Sustained Islet Allograft Function After Peritransplant Treatment Using Exenatide With and Without Everolimus

Islet transplantation represents now a feasible therapeutical option for selected patients with brittle type 1 diabetes mellitus. Islet graft function has progressively improved over time with a success rate in some centers similar to that of whole pancreas transplantation. The first phases after transplantation appear to be critical. Transplanted islets are exposed to an inflammatory reaction1 that, together with glucotoxicity2 in the case of suboptimal glycemic control results in significant reduction of cellular vitality. For these reasons, different protocols of recipient treatment were proposed, such as anti-inflammatory drugs3 or long-acting glucagon-like peptide 1 analogues to improve insulin secretion and overall metabolic balance.4 The mammalian target of rapamycin inhibitors in particular have a significant anti-inflammatory effect; in comparison to sirolimus, everolimus proved to have a most potent effect, higher bioavailability, and a shorter half-life.5 Ten patients affected by type 1 diabetes mellitus (7 with brittle diabetes and 3 already under immunosuppression therapy for a previous kidney transplantation) were treated for 1 month after intrahepatic islet allotransplantation with low-dose exenatide 5 μg twice/day and 6 of them with everolimus 3 mg 12 hours before and 12 to 18 hours after the first islet transplantation, too. The immunosuppression therapy included induction with polyclonal ALG (or Basiliximab in the case of islet after kidney recipient or of a second islet transplant) and maintenance with tacrolimus and mycophenolate mofetil. They received 1 or 2 (in 5 patients) islet infusions with a mean of 9.700 ± 3.200 Islet Equivalent/kg body weight. Follow-up lasted from 12 to 69 months (mean, 45 ± 12 months; total patient-months, 450). No primary nonfunction was reported. At least a partial function (HbA1c <52 mmol and C-peptide >0.3 ng/ml) was obtained within 3 months after transplantation, and in 9 of 10 patients, this function was maintained up to the last available follow-up (Figure 1). One patient lost partial function after 3 months, in parallel with a rapid increase of antiglutamic acid decarboxylase antibodies immune titer (up to 160 IU/mL). Eight of 10 patients obtained insulin independence, and 5 of them are to date still insulin-free at last follow-up. Four of these patients were of the group treated with everolimus. Side effects of the procedures include 2 intraabdominal hematomas, 1 requesting surgical drainage, 2 thrombosis in branches of portal or mesenteric vein, 2 hemorrhages requiring transfusion, 9 infections (cytomegalovirus infection reactivation in 5), and 1 skin basalioma. Islet transplantation stabilized chronic diabetic complications with 2 exceptions: in 1 case, a progression of retinopathy and in another case worsening of gastroparesis was observed. No hypoglycemic episodes were reported in all the 9 patients with graft function.FIGURE 1: A, The follow up in individual patients. Time 0 is time to last procedure (first or second in the case of 2 transplants). Complete insulin independence is represented by white column, partial graft function (partial insulin need, HbA1c < 52 mmol and C-peptide >0.3 ng/ml) by gray column, graft failure by black column. Patients 1, 2, 5, 6, 7, and 10 received everolimus treatment. B, The HbA1c and c-peptide values of 9 recipients with still graft function are represented during different time period follow up. Values are median and interquartile range (25 and 75).In this pilot study in a small cohort of patients, a peritransplant pharmacological treatment targeting inflammation and metabolic demand in addition to immunosuppression apparently improved overall islet graft function in the medium-term follow-up. Indeed, these data are limited to only a small subset of subjects with uncontrolled comparisons, and therefore, it is impossible to draw definitive conclusions. In the whole, these data offer the rationale for further larger controlled study.

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