Molecular Rejection Signatures in Pancreas Transplant Biopsies

Pancreas allograft rejection remains a key contributor to graft failure, yet its diagnosis relies on histological criteria. In this study, we applied the Molecular Microscope® Diagnostic System (MMDx) kidney-derived algorithm developed for organ transplant rejection to pancreas transplant biopsies to evaluate its potential diagnostic performance and clinical utility. We analyzed 124 pancreas allograft biopsies obtained between April 2019 and May 2025. Molecular and histologic classifications were compared and related to pancreas graft survival. MMDx classified 93/124 biopsies (75%) as no-rejection, 12 (10%) as possible rejection, and 19 (15%) as rejection, whereas histology identified rejection in 65/112 biopsies (58%) and 25 (22%) as indeterminate cases. Concordance between histology and MMDx was low (Cohen's κ = 0.14, p<0.001). However, acute cellular rejection histologic grading in pancreatic biopsies correlated strongly with molecular scores for interstitial inflammation (ρ=0.63, p=1.4×10^-11), TCMR (ρ=0.54, p<3.0×10^-8) and acute kidney injury (ρ=0.54, p=3.14×10^-8). By MMDx, pancreatic biopsies with rejection (HR=6.94, 95% CI 2.58-18.70, p<0.001) and possible rejection (HR=3.58, 95%CI 0.93-13.86, p=0.06) had inferior three-year graft survival compared to NR, while histologic diagnosis had not. Molecular assessment using the kidney-derived MMDx algorithm identifies fewer rejection cases than histology but provides superior prediction of graft outcome.