In children, adult patients and dogs, we will seek to determine whether the pathogenesis of hyperparathyroidism in moderately severe renal insufficiency is critically dependent on a diminished plasma concentration of 1,25-dihydroxy vitamin D (1,25-(OH)2D) that is caused by a reversible, inoganic phosphate (P)-mediated suppression of 25-OH-vitamin D-1alpha-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 dogs with moderate renal insufficiency. In P-restricted affected children we will determine whether the post-breakfast serum phosphate (P) is much lower than that in the morning fasting state. When P is restricted in the adult patients, we will determine whether they, like affected children, increase their 1,25-(OH)2D to normal values and reduce to normal their serum concentrations of immunoreactive parathyroid hormone (iPTH), and whether such an increase in 1,25-(OH)2D precedes such a decrease in iPTH, and corrects an abnormal """"""""set point"""""""" for release of PTH. When P restriction is experimentally relaxed for 6 days, we will determine the courses of th preditable increase in iPTH and decrease in 1,25-(OH)2D. Then, coincident with such relaxation of P restriction, we will then orally administer 1,25- (OH)2D3 in an amount and schedule that maintains 1,25-(OH)2D near normal mean values and hope to prevent or attenuate the ncrease in iPTH. If so, the oral 1,25-(OH)2D3 will be stopped during experimental relaxation of phosphorus restriction, whereupon we expect iPTH to increase rapidly. We will determine whether: orally administred 1,25-(OH)2D3 can, by inducing near-normal plasma concentrations, reverse hyperparathyroidism without restricting dietary phosphorus. In adult patients with MRI we will determine whether reduced values of 1,25-(OH)2D reflect a decreased production rate (PR) of 1,25- (OH)2D or an increased rate of metabolic clearance by employing an equilibrium infusion technique using tritiated 1,25-(OH)2D. In the uremic dog, we will determine whether the previously demonstrated reversal of hyperparathyroidism induced by phosphorus restriction depends on an increase in 1,25(OH)2D. By studying normal men, patients with primary hyperparathyroidism, idiopathic hypercalciuria (""""""""absorptive""""""""), osteoporosis and normal elderly subjects, we will determine whether dietary P importantly affects serum (P) after the morning fasting value and thereby mediates disorders in the PR and plasma concentration of 1,25- (OH)2D.
