title: Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation.
abstract: 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.
authors.affiliation: Department of Nephrology, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kaesler
authors.affiliation: VitaK BV, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Elke
authors.initials: E
authors.lastname: Magdeleyns
authors.affiliation: VitaK BV, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Herfs
authors.affiliation: Department of Environmental and Social Medicine, University Hospital of the RWTH Aachen, Aachen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schettgen
authors.affiliation: Department of Cardiology, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Vincent
authors.initials: V
authors.lastname: Brandenburg
authors.affiliation: Department of Internal Medicine IV, Saarland University Medical Centre, Homburg, Germany.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fliser
authors.affiliation: VitaK BV, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: Vermeer
authors.affiliation: Department of Nephrology, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Floege
authors.affiliation: Department of Nephrology, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schlieper
authors.affiliation: Department of Nephrology, RWTH University Hospital Aachen, Aachen, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Krüger
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002114:Calcinosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D002135:Calcium-Binding Proteins / Q000097:blood; D019735:Carbon-Carbon Ligases / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000097:blood; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014511:Uremia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D014812:Vitamin K / Q000008:administration & dosage* / Q000378:metabolism*; D010837:Vitamin K 1 / Q000378:metabolism; D024482:Vitamin K 2 / Q000378:metabolism; D014813:Vitamin K Deficiency / Q000097:blood / Q000378:metabolism; D000097568:Matrix Gla Protein
chemical_list: D002135:Calcium-Binding Proteins; D019735:Carbon-Carbon Ligases; D016326:Extracellular Matrix Proteins; D016660:NAD(P)H Dehydrogenase (Quinone); D014812:Vitamin K; D010837:Vitamin K 1; D024482:Vitamin K 2; D000097568:Matrix Gla Protein; C020660:glutamyl carboxylase