Genetic testing in kidney transplantation and living kidney donor risk assessment

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 hypothesize that genetic testing could identify a genetic etiology in at least 20% of recipients and inform risk stratification in LKDs.

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/1.73m², or a urine albumin to creatinine ratio of 3 mg/mmol or more.

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.

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.