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

产品说明：新生儿的尿路疾病可导致婴儿死亡、肾衰竭，而幸存者则会导致成年后的慢性肾病（CKD）和早期心脏病。在西半球，尽管有纳塔尔孕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病病例的大多数，占这部分人口保健支出的24%。在第三世界国家，没有先进的产妇护理和成像模式，这些条件导致婴儿死亡。这就需要国际社会协调和整合该地区的努力，包括印度，以便早期筛查CKD。大多数这些疾病不会引起症状，因此是无声的杀手，不会被发现。目前的常规尿液检测不够敏感，无法发现这些情况。通过低成本的诊断，这些严重的条件下，护理点的筛查诊断测试在此补助金提出的治疗，可以导致治愈大多数新生儿和婴儿先天性泌尿道疾病。这些疾病的严重程度各不相同，如果不及时诊断或治疗，可能会进行性发展，导致死亡和发病。早期发现和治疗已在试点研究中显示，以减轻慢性肾脏和心脏病的负担，在青少年和成年人出生与这些条件。根据已知的发病率，预计通过这种诊断测试的早期检测可能导致成年期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，该研讨会进而促成了PAR-11-044。 在过去的5年里，我们发现了先天性梗阻性尿路病的尿生物标志物，主要集中在人类肾盂输尿管连接部梗阻（UPJO）。使用基于质谱（MS）的蛋白质组学方法，我们已经确定了婴儿UPJO的生物标志物。由于先进的MS技术不适合常规临床使用，我们建议将这种复杂的技术转化为易于使用的多重蛋白质阵列，用于即时护理应用。拟议的诊断筛查工具包将很简单，可由中级供应商操作。我们的首要假设是，可以开发一种多重尿液检测（试纸）来鉴定先天性梗阻性尿路病中多达六种候选蛋白质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精确地从排泄的尿液混合物中捕获生物标志物。目的2：将通过基于MS的定量验证这些多重尿液检测结果 在新生儿和婴儿中的测定。 拟议研究的潜在临床影响是实质性的。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，以促进早期和即时检测未知的无症状梗阻性肾病，并可能挽救许多生命。

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.