Urolithiasis is a significant urological disease afflicting a large percentage of US population costing approximately 2.39 billion dollars/year. Nearly two-thirds of the urinary stones contain calcium oxalate. Chances of stone recurrence within 10 years of the first episode are over 60 percent. To reduce the likelihood of recurrence it is necessary to understand the mechanisms involved in stone formation and to determine urinary markers of stone initiation. This project is aimed towards developing an understanding of the processes involved and identification of urinary markers which can be utilized to determine the onset of nephrolithiasis. It is our hypothesis that calcium oxalate stone formation involves a cascade of events which starts with hyperoxaluria. A moderate hyperoxaluric challenge induces increased production of crystallization modulators such as osteopontin which interact with calcium as well as the calcific crystals and facilitate their removal from the renal tubules. Significantly high level of oxalate however, injures the renal epithelial cells. The injury results in promotion of crystal formation and their retention within the renal tubules by providing substrates for crystal nucleation, agents for crystal aggregation and by creating sites for crystal adherence to the renal epithelial cells. Crystallization modulators produced by the injured cells maybe abnormal and/or functionally inadequate. Production of such atypical modulators can indicate initiation of the stone forming cascade. We want to test this hypothesis using, 1. an animal model of calcium oxalate nephrolithiasis and, 2. cell culture experiments. In the animal model hyperoxaluria is induced in male rats. In cell culture experiments renal epithelial cell; MDCK and LLC-PK1 are exposed to oxalate and calcium oxalate crystals. We can follow various events of nephrolithiasis in the animal model and cats explore the outcome of renal epithelial cell exposure to oxalate and calcium oxalate crystals in the cell cultures.
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