Molecular diagnostics in pancreas transplantation: past, present, and future

Pancreas transplantation is the gold standard endocrine replacement therapy for patients with type 1 diabetes (T1D) and chronic kidney disease. Histological assessment remains the cornerstone for diagnosing pancreas graft rejection, relying on the Banff classification to standardize interpretation. Transcriptomic analyses have transformed transplantation research by enabling gene expression profiling within allografts. Studies utilizing bulk RNA (RNA-seq) and single-cell RNA sequencing (scRNA-seq) have advanced understanding of immune-mediated graft injury. However, pancreas transplantation research remains limited by small single-center cohorts, while extrapolation from other solid organ transplants is constrained by the unique structural and functional characteristics of the pancreas graft. These challenges partially arise from the distinct compartments involved in major pancreas allograft pathologies, including exocrine injury in alloimmune-rejection response and endocrine islet injury in a myriad of post-transplant beta cell stressors (i.e., T1D recurrence, CNI-toxicity, or metabolic syndrome). The application of molecular diagnostics in pancreas transplant biopsies has been demonstrated, including clinical-grade microarray technology. Nevertheless, pancreas-specific gene expression markers remain underexplored, and robust evidence regarding their clinical utility is lacking. This review conceptualizes pancreas allograft injury as a dual-compartment process involving both exocrine rejection and endocrine islet injury, thereby providing an interpretive framework for evaluating emerging molecular diagnostics in pancreas transplantation.