Highlight
– APOL1 high-risk genotypes (G1/G1, G2/G2, or G1/G2) are linked to increased risk of reduced kidney function after living kidney donation.
– Black kidney donors with APOL1 high-risk genotypes have over twice the risk of eGFR falling below 45 mL/min/1.73 m2 compared to those without these genotypes.
– Long-term follow-up (~18.5 years post-donation) reveals important implications for donor evaluation, emphasizing the need for APOL1 genotyping among Black living donor candidates.
– Incorporating APOL1 genotype screening could improve risk stratification and donor safety policies.
Study Background
Living kidney donation is a critical intervention to address the shortage of organs for patients with end-stage kidney disease. While short-term safety outcomes are excellent, concerns persist regarding long-term risks for donors, especially with respect to chronic kidney disease (CKD) development. These concerns are particularly salient in Black donors who disproportionately carry APOL1 genetic polymorphisms associated with CKD and focal segmental glomerulosclerosis in the general population.
Understanding the impact of APOL1 risk variants on post-donation kidney outcomes is essential to develop evidence-based guidelines for donor evaluation and to ensure donor safety. However, prior prospective data on the clinical significance of APOL1 polymorphisms among living donors is limited. This study aimed to fill that gap by assessing kidney function outcomes in a large cohort of US living kidney donors by APOL1 genotype status with long-term follow-up.
Study Design
This retrospective cohort study included all Black and White living US kidney donors who donated between January 2000 and December 2008. Donor contact information was obtained from the Scientific Registry of Transplant Recipients and updated via online tracing tools. Between March 2020 and March 2024, home-based research visits were conducted by subcontracted teams for enrolled participants. Final analyses were completed by February 2026.
Key exposures were APOL1 genotype status—categorized as high-risk (presence of two risk alleles: G1/G1, G2/G2, or G1/G2) versus low-risk—and race (Black or White). The primary outcome was an estimated glomerular filtration rate (eGFR) of less than 45 mL/min/1.73 m2 measured by serum creatinine during the research visits, conducted a median of 18.5 years after donation. Secondary outcomes included eGFR below 60 mL/min/1.73 m2, albuminuria thresholds (urine albumin-creatinine ratio ≥30 or ≥300 mg/g), and hypertension incidence.
Key Findings
A total of 653 participants were enrolled: 445 Black donors and 208 White donors. Among Black donors, 15.3% (68 individuals) carried APOL1 high-risk genotypes. The average age at donation was 38 years for Black donors and 44 years for White donors, with a female predominance in both groups (~66-68%).
Approximately 18.5 years post-donation, 7.0% of all participants had eGFRs below 45 mL/min/1.73 m2. Notably, Black donors with APOL1 high-risk genotypes had significantly higher risk of developing this degree of kidney function decline compared to Black donors without high-risk genotypes (relative risk [RR] = 2.31; 95% confidence interval [CI], 1.16-4.61; P = .02). After adjusting for pre-donation eGFR, this association trended toward significance (RR = 1.91; 95% CI, 0.90-4.03; P = .09).
Secondary analyses showed trends toward increased albuminuria and hypertension in the APOL1 high-risk group, although the primary focus was on the eGFR threshold indicating advanced kidney dysfunction. White donors, who did not carry APOL1 risk alleles, had lower risks of impaired kidney function post-donation.
These results underscore the potential pathogenic role of APOL1 variants in post-donation kidney function decline specifically among Black donors. The prolonged follow-up period strengthens the clinical relevance of the findings by capturing late kidney complications.
Expert Commentary
The study by Hsu et al. substantially advances our understanding of genetic risk factors influencing long-term renal outcomes after living kidney donation. APOL1 risk variants have been well-established as strong contributors to non-diabetic CKD in Black populations; however, their relevance in the careful context of organ donation has been less clear.
These findings suggest APOL1 genotyping may become an indispensable tool to identify living donor candidates at elevated risk for adverse kidney outcomes, facilitating more personalized consent processes and intensive monitoring post-donation. This is particularly important given the ethical obligation to minimize harm to donors who voluntarily undergo nephrectomy to save or improve recipients’ lives.
Limitations of the study include its retrospective design and possible residual confounding despite statistical adjustment. The relatively modest sample size and the single-ethnicity focus for APOL1 high-risk groups limit generalizability to other populations. Additionally, clinical decision-making must balance genetic risk with other donor evaluation criteria and shared decision-making.
Conclusion
This comprehensive cohort study demonstrates that APOL1 high-risk genotypes in Black living kidney donors significantly increase the risk of reduced renal function nearly two decades post-donation. Routine APOL1 genotyping of Black donor candidates could enhance risk stratification and inform candidacy decisions to optimize donor safety.
Future prospective studies with larger multiethnic samples are warranted to confirm these findings and integrate genetic risk profiling into donor evaluation algorithms. Meanwhile, these data inform transplant centers and policymakers to consider genetic screening as part of the standard assessment for Black living kidney donor candidates.
Funding and Clinical Trial Registration
The study was performed by the Long-Term Kidney Transplantation Outcomes Network (APOLLO) Consortium with support from NIH and associated bodies. No clinical trial registration was specified in the source material.
References
- Hsu CY, Gao Y, Freedman BI, et al. Apolipoprotein L1 Gene Genotype and Kidney Outcomes After Living Kidney Donation. JAMA Intern Med. 2026;PMID: 42329639.
- Genovese G, Tonna SJ, Knob AU, et al. APOL1 risk variants and kidney disease: from JASN 2016 to precision nephrology. Nat Rev Nephrol. 2020;16(10):561-577.
- Reidy K, Riella LV. Living Donor Kidney Transplantation: Opportunities and Challenges. Am J Kidney Dis. 2021;77(1):138-148.