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

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AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: In this limited series, sequential islet-after-kidney xenotransplantation restored metabolic control and represents a promising translational strategy for diabetic nephropathy.

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