Plasma pyrophosphate and vascular calcification in chronic kidney disease

O’Neill, W. Charles; Sigrist, Mhairi K.; McIntyre, Christopher W.

doi:10.1093/ndt/gfp362

Cited by 138 publications

(111 citation statements)

References 19 publications

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“…Nevertheless, it is becoming apparent that systemic pyrophosphate levels play a key role in preventing unwanted soft tissue calcification. As already mentioned plasma pyrophosphate is reduced in patients with vascular calcification [81,82].…”

Section: Circulating Pyrophosphatesupporting

confidence: 51%

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Pyrophosphate: a key inhibitor of mineralisation

Orriss

Arnett

Russell

2016

Current Opinion in Pharmacology

145

105

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Section: Circulating Pyrophosphatesupporting

confidence: 51%

“…Vascular calcification is particularly common in patients with advanced chronic kidney disease, where it is inversely correlated with circulating pyrophosphate levels [81,82]. Early work reported that aortic calcification was inhibited by pyrophosphate injections [83].…”

Section: Pyrophosphate and Vascular Calcificationmentioning

confidence: 99%

Pyrophosphate: a key inhibitor of mineralisation

Orriss

Arnett

Russell

2016

Current Opinion in Pharmacology

145

105

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“…Recent studies support the hypothesis that these associations are mediated by vascular calcification (14,15), although medial calcification is seen almost exclusively in patients with advanced kidney disease and diabetes and not in the general population (16). These findings are clinically relevant because medial and intimal vascular calcification have been shown to predict cardiovascular risk in dialysis patients (17) and the general population (18).…”

mentioning

confidence: 74%

Serum Alkaline Phosphatase and Phosphate and Risk of Mortality and Hospitalization

Abramowitz

Muntner

Coco³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Background and objectives: Elevated alkaline phosphatase (AlkPhos) and phosphate levels are associated with cardiovascular morbidity and mortality in patients receiving dialysis. A retrospective cohort study was conducted to test these associations in outpatients with an estimated GFR >60 ml/min/1.73 m 2 .Design, setting, participants, & measurements: Patients with serum AlkPhos and phosphate levels measured between 2000 and 2002 (n ‫؍‬ 10,743) at Montefiore Medical Center (MMC) clinics were followed through September 11, 2008 (median 6.8 years). Mortality data were obtained via Social Security Administration records (n ‫؍‬ 949 deaths). Hospitalization data were obtained from MMC records.Results: The mean age was 51 years, 64% were women, 22% were white, 26% were non-Hispanic black, 16% were Hispanic, 13% had a diagnosis of hypertension, 9% had diabetes mellitus, and 8% had cardiovascular disease at baseline. AlkPhos and phosphate were independently associated with mortality and cardiovascular-related hospitalization after multivariable adjustment. Comparing patients in the highest (>104 U/L) versus lowest quartile of AlkPhos (<66 U/L), the adjusted hazard ratio (HR) for mortality was 1.65 (P trend across quartiles <0.001). For the highest compared with the lowest quartile of serum phosphate (>3.8 mg/dl versus <3.0 mg/dl), the adjusted HR for mortality was 1.29 (P trend across quartiles ‫؍‬ 0.008). High AlkPhos but not phosphate levels were also associated with all-cause, infection-related, and fracture-related hospitalization.Conclusions: Higher levels of serum AlkPhos and phosphate were associated with increased mortality and cardiovascularrelated hospitalization in an inner-city clinic population. Further studies are needed to elucidate mechanisms underlying these associations.

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“…However, it is not clear whether ePP i levels in vessels in vivo are controlled by local activity of these enzymes rather than by systemic activity via circulating ePP i levels and whether this affects vascular calcification. Although circulating PP i levels are inversely proportional to arterial calcification in patients with advanced chronic kidney disease (14), the correlation is weak and the role of PP i metabolism in the arterial wall has never been investigated.…”

mentioning

confidence: 99%

Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle

Villa‐Bellosta

Wang

Millán

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

127

145

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Villa-Bellosta R, Wang X, Millán JL, Dubyak GR, O'Neill WC. Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle. Am J Physiol Heart Circ Physiol 301: H61-H68, 2011. First published April 13, 2011; doi:10.1152/ajpheart.01020.2010 is an important endogenous inhibitor of vascular calcification, but it is not known whether systemic or local vascular PPi metabolism controls calcification. To determine the role of ePP i in vascular smooth muscle, we identified the pathways responsible for ePPi production and hydrolysis in rat and mouse aortas and manipulated them to demonstrate their role in the calcification of isolated aortas in culture. Rat and mouse aortas contained mRNA for ectonucleotide pyrophosphatase/phosphodiesterases (NPP1-3), the putative PP i transporter ANK, and tissue-nonspecific alkaline phosphatase (TNAP). Synthesis of PPi from ATP in aortas was blocked by ␤,␥-methylene-ATP, an inhibitor of NPPs. Aortas from mice lacking NPP1 (Enpp1 Ϫ/Ϫ ) did not synthesize PPi from ATP and exhibited increased calcification in culture. Although ANK-mediated transport of PPi could not be demonstrated in aortas, aortas from mutant (ank/ank) mice calcified more in culture than did aortas from normal (ANK/ANK) mice. Hydrolysis of PPi was reduced 25% by ␤,␥-methylene-ATP and 50% by inhibition of TNAP. Hydrolysis of PP i was increased in cells overexpressing TNAP or NPP3 but not NPP1 and was not reduced in Enpp1 Ϫ/Ϫ aortas. Overexpression of TNAP increased calcification of cultured aortas. The results show that smooth muscle NPP1 and TNAP control vascular calcification through effects on synthesis and hydrolysis of ePPi, indicating an important inhibitory role of locally produced PP i. Smooth muscle ANK also affects calcification, but this may not be mediated through transport of PP i. NPP3 is identified as an additional pyrophosphatase that could influence vascular calcification. medial calcification; alkaline phosphatase; ectonucleotide pyrophosphorylase; adenosine 5=-triphosphate; ankyrin EXTRACELLULAR INORGANIC PYROPHOSPHATE (ePP i ) is a potent suppressor of vascular calcification both in vitro (8) and in vivo (13, 18) through its ability to inhibit hydroxyapatite formation (10). The importance of endogenous ePP i homeostasis in human cardiovascular function is demonstrated by the severe arterial calcification that occurs in the absence of a synthetic enzyme (17). Cells contain ectoenzymes capable of synthesizing and hydrolyzing ePP i , and our previous studies in cultured vascular smooth muscle cells have implicated them in the control of ePP i levels (15). However, it is not clear whether ePP i levels in vessels in vivo are controlled by local activity of these enzymes rather than by systemic activity via circulating ePP i levels and whether this affects vascular calcification. Although circulating PP i levels are inversely proportional to arterial calcification in patients with advanced chronic kidney disease (14), the correlation is weak and the role of PP i metabolism in the arterial...

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Plasma pyrophosphate and vascular calcification in chronic kidney disease

Cited by 138 publications

References 19 publications

Pyrophosphate: a key inhibitor of mineralisation

Pyrophosphate: a key inhibitor of mineralisation

Serum Alkaline Phosphatase and Phosphate and Risk of Mortality and Hospitalization

Extracellular pyrophosphate metabolism and calcification in vascular smooth muscle

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