DISORDERED VITAMIN D METABOLISM IN RENAL INSUFFICIENCY

在儿童、成人患者和狗中，我们将试图确定是否 引起甲状旁腺素升高的低钙血症的发生 中重度肾功能不全严重依赖于 1，25-二羟基维生素kD（1，25-（OH）2Dp）的血浆浓度降低 它损害肠道对钙的吸收和骨吸收， 一种可逆的无机磷酸盐（Pi）介导的抑制， 25-OH-维生素D-1 α-羟化酶，在不增加血清 磷的浓度。 为了验证这一假设，我们计划限制 儿童、成人患者和中度 肾功能不全 当磷在成人患者中被限制时， 我们将确定它们是否影响了儿童， 1，25-（OH）2Dp降至正常值，并将其血清降至正常 免疫反应性甲状旁腺激素（iPTH）的浓度。 当 磷限制实验放宽6天，我们将首先 确定iPTH可预测增加的时间进程， 减少1，25-（OH）2Dp。 然后，与此同时， 磷限制，然后我们将口服1，25-（OH）2D 3 保持1，25-（OH）2Dp接近正常值的量和时间表 并期望防止或减弱iPTH的增加。 如果是这样， 1，25-（OH）2D 3将在磷松弛的第7天停止 限制，因此我们预计iPTH将迅速增加。 我们将 确定：口服1，25-（OH）2D 3是否可以通过诱导 接近正常的血浆浓度，逆转甲状旁腺功能亢进， 限制膳食磷;碱疗法，维持纠正 酸中毒使1，25-（OH）2D增加至正常值。 成人患者中 MRI和未校正的RTA，我们将确定是否降低了 1，25-（OH）2D反映了1，25-（OH）2D或 通过采用平衡输注增加代谢清除率 技术和单次推注技术，这两种技术都需要 氚化1，25-（OH）2D。 在尿毒症犬中，我们将确定 先前证明逆转高甲状旁腺激素诱导的四个 磷限制的天数取决于1，25-（OH）2Dp的增加。 当血浆中的1，25-（OH）2D浓度升高时， 磷浓度降低，通过静脉给药 马来酸，已被证明会损害肾脏产生 1，25-（OH）2D 3在大鼠和鸡中。

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.