Pyrophosphate in Vascular Calcification of Renal Failure

描述(由申请人提供)：尽管终末期肾病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，也是发病的首要原因{{3464}}。虽然涉及一个以上的疾病过程，原因是多方面的，但血管钙化是普遍存在的，当然是一个重要的因素。这种钙化发生在大动脉和小动脉的中段，也被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，这是终末期肾病死亡的一个重要风险因素。动脉钙化也会损害为血液透析供应动静脉瘘和移植物所必需的扩张。解决这一问题的临床方法仍然是控制循环中的钙和磷浓度，尽管这一事实尚未得到证实，而且大量数据表明，内源性钙化抑制物的缺乏起到了重要作用。我们最近在一个使用培养的大鼠主动脉的新的模型系统中表明，焦磷酸盐是血管钙化的重要内源性抑制物。我们还发现血液透析患者的血浆焦磷酸盐水平降低，并在透析期间进一步下降，这表明预防终末期肾病血管钙化的策略应该建立在检测和纠正局部或全身性焦磷缺乏的基础上。该方案的目的是确定尿毒症血管平滑肌PPI缺乏的原因，PPI和双膦酸盐在体外和体内预防血管钙化，并确定肾功能衰竭患者血浆PPI水平降低的原因和临床意义。这些目标将通过在人和动物体内的研究以及在体外培养的大鼠主动脉的研究来实现。我们将结合PPI在大鼠主动脉中的代谢研究和人体内血浆焦磷酸的动力学研究。这些发现将与患者的血管钙化相关，通过腹部CT扫描和乳房X光检查进行量化。这一结果将为肾功能衰竭的血管钙化建立一个新的范例，并为在人类进行重要的临床试验奠定基础。

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.