Inhibiting the progression of arterial calcification with vitamin K in HemoDialysis patients (iPACK-HD) trial: rationale and study design for a randomized trial of vitamin K in patients with end stage kidney disease

Rachel M Holden, Sarah L Booth, Andrew G Day, Catherine M Clase, Deborah Zimmerman, Louise Moist, M Kyla Shea, Kristin M McCabe, Sophie A Jamal, Sheldon Tobe, Jordan Weinstein, Rao Madhumathi, Michael A Adams, Daren K Heyland, Rachel M Holden, Sarah L Booth, Andrew G Day, Catherine M Clase, Deborah Zimmerman, Louise Moist, M Kyla Shea, Kristin M McCabe, Sophie A Jamal, Sheldon Tobe, Jordan Weinstein, Rao Madhumathi, Michael A Adams, Daren K Heyland

Abstract

Background: Cardiovascular disease, which is due in part to progressive vascular calcification, is the leading cause of death among patients with end stage kidney disease (ESKD) on dialysis. A role for vitamin K in the prevention of vascular calcification is plausible based on the presence of vitamin K dependent proteins in vascular tissue, including matrix gla protein (MGP). Evidence from animal models and observational studies support a role for vitamin K in the prevention of vascular calcification. A large-scale study is needed to investigate the effect of vitamin K supplementation on the progression of vascular calcification in patients with ESKD, a group at risk for sub-clinical vitamin K deficiency.

Methods/design: We plan a prospective, randomized, double-blind, multicenter controlled trial of incident ESKD patients on hemodialysis in centers within North America. Eligible subjects with a baseline coronary artery calcium score of greater than or equal to 30 Agatston Units, will be randomly assigned to either the treatment group (10 mg of phylloquinone three times per week) or to the control group (placebo administration three times per week). The primary endpoint is the progression of coronary artery calcification defined as a greater than 15% increase in CAC score over baseline after 12 months.

Discussion: Vitamin K supplementation is a simple, safe and cost-effective nutritional strategy that can easily be integrated into patient care. If vitamin K reduces the progression of coronary artery calcification it may lead to decreased morbidity and mortality in men and women with ESKD.

Trial registration: NCT 01528800.

Trial registration: ClinicalTrials.gov NCT01528800.

Keywords: Coronary artery calcification; End stage kidney disease; Hemodialysis; Randomized controlled trial; Vitamin K.

References

    1. Levin A, Hemmelgarn B, Culleton B, Tobe S, McFarlane P, Ruzicka M, et al. Guidelines for the management of chronic kidney disease. CMAJ. 2008;179(11):1154–62. doi: 10.1503/cmaj.080351.
    1. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32(5 Suppl 3):S112–9. doi: 10.1053/ajkd.1998.v32.pm9820470.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) Kidney Int Suppl. 2009;76(113):S1–130.
    1. Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, et al. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost. 2007;5(12):2503–11. doi: 10.1111/j.1538-7836.2007.02758.x.
    1. Holden RM, Booth SL. Vascular calcification in chronic kidney disease: the role of vitamin K. Nat Clin Pract Nephrol. 2007;3(10):522–3. doi: 10.1038/ncpneph0601.
    1. Holden RM, Sanfilippo AS, Hopman WM, Zimmerman D, Garland JS, Morton AR. Warfarin and aortic valve calcification in hemodialysis patients. J Nephrol. 2007;20(4):417–22.
    1. Holden RM, Iliescu E, Morton AR, Booth SL. Vitamin K status of Canadian peritoneal dialysis patients. Perit Dial Int. 2008;28(4):415–8.
    1. Holden RM, Morton AR, Garland JS, Pavlov A, Day AG, Booth SL. Vitamins K and D status in stages 3–5 chronic kidney disease. Clin J Am Soc Nephrol. 2010;5(4):590–7. doi: 10.2215/CJN.06420909.
    1. McCabe KM, Booth SL, Fu X, Shobeiri N, Pang JJ, Adams MA, et al. Dietary vitamin K and therapeutic warfarin alter the susceptibility to vascular calcification in experimental chronic kidney disease. Kidney Int. 2013;83(5):835–44. doi: 10.1038/ki.2012.477.
    1. Pilkey RM, Morton AR, Boffa MB, Noordhof C, Day AG, Su Y, et al. Subclinical vitamin K deficiency in hemodialysis patients. Am J Kidney Dis. 2007;49(3):432–9. doi: 10.1053/j.ajkd.2006.11.041.
    1. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68(4):1815–24. doi: 10.1111/j.1523-1755.2005.00600.x.
    1. Bellasi A, Kooienga L, Block GA, Veledar E, Spiegel DM, Raggi P. How long is the warranty period for nil or low coronary artery calcium in patients new to hemodialysis? J Nephrol. 2009;22(2):255–62.
    1. Shea MK, O’Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009;89(6):1799–807. doi: 10.3945/ajcn.2008.27338.
    1. Budoff MJ, Kessler P, Gao YL, Qunibi W, Moustafa M, Mao SS. The interscan variation of CT coronary artery calcification score: analysis of the Calcium Acetate Renagel Comparison (CARE)-2 study. Acad Radiol. 2008;15(1):58–61. doi: 10.1016/j.acra.2007.08.011.
    1. Garland JS, Holden RM, Groome PA, Lam M, Nolan RL, Morton AR, et al. Prevalence and associations of coronary artery calcification in patients with stages 3 to 5 CKD without cardiovascular disease. Am J Kidney Dis. 2008;52(5):849–58. doi: 10.1053/j.ajkd.2008.04.012.
    1. Cheung AM, Tile L, Lee Y, Tomlinson G, Hawker G, Sche J, et al. Vitamin K supplementation in postmenopausal women with osteopenia (ECKO trial): a randomized controlled trial. PLoS Med. 2008;5(10):e196. doi: 10.1371/journal.pmed.0050196.
    1. Chertow GM, Burke SK, Raggi P, Treat to Goal Working Group Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002;62(1):245–52. doi: 10.1046/j.1523-1755.2002.00434.x.
    1. Raggi P, Chertow GM, Torres PU, Csiky B, Naso A, Nossuli K, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant. 2011;26(4):1327–39. doi: 10.1093/ndt/gfq725.
    1. Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: improved reproducibility of calcium scoring with an electron-beam CT volumetric method. Radiology. 1998;208(3):807–14. doi: 10.1148/radiology.208.3.9722864.
    1. Budoff MJ, Young R, Lopez VA, Kronmel RA, Nasir K, Blumentahal RS, et al. Progression of coronary calcium and incident coronary heart disease events: MESA (Multi-Ethnic Study of Atherosclerosis) J Am Coll Cardiol. 2013;61(12):1231–9. doi: 10.1016/j.jacc.2012.12.035.
    1. Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71(5):438–41. doi: 10.1038/sj.ki.5002059.
    1. Raggi P, Callister TQ, Shaw LJ. Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol-lowering therapy. Arterioscler Thromb Vasc Biol. 2004;24(7):1272–7. doi: 10.1161/01.ATV.0000127024.40516.ef.
    1. Jindal K, Chan CT, Deziel C, Hirsch D, Soroka SD, Tonelli M, et al. Hemodialysis clinical practice guidelines for the Canadian Society of Nephrology. J Am Soc Nephrol. 2006;17(3 Suppl 1):S1–27.
    1. Wald R, Tentori F, Tighiouart H, Zager PG, Miskulin DC. Impact of the Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in a large dialysis network. Am J Kidney Dis. 2007;49(2):257–66. doi: 10.1053/j.ajkd.2006.11.027.
    1. Barreto DV, Barreto FC, de Carvalho AB. Phosphate binder impact on bone remodeling and coronary calcification–results from the BRiC study. Nephron. 2008;110(4):c273–83.
    1. Braun J, Asmus HG, Holzer H, Brunkhorst R, Krause R, Schulz W, et al. Long-term comparison of a calcium-free phosphate binder and calcium carbonate–phosphorus metabolism and cardiovascular calcification. Clin Nephrol. 2004;62(2):104–15. doi: 10.5414/CNP62104.
    1. Qunibi W, Moustafa M, Muenz LR, He DY, Kessler PD, Diaz-Buxo JA, et al. A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study. Am J Kidney Dis. 2008;51(6):952–65. doi: 10.1053/j.ajkd.2008.02.298.
    1. Booth SL, Al RA. Determinants of vitamin K status in humans. Vitam Horm. 2008;78:1–22.
    1. Thijssen HH, Drittij-Reijnders MJ, Fischer MA. Phylloquinone and menaquinone-4 distribution in rats: synthesis rather than uptake determines menaquinone-4 organ concentrations. J Nutr. 1996;126(2):537–43.
    1. Spronk HM, Soute BA, Schurgers LJ, Cleutjens JP, Thijssen HH, De May JG, et al. Matrix Gla protein accumulates at the border of regions of calcification and normal tissue in the media of the arterial vessel wall. Biochem Biophys Res Commun. 2001;289(2):485–90. doi: 10.1006/bbrc.2001.5996.
    1. Lomashvili KA, Wang X, Wallin R, O’Neill WC. Matrix Gla protein metabolism in vascular smooth muscle and role in uremic vascular calcification. J Biol Chem. 2011;286(33):28715–22. doi: 10.1074/jbc.M111.251462.
    1. Kohlmeier M, Saupe J, Shearer MJ, Schaefer K, Asmus G. Bone health of adult hemodialysis patients is related to vitamin K status. Kidney Int. 1997;51(4):1218–21. doi: 10.1038/ki.1997.166.
    1. Westenfeld R, Krueger T, Schlieper G, Cranenburg EC, Magdeleynds EJ, Heidenreich S et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis. 2012;59(2):186–95.
    1. Cranenburg EC, Schurgers LJ, Uiterwijk HH, Beulens JW, Dalmeijer GW, Westerhuis R, et al. Vitamin K intake and status are low in hemodialysis patients. Kidney Int. 2012;82(5):605–10. doi: 10.1038/ki.2012.191.
    1. Cranenburg EC, Brandenburg VM, Vermeer C, Stenger M, Muhlenbruch G, Mahnken AH, et al. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thromb Haemost. 2009;101(2):359–66.
    1. Braam LA, Hoeks AP, Brouns F, Hamulyak K, Gerichhausen MJ, Vermeer C. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost. 2004;91(2):373–80.

Source: PubMed

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