What is Calciphylaxis?

Calciphylaxis and Calcification Inhibitors

Most predisposing factors to calciphylaxis involve a dysregulation in the balance of local and systemic calcium-regulatory factors. Current data focus on the importance of matrix Gla protein (MGP) and fetuin-A (alpha2-Heremans Schmid Glykoprotein, AHSG) as prototypic calcification inhibitors.

MGP is a 10 kD protein exclusively expressed in vascular smooth muscle cells (VSMC) and chondrocytes. This protein requires post-translational vitamin K-dependent gamma-carboxylation for activation. Accordingly, warfarin treatment suppresses MGP activation. Knockout of the MGP gene in mice (MGP-/-) causes severe medial calcification of large arteries with subsequent rupture of the ossified aorta; MGP-/- mice actually die of internal arterial haemorrhage at the age of 6 – 8 weeks. MGP acts purely as local inhibitor, and systemic over expression is not capable of counteracting arterial calcification induced by MGP-/-. Analogously, medial calcification can also be induced by treatment with vitamin K antagonists. In rats, warfarin-induced vascular calcification can be partially reversed by feeding supraphysiological doses of vitamin K1 or K2 following withdrawal of warfarin, whereas calcification progresses when only low doses of vitamin K are fed.

A second potentially important calcification inhibitor is fetuin-A. Fetuin-A is a 60-kD glycoprotein produced in the liver and probably the most potent circulating calcification inhibitor. Extracellular concentrations are as high as 0.5 – 1.0 g/l under normal conditions; in fact, fetuin-A represents a major proportion of the alpha2-band on serum electrophoresis. Importantly, this glycoprotein is regulated as a negative phase reactant. Thus, in situations of acute or chronic inflammation, blood and tissue levels of this calcification inhibitor may drop significantly and deficiency may occur. Of note, most of the very rare cases of calciphylaxis in patients with normal renal function were reported in active chronic inflammatory diseases.

Fetuin-A knockout (fetuin-A-/-) mice spontaneously develop massive organ and soft-tissue calcification. A large proportion of patients on dialysis show fetuin-A serum levels below the normal range, and fetuin-A deficiency is related to increased all-cause and cardiovascular mortality in this patient group. In some calciphylaxis patients, very low fetuin-A serum levels (range: 0.09 – 0.25 g/l) have been detected in the context of highly elevated CRP levels.