Porcine islet-after-kidney transplantation in with cure of diabetes and six months of stable graft function in life-supporting pig-to-baboon model
Hayato Iwase1, Weili Chen1, Daniel L Eisenson1, Yu Hisadome1, Wanxing Cui2, Michelle R Santillan1, David H Sachs3, Zhaoli Sun1, Daniel Warren1, Kazuhiko Yamada1.
1Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, United States; 2Cell Therapy and Manufacturing, Medstar Georgetown University Hospital, Washington DC, United States; 3Columbia Center for Transplantation Immunology, Columbia University, New York, NY, United States
Introduction: Combined islet and kidney xenotransplantation (XTx) 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 and diabetes. Although durable porcine islet function has been reported in pig to non-human primate (NHP) model, no study has described durable function of both porcine kidney and islets in NHP XTx model. In this report, we achieved six months of life-supporting function of porcine islet and kidney grafts in baboon with delayed islet transplantation and co-transplant of vascularized thymic lobe (VTL).
Methods: Pig-to-baboon kidney, VTL, and islet transplantation was performed sequentially in one baboon using two GalTKO.hCD55 source pigs due to varying size requirements by organ. Source pigs were obtained from the NSRRC (University of Missouri-Columbia, USA); baboon was obtained from MD Anderson. Baboon recipient underwent VTL and kidney graft transplantation on Day 0 from a size-matched GalTKO.hCD55 source pig (10.7kg), followed by islet transplantation on POD 11 from a large GalTKO.hCD55 source pig (95.0 kg). Islet isolation yielded 101K IEQs (194K IPN). The baboon recipient underwent induction with rATG and Rituximab prior to XTx and immunosuppression was maintained with anti-CD40mab and MMF. Streptozotocin was given twice at 100mg/kg on POD5 and 50mg/kg on POD9 to induce IDDM prior to islet XTx
Results: The baboon recipient maintained normal serum creatinine with no evidence of rejection for six months following kidney and islet transplant but was euthanized due to pyelonephritis in setting of stent occlusion on POD180. Immediately after islet XTx, hyperglycemia was reversed with normalization of blood sugars from >250mg/dL (pre-transplant) to 80-110 mg/dL (Fig 1A). No exogenous insulin treatment was required after islet XTx. Post-mortem evaluation of liver confirmed presence of insulin-staining islets (Fig 1B).
Conclusion: Although additional cases are required, to our knowledge, this is the first demonstration of durable 6 months normoglycemia and stable creatinine with porcine kidney and islets in a diabetic and life-supporting pig-to-baboon combined kidney and islet XTx model.
