The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Outcomes in the highest panel reactive antibody recipients of deceased donor kidneys under the new kidney allocation system.

Since the institution of the new kidney allocation system in December 2014, kidney transplant candidates with the highest calculated panel reactive antibodies (cPRA) of 99-100 have been transplanted at much higher rates. However, concerns have been raised that outcomes in these patients might be impaired due to higher immunological risk and longer cold ischemia times resulting from long-distance sharing of kidneys. Here, we compare outcomes at the University of Wisconsin between study patients with cPRA 99-100 and all other recipients of deceased donor kidneys transplanted between 12/04/2014 and 12/31/2015. All patients had at least 6 months post-transplant follow-up. The mean follow-up was 13.9±3 months in cPRA ≥99% and 12.3±3.5 months in cPRA ≤98%. There was a total of 152 transplants, 25 study patients, and 127 controls. No statistically significant differences were found between the two groups in delayed graft function, rejection, kidney function, graft and patient survival, or infections. We conclude that transplanting the most highly sensitized patients with kidneys shared outside their local donation service areas is associated with excellent short-term outcomes that are comparable to controls.

The Importance and Utility of Hemoglobin A1c Levels in the Assessment of Donor Pancreas Allografts.

BACKGROUND: Hemoglobin A1C (HbA1c) levels are often obtained in potential pancreas graft donors to assess the overall long-term functional glycemic control or the possibility of unrecognized diabetes. Although routinely measured, the impact of donor HbA1c levels on pancreas graft outcomes has not been reported. Here, we researched the relationship between donor HbA1c levels and postoperative pancreas graft survival. METHODS: Data from 266 pancreas transplant patients including 182 simultaneous kidney-pancreas and 84 pancreas alone transplants were reviewed for the study. The patients were separated into groups according to their HbA1c levels (5 groups: HbA1c < 5.0, 5.0-5.4, 5.5-5.9, ≥6.0 % and not available, or 2 groups: HbA1c <5.7, ≥5.7%). Overall, death-censored and technically successful pancreas graft survival and rejection rates of each group were compared. In the case of technically successful graft survival, graft losses due to technical problems in the first 60 days were excluded. RESULTS: All groups were similar with regard to donor variables including age, sex, ABO blood type, ethnicity, donor type and recipient variables including recipient age, sex, induction agents and maintenance treatment. Mean follow-up time was 4.2 ± 1.97 years. The overall graft survivals and death censored graft survivals among groups were not statistically different from one other (P > 0.05). Additionally, excluding early technical losses in 18 patients did not reveal any differences in graft survivals. Patient survival and biopsy-proven acute rejections were statistically similar among HbA1c strata. CONCLUSIONS: This univariate retrospective analysis of a single center/organ procurement organization use of HbA1c shows that donor HbA1c levels between 3.5 and 6.2 in otherwise transplantable pancreata are not associated with different short-term outcomes.

National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities.

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

Posttransplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management.

BACKGROUND: Posttransplant diabetes mellitus (PTDM), associated with the use of immunosuppressants, occurs at varying rates in kidney transplant recipients. METHODS: Five transplant centers conducted a retrospective review of 435 kidney recipients completing at least 6 months of follow-up to determine risk factors, incidence, and management strategies for posttransplant glucose intolerance. A distinction was made between hyperglycemia and diabetes. RESULTS: The incidence of PTDM was found to be 4.9%. Among tacrolimus-treated patients it was 5.7%, compared with 3.3% among cyclosporine-treated patients (P=0.453). Mean daily maintenance doses of prednisone and mycophenolate mofetil (MMF) were significantly lower in tacrolimus-treated patients. Significantly more tacrolimus-treated patients were prednisone-free (9.0%/0%; P<0.001). Logistic regression analysis revealed that the absence of an antiproliferative agent correlated with the development of PTDM (odds ratio=3.56; P=0.01). CONCLUSIONS: Based on this study, we propose management guidelines specifically for glucose intolerance developing after renal transplantation. Maintenance of blood glucose levels within strict limits is recommended, and the contribution of immunosuppressive agents to the development of PTDM is accounted for. Gradual tapering of prednisone and tacrolimus is proposed for patients who develop PTDM but also bear minimal risk of rejection. Tapering and eventual withdrawal of insulin should be attempted once blood glucose levels normalize. Switching to the alternative calcineurin inhibitor should only be considered as a late intervention. Tacrolimus therapy should be considered even in patients at high risk for diabetes, because the benefit of reduced acute rejection incidence and severity, as demonstrated in other studies, outweighs the risk of PTDM.