Pyrophosphate and Diphosphonates in Calcium Metabolism and Their Possible Role in Renal Failure

Russell, R. G. G.

doi:10.1001/archinte.1969.00300210053007

Cited by 45 publications

(16 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In any event, the highest values found are far from those representing the apparent solubility of PPi in plasma equilibrated with crystalline calcium pyrophosphate dihydrate (5) . 8 Elevated levels of plasma PPi in uremic subjects have been reported previously by Russell, Bisaz, and Fleisch (22). Only one of five samples in our series was above the normal range, although the mean of the remaining four was 2.8 /AM.…”

Section: Resultssupporting

confidence: 74%

Measurement of Inorganic Pyrophosphate in Biological Fluids, ELEVATED LEVELS IN SOME PATIENTS WITH OSTEOARTHRITIS, PSEUDOGOUT, ACROMEGALY, AND UREMIA

Silcox¹,

McCarty²

1973

J. Clin. Invest.

View full text Add to dashboard Cite

A B S T R A C T A rapid and relatively simple method for measurement of inorganic pyrophosphate (PPi) in biological samples has been described. The mean ±SEM of plasma samples from 94 normal subjects was 1.8± 0.06 AM, giving a normal range (99% confidence limits) of 0.16 -3.40 iimo/liter. Analysis of 17 plasma samples in duplicate showed a standard deviation of 0.18, giving a 99% probability that a single determination of plasma PPi would be ±0.68 4M of the true value.The mean PPi levels in plasma from subjects with osteoarthritis, pseudogout, acromegaly, and uremia were significantly greater than the normal mean (P < 0.01). Samples from rheumatoid arthritis showed PPi levels distributed about a mean identical to the normal mean. Plasma inorganic orthophosphate levels correlated positively with PPi levels in samples from normal subjects and in samples from patients with osteoarthritis, pseudogout, and uremia, but not with acromegaly. This correlation was statistically significant only in the normal samples and in those from patients with osteoarthritis.

show abstract

Section: Resultssupporting

confidence: 74%

Measurement of Inorganic Pyrophosphate in Biological Fluids, ELEVATED LEVELS IN SOME PATIENTS WITH OSTEOARTHRITIS, PSEUDOGOUT, ACROMEGALY, AND UREMIA

Silcox¹,

McCarty²

1973

J. Clin. Invest.

View full text Add to dashboard Cite

show abstract

“…Pyrophosphate inhibits hydroxyapatite formation in vitro (26,29,30), and exogenous pyrophosphate inhibits aortic calcification in rats that are given large doses of vitamin D 3 (31,32). Diphosphonates, which are analogs of pyrophosphate, exhibit the same properties (33,34). It is likely that the inhibition by endogenous pyrophosphate demonstrated in cultured rat aortas also occurs in vivo because the concentration that maximally inhibited calcification in injured aortas (~3 M) is similar to that reported for normal human plasma (35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 69%

Phosphate-Induced Vascular Calcification

Lomashvili¹,

Cobbs²,

Hennigar³

et al. 2004

Journal of the American Society of Nephrology

291

248

View full text Add to dashboard Cite

Abstract. Hyperphosphatemia is thought to underlie medial vascular calcification in advanced renal failure, but calcification can occur in other conditions in the absence of hyperphosphatemia, indicating that additional factors are important. To identify these factors, a model of medial calcification in rat aorta in vitro was developed. Aortic rings from rats were incubated in serum-free medium for 9 d, and calcification was measured as incorporation of 45 Ca and confirmed by histology and x-ray diffraction. No calcification occurred in normal vessels despite elevated free Ca 2ϩ and PO 4 3Ϫ concentrations of 1.8 mM and 3.8 mM, respectively, but mechanical injury resulted in extensive calcification in the media. Co-incubation studies revealed that normal aortas produced a soluble inhibitor of calcification in injured vessels that was destroyed by alkaline phosphatase. Culture of normal aortas with alkaline phosphatase resulted in calcification of the elastic lamina identified as hydroxyapatite by x-ray diffraction. This effect of alkaline phosphatase was not due to dephosphorylation of osteopontin (OPN), and calcification was not increased in aortas from OPN-deficient mice. The inhibitor was identified as pyrophosphate on the basis of the calcification induced in aortas cultured with inorganic pyrophosphatase, the inhibition of calcification in injured aortas by pyrophosphate, and the production of inhibitory levels of pyrophosphate by normal aortas. No calcification occurred under any conditions at a normal PO 4 3Ϫ concentration. It is concluded that elevated concentrations of Ca 2ϩ and PO 4 3Ϫ are not sufficient for medial vascular calcification because of inhibition by pyrophosphate. Alkaline phosphatase can promote calcification by hydrolyzing pyrophosphate, but OPN is not an endogenous inhibitor of calcification in rat aorta.Arterial calcification is common in patients with advanced renal failure and ESRD and is thought to contribute to their increased cardiovascular mortality (1). Two distinct forms of calcification are recognized (2,3). Intimal calcification occurs in atheromatous disease and is associated with inflammatory cells (3), whereas medial calcification occurs in the matrix between smooth muscle cells in the absence of atherosclerosis and inflammatory cells (2,4). Medial calcification commonly occurs in advanced renal failure (4,5), where it is thought to result from plasma concentrations of Ca 2ϩ and PO 4 3Ϫ that exceed the solubility product for calcium phosphate. However, medial calcification is also seen in diabetes and with aging in the presence of normal serum Ca 2ϩ and PO 4 3Ϫ concentrations (6), indicating that hyperphosphatemia is not required for medial calcification.Considerable data suggest that vascular calcification is a spontaneous event, even at normal calcium and phosphate concentrations, that is prevented by inhibitory factors within the vessel wall. Several proteins have been implicated in this process. Mice deficient in matrix Gla protein (MGP) develop rapid and severe medial ...

show abstract

“…In uremic patients, the active secretion by sweat glands of calcium, phosphate and magnesium -in contrast to the secretion of monovalent ions [11] -could also contribute to the removal of calcium and phosphate from the skin. An increase in local or systemic inhibitors of calcification, such as magnesium and inorganic pyrophosphate [1,13], might stabilize the initial amorphous calcium phos phate deposits and delay or prevent conversion to crystalline hydroxyapatite. These crystal inhibitors were found to be present in increased amounts in visceral amorphous calcium phosphate deposits [1], but an increase in pyro phosphate has, to our knowledge, not been demonstrated in the skin.…”

Section: Discussionmentioning

confidence: 99%