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Organ Replacement Technologies: A New Frontier: Organogenesis: A Possible Future Alternative for Kidney Replacement

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Organogenesis: A Possible Future Alternative for Kidney Replacement

"One novel solution to the shortage of human organs available for transplantation envisions "growing" new organs in situ via xenotransplantation of developing organ primordia from animal embryos," Marc R. Hammerman, MD, Professor and Director of the Renal Division at the Washington University School of Medicine in St. Louis, Missouri, told Medscape (personal communication, 2/12/03). "Our long-term goal is to establish the clinical applicability for xenotransplantation of developing organs into humans as a means to increase renal function or control diabetes mellitus."

Embryonic kidneys taken from animal donors early during organogenesis can be transplanted in cellular form as renal primordia, or metanephroi.[14] In animal hosts, they differentiate, grow, develop a vascular supply from the host, and display excretory function. They can be stored for up to 3 days in vitro before transplantation without loss of growth or function after implantation, and they can be transplanted across concordant xenogeneic species, such as rat to mouse, as well as across highly distinct species, such as pig to rodent.

Growth factors enhance transplant function, improving inulin clearance in transplanted metanephroi and doubling the survival of recipients in a nephrectomized rat model.

Pancreatic primordia transplanted intraperitoneally also grow, differentiate, and secrete insulin, with preferential differentiation of islet rather than acinar components.

Before xenotransplantation of developing organs into humans is clinically feasible, several challenges must be met. Vascularization of the graft by the host is a critical problem, and Hammerman says that the solution is probably decades away. Long-term, life-sustaining function of transplanted metanephroi or pancreatic primordia must be demonstrated in a pig-to-primate model. Because pig kidneys are comparable in size and function to human kidneys, and pigs are plentiful and can be bred to be pathogen-free, pigs could be an ideal species for human transplantation.

But first, hyperacute rejection related to xenoreactive antibodies must be overcome. In humans, about 85% of natural antibodies binding to pig cells are directed against galactose-alpha-1,3-galactose (alpha-gal), a sugar expressed in endothelial cells of most mammals, but not in humans and primates.[15,16] Genetic engineering could theoretically help overcome this challenge by developing transgenic pigs that do not express the alpha-gal antigen.[17]

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