Clinical Pathophysiology of Nephrolithiasis

项目SUMIVIARY(请参阅说明)： 我们以前的工作表明，钙(Ca)结石(SF)合并特发性高钙尿(IH)可降低肾小管钙重吸收，这在餐后最为明显。近端小管(PT)钙重吸收在草酸钙SF(ICSF)中减少，但在磷酸钙(CAP)SF(IPSF)中没有，这意味着IPSF中其他小管位置肯定受到影响。ICSF和IPSF在肾脏中矿物质沉积的位置也不同--间质斑块和小管塞。这些实验使用通用临床研究中心的方案来研究ICSF和IPSF与正常对照(N)的异常钙重吸收部位。我们假设ICSF的TAL-Ca重吸收增加，通过血管冲洗促进斑块的形成。我们使用呋塞米(Fur)阻断粗大的升支(TAL)转运，以确认使用锂盐清除剂发现的PT转运减少(目标1.1a)，并测量绝对TAL钙重吸收(目标1.1b)。我们还预测，IPSF的TAL钙重吸收减少，也导致TAL重碳酸盐吸收减少，导致尿液pH升高和头状SS促进小管堵塞(AIM 1.1c)。我们测试了几个潜在的肾钙重吸收信号与钙转运的关系，寻找与时间分辨方案中转运变化的不同步，以及ICSF、IPSF和N(目标1.2a，b)之间信号水平和钙重吸收的回归差异，以寻找潜在的药物靶点。噻嗪(TZ)是预防钙结石和降低尿钙的主要治疗方法；动物实验表明，TZ可增加PT钙的重吸收。如果TZ在人体内增加PT的重吸收，它可能会减少斑块的形成和结石的复发(目标1.3)。在许多CaSF中，骨化三醇水平升高，非高钙剂量的骨化三醇给N可以重现IH的结果，包括在低钙饮食中无法保存钙。我们将测试骨化三醇是否可以像在IH中看到的那样减少PT-Ca重吸收(目标1.4)。项目1中研究的所有SF都将在项目2和3中进行活检和组织研究，因此生理学研究的结果可以与组织病理学数据相结合来测试项目AIMS(PI-6)，该项目将组织钙水平、矿物质沉积、转运体和受体与钙转运联系起来。

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.