Tubular regeneration and renal cell carcinoma following kidney transplantation - pathomechanisms

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The incidence of malignancy after renal transplantation is increased 2-4-fold compared with the normal population, and deaths from malignancy occur in approximately 16% of cases after 5 years. In addition to the pro-carcinogenic effect of calcineurin inhibitor-based immunosuppression, immunological mechanisms due to the ischemia-reperfusion injury inevitable during transplantation also play a role. This transplantation-induced acute renal failure is usually reversible, although the actual regenerative capacity of renal tubules is unclear and to what extent proliferation of progenitor cells and hypertrophy of differentiated tubule cells merely represent a dynamic response to the acute loss of tissue and function. Furthermore, acute tissue injury leads to DNA alteration and repair through extensive proliferation of stem cell populations and/or polyploid genome alterations of differentiated cells. All also potential mechanisms for tumorigenesis. In a mouse model, contrary to initial assumptions, a crucial role of Pax2+ progenitor cells in tubule regeneration has recently been demonstrated. As a consequence of ischemia-reperfusion damage, malignancy was also observed in approximately 50% of cases. The actual influence of these cells on regeneration and on the other hand malignancy development after kidney transplantation will now be investigated in this work in a murine kidney transplantation model. The aim of this project is to establish a tumor-in-kidney transplantation model based on our experience with murine kidney transplantation and studies on tubule regeneration in acute drug-induced kidney injury. This model will be used to investigate the role of Pax2+ tubular epithelial cells on tubule regeneration and tumorigenesis. Specially genetically modified mice (Pax2.rtTA; TetO.Cre;R26.Confetti) are available to study this issue. Clonal lineage tracing of Pax2+ progenitor cells can be performed in these animals. In addition, the immunological influence on Pax2+ progenitor cells by allogeneic transplantation under continuous immunosuppression will also be investigated. Finally, potential nephro-protective effects of different pro-proliferative substances will be investigated. For the project presented here, an animal experiment application approved by the government of Upper Bavaria already exists. Based on the findings of this project, we expect to investigate new approaches to minimize ischemia-reperfusion-induced renal injury and thus stabilize renal function after kidney transplantation as well as a resulting improvement in long-term graft survival. Furthermore, we expect to be able to develop approaches to prevent the development of renal cell carcinomas in the kidney grafts.