A rapid non-invasive urinary test for the detection of obstructive uropathy

描述：新生儿的尿路疾病可能会导致婴儿死亡、肾功能衰竭，而在存活的人中，会在成年后导致慢性肾脏疾病(CKD)和早期心脏病。在西半球，尽管有产前产妇护理和先进的成像技术，但尿路梗阻性疾病占终末期肾脏疾病的大多数，并占这部分人口医疗保健支出的24%。在第三世界国家，没有先进的产妇护理和成像手段，这些情况会导致婴儿死亡。这就需要国际社会协调和整合这一区域--包括印度--的努力，以便及早筛查慢性病。这些情况中的大多数不会引起症状，因此是沉默的杀手，不会被发现。目前的常规尿检不够敏感，无法发现这些情况。通过这笔赠款中建议的低成本、护理点筛查诊断测试来诊断这些严重疾病，然后进行治疗，可以治愈大多数患有先天性尿路疾病的新生儿和婴儿。这些疾病的严重程度各不相同，如果不加以诊断或治疗，可能会逐渐发展，并导致死亡和发病。初步研究表明，早期发现和治疗可以减轻患有这些疾病的青少年和成年人的慢性肾脏和心脏病负担。根据已知的发病率，预计这种诊断测试的早期检测可能会导致成年后CKD负担总体减少10%。这一目标在2008年印度海得拉巴研讨会上被明确确定为优先事项，这反过来又导致了PAR-11-044。在过去的5年里，我们发现了先天性梗阻性尿病的尿液生物标志物，主要集中在人类输尿管肾盂连接部梗阻(UPJO)。使用基于质谱仪(MS)的蛋白质组学方法，我们已经在婴儿中识别了UPJO的生物标志物。由于先进的MS技术不适合常规的临床使用，我们建议将这项复杂的技术转化为一种易于使用的多路复用蛋白质阵列，用于医疗保健应用。拟议的诊断筛查试剂盒将很简单，可能由中层提供者操作。我们的主要假设是，可以开发一种多重尿检(试纸)来识别先天性梗阻性尿路疾病中最多六个候选蛋白生物标志物的表达水平。目的1：将测试所提出的多重蛋白质阵列将选择性地和准确地捕获排尿混合物中的生物标志物。目标2：将检验这些多重尿检结果是否通过基于MS的量化来验证 新生儿和婴儿的化验。这项拟议研究的潜在临床影响是巨大的。我们的目标是开发一种易于使用、精确、可重复和准确的诊断工具，以促进对未知的静止性梗阻性肾脏疾病的早期和即时检测，并可能挽救许多人的生命。

DESCRIPTION: Diseases of the urinary tract in newborns can lead to infant death, kidney failure, and in those who survive, to chronic kidney disease (CKD) and early heart disease in adulthood. In the western hemisphere, despite the availability of pre natal maternal care and advanced imaging, obstructive diseases of the urinary tract account for the majority of cases of end stage kidney disease and consume 24% of health care expenditure in this segment of population. In third world countries, where sophisticated maternal care and imaging modalities are not available, these conditions lead to infant mortality. This has necessitated an internationa coordination and integration of efforts in this region- including India for the purpose of early screening for CKD. Most of these conditions do not cause symptoms and therefore are silent killers and go undetected. Current routine urinary testing is not sensitive enough to uncover these conditions. The diagnosis of these serious conditions through the low cost, point of care screening diagnostic test proposed in this grant followed by treatment, can lead to cure in a majority of newborns and infants with congenital diseases of the urinary tract. These conditions have a variable degree of severity and if left undiagnosed or untreated can be progressive and lead to mortality and morbidity. Early detection and treatment has been shown in pilot studies to lessen the burden of chronic kidney and heart disease in adolescents and adults born with these conditions. Based on known incidences, it is anticipated that early detection by this diagnostic test may result in a 10% overall reduction of the CKD burden in adulthood. This objective was clearly identified as a priority at the 2008 Hyderabad workshop, India, which in turn has led to PAR-11-044. For the past 5 years, we discovered urinary biomarkers of congenital obstructive uropathy focusing on human ureteropelvic junction obstruction (UPJO). Using a mass spectrometry (MS)-based proteomics approach we have identified biomarkers of UPJO in infants. Since the advanced MS technology is not suited for routine clinical use, we are proposing to translate this sophisticated technology to an easy to use multiplexed protein array for a point-of-care application. The proposed diagnostic screening kit will be simple and may be operated by mid-level providers. Our overarching hypothesis is that a multiplexed urinary test (dipstick) can be developed to identify the expression levels of up to six candidate protein biomarkers in congenital obstructive uropathy. Aim 1: will test that the proposed multiplexed protein array will selectively and precisely capture the biomarkers from a voided urine mixture. Aim 2: will test that these multiplex urinary test results are validated by MS-based quantification assays in newborns and infants. The potential clinical impact of the proposed study is substantial. Our goal is to develop a point of care, easy to use, precise, reproducible and accurate diagnostic tool to facilitate early and instantaneous detection of unknown silent obstructive kidney disease and may save many lives.