A novel urinary biomarker of diabetic nephropathy

糖尿病肾病的新型尿液生物标志物

• 批准号: 9192112
• 负责人: WENZHENG ZHANG
• 金额: $ 23.7万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192112
• 关键词: novel; urinary; biomarker; diabetic; nephropathy

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is characterized by increased urinary albumin excretion and declined renal function. Changes in albumin excretion are considered the hallmark of the onset or progression of DN. However, some diabetic patients have advanced changes in renal pathology and progressive decline in kidney function even though their urine albumin levels are in the normal range. This limits albumin excretion as an accurate surrogate marker for renal function decline. Although several urine-based proteins have emerged as potential markers of DN, none of them have been used clinically. Water channel AQP5 functions in the generation of saliva, tears, and pulmonary secretions, but is barely detectable in normal kidneys. We hypothesize that AQP5 is a novel urine marker of DN and can improve the prediction of DN progression. We have reported detectable AQP5 in the kidney biopsies from 17/17 patients with DN and 0/15 normal controls. We also have found AQP5 in kidney biopsies from 10/10 patients with chronic kidney disease of unknown cause. Moreover, our preliminary data show that urine AQP5 1) is significantly higher in DN than in DM and normal controls, and in DN stage V than in stage III; 2) correlates with serum creatinine, urine microalbumin, and multiple other known risk factors of DN; 3) improves the clinical models in distinguishing DN from normal controls and DM; and 5) has a high stability over prolonged frozen storage. Our preliminary study is limited due to exclusion of children and young adults, and a lack of analyses of daily variation of urine AQP5 and longitudinal samples. Hence, we propose to measure urine AQP5 in 3 first-morning void urine samples from each of 170 subjects. They are >6 years old and consist of normal controls and patients with either DM or DN at various stages. We will also measure AQP5 in a urine repository from a multinational clinical trial with >1000 DN patients. These patients have prospectively followed up for up to 2 years. We will focus on the 60 progressors and 60 carefully-matched non-progressors. Multiple logistic regression, ROC, ANOVA, and other statistical analyses will be performed. We expect that urine AQP5 will increase the sensitivity and specificity of clinical models in distinguishing DN from DM and normal controls and improve prediction of DN progression. Our study thus addresses important clinical and translational questions and are potentially of high clinical and public health impact. It is novel since neither AQP5 as a marker of any disease nor AQP5 urine test has never been reported. It may result in development of a new urine test that allows identification and close surveillance of individuals at risk, prediction of DN progression, and thu reduction of the medical costs. If successful, this project may lay a solid foundation of full-scal clinical studies with subjects including those in other clinical settings such as acute kidney injuy and chronic kidney disease of unknown etiology to determine the true broad clinical utility and the spectrum validity and specificity of AQP5 as a novel diagnostic and prognostic marker for DN.

描述（由申请人提供）：糖尿病肾病（DN）的特征是尿白蛋白排泄增加和肾功能下降。白蛋白排泄的变化被认为是DN发生或进展的标志。然而，一些糖尿病患者即使尿白蛋白水平在正常范围内，也会出现肾脏病理学的晚期变化和肾功能的进行性下降。这限制了白蛋白排泄作为肾功能下降的准确替代标志物。虽然几种尿蛋白已经成为DN的潜在标志物，但它们都没有在临床上使用。水通道AQP 5在唾液、眼泪和肺分泌物的产生中起作用，但在正常肾脏中几乎检测不到。我们推测AQP 5是一种新的糖尿病肾病尿液标志物，可以提高糖尿病肾病进展的预测。我们报道了17/17例DN患者和0/15例正常对照的肾活检中可检测到AQP 5。我们还在10/10的不明原因慢性肾病患者的肾活检中发现了AQP 5。此外，我们的初步数据显示：1）DN患者尿AQP 5水平显著高于DM和正常对照组，DN V期患者尿AQP 5水平显著高于III期患者; 2）与血清肌酐、尿微量白蛋白和多种其他已知的DN危险因素相关; 3）改善了区分DN与正常对照组和DM的临床模型; 5）在长期冷冻储存中具有较高的稳定性。我们的初步研究是有限的，由于排除了儿童和年轻人，并缺乏分析的尿液AQP 5和纵向样本的每日变化。因此，我们建议从170名受试者中的每一个中测量3个第一晨尿样品中的尿AQP 5。他们年龄>6岁，包括正常对照组和不同阶段的DM或DN患者。我们还将测量来自具有>1000名DN患者的多国临床试验的尿液储存库中的AQP 5。对这些患者进行了长达2年的前瞻性随访。我们将重点关注60名进展者和60名仔细匹配的非进展者。将进行多元逻辑回归、ROC、ANOVA和其他统计分析。我们期望尿AQP 5将增加临床模型区分DN与DM和正常对照的敏感性和特异性，并改善对DN进展的预测。因此，我们的研究解决了重要的临床和转化问题，并可能具有很高的临床和公共卫生影响。由于AQP 5作为任何疾病的标志物或AQP 5尿液检测从未报道，因此是新颖的。它可能会导致一种新的尿液测试的开发，可以识别和密切监测高危个体，预测DN进展，从而降低医疗费用。如果成功的话，该项目可能会奠定一个坚实的基础，全规模的临床研究的主题，包括在其他临床设置，如急性肾损伤和慢性肾脏疾病的病因不明，以确定真正的广泛的临床效用和光谱有效性和特异性的AQP 5作为一种新的诊断和预后指标DN。