Novel Diagnostics and Therapeutic Targets for Calcification in CKD

CKD 钙化的新诊断和治疗靶点

• 批准号: 9978819
• 负责人: Tamara Isakova
• 金额: $ 43.79万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978819
• 关键词: Affect; Arterial Fatty Streak; Back; Bile Acids; Biological Assay; Biological Markers; Cardiovascular Diseases; Cessation of life; Characteristics; Cholic Acids; Choline; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Clinical Data; Cohort Studies; Data; Deoxycholic Acid; Development; Diabetes Mellitus; Disease; Disease Management; Disease Progression; Drops; End stage renal failure; Event; Evolution; Excretory function; Fasting; Frequencies; Future; Generations; Heart failure; High Prevalence; Individual; Intervention; Intervention Studies; Kidney Failure; Kidney Transplantation; Laboratories; Lead; Left Ventricular Hypertrophy; Left Ventricular Mass; Longitudinal cohort; Measurement; Measures; Medial; Metabolism; Minerals; Mission; Observational Study; Outcome; Pathogenesis; Patient Care; Patients; Physiologic pulse; Prevalence; Renal function; Research; Risk; Risk Factors; Risk stratification; Sampling; Serum; Smooth Muscle Myocytes; Testing; Time; Translating; Transplant Recipients; Validation; Vascular Smooth Muscle; Vascular calcification; Work; adjudicate; arterial stiffness; calcification; calcification inhibitor; candidate marker; clinical care; cohort; coronary artery calcification; design; endoplasmic reticulum stress; glomerular filtration; graft failure; high risk; high risk population; improved outcome; indexing; innovation; inorganic phosphate; insight; mortality; new therapeutic target; novel; novel diagnostics; novel strategies; premature; prevent; promoter; prospective; research study; screening; tool

PROJECT SUMMARY Chronic kidney disease (CKD) predisposes affected individuals to high rates of end stage renal disease (ESRD), cardiovascular disease (CVD) and premature death. Despite increasing utilization of interventions that target traditional risk factors, the frequency of adverse clinical events remains high. Novel strategies targeting non-traditional risk factors are urgently needed to improve outcomes. Vascular calcification is a non- traditional risk factor for CKD progression and CVD in CKD. Validation of novel screening tests to define high- risk individuals before they develop vascular calcification and insights into novel vascular calcification mechanisms in CKD would enhance risk stratification and CVD and CKD management and potentially prevent adverse clinical events. Backed by strong preliminary data, we will efficiently leverage the Chronic Renal Insufficiency Cohort (CRIC) Study to advance the vascular calcification field by evaluating the novel T50 assay as a candidate biomarker and elevated levels of deoxycholic acid as a possible modifiable disease mechanism. T50 is a novel serum assay that quantifies calcification propensity by measuring the net effect of calcification inhibitors and promoters. Our preliminary data from 184 patients with stage 3-4 CKD demonstrate that low T50, which reflects increased calcification propensity, is strongly and independently associated with progression of aortic stiffness and with mortality. We will comprehensively evaluate T50 in the CRIC Study, which has detailed clinical data, serial measures of left ventricular hypertrophy, arterial stiffness and coronary artery calcification, and adjudicated CKD and CVD events. In Aim 1, we will study T50 and its relationships with clinical characteristics, mineral metabolites, prevalence and progression of arterial stiffness, coronary artery calcification and left ventricular hypertrophy, and with risks of ESRD, CVD and death in the entire CRIC cohort (n=3472). In Aim 2, we will obtain 3 annual measurements of T50 in the randomly selected CRIC's longitudinal mineral metabolism subcohort (n=1200) to define change in T50 over time, relate this evolution in vascular calcification propensity to progression of disordered mineral metabolism and to loss of kidney function, and examine how changes in T50 affect risks of ESRD, CVD events and death. Deoxycholic acid is a bile acid metabolite derived from choline. Our preliminary data demonstrate that deoxycholic acid levels are elevated in CKD and induce vascular calcification by promoting endoplasmic reticulum stress in vascular smooth muscle cells. In our post-hoc analysis of a phosphate binder study (n=112, CKD 3-4), an elevated deoxycholic acid level was independently associated with greater coronary artery calcification. Deoxycholic acid levels may be lowered by targeting its generation and excretion. To advance this potentially modifiable mechanism of vascular calcification, in Aim 3, we will examine elevated deoxycholic acid as a risk factor for intermediate and hard outcomes in the entire CRIC cohort (n=3472). We anticipate that our results will have major clinical implications, lead to future interventional studies in CKD and catalyze further laboratory work.

项目总结 慢性肾脏病(CKD)使患者易患终末期肾病。 (ESRD)、心血管疾病(CVD)和过早死亡。尽管干预措施的使用率越来越高 以传统风险因素为目标，不良临床事件的频率仍然很高。新战略 迫切需要针对非传统风险因素来改善结果。血管钙化是一种非 CKD进展和CVD的传统危险因素。验证新的筛查试验以确定高风险 发生血管钙化前的风险个体和对新血管钙化的洞察 CKD的机制将加强风险分层以及CVD和CKD管理，并有可能预防 不良临床事件。在强劲的初步数据的支持下，我们将有效地利用慢性肾脏 不充分队列(CRIC)研究通过评估新的T50分析来推进血管钙化领域 作为候选生物标志物和脱氧胆酸水平升高作为一种可能的可修改疾病 机制。T50是一种新的血清测定方法，它通过测量钙化倾向的净效应来量化钙化倾向 钙化抑制剂和促进剂。我们对184名3-4期CKD患者的初步数据显示 反映钙化倾向增加的低T50与 主动脉僵硬的进展和死亡率。我们将在CRIC研究中全面评估T50， 它有详细的临床数据，左心室肥厚，动脉僵硬和冠状动脉病变的一系列测量 动脉钙化，并判定CKD和CVD事件。在目标1中，我们将研究T50及其关系 临床特征、矿物质代谢产物、动脉硬化的患病率和进展、冠状动脉 动脉钙化和左心室肥厚，并有终末期肾病、心血管疾病和死亡的整个CRIC风险 队列(n=3472)。在目标2中，我们将获得随机选择的CRIC的T50的3个年度测量值 纵向矿物质代谢亚群(n=1200)定义T50随时间的变化，将这种演变与 血管钙化倾向矿物质代谢紊乱进展及肾功能丧失 功能，并检查T50的变化如何影响终末期肾病、心血管事件和死亡的风险。脱氧胆酸是一种 胆碱衍生的胆汁酸代谢物。我们的初步数据显示，脱氧胆酸水平 CKD升高并通过促进血管内质网应激诱导血管钙化 平滑的肌肉细胞。在我们对磷酸盐粘结剂研究(n=112，CKD 3-4)的后期分析中，升高的 脱氧胆酸水平与冠状动脉钙化程度独立相关。脱氧胆碱 通过针对其生成和排泄，可以降低酸的水平。为了推进这一潜在的可修改 血管钙化的机制，在目标3中，我们将检查脱氧胆酸升高作为血管钙化的危险因素 整个审评委队列中的中级和硬成果(n=3472)。我们预计我们的结果将会有 主要的临床意义，导致未来CKD的干预性研究，并催化进一步的实验室工作。