Pyrophosphate in Vascular Calcification of Renal Failure

描述（由申请人提供）：尽管ESRD患者的护理有了显著改善，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}}。虽然涉及不止一种疾病过程，原因也多种多样，但血管钙化是普遍存在的，肯定是一个重要因素。这种钙化发生在大动脉和小动脉的介质中，也被称为Monckeberg动脉硬化。除了引起或促成缺血性事件外，钙化还可降低动脉顺应性，从而导致脉压增加，这是ESRD死亡的一个强风险因素。动脉钙化也会损害血液透析所需的动静脉内瘘和移植物的扩张。临床上解决这一问题的方法仍然是控制循环中的钙和磷酸盐浓度，尽管事实上这是未经证实的，而且现在大量的数据表明，内源性钙化抑制剂的缺乏起着重要的作用。我们最近在一个新的模型系统中使用培养的大鼠主动脉，焦磷酸盐是血管钙化的一个重要的内源性抑制剂。我们还发现血液透析患者血浆焦磷酸盐水平降低，并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。本提案的目的是确定尿毒症血管平滑肌中PPi缺乏的原因，PPi和二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。这些目标将通过人体和动物体内研究以及培养大鼠主动脉的体外研究来解决。我们将结合联合收割机的代谢研究PPi在大鼠动脉与动力学研究血浆焦磷酸在人类。这些发现将与患者的血管钙化相关，通过腹部CT扫描和乳腺X线摄影进行定量。这些结果将为肾衰竭中血管钙化建立一个新的范例，并为重要的人体临床试验奠定基础。

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.