Vitamin K2 Supplementation and Vascular Calcification

Renal Disease Clinical Trial

Official title:

Effect of Vitamin K2 Supplementation on Vascular Calcification in Hemodialysis Patients: a Controlled Randomized Trial.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04539418
• Other study ID #: UCASAL-VITK
• Status: Completed
• Phase: Phase 4
• Start date: December 1, 2016
• Est. completion date: June 30, 2017

Study information

• Verified date: September 2020
• Source: Catholic University of Salta
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Vascular calcification is the leading cause of death in patients with end stage renal disease (ESRD) in hemodialysis. The protein matrix Gla vitamin K dependent (MGP) is a potent inhibitor of the vascular calcification. Objective: To evaluate the effect of vitamin K2 on vascular calcification in patients on hemodialysis. Materials and Methods: A prospective, randomized, double-blind study will be performed. The study subjects will be divided into a control (1000 µl of saline) or treated group (1000 µl containing 2000 µg of Vitamin K2). Vitamin K2 will be administered three times a week intravenously at the end of each dialysis session. Blood samples for biochemical determinations and vascular calcification will be assessed before and after 6 months of treatment through carotid Doppler ultrasound.

Description:

This study is designed according to the ethical reference framework for biomedical research of the Declaration of Helsinki. Its design is prospective, randomized, double blind. Study subjects will be assigned either Arm 1 or control (vial with 1000 μL of saline) or Arm 2 or treated group (vial with 1000 μL containing 2000 μg of Vitamin K2). The trial protocol was approved by the ethics committee of the Catholic University of Salta and written informed consent will be made available to all patients who agree to participate and meet the inclusion criteria. Vascular calcification will be evaluated at the beginning of the study to determine the presence of vascular calcification and at the end of the study to assess changes, if any. The carotid artery examination will be performed with a GE VIVID 5 (GE Healthcare, Little Chalfont, Buckinghamshire, UK) with a 7.5 MHz linear probe. The protocol used to obtain images is consistent with the recommendations of the American Society of Echocardiography. Longitudinal images will be obtained by means of B-mode ultrasound, the maximum and the global median intima thickness (EIM) value of the common carotid artery and the presence of carotid plaques (defined as isolated and focal areas of the abnormal intima that protrude into the lumen more than 1.5 mm or at least 50% of the surrounding total mean intimate value). The EIM represents the thickness of the intima, plus the component of the mean of the vessel wall; with an automated computerized system of the equipment, on the distal wall of both common carotid arteries, 1 cm below the carotid bulb, along a 10 mm long straight arterial segment. Patients may be stratified into 3 groups according to the EIM value: EIM patients with <0.5 mm are considered disease-free; patients with IMD between 0.6-1 mm will be considered to be non-significantly affected by the disease; patients with IMD> 1 mm will be grouped as affected by significant disease (Table 1). Therefore, carotid atherosclerosis is considered in the presence of plaques or an EIM> 1 mm. 2.5.3 Table 1. Thickness of the intima plus the component of the mean in the wall of a vessel associated or not with the presence of vascular calcification.

EIM VALUE Presence or not of vascular calcification <0,5 mm Patients without vascular calcification 0,6-1 mm Patients non-significantly affected by the disease > 1 mm Patients significantly affected by the disease

Recruitment information / eligibility

• Status: Completed
• Enrollment: 59
• Est. completion date: June 30, 2017
• Est. primary completion date: March 1, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Men or women =18 years old

• A period not less than 6 months in HD

• Life expectancy = 18 months

• Signed informed consent

Exclusion Criteria:

• Patients under treatment with phosphorus chelators

• Patients who do not want to participate in the study

Related Conditions & MeSH terms

• Calcinosis
• Renal Disease
• Vascular Calcification

Intervention

Drug:
• Vitamin K 2
Patients will be monitored during the whole protocol.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Catholic University of Salta

References & Publications (32)

Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004 Aug;15(8):2208-18. — View Citation

Brandenburg VM, Schurgers LJ, Kaesler N, Püsche K, van Gorp RH, Leftheriotis G, Reinartz S, Koos R, Krüger T. Prevention of vasculopathy by vitamin K supplementation: can we turn fiction into fact? Atherosclerosis. 2015 May;240(1):10-6. doi: 10.1016/j.ath — View Citation

Caluwé R, Pyfferoen L, De Boeck K, De Vriese AS. The effects of vitamin K supplementation and vitamin K antagonists on progression of vascular calcification: ongoing randomized controlled trials. Clin Kidney J. 2016 Apr;9(2):273-9. doi: 10.1093/ckj/sfv146 — View Citation

Caluwé R, Vandecasteele S, Van Vlem B, Vermeer C, De Vriese AS. Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study. Nephrol Dial Transplant. 2014 Jul;29(7):1385-90. doi: 10.1093/ndt/gft464. Epub 2013 Nov 26. — View Citation

Cannata-Andía JB, Rodríguez-García M, Carrillo-López N, Naves-Díaz M, Díaz-López B. Vascular calcifications: pathogenesis, management, and impact on clinical outcomes. J Am Soc Nephrol. 2006 Dec;17(12 Suppl 3):S267-73. Review. — View Citation

Cranenburg EC, Schurgers LJ, Uiterwijk HH, Beulens JW, Dalmeijer GW, Westerhuis R, Magdeleyns EJ, Herfs M, Vermeer C, Laverman GD. Vitamin K intake and status are low in hemodialysis patients. Kidney Int. 2012 Sep;82(5):605-10. doi: 10.1038/ki.2012.191. E — View Citation

De Vriese AS, Caluwé R, Bailleul E, De Bacquer D, Borrey D, Van Vlem B, Vandecasteele SJ, Emmerechts J. Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis. 2015 Jul;66(1):91-8. doi: 10.1053/j.ajkd.2015.01.022. Epub 2015 Mar 21. — View Citation

Georgianos PI, Pikilidou MI, Liakopoulos V, Balaskas EV, Zebekakis PE. Arterial stiffness in end-stage renal disease-pathogenesis, clinical epidemiology, and therapeutic potentials. Hypertens Res. 2018 May;41(5):309-319. doi: 10.1038/s41440-018-0025-5. Ep — View Citation

Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000 May 18;34 — View Citation

Gundberg CM, Lian JB, Booth SL. Vitamin K-dependent carboxylation of osteocalcin: friend or foe? Adv Nutr. 2012 Mar 1;3(2):149-57. doi: 10.3945/an.112.001834. Review. — View Citation

Hur DJ, Raymond GV, Kahler SG, Riegert-Johnson DL, Cohen BA, Boyadjiev SA. A novel MGP mutation in a consanguineous family: review of the clinical and molecular characteristics of Keutel syndrome. Am J Med Genet A. 2005 May 15;135(1):36-40. Review. — View Citation

Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura T, Nakamura T, Sato T, Yamazaki K. Randomized controlled study on the prevention of osteoporotic fractures (OF study): a phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab. 2009;2 — View Citation

January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; American College of Cardiology/American Heart Association Task Force on — View Citation

Jono S, Nishizawa Y, Shioi A, Morii H. Parathyroid hormone-related peptide as a local regulator of vascular calcification. Its inhibitory action on in vitro calcification by bovine vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1997 Jun;17(6 — View Citation

Kaesler N, Magdeleyns E, Herfs M, Schettgen T, Brandenburg V, Fliser D, Vermeer C, Floege J, Schlieper G, Krüger T. Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation. Kidney Int. 2014 Aug;86(2):286-93. doi: 10.1038/ki.2013.530 — View Citation

Krüger T, Floege J. Vitamin K antagonists: beyond bleeding. Semin Dial. 2014 Jan-Feb;27(1):37-41. doi: 10.1111/sdi.12175. Review. — View Citation

London GM, Guérin AP, Marchais SJ, Métivier F, Pannier B, Adda H. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant. 2003 Sep;18(9):1731-40. — View Citation

Malluche HH, Monier-Faugere MC. Understanding and managing hyperphosphatemia in patients with chronic renal disease. Clin Nephrol. 1999 Nov;52(5):267-77. Review. — View Citation

Moe SM, Chen NX. Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2008 Feb;19(2):213-6. Epub 2007 Dec 19. Review. — View Citation

Pucaj K, Rasmussen H, Møller M, Preston T. Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7. Toxicol Mech Methods. 2011 Sep;21(7):520-32. doi: 10.3109/15376516.2011.568983. Epub 2011 Jul 25. — View Citation

Rumberger JA, Brundage BH, Rader DJ, Kondos G. Electron beam computed tomographic coronary calcium scanning: a review and guidelines for use in asymptomatic persons. Mayo Clin Proc. 1999 Mar;74(3):243-52. Review. Erratum in: Mayo Clin Proc 1999 May;74(5): — View Citation

Scheiber D, Veulemans V, Horn P, Chatrou ML, Potthoff SA, Kelm M, Schurgers LJ, Westenfeld R. High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification. Nutrients. 2015 Aug 18;7(8):6991-70 — View Citation

Schoppet M, Shroff RC, Hofbauer LC, Shanahan CM. Exploring the biology of vascular calcification in chronic kidney disease: what's circulating? Kidney Int. 2008 Feb;73(4):384-90. Epub 2007 Nov 28. Review. — View Citation

Schurgers LJ, Barreto DV, Barreto FC, Liabeuf S, Renard C, Magdeleyns EJ, Vermeer C, Choukroun G, Massy ZA. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary repor — View Citation

Shroff RC, McNair R, Figg N, Skepper JN, Schurgers L, Gupta A, Hiorns M, Donald AE, Deanfield J, Rees L, Shanahan CM. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation. 2008 Oct 21;118(17):1 — View Citation

Szczerba E. [Summary of the article: Patel MR, Mahaffey KW, Garg J et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med, 2011; 365: 1557-1559]. Kardiol Pol. 2012;70(1):102-3. Polish. — View Citation

Theuwissen E, Cranenburg EC, Knapen MH, Magdeleyns EJ, Teunissen KJ, Schurgers LJ, Smit E, Vermeer C. Low-dose menaquinone-7 supplementation improved extra-hepatic vitamin K status, but had no effect on thrombin generation in healthy subjects. Br J Nutr. — View Citation

Vissers LE, Dalmeijer GW, Boer JM, Monique Verschuren WM, van der Schouw YT, Beulens JW. Intake of dietary phylloquinone and menaquinones and risk of stroke. J Am Heart Assoc. 2013 Dec 10;2(6):e000455. doi: 10.1161/JAHA.113.000455. — View Citation

Vo TM, Disthabanchong S. Are there ways to attenuate arterial calcification and improve cardiovascular outcomes in chronic kidney disease? World J Cardiol. 2014 May 26;6(5):216-26. doi: 10.4330/wjc.v6.i5.216. Review. — View Citation

Westenfeld R, Krueger T, Schlieper G, Cranenburg EC, Magdeleyns EJ, Heidenreich S, Holzmann S, Vermeer C, Jahnen-Dechent W, Ketteler M, Floege J, Schurgers LJ. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patient — View Citation

Winkelmayer WC, Patrick AR, Liu J, Brookhart MA, Setoguchi S. The increasing prevalence of atrial fibrillation among hemodialysis patients. J Am Soc Nephrol. 2011 Feb;22(2):349-57. doi: 10.1681/ASN.2010050459. Epub 2011 Jan 13. — View Citation

Zhang YT, Tang ZY. Research progress of warfarin-associated vascular calcification and its possible therapy. J Cardiovasc Pharmacol. 2014 Jan;63(1):76-82. doi: 10.1097/FJC.0000000000000008. Review. — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	EFFECT OF VITAMIN K2 ON VASCULAR CALCIFICATION	Changes in the VC (changes in the intimate thickness of carotide artery versus baseline).	6 months
Primary	CHANGES IN THE PRODUCT PHOSPHORUS CALCIUM	Changes in the product phosphorus calcium versus baseline	6 months
Primary	CHANGES IN PTHi SERUM LEVELS	Not significant changes in PTHi serum levels versus baseline	6 months