In children, adult patients and dogs, we will attempt to determine whether the lathogenesis of the hyocalcemia that evokes hyperparathyroidism in moderately severe renal insufficiency is critically dependent on a diminished plasma concentration of 1,25-dihydroxy vitamin kD (1,25-(OH)2Dp) that impairs gut absorption and bone resorption of calcium and is caused by a reversible, inorganic phosphate (Pi)-mediated suppression of 25-OH-vitiamin D-la-hydroxylase, in the absence of increased serum concentrations of phosphorus. To test this hypothesis, we plan to restrict dietary phosphorus in children, adult patients and in dog with moderate renal insufficiency. When phosphorus is restricted in the adult patients, we will determine whether they affected children, increase their 1,25-(OH)2Dp to normal values and reduce to normal their serum concentrations of immunoreactive parathyroidhormone (iPTHs). When phosphorus restriction is experimentally relaxed for 6 days, we will first determine the time courses of the predictable increase in iPTHs and decrease in 1,25-(OH)2Dp. Then, coincident with such relaxation of phosphorus restriction, we will then orally administer 1,25-(OH)2D3 in an amount and schedule that maintains 1,25-(OH)2Dp near the near-normal value and expect to prevent or attenuate the increase in iPTHs. If so, the oral 1,25-(OH)2D3 will be stopped on day seven of relaxation of phosphorus restriction, whereupon we expect iPTHs to increase rapidly. We will determine whether: orally administered 1,25-(OH)2D3 can, by inducing near-normal plasma concentrations, reverse hyperparathyroidism without restricting dietary phosphorus; alkali therapy that sustains correction of acidosis increases 1,25-(OH)2D to normal values. In adult patients with MRI nad with uncorrected RTA, we will determine whether reduced valued of 1,25-(OH)2D reflect decreased rates of sunthesis of 1,25-(OH)2D or increased rates of metabolic clearance by employing an equilibrium infusion tehcnique and a single bolus injection technique, both of which require tritiated 1,25-(OH)2D. In the uremic dog, we will determine whether the previously demonstrated reversal of hyperparathyroidism induced in four days by phosphorus restriction depends on the increase in 1,25-(OH)2Dp. The anticipated increase in 1,25-(OH)2D will be prevented while the plasma concentration of phosphorus isdecreased, by intravenously administered maleic acid, which has been shown to impair the renal production of 1,25-(OH)2D3 in the rat and chick.
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