Optimizing Kidney Stone Management Using Metallomics and Metabolomics

 描述(申请人提供)：肾结石影响了近10%的美国人口，每年给美国医疗保健系统增加50亿美元的经济负担。在尿路结石的提取方面已经取得了长足的进步，但在了解或预防结石的发病机制方面进展甚微。虽然我们将患者的结石和尿液送去进行化学分析，但结果通常对临床决策几乎没有影响。技术 对于石头的分析没有进步，仍然是初级的、不可靠的和不可重现的。此外，传统的24小时尿检不能准确预测未来的结石事件，因此在预防结石复发方面作用有限。最常见的肾结石(~85%)是钙基结石，通常由草酸钙和/或磷酸钙组成。监测尿钙可能是有用的，但不能提供完整的风险评估，为了改变全身钙稳态而改变钙摄入量对结石形成没有重大影响。需要新的肾结石生物标志物来改善肾结石的临床治疗。我们的良性泌尿外科跨学科研究发展中心最近使用果蝇黑腹果蝇结石形成模型表明，除钙以外的金属，包括锌和锶，在肾结石中扮演着令人惊讶的重要角色。例如，简单地增加饮食中的锌会强烈促进结石的形成，而螯合锌或抑制锌转运蛋白则会显著减少结石的数量。我们为该中心重新提供资金的建议旨在将这些发现转化为人类肾结石疾病，重点是确认重金属在人类患者队列中形成结石的重要性，并展示对尿液和结石样本进行全面的金属组学和靶向代谢组学分析对预测症状性结石发作的价值。我们将在加州大学旧金山分校的泌尿系结石诊所跟踪观察高尿酸尿症和/或低柠檬酸尿症的钙基结石患者。结石和尿样将在我们的分析核心设施的一个广泛的金属组学和代谢组学小组中收集和分析。来自人体结石和尿液的金属组学和代谢组学研究的综合结果将使我们能够建立新的诊断和治疗算法模型，以增强或取代目前实践中已有35年历史的测试方法。我们的目标是找出 金属和代谢物生物标记物的最佳组合，以揭示尿路结石病理生理学的新方面，并开发实用的诊断和治疗工具。这些方法将为广大泌尿外科社区创造急需的现代资源，并将为开展针对复发性肾结石患者的大规模干预研究提供必要的科学基础。

 DESCRIPTION (provided by applicant): Kidney stone disease affects nearly 10% of the US population and annually adds $5 billion in financial burden to the US healthcare system. Great strides have been made in the extraction of urinary stones, yet little progress has been made in understanding or preventing stone pathogenesis. While we send patient stones and urine for chemical analysis, the results typically have little impact on clinical decision-making. Techniques for stone analysis have not advanced and remain rudimentary, unreliable, and unreproducible. Moreover, traditional 24-hour urine testing does not correctly predict future stone events and thus has limited utility in preventing stone recurrence. The most common (~85%) of kidney stones are calcium-based stones, usually composed of calcium oxalate and/or calcium phosphate. Monitoring urinary calcium can be useful, but does not provide a complete assessment of risk, and modifying calcium intake in order to change whole body calcium homeostasis does not had a significant impact on stone formation. New biomarkers of kidney stone disease are needed to improve the clinical management of kidney stone disease. Our Developmental Center for Interdisciplinary Research in Benign Urology has recently shown that metals other than calcium, including zinc and strontium, play a surprisingly important role in nephrolithiasis, using a Drosophila melanogaster model of stone formation. For example, simply increasing dietary zinc strongly promotes stone formation while chelating zinc or inhibiting zinc transporters dramatically reduces the number of stones. Our proposal to renew funding for the Center aims to translate these findings to human kidney stone disease by focusing on confirming the importance of heavy metals in stone formation in a human cohort of patients and demonstrating the value of comprehensive metallomic and targeted metabolomics analysis of urine and stone samples for predicting symptomatic stone episodes. We will follow a homogenous group of calcium-based stone formers with hyperuricosuria and/or hypocitraturia in our urinary stone clinic at the University of California San Francisco. Stone and urine samples will be collected and analyzed for a broad metallomic and metabolomics panel at our Analytic Core Facility. The combined results of both the metallomic and metabolomic findings from human stones and urine will then allow us to model new diagnostic and therapeutic algorithms to augment or replace the 35-year-old testing method currently in practice. Our goal is to identify the optimal composition of metal and metabolite biomarkers to reveal new aspects of urinary stone pathophysiology and to develop practical diagnostic and therapeutic tools. These methods will create a much-needed modern resource for broad urology community and will provide the necessary scientific foundation to launch a large intervention study in patients with recurrent kidney stone disease