Initial angiogenic response in reduced renal mass after transplantation

Shortage of organs is a major problem in kidney transplantation and requires novel strategies to increase the number of kidney transplants. To reduce the shortage of kidneys, we have proposed transplantation of two halves of one kidney into two recipients (hemirenal transplantation, HRT) and have shown its feasibility in pig and human kidneys. However, reduced renal mass can lead to progressive renal failure in rodents and can reduce the longevity of kidney transplants in humans. Recent studies suggest that derangement of angiogenesis plays a role in the progressive renal failure after reduction in renal mass in rodents. However, since the renal physiology of rats is different from that of large animals, we studied angiogenesis in reduced renal mass transplants in pigs and determined if the reduction in renal mass has the same effect in large animals as that in rodents.

Kidney autotransplantation was performed in domestic outbred swine. Heminephrectomy of the autotransplanted kidney and nephrectomy of the contralateral kidney were performed 1 week after transplantation to reduce the renal mass. Four weeks after transplantation, the pigs were sacrificed and the hemirenal and control nephrectomy specimens were processed for morphometric analysis of glomerular capillary density and immunohistochemical analysis of VEGF expression. Soluble extracts from the kidneys were tested in an in vitro angiogenesis assay to determine their activity to influence angiogenesis. Statistical analysis with ANOVA was performed on the glomerular capillary density in kidney specimens.

All these parameters of angiogenesis were increased in the reduced renal mass autotransplants as compared to normal kidneys or whole kidney autotransplants. Glomerular capillary density was increased significantly after reduction in renal mass. VEGF expression also was increased progressively by the third week after reduction in renal mass. Soluble extract from the reduced renal mass transplants significantly increased the in vitro angiogenesis.

This is the first study to demonstrate that angiogenesis is increased in the initial stages of reduction in renal mass after transplantation in a large animal model. Increased angiogenesis was found in this model earlier than reported in small animal models (2 weeks in pigs versus 6 weeks in rats). Taken together with other studies, our data suggest that derangement in angiogenesis could play an important role in long-term graft function after hemirenal transplantation.