Potential treatment of calciphylaxis with vitamin K2: Comment on the article by Jacobs-Kosmin and DeHoratius

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Potential Treatment of Calciphylaxis With Vtamin K2: Comment on the Article by Jacobs-Kosmin And DeHoratius

To the Editors:

I read with interest the recent article in Arthritis Care & Research by Jacobs-Kosmin and DeHoratius describing a patient with calciphylaxis (1). Although the authors outlined several candidate mechanisms to explain this poorly understood condition, I wish to make some additional comments regarding the likely contribution of vitamin K deficiency to the pathophysiology of calciphylaxis.

Vitamin K functions solely as a cofactor for γ-glutamyl carboxylase, which is an endoplasmic reticulum enzyme that substitutes carboxyl groups for glutamic acid (glutamyl) residues on a series of proteins collectively called Gla proteins, thus rendering the proteins physiologically active (2, 3). Functionally, vitamin K1 (phylloquinone) acts primarily in the liver with clotting factors as substrates, while the primary targets of vitamin K2 (menaquinone) are osteocalcin, matrix Gla protein (MGP), and protein S. MGP is a strong inhibitor of vascular calcification. Although its expression is vitamin D3 dependent, the carboxylation that renders it active is vitamin K2 dependent (4).

Price et al (5) developed a now classic model in which they treated rats with doses of warfarin sufficient to block all oxidized vitamin K reductase activity. To prevent bleeding, they provided the animals with vitamin K1, which is an antidote for warfarin in the liver but not in extrahepatic tissues. Luo et al (6) generated an MGP knockout mouse that develops severe vascular calcification and dies by 8 weeks from aortic rupture, and they have taken advantage of this system to isolate some aspects of the arterial calcification mechanism. Price et al (5) reported that rats cotreated with warfarin and vitamin K1 show extensive medial calcification similar to MGP knockout mice, thus demonstrating that carboxylation is required to inhibit arterial calcification. Warfarin increases local expression of MGP messenger RNA (mRNA) in calcifying arteries but decreases serum MGP, both of which can be largely blocked by vitamin K2 (7). Therefore, vitamin K2 deficiency reduces MGP activity, thus impairing its function as a principal mediator for vascular decalcification.

In vitro, when vascular smooth muscle cells calcify, MGP is up-regulated when hydroxyapatite is first detected (8, 9). In arteries, MGP inhibits calcification and decreases expression of MGP mRNA, and it is routinely found during progression of intimal and medial calcification (7, 10). Calcification is always found immediately adjacent to smooth muscle cells, the putative origin of these bone-specific molecules (8), and is most abundant at the margins of calcified segments. Because the primary physiologic activity of carboxylated MGP is to bind calcium for transport, this suggests that MGP is locally up-regulated in response to calcification rather than functioning as a cause of calcium deposition (11). Consistent with this observation, it is known that extrahepatic tissues including bone and arteries accumulate K2 preferentially to K1. In arteries, K2 accumulates at the interface of normal vascular tissue (intima and media) and calcified regions (12). In addition, K2 has been shown to up-regulate the RNA of RANKL (13) and may influence calcification mediated by cytokines generated by activation of that transcription system.

Vitamin K1 is found primarily in green leafy vegetables and vegetable oils, whereas K2 is found primarily in meat, milk products, cheese, eggs, and natto (fermented soybeans). It would not be unusual for such K2-rich diets to be at least partially prohibited in patients with renal failure. In fact, it has been estimated that 5–15% of apparently healthy people have undetectable serum vitamin K levels (14). Longer chain menaquinones can be synthesized by intestinal bacteria, though that does not appear to be a significant source of these molecules (15). Although the etiology of calciphylaxis is probably multifactorial, it seems plausible from what we understand of its biochemistry and physiology that vitamin K2 deficiency may play a central role in the pathogenesis of this condition. In addition to local care of skin ulcerations, careful monitoring of calcium and phosphate levels in dialysis patients (16), and intravenous sodium thiosulphate (17–19), vitamin K2 may prove to be an effective, nontoxic therapy for this devastating disease.

Robert Levy MD*, * Cave Creek, AZ.

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