DISORDERED VITAMIN D METABOLISM IN RENAL INSUFFICIENCY

在儿童、成人患者和狗身上，我们将寻求确定 中度甲状旁腺机能亢进症的发病机制 严重的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(P)介导的 25-OH-维生素D-1α-羟基酶的抑制 没有升高的血清磷浓度。为了测试 在这个假设下，我们计划限制儿童饮食中的磷， 成年患者和中度肾功能不全的狗。在……里面 P限制受影响的儿童我们将确定是否 早餐后血磷(P)显著低于正常对照组。 早晨的禁食状态。当P仅限于成年患者时， 我们将确定他们是否像受影响的儿童一样，增加 他们的1，25-(OH)2D恢复到正常值，并将他们的 甲状旁腺激素免疫反应性血清浓度 (IPTH)，以及1，25-(OH)2D的这种增加是否先于 IPTH的这种下降，并纠正了 释放甲状旁腺素。当P限制被实验性地放宽时 6天内，我们将确定可预见的增加的进程 IPTH，1，25-(OH)2D减少。然后，不约而同地 放宽P限制后，我们将口服1，25- (OH)2D3的量和时间表，保持1，25-(OH)2D 接近正常平均值，并希望防止或减弱 IPTH增加。如果是，将停止口服1，25-(OH)2D3 在实验性放松磷限制的过程中， 因此，我们预计iPTH将迅速增长。我们会 确定口服1，25-(OH)2D3是否可以，通过 诱导接近正常的血浆浓度，逆转 不限制饮食磷的甲状旁腺机能亢进症。在……里面 我们将对成年患者进行MRI检查，以确定是否降低了价值 反映了1，25-(OH)2D的产量(PR)下降了1，25- (OH)2D或通过采用以下方法提高代谢清除率 1，25-(OH)2D氚平衡输注技术。在……里面 尿毒症犬，我们将确定之前是否 甲状旁腺功能亢进症的逆转 磷的限制取决于1，25(OH)2D的增加。通过 研究正常男性，原发性甲状旁腺功能亢进症患者， 特发性高钙尿(“吸收”)、骨质疏松症和正常 老年受试者，我们将确定饮食P是否重要 影响清晨空腹后的血清(P)值，从而 调节PR和血浆1，25-羟色胺浓度的紊乱 (哦)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.