Sadeghi-Alavijeh, Omid; Chan, Melanie MY; Tzoumkas, Konstantinos; Doctor, Gabriel T; Gale, Daniel P; (2025) Quantifying APOL1, Human Leukocyte Antigen, and Other Genetic Contributions to Unexplained Kidney Failure. American Journal of Kidney Diseases 10.1053/j.ajkd.2025.07.005. (In press).

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Abstract

RATIONALE & OBJECTIVE: Unexplained kidney failure (uKF) affects 15% of individuals needing kidney replacement therapy. The lack of a clear diagnosis creates uncertainty about recurrence, familial risk, and trial eligibility. This study sought to identify genetic variants underlying uKF. STUDY DESIGN: Genomic analyses were conducted using whole genome sequencing (WGS) that were reviewed by a multidisciplinary team who identified candidate pathogenic variants. A case-control study was implemented for single and structural variants to perform gene-based and polygenic risk score association testing. SETTING & PARTICIPANTS: The study recruited 218 patients with uKF onset before age 50 from the UK's 100,000 Genomes Project. Association analysis was performed in 180 uKF cases who remained unsolved after clinical analysis and constituted the non-monogenic uKF cohort (NM-uKF). 26,373 controls were derived from the unaffected relatives of non-renal probands. EXPOSURES: Candidate variants in 537 genes were assessed at a structural and single variant level in the 218 recruited patients as were high-risk APOL1 genotypes and polygenic risk scores for chronic kidney disease and various glomerulonephritides. OUTCOME: The primary outcomes were establishing a genetic diagnosis and the associations between genetic findings, age, family history, and ancestry. ANALYTICAL APPROACH: Candidate variants were reviewed for pathogenicity. Gene-based and structural variant analyses and high-risk APOL1 genotype assessments were performed. Polygenic risk scores and post-hoc HLA associations were also investigated. RESULTS: Monogenic diagnoses were made in 38 of 218 patients (17%) using WGS via the clinical arm of the 100,000 Genomes Project. Median uKF onset was 36 years. Diagnoses were less frequent in patients aged 36 or older, irrespective of family history. Three older patients without a family history had pathogenic variants in type IV collagen genes. Among individuals with recent African ancestry, high-risk APOL1 genotypes were significantly more common in those with uKF (52% vs. 8.4% in those without uKF, P<0.001). An elevated steroid sensitive nephrotic syndrome (SSNS) polygenic risk score was observed in those with high-risk APOL1 genotypes and uKF, partly due to differences at HLA-DQB1*03:19. LIMITATIONS: Potential limitations include the small sizes of subgroups and use of short-read WGS. CONCLUSIONS: WGS yielded a monogenic diagnosis in 17% of patients with uKF, with no additional solved cases arising from the case-control analysis. These findings underscore APOL1's role in those with recent African ancestry and suggest a genetic architecture distinct from common chronic kidney disease.

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