Clinical Pathophysiology of Nephrolithiasis

项目概要（见说明）： 我们先前的工作已经表明，钙（Ca）结石形成者（SF）与特发性高钙尿症（IH）有减少肾小管钙重吸收，这是最显着的饭后。近端小管（PT）钙重吸收似乎在草酸钙SF（ICSF）中减少，但磷酸钙（CaP）SF（IPSF）未减少，这意味着IPSF中其他小管部位必须受到影响。ICSF和IPSF在肾脏中的矿物质沉积部位也不同-间质斑块与小管栓塞。这些实验使用通用临床研究中心的方案来研究ICSF和IPSF中与正常人（N）相比的异常钙重吸收的部位。我们假设ICSF中TAL Ca重吸收增加，通过血管冲洗促进斑块形成。我们使用呋塞米（Fur）阻断粗升支（TAL）转运，以证实使用锂清除发现的PT转运减少（Aim 1.1a），并测量绝对TAL Ca重吸收（Aim 1.1b）。我们还预测IPSF中TAL Ca重吸收减少，并且还导致TAL碳酸氢盐吸收减少，导致尿液pH和CaP SS增加，从而促进小管堵塞（目的1.1c）。我们测试了几种肾钙重吸收的潜在信号与钙转运的关系，在时间分辨方案中寻找与转运变化的不同步性，以及ICSF，IPSF和N之间信号水平和钙重吸收回归的差异（目的1.2a，b），寻找潜在的药物靶点。噻嗪（TZ）是预防钙结石的主要治疗药物，可降低尿钙;动物实验表明，TZ可增加PT钙重吸收。如果TZ增加了人体PT重吸收，则可能减少斑块形成以及结石复发（目的1.3）。在许多Ca SF中骨化三醇水平升高，以非高钙剂量给予N骨化三醇可重现IH的发现，包括在低钙饮食中无法保存Ca。我们将测试骨化三醇是否可以减少IH中所见的PT Ca重吸收（目标1.4）。项目1中研究的所有SF将在项目2和3中进行活检和组织研究，因此生理学研究结果可与组织病理学数据相结合，以测试项目目标（PI-6），将钙转运与组织钙水平、矿物质沉积、转运蛋白和受体相关。

PROJECT SUMIVIARY (See instructions): Our prior work has shown that calcium (Ca) stone formers (SF) with idiopathic hypercalciuria (IH) have decreased renal tubule Ca reabsorption which is most marked after meals. Proximal tubule (PT) Ca reabsorption appears to be decreased in Ca oxalate SF (ICSF) but not Ca phosphate (CaP) SF (IPSF), meaning that other tubule sites must be affected in IPSF. ICSF and IPSF also differ in the site of mineral deposition in their kidneys - interstitial plaque vs. tubule plugs. These experiments use a Gerneral Clinical Research Center protocol to study the sites of abnormal Ca reabsorption in ICSF and IPSF compared with normals (N). We hypothesize that TAL Ca reabsorption will be increased in ICSF, fostering plaque via vas wash-down. We use furosemide (Fur) blockade of thick ascending limb (TAL) transport to confirm the decreased PT transport discovered using lithium clearnace (Aim 1.1a), and to gauge absolute TAL Ca reabsorption (Aim 1.1b). We also predict that TAL Ca reabsorption is decreased in IPSF, and also results in decreased TAL bicarbonate absorption, resulting in increased urine pH and CaP SS which promotes tubule plugging (Aim 1.1c). We test several potential signallers of renal Ca reabsorption for a relationship to Ca transport, looking for dyssynchrony with transport changes in a time resolved protocol, and differences in regression of signaller levels and Ca reabsorption between ICSF, IPSF, and N (Aim 1.2a,b), seeking potential drug targets. Thiazide (TZ) is a main treatment for Ca stone prevention and lowers urine Ca; animal experiments suggest that PT Ca reabsorption is increased with TZ. If PT reabsorption is increased by TZ in humans, it may reduce plaque formation as well as stone recurrence (Aim 1.3). Calcitriol levels are elevated in many Ca SF, and administration of calcitriol to N in non-hypercalcemic doses can reproduce findings of IH, including inability to conserve Ca on a low Ca diet. We will test whether calcitriol can decrease PT Ca reabsorption as seen in IH (Aim 1.4). All SF studied in Project 1 will have biopsy and tissue studies in Projects 2 and 3, so results of physiology studies can be combined with histopathologic data to test project aims (PI-6) relating Ca transport to tissue Ca levels, mineral deposits, transporters and receptors.