The Potential of Composite Pig Islets-Kidney Xenotransplantation to Cure Diabetes and Renal Failure: A Suggested...

One-third of patients with diabetes will develop end-stage kidney disease, and approximately one-half of the patients requiring kidney transplantation in the U.S. suffer from diabetes. In 2002, Yamada, Sachs, and their colleagues explored the renal subcapsular site for islet implantation in a partially inbred miniature swine model. All pancreatectomized pigs that received autologous islets under the renal capsule maintained normoglycemia. The transplantation of a composite islets-kidney (i.e., the kidney with the revascularized autologous islets) into another pancreatectomized, bilaterally nephrectomized pig provided successful renal and islet function. In 2011, this model was extended successfully to nonhuman primates (NHPs). There are several hurdles to be overcome if this model is to be successfully translated into clinical practice, and xenotransplantation might resolve this problem. Pancreases harvested from gene-edited pigs could be sources of islets that could be isografted beneath the renal capsule of an identical cloned littermate. After allowing the islets to become vascularized over a period of 6-12 weeks, during which no immunosuppressive therapy would be required, the composite islets-kidney would then be transplanted into an immunosuppressed NHP or human recipient. On reperfusion of the graft, both renal and islet function should rapidly return. If sufficient islets have been transplanted with the kidney and the immunosuppressive regimen is successful, normoglycemia and normal renal function should be quickly achieved. However, a large number of genetically engineered neonatal donor piglets will be required to manufacture one therapeutic patient dose of islets, which may prove to be a logistical problem. Alternative approaches are discussed.

Autologous islet implantation in the kidney subcapsular space of pigs and baboons and subsequent allotransplantation of the composite islet-kidney graft have been demonstrated to be successful, but the limited availability of human islets limits this approach in clinical practice. The implantation of neonatal pig islets under the kidney capsule of an identical cloned piglet and subsequent transplantation into a human patient with diabetic nephropathy could potentially correct both diabetes and renal failure. Neonatal pig islets can become revascularized in cloned littermates in the absence of immunosuppressive therapy, but a very large number of donors may be required.