Combined islet and kidney xenotransplantation for diabetic nephropathy: an update in ongoing research for a clinically relevant application of porcine islet transplantation.

Combined islet and kidney xenotransplantation for the treatment of diabetic nephropathy represents a compelling and increasingly relevant therapeutic possibility for an ever-growing number of patients who would benefit from both durable renal replacement and cure of the underlying cause of their renal insufficiency: diabetes. Here we briefly review immune barriers to islet transplantation, highlight preclinical progress in the field, and summarize our experience with combined islet and kidney xenotransplantation, including both challenges with islet-kidney composite grafts as well as our recent success with sequential kidney followed by islet xenotransplantation in a pig-to-baboon model.

Pretransplant Screening for Prevention of Hyperacute Graft Loss in Pig-to-primate Kidney Xenotransplantation.

BACKGROUND: Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation. METHODS: We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays. RESULTS: High complement-dependent cytotoxicity was associated with HAR/AHXR as expected. However, we also found that high levels of IgG were independently associated with HAR/AHXR, and we developed 2 indices to interpret and predict the risk of IgG-mediated HAR/AHXR. CONCLUSIONS: Based on the data in this study, we have established a new 2-step screening, which will be used for future clinical kidney xenotransplantation trials.

Vascularized Islet Transplantation as Composite Islet-Kidney Grafts with Nanoparticle-Labeled Islets in Large Animal Preclinical Transplant Models.

Although there are many patients with diabetes and end-stage renal failure (DM/ESRD) who would benefit from a transplantation strategy that addresses both their ESRD and its underlying cause, current methods of islet and kidney transplantation using live donors have had only limited success. The first major obstacle is that the number of islets obtained from a live donor partial pancreatectomy is generally insufficient to cure diabetes in recipients, as large numbers of intraportally administered islets are lost due to ischemia before they are engrafted and vascularized in the recipient liver. To overcome this hurdle, we have developed a strategy to transplant islets as a vascularized graft. Autologous prevascularization of donor islets under the donor's own renal capsule prior to transplantation preserves islets and thus achieves normal glycemic control in diabetic recipients in our preclinical transplant models with a limited donor pancreas resection. In addition, from an immunological perspective, the innate tolerogenic qualities of the kidney provide immunoprotection for the engrafted, vascularized islets when they are transplanted as part of the composite islet-kidney (I-K) grafts. This "Trojan Horse" approach of transplanting a composite I-K eliminates the lengthy time which is otherwise required for vascularization of intraportally administered free islets, minimizing loss of islets to ischemic damage and facilitating the induction of tolerance. We have also recently developed a strategy to further minimize the required size of resected donor pancreas to prepare composite I-K graft using a novel, synthesized, small interfering RNA (siRNA)-nanoparticle probe. In this chapter, we introduce our living donor transplantation strategy to cure diabetic nephropathy using composite I-K graft.

Progress in islet xenotransplantation: Immunologic barriers, advances in gene editing, and tolerance induction strategies for xenogeneic islets in pig-to-primate transplantation.

Islet transplantation has emerged as a curative therapy for diabetes in select patients but remains rare due to shortage of suitable donor pancreases. Islet transplantation using porcine islets has long been proposed as a solution to this organ shortage. There have already been several small clinical trials using porcine islets in humans, but results have been mixed and further trials limited by calls for more rigorous pre-clinical data. Recent progress in heart and kidney xenograft transplant, including three studies of pig-to-human xenograft transplant, have recaptured popular imagination and renewed interest in clinical islet xenotransplantation. This review outlines immunologic barriers to islet transplantation, summarizes current strategies to overcome these barriers with a particular focus on approaches to induce tolerance, and describes an innovative strategy for treatment of diabetic nephropathy with composite islet-kidney transplantation.