Early Validation of Urinary Biomarkers of Renal Obstruction

肾梗阻尿液生物标志物的早期验证

• 批准号: 10019129
• 负责人: Richard Sang-yong Lee
• 金额: $ 10万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019129
• 关键词: Binding Proteins; Biological Markers; Calmodulin; Child; Clinical; Cohort Studies; Data; Decision Making; Development; Diagnostic; Diagnostic radiologic examination; Drainage procedure; Early Diagnosis; Elastin; Exhibits; Extracellular Matrix; Family; Funding; Gelatinase A; Goals; HSPB1 gene; Health; Human; Hydronephrosis; Image; Individual; Intervention; Kidney; LCN2 gene; Lead; Matrilysin; Matrix Metalloproteinases; Methodology; Monitor; Nitric Oxide; Nitrogen Oxides; Obstruction; Operative Surgical Procedures; Patients; Performance; Population; Production; Proteins; Reaction; Reactive Oxygen Species; Regulation; Renal function; Risk; S100P gene; Sampling; Signal Transduction; Stratification; Stress; Ultrasonography; Uncertainty; Ureteropelvic junction obstruction; Urine; Validation; biomarker performance; biomarker validation; candidate marker; candidate validation; clinical application; clinically significant; cohort; experimental study; extracellular; follow-up; imaging modality; improved; kidney dysfunction; novel; prenatal; prevent; protein profiling; renal damage; response; tool; urinary

Up to 2-­5% of all prenatal ultrasounds identify hydronephrosis. Ureteropelvic junction obstruction (UPJO) typically manifests with hydronephrosis, but not all patients with hydronephrosis have clinically significant obstruction, and many spontaneously resolve. Patients typically undergo extensive serial invasive imaging to identify which children require surgical intervention, as renal obstruction can lead to abnormal renal maturation or loss of kidney function. None of these current imaging methods are predictive. Without doubt, development of a stratifying biomarker capable of identifying children with hydronephrosis who are at-­ risk for renal damage is the most pressing clinical need, since early diagnosis and surgical intervention can prevent progressive renal damage, and better stratification would reduce invasive imaging. Our initial funding period has produced a “best” panel of 34 non-­invasive urinary biomarkers that have the ability to identify children with hydronephrosis who have clinical parameters consistent with renal dysfunction. Moreover, these markers improved after UPJO correction demonstrating their significant potential to be used serially during longitudinal observation of hydronephrosis. Functional assessment of the novel putative biomarkers as a non-­invasive assessment of stress-­related damage at the sub-­cellular level demonstrated a simultaneous regulation of Ca2+ signaling and production of nitrogen oxide (NO) with previously-­observed response to reactive oxygen species (ROS) during renal damage, as well as modulators of matrix metalloproteinases related to extracellular matrix remodeling (ECM). From this data, we hypothesize that these biomarkers will identify patients with hydronephrosis at-­risk for renal damage and will function as early markers of ongoing renal dysfunction prior to clinical radiographic changes. We predict that these non-­invasive biomarkers in combination with ultrasound could become the new paradigm for indicating when additional imaging or surgical intervention is needed. We will challenge this hypothesis with the following specific aims: 1): Validate the identified candidate biomarkers in a new study cohort of UPJO patients to distinguish at-­risk patients with hydronephrosis. 2) Determine and validate which candidate markers can predict renal dysfunction in a longitudinal observation cohort. This proposal will rigorously validate urinary biomarkers that have the potential to substantially improve the management of a very large population of children with hydronephrosis. These novel studies will be the first state-­of-­the-­art validation of the candidate markers as a UPJO diagnostic tool. These highly translational experiments are of direct relevance to human health, as the findings may develop a new clinical paradigm that has the ultimate potential of decreasing invasive imaging and improve surgical decision making.

高达 2-5% 的产前超声检查可发现肾积水。肾盂输尿管连接部梗阻 (UPJO) 通常表现为肾积水，但并非所有肾积水患者都有临床意义 阻塞，许多会自行解决。患者通常会接受广泛的连续侵入性成像以 确定哪些儿童需要手术干预，因为肾梗阻可能导致肾脏成熟异常 或肾功能丧失。目前的这些成像方法都不是预测性的。毫无疑问， 开发一种分层生物标志物，能够识别患有肾积水的儿童： 肾损伤的风险是最紧迫的临床需求，因为早期诊断和手术干预可以 防止进行性肾损伤，更好的分层将减少侵入性成像。 我们最初的资助期已经产生了一个由 34 种非侵入性尿液生物标志物组成的“最佳”小组，它们具有 识别临床参数与肾功能不全一致的肾积水儿童。 此外，这些标记在 UPJO 校正后得到改善，证明了它们的巨大应用潜力 在肾积水的纵向观察过程中连续进行。新假设的功能评估 生物标志物作为亚细胞水平上应激相关损伤的非侵入性评估表明 与之前观察到的同时调节 Ca2+ 信号传导和氮氧化物 (NO) 的产生 肾损伤期间对活性氧 (ROS) 的反应以及基质调节剂 与细胞外基质重塑（ECM）相关的金属蛋白酶。根据这些数据，我们假设这些 生物标志物将识别有肾损伤风险的肾积水患者，并将作为早期标志物 临床放射学变化之前持续的肾功能障碍。我们预测这些非侵入性 生物标志物与超声波相结合可能成为指示何时需要额外补充的新范例 需要影像学或手术干预。我们将通过以下具体目标来挑战这一假设：1）： 在新的 UPJO 患者研究队列中验证已确定的候选生物标志物，以区分高危患者 患有肾积水。 2) 确定并验证哪些候选标志物可以预测肾功能不全 纵向观察队列。 该提案将严格验证尿液生物标志物，这些标志物有可能大幅改善 管理大量肾积水儿童。这些新颖的研究将是第一个 对候选标记物作为 UPJO 诊断工具进行最先进的验证。这些高度转化的 实验与人类健康直接相关，因为研究结果可能会开发出一种新的临床范式 具有减少侵入性成像并改善手术决策的最终潜力。