Genetic etiology associated with post‑transplant outcomes in a retrospective cohort of pediatric kidney transplant recipients based on genomics analysis

Abstract

To determine whether genetic etiology, as determined by whole-exome sequencing (WES) and copy-number variant (CNV) analysis, is associated with graft survival and early injury profiles in pediatric kidney transplant recipients. We conducted a single-center, retrospective cohort study of children (< 18 years) who underwent primary kidney transplantation between January 1, 2019, and December 31, 2024, and had available WES. Genomic variants were interpreted according to ACMG/AMP standards with integrated intragenic-CNV interrogation and multidisciplinary review. Recipients were classified as gene-positive (pathogenic/likely pathogenic variants or clinically concordant variants of uncertain significance in established kidney-disease genes) or gene-negative (no highly suspicious variants). The primary clinical outcome was graft survival. Secondary outcomes included kidney function (serum creatinine and eGFR), urinary biomarkers at 6 months post-transplantation, and serial measurements every 6 months through year 3. Among 110 recipients (60.0% male; median age at transplant 12.7 years; median follow-up 29.4 months), the gene-positivity rate was 56.4%. The most frequently altered genes were COL4A5 ( n = 8), WT1 ( n = 8), and NPHP3 ( n = 7); NPHP1 alterations were predominantly multi-exon deletions. Complement-pathway variants ( CFHR3 , CFHR5 ) were identified in two recipients. Of the 98 recipients included in prognostic analyses, graft survival was higher in the gene-positive group than in the gene-negative group (97.6% vs. 85.5%; log-rank P = 0.049, HR = 0.15, 95% CI: 0.03–0.78). At 6 months post-transplantation, mean eGFR was slightly lower in the gene-positive group but remained within expected pediatric allograft ranges. All instances of markedly elevated urinary microalbumin (> 600 mg/L) occurred in the gene-negative group, and dipstick proteinuria was less frequent in gene-positive recipients; urine occult blood did not differ between groups. In this exploratory analysis, genetic etiology classification using WES with intragenic CNV analysis was associated with a trend toward higher graft survival and early proteinuria differences that were suggestive but not sustained, warranting cautious interpretation and further validation. These hypothesis-generating findings suggest that, once validated, pre-transplant genetic testing might help guide genotype-informed counseling, individualized surveillance intensity, and targeted living donor evaluation. However, due to the small number of graft loss events ( n = 6) and extreme microalbumin outliers ( n = 4), larger prospective studies are needed to determine the potential value of pre-transplant genetic testing before clinical implementation in pediatric kidney transplantation.