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.

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.