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.

MRP reports no competing conflicts, but has previously served on advisory boards for Takeda, Synklino and Clirnet.

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).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

In South Africa, the University of Cape Town Human Research Ethics Committee (HREC 927/2014) gave ethical approval for this work. In the US the Johns Hopkins University School of Medicine Institutional Review Board (IRB00141138) gave ethical approval for this work as part of the multi-center observational HOPE in Action study (ClinicalTrials.gov: NCT03500315) along with each local transplant center.

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Yes

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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.

All data produced in the present study are available upon reasonable request to the authors.