Pyrophosphate in Vascular Calcification of Renal Failure

焦磷酸盐在肾衰竭血管钙化中的作用

• 批准号: 7610974
• 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
• 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/7610974
• 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 Failure; Kinetics; Lead; Mammography; Medial; Monckeberg Arteriosclerosis; Morbidity - disease rate; Natural History; Patient Care; Patients; Plasma; Play; Process; Production; Pulse Pressure; Rattus; Risk Factors; Role; Smooth Muscle Myocytes; Solutions; 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

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患者的护理显着改善，但死亡率仍然很高。血管疾病是主要的罪魁祸首，也是发病{{3464}}的主要原因。尽管涉及多个疾病过程，并且原因是多重的，但血管钙化很普遍，当然是一个重要因素。这种钙化发生在大型和小动脉的培养基中，也称为蒙克贝格的动脉硬化。除了引起或导致缺血性事件外，钙化还可以降低动脉依从性，从而导致脉压增加，这是ESRD死亡的强大风险因素。动脉钙化还会损害为血液透析提供动静脉瘘和移植物所需的扩张。该问题的临床方法仍然可以控制循环钙和磷酸盐浓度，尽管事实尚未证实和丰富的数据表明，钙化内源性抑制剂的缺陷起着重要作用。我们最近在使用培养大鼠主动脉的新模型系统中表明，焦磷酸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水平降低，并在透析过程中进一步下降，这表明预防ESRD中血管钙化的策略应基于对局部或系统性焦磷酸盐缺乏症的检测和纠正。该提案的目标是确定尿毒症血管平滑肌PPI缺乏的原因，PPI和双膦酸盐预防体外和体内血管钙化，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在培养大鼠主动脉的体外研究中解决。我们将在大鼠主动脉中PPI的代谢研究与人类血浆焦磷酸血浆的动力学研究相结合。这些发现将与患者的血管钙化相关，并通过腹部CT扫描和乳房X线摄影进行定量。结果将建立一个新的肾衰竭血管钙化范式，并构成人类重要的临床试验的基础。