Jacqueline V. Ferreira

Islet Transplantation in Type 1 Diabetes Mellitus Using Cultured Islets and Steroid-Free Immunosuppression: Miami Experience

Following the success obtained with transplantation of fresh human islets under steroid‐free immunosuppression, this trial evaluated the transplantation of islets that had undergone a period of in vitro culture and the potential of tumor necrosis factor (TNF‐α) blockade to improve islet engraftment. Subjects included 16 patients with type 1 diabetes mellitus (T1DM); half were randomly assigned to receive Infliximab immediately preceding initial infusion. Immunosuppression consisted of daclizumab induction and sirolimus/tacrolimus maintenance. Out of 16 subjects 14 achieved insulin independence with one or two islet infusions; adverse events precluded completion in two. Without supplemental infusions, 11/14 (79%) subjects were insulin independent at 1 year, 6/14 (43%) at 18 months; these same subjects remain insulin independent at 33 ± 6 months. While on immunosuppression, all patients maintained graft function. Out of 14 patients, 8 suffered chronic partial graft loss, likely immunological in nature, 5 of these received supplemental infusions. Currently, 11 subjects remain on immunosuppression, 8 (73%) are insulin independent, two with supplemental infusions. Insulin independent subjects demonstrated normalization of HbA1c, fructosamine and Mean Amplitude of Glycemic Excursions (MAGE) values. No clinical benefit of infliximab was identified. These results demonstrate that transplantation of cultured human islet allografts results in reproducible insulin independence in all subjects under this immunosuppressive regimen, comparable to that of freshly transplanted islets (Edmonton protocol).

The bag method for islet cell infusion.

As islet cell transplantation gains increasing interest following results published by the Edmonton group, results that have been successfully reproduced by several centers nationwide and abroad, the need of guidelines to standardize the procedure becomes highly important. We detail the key steps of the infusion procedure utilizing a closed gravity fed bag system utilized at our institution since 1990, which consists of a 600-ml transfer bag and a 150-ml rinse bag connected via sterile tubing. The use of gravity allows for a control rate of infusion as well as providing a safety mechanism through natural reduction of flow that parallels any increase in portal pressure, therefore allowing the operator to prevent precipitous pressure rises. Reports on significant rise in portal pressures during islet cell infusion as well as portal vein thrombosis have been published. Infusion at these centers was carried out using a syringe method. Using our technique, portal vein thrombosis (partial or complete) was not detected in any of the infusions performed at our institution. This method may be of assistance to minimize some of the observed complications associated with islet transplant procedures and has now been adapted by most centers performing clinical islet transplantation.

Evaluation of metabolic control using a continuous subcutaneous glucose monitoring system in patients with type 1 diabetes mellitus who achieved insulin independence after islet cell transplantation

This study evaluated the Medtronic MiniMed Continuous Glucose Monitoring System (CGMS) in patients with type 1 diabetes mellitus who underwent successful islet cell transplantation (ICT). The results are compared to standardized self-monitoring (SMBG) of hyperglycemia and mean amplitude of glycemic excursions (MAGE). We studied 19 patients (mean age 40.0 ± 6.7 years) in three groups: six patients post-ICT, seven patients awaiting ICT, and six normal volunteers (controls). Continuous glucose monitoring post-ICT showed remarkable glucose stability compared with patients awaiting ICT. The CGMS group showed modestly higher glucoses (mean 111.5 mg/dl) compared with controls (88 mg/dl). Postprandial glucoses in ICT recipients rarely exceeded 180 mg/dl and were similar to controls. There was no difference in asymptomatic hypoglycemia between control and post-ICT groups. However, a higher incidence of hypoglycemia was observed in patients awaiting ICT. HbA1c and MAGE pre- and post-ICT were 8.3 ± 0.9% and 6 ± 0.3% (p < 0.001) and 109 ± 34 and 41 ± 11 (p < 0.001), respectively. No complications were associated with CGMS. This study suggests ICT significantly improves metabolic control and rate of hypoglycemia when compared with controls and patients awaiting ICT. Similar improvement in metabolic control was observed with SMBG, HbA1c, and MAGE. Although CGMS was not demonstrated to be a superior tool for routine assessment in ICT, it is very helpful in special clinical situations.

Resolution of neurotoxicity and β-cell toxicity in an islet transplant recipient following substitution of tacrolimus with MMF

Calcineurin inhibitors such as tacrolimus have well-recognized efficacy in organ transplantation but side effects of nephrotoxicity, neurotoxicity, and β-cell toxicity that can be particularly detrimental in islet transplantation. Neuro- and nephrotoxicity have been demonstrated in multiple islet transplant recipients despite the relatively low serum maintenance levels typically used (3–5 ng/ml). We describe a single patient in whom symptoms and signs of neurotoxicity necessitated substitution of tacrolimus with mycophenolate mofetil (MMF), which resulted in complete symptom resolution over the subsequent 9 months. Concomitantly noted were an almost immediate improvement in glycemic control and an improved response to stimulation testing, suggesting remission of tacrolimus-induced β-cell toxicity and insulin resistance. At 18 months post-“switch,” 30 months posttransplant, the patient remains insulin independent with good glycemic control. The goal to remove calcineurin inhibitors from regimens of islet transplantation is a worthy one.

Cytomegalovirus Prevalence and Transmission After Islet Allograft Transplant in Patients with Type 1 Diabetes Mellitus

Cytomegalovirus (CMV) serological status of transplant donors and recipients has important implications on antiviral prophylaxis, morbidity/mortality, donor selection and hospital stay. We evaluated CMV prevalence in our islet transplant candidates (ITC) in comparison with organ donors. We correlated the CMV serological status of our ITC with serology for Epstein‐Barr virus and Parvovirus B19, auto‐antibodies, patients age, age at DM onset, duration of DM, gender, race, ABO group, HLA haplotype and C‐peptide levels. Cytomegalovirus transmission after islet transplant using the Edmonton regimen was also evaluated. Cytomegalovirus seropositivity varied according to patient group, age, gender and race. Type 1 DM patients had reduced odds of CMV seropositivity when compared with organ donors. In all groups studied, older patients, females, and non‐Caucasians were more likely to be CMV seropositive. In addition, no CMV reactivation, infection or disease was observed among our transplanted patients using this steroid‐free regimen even after donor/recipient CMV mismatch.