DISORDERED VITAMIN D METABOLISM IN RENAL INSUFFICIENCY

在儿童、成人患者和狗身上，我们将尝试确定 引起甲状旁腺功能亢进症的低钙血症的发病机制 中重度肾功能不全严重依赖于 降低1，25-二羟基维生素KD(1，25-(OH)2DP)的血浆浓度 这会损害肠道对钙的吸收和骨吸收，由 一种可逆的无机磷(PI)介导的抑制作用 25-OH-维生素D-La-羟基酶，无血清升高 磷的浓度。为了检验这一假设，我们计划限制 儿童、成人患者和患有中度疾病的狗的膳食磷 肾功能不全。当磷在成年患者中受到限制时， 我们将确定它们是否会影响儿童，增加他们的 1，25-(OH)2DP降至正常值，血清降至正常 免疫反应性甲状旁腺激素(IPTHs)浓度。什么时候 磷限制试验性放宽6天，我们将首先 确定iPTH和iPTH可预测增加的时间进程 1，25-(OH)2DP降低。然后，与这种放松相一致的是， 限制磷，然后我们将口服1，25-(OH)2D3在一个 保持1，25-(OH)2DP接近正常值的量和时间表 并期望防止或减缓iPTH的增加。如果是这样的话，口头上 1，25-(OH)2D3将在磷松弛的第七天停止 限制，因此我们预计iPTH将迅速增加。我们会 确定口服1，25-(OH)2D3是否可以，通过诱导 血浆浓度接近正常，逆转甲状旁腺功能亢进症 限制饮食中的磷；维持纠正的碱疗法 酸中毒使1，25-(OH)2D升高至正常值。在成年患者中， MRI与未校正的RTA，我们将确定是否减少的价值 1，25-(OH)2D反映了1，25-(OH)2D或 通过采用平衡输液提高代谢清除率 技术和单次注射技术，这两种技术都需要 1，25-(OH)2D。在尿毒症犬中，我们将确定是否 先前证实的4例甲状旁腺功能亢进症的逆转 限磷天数取决于1，25-(OH)2DP的增加。 1，25-(OH)2D的预期增加将被阻止，而血浆 通过静脉给药降低磷的浓度 顺丁烯二酸，它已被证明损害肾脏产生 1，25-(OH)2D3在大鼠和雏鸡体内。

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.