KIDNEY RESPONSE TO RADIATION AND CHEMOTHERAPY

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DESCRIPTION: The goal of this project is to use rodent models to study the mechanism of late radiation-induced tissue injury. The proposal is based on the discovery that radiation nephropathy is a major complication of the total body irradiation used in bone marrow transplantation (BMT), that the rat is an excellent model for this nephropathy, and the discovery that angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) blockers could be used to treat BMT nephropathy. The studies are strongly influenced by the finding that ACE inhibitors and AII blockers can permanently interfere with the development of BMT nephropathy even when treatment is started after irradiation and is not continued indefinitely. These findings cast doubt on the standard mechanistic explanations for late radiation injury, and open up the possibility that normal tissue radiation injuries can be treated, or even prevented, by post-irradiation interventions. The specific aims of this proposal are: 1) To test the hypothesis that radiation-induced activation of the renin-angiotensin system (RAS) is the cause of radiation (and BMT) nephropathy. 2) To test the hypothesis that fibrosis is a cause , rather than a consequence , of radiation nephropathy. 3) To test the hypothesis that AT1 receptor antagonists are preferentially effective in the prophylaxis and treatment of radiation (and BMT) nephropathy. 4) To retrospectively assess the factors influencing the incidence of BMT nephropathy in humans. 5) To determine in a prospective randomized clinical trial whether captopril can be used to lower the incidence of BMT nephropathy. 6) To determine the basis for the dependence of renal tolerance on age-at-irradiation, and whether the change in tolerance is related to the decreased effectiveness of ACE inhibitors in older animals. 7) To determine the conditions under which pulsed low dose rate (LDR) and continuous LDR produce clinically equivalent normal tissue injury.