Hypercalciuria is one of the risk factors for Ca-oxalate/apatite kidney stone. Serum levels of 1,25-(OH)2-vitamin D are often elevated among hypercalciuric stone-formers, independent of parathyroid hormones. 1,25-(OH)2-D is a critical determinant of both daily and fasting urinary Ca excretion because of the effects of this hormone to augment intestinal Ca absorption and to stimulate net bone resorption. All of the factors regulating renal 1,25-(OH)2-D synthesis and thus serum 1,25-(OH)2-D concentrations have not been defined but previous studies have suggested that PO4, in addition to Ca and PTH, as well as caloric intake or some other feature of diet composition, are important. We propose to continue studies in Ca-stone formers and in healthy adults to 1) determine whether Ca-stone formers exhibit increased rates of net intestinal Ca absorption independent of prevailing serum 1,25-(OH)2-D concentrations, 2) the roles of dietary intake of calories, animal as opposed to vegetable-cereal protein and sugar as opposed to complex carbohydrate as determinants of serum 1,25-(OH)2-D levels and whether such factors are mediated by PO4, insulin, growth hormone or somatomedin-C 3) whether Ca-stone formers with absolutely elevated serum 1,25-(OH)2-D levels exhibit elevated serum insulin, GH and somatomedin-C levels when fasting, on an integrated basis over 24-hours and after acute nutrient loading. In addition, we will continue studies of the in vitro regulation of 1,25-(OH)2-D3 production by primary cultures of mouse kidney cortical cells in serum-free medium. This system requires further characterization, especially with respect to the production of 19-nor-10-keto-25-OH-D3, a cross-reacting 25-OH-D3-metabolite. The effects on 1,25-(OH)2-D3 production of gastronintestinal hormones, endogenous opioids and the interaction of these hormones with PTH, as well as the effects of the original sex of the cells and of added sex steroids will be evaluated.
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