Metabolic outcomes of islet transplantation and correlation of graft function with hepatic imaging and immune response

Abstract

Introduction Recipients of an islet transplant at all UK NHS-funded centres were invited to take part in an ethically approved experimental medicine follow-up study. Objectives were to determine metabolic outcomes post-intervention and identify potential surrogate markers for graft failure. Methods Assessment of islet recipients was undertaken pre-transplant, 1 month post-transplant and 3-6 monthly thereafter. Clinical review included HbA1c, hypoglycaemia frequency, insulin requirements, donor specific antibody (DSA) screening, magnetic resonance imaging (MRI) for hepatic fat assessment and continuous glucose monitoring (CGM) one week prior to standardised meal tolerance test (MTT). Results Twenty recipients received 35 islet infusions (single graft:n=7; two:n=11; three:n=2; transplant mass per recipient (median[IQR]) 8770(6536-13045) IEQ/kg), with all recipients receiving induction and maintenance immunosuppression. Graft function was maintained in 80% of recipients at 24(13.5-36) months. Frequency of severe hypoglycaemia reduced from 20(7-50) to 0.3(0-1.6) episodes per patient-year (p<0.001), with improved hypoglycaemia awareness (Gold score: pre-transplant 6(5-7); post-transplant 3(1.5-4.5); p<0.03) and HbA1c 6.2(5.7-8.4)% post-transplant, and cessation of exogenous insulin in 45% of recipients. In a single site sub-study, CGM demonstrated a continuous relationship between stimulated C-peptide and glucose variability, hyperglycaemia risk and hypoglycaemia risk. No significant difference in liver fat fraction was noted pre and post-transplant (p=0.94), and no direct correlation with 90 minute C-peptide on MTT at 12 months was identified. DSA was detected in 5/23(21.7%) grafts in 14 recipients and was associated with rapid graft failure. Conclusions The primary goals of the UK islet transplant program to prevent recurrent life-threatening hypoglycaemia and restore optimal glycaemic control in recipients have been attained up to 36 months post-transplant. Demonstration of a continuous relationship between endogenous C-peptide secretory capacity and parameters of glycaemic control has substantial implications for therapeutic interventions maintaining endogenous insulin production in individuals with type 1 diabetes. Therapeutic interventions preventing DSA formation post-transplant might improve graft outcomes.