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
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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)