Combined Islet and Kidney Xenotransplantation for Diabetic Nephropathy: Investigation of Pre-Vascularized Composite Grafts versus Sequential Islet-After-Kidney Transplantation in a Pig-to-Nonhuman Primate Model of Xenotransplantation.
Combined renal and islet xenotransplantation could provide a durable treatment for end-stage diabetic nephropathy. In this feasibility-focused study, we evaluated two complementary approaches for clinical translation: (1) pre-vascularized composite islet-kidney (I-K) grafts and (2) sequential islet-after-kidney xenotransplantation with vascularized thymic lobe (VTL) co-transplantation as an adjunct immune tolerance strategy.
Composite I-K grafts were generated in nine MHC-matched, minor-antigen-mismatched miniature swine pairs by implanting adult porcine islets beneath the renal capsule of juvenile kidney donors followed by pre-vascularization under tacrolimus-based immunosuppression. Separately, three baboons underwent GalTKO.hCD55 kidney and VTL xenotransplantation, followed by streptozocin-induced diabetes and intraportal adult porcine islet infusion from a separate donor. Renal/metabolic function, porcine C-peptide, histology, and immune profiling were assessed.
Composite I-K grafts demonstrated limited islet survival with peri-islet inflammation on histology at the graft preparation stage and were not advanced to pig-to-NHP xenotransplantation in this study. Sequential islet-after-kidney transplantation restored insulin-independent euglycemia in all recipients. Porcine C-peptide was detectable in the long-term survivor with intrahepatic insulin-positive islets at necropsy. Infection-associated thrombotic microangiopathy limited survival in two animals; in the 180-day survivor, anti-porcine hypo-responsiveness and evidence of thymopoiesis within the VTL graft were observed.
In this limited series, sequential islet-after-kidney xenotransplantation restored metabolic control and represents a promising translational strategy for diabetic nephropathy.
Composite I-K grafts were generated in nine MHC-matched, minor-antigen-mismatched miniature swine pairs by implanting adult porcine islets beneath the renal capsule of juvenile kidney donors followed by pre-vascularization under tacrolimus-based immunosuppression. Separately, three baboons underwent GalTKO.hCD55 kidney and VTL xenotransplantation, followed by streptozocin-induced diabetes and intraportal adult porcine islet infusion from a separate donor. Renal/metabolic function, porcine C-peptide, histology, and immune profiling were assessed.
Composite I-K grafts demonstrated limited islet survival with peri-islet inflammation on histology at the graft preparation stage and were not advanced to pig-to-NHP xenotransplantation in this study. Sequential islet-after-kidney transplantation restored insulin-independent euglycemia in all recipients. Porcine C-peptide was detectable in the long-term survivor with intrahepatic insulin-positive islets at necropsy. Infection-associated thrombotic microangiopathy limited survival in two animals; in the 180-day survivor, anti-porcine hypo-responsiveness and evidence of thymopoiesis within the VTL graft were observed.
In this limited series, sequential islet-after-kidney xenotransplantation restored metabolic control and represents a promising translational strategy for diabetic nephropathy.
Authors
Schulick Schulick, Eisenson Eisenson, Chen Chen, Cui Cui, Shirini Shirini, Hisadome Hisadome, Babadi Babadi, Santillan Santillan, Koenig Koenig, Gu Gu, Sachs Sachs, Bottino Bottino, Chen Chen, Cui Cui, Sun Sun, Warren Warren, Shimizu Shimizu, Iwase Iwase, Yamada Yamada
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