VISUALIZATION AND PATHOPHYSIOLOGY OF RENAL STONE PRECURSOR LESIONS

项目总结(见说明)： 肾结石(NL)很常见，有症状的结石发作会导致巨大的疼痛、痛苦和经济成本。已经花费了大量的努力来定义增加尿液过饱和度(SS)的代谢异常，从而有利于结石的生长。然而，目前可用的减少尿SS的治疗方法并不完全有效。因此，需要对其他致病因素有新的认识，以提出新的预防策略。最近的研究强调了NL前体病变的重要性，包括Randall的斑块和远端小管腔内的塞子。古尔的初步数据表明， 所谓的“特发性”CaOx结石的子集也可能起源于管状堵塞。临床肾结石研究一直滞后，因为结石通过是许多早期事件的最终结果，而这一系列事件可能在表面上相似的患者之间有所不同。导致尿SS的因素(如钙排泄)显然很重要，但其他因素，如细胞对SS和晶体或蛋白质结晶抑制物的反应也有助于结石的形成。我们假设，研究结石发病机制的临床研究可能被(未知的)各种潜在的肾脏病理所混淆。因此，我们计划通过直接的内窥镜可视化来仔细地对肾结石前体病变进行表型。这些细心分型的患者将被用于开发成像算法，以非侵入性地表征结石成分和前驱病变，确定有斑块和无斑块患者的乳头组织的基因表达，并确定不同患者类型的尿液和结石微生物组。 具体目标是： 目的1准确定位特发性CaQx结石(n=220)、肠源性高草酸尿症(n=15)、原发性高草酸尿症(n=5)、尿酸结石(n=20)、帽状结石(n=30)、胱氨酸结石(n=5)和对照组(n=30)患者经皮肾镜取石术后肾结石的位置和前驱病变。 目标2：定义预测结石脆性的双能量CT算法 目的3：确定乳头尖部活检组织中最大和最小斑块和栓子的基因表达谱。 目的：研究不同类型结石患者尿液和肾结石的微生物群特征。 这些目标建立在我们的多学科小组在过去4年收集的初步数据基础上。

PROJECT SUMMARY (See instructions): Nephrolithiasis (NL) is common, and symptomatic stone episodes cause significant pain, suffering, and economic cost. Much effort has been expended to define metabolic abnormalities that increase urinary supersaturation (SS), and thereby favor stone growth. However, currently available treatments that reduce urinary SS are not completely effective. Therefore, new understanding of additional pathogenic factors is needed to suggest new preventative strategies. Recent studies highlight the importance of NL precursor lesions, including Randall's plaques and plugs within distal tubular lumens. Qur preliminary data suggest that a subset of so-called "idiopathic" CaOx stones may also begin from tubular plugs. Clinical kidney stone research has lagged because stone passage is the final result of many earlier events, and this series of events likely differs between apparently similar patients. Contributors to urinary SS (e.g. calcium excretion) are clearly important, but other factors such as cellular responses to SS and crystals or protein crystallization inhibitors also contribute to stone formation. We hypothesize that clinical studies to investigate stone pathogenesis have likely been confounded by the (unknown) variety of underlying renal pathologies. Therefore, we plan to carefully phenotype renal stone precursor lesions by direct endoscopic visualization. These carefully pheontyped patients will be used to develop imaging algorithms to noninvasively characterize stone composition and precursor lesions, to define the gene expression of papillary tissue of patients with and without plaque, and determine the urine and stone microbiome of diverse patient types. Specific Aims are: Aim 1 Accurately map kidney stone location and precursor lesions after percutaneous nephrolithotomy in defined groups of patients with idiopathic CaQx stones (n=220), enteric hyperoxaluria (n=15), primary hyperoxaluria (n=5); uric acid stones (n=20); CaP stones (n=30), cystine stones (n=5), and controls without stones (n=30) Aim 2: Define dual energy CT algorithms to predict stone fragility Aim 3: Determine the gene expression profile of papillary tip biopsies with maximal and minimal plaque and plugs. Aim 4: Characterize the microbiome of urine and kidney stones of patients with diverse types of stones. These aims build upon the preliminary data assembled by our multidisciplinary group over the last 4 years.