METANEPHROS TRANSPLANTATION BETWEEN NON-HISTOCOMPATIBLE RATS RESULTS IN REJECTION WHILST INBRED TRANSPLANTS ARE NOT REJECTED AND DEMONSTRATE MEASUREABLE FUNCTION.

Abstract

P1203 Aims: Loss of kidney function resulting in end-stage renal failure is a major clinical problem with a wide variety of causes. One potential approach is transplantation of foetal kidney rudiments with subsequent, microsurgical connection of the transplant ureter to the recipient excretory tract. Methods: We have transplanted E14-E15.5 metanephroi to the abdominal cavity of more than 100 inbred (Lewis) rats. These animals were reexplored after 17-21 days and microsurgical anastamosis of the transplant ureter to the host excretory tract performed wherever possible. At a third procedure urine of metanephric origin was collected after diversion or removal of remaining host renal tissue. Glomerular filtration rates were estimated. Using identical methodology, we transplanted 126 E14-E15.5 sprague-dawley (outbred) metanephroi into the abdominal cavity of 36 sprague-dawley rats. In addition, we transplanted 10 sprague-dawley metanephroi to 2 nude rats. Outbred transplants were assessed after 7, 12, 16, 21 and 25 days following implantation Results: Inbred transplants undergo growth and differentiation with essentially normal renal histology. The transplants develop cystic dilatation of their excretory tracts which contain fluid with a more than 10-fold higher concentration of urea than plasma consistent with production of urine. Following successful microsurgical connection of transplant ureters to the recipient urinary tract, we have also demonstrated metanephric urine production and measureable glomerular filtration of up to 62.6 (+/- 6.8) μls/min/100g body weight. All transplants between outbred animals were identifiable at 7 and 12 days whilst thereafter, decreasing proportions were identifiable with only 61% of transplants present after 25 days. Histology showed all normal renal components present in all transplants after 7 days, whilst at the later time points, there was progressive immunological rejection with destruction of renal tissue architecture. This is confirmed on immunostaining for a variety of markers including MHC, macrophages and the T cell receptor. After 25 days, those transplants still identifiable showed near total rejection or fibrosis. No outbred transplants exhibited cystic dilatation and, whilst in 7 animals anatomical connection of the transplant ureter to the host ureter was possible, none made metanephric urine. Transplants of sprague-dawley metanephroi to nude rats showed normal growth and histology without any demonstrable rejection. Conclusions: These findings are in keeping with many previous experiments on the transplantation of embryonic tissues but distinct from previous reports of abdominal metanephros transplantation utilising outbred or non-histocompatible rat strains. The severity and kinetics of the rejection observed in our model is in keeping with that seen in solid organ transplants. Reproduceible transplant growth and function is demonstrated in an inbred rat model. Extensive data exists on the effects of current, clinical immunosuppressives on renal development from the offspring of mothers receiving immunosuppression but in such cases the developing metanephros is separated from the circulating drug by two circulations and a placenta. The direct effects of these drugs on the growth and development of metanephric transplants are largely unknown. These findings suggest that a permissive immunosuppressive regime will be necessary for successful transplantation of foetal anlagen between non-identical individuals.