Urolithiasis is a major health problem in the United States, and the incidence and frequency of these stone appears to be increasing in this country. The prevalence of urinary tract stone disease is estimated to be 2-20 per 10,000. Chances of recurrence within 10 years are nearly 60%. The current cost to the nation for treating kidney stones is approximately $2.39 billion/year. Treatment program includes medications, open surgery, percutaneous techniques and extracorporeal shock wave lithotripsy. Despite recent advances in treatment, stone recurrence can be reduced by only 50%. Our working hypothesis is that free radical induced cell injury is central to the process of urolithiasis and that prevention of injury will prevent calcium oxalate nucleation, retention and deposition. Hyperoxaluria and calcium oxalate crystalluria are often associated with increased excretion of tubular marker enzymes, a finding consistent with damage to renal tubular cells. Moreover, these changes are observed even in the absence of crystalluria, suggesting oxalate induced membrane damage is not solely to injury produced by calcium oxalate crystals. We are the first to demonstrate the molecular mechanism of oxalate induced free radical production and first to demonstrate that the binding of calcium oxalate crystals in renal tubular membranes occurs via peroxidative injury. The oxidant and antioxidant balance is therefore a critical determinant of cell sensitivity to free radical injury and a major impact on the magnitude of stone crystal nucleation on the injured renal tubular epithelium and the development of stone nidus. We propose to test this hypothesis in an animal model and renal epithelial cells in culture. Hyperoxaluria is induced in male rats. In cell culture experiments, renal epithelial cells are exposed to oxalate and/or calcium oxalate monohydrate crystals. The effect of antioxidants on these experimental models will be tested. These studies will provide valuable information on the importance of antioxidants and, whether antioxidants offer promise as a therapeutic agent for recurrent stone formers.
