Thursday, September 21, 2023
9/21/2023
Project Summary Calcium oxalate stone disease occurs in nearly 10% of the U.S. population and contributes significantly to health care costs and negatively impacts quality of life. The amount of oxalate excreted in urine is a known risk factor for calcium oxalate stone disease. Approximately 50% of urinary oxalate is derived from the diet and the remaining from endogenous synthesis. The metabolism of ascorbic acid (AA), an important antioxidant, is a source of urinary oxalate derived from endogenous synthesis. However, the contribution of this source to urinary oxalate excretion is not well defined. Prior experiments have been hampered by 1) a lack of control of dietary oxalate to urinary oxalate excretion and 2) the confounding generation of oxalate from AA in non- acidified urine samples. The turnover of AA each day is approximately 80 mg and could feasibly result in the formation of up to 40 mg of oxalate per day. We have measured the contribution of AA turnover to urinary oxalate excretion with carbon-13 labelled AA oral dosing in a small number of normal adults and have confirmed that AA contributes 40 -50 % of the endogenous oxalate excreted in urine. These preliminary findings suggest AA turnover is a major source of urinary oxalate derived from endogenous synthesis. In this proposal we will assess the conversion of AA to oxalate in non-stone forming adults and CaOx stone forming adults using the stable isotope of AA, carbon-13 AA. We will further examine the effects of obesity, which is known to be associated with systemic oxidative stress and a decreased plasma AA concentration, on this conversion as well as increased oxalate excretion. Subjects in nutritional studies will ingest known amounts of food-derived AA in diets also controlled in their contents of oxalate, calcium and other nutrients. Experiments will be conducted in cultured cells and mouse models to systematically examine the relationships between AA and oxalate, the role of pro-oxidants in this process, the role of mitochondria and AA transport into this organelle, and to determine whether antioxidants can blunt oxalate formation from AA. If these studies are successful they will open new avenues of research for decreasing urinary oxalate excretion and kidney stone formation.
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