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Kidney Int. 2014 Aug;86(2):286-93. doi: 10.1038/ki.2013.530. Epub 2014 Jan 15.

Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation.

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Department of Nephrology, RWTH University Hospital Aachen, Aachen, Germany.
VitaK BV, University of Maastricht, Maastricht, The Netherlands.
Department of Environmental and Social Medicine, University Hospital of the RWTH Aachen, Aachen, Germany.
Department of Cardiology, RWTH University Hospital Aachen, Aachen, Germany.
Department of Internal Medicine IV, Saarland University Medical Centre, Homburg, Germany.


In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.

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