Phosphate binders affect vitamin K concentration by undesired binding, an in vitro study.

BACKGROUND: Vascular calcification is a major contributing factor to mortality in end stage renal disease (ESRD). Despite the efficacy of phosphate binders to improve hyperphosphatemia, data on vascular calcification are less clear. There seems to be a difference in attenuation or delay in progression between different binders. In this in vitro experiment we tested whether phosphate binders could limit bioavailability of vitamin K2 by undesired binding. Vitamin K-deficiency limits activation of the vascular tissue mineralization inhibitor matrix γ-carboxyglutamate (Gla) protein (MGP) thereby exacerbating vascular calcification. METHODS: In this experiment vitamin K2 (menaquinone-7; MK-7) binding was assessed by adding 1 mg of vitamin K2 to a medium with pH 6 containing 67 mg phosphate binder with either 7 mg of phosphate or no phosphate. Five different phosphate binders were tested. After five and a half hours vitamin K was analyzed by HPLC. All experiments were performed in triplicate. RESULTS: Sucroferric-oxyhydroxide and sevelamer carbonate did not significantly bind vitamin K2, both in solution only containing vitamin K2 or in combination with phosphate. Calcium acetate/magnesium carbonate binds vitamin K2 strongly both in absence (p = 0.001) and presence of phosphate (p = 0.003). Lanthanum carbonate significantly binds vitamin K2 in solution containing only vitamin K2 (p = 0.005) whereas no significant binding of vitamin K2 was observed in the solution containing vitamin K2 and phosphate (p = 0.462). Calcium carbonate binds vitamin K2 significantly in a solution with vitamin K2 and phosphate (p = 0.009) whereas without phosphate no significant binding of vitamin K2 was observed (p = 0.123). CONCLUSIONS: Sucroferric-oxyhydroxide and sevelamer carbonate were the only binders of the five binders studied that did not bind vitamin K2 in vitro. The presence or absence of phosphate significantly interferes with vitamin K2 binding so phosphate binders could potentially limit bioavailability vitamin K2.

The influence of phosphate, calcium and magnesium on matrix Gla-protein and vascular calcification: a systematic review.

Vitamin K-dependent matrix Gla protein (MGP) is a key inhibitor of vascular calcification (VC). MGP is synthesized by chondrocytes and vascular smooth muscle cells (VSMC) and the absence or inactivity of MGP results in excessive calcification of both growth plate and vasculature. Apart from its vitamin K dependency little is known about other factors that influence MGP metabolism. Phosphate, calcium and magnesium are involved in bone mineralization and play an important role in VC. In this review we provide a summary of the effect of phosphate, calcium, and magnesium on MGP metabolism. Elevated phosphate and calcium levels promote VC, in part by increasing the release of matrix vesicles (MV) that under the influence of calcium and phosphate become calcification competent. Phosphate and calcium simultaneously induce an upregulation of MGP protein and gene expression, which possibly inhibits calcification. Elevated phosphate levels did not change MGP protein levels in MV. On the contrary, elevated calcium concentrations caused a decrease of MGPloading in MV, which might in part explainthe calcifying effects of MV. Magnesium is a known inhibitor of VC. However, magnesium has been shown to have an inhibitory effect on MGP synthesis induced through downregulation of the calcium-sensing receptor and hereby causing a decrease in calcium induced MGP upregulation. There might also be stimulatory effect of magnesium on MGP in which the TRPM7 channel is involved. In conclusion there is a clear interaction between MGP and phosphate, calcium and magnesium. The upregulation of MGP by phosphate and calcium might be a cellular response that possibly results in the mitigation of VC.