Biomarkers for Urinary Tract Infection and Pyelonephritis

尿路感染和肾盂肾炎的生物标志物

基本信息

批准号：
10619502
负责人：
Nader Shaikh
金额：
$ 54.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10619502
关键词：
Acute Cystitis Address Affect Age Antibiotics Bacteria Bedside Testings Biological Markers Biological Specimen Banks Bladder Catheterization Child Classification Clinical Clinical Trials Culture-independent methods Cystitis DMSA Development Diagnosis Enrollment Escherichia coli Escherichia coli Infections Exhibits Fever Future Gender Goals Growth Hour IL8 gene Image Immunoassay Incidence Infection Infective cystitis Inflammatory Interferons Interleukin-2 Interleukin-9 Kidney LCN2 gene Measures Medical center Messenger RNA Methods Modeling Neurogenic Bladder Organism Population Prevalence Protein Analysis Proteins Pyelonephritis RNA RNA library Reference Standards Research Personnel Risk Sampling Scanning Severities Site Specificity Specimen Subgroup Testing Time Training Ultrasonography United States Urinary tract infection Urine Validation Writing accurate diagnosis acute pyelonephritis aged antimicrobial bacterial resistance design diagnosis standard genetic signature indexing individualized medicine kidney infection leukocyte esterase neutrophil novel point of care testing predictive modeling renal scarring stem transcriptome sequencing transcriptomics treatment duration ultrasound urinary

项目摘要

ABSTRACT Our current bedside tests for urinary tract infections (UTI) are not sufficiently accurate. The best available test for UTI, the leukocyte esterase (LE) test, has a sensitivity of only 79%, meaning that 21% of children with a true UTI are missed, placing them at increased risk for permanent renal scarring. The 87% specificity of the LE test means that 13% of those without UTI will be incorrectly diagnosed as having UTI and receive antimicrobial treatment. Accordingly, development of more sensitive and specific tests for the diagnosis of UTI, which is our first aim, represents an important contribution. We will collect urine specimens from 3,334 consecutive febrile children aged 1 month to 3 years with presumed UTI and, in a sample of cases and controls from this larger population, we will perform transcriptomics (mRNA) and multiplex inflammatory protein analysis to identify urinary markers that distinguish children with UTI from febrile children without UTI. Promising markers will be validated in a sample selected from 3,334 children from a second site. A second limitation in the current clinical approach to UTI stems from the lack of reliable markers to distinguish children with bladder infection from children with kidney infection (pyelonephritis). Because accurate markers for pyelonephritis have not been identified, all febrile children with UTI are generally assumed to have pyelonephritis (i.e., treated with antibiotics for 10 days and undergo renal ultrasonography) even though approximately only 40% have pyelonephritis. To identify accurate markers for pyelonephritis, which is our second aim, we will enroll 100 febrile children with UTI and perform transcriptomics and multiplex inflammatory protein analysis on their urine samples. Pyelonephritis will be confirmed using Tc99m-dimercaptosuccinic acid (DMSA) scan. We will validate promising markers in an independent sample of 100 children from a second site. Diagnosis of UTI is especially challenging in children with infections caused by bacteria other than Escherichia coli. Accordingly, our third aim will be to develop tests for the diagnosis of UTI in these children. Features that will differentiate our study include (1) enrollment of consecutive febrile subjects (which will minimize bias);; (2) use of catheterization to collect all urine samples (which will minimize misclassification);; (3) timely processing of the urine samples, (4) use of a novel method of assembling high-quality RNA libraries from small amounts of urine, and (5) selection of different sites for training and validation. Results from the proposed project are expected to (1) identify easy to measure urinary proteins that can be used to accurately diagnose UTI in children with and without E. coli infection, (2) develop RNA signatures for UTI and pyelonephritis which can be used as a gold standard in future studies, and (3) establish a large specimen bank for use in future studies.

抽象的我们目前的尿路感染 (UTI) 床边测试不够准确。对于 UTI，白细胞酯酶 (LE) 测试的敏感性仅为 79%，这意味着 21% 的儿童患有尿路感染真正的 UTI 被遗漏，使他们面临永久性肾疤痕的风险增加 LE 的特异性为 87%。测试意味着 13% 没有尿路感染的人将被错误诊断为患有尿路感染并接受抗菌药物治疗因此，开发更敏感和更具体的测试来诊断尿路感染，这是我们的目标。第一个目标是一项重要贡献。我们将连续收集 3,334 名发烧患者的尿液样本。 1 个月至 3 岁的儿童，推测患有尿路感染，并且在病例和对照样本中，该样本更大。人群，我们将进行转录组学 (mRNA) 和多重炎症蛋白分析来识别尿液标记物可以区分患有尿路感染的儿童和没有尿路感染的发热儿童。在从第二个站点选取的 3,334 名儿童的样本中进行了验证。当前临床的第二个限制治疗尿路感染的方法源于缺乏可靠的标记物来区分患有膀胱感染的儿童患有肾脏感染（肾盂肾炎）的儿童。因为目前还没有准确的肾盂肾炎标记物。经鉴定，所有患有尿路感染的发热儿童通常被认为患有肾盂肾炎（即接受抗生素治疗） 10 天并接受肾脏超声检查），尽管大约只有 40% 患有肾盂肾炎。确定肾盂肾炎的准确标记物，这是我们的第二个目标，我们将招募 100 名发热儿童 UTI 并对他们的尿液样本进行转录组学和多重炎症蛋白分析。我们将使用 Tc99m-二巯基丁二酸 (DMSA) 扫描来确认肾盂肾炎。来自第二个地点的 100 名儿童的独立样本中的标记物尤其有前景。对患有大肠杆菌以外的细菌引起的感染的儿童具有挑战性。因此，这是我们的第三个目标。我们的目标是开发诊断这些儿童尿路感染的测试，这将使我们的研究与众不同。包括（1）连续发热受试者的注册（这将最大限度地减少偏差）；；（2）使用导管插入术收集所有尿液样本（这将最大限度地减少错误分类）；；（3）及时处理尿液样本，（4）使用一种从少量尿液中组装高质量 RNA 文库的新方法，以及 (5) 选择不同地点的培训和验证。拟议项目的结果预计 (1) 易于识别测量尿蛋白，可用于准确诊断有或没有大肠杆菌的儿童尿路感染感染，(2) 开发 UTI 和肾盂肾炎的 RNA 特征，可用作以下方面的黄金标准：未来的研究，以及（3）建立一个大型样本库以供未来的研究使用。