Challenge for xeno renal regenerative therapy for fetus

Introduction: Fetuses with severe renal failure due to malformation or hypoplasia of the kidney and urinary system are difficult to keep alive because they cannot receive hemodialysis immediately after birth. It is worthwhile saying that we have proposed the creation method of a new urinary excretory system by transplanting the kidney and urinary system of heterologous fetuses. This study aims to develop a novel treatment for fetuses with severe renal failure. First, we investigated the immunological advantage of transplanting the kidney and urinary system of fetuses to other fetuses, by transplanting into a rat fetus in the mother’s womb. Second, we developed clinical transplant system and tested it by transplanting into a pig fetus. Method: First, E14.0 fetal kidneys of Sprague-Dawley(SD)-Tg(CAG-EGFP) rats were subcutaneously transplanted into SD rat fetuses(E18.0) through the uterus using an 18G needle, and natural childbirth was attempted. After birth, the transplanted tissue was harvested and histologically assessed for fetal kidney growth and rejection. Second, in order to implant pig fetal kidneys through the fetal skin, we have developed a system in which the implantation site is occluded with a gold marker. Then E30.0 fetal kidneys of microminiature pigs(MMPs) with the gold marker were transplanted into the perirenal muscle layer of MMP fetuses. Sixteen days later, a caesarean section was performed and we attempted to harvest the transplanted tissue. Results: Four days after transplantation of SD-Tg rat fetal kidneys, we succeeded in obtaining live fetuses by natural childbirth. In some fetuses, a GFP-positive tissue was confirmed under a fluorescence stereomicroscope. Twenty-eight days after transplantation, it was harvested. Histologically, glomerular and tubular structures were observed, and the transplanted fetal kidney was more grown than at the time of transplantation. In addition, some renal tubules were dilated, suggesting that the fetal kidney was producing urine. No rejection was identified during the observation period of this study. This result suggests two types of immune tolerance. That is tolerance in allografts between SD rats and against GFP. Moreover, we successfully performed a fetal kidney transplantation of MMPs by transplanting with a gold marker, which served to plug the needle entry site at the time of transplantation. Conclusion: By allogeneic fetal kidney transplantation into rat fetuses, we successfully created an exogenous kidney, which has the ability to produce urine. We identified immune tolerance in allografts between SD rats and against GFP. Furthermore, we established the world’s first method of transplanting pig fetal kidneys into fetuses. This work was supported by the Japan Agency for Medical Research and Development (AMED; grant no. 23bm1223003h0002), JST FOREST Program (grant no. JPMJFR2011). References: 1. Simone Sanna-Cherchi et al. Kidney Int. 2009 Sep;76(5):528-33. 2. Shinya Yokote et al. Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):12980-5. 3. Marc J Clancy et al. Transplantation. 2009 Jul 27;88(2):151-9.