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.

抽象的我们目前针对尿路感染（UTI）的床头测试不够准确。最好的测试对于UTI，白细胞酯酶（LE）测试的灵敏度仅为79％，这意味着21％的儿童患有A 错过了真正的UTI，使它们面临着永久性肾脏疤痕的风险。 LE的87％特异性测试意味着，没有UTI的人中有13％将被错误诊断为具有UTI并接受抗菌剂治疗。根据开发对UTI诊断更敏感和更具体的测试，这是我们的第一个目标是一个重要的贡献。我们将连续3334次收集尿液标本假定UTI的1个月至3岁的儿童，在此较大的案例和对照样本中人群，我们将执行转录组学（mRNA）和多重炎症蛋白分析以鉴定将UTI儿童与没有UTI的高热儿童区分开的尿道标记。有希望的标记将是在从第二个地点的3334名儿童中选择的样本中进行了验证。当前诊所的第二个限制 UTI的方法是由于缺乏可靠的标记来区分膀胱感染儿童与肾脏感染的儿童（肾盂肾炎）。因为吡咯肾上腺炎的准确标记尚未鉴定出，所有有UTI的热火儿童通常都被分配为肾上腺炎（即用抗生素治疗即使只有大约40％的肾上腺炎，也要进行10天的肾脏超声检查。到确定肾上腺炎的准确标记，这是我们的第二个目标，我们将招募100名热火儿童对尿液样品的UTI并进行转录组和多重炎症蛋白分析。使用TC99M-二甲状腺素核酸（DMSA）扫描将确认肾盂肾炎。我们将验证在第二个地点的100名儿童的独立样本中有希望的标记。 uti的诊断是专门的除大肠杆菌以外的细菌引起的感染儿童中挑战。根据以下内容，我们的第三个目标将开发儿童诊断UTI的测试。可以区分我们的研究的功能包括（1）连续的高温受试者的注册（这将使偏见最小化）；（2）将导管插入到收集所有尿液样本（这将最大程度地减少错误分类）；（3）及时处理尿液样品，（4）使用一种新的方法来组装少量尿液中的高质量RNA库，（5）选择培训和验证的不同站点。拟议项目的结果有望（1）轻松确定测量可用于准确诊断有和没有大肠杆菌儿童的尿路运动的尿蛋白感染，（2）开发用于UTI和肾上腺炎的RNA签名，可以用作黄金标准未来的研究以及（3）建立一个大型标本库，用于未来的研究。