Whole-exome sequencing of kidney transplant recipients and donors: insights into end-stage renal disease and post-transplant genetic risk.

backgroundKidney transplantation is the preferred treatment for end-stage renal disease (ESRD), yet challenges persist in long-term graft survival and post-transplant complications. Genomic profiling, especially whole-exome sequencing (WES), offers new opportunities to personalize donor-recipient matching and predict transplant outcomes. This study aimed to explore the genetic landscape of both transplant recipients and donors using WES.

methodsThis prospective cohort study included 64 kidney transplant recipients (51 adults, 13 pediatric) and 61 donors in Kazakhstan. WES was performed to identify monogenic causes of ESRD, evaluate rejection-associated immune polymorphisms (31 SNPs), and screen for post-transplant risk using a 355-gene Transplant Morbidity Panel. Variants were classified following ACMG/AMP guidelines, and allele frequencies were compared to global reference datasets.

resultsAmong recipients, pathogenic/likely pathogenic variants were found in 15.4% of pediatric and 9.1% of adult cases, with additional variants of uncertain significance detected in 23.1% and 23.6%, respectively. WES identified monogenic nephropathies including Alport syndrome, cystinuria, and polycystic kidney disease. In donors, 13.1% carried variants associated with latent renal or systemic conditions despite no clinical manifestation at donation. The APOE p.Cys130Arg variant, linked to lipid dysregulation, was observed more frequently in recipients (allele frequency 0.17) than donors (0.09), though not statistically significant. Among the 31 SNPs evaluated, significant associations with acute rejection were observed for IL1B rs1143634 and TP53 rs1625895 under dominant models. IL1B carriers showed increased rejection risk (OR = 4.62, p = 0.039), whereas TP53 carriers appeared protected (OR = 0.058, p = 0.027). Given the limited number of rejection cases, these findings should be considered exploratory and require validation in larger cohorts. Additionally, 44.3% of recipients carried at least one pathogenic or likely pathogenic variant in the Transplant Morbidity Panel, particularly in genes related to malignancy, cardiomyopathy, and monogenic diabetes.

conclusionsThis study provides one of the first applications of WES in a Central Asian kidney transplant population. Findings highlight the prevalence of monogenic and comorbid risk variants in both recipients and donors and support the use of genomic screening for improving pre- and post-transplant care. The identification of immune-related SNPs and extra-renal findings further underscores the utility of WES for personalized transplant management. Integration of genomics into transplant workflows may help address the ongoing gap between clinical need and transplant outcomes, particularly in low-resource settings.