DISORDERED VITAMIN D METABOLISM IN RENAL INSUFFICIENCY

在儿童、成人患者和狗中，我们将寻求确定 甲状旁腺功能亢进的发病机制是否在中度 严重肾功能不全严重依赖于 1，25-二羟基维生素D（1，25-（OH）2D）的血浆浓度 这是由可逆的，无机磷酸盐（P）介导的 抑制25-OH-维生素D-1 α-羟化酶， 无血清磷浓度升高。 测试 根据这一假设，我们计划限制儿童的膳食磷， 成人患者和中度肾功能不全犬。 在 受P限制影响的儿童，我们将确定是否 早餐后血磷（P）明显低于早餐后， 晨起禁食状态 当P限制在成年患者时， 我们将确定他们是否会像受影响的儿童一样， 他们的1，25-（OH）2D正常值，并减少到正常的， 血清免疫反应性甲状旁腺激素浓度 （iPTH），以及1，25-（OH）2D的这种增加是否先于 这种iPTH的降低，并纠正异常的“设定点”， 释放PTH。 当P限制在实验上放松时， 6天后，我们将确定可预测的增长的过程， iPTH和1，25-（OH）2D降低。 然后，与此同时， 放宽对磷的限制，我们将口服1，25- （OH）2D 3，其量和时间表维持1，25-（OH）2D 接近正常的平均值，并希望防止或减轻 iPTH升高。 如果是，将停止口服1，25-（OH）2D 3 在磷限制的实验放松期间， 因此我们预计iPTH会迅速增加。 我们将 确定是否：口服1，25-（OH）2D 3可以，通过 诱导接近正常的血浆浓度，逆转 甲状旁腺功能亢进而不限制膳食磷。 在 我们将通过MRI确定成人患者的值是否降低 1，25-（OH）2D的降低反映了1，25-（OH）2D的生产速率（PR）的降低。 （OH）2D或代谢清除率增加， 使用氚化1，25-（OH）2D的平衡注入技术。 在 尿毒症狗，我们将确定是否以前 证实了由以下因素引起的甲状旁腺功能亢进的逆转： 磷限制取决于1，25（OH）2D的增加。 通过 研究对象为正常男性，原发性甲状旁腺功能亢进患者， 特发性高钙尿症（“吸收性”）、骨质疏松症和正常 老年受试者，我们将确定膳食P是否重要 影响早晨空腹后的血清（P）值， 介导PR和1，25- （OH）2D。

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.