Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol

Nephrology Dialysis Transplantation, Sep 2014

Background Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients.

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Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol

Nephrol Dial Transplant Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial ): a rationale and study protocol Thilo Krueger 0 1 2 3 5 7 9 13 Georg Schlieper 0 1 2 3 5 7 9 13 Leon Schurgers 0 1 2 3 5 7 9 11 Tom Cornelis 0 1 2 3 5 7 9 10 Mario Cozzolino 0 1 2 3 5 7 9 17 Johannes Jacobi 0 1 2 3 5 7 9 16 Michel Jadoul 0 1 2 3 5 7 9 15 Markus Ketteler 0 1 2 3 5 7 9 14 Lars C. Rump 0 1 2 3 5 7 9 16 Peter Stenvinkel 0 1 2 3 5 7 9 18 Ralf Westenfeld 0 1 2 3 5 7 9 12 Andrzej Wiecek 0 1 2 3 5 6 7 9 Sebastian Reinartz 0 1 2 3 5 7 8 9 Ralf-Dieter Hilgers 0 1 2 3 4 5 7 9 Jürgen Floege 0 1 2 3 5 7 9 13 0 Hypertension, University of Erlangen-Nuremberg , Erlangen , Germany 1 University Medical Center , Maastricht , The Netherlands 2 (CARIM), University of Maastricht , Maastricht , The Netherlands 3 The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved 4 Institute of Medical Statistics, RWTH University Aachen , Aachen , Germany 5 and Metabolic Diseases, Medical University of Silesia , Katowice , Poland 6 Department of Nephrology , Endocrinology 7 University Hospital of Duesseldorf , Germany 8 Department of Radiology, Uniklinik RWTH Aachen , Aachen 9 catholique de Louvain , Brussels , Belgium 10 Department of Internal Medicine, Division of Nephrology , Maastricht 11 Cardiovascular Research Institute Maastricht 12 Department of Cardiology, University Hospital of Duesseldorf , Duesseldorf , Germany 13 Department of Nephrology and Immunology, Uniklinik RWTH Aachen , Aachen , Germany 14 Department of Nephrology, Klinikum Coburg , Coburg , Germany 15 Division of Nephrology, Cliniques universitaires Saint-Luc Université 16 Department of Nephrology 17 Renal Division, University of Milan , Milan , Italy 18 Department of Renal Medicine, Karolinska University Hospital at Huddinge , Stockholm Correspondence and offprint requests to: T. Krueger; E-mail: haemodialysis; matrix Gla protein; vascular calcification; vitamin K - A B S T R A C T Background. Patients on haemodialysis (HD) exhibit increased cardiovascular mortality associated with accelerated vascular calcification (VC). VC is influenced by inhibitors such as matrix Gla protein (MGP), a protein activated in the presence of vitamin K. HD patients exhibit marked vitamin K deficiency, and supplementation with vitamin K reduces inactive MGP levels in these patients. The VitaVasK trial analyses whether vitamin K1 supplementation affects the progression of coronary and aortic calcification in HD patients. Methods. VitaVasK is a prospective, randomized, parallel group, multicentre trial (EudraCT No.: 2010-021264-14) that will include 348 HD patients in an open-label, two-arm design. After baseline multi-slice computed tomography (MSCT) of the heart and thoracic aorta, patients with a coronary calcification volume score of at least 100 will be randomized to continue on standard care or to receive additional supplementation with 5 mg vitamin K1 orally thrice weekly. Treatment duration will be 18 months, and MSCT scans will be repeated after 12 and 18 months. Primary end points are the progression of thoracic aortic and coronary artery calcification (calculated as absolute changes in the volume scores at the 18-month MSCT versus the baseline MSCT). Secondary end points comprise changes in Agatston score, mitral and aortic valve calcification as well as major adverse cardiovascular events (MACE) and all-cause mortality. VitaVask also aims to record MACE and all-cause mortality in the follow-up period at 3 and 5 years after treatment initiation. This trial may lead to the identification of an inexpensive and safe treatment or prophylaxis of VC in HD patients. I N T R O D U C T I O N A N D R A T I O N A L E Patients on haemodialysis (HD) suffer from extensive cardiovascular calcifications (VCs). VC is an independent risk factor and might explain the excessively increased cardiovascular mortality in this population [1, 2]. In the past, the development of VC was discovered to be actively regulated and influenced by inhibitors of calcification [e.g. matrix Gla protein (MGP), fetuin-A] [3–5]. MGP is a powerful vascular wallbased inhibitor of VC. It is produced by vascular smooth muscle cells and requires vitamin K-dependent post-translational modification, namely gamma carboxylation, to be fully active. The role of MGP was discovered in knock-out mice, that died from rupture of a massively calcified aorta [6]. Warfarin, a vitamin K antagonist, inhibits the activation of MGP thereby mimicking the MGP knock-out phenotype. Indeed, functional vitamin K deficiency, induced by warfarin, accelerates VC in the normal population [7] and in HD patients [8], as well as in rodents [9]. Warfarin is also a potent risk factor for the development of calciphylaxis, a life-threatening complication in HD patients characterized by calcified cutaneous vessels [10]. In rodents, warfarin-induced VC can be inhibited and even regressed b (...truncated)


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Thilo Krueger, Georg Schlieper, Leon Schurgers, Tom Cornelis, Mario Cozzolino, Johannes Jacobi, Michel Jadoul, Markus Ketteler, Lars C. Rump, Peter Stenvinkel, Ralf Westenfeld, Andrzej Wiecek, Sebastian Reinartz, Ralf-Dieter Hilgers, Jürgen Floege. Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol, Nephrology Dialysis Transplantation, 2014, pp. 1633-1638, 29/9, DOI: 10.1093/ndt/gft459