Integrating Tissue Gene Expression Profiling With Histopathology in Pediatric Kidney Recipients

ABSTRACT Background Banff classification is the standard for diagnosing kidney allograft rejection, but histologic evaluation is limited by sampling error, interobserver variability, and interpretive subjectivity. The Molecular Microscope Diagnostic System (MMDx) evaluates tissue gene expression to classify rejection phenotypes and may clarify ambiguous histologic findings. Although utilized in adults, its clinical impact in pediatric kidney recipients is not well defined. Methods We performed a single‐center retrospective study of pediatric kidney transplant recipients who underwent allograft biopsy between September 2023 and September 2025. Histologic diagnoses using 2022 Banff criteria were compared with MMDx molecular interpretations. Agreement between Banff scores and MMDx classifiers was assessed. Discrepancies were defined as discordance in rejection versus no rejection or rejection subtype classification, and changes in clinical management were described. Results Forty‐two biopsies from 38 recipients were analyzed. MMDx scores correlated with Banff indices (TCMR r = 0.55, ABMR r = 0.73, p < 0.001). Rejection vs. no rejection discordance occurred in 24% of biopsies ( κ = 0.53) while subtype discordance occurred in 38% ( κ = 0.38). In five of seven borderline TCMR cases, MMDx indicated no rejection, and graft function remained stable without treatment. Clinical management changed in 19% of biopsies following MMDx review, typically resulting in an increase in immunosuppression in settings of molecularly diagnosed rejection with equivocal histology. Conclusions MMDx correlates with histologic assessment and can provide diagnostic clarification in ambiguous pediatric kidney allograft biopsies. Complementary use of histology and molecular diagnostics may inform clinical decision making; prospective studies are needed to determine effects on long‐term outcomes.