Abstract
BackgroundExtracellular pyrophosphate is a potent endogenous inhibitor of vascular calcification, which is degraded by alkaline phosphatase (ALP) and generated by hydrolysis of ATP via ectonucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1). ALP activity (as routinely measured in clinical practice) represents the maximal activity (in ideal conditions), but not the real activity (in normal or physiological conditions). For the first time, the present study investigated extracellular pyrophosphate metabolism during hemodialysis sessions (including its synthesis via eNPP1 and its degradation via ALP) in physiological conditions.Methods and Findings45 patients in hemodialysis were studied. Physiological ALP activity represents only 4–6% of clinical activity. ALP activity increased post-hemodialysis by 2% under ideal conditions (87.4 ± 3.3 IU/L vs. 89.3 ± 3.6 IU/L) and 48% under physiological conditions (3.5 ± 0.2 IU/L vs. 5.2 ± 0.2 IU/L). Pyrophosphate synthesis by ATP hydrolysis remained unaltered post-hemodialysis. Post-hemodialysis plasma pH (7.45 ± 0.02) significantly increased compared with the pre-dialysis pH (7.26 ± 0.02). The slight variation in pH (~0.2 units) induced a significant increase in ALP activity (9%). Addition of phosphate in post-hemodialysis plasma significantly decreased ALP activity, although this effect was not observed with the addition of urea. Reduction in phosphate levels and increment in pH were significantly associated with an increase in physiological ALP activity post-hemodialysis. A decrease in plasma pyrophosphate levels (3.3 ± 0.3 μmol/L vs. 1.9 ± 0.1 μmol/L) and pyrophosphate/ATP ratio (1.9 ± 0.2 vs. 1.4 ± 0.1) post-hemodialysis was also observed.ConclusionExtraction of uremic toxins, primarily phosphate and hydrogen ions, dramatically increases the ALP activity under physiological conditions. This hitherto unknown consequence of hemodialysis suggests a reinterpretation of the clinical value of this parameter.
Highlights
Vascular calcification (VC), or ectopic calcification in vessels, is highly prevalent in patients with chronic hemodialysis, and is associated with cardiovascular events and all-cause mortality [1,2]
Extracellular pyrophosphate is a potent endogenous inhibitor of vascular calcification, which is degraded by alkaline phosphatase (ALP) and generated by hydrolysis of ATP via ectonucleotide pyrophosphatase/phosphodiesterase 1
ALP activity increases after hemodialysis in physiological conditions Standard protocols for the quantification of ALP activity utilize a buffer that results in maximal ALP activity
Summary
Vascular calcification (VC), or ectopic calcification in vessels, is highly prevalent in patients with chronic hemodialysis, and is associated with cardiovascular events and all-cause mortality [1,2]. Plasma phosphate and calcium phosphate product correlate with mortality risk in chronic hemodialysis patients, a number of studies indicate that this is not the full explanation. PPi is generated enzymatically by extracellular ATP hydrolysis via ectonucleotide pyrophosphatase/phosphodiesterase (eNPP) and is degraded to Pi by alkaline phosphatase (ALP)[10]. The addition of ALP in culture media causes vascular smooth muscle calcification[12], and in vivo overexpression of ALP in smooth muscle cells results in excessive VC[12]. Extracellular pyrophosphate is a potent endogenous inhibitor of vascular calcification, which is degraded by alkaline phosphatase (ALP) and generated by hydrolysis of ATP via ectonucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1). The present study investigated extracellular pyrophosphate metabolism during hemodialysis sessions (including its synthesis via eNPP1 and its degradation via ALP) in physiological conditions
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