A Multi-Modal Approach to Islet and Pancreas Transplantation With Calcineurin-Sparing Immunosuppression Maintains Long-Term Insulin Independence in Patients With Type I Diabetes

Transpl Int. 2023 Jun 8:36:11367. doi: 10.3389/ti.2023.11367. eCollection 2023.

Abstract

Long-term success in beta-cell replacement remains limited by the toxic effects of calcineurin inhibitors (CNI) on beta-cells and renal function. We report a multi-modal approach including islet and pancreas-after-islet (PAI) transplant utilizing calcineurin-sparing immunosuppression. Ten consecutive non-uremic patients with Type 1 diabetes underwent islet transplant with immunosuppression based on belatacept (BELA; n = 5) or efalizumab (EFA; n = 5). Following islet failure, patients were considered for repeat islet infusion and/or PAI transplant. 70% of patients (four EFA, three BELA) maintained insulin independence at 10 years post-islet transplant, including four patients receiving a single islet infusion and three patients undergoing PAI transplant. 60% remain insulin independent at mean follow-up of 13.3 ± 1.1 years, including one patient 9 years after discontinuing all immunosuppression for adverse events, suggesting operational tolerance. All patients who underwent repeat islet transplant experienced graft failure. Overall, patients demonstrated preserved renal function, with a mild decrease in GFR from 76.5 ± 23.1 mL/min to 50.2 ± 27.1 mL/min (p = 0.192). Patients undergoing PAI showed the greatest degree of renal impairment following initiation of CNI (56% ± 18.7% decrease in GFR). In our series, repeat islet transplant is ineffective at maintaining long-term insulin independence. PAI results in durable insulin independence but is associated with impaired renal function secondary to CNI dependence.

Keywords: immune tolerance; immunosuppression; insulin independence; islet transplant; pancreas transplant.

MeSH terms

  • Calcineurin
  • Calcineurin Inhibitors / therapeutic use
  • Diabetes Mellitus, Type 1* / drug therapy
  • Diabetes Mellitus, Type 1* / surgery
  • Humans
  • Immunosuppression Therapy / methods
  • Immunosuppressive Agents / therapeutic use
  • Insulin / therapeutic use
  • Islets of Langerhans Transplantation* / methods
  • Pancreas Transplantation*

Substances

  • Insulin
  • Calcineurin
  • Calcineurin Inhibitors
  • Immunosuppressive Agents

Grants and funding

This work was supported by a grant from the Juvenile Diabetes Research Foundation (4-2004-372) and the UCSF islet facility is supported in part by the National Institutes of Health grants P30 DK63720, UO1 AIO65193, and CRC grant UL1 RR024131. SW, YK, and CW were supported by a NIAID Training Grant from the National Institutes of Health under an award to the University of California, San Francisco (T32AI125222). YK was supported by the Jon Fryer Resident Scientist Scholarship from the American Society of Transplant Surgeons.