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

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.

Metastatic Donor-derived Malignancies Following Simultaneous Pancreas-kidney Transplant: Three Case Reports and Management Strategies.

Stopping immunosuppression in a transplant patient with donor-derived malignancy offers the theoretical benefit that reconstitution of the patient's immune system will allow "rejection" of the malignancy, as the malignancy also originates from allogeneic tissue. However, this option exists with the caveat that the patient's allograft(s) will likely be rejected too. In simultaneous pancreas-kidney (SPK) recipients, the normal continued functioning and possible absence of malignancy in either the unaffected kidney or pancreas further complicate this decision. METHODS: The charts of 3 patients with donor-derived metastatic malignancies after SPK were retrospectively reviewed in detail. We provide treatment and management recommendations based on successful outcomes and a review of the existing literature. RESULTS: Consistent with a broad review of the literature, in all 3 cases, complete immunosuppression cessation, removal of both grafts, and in 1 case treatment with an immune checkpoint inhibitor to augment the immune response was successful. One patient is doing well 1 year after successfully undergoing kidney retransplantation, while a second patient is active on the waitlist for SPK retransplantation after no evidence of metastatic disease for 2 years. CONCLUSION: The successful management of metastatic donor-derived malignancies requires allograft removal, immunosuppression cessation, and adjuvant therapy that includes occasional use of checkpoint inhibitors to augment the immune response.

Long-term follow-up of beta cell replacement therapy in 10 HIV-infected patients with renal failure secondary to type 1 diabetes mellitus.

The approach to transplantation in human immunodeficiency virus (HIV)-positive patients has been conservative due to fear of exacerbating an immunocompromised condition. As a result, HIV-positive patients with diabetes were initially excluded from beta cell replacement therapy. Early reports of pancreas transplant in patients with HIV described high rates of early graft loss with limited follow-up. We report long-term follow-up of islet or pancreas transplantation in HIV-positive type 1 diabetic patients who received a kidney transplant concurrently or had previously undergone kidney transplantation. Although 4 patients developed polyoma viremia, highly active antiretroviral therapy and adequate infectious prophylaxis were successful in providing protection until CD4+ counts recovered. Coordination with HIV providers is critical to reduce the risk of rejection by minimizing drug-drug interactions. Also, protocols for prophylaxis of opportunistic infections and strategies for monitoring and treating BK viremia are important given the degree of immunosuppression required. This series demonstrates that type 1 diabetic patients with well-controlled HIV and renal failure can be appropriate candidates for beta cell replacement, with a low rate of infectious complications, early graft loss, and rejection, so excellent long-term graft survival is possible. Additionally, patients with HIV and cardiovascular contraindications can undergo islet infusion.