Biomarkers of Chronic Kidney Disease

 描述（由申请人提供）：慢性肾脏疾病（CKD）影响>10%的美国成年人口，每年花费数百亿美元，并可导致进行性肾衰竭，心血管疾病（CVD）和早期死亡。虽然我们对CKD的流行病学有了很大的了解，但CKD发生和进展的潜在机制仍然不太清楚。在这项提案中，这是CKD生物标志物联盟第1阶段的延续，我们试图测试有前途的肾损伤生物标志物预测非蛋白尿和蛋白尿个体CKD发病率和进展的能力;此外，我们建议作为联盟生物标志物测量的开发，质量控制和验证网站。我们提出测量肾小管损伤和炎症的新生物标志物，我们假设这两种损伤的关键途径与糖尿病和非糖尿病肾病的CKD进展相关。待检测的生物标志物包括肾损伤分子-1，一种几乎仅在近端小管中表达的跨膜糖蛋白，以响应有害刺激;尿补体片段，在CKD BioCon的第1阶段中被确定为有希望的生物标志物;可溶性肿瘤坏死因子-a受体1和2（sTNFR 1和sTNFR 2）。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志物：Frachial Heart研究（FHS），一项对超过2，948名具有可用基线血浆样本和超过10年随访数据的个体的前瞻性研究;来自瑞典乌普萨拉的另外两项基于社区的队列研究，ULSAM（N = 778）和PIVUS（N = 815）;肾素-血管紧张素系统研究（RASS），包括254名16-65岁的T1 D参与者，他们在基线时和5年随访后接受了肾脏活检，每6个月采集一次血液和尿液样本; 260名参与者的皮马印第安人队列（111例在研究结束时活检）2型糖尿病（T2 D）患者，在中位随访10年期间每两年采集一次可用的血浆和尿液样本;和波士顿肾活检队列（U 01 DK 093574，CKD生物标志物联盟的辅助研究），这是一项正在进行的前瞻性研究（迄今为止N = 649），其中在自体肾活检时采集血液和尿液样本。在目标1中，我们将测试生物标志物（独立于白蛋白尿和eGFR）是否与将来发生CKD或CKD进展相关。在目标2中，我们将检测生物标志物与肾活检组织病理学结果的相关性。在目标3中，我们建议将布里格姆妇女医院作为联盟生物标志物测量的核心实验室，并继续努力确保联盟使用的检测方法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.