Sequential Islet-After-Kidney Xenotransplantation Restores Euglycemia in Diabetic Nonhuman Primates

End-stage diabetic nephropathy presents a significant clinical challenge, often requiring both kidney replacement therapy and intensive insulin management for type 1 diabetes. Current treatments, including isolated islet transplantation, face limitations such as the need for lifelong immunosuppression and the scarcity of human donor organs. Xenotransplantation, particularly using porcine islets and kidneys, offers a potential solution to organ shortage. However, overcoming immune rejection and ensuring long-term graft function remain critical hurdles, necessitating strategies for robust immune tolerance.

This feasibility study evaluated two xenotransplantation approaches: (1) pre-vascularized composite islet-kidney (I-K) grafts and (2) sequential islet-after-kidney xenotransplantation. Composite I-K grafts were prepared in nine miniature swine pairs by implanting adult porcine islets under the renal capsule, followed by pre-vascularization under tacrolimus-based immunosuppression. Separately, three baboons underwent GalTKO.hCD55 kidney and vascularized thymic lobe (VTL) xenotransplantation. These baboons were then made diabetic via streptozocin and received 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 and peri-islet inflammation during the graft preparation stage, preventing their advancement to pig-to-NHP xenotransplantation. In contrast, sequential islet-after-kidney transplantation successfully restored insulin-independent euglycemia in all three baboon recipients. Porcine C-peptide was consistently detectable in the long-term survivor, with intrahepatic insulin-positive islets confirmed at necropsy. Infection-associated thrombotic microangiopathy, however, limited survival in two animals. > In the 180-day survivor, researchers observed significant anti-porcine hypo-responsiveness and clear evidence of thymopoiesis within the VTL graft, indicating a potential for immune tolerance induction. This suggests the VTL co-transplantation strategy contributed to mitigating xenograft rejection.