Genetic testing in kidney transplantation and living kidney donor risk assessment

Introduction The cause of kidney failure in kidney transplant recipients remains unknown in 20–45% of cases. Outcomes for living kidney donors (LKDs) are generally excellent, with only 8% experiencing complications post-donation. Here, we hypothesized that genetic testing could identify a genetic etiology in at least 20% of recipients and inform risk stratification in LKDs. Methods Genetic testing was performed in 231 transplant recipients and 46 prospective LKDs by means of exome sequencing of 409 chronic kidney disease (CKD)-associated genes. We also assessed 122 retrospective LKDs who developed adverse kidney outcomes post-donation which were defined by at least two of the three criteria: hypertension, a glomerular filtration rate under 60 mL/min/1.73m 2 , or a urine albumin to creatinine ratio of 3 mg/mmol or more. Results Pathogenic or likely pathogenic (P/LP) variants were identified in 23% of recipients, most commonly involving genes associated with cystic kidney disease and glomerulopathies. Among the recipients with a genetic diagnosis, there was a 37% rate of reclassification to a different phenotype post genetic testing. Among prospective LKDs, 4% had P/LP variants. In the retrospective cohort of LKDs with adverse kidney outcomes post donation, 19% carried P/LP variants. Conclusions Genetic testing yielded a high diagnostic rate and frequently reclassified CKD etiology in transplant recipients, underscoring its diagnostic utility. Universal genetic testing of asymptomatic LKDs had a yield of 4%, although our prospective LKD cohort had limited sample size. In contrast, high proportion of LKDs with adverse kidney outcome post-donation were found to carry P/LP variants in CKD-associated genes. Our findings suggest that targeted genetic testing of high-risk donors may be a preferred over universal testing strategy to optimize donor selection in LKDs. However, further evaluation is warranted to ensure this approach appropriately balances donor safety with equitable access.