Urolithiasis is a major health problem in the United States, and the incidence and frequency of stone formation appears to be increasing in this country. The current cost to the nation for treating kidney stones is approximaately 2.39 billion dollars/year. About two thirds of the stones contain calcium oxalate. Chances of recurrences within 10 years are nearly 60 percent. Treatment program includes medications, open surgery, percutaneous techniques and extra corporeal shock wave lithotripsy. Despite recent advances in treatment, stone recurrence can be reduced by only 50 percent. To reduce the likelihood of stone recurrence it is necessary to determine and understand the mechanisms involved in stone formation. Our working hypothesis is that cell injury is central to the process of urolithiasis and that prevention of cell injury will prevent calcium oxalate formation, 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 that oxalate induced membrane damage is not due solely to injury produced by calcium oxalate crystals. Our studies have suggested that oxalate induces peroxidative injury to the kidney tubules which can alter membrane permeability, and result in the deterioration of ability of the cells to maintain normal ionic environment. The oxidant and antioxidant balance is therefore likely to be 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 cell culture (LLC-PK1 and MDCK). In an animal model hyperoxaluria is induced in male rats. In cell culture experiments, renal epithelial cells in culture are exposed to oxalate and 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 in decreasing oxalate synthesis and deposition and, whether antioxidants offer promise as a therapeutic agent for recurrent stone formation.
