A case of recurrent type 1 diabetes mellitus with insulitis of transplanted pancreas in simultaneous pancreas–kidney transplantation from cardiac death donor

Abstract

Aims/hypothesis A 41-year-old woman undergoing simultaneous pancreas-kidney transplantation from an HLAmismatched cardiac death donor abruptly developed overt hyperglycaemia under standard immunosuppressive therapy at 48 months after transplantation. Unexpectedly, we found insulitis in the transplanted pancreas and characterised the insulitis. Methods Pancreas graft biopsies were performed 3 years before and after the development of hyperglycaemia and the specimens were examined histologically. Results Insulitis was absent in the first biopsy, although oxidative DNA changes revealed by 8-hydroxy-2′-deoxyguanosine (8-OHdG) staining were diffusely present both in islet cells and exocrine cells. No Ki67-positive proliferating cells were seen in the islets. Anti-glutamic acid decarboxylase antibody was undetectable 6 months earlier but increased to 6.3 U/l at the development of hyperglycaemia. The level of anti-insulinoma-associated protein 2 antibody was 18.5 U/l. Insulin secretion was severely suppressed and insulin therapy was resumed. In the second biopsy, although acute allograft rejection was minimal, insulin-positive beta cells were markedly reduced, and glucagon-positive alpha cells predominated. CD3-positive T lymphocytes, CD8-positive cytotoxic T lymphocytes and CD68-positive macrophages infiltrated around and into islets. The infiltrating cells expressed Fas ligand as well as granzyme B. More than 80% of islets were affected by insulitis. 8-OHdG-positive cells were also present in islets and exocrine tissue. The percentage of Ki67-positive cells in total islet cells was 1.5%. There were no TUNEL-positive apoptotic cells in the islet cells. Conclusions/interpretation The histological features of insulitis in transplanted pancreas were consistent with common type 1 diabetes mellitus, but the clinical course of the recurrence appeared to be more rapid.

Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas–Kidney Transplants

“…Instead, T1D recurrence was observed in nine identical twins or HLA‐identical siblings who received no or minimal immunosuppression for living‐related grafts 13, 14, 15. Later studies contributed evidence that recurrence of islet autoimmunity may occur regardless of HLA matching 18, 24 and despite immunosuppression 11, 12, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 35. We initially reported 11 three patients in whom T1D recurrence was characterized by 1 hyperglycemia requiring insulin with impaired insulin secretion; 2 seroconversion of autoantibodies years prior to recurrence; 3 circulating autoreactive T cells around the time of diagnosis, often with simultaneous detection in pancreas transplant and associated lymph nodes; 4 insulitis and/or beta cell loss in the pancreas transplant biopsy, with no or minimal rejection; and 5 lack of laboratory evidence of rejection (unchanged urine amylase and serum creatinine levels).…”

“…However, another potential cause of immunological failure is T1D recurrence 11, 12. A growing literature suggests that islet autoimmunity may become reactivated and affect the endocrine function of pancreas transplants 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29.…”

Outcomes From Pancreatic Transplantation in Donation After Cardiac Death

“…39 Nine of the 18 studies reported the cause of donor death. 7,[19][20][21]24,25,33,35,36 Etiologies included cerebral trauma, motor vehicle accidents, intracranial haemorrhage, and cerebral anoxia. Three studies reported that anoxic brain injury was more common in DCD donors relative to DBD donors.…”

“…We identified 2 studies reporting on the graft outcome from exclusively donors with anoxic brain injury, with variable findings. The first report was a case study by IshidaOku et al, 35 in which the recipient developed insulinitis and another by the same author 31 which reported a recipient with subsequent good graft function as assessed by glycemic control and insulin secretion.…”

Recurrence of Secondary Glomerular Disease after Renal Transplantation

“…This low risk may depend on the short duration of follow-up because the mean interval between the onset of insulindependent diabetes and the development of overt nephropathy in renal transplant recipients requires several years (87). A more recent series demonstrated a histologic recurrence in almost 40% of diabetic patients in a mean of 6.7 years after transplantation (88). Cases of recurrent DN have also been reported in patients with type 1 diabetes who were receiving a simultaneous pancreas and kidney transplantation (89).…”