were significantly more likely to experience a negative composite outcome (p<0.02 for both cohorts independently), which led to an adjusted hazard ratio of a poor composite outcome of 2.9 (95% CI 1.1–7.4) and 10.1 (95% CI 2.4–42.7) in the SA and US cohorts, respectively. Conclusions and relevance In two independent studies, the presence of one APOL1 RRV in a donor kidney led to significantly worse post-transplant outcomes while recipient APOL1 genotype was not associated with outcomes. Further research into the interaction between the allograft environment and donor APOL1 genotype in PWH is required. Question Do APOL1 renal risk variants (G1/G2) influence the outcomes of kidney transplantation in people with HIV (PWH)? Findings In two of the largest cohorts of PWH who are also kidney transplant recipients, the presence of even one donor APOL1 renal risk variant was associated with an adjusted hazard ratio of a poor composite outcome of 10.1 (95%CI=2.4-42.7) and 2.9 (95%CI=1.1-7.4) in the US and SA cohorts, respectively. Recipient APOL1 genotype was not associated with graft outcomes. Meaning This may have implications for allocation of allograft kidneys in PWH, as well as informing the need for therapies targeting APOL1 gene expression in kidney transplant recipients. Introduction The outcomes of kidney transplantation in people with HIV (PWH) with controlled HIV replication are equivalent to those of people without HIV 1 , and for recipients with HIV regardless of donor HIV status 2 . Accordingly, kidney transplantation from donors with HIV to recipients with HIV (HIV D+/R+) is now a standard care option in the United States of America (US) 3 . While this has already reduced organ waiting times for PWH 4 , as well as reducing waitlists overall, there remains a need to further improve long-term graft function and survival. The discovery of apolipoprotein L1 gene ( APOL1 ) risk alleles as contributors to genetic risk for kidney disease in those of recent African ancestry, has fundamentally altered our understanding of the contribution of continental ancestry to progressive chronic kidney disease (CKD) 5 . These APOL1 renal risk variants (RRV; labelled G1: S342G and I384M; and G2: del N388 and Y389) afford protection against trypanosomiasis seen in Central and West Africa, but are also associated with progressive CKD and significantly contribute to genetic risk of CKD, particularly in PWH, in whom penetrance is the highest 6 . These RRV are largely absent in Americans of European descent and are significantly more common in West Africans 7 and African Americans 8 . In US population-based studies, approximately 37% of African Americans carry one RRV while 13% carry two 9 . The G1 and G2 RRV are also present in South African populations, with population frequencies of 7.3% - 10.0% and 14.9% - 23.7% respectively 10 . Locally-synthesised APOL1 protein variants mediate kidney toxicity through various mechanisms, including induction of mitochondrial and other intracellular toxicities in kidney podocytes, in part through a pore-forming mechanism, manifested especially in individuals with two APOL1 RRV in any combination 11 . The expression of APOL1 is upregulated by interferon gamma 12 , whose expression is also increased in HIV and may represent the link between APOL1 RRV carriage and harmful expression leading to CKD 13 . Donor APOL1 RRV are also associated with shorter renal allograft survival in KTR without HIV, and this helps to explain the shorter allograft survival seen in African American KTR 14 . The utility of pre-implantation APOL1 genotyping is currently uncertain, and further studies are required to better evaluate such an approach 15 . The presence of donor or recipient APOL1 RRV in HIV-positive deceased donor kidneys may influence renal allograft survival in PWH who receive kidney transplants. To date, there are a lack of data on the influence of APOL1 RRV and outcomes of kidney transplantation in PWH, where the additional presence of HIV may significantly influence APOL1 expression. A better understanding of the relative importance of donor versus recipient APOL1 genotype may lead to improved overall outcomes. We aimed to determine this in two independent cohorts of kidney transplantation in PWH, one in South Africa (SA) and one in the US. Methods South African study cohort The SA population in this study has been described previously 16 , 17 . Briefly, SA KTR with HIV receiving kidneys from deceased donors with HIV (HIV D+/R+), and their respective donors, had peripheral blood mononuclear cells (PBMC) collected, processed and frozen at −112°F prior to transplantation and at several follow-up time points, which were subsequently used for APOL1 genotyping. When available recipient pre-transplant samples were used for genotyping. All recipients and donors that had an available PBMC sample were tested for this study. The groups analysed here were not significantly different than the full cohort (Table S1 & S2). All participants provided informed consent, and the study was approved by the University of Cape Town Human Research Ethics Committee (UCT HREC 927/2014). 1 United States study cohort The US population in this study was taken from the HOPE in Action Kidney transplantation clinical trial, which examined the safety and efficacy of HIV D+/R+ transplantation vs donation from donors without HIV (HIV D-/R+) 2 . This population has been described in detail previously 2 . Briefly, between April 2018 and September 2022, 198 individuals with HIV underwent kidney transplantation under the multi-center observational HOPE in Action study (ClinicalTrials.gov: NCT03500315 ). There were 99 transplants in each trial arm (HIV D+/R+ and D-/R+). Similar to the SA cohort, recipients and donors from both HIV D+/R+ and D-/R+, had peripheral blood mononuclear cells (PBMC) collected, processed and frozen at −112°F prior to transplantation, and at several follow-up time points. The pre-transplant PBMC aliquots were subsequently used for APOL1 genotyping. All recipients and donors with available PBMC for genomic testing were included for this analysis. The groups analysed here were not significantly different than the full cohort (Table S3 & S4). All participants provided consent, and the study was approved centrally by the Johns Hopkins University School of Medicine Institutional Review Board (IRB00141138) and by each local transplant center. APOL1 genotyping Genomic DNA was extracted from PBMC obtained from deceased kidney donors and recipients in both cohorts using the DNeasy Blood and Tissue kit (Qiagen, Hilden, Germany) following the manufacturer’s protocol. Samples from both cohorts were analysed at the same US National Institutes of Health laboratory using custom TaqMan probe-based assays specific for APOL1 G1 SNPs (rs73885319 and rs60910145) and the G2 deletion (rs717185313) (ThermoFisher Scientific, Waltham MA, US) 18 . Non-risk APOL1 RRV are designated as G0, G1, and G2 genotype calls were visually inspected for quality control. All samples showed consistent allele calls with 100% concordance across triplicate samples and only allowed genotypes were observed. Statistical analyses Variables were compared by APOL1 RRV status using the Mann-Whitney (Wilcoxon rank-sum test) for numerical variables (age, median CD4 count) and Fisher’s exact test for categorical variables (sex, self-reported race, outcomes). Kaplan-Meier survival curves were used to illustrate composite survival by APOL1 RRV status and compared using log-rank test. The Cox proportional hazards model was used to generate hazard ratios and its 95% confidence interval (CI) to show the magnitude of effect for the presence of one APOL1 RRV compared to none. Model was adjusted for age, hypertension and diabetes melitus and proportional hazard assumption was evaluated using Schoenfeld residual plots. Each cohort was examined individually, as well as in a combined analysis. Results Genomic DNA was available for 21 donors and 43 recipients from SA (HIV D+/R+), 38 of whom had matched donor genotyping available ( Table 1 ). In the US cohort, genomic DNA was available for 119 recipients, all of whom were PWH ( Table 1 ). Of these, 72 had donor genotyping available, of whom 49 were HIV D+/R+ ( Figure S1 ). Overall, recipients in both cohorts were older than donors, and while evenly split between male (51%) and female (49%) in the SA cohort, recipients were predominantly male in the US cohort (86%). Most recipients in both cohorts were Black African or African American, while donors were majority male and had significantly greater racial diversity. When comparing the US and SA cohorts, US donors also had a higher CD4 count, were more likely to be white race and less likely to carry APOL1 RRV; this was similar when restricting the comparison to US donors with HIV ( Table S5-S7 ). Donors from both cohorts had relatively low rates of dual APOL1 RRV carriage with only one donor in the US cohort and no donors in the SA cohort carrying two APOL1 RRV ( Table 1 ). Conversely, recipients in both cohorts had significantly higher rates of APOL1 RRV carriage, with 39% and 42% carrying two RRV in the SA and US cohorts respectively. HIV-associated nephropathy (HIVAN) was the original cause of native kidney failure in 15 of the 17 (88.2%) KTR with two APOL1 RRV in the SA cohort and in 11 of 51 with two APOL1 RRV (21%) in the US cohort. View this table: View inline View popup Download powerpoint Table 1: HIV-positive kidney transplant recipients and donor characteristics in South African and United States HOPE cohorts The median follow-up time after transplantation to first outcome was 3.58 (0.86-6.99) years and 1.60 (1.4-2.4) years in the SA and US cohorts respectively. Overall, five recipients (13.2%) in the SA cohort and 14 recipients (11.8%) in the US cohort died during the study periods ( Table 2 ). The most common cause of death in both cohorts was infection, primarily due to COVID-19 pneumonia, which accounted for three (60%) and four (28.6%) of the deaths in the SA and US cohorts, respectively. View this table: View inline View popup Download powerpoint Table 2: Recipient outcomes by APOL1 recipient risk allele status in South African and United States HOPE cohorts The presence of one APOL1 RRV in the donor was associated with a significantly increased likelihood of biopsy-proven kidney rejection (SA p=0.005 and US p=0.030) and death (US cohort only, p=0.001) for the recipient ( Table 3 ). The composite of a first event (HIVAN, biopsy-proven rejection, graft failure or death) was observed in 11 of 12 SA recipients (92%) whose donor carried one APOL1 RRV compared to 11 of 26 (42%) in those whose donor had zero APOL1 RRV (p = 0.004; Table 3 ). Similarly, a poor composite outcome was noted in five of the seven US recipients (71%) whose donor carried one APOL1 RRV compared to four of 42 (9%) whose donor had zero APOL1 RRV (p = 0.001; Table 3 ). In the US cohort, there were no donors without HIV with APOL1 RRV, so we could not determine the impact of HIV status on this association. Cox regression analysis showed a significantly increased risk of a poor composite outcome in KTR whose donors carried one versus zero APOL1 RRV, with hazard ratios of 8.36 (95% CI = 2.2–31.4) for the US cohort and 2.9 (95% CI = 1.2– 6.8) for the SA cohort. After adjusting for recipient age, diabetes and hypertension, the adjusted hazard ratio (aHR) of a poor composite outcome in KTR whose donor carried one versus zero APOL1 RRV was 10.1 (95%CI=2.4-42.7) and 2.9 (95%CI=1.1-7.4) in the US and SA cohorts, respectively. View this table: View inline View popup Download powerpoint Table 3: Recipient outcomes by donor APOL1 risk allele status in South African and United States HOPE cohorts Kaplan-Meier estimations for a composite first event in KTR by donor APOL RRV status also demonstrated increased rates of a composite outcome of HIVAN, biopsy-proven rejection, graft failure or death in KTR of donor kidneys with one APOL1 RRV in both the US and SA cohorts (p<0.02, Figure 1 ), as well as when the cohorts were combined for analysis (p<0.001; Figure S2 ). Similar findings were observed in the US cohort when including KTR who received kidneys from donors with one or two risk APOL1 RRV (p=0.05), as well as when limited to donors with HIV (p=0.01; Figure S3 and S4 ). No recipient in the SA cohort received a kidney from a donor with two APOL1 RRV, preventing us from evaluating this outcome. On sub-analysis of data combining both cohorts ( Figure S5A-D ), inferior graft outcomes were observed in KTR of donors with 1 APOL1 RRV, driven primarily by increased rates of deaths (p<0.001) and rejection (p<0.001), but not for graft loss (p=0.76) or onset of HIVAN in the graft (p=0.101; Figure S5A-D ). Download figure Open in new tab Figure 1: Kaplan-Meier estimations for a time to first outcome of a composite endpoint consisting of rejection (biopsy proven ABMR/ TCMR), HIVAN, graft lost or death) in kidney recipients by donor APOL1 risk variant status in kidney recipients living with HIV in the US HOPE in Action (A) and the South African HIV D+/R+ (B) cohorts. Conversely, recipient outcomes were not associated with recipient APOL1 genotype (carriage of zero versus one or two APOL1 RRV) and a composite of poor outcomes (first event of HIVAN, biopsy-proven rejection, graft failure or death) was similar in both groups (SA cohort: 10 of 18 [56%] versus 12 of 20 [60%], p=0.780; US cohort: 11 of 44 [25%] versus 21 of 75 [28%], p=0.880, Table 2 ). Discussion In this study of PWH enrolled in two independent KTR cohorts in SA and the US, the presence of a single donor APOL1 RRV was associated with highly similar findings in both cohorts of significantly worse outcomes in the renal allograft recipients compared to recipients receiving kidneys from donors with zero APOL1 RRV. Although dual APOL1 RRV carriage in KTR was common in both cohorts, the presence of either one or two APOL1 RRV in KTR was not associated with worse kidney allograft outcomes compared to KTR with zero APOL1 RRV. The two cohorts were similar in their baseline demographic characteristics, although recipients in the US tended to be older and to have greater racial diversity. US donors were also less likely to carry APOL1 RRV, in keeping with a lower proportion of participants with recent African ancestry. In the general population, APOL1-mediated kidney disease (AMKD) follows a largely recessive inheritance pattern. Similarly, studies investigating the influence of APOL1 on transplant outcomes have largely focused on the effect of two APOL1 RRV in kidney donors 19 . However, a recent large prospective cohort study of CKD from West Africa demonstrated a clear gene dose effect, with any single APOL1 RRV (G1 or G2) being associated with an 18% higher odds of CKD and a 61% higher odds of having focal segmental glomerulosclerosis 7 . This is in keeping with other smaller studies that have also demonstrated a small increase in risk for CKD in APOL1 RRV heterozygotes 20 . This may be especially important in the setting of kidney transplantation, where the graft kidney is exposed to additive environmental insults including traumatic injury leading to brain death, cold ischemic time, reduced functional kidney mass, and exposure to nephrotoxic medications. Recently, stabilization of hypoxia-inducible transcription factors by hypoxia has been shown to activate transcription of APOL1 in podocytes and tubular cells 21 . Furthermore, within the context of HIV infection, the recipient environment may be especially primed for injurious APOL1 expression, with consequent AMKD. APOL1 is an interferon-stimulated gene, and even with complete viral suppression in HIV, as in the present study, persistent immune dysregulation and enhanced interferon production is evident, which we speculate may upregulate expression of even one RRV and result in AMKD in this setting 22 . The presence of one APOL1 RRV was associated with increased risk for allograft rejection in both cohorts, and to our knowledge this association has not been reported previously. Given the relatively small size of this study, these findings should be interpreted with caution. In a large cohort examining the presence of focal and segmental collapsing glomerular lesions typical of AMKD in KTR who were carriers of two APOL1 RRV, concomitant rejection was seen in 61% of patients 23 . In the US cohort, there was also an association between COVID-19 related mortality and APOL1 RRV. This agrees with the findings by Hung et al. who recently reported the association of dual APOL1 RRV carriage with acute kidney injury and death in a large cohort of African American veterans hospitalized with COVID-19 24 . The present findings are in keeping with other studies that have shown an association between graft failure and APOL1 RRV carriage by donors rather than by recipients. In one study of 136 African American deceased donor kidneys and their respective recipients, the presence of two APOL1 RRV in donors was more important in determining outcomes than cold ischemic time or HLA mismatch. The same study also showed that worse allograft outcomes with African American donor kidneys could be solely attributed to donor APOL1 genotype rather than to race 25 . Similar to the present study, another small retrospective study of 119 African American kidney transplant recipients reported that recipient carriage of two APOL1 RRV was not associated with inferior transplant outcomes 26 . However, one study did demonstrate inferior graft outcomes at one year in recipients with two APOL1 RRV, although donor genotype was not reported in the study and outcomes were similar at three years 27 . Zhang et al also recently described an increased risk of death-censored allograft loss and rejection in recipients with one or two APOL1 RRV’s and this was independent of donor genotype 28 . Interestingly, the same study also showed that APOL1 RRV may alter immune cell function, in particular T cell and NK cell function, which could have an impact on rejection. Uncertainty remains regarding the relative importance of donor versus recipient APOL1 genotypes and further research is currently underway to explore this question 29 . Our findings have important implications for transplantation in PWH, but will require confirmation in a larger study. In this regard, the National Institutes of Health-sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes and includes PWH 29 . Strategies to prevent AMKD in the setting of HIV have not been tested, but could include selection of antiretroviral therapy shown to reduce interferon expression 30 . Additionally, phase 2/3 studies of inaxaplin, a small molecule inhibitor of AMKD are currently underway and may be a promising adjunct in KTR whose donors carry APOL1 RRV 31 . While the role of screening donors and recipients for APOL1 RRV is currently unclear and complicated by the need to consider APOL1 haplotype, as well as any potential unintended consequences such as implications for health insurance or stigmatization, the British Transplantation Society has recently recommended offering APOL1 genotyping to all potential living donors. As therapies directed against AMKD become available, the role of testing may become clearer. The present study has limitations. First, the study populations in each cohort were relatively small, but the identical findings in two different cohorts, as well as the combined data, suggest that the findings are robust. We also only had one donor with two APOL1 RRV, and no donors without HIV with one or two APOL1 RRV, limiting our ability to assess any increased risk afforded by these factors. Second, we were unable to test for additional APOL1 haplotypes, and it is possible that such data may alter our understanding of variant risk and the role of one versus two APOL1 RRV. One major strength of the present study was the ability to compare and combine the two largest independent cohorts of HIV D+/R+ kidney transplantation on different continents over a similar study period. Conclusion In summary, we have shown that kidney allograft outcomes are worse in PWH who receive kidneys from deceased donors with one APOL1 RRV, while recipient APOL1 genotype did not influence graft outcomes. The mechanisms for the former remain unclear, although it is possible that toxic expression of APOL1 is enhanced in KTR who also have HIV and by the transplant process itself, including concomitant medications. These findings should be confirmed in a larger cohort and further research into the interplay between the allograft environment and donor APOL1 genotype in PWH is required. Data Availability All data produced in the present study are available upon reasonable request to the authors. Author contributions RF, ADR – Wrote first draft of paper; JH, JBK, MTS – performed and oversaw laboratory work; RF, ADR, EM, CMD, AART - planned the laboratory study; CMD, DS, AART, ADR, JO – planned and oversaw the US transplant study; EM, ADR, KM – planned and oversaw the SA transplant study; MR, KM – analyzed primary data; MR, SF, RFM, PS, AG, SM, VS, MRP, MM, JH, GH, MM, CS, JS, EB, DS, CMD, AART – US cohort clinical team; SB – reviewed US pathology; RF, AR, CD and EM interpreted the data; and all authors reviewed and approved the final manuscript. Supplemental figure legends Figure S1: Flow of US HOPE cohort. * indicates one donor with 2 APOL1 RRV removed for purposes of comparison. Figure S2: Kaplan-Meier estimation for a composite first event in KTR by donor APOL RRV status in combined US and SA cohorts Figure S3: Kaplan-Meier estimation for a composite first event in KTR by donor APOL RRV status in US HOPE cohort including all donors (HIV+ and HIV-) Figure S4: Kaplan-Meier estimation for a composite first event in KTR by donor APOL RRV status in US HOPE cohort limited to HIV+ donors Figure S5: Kaplan-Meier estimation for first event of death (A), biopsy-proven rejection (B), graft loss (C), and HIVAN (D) in KTR by donor APOL RRV status in combined US and SA cohorts Data sharing statement Data will be made available upon request with approval and appropriate data use agreements. Please send requests for data from the US study to christinedurand{at}jhmi.edu , and from the South African study to elmimuller{at}sun.ac.za . Additional acknowledgements for HOPE in Action team University of Alabama at Birmingham: Katherine Basinger, RN, CCRP; Darnell Mompoint Williams; DNP University of Arkansas for Medical Sciences: Emmanouil Giorgakis, MD University of California, San Diego: Layla Myers University of California, San Francisco: Ada Chao, Joanne Kwon University of California, Los Angeles: Adreanne Rivera Yale University School of Medicine: Ricarda Tomlin, BS, CCRP MedStar Georgetown Transplant Institute: Rochell Yacat Miami Transplant Institute: Shweta Anjan, MD, Isabel Vital, Carlos Munoz, Lissett Moni Emory University: Jeryl Huckaby, MSCRA, CCRC; William Kitchens, MD Northwestern University: Michelle Callegari, Zachary C Dietch, MD. Rush University Medical Center: Rebecca Lai University of Illinois at Chicago: Kelly Bruno Indiana University: Mary Balmes-Fenwick Ochsner Clinic Foundation: Angela R. Smith, MBA Massachusetts General Hospital: Kerry Crisalli, RN Johns Hopkins University: Jamie Wiles, RN University of Maryland, Institute of Human Virology: John Baddley, MD; Lisa Anderson Columbia University Medical Center: Dominique Piquant Icahn School of Medicine at Mount Sinai: Brandy Haydel, CCRC Weill Cornell Medical College: Britta Witting NYU Langone Transplant Institute: Rebecca Dieter, PharmD University of Cincinnati: Senu Apewokin, MD, FACP; Jenny Baer, RN University of Pittsburgh Medical Center: Ellie Morell University of Pennsylvania: Maryann Najdzinowicz, RN Methodist Health System Clinical Research Institute: Jose A. Castillo-Lugo, MD; Karen Castro University of Texas Southwestern Medical Center: Ricardo M. La Hoz, MD; Jarrett Hubbard Acknowledgements The authors would first like to thank the patients, donors and their families, and clinical teams who made this work possible. We would also like to thank the full HOPE in Action team (see list in supplemental data). Footnotes Funding: This work was supported in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH); Division of Intramural Research, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH); U.S.-South Africa Program for Collaborative Biomedical Research (1U01AI152153-01 and U01AI177211); and NIAID (U01AI134591, U01AI177211, R01AI20938 and R01DK131926). Type of study: Original Genetic Association Study Conflicts of interest: MRP reports no competing conflicts, but has previously served on advisory boards for Takeda, Synklino and Clirnet. References 1. ↵ Muller E , Barday Z , Mendelson M , Kahn D . HIV-positive-to-HIV-positive kidney transplantation--results at 3 to 5 years . The New England journal of medicine . Feb 12 2015 ; 372 ( 7 ): 613 – 20 . doi: 10.1056/NEJMoa1408896 OpenUrl CrossRef PubMed 2. ↵ Durand CM , Massie A , Florman S , et al. 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Clinical Journal of the American Society of Nephrology . 2018 ; 13 ( 6 ): 940 – 942 . OpenUrl FREE Full Text 30. ↵ Grozdeva R , Ivanov D , Strashimirov D , et al. Relationship between Modern ART Regimens and Immunosenescence Markers in Patients with Chronic HIV Infection . Viruses . 2024 ; 16 ( 8 ): 1205 . OpenUrl PubMed 31. ↵ A Phase 2/3 Adaptive, Double-blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of VX-147 in Adult and Pediatric Subjects With APOL1-mediated Proteinuric Kidney Disease . National Library of Medicine (US) . https://clinicaltrials.gov/study/NCT05312879 View the discussion thread. Back to top Previous Next Posted April 16, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Blumberg , David Wojciechowski , Jonah Odim , Allan Massie , Miruthula Tamil Selvan , Serena Bagnasco , Dorry Segev , Aaron AR Tobian , Elmi Muller , Christine M Durand , Andrew D Redd medRxiv 2025.04.15.25325856; doi: https://doi.org/10.1101/2025.04.15.25325856 Share This Article: Copy Citation Tools APOL1 genotype and patient outcomes in US and South African transplant recipients with HIV who received kidneys from donors with HIV Robert Freercks , Moreno Rodrigues , Kathryn Manning , Jurgen Heymann , Jeffrey B. Kopp , Savania Nagiah , Meenakshi Rana , Sander Florman , Rachel Friedman-Moraco , Peter Stock , Alexander Gilbert , Shikha Mehta , Valentina Stosor , Marcus R Pereira , Michele I Morris , Jonathan Hand , Ghady Haidar , Maricar Malinis , Carlos A. Q. Santos , Joanna Schaenman , Emily A. 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