KIDNEY RESPONSE TO RADIATION AND CHEMOTHERAPY

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The long-term goa of this project is to use a rodent renal tolerance model to study the late response of slow renewal tissues to irradiation, and the impact of anti-neoplastic drug treatment on this late response. The discovery that radiation nephropathy is a major complication associated with the total body irradiation (TBI) used for human bone marrow transplant (BMT) conditioning has added a major preclinical component of this project. The project now has two complementary foci, the use of the rat radiation nephritis model as a general model for studying the late normal tissue effects of radiotherapy; and the use of the rat BMT model to study the cause, treatment and prevention of BMT nephropathy. Proposed studies of the radiobiology of late responding normal tissue are influenced by the discovery that repair of renal radiation damage after low doses per fraction follows neither the linear-quadratic (alpha/beta) model nor a simple mono-exponential repair model. The studies are designed to: Confirm that the kinetics of repair of radiation damage in the rat kidney do not follow simple mono-exponential repair kinetics, and determine the mechanism for the dependence of repair kinetics on the level of damage. Determine whether the deviance of renal tolerance from the linear- quadratic (alpha/beta) model is statistically and/or biologically significant. Determine the relationship between renal tolerance and dose-rate; assess how it comes with the predictions of standard models; and determine how low dose rate and high dose rate irradiation interact. Proposed studies of BMT nephropathy are heavily based on the recent findings that the development of radiation nephritis and BMT nephropathy can be retarded, and possibly prevented, by treatment with captopril, an angiotensin converting enzyme (ACE inhibitor. The studies are designed to: Determine the role ACE inhibitors, calcium-channel blockers, and other anti-hypertensive regimens in the prevention and treatment of BMT nephropathy. Determine the mechanism by which captopril retards the development of radiation nephritis. Determine the role of endothelium-derived relaxing factor deficiency in experimental BMT nephropathy. Complete the on-going study of whether nephrotoxic drugs used in conjunction with BMT enhance or accelerate the development of radiation nephritis.