Pancreas transplantation: associations with graft failure and measures of function

Pancreas transplantation, either as a simultaneous pancreas kidney (SPK) or an isolated pancreas (IP), is a successful treatment option for some people with diabetes; however, grafts at the highest risk of failing are difficult to identify, and a means of monitoring graft function effectively post-transplant is lacking. The work in this thesis aimed to identify factors associated with pancreas graft failure and explore metabolic features of early graft dysfunction. First, the published Pancreas Donor Risk Index tool was predictive using UK National data in SPK but not IP transplantation, suggesting greater influence of recipient and post-transplant factors in determining IP graft survival. HLA antibody monitoring showed that the development of de novo DSA post-transplant was associated with poorer graft outcomes, particularly in IP transplant; and assessment of ICA and GADA autoantibodies also showed a deleterious effect of pre-transplant autoantibody positivity in IP transplantation; suggesting IP recipients may be immunological disparate to those receiving SPK. A retrospective analysis of early post-transplant oral glucose tolerance tests showed impaired glucose tolerance to be associated with later graft failure, and led to prospective studies examining glucose homeostasis in the early post-transplant period. Early impaired glucose tolerance was correlated to hyperglycaemia detected on continuous glucose monitoring. Analysis of patients pre- and post-transplant confirmed complete normalisation of glucagon concentrations early post-transplant and early impairment in insulin secretion. A comparison of the response to oral and intravenous glucose demonstrated that insulin secretion may be affected by the absence of the incretin effect early after pancreas transplantation, associated with reduced GLP-1 but normal GIP concentrations evident post-transplant. The incretin effect became established by 3 months post-transplant, and was associated with an increased GLP-1 response. Together these studies demonstrated novel features associated with high risk of graft failure which could help to identify patients who may benefit from therapeutic interventions aimed at improving graft outcomes.