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

Abstract

Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas–kidney allografts for T1D recurrence and its risk factors. With long‐term follow‐up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D‐associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor–recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D‐predisposing HLA‐DR3/DR4 genotype in the recipient and donor–recipient sharing of HLA‐DR alleles, especially HLA‐DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.

HLA-A, -B, -C, -DR, and -DQ Matching in Pancreas Transplantation: Effect on Graft Rejection and Survival

“…This may result in greater difficulty in finding highly matched donors for particular recipient subgroups. Additionally, particular donor HLA alleles, such as DR3, are associated with diabetes recurrence (34) and may wish to be avoided. Matching of DR3 may have dual results: reduced alloimmune rejection but increased recurrent autoimmunity.…”

Pancreas transplantation

“…Fifteen of these patients underwent pancreas transplant biopsy and insulitis was demonstrated in 13 of them. 130 For this question to be answered, detailed studies of larger cohorts of patients with consistent criteria for recurrent autoimmunity are needed.…”

Biomarkers in pancreas transplant

“…Approximately 60% of our SPK recipients were classified as autoantibody negative at the time of transplantation, and 40% tested positive for autoantibodies (26). The presence of autoantibodies pre-transplant did not have an impact on outcome.…”

“…Multiple autoantibodies are a risk factor for the development of T1D in relatives (27). Similar to the development of T1D in the native pancreas, autoantibodies are a risk factor for disease recurrence in the transplanted pancreas (26). Patients who developed T1DR had higher prevalence of all antibodies post PT (Figure 2).…”

“…Similarly they shared HLA-DR alleles with their donors at an increased frequency. Finally carrying HLA-DR 3/DR4 genotype and sharing HLA-DR alleles with the donor were associated with autoantibody conversion (26). …”