Novel Diagnostics and Therapeutic Targets for Calcification in CKD

CKD 钙化的新诊断和治疗靶点

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要慢性肾脏疾病（CKD）容易影响个体，终结阶段肾脏疾病率很高（ESRD），心血管疾病（CVD）和过早死亡。尽管增加了干预措施该针对传统风险因素，不良临床事件的频率仍然很高。新型策略迫切需要针对非传统风险因素来改善预后。血管钙化是一种非 CKD中CKD进展的传统危险因素和CKD中的CVD。验证新型筛选测试以定义高在发展血管钙化和对新型血管钙化的洞察力之前的风险 CKD中的机制将增强风险分层以及CVD和CKD管理，并有可能阻止不良临床事件。在强大的初步数据的支持下，我们将有效利用慢性肾脏通过评估新型T50测定作为候选生物标志物和脱氧胆酸水平升高作为可能的可修改疾病机制。 T50是一种新型的血清测定法，通过测量的净效应来量化钙化倾向钙化抑制剂和启动子。我们来自184例3-4 CKD患者的初步数据证明了反映钙化倾向增加的低T50与主动脉僵硬和死亡率的进展。我们将在CRIC研究中全面评估T50，具有详细的临床数据，左心室肥大，动脉僵硬和冠状动脉的序列测量动脉钙化以及裁定的CKD和CVD事件。在AIM 1中，我们将研究T50及其关系具有临床特征，矿物代谢产物，动脉僵硬的患病率和进展，冠状动脉动脉钙化和左心室肥大，并在整个CRIC中具有ESRD，CVD和死亡的风险队列（n = 3472）。在AIM 2中，我们将在随机选择的CRIC中获得3年的T50年度测量纵向矿物质代谢亚物质（n = 1200），以定义T50随时间的变化，将这种演变相关联无序矿物代谢进展和肾脏丧失的血管钙化倾向功能，并检查T50的变化如何影响ESRD，CVD事件和死亡的风险。脱氧胆酸是衍生自胆碱的胆汁酸代谢产物。我们的初步数据表明脱氧胆酸水平是 CKD升高并通过促进血管内质网应激诱导血管钙化平滑肌细胞。在我们对磷酸盐粘合剂研究的事后分析（n = 112，CKD 3-4）中，脱氧胆酸水平与更大的冠状动脉钙化独立相关。脱氧酸水平可以通过靶向其产生和排泄来降低。推进这种潜在的修改血管钙化的机制，在AIM 3中，我们将研究升高的脱氧胆酸作为危险因素整个CRIC队列中的中级和硬性结果（n = 3472）。我们预计我们的结果将有主要的临床意义，导致CKD的未来介入研究并促进进一步的实验室工作。