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Pyrophosphate in vascular calcification of renal failure

焦磷酸盐在肾衰竭血管钙化中的作用

基本信息

批准号：
7388878
负责人：
W CHARLES O'NEILL
金额：
$ 29.78万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388878
关键词：
Abdomen Address Animals Aorta Arterial Fatty Streak Arteries Arteriovenous fistula Atherosclerosis Attention Biological Models Cells Cessation of life Clinical Clinical Trials Data Defect Detection Dialysis procedure Dilatation - action Diphosphates Disease Elastin Electron Beam Tomography End stage renal failure Event Functional disorder Goals Hemodialysis Human Hydrolysis Hydroxyapatites In Vitro Inflammatory Kidney Diseases Kidney Failure Kinetics Lead Mammography Medial Monckeberg Arteriosclerosis Morbidity - disease rate Natural History Pathological Dilatation Patient Care Patients Physical Dialysis Plasma Play Process Production Pulse Pressure Rate Rattus Risk Factors Role Smooth Muscle Myocytes Solutions Staging Uremia Vascular Diseases Vascular Smooth Muscle Vascular calcification Vitamin D X-Ray Computed Tomography analog base bisphosphonate bone calcification calcification inhibitor calcium phosphate clinically significant coronary artery calcification in vitro Model in vivo inhibitor/antagonist metabolic abnormality assessment mortality prevent

项目摘要

DESCRIPTION (provided by applicant): Despite significant improvements in the care of patients with ESRD, mortality remains very high. Vascular disease is the major culprit and is also the leading cause of morbidity {{3464}}. Although more than one disease process is involved and the causes are multiple, vascular calcification is prevalent and is certainly an important factor. This calcification occurs in the media of large and small arteries and is also known as Monckeberg's arteriosclerosis. In addition to causing or contributing to ischemic events, the calcification can decrease arterial compliance and thereby lead to increased pulse pressure, which is a strong risk factor for death in ESRD. Arterial calcification can also impair the dilatation necessary to supply the arteriovenous fistulae and grafts for hemodialysis. The clinical approach to this problem remains the control of circulating calcium and phosphate concentrations despite the fact that it is unproven and abundant data now indicate that deficiencies of endogenous inhibitors of calcification play an important role. We have recently shown, in a new model system using cultured rat aorta, that pyrophosphate is an important endogenous inhibitor of vascular calcification. We have also found that plasma pyrophosphate levels are reduced in hemodialysis patients and decline further during dialysis, suggesting that strategies to prevent vascular calcification in ESRD should be based on the detection and correction of local or systemic pyrophosphate deficiency. The goals of this proposal are to determine the cause of PPi deficiency in uremic vascular smooth muscle, to PPi and bisphosphonates prevent vascular calcification in vitro and in vivo, and to determine the cause and clinical significance of reduced plasma PPi levels in patients with renal failure. These aims will be addressed with studies in vivo in both humans and animals, and in studies in vitro in cultured rat aorta. We will combine metabolic studies of PPi in rat aortas with kinetic studies of plasma pyrophosphate in humans. The findings will be correlated with vascular calcification in patients, quantitated by abdominal CT scanning and mammography. The results will establish a new paradigm for vascular calcification in renal failure and form the basis for important clinical trials in humans.

描述（由申请人提供）：尽管 ESRD 患者的护理有了显着改善，但死亡率仍然很高。血管疾病是罪魁祸首，也是发病的主要原因{{3464}}。尽管涉及不止一种疾病过程且原因多种多样，但血管钙化很普遍，并且无疑是一个重要因素。这种钙化发生在大动脉和小动脉的中层，也称为蒙克伯格动脉硬化。除了引起或促成缺血事件外，钙化还会降低动脉顺应性，从而导致脉压升高，这是 ESRD 死亡的一个重要危险因素。动脉钙化还会损害血液透析所需的动静脉瘘和移植物的扩张。解决这个问题的临床方法仍然是控制循环钙和磷酸盐浓度，尽管这一点尚未得到证实，而且现在大量数据表明内源性钙化抑制剂的缺陷起着重要作用。我们最近在使用培养的大鼠主动脉的新模型系统中表明，焦磷酸盐是血管钙化的重要内源性抑制剂。我们还发现，血液透析患者的血浆焦磷酸盐水平降低，并且在透析过程中进一步下降，这表明预防 ESRD 血管钙化的策略应基于检测和纠正局部或全身焦磷酸盐缺乏症。该提案的目标是确定尿毒症血管平滑肌中PPi缺乏的原因，PPi和双膦酸盐在体外和体内预防血管钙化，并确定肾衰竭患者血浆PPi水平降低的原因和临床意义。这些目标将通过人类和动物的体内研究以及培养的大鼠主动脉的体外研究来实现。我们将把大鼠主动脉中 PPi 的代谢研究与人类血浆焦磷酸盐的动力学研究结合起来。研究结果将与患者的血管钙化相关，通过腹部 CT 扫描和乳房 X 光检查进行定量。研究结果将为肾衰竭血管钙化建立新的范例，并为人类重要临床试验奠定基础。