The effects of vitamin D and its receptor in normal subjects and kidney stone formers

grantor: University of TorontoVitamin D exists in two major forms, as the D$\sb2$ and D$\sb3$ form. It is accepted that vitamin D$\sb2$ and vitamin D$\sb3$ exert different biological effects in all animal species tested. Yet in humans, vitamin D$\sb2$ and D$\sb3$ are presumed to have equivalent biological effects. To test this assumption in humans, I compared the ability of equimolar quantities of ingested vitamin D$\sb2$ or D$\sb3$ to increase serum 25-hydroxyvitamin D (25(OH)D), the clinical measure of vitamin D nutrition. Vitamin D may also play an important role in hypercalciuric calcium stone formation because calcitriol, the hormonal form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)$\sb2$D), controls calcium homeostasis. Available data support the hypothesis that disordered 1,25(OH)$\sb2$D production is one cause of idiopathic hypercalciuria (IH). I tested the hypothesis that patients with idiopathic hypercalciuria may have an exaggerated inverse relationship between serum 1,25(OH)$\sb2$D and 25(OH)D in the physiologic range. IH patients challenged with a vitamin D supplement should therefore exhibit a larger fall in serum 1,25(OH)$\sb2$D than controls. For 1,25(OH)$\sb2$D to exert its effects, it must bind to the vitamin D receptor (VDR). Genetic VDR polymorphisms have been reported to predict bone mass. Since vitamin D plays an important role in calcium metabolism, I investigated whether these VDR polymorphisms are associated with hypercalciuria. The results showed that vitamin D$\sb3$ is more potent than vitamin D$\sb2$ at elevating serum 25(OH)D. Thus, the assumption of D$\sb3$ and D$\sb2$ equivalence may be erroneous and should be reconsidered. In addition, only a small sub-group of IH stone formers have an inverse relationship between serum 25(OH)D and 1,25(OH)$\sb2$D. Finally, I found no association between VDR polymorphism and stone formers in comparison to controls. However, there was an association between VDR polymorphism and urinary calcium excretion, suggesting that VDR may exert a weak effect on renal calcium metabolism.M.Sc