Pathogenesis of Calcium Nephrolithiasis

特发性钙（Ca）结石形成者（ICSF）有乳头状钙化：间质斑块或导管堵塞 (DP)这可能锚结石生长。草酸钙（CaOx）结石与斑块、磷灰石（AP）结石相关 关于DP肾钙重吸收（rCa）减少是特发性高钙尿症（IH）的特征; rCa降低促进斑块和DP以及结石，是PPG的主题。在项目2中， 分级量表（PGS）将用于量化内镜结石手术期间的斑块和DP，并选择 ICSF将IH作为项目1和3的主题，以便生理学（项目1）和组织研究（项目3）将 在相似的ICSF上进行，选择斑块或DP的高分。PGS的能力， 具有结石形成的临床和组织病理学特征，并具有结石复发的风险， 目标2.1和2.5。儿童结石患者的乳头状外观是否与成人相似，将在 目标2.2.目的1.1a和3.1a-b将测试斑块是否由近端小管中rCa降低引起。动物 模型提示炎症介质或活性氧在结石形成中起作用，我们 将在ICSF的尿液（目标1.3）和组织（3.2.1a-c、3.2.2、3.3a-b）中检测斑块或DP。DP能否 将在目标3.3c中测试通过炎性“场效应”传播。我们预测DP将与Ca 尿中磷酸盐过饱和（目标1.1b），结石中存在AP（目标2.3），肾 损害（目标2.4）。DP诱导的炎症引起疼痛的可能性将在目标2.6中探索。我们 将比较2种常见结石治疗（低钠饮食加或不加柠檬酸钾）对节段性rCa的影响 在对照组和ICSF中，使用内源性锂清除率和尿外泌体标记物研究对两者的影响 近端（目标1.2）和远端（目标1.4）肾单位rCa，以及对过夜尿Ca（目标1.5）和 尿SS和亚稳态上限（目标1.6）。

Idiopathic calcium (Ca) stone formers (ICSF) have papillary calcifications: interstitial plaque or ductal plugging (DP), which may anchor stone growth. Ca oxalate (CaOx) stones associate with plaque, apatite (AP) stones with DP. Decreased renal Ca reabsorption (rCa) is characteristic of idiopathic hypercalciuria (IH); how decreased rCa promotes plaque and DP, as well as stones, is a theme of the PPG. In Project 2 a papillary grading scale (PGS) will be used to quantify plaque and DP during endoscopic stone surgery, and to select ICSF with IH as subjects for Projects 1 and 3, so that physiology (Project 1) and tissue studies (Project 3) will be done on similar ICSF, chosen for high scores for either plaque or DP. The ability of the PGS to correlate with clinical and histopathologic features of stone formation, and with risk of stone recurrence will be tested in aims 2.1 and 2.5. Whether papillary appearance in pediatric stone formers is similar to adults will be tested in aim 2.2. Aims 1.1a and 3.1a-b will test whether plaque is caused by decreased rCa in proximal tubule. Animal models suggest that inflammatory mediators or reactive oxygen species play a role in stone formation, and we will test this in urine (aim 1.3) and tissue (3.2.1a-c, 3.2.2, 3.3a-b) of ICSF with plaque or DP. Whether DP can propagate via an inflammatory "field effect" will be tested in aim 3.3c. We predict DP will associate with Ca phosphate supersaturation in urine (aim 1.1b), with presence of AP in stones (aim 2.3), and with renal impairment (aim 2.4). The possibility that DP-induced inflammation causes pain will be explored in aim 2.6. We will compare the effects of 2 common stone treatments, low Na diet with or without Kcitrate, on segmental rCa in controls and ICSF, using endogenous lithium clearance and urine exosomal markers to study effects on both proximal (aim 1.2) and distal (aim 1.4) nephron rCa, as well as effects on overnight urine Ca (aim 1.5), and on urine SS and upper limit of metastability (aim 1.6).