Assistant Professor
Department of Surgery
The Johns Hopkins University School of Medicine
Combined islet and kidney xenotransplantation for diabetic nephropathy: islet-after-kidney transplantation with cure of diabetes and six months of stable graft function in life-supporting pig-to-baboon xenotransplantation
Hayato Iwase1, Weili Chen1, Daniel Eisenson1, Yu Hisadome1, Wanxing Cui2, Michelle Santillan1, Alexander Schulick1, Kasra Shirini1, Saghar Babadi1, Du Gu1, Amanda Maxwell3, Kristy Koenig1, Savannah Windley1, Zhaoli Sun1, Daniel Warren1, Andrew Cameron1, 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; 3Research Animal Resources, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
Introduction: Diabetes is a leading cause of end stage renal disease. Combined islet and kidney transplantation (Tx) through islet-after-kidney Tx may prove curative for patients with diabetic nephropathy. Preclinical studies of pig-to-NHP XTx have demonstrated prolonged survival of porcine kidney or islet xenografts. However, no study to date has described durable function of both porcine kidney and islets in a NHP XTx model. Here we report the first case of combined porcine kidney and islet pig-to-NHP XTx resulting in six months life-supporting function of porcine kidney and islet xenografts with stable renal function and normoglycemia in a diabetic baboon with delayed islet-after-kidney XTx.
Methods: Two baboon recipients (MD Anderson) underwent vascularized thymic lobe (VTL) and kidney XTx from a size-matched GalTKO.hCD55 pig (10.7kg and 13kg) on day 0, followed by islet Tx from a large GalTKO.hCD55 pig (95kg and 130kg) (NSRRC: University of Missouri) on POD 11 and 19. Islet isolation yielded 101K and 254K IEQs (194K and 379K IPN). The baboon recipients underwent induction with rATG and Rituximab prior to XTx and immunosuppression was maintained with anti-CD40mab, CTLA4-Ig, MMF. Streptozotocin was given twice at 100mg/kg on POD 5, 50mg/kg on POD 9 in case1, 120mg/kg on POD 13, 60mg/kg on POD 16 in case2 to induce IDDM prior to islet XTx.
Results: Diabetic induced by high-dose STZ and nephrectomized baboon recipients demonstrated normal serum creatinine and normoglycemia with islet-after-kidney XTx. Both baboons maintained normal blood glucose (BG) levels and normal creatinine levels after XTx. One recipient maintained normal serum creatinine with no evidence of rejection for six months but was euthanized due to sepsis related to pyelonephritis on POD180. Immediately after islet Tx, hyperglycemia was reversed with normalization of BG from >250mg/dL to 80-110 mg/dL without any exogenous insulin treatment. Post-mortem evaluation of liver confirmed presence of insulin-staining islets, and VTL graft was viable. ELISpot assay at necropsy demonstrated pig-specific unresponsiveness. The other recipient also maintained normal BG levels after delayed islet Tx, but developed acute deterioration triggered by post-obstructive nephropathy and was euthanized on POD50.
Conclusion: Although further studies will be required, our findings in islet-after-kidney XTx are promising and represent the first demonstration of successfully cure of diabetes and end stage renal disease with the evidence of donor specific unresponsiveness in vitro in diabetic and nephrectomized NHP receiving pig kidney, VTL, and islet XTx.