Clinical Pathophysiology of Nephrolithiasis

肾结石的临床病理生理学

• 批准号: 8231162
• 负责人: ELAINE M WORCESTER
• 金额: $ 27.77万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231162
• 关键词: Achievement; Affect; Angiotensin II; Animal Experiments; Bicarbonates; Biopsy; Bone Diseases; Calcitriol; Calcium; Calcium Oxalate; Calculi; Chlorthalidone; Clinical; Clinical Research; Cyclic AMP; Data; Deposition; Diet; Diuresis; Dose; Drug Delivery Systems; Excretory function; Exhibits; Fasting; Fostering; Functional disorder; Furosemide; Gene Targeting; Glucagon; Hospitalization; Hour; Human; Inbred Strains Rats; Instruction; Insulin; Kidney; Kidney Calculi; Lead; Limb structure; Lithium; Location; Measurement; Measures; Minerals; Mus; Nephrolithiasis; Operative Surgical Procedures; Oxalates; Pathogenesis; Patients; Physiology; Plasma; Prevention; Protocols documentation; Recruitment Activity; Rectum; Recurrence; Renal tubule structure; Renin; Research; Role; Sampling; Serum; Signal Transduction; Site; Testing; Thiazide Diuretics; Thick; Time; Tissues; Translations; Urine; Water; Work; absorption; animal data; calcium phosphate; feeding; glucagon-like peptide 1; human disease; hypercalciuria; inorganic phosphate; interstitial; prevent; receptor; research study; thiazide

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.

项目Sumiviary（请参阅说明）： 我们先前的工作表明，具有特发性高钙尿液（IH）的钙（CA）石材（SF）的肾小管Ca可吸收降低，这是饭后最明显的。近端小管（PT）Ca的重吸收似乎在草酸盐SF（ICSF）中降低，但不能减少磷酸盐（CAP）SF（IPSF），这意味着在IPSF中必须影响其他小管位点。 ICSF和IPSF的肾脏沉积部位在肾脏沉积部位也​​有所不同 - 间隙斑块与小管塞。这些实验使用Gerneral临床研究中心方案来研究ICSF和IPSF异常CA重吸收的位点，而不是正常的（n）。我们假设ICSF中将增加TAL CA的重吸收，从而通过VAS洗涤来促进斑块。我们使用速度（毛皮）阻断厚的上升肢（TAL）传输来确认使用锂透明液（AIM 1.1A）发现的PT转运减少，并评估绝对的TAL CA重吸收（AIM 1.1B）。我们还预测，IPSF中TAL CA的重吸收会减少，并且还会导致TAL碳酸氢盐吸收降低，从而导致尿液pH和CAP SS增加，从而促进小管塞（AIM 1.1C）。我们测试了肾脏CA的几个潜在信号器，以吸收与CA运输的关系，寻找与时间解决方案中的转运变化以及信号器水平的回归以及ICSF，IPSF，IPSF和N之间的CA回归差异（AIM 1.2A，B）之间的差异（AIM 1.2A，B），以寻求潜在的药物靶标。噻嗪类（TZ）是预防Ca石材的主要治疗方法，降低了尿液Ca；动物实验表明，PT Ca通过TZ增加了重吸收。如果人类中TZ增加了PT的重吸收，则可以减少牙菌斑的形成和石材复发（AIM 1.3）。在许多Ca SF中，骨化三醇水平升高，在非高钙血症剂量的钙三醇中施用N到N可以再现IH的发现，包括无法在低Ca饮食中保存CA。我们将测试钙三醇是否可以降低IH（AIM 1.4）的PT Ca重吸收。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，因此可以将生理学研究的结果与组织病理学数据结合使用，以测试项目目标（PI-6），将CA转运到组织CA水平，矿物质沉积物，转运蛋白和受体和受体。