Biomarkers of Kidney Pathology

描述（由申请人提供）：慢性肾脏疾病影响美国约2600万至3000万成年人，并与大量发病率和死亡率相关。在临床实践中，CKD的根本原因和个体患者的进展风险通常未知。然而，几种病理过程似乎在不同病因的进行性肾脏疾病中很常见，包括进行性肾小管间质纤维化、肾小管萎缩、肾小球硬化、毛细血管稀疏和血管硬化。小说 CKD病理学的非侵入性生物标志物可提供个体中导致CKD的潜在病理生物学过程的澄清，从而实现早期诊断和更准确的预后。该提案是CKD生物标志物联盟（U 01 DK 085660）的辅助研究，该联盟是一组具有广泛生物标志物专业知识的研究者，他们可以获得来自许多CKD患者队列的样本。该提案描述了一项前瞻性队列研究，涉及从接受自体肾活检的患者中采集生物样本，这是确定CKD病因的金标准。我们将从马萨诸塞州波士顿的两家医院招募参与者，并测量新生物标志物的尿液和组织水平，包括KIM-1、NAG、NGAL、MCP-1、L-FABP、IL-18、HGF、VEGF、IP-10和CTGF。在特定目标1中，我们将尿生物标志物测量与13种组织学评分相关联，这些评分捕获系膜、肾小管、肾小球、肾小球和小动脉中的炎症、纤维化和缺血性病理过程;将对最有希望的生物标志物进行进一步免疫组织化学分析，以确定其组织分布及其与尿水平的相关性。在特定目标2中，我们将检验尿液和组织生物标志物与肾功能下降（定义为血清肌酐加倍或需要肾脏替代治疗）的前瞻性相关性。我们预计将招募超过900名参与者，中位随访时间约为5年。该辅助提案将与U 01联盟研究者合作并整合，并将促进动物研究、大型队列研究和活检队列结果的多向转化。尿液、血浆和DNA样本将与联盟共享，用于未来的研究。 公共卫生相关性：慢性肾脏疾病是一个主要的公共卫生威胁，目前的诊断和评估预后的方法是不够的。慢性肾脏的新生物标志物的开发将通过诸如本文提出的研究来促进，在该研究中，我们将比较新生物标志物的尿液和组织水平与经历肾脏活检的个体的实际病理结果，这是“金标准”诊断工具。更好的生物标志物有望转化为越来越多的慢性肾病患者的护理改善。

DESCRIPTION (provided by applicant): Chronic kidney disease affects approximately 26 to 30 million adults in the United States and is associated with substantial morbidity and mortality. The underlying causes of CKD and risk for progression in an individual patient are frequently not known in clinical practice. Nevertheless, several pathological processes appear to be common across progressive kidney diseases of diverse etiologies, including progressive tubulointerstitial fibrosis, tubular atrophy, glomerulosclerosis, capillary rarefaction, and vascular sclerosis. Novel non-invasive biomarkers of CKD pathology may provide clarification of the underlying pathobiological processes responsible for CKD in an individual, enabling earlier diagnosis and more accurate prognosis. This proposal is an ancillary study to the CKD Biomarker Consortium (U01DK085660), a group of investigators with wide-ranging biomarker expertise who have access to samples from a number of cohorts of individuals with CKD. The proposal describes a prospective cohort study involving biological sample collection from patients undergoing native kidney biopsy, the gold standard determination for identifying the cause(s) of CKD. We will enroll participants from two hospitals in Boston, Massachusetts and measure urinary and tissue levels of novel biomarkers, including KIM-1, NAG, NGAL, MCP-1, L-FABP, IL-18, HGF, VEGF, IP-10, and CTGF. In Specific Aim 1, we will correlate urinary biomarker measurements with 13 histologic scores that capture inflammatory, fibrotic, and ischemic pathological processes in the mesangium, tubules, glomeruli, interstitium, and arterioles; further immunohistochemistry will be performed on the most promising biomarkers to identify their tissue distribution and correlation with urinary levels. In Specific Aim 2, we will test the prospective associations of urinary and tissue biomarkers with renal function decline, defined as a doubling of serum creatinine or the need for renal replacement therapy. We anticipate enrollment of over 900 participants with median follow-up of approximately 5 years. This ancillary proposal will be collaborative and integrated with U01 Consortium investigators and will facilitate multidirectional translation of findings across animal studies, large cohort studies, and the biopsy cohort. Urine, plasma, and DNA samples will be shared with the Consortium for future studies. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a major public health threat for which the current methods of diagnosis and assessing prognosis are inadequate. The development of new biomarkers of chronic kidney will be facilitated by studies such as the one proposed here, where we will compare urinary and tissue levels of novel biomarkers with actual pathological findings from individuals who have undergone kidney biopsy, which is the "gold standard" diagnostic tool. Better biomarkers are expected to translate into improved care for the growing number of individuals with chronic kidney disease.