Islet transplantation using donors after brain and cardiac death: A multicenter clinical trial in Japan

Background: Islet transplantation for C-peptide-negative type 1 diabetes restores endogenous insulin secretion and hypoglycemia awareness. Islets isolated from more than one donor pancreas are often required to achieve normal glycemic control. In Japan, owing to donor shortage, islet transplantation is performed not only using donors after brain death (DBD) but also using donors after cardiac death (DCD) and elderly donors. To verify the effectiveness of islet transplantation, a clinical trial of islet transplantation was conducted in Japan, and the results were reported. Methods: This multicenter, single-arm study aimed to evaluate the clinical efficacy and safety of an immunosuppressive therapy for allogeneic islet transplantation using DBD and DCD. Immunosuppressive regimen included antithymocyte globulin, calcineulin inhibitor, and mycophenolate mofetil. The primary endpoint was an HbA1c level of <7.4% at day 365 and absence of severe hypoglycemic events (SHEs) from 1 month to 1 year after the first transplantation was performed. Results: Twenty-one islet isolations were performed from 5 DCD and 16 DBD; 16 isolations met the transplant criteria, and the isolated islets were transplanted. The mean age of the donors was 45.0 (19–68) years, and the cold ischemia time was 411 ± 132 min. Eight recipients with evaluation data at 1 year after the initial transplantation were included in the efficacy analysis. Of the eight recipients, three, three, and two recipients received one, two, and three islet infusions, respectively. Six recipients (75%) achieved the primary endpoint. The median HbA1c level was 6.2% and 6.4% at 1 year and 2 years, respectively. No complications associated with intraportal transplantation, such as intraperitoneal hemorrhage or portal vein embolism, were observed. Two recipients (25%) achieved insulin independence. The median creatinine level was 0.79 mg/dL before transplantation and 0.73 mg/dL at 1 year after the initial transplantation, indicating that renal function was maintained. As an adverse event, severe leukopenia was initially observed in one patient. No infectious complications occurred in any of the recipients. Conclusion: Islet transplantation provides near-normal glycemic control and protection from SHEs for type 1 diabetes patients in Japan, where donors are few. Future studies are needed to confirm whether long-term graft survival can be achieved and whether preventing the progression of diabetic complications is possible.