Biomarkers of Chronic Kidney Disease

 描述(申请人提供)：慢性肾脏病(CKD)影响美国10%的成年人口，每年造成数百亿美元的损失，并可导致进行性肾功能衰竭、心血管疾病(CVD)和早期死亡。虽然我们对慢性肾脏病的流行病学了解很多，但慢性肾脏病的发生和发展的潜在机制仍然不太清楚。这项提案是CKD生物标记物联盟第一阶段的延续，我们试图测试有前景的肾脏损伤生物标记物预测非蛋白尿症和蛋白尿症患者CKD发生和进展的能力；此外，我们建议作为该联盟生物标记物测量的开发、质量控制和验证场所。我们提出了新的肾小管损伤和炎症生物标志物的测量方法，我们推测这两种损伤途径与糖尿病和非糖尿病肾病的CKD进展有关。需要检测的生物标志物包括肾损伤分子-1，一种几乎只在近端小管对损伤刺激做出反应的跨膜糖蛋白；尿补体片段，被认为是CKD Biocon第一阶段的有希望的生物标志物；以及可溶性肿瘤坏死因子-a受体1和2(sTNFR1和sTNFR2)。我们将在独特的前瞻性队列研究中测量联盟和外部专家小组批准的生物标记物：弗雷明翰心脏研究(FHS)，这是一项针对2948人的前瞻性研究，拥有超过10年的基线血浆样本和随访数据；另外两项来自瑞典乌普萨拉、ULSAM(N=778)和PIVUS(N=815)的社区队列研究；肾素-血管紧张素系统研究(RASS)，由254名16-65岁的T1D参与者组成，他们在基线和5年后接受肾活检，每6个月收集一次血和尿样；由260名2型糖尿病(T2D)患者组成的PIMA印度队列(在研究结束时进行了111次活检)和波士顿肾脏活检队列(U01DK093574，CKD生物标记物联合会的辅助研究)，这是一项正在进行的前瞻性研究(N=649)，其中血液和尿样在进行天然肾脏活检时采集。在目标1中，我们将测试独立于蛋白尿和EGFR的生物标志物是否与CKD或CKD进展的未来发展相关。在目标2中，我们将测试生物标记物与肾活检组织病理学结果的相关性。在目标3中，我们建议建立布里格姆妇女医院作为该联盟生物标记物测量的核心实验室，并继续努力确保整个联盟使用的分析的可靠质量控制和验证。

 DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects >10% of the adult US population, costs tens of billions of dollars annually, and can lead to progressive kidney failure, cardiovascular disease (CVD), and early mortality. Although we understand much about the epidemiology of CKD, the underlying mechanisms of CKD initiation and progression remain less well understood. In this proposal, which represents a continuation of Phase 1 of the CKD Biomarker Consortium, we seek to test the ability of promising biomarkers of kidney injury to predict CKD incidence and progression in non-proteinuric and proteinuric individuals; furthermore, we propose serving as a development, quality control, and validation site for biomarker measurements for the Consortium. We propose measurement of novel biomarkers of tubular injury and inflammation, two key pathways of injury that we hypothesize are associated with CKD progression in both diabetic- and non-diabetic kidney disease. Biomarkers to be tested included kidney injury molecule-1, a transmembrane glycoprotein expressed almost exclusively in the proximal tubule in response to injurious stimuli; urinary complement fragments, which were identified as promising biomarkers in Phase 1 of CKD BioCon; and soluble tumor necrosis factor-a receptors 1 and 2 (sTNFR1 and sTNFR2). We will measure biomarkers approved by the Consortium and external expert panel in unique prospective cohort studies: the Framingham Heart Study (FHS), a prospective study of over 2,948 individuals with available baseline plasma samples and follow-up data over more than one decade; two other community-based cohort studies from Uppsala, Sweden, ULSAM (N = 778) and PIVUS (N = 815); the Renin-Angiotensin System Study (RASS), comprised of 254 T1D participants aged 16-65 years who underwent kidney biopsy for research purposes at baseline and after 5 years of follow-up with blood and urine samples collected every six months; the Pima Indian Cohort of 260 participants (111 biopsied at end of study) with type 2 diabetes mellitus (T2D) with available plasma and urine samples collected every two years during a median follow-up of 10 years; and the Boston Kidney Biopsy Cohort (U01DK093574, ancillary study to CKD Biomarkers Consortium), an ongoing prospective study (N = 649 to date) in which blood and urine samples are obtained at the time of native kidney biopsy. In Aim 1 we will test whether biomarkers, independently of albuminuria and eGFR, are associated with future development of incident CKD or CKD progression. In Aim 2, we will test the associations of biomarkers with histopathologic findings on kidney biopsy. In Aim 3, we propose establishing Brigham and Women's Hospital as a core laboratory for biomarker measurements for the Consortium and to continue of our efforts to ensure reliable quality control and validation of assays in use across the Consortium.