Biomarkers of Kidney Pathology

描述(申请人提供)：慢性肾脏疾病在美国影响大约2600万至3000万成年人，并与相当大的发病率和死亡率有关。CKD的潜在原因和个体患者进展的风险在临床实践中往往是未知的。然而，不同病因的进展性肾脏疾病似乎有几个共同的病理过程，包括进行性肾小管间质纤维化、肾小管萎缩、肾小球硬化、毛细血管疏松和血管硬化。小说 CKD病理的非侵入性生物标志物可能提供对个体CKD的潜在病理生物学过程的澄清，使更早的诊断和更准确的预后成为可能。这项建议是CKD生物标记物联盟(U01DK085660)的辅助研究，该联盟是一组拥有广泛生物标记物专业知识的调查人员，他们可以从许多CKD患者的队列中获得样本。该建议描述了一项前瞻性队列研究，涉及从接受自然肾活检的患者收集生物样本，这是确定慢性肾脏病病因的金标准(S)。我们将从马萨诸塞州波士顿的两家医院招募参与者，并测量尿液和组织中新生物标志物的水平，包括KIM-1、NAG、NGAL、单核细胞趋化蛋白-1、L-FABP、IL-18、肝细胞生长因子、血管内皮生长因子、IP-10和CTGF。在具体目标1中，我们将尿液生物标记物的测量与13个组织学评分相关联，这些组织学评分捕捉系膜、肾小管、肾小球、间质和小动脉的炎症、纤维化和缺血的病理过程；进一步对最有希望的生物标记物进行免疫组织化学，以确定它们的组织分布和与尿液水平的相关性。在特定的目标2中，我们将测试尿液和组织生物标志物与肾功能下降的预期相关性，肾功能下降的定义是血肌酐增加一倍或需要肾脏替代治疗。我们预计将有900多名参与者参加，平均随访时间约为5年。这项辅助建议将与U01联盟的研究人员合作和整合，并将促进跨动物研究、大型队列研究和活检队列的多方向转换结果。尿液、血浆和DNA样本将与该联盟共享，用于未来的研究。

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.