Crystal Interactions in Renal Stone Disease

描述(由申请人提供)：肾结石是一种严重的健康问题，与巨大的疼痛、痛苦和经济成本有关。到70岁时，5%至15%的人口将出现结石的症状发作，其中至少50%的人将复发结石疾病。特发性草酸钙结石占结石形成患者的大多数。人们普遍认为，特发性结石患者没有明显的解剖、代谢或生理异常。 特发性CaOx结石病似乎既需要尿液中钙和草酸的过饱和，也需要晚期收集管中的组织损伤以使晶体附着，从而启动结石的发展。受伤地点似乎高度局限于结石的位置。到目前为止，动物研究使用了戏剧性的高草酸条件，这可能限制了我们观察特发性CaOx结石患者慢性轻度高草酸尿引起的早期事件的能力。到目前为止，还没有动物研究探索慢性暴露于低水平草酸的潜在影响，就像在特发性结石患者中可能看到的那样。 这笔赠款的重点是将尿晶附着到受损的肾乳头状尖端尿路上皮，以及允许晶体附着的条件和事件。我们将研究长期暴露于低至轻度草酸水平，这可能与乳头状管或血管损伤有关。需要检验的假设是，CaOx晶体附着到晚收集管尿路上皮依赖于局部损伤，这种损伤可能起源于晚收集管或与小管晶体附着位置密切相关的血管系统。我们还假设，在特发性草酸钙结石患者中可以看到的慢性低水平草酸盐暴露可能足以导致这种损伤。这项拨款提案包含三个具体目标，以检验这一假设。 具体目标I：确定长期暴露于草酸水平是否不足以形成广泛的CaOx晶体，是否会导致正常肾小管生理的破坏，并引发与有效的尿路上皮晶体附着和结石形成相关的损伤。 具体目标II：确定有效的晶体附着所必需的小管损伤是否源于草酸引起的相关血管系统的变化。 具体目标三：确定与草酸相关的损伤导致有效的CaOx晶体附着和结石形成是否会因其他血管和小管损伤的存在而加剧，例如与高血压相关的损伤。

DESCRIPTION (provided by applicant): Kidney stone disease is a substantial health problem associated with significant pain, suffering, and economic costs. By the age of 70, 5% to 15% of the population will have a symptomatic episode of a stone and at least 50% of these individuals will have recurrent stone disease. Idiopathic calcium oxalate stone disease accounts for the majority of stone forming patients. It is generally accepted that idiopathic stone patients do not have dramatic anatomic, metabolic, or physiologic abnormalities. Idiopathic CaOx stone disease appears to require both supersaturation of the urine with respect to calcium and oxalate and tissue injury in the late collecting duct for crystals to attach, initiating stone development. The injury site appears to be highly localized to the site of the stone. Animal studies to date have used dramatic hyperoxaluric conditions that may have limited our ability to see the early events resulting from chronic mild hyperoxaluria as seen in idiopathic CaOx stone patients. No animal studies to date have explored the potential impact of chronic exposure of low levels of oxalate as might be seen in the idiopathic stone patients. This grant focuses on the attachment of urinary crystals to injured kidney papillary tip urothelium and the conditions and events that allow for crystal attachment. We will study long-term exposure of low to mild oxalate levels that might be associated with papillary tubular or vascular injury. The hypothesis to be tested is that CaOx crystal attachment to late collecting duct urothelium is dependent on localized injury that may originate in either the late collecting duct or in the vasculature intimately associated with the tubule crystal attachment site. We also hypothesize that chronic low levels of oxalate exposure as may be seen in idiopathic calcium oxalate stone patients may be sufficient to induce this injury. This grant proposal contains three Specific Aims to test this hypothesis. Specific Aim I: To determine if chronic exposure to oxalate levels insufficient for widespread CaOx crystal formation leads to the disruption of normal tubule physiology and the initiation of injury associated with effective urothelial crystal attachment and stone formation. Specific Aim II: To determine if tubule injury necessary for effective crystal attachment stems from oxalate-induced changes in the associated vasculature. Specific Aim III: To determine if oxalate-associated injury leading to effective CaOx crystal attachment and stone formation is exacerbated by the presence of other vascular and tubule injuries such as that associated with hypertension.