Rigorous, evidence-based policies for living donor candidate selection require accurate data on long-term postdonation outcomes. Such data have historically been limited by short follow-up periods and underrepresentation of racial and ethnic minority groups.

Black donors carry a disproportionately higher risk of post-donation chronic kidney disease (CKD) and end-stage kidney disease (ESKD) compared with White donors, at two- to threefold higher rates in administrative data analyses. The apolipoprotein L1 gene (APOL1) — which harbours variants (G1 and G2) conferring increased CKD risk in individuals with recent African ancestry — is a plausible biological explanation for this disparity. However, routine APOL1 genotyping of Black donor candidates remains controversial and is not yet standard practice at many transplant centres.
 

The Living Donor Extended Time Outcomes (LETO) study is a retrospective cohort ancillary to the NIDDK-funded APOLLO trial. 

Participants: 445 Black donors (from 136 transplant centres) and 208 White donors (from 76 centres).

APOL1 genotyping was performed at a CLIA-certified laboratory for G1 (rs73885319; rs60910145) and G2 (rs71785313) variants using TaqMan assays. Participants with two kidney risk alleles (G1/G1, G2/G2, or G1/G2) were classified as high-risk.

Modified Poisson regression with robust variance was used to calculate relative risks. An adjustment was made for pre-donation eGFR where differential distribution was identified between APOL1 groups.

Among 445 Black living kidney donors assessed at a median of 18.5 years post-donation, 68 (15.3%) carried APOL1 high-risk genotypes. At the time of the home visit, Black donors with high-risk genotypes had significantly worse kidney outcomes across multiple measures, as shown in the interactive chart below.

For the primary outcome of eGFR <45 mL/min/1.73 m², 14.7% of high-risk donors versus 6.4% of donors without high-risk genotypes met this threshold (unadjusted RR 2.31; 95% CI, 1.16–4.61; P = .02). After adjusting for pre-donation eGFR — which was already lower at baseline in the high-risk group — the relative risk attenuated to 1.91 (95% CI, 0.90–4.03; P = .09), with the confidence interval crossing the null.

For eGFR <60 mL/min/1.73 m², high-risk donors had a 50% higher risk (RR 1.50; 95% CI, 1.18–1.90), which remained statistically significant after adjustment (adjusted RR 1.34; 95% CI, 1.08–1.67). Severe proteinuria (UACR ≥300 mg/g) was nearly four times more common in the high-risk group (RR 3.84; 95% CI, 1.11–13.22).

In age-stratified analysis, the association between APOL1 high-risk genotype and eGFR <45 mL/min/1.73 m² was markedly stronger among donors older than the median age of 38 years at donation (RR 4.19; 95% CI, 1.82–9.63) compared with younger donors (RR 0.82; 95% CI, 0.19–3.48).

Three donors (all Black) progressed to ESKD over the follow-up period; one was in the APOL1 high-risk group. Carriers of a single APOL1 risk variant (G1/G0 or G2/G0) did not have higher rates of adverse outcomes than those with no risk variants.

These findings provide the most robust long-term evidence to date that APOL1 high-risk genotypes confer meaningful additional kidney risk after living donation in Black individuals. The unadjusted doubling of risk for eGFR <45 mL/min/1.73 m² — in a cohort assessed nearly two decades post-donation — adds to a growing body of evidence that donor selection frameworks must account for genetic risk beyond race alone.

The attenuation of the primary outcome after adjusting for pre-donation eGFR is not necessarily reassuring: the investigators argue that lower pre-donation eGFR in the high-risk group is itself likely a consequence of APOL1 genotype, meaning adjustment may obscure rather than clarify the true causal effect.

The findings support universal APOL1 genotyping for all living donor candidates with recent African genetic ancestry. Critically, however, the authors emphasise that a high-risk result should not be an automatic bar to donation. For the approximately 85% of Black candidates without high-risk genotypes, genotyping may actually provide reassurance and facilitate donation. For those with high-risk genotypes, the information enables individualised risk communication, shared decision-making, and appropriate long-term surveillance planning.

South Africa’s transplant landscape makes these findings particularly relevant. Kidneys available for transplantation are scarce, and in a healthcare environment where access to long-term dialysis in the public sector remains constrained, the long-term health of living donors demands careful, equitable attention.

Local data on APOL1 variant prevalence in South African populations is beginning to emerge. A 2023 master’s dissertation from the University of the Free State (Notani MD, UFS²) examined APOL1 G1 and G2 variant frequencies in 220 participants of African descent in Bloemfontein, across four groups stratified by HIV status and the presence of kidney disease indicators. The study found that all tested APOL1 risk variants were present in this South African population  and notably that the G2 variant was more prevalent than G1,  a pattern that differs from the 1000 Genomes Africa reference frequencies. The G2/G2 frequency in this cohort (0.0455) was higher than the 1000 Genomes Africa benchmark (0.017), while G1/G1 frequency (0.0045) was markedly lower than the reference (0.080).
 

The key message for local clinicians is that genotyping is about improving informed consent and shared decision-making, not excluding donors, and that a high-risk result should trigger enhanced post-donation monitoring rather than automatic disqualification. The age-stratified findings from LETO are particularly actionable: the markedly higher risk in donors older than 38 suggests that age and genotype together should inform the risk discussion in a way that neither factor alone can achieve.

As transplant programmes continue to evolve in South Africa, integrating genetic risk assessment into donor evaluation — where feasible and accessible — represents a meaningful step toward more equitable, evidence-based donation practice.

Hsu CY, Gao Y, Freedman BI, Lunn MR, Muiru AN, Schnitzler MA, Divers J, Mannon RB, Palmer ND, Karger AB, Lentine KL, Park M; Long-Term Kidney Transplantation Outcomes Network (APOLLO) Consortium. Apolipoprotein L1 Gene Genotype and Kidney Outcomes After Living Kidney Donation. JAMA Intern Med. 2026 Jun 22:e260996. doi: 10.1001/jamainternmed.2026.0996. Epub ahead of print. PMID: 42329639; PMCID: PMC13288191.   

1. Notani MD. Prevalence of APOL1 risk variants in HIV-positive compared to HIV-negative individuals with evidence of kidney disease. MSc dissertation (Genetics), University of the Free State, Bloemfontein, 2023. Available at: https://scholar.ufs.ac.za/items/e9f0f4c1-1df1-400e-82b9-683dc5d140b9 [Accessed June 2025]

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