Biomarkers of Kidney Pathology

描述（由申请人提供）：慢性肾病影响着美国大约 26 至 3000 万成年人，并与大量的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进展的风险通常是未知的。然而，多种病因的进行性肾脏疾病中的一些病理过程似乎是常见的，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以阐明导致个体 CKD 的潜在病理生物学过程，从而实现更早的诊断和更准确的预后。该提案是 CKD 生物标志物联盟 (U01DK085660) 的一项辅助研究，该联盟由一群拥有广泛生物标志物专业知识的研究人员组成，他们可以获取许多 CKD 患者群体的样本。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采集生物样本，这是确定 CKD 病因的金标准。我们将招募来自马萨诸塞州波士顿两家医院的参与者，并测量新型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。在具体目标 1 中，我们将尿液生物标志物测量与 13 个组织学评分相关联，这些组织学评分捕获系膜、肾小管、肾小球、间质和小动脉中的炎症、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的免疫组织化学分析，以确定其组织分布以及与尿液水平的相关性。在具体目标 2 中，我们将测试尿液和组织生物标志物与肾功能下降的前瞻性关联，肾功能下降定义为血清肌酐加倍或需要肾脏替代治疗。我们预计将有超过 900 名参与者入组，中位随访时间约为 5 年。该辅助提案将与 U01 联盟研究人员合作和整合，并将促进动物研究、大型队列研究和活检队列中研究结果的多向转化。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还不够。慢性肾脏病新生物标志物的开发将通过本文提出的研究来促进，我们将比较尿液和组织中新型生物标志物的水平与接受肾活检的个体的实际病理结果，肾活检是“金标准”诊断工具。更好的生物标志物有望转化为对越来越多的慢性肾病患者的更好的护理。

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.