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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069681-02
Application #
7195036
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Kimmel, Paul
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
2
Fiscal Year
2007
Total Cost
$307,477
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Villa-Bellosta, Ricardo; O'Neill, W Charles (2018) Pyrophosphate deficiency in vascular calcification. Kidney Int 93:1293-1297
Lomashvili, Koba A; Narisawa, Sonoko; Millán, Jose L et al. (2014) Vascular calcification is dependent on plasma levels of pyrophosphate. Kidney Int 85:1351-6
Lomashvili, Koba A; Wang, Xiaonan; O'Neill, W Charles (2014) Role of local versus systemic vitamin D receptors in vascular calcification. Arterioscler Thromb Vasc Biol 34:146-51
Tolouian, Ramin; Connery, Sean M; O'Neill, W Charles et al. (2012) Using a filtration technique to isolate platelet free plasma for assaying pyrophosphate. Clin Lab 58:1129-34
Villa-Bellosta, Ricardo; Wang, Xiaonan; Millan, Jose Luis et al. (2011) Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle. Am J Physiol Heart Circ Physiol 301:H61-8
Lomashvili, Koba A; Wang, Xiaonan; Wallin, Reidar et al. (2011) Matrix Gla protein metabolism in vascular smooth muscle and role in uremic vascular calcification. J Biol Chem 286:28715-22
Sutliff, Roy L; Walp, Erik R; El-Ali, Alexander M et al. (2011) Effect of medial calcification on vascular function in uremia. Am J Physiol Renal Physiol 301:F78-83
Morava, Eva; Kühnisch, Jirko; Drijvers, Jefte M et al. (2011) Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family. J Clin Endocrinol Metab 96:E189-98
O'Neill, W Charles; Lomashvili, Koba A; Malluche, Hartmut H et al. (2011) Treatment with pyrophosphate inhibits uremic vascular calcification. Kidney Int 79:512-7
Prosdocimo, Domenick A; Wyler, Steven C; Romani, Andrea M et al. (2010) Regulation of vascular smooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia. Am J Physiol Cell Physiol 298:C702-13

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