Clinical trial NCT01101698: Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
Official title: Influence of Vitamin K2 Administration on Vessel Calcification Markers in Patients With Chronic Kidney Disease
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Kidney Diseases
Coronary Artery Calcification
Keywords: Vitamin K
chronic kidney disease
coronary artery calcification
intima media thickness
Lead sponsor: Medical University of Lodz
Sponsor class: OTHER
First posted: 2010-04-12
Enrollment: 60
Sex: ALL
Minimum age (years): 30
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Vessel calcification is a recognised cardiovascular morbidity risk factor in patients with chronic kidney disease (CKD). Recent reports indicate a significant role of Matrix Gla-protein (MGP) in decreasing calcification processes. MGP is excretion protein whose mechanism of action is not yet fully explained and which to be activated requires phosphorylation and carboxylation where cofactor is vitamin K. These observations indicate that shortage of vitamin K is a significant risk factor for the development of vessel calcification. Another calcification risk factor in CKD patients are calcium-phosphate disturbances and insufficiency of vitamin D3 which in physiological concentration stimulates MGP transcription. The aim of this study is estimation of influence of vitamin K2 administration over the period of 9 months on vessel calcification in 3.- 5. stage CKD patients.

It is a prospective, randomised double-blind study carried out in parallel groups. 60 patients with CKD (GFR 15-60 ml/min) with calcium score \>10 (Agatston scoring system) will be qualified for the study. On the basis of randomised selection, patients will be divided into two groups: 30 patients will be given 90 μg vitamin K2 + 10 μg and cholecalciferol 30 patients will be given only 10 μg cholecalciferol. After a 9-month treatment the image diagnostic will be carried out in order to estimate the degree of vessel calcification.

Detailed description: Vessel calcification is a recognised cardiovascular morbidity risk factor in patients with chronic kidney disease (CKD). Recent reports indicate a significant role of Matrix Gla-protein (MGP) in decreasing calcification processes. MGP is excretion protein whose mechanism of action is not yet fully explained and which to be activated requires phosphorylation and carboxylation where cofactor is vitamin K. Immunohistochemical tests showed a high level of un-carboxylated MGP in calcified vessels. These observations indicate that shortage of vitamin K is a significant risk factor for the development of vessel calcification. On the other hand CKD patients often display shortages of this vitamin. Another calcification risk factor in CKD patients are calcium-phosphate disturbances and insufficiency of vitamin D3 which in physiological concentration stimulates MGP transcription. Cranenburg et al. showed a decrease vessel calcification in dialysis patients treated with vitamin K2. Vitamin K2 exists in two forms K1 and K2, however only the K2 form displays calcification decreasing properties. There are currently no similar studies in patients with chronic kidney disease who do not require renal replacement therapy.

The aim of study. The aim of this study is estimation of influence of vitamin K2 administration over the period of 9 months on vessel calcification in 3.- 5. stage CKD patients.

Materials and methods. It is a prospective, randomised double-blind study carried out in parallel groups. 60 patients with CKD (GFR 15-60 ml/min) whose renal replacement therapy is to commence not earlier than in 9 months are planned to be qualified for the study. After familiarizing the patients with the aims of the study and obtaining their written consent, non-invasive tests will be carried out in order to estimate the presence and degree of vessel calcification: common carotid artery intima media thickness (CCA-IMT) by ultrasound examination, coronary artery calcium score (CACS) by multiscan CT as well as the presence of calcified heart valves by ultrasound examination. Patients with calcium score \>10 (Agatston scoring system) will be qualified for the study. On the basis of randomised selection, patients will be divided into two groups: 30 patients will be given 90 μg vitamin K2+10 μg cholecalciferol (Vitamin D)and 30 patients will be given only 10 μg cholecalciferol. After a 9-month treatment the image diagnostic will be carried out in order to estimate the degree of vessel calcification. Patients and their basic laboratory test will be evaluated during the study period by a nephrologists on a monthly basis. First, at the commencement of the study, then after 3, 6 and finally after 9 months during the last visit, 10 ml of serum and plasma will be taken and frozen in order to conduct special marking tests: phosphorylated MGP (pMGP), uncarboxylated MGP (ucMGP), 25-OH cholecalciferol, hsCRP.

Scheduling Study Visits:

Visit 0 Screening Period

1. Review of inclusion and exclusion criteria
2. Obtain informed consent
3. Obtain weight and height
4. Obtain CACS, CCA-IMT
5. Obtain heart ultrasonography
6. Review concomitant therapy

Visit 1 - Randomization

1. Review of inclusion and exclusion criteria
2. Medical history for concomitant disorders (hypertension, heart ischemic diseases, diabetes mellitus)
3. Collect blood for serum chemistry (creatinine, albumin, intact PTH, calcium, phosphor, uric acid, lipids, glucose, kaolin-kephalin time, prothrombin index and blood morphology.
4. Collect blood for pMGP, ucMGP, 25-OH cholecalciferol, hsCRP
5. Review concomitant therapy
6. Randomization to: 90 μg vitamin K2+10μg cholecalciferol or 10μg cholecalciferol (Vitamin D) during 9 months

Visit 2,4,5,7,8 Visits every month

1. Complete physical examination
2. GFR obtain
3. Drug dispension

Visit 3,6 and after 9 months:

1. Complete physical examination
2. GFR obtain
3. Collect blood for serum chemistry (creatinine, albumin, intact PTH, calcium, phosphor, uric acid, lipids, glucose, kaolin-kephalin time, prothrombin index and blood morphology.
4. Collect blood for pMGP, ucMGP, 25-OH cholecalciferol, hsCRP
5. Obtain CACS, CCA-IMT
6. Obtain heart ultrasonography
7. Review concomitant therapy

Eligibility criteria: Inclusion Criteria:

1. Subject with chronic kidney disease (creatinine clearance 15-60 ml/min/1,73m2 by Cockroft-Gault formula)
2. Patient has a life without dialysis therapy of more than 9 months
3. Subject in 30-70 years of age
4. Calcium score \>10 (as per Agatston scoring system)

Exclusion Criteria:

1. Atherosclerosis generalisata (myocardial infarction treated with PTCA - Percutaneous Transluminal Coronary Angioplasty or CABG - Coronary Artery Bypass Graft, symptomatic heart insufficiency, cerebrovascular accident)
2. Subject with a history of cardiac abnormalities, including symptomatic or asymptomatic arrhythmias (atrial fibrillation)
3. Patient with cardiac pacemaker
4. Subject requires long-term use of vitamin K antagonists

Primary outcomes:
measure: Changes in coronary artery calcification score
timeFrame: 9 months
Secondary outcomes:
measure: Changes in common carotid artery intima media thickness
timeFrame: 9 months
Other outcomes:
Locations:
city: Łódź
country: Poland
facility: Department of Nephrology, Hypertension and Kidney Transplantation
Study officials:
References:
citation: Pilkey RM, Morton AR, Boffa MB, Noordhof C, Day AG, Su Y, Miller LM, Koschinsky ML, Booth SL. Subclinical vitamin K deficiency in hemodialysis patients. Am J Kidney Dis. 2007 Mar;49(3):432-9. doi: 10.1053/j.ajkd.2006.11.041.
citation: Schurgers LJ, Cranenburg EC, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. 2008 Oct;100(4):593-603.
citation: Cranenburg EC, Vermeer C, Koos R, Boumans ML, Hackeng TM, Bouwman FG, Kwaijtaal M, Brandenburg VM, Ketteler M, Schurgers LJ. The circulating inactive form of matrix Gla Protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res. 2008;45(5):427-36. doi: 10.1159/000124863. Epub 2008 Apr 10.
citation: Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, Kaczmarska M, Stefanczyk L, Vermeer C, Maresz K, Nowicki M. Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3-5. Pol Arch Med Wewn. 2015;125(9):631-40. doi: 10.20452/pamw.3041. Epub 2015 Jul 15.