Novel approaches to pancreas allograft surveillance

Pancreas transplantation is a successful treatment option for selected patients with advanced complications of diabetes. It offers insulin independence, stabilisation of diabetic complications, and improved survival. However, these are largely conditional on long term pancreas allograft survival. Pancreas graft survival is poorer than that of other transplanted organs and this is mainly due to the absence of accurate and reliable techniques for monitoring the pancreas allograft. Irreversible damage has usually occurred to the pancreas before rejection is diagnosed, such that treatment which would otherwise have been effective, brings no benefit. This thesis describes a number of novel approaches to pancreas allograft surveillance, aiming to identify graft injury early enough that treatment can be initiated before permanent damage occurs. • The Homeostatic Model Assessment (HOMA) model has been modified to allow for systemic venous drainage of the endocrine pancreas. HOMAtx has been validated in a cohort of pancreas transplant patients with insulin secretion and sensitivity correlating well with the HOMAtx-derived outputs of %B and %S respectively. A lower threshold for beta cell function (%B) was identified that had a 100% sensitivity and 84.1% specificity for detecting diabetic glucose tolerance during oral glucose tolerance testing. • Urinary C-peptide creatinine ratio (UCPCR) has been assessed as a marker of pancreas allograft function. Good correlation with serum C-peptide has been confirmed and the use of patient-directed remote monitoring via home UCPCR samples has been shown to be a potential tool for future allograft surveillance. • The use of a donor-specific vascularised composite allograft or ‘sentinel skin flap’ to detect rejection in pancreas transplantation has been evaluated. Although isolated skin rejection was observed in 10% of patients, there was no associated rejection of the primary visceral allografts, suggesting that the SSF might be identifying an early alloimmune response and allowing treatment before clinical rejection has occurred. Together, these studies represent novel approaches to pancreas allograft surveillance that may deliver incremental improvements that are required to advance overall outcomes.