Biomarkers for Acute Pyelonephrititis in Children

描述(申请人提供)：尿路感染(UTI)，每年影响美国3%的幼儿，是儿童最常见的严重细菌感染。1在一些尿路感染的儿童中，感染局限于膀胱(膀胱炎)。在其他病例中，细菌成功地从膀胱上升到肾脏，导致急性肾盂肾炎(APN)。APN是儿童获得性肾瘢痕形成的主要原因之一。由于不可能在临床上区分膀胱炎儿童和APN儿童，而且APN的标志物尚未确定，目前所有尿路感染儿童都被当作APN儿童进行治疗。目前的指南建议所有患有尿路感染的幼儿接受长程抗生素治疗(7-14天)，并接受后续的成像测试。这导致了对尿路感染儿童过度使用影像和抗菌药。我们提出了一种替代策略，即在发病时测量血液和/或尿液生物标记物，以将儿童分成不同的病理生理亚组(膀胱炎与APN)。这将使临床医生能够个体化治疗尿路感染，并减少不必要的抗菌药和成像测试的使用。作为NIAID资助的一项为期7年的研究的一部分，该研究旨在比较短程抗菌药对尿路感染儿童的疗效，我们将招募迄今规模最大的尿路感染儿童样本之一(目标n=746)。通过在陈述时收集更多的血液和尿液样本，以及通过进行早期DMSA肾脏扫描(以识别APN)，我们将能够以最低的额外成本识别准确区分APN儿童和膀胱炎儿童的生物标志物。我们将采取循序渐进的方法来实现这些目标。首先，我们将确定5种先前识别的蛋白(尿IL-6、尿IL-8、尿IL-12、尿巨噬细胞抑制因子和血清降钙素原)在鉴别APN和膀胱炎中的准确性。下一步，通过检测APN和膀胱炎患者白细胞中差异表达的基因，我们将开发一种基于RNA的图谱，可以准确地区分APN和膀胱炎。最后，我们将使用临床变量、以前研究的蛋白质和基于RNA的图谱来构建预测规则，以区分APN儿童和膀胱炎儿童。这项辅助研究中开发的预测规则将提供一种根据APN的存在或不存在对分析进行分层的准确方法，从而显著增强母体研究。 公共卫生相关性：这笔赠款中开发的血液和尿液测试将使医生能够区分患有肾脏感染的儿童和患有膀胱感染的儿童。通过这种方式，患有膀胱炎的儿童不会有永久性肾脏损伤的风险，他们可以使用更少的抗生素治疗，而且不需要执行目前推荐的任何成像测试。这一方法可以显著减少尿路感染儿童的抗生素使用和辐射暴露。

DESCRIPTION (provided by applicant): Urinary tract infection (UTI), which affects 3% of young children in the United States annually, is the most common serious bacterial infection in children.1 In some children with UTI, infection is localized to the bladder (cystitis). In others, bacteria successfully ascend from the bladder to the kidney causing acute pyelonephritis (APN). APN is one of the principal causes of acquired renal scarring in children. Because it is not possible to differentiate between children with cystitis and APN on clinical grounds, and because markers for APN have not been identified, all children with UTI are currently managed as if they have APN. Current guidelines recommend that all young children with UTI receive treatment with long-course antibiotics (7-14 days) and undergo follow-up imaging tests. This has resulted in an overuse of imaging and antimicrobials for children with UTI. We propose an alternate strategy in which measurement of blood and/or urine biomarkers at the time of presentation is used to stratify children into pathophysiologically distinct subgroups (cystitis vs. APN). This will allow clinicians to individualize the treatment of UTI and to reduce unnecessary use of antimicrobials and imaging tests. As part an NIAID-funded 7-year study designed to compare the efficacy of short-course antimicrobials for children with UTI, we will be enrolling one of the largest samples of children with UTI to date (target n=746). By collecting additional blood and urine samples at the time of presentation from the first 160 children being considered for that study, and by conducting an early DMSA renal scan (to identify APN), we will be able to identify biomarkers that accurately differentiate children with APN from children with cystitis at a minimal additional cost. We will use a step-wise approach to achieve these aims. First, we will determine the accuracy of 5 previously identified proteins (urine IL-6, urine IL-8, urine IL-12, urine macrophage inhibitory factor, and serum procalcitonin) in differentiating APN from cystitis. Next, by examining genes that are differentially expressed in leukocytes from patients with APN and cystitis, we will develop an RNA-based profile that can accurately distinguish APN from cystitis. Finally, we will construct a prediction rule using clinical variables, previously studied proteins, and the RNA-based profile, to differentiate children with APN from children with cystitis. The prediction rules developed in this ancillary study will significantly enhance the parent study by providing an accurate method of stratifying the analysis according to the presence or absence of APN. PUBLIC HEALTH RELEVANCE: The blood and urine tests developed in this grant will allow doctors to differentiate children with kidney infection from children with bladder infection. In this way, children with bladder infection, who are not at risk for permanent kidney damage, can be treated with fewer days of antibiotics and without performing any of the currently recommended imaging tests. This approach could lead to significant reductions in the use of antibiotics and the exposure to radiation in children with urinary tract infections.