Muhammad M. Hafiz

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).

Immunosuppression and procedure-related complications in 26 patients with type 1 diabetes mellitus receiving allogeneic islet cell transplantation

Background. The success of sirolimus and low-dose tacrolimus in islet cell transplantation has influenced many transplant centers to utilize this novel regimen. The long-term safety and tolerability of this steroid-free immunosuppressive protocol for allogeneic islet transplantation has yet to be determined. Methods. We transplanted 26 adult patients with long standing type 1 diabetes mellitus between April 2000 and June 2004. Immunosuppression consisted of induction with daclizumab and maintenance therapy with tacrolimus and sirolimus. Adverse events (AEs) in patients were followed and graded using the Common Terminology Criteria for Adverse Events, version 3.0 (National Cancer Institute). Results. To date, the majority of patients were able to remain on the immunosuppression combination for up to 22±11 months. Four patients were successfully converted to Mycophenolate Mofetil due to tacrolimus-related toxicity. Withdrawal from immunosuppression was decided in four patients due to hypereosinophilic syndrome, parvovirus infection, aspiration pneumonia, and severe depression, respectively. Six patients required filgrastim therapy for neutropenia. Transient elevation of liver enzymes was observed in most patients early after islet infusion. Increased LDL in 20 patients required medical treatment. Conclusion. There was a varying range of AEs, most of them mild and self-limiting; however, some required urgent medical attention. The majority of patients were able to tolerate and remain on this effective regimen. To date, no deaths, cytomegalovirus disease, graft-versus-host disease, or posttransplant lymphoproliferative disease has been observed.

Alterations of the female reproductive system in recipients of islet grafts

Background. Transplantation of allogeneic tissues is becoming a wider practice for the replacement of organ function lost to congenital or acquired pathologies. Chronic immunosuppression remains a necessity to prevent organ rejection, despite increased risks of infection, organ toxicity, and malignancies. Abnormalities of female gonadal function in patients of reproductive age are recognized, however, pathological alterations of the reproductive system in patients treated with new generation immunosuppressive drugs are still poorly documented. Methods. We report herein our observations of abnormalities of the reproductive system in 13 female recipients of allogeneic islets for type 1 diabetes, under immunosuppression therapy based on daclizumab induction and tacrolimus/sirolimus maintenance. Results. Menstrual cycle alterations and clinically significant ovarian cysts were frequently observed in our patients, some requiring medical or surgical intervention. All ovarian cysts appeared of benign nature. Conclusions. Our findings suggest that pre- and posttransplant evaluation of female patients should include menstrual history, baseline pelvic ultrasound, and hormonal levels to assess the presence and monitor the progression of such alterations.

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.

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.