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，也是发病的首要原因{{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，当然是一个重要因素。这种钙化发生在大动脉和小动脉的中间，也被称为Monckeberg动脉硬化。钙化除了引起或促成缺血事件外，还会降低动脉顺应性，从而导致脉压升高，这是ESRD患者死亡的一个重要危险因素。动脉钙化也会损害为血液透析提供动静脉瘘和移植物所需的扩张。临床解决这一问题的方法仍然是控制循环钙和磷酸盐浓度，尽管事实尚未得到证实，现在有大量数据表明内源性钙化抑制剂的缺乏起着重要作用。我们最近在培养大鼠主动脉的新模型系统中发现焦磷酸盐是一种重要的内源性血管钙化抑制剂。我们还发现血液透析患者血浆焦磷酸盐水平降低，并在透析期间进一步下降，这表明预防ESRD血管钙化的策略应基于局部或全身焦磷酸盐缺乏的检测和纠正。本研究的目的是确定尿毒症血管平滑肌中PPi缺乏的原因，在体外和体内研究中，PPi和双膦酸盐对血管钙化的预防作用，确定肾功能衰竭患者血浆PPi水平降低的原因和临床意义。这些目标将在人类和动物的体内研究以及在体外培养的大鼠主动脉的研究中得到解决。我们将把大鼠主动脉中PPi的代谢研究与人血浆焦磷酸盐的动力学研究结合起来。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线摄影进行量化。该结果将为肾衰竭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.