Pathogenesis of Calcium Nephrolithiasis

特发性钙结石(ICSF)有乳头状钙化：间质斑块或导管堵塞 (DP)，这可能会锚定石块生长。草酸钙(CaOx)结石与斑块、磷灰石(AP)结石相关 与DP一起。肾钙重吸收减少(RCA)是特发性高钙尿症(IH)的特征； 减少的RCA促进斑块和DP，以及结石，是PPG的一个主题。在项目2中，乳头状结构 在内窥镜结石手术中，将使用分级量表(PGS)来量化斑块和DP，并选择 ICSF和IH作为项目1和3的主题，因此生理学(项目1)和组织研究(项目3)将 在类似的ICSF上进行，选择斑块或DP得分较高的患者。PGS的关联能力 有结石形成的临床和组织病理学特征，以及有结石复发风险的患者将在 目标为2.1和2.5。儿童结石患者的乳头外观是否与成人相似，将在 目标2.2。AIMS 1.1a和3.1a-b将测试斑块是否由近端小管RCA减少引起。动物 模型表明炎症介质或活性氧物种在结石形成中起作用，我们 将在有斑块或DP的ICSF的尿液(AIM 1.3)和组织(3.2.1a-c，3.2.2，3.3a-b)中进行检测。DP是否可以 通过炎性“场效应”传播将在AIM 3.3c中进行测试。我们预测DP将与案例相关联 尿磷过饱和(目标1.1b)，结石中存在AP(目标2.3)，以及肾脏 减损(目标2.4)。目标2.6将探讨DP引起的炎症导致疼痛的可能性。我们 将比较两种常见的结石治疗方法，低钠饮食加或不加柠檬酸盐对节段性RCA的影响 在对照组和ICSF中，使用内源性锂清除和尿液外体标志物来研究对两者的影响 近端(Aim 1.2)和远端(Aim 1.4)肾单位RCA，以及对夜间尿钙的影响(Aim 1.5)，以及 尿SS和亚稳上限(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).