Insulin independence after conversion to tacrolimus and sirolimus-based immunosuppression in islet-kidney recipients

The Edmonton protocol, a glucocorticoid-free immunosuppressive regimen including sirolimus, tacrolimus, and daclizumab, has dramatically improved the outcome of islet transplantation (1). Since 1992, 50 patients were grafted locally or within the GRAGIL network with islets isolated in Geneva (2,3). Among them, two type I diabetic islet-kidney graft recipients (32- and 42-year-old women; islet grafts: 7,992 and 7,927 EIN/kg) with elevated and stable C-peptide secretion but persisting insulin dependence were selected to evaluate the impact of the Edmonton regimen on glucose regulation. Immunosuppression was converted from cyclosporine, mycophenolate, and steroids to tacrolimus (target trough levels: 3–6 ng/mL) and sirolimus (target trough levels: 7–10 ng/mL), 7 months after transplantation. After reaching steady state, steroids were slowly reduced. Subcutaneous insulin therapy was adapted with the goal to maintain glycemia and HbA1c within normal ranges. Both patients became insulin independent after conversion (6 and 20 U of insulin per day before conversion) and remained so after 6 months and 2 years of follow-up (Fig. 1). HbA1c as well as glycemic and c-peptide profiles remained stable. No hypoglycemic event (glycemia less than 4 mmol/L) happened after conversion. Both had stable body weight (50 and 56 kg) and physical activity. According to HOMA-IR (calculated as follows: [fasting insulin concentration (μU/mL) × fasting glucose concentration (mmol/L)/22.5]; upper range: 3), the first patient did not present insulin resistance at the available time points (2 and 0 months before and 2 months after conversion). The second patient presented some degree of insulin resistance, which improved over time and disappeared when daily prednisone dose was below 5 mg (HOMA-IR was 7.9, 4.4, and 2.6 at 6, 2, and 0 months before conversion). By the time of conversion and thereafter, HOMA did not reveal insulin resistance (HOMA-IR was 2.98 and 2.6 at 2 and 6 months after conversion). Figure 1: Metabolic follow-up and daily prednisone doses after simultaneous islet-kidney transplantation. The time course is indicated relative to the time point of conversion in immunosuppression (=time 0). Normal range of HbA1c: 4% to 6.4%. Case 1 (top); case 2 (bottom).Kidney function, blood pressure, and cholesterol and triglycerides profiles remained stable during the follow-up (6 months and 2 years) with unmodified medications. No acute kidney rejection occurred. Both patients developed mild mouth ulcers, which were partly controlled by careful rinsing after each administration of sirolimus syrup. The first patient had advanced coronary heart disease and a past history of cerebral strokes with obstruction of the intracranial part of both internal carotid arteries. She died 6 months after conversion at home of unknown causes. She did not present any hypo- or hyperglycemic events in the days before her death. Although the family declined autopsy, death was likely related to a new stroke. The second patient required cholecystectomy 7 weeks after conversion because of acute cholecystitis and an amputation of a necrotic toe because of diabetic macroangiopathy. During these episodes, it was not necessary to reintroduce insulin therapy. These data indicate that steroid-free, sirolimus-based immunosuppression can be beneficial for islet transplants, particularly in the context of borderline engrafted islet mass. Insulin-dependent patients with stable islet graft function, who are immunosuppressed with cyclosporine and prednisone, may benefit from conversion to tacrolimus and sirolimus-based immunosuppression with lowering of prednisone doses. Christian Toso Philippe Morel Pascal Bucher Zoltan Mathe Sandrine Demuylder-Mischler Domenico Bosco Thierry Berney José Oberholzer James Shapiro José Oberholzer Jacques Philippe

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