Identification of Urinary Biomarkers for Stent Associated Symptoms in Humans

(请保存在Word中，不要保存为PDF) 输尿管镜检查后放置输尿管支架以取出肾结石会导致严重的并发症，大多数留置支架的患者报告生活质量下降、疼痛和影响他们日常生活的尿路症状。开发新的治疗方法来改善输尿管支架引起的症状的一个关键障碍是缺乏对尿液分子如何影响输尿管镜检后的机制和患者体验的了解。 在这里，我们建立在我们最近的发现基础上，支架引起的输尿管平滑肌功能障碍、蠕动停止以及由此导致的肾积水是由牵张引起的输尿管炎症引起的。我们将利用我们的分析流程，确定前列腺素E2(PGE2)和1-甲基烟酰胺(1-MNA)作为支架引起的输尿管炎症变化和功能障碍的生物标志物。我们有一个跨学科的团队，通过结合使用分析化学、输尿管生理学和临床流行病学的专业知识，独特地准备发现和验证支架症状的尿液生物标志物。这项拟议的研究测试了中心假设，即留置输尿管支架在人类中引发类似的机制，至少PGE2和1-MNA是人类支架相关输尿管功能障碍和症状的尿液生物标志物。通过这样做，拟议的研究将确定可能成为新疗法预防支架症状的靶点的途径。在这项建议中，我们使用NIDDK支持的泌尿系结石疾病研究网络进行的这项研究中的484名青少年和成人参与者中的50人的数据和尿样来生成关键的初步数据，这些参与者接受了输尿管镜检并放置了输尿管支架，以加强对支架相关症状(支架)的了解。在目标1中，我们确定了PGE2和1-MNA与支架症状的关系。我们将评估术前尿液中这些假定的生物标志物与患者报告的疼痛强度、疼痛干扰和输尿管镜支架置入术后的尿路症状之间的关系。在目标2中，我们将使用我们的非定向分析方法来扩大尿液生物标记物的列表，以量化和识别输尿管梗阻和支架相关症状的未知生物标记物。这项拟议的工作提供了关键的初步数据，验证了人类支架相关输尿管炎症变化和功能障碍的已知和新的尿液生物标志物。一旦在较小的队列中得到验证，它们与支架相关疼痛和不适的关联可以在更大的患者队列中进一步验证，并纳入现有的支架并发症预测模型，以确定更有可能出现严重症状的患者。这将构成后续R01申请的基础。

(PLEASE KEEP IN WORD, DO NOT PDF) Ureteral stents placed after ureteroscopy to remove kidney stones cause significant morbidity, with most patients with an indwelling stent reporting impaired quality of life, pain, and urinary symptoms affecting their everyday life. A critical barrier to developing new treatments to improve symptoms caused by ureteral stents is a lack of understanding of how molecules in the urine contribute to mechanisms and patient experiences after ureteroscopy. Here, we build on our recent discoveries that stent-induced ureteral smooth muscle dysfunction, cessation of peristalsis, and resultant hydronephrosis are driven by stretch-induced inflammation of the ureter. We will leverage our analytical pipeline that identified prostaglandin E2 (PGE2) and 1-methylnicotinamide (1-MNA) as biomarkers for stent-induced ureteral inflammatory changes and dysfunction in pigs. We have an interdisciplinary team that is uniquely poised to discover and validate urinary biomarkers of stent symptoms by combining expertise in using analytic chemistry, ureteral physiology, and clinical epidemiology. The proposed research tests the central hypothesis that that indwelling ureteral stents trigger similar mechanisms in humans and that at least PGE2 and 1-MNA are urinary biomarkers for stent-associated ureteral dysfunction and symptoms in humans. In doing so, the proposed studies will identify pathways that could be targets for novel therapeutics to prevent stent symptoms. In this proposal, we generate key preliminary data using data and urine samples from 50 of the 484 adolescent and adult participants who underwent ureteroscopy with ureteral stent placement and enrolled in the Study to Enhance Understanding of sTent-associated Symptoms (STENTS) conducted by the NIDDK-supported Urinary Stone Disease Research Network. In Aim 1, we determine the association between PGE2 and 1-MNA and stent symptoms. We will evaluate the association between these putative biomarkers in pre-operative urine, and the course of patient-reported pain intensity, pain interference, and urinary symptoms after ureteroscopy with stent placement. In Aim 2, we will expand the list of urine biomarkers using our untargeted analytical approach to quantify and identify unknown biomarkers for ureteral obstruction and stent-associated symptoms. The proposed work provides key preliminary data validating known and new urinary biomarkers for stent-associated ureteral inflammatory changes and dysfunction in humans. Once validated in a smaller cohort, their association with stent-associated pain and discomfort can be further validated in a larger patient cohort and incorporated into existing predictive models for stent-complications to identify patients more likely to develop severe symptoms. This will form the basis of a subsequent R01 application.