Vitamin K in CKD: A Game-Changer or By-Stander.

Patients with chronic kidney disease (CKD) are known to have aggressive and complex cardiovascular disease (CVD) burden and the absolute risk of death increases exponentially with the stages of CKD1Tonelli M. Wiebe N. Culleton B. et al.Chronic kidney disease and mortality risk: a systematic review.J Am Soc Nephrol. 2006; 17: 2034-2047Google Scholar. Two major pathways in CKD that are yet to be amenable to therapeutic approaches are accelerated atherosclerosis and vascular calcification2Raggi P. Boulay A. Chasan-Taber S. et al.Cardiac calcification in adult hemodialysis patients. A link between end-stage renal disease and cardiovascular disease?.J Am Coll Cardiol. 2002; 39: 695-701Google Scholar. In addition to the traditional cardiovascular risk factors3Jankowski J. Floege J. Fliser D. et al.Cardiovascular Disease in Chronic Kidney Disease: Pathophysiological Insights and Therapeutic Options.Circulation. 2021; 143: 1157-1172Google Scholar, numerous CKD-related risk factors including inflammation, oxidative stress, uremic toxins and perturbed mineral metabolism can escalate vascular calcification pathogenesis and have been identified as predictors of poor cardiac outcomes and survival in patients with CKD4Tonelli M. Sacks F. Pfeffer M. et al.Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.Circulation. 2005; 112: 2627-2633Google Scholar,5Menon V. Gul A. Sarnak M.J. Cardiovascular risk factors in chronic kidney disease.Kidney Int. 2005; 68: 1413-1418Google Scholar. Several interventions targeting mineral bone disorder and related pathways (Figure 1) have been studied but demonstrated mixed findings on intermediate outcomes such as attenuation of vascular calcification and even less evidence to translate into a meaningful cardiovascular outcome for patients with kidney failure. Despite the efficacy of phosphate binders in reducing serum phosphate, there is no clear evidence that either calcium or non-calcium based binders lead to reduction in mortality compared to placebo6Palmer S.C. Gardner S. Tonelli M. et al.Phosphate-Binding Agents in Adults With CKD: A Network Meta-analysis of Randomized Trials.American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016; 68: 691-702Google Scholar. Calcimimetics work by modulating secondary hyperparathyroidism but failed to demonstrate a mortality benefit or regression of aortic calcification among patients undergoing dialysis7Investigators E.T. Chertow G.M. Block G.A. et al.Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis.The New England journal of medicine. 2012; 367: 2482-2494Google Scholar. Other interventions such as bisphosphonate and denosumab act by reducing calcium deposition in vascular walls but neither agent have been proven to improve vascular function or calcification scores in this cohort8Iseri K. Watanabe M. Yoshikawa H. et al.Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial.Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2019; 34: 1014-1024Google Scholar. There are however limited studies utilizing these agents in patients with advanced CKD due to the anecdotal concerns of adynamic bone disease with bisphosphonate9Toussaint N.D. Elder G.J. Kerr P.G. Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue.Clin J Am Soc Nephrol. 2009; 4: 221-233Google Scholar, and reported severe hypocalcemia with denosumabs1. Another widely available intervention is magnesium, which works by inhibiting phosphate absorption from the gut and hydroxyapatite formation the vesselss2. A recent well-designed trial in CKD did not demonstrate an impact on the progression of vascular calcification after 12 months of magnesium supplementations3. A new novel agent, SNF472 acts by selectively inhibiting hydroxyapatite formation and crystallisation and has demonstrated promising efficacy in attenuating coronary artery calcification and aortic calcification in the hemodialysis populations4. Other agents such as sodium thiosulphate acts as a calcium chelators5 and is mainly used in the setting of calciphylaxis. Whilst there are signals to support reduction in calcification burden, sodium thiosulphate is yet to demonstrate convincing evidence on improvement of calciphylaxis associated skin lesions or on mortalitys6. A current contemporary player in this field is Vitamin K, an essential cofactor for carboxylation and activation of several potent calcification inhibitors including osteocalcin, matrix gla protein (MGP) and gla-rich proteins7. Vitamin K deficiency is seen in over 50 percent of patients on maintenance hemodialysiss8 with co-existing high levels of the inactive form of MGP. The findings pertaining to vitamin K supplementation to substantively reduce the inactive form of MGP opened many promises that vitamin K replacement and supplementation may be a game changer to attenuate progression of vascular calcification in CKD. There are two main forms of vitamin K; phylloquinone, K1 primarily found in green vegetables, and menaquinone, K2 found in fermented products or following conversion from K1 in the gut by a human homologue of Escherichia coli prenyltransferase [UbiA prenyltransferase containing 1 (UBIAD1)]s9, s10. It is important to note that the bioavailability of vitamin K2 can be reduced with the use of phosphate binders through undesired binding in the gastrointestinal tracts11. Dietary intake of vitamin K is also generally reduced in patients undergoing dialysis due to concurrent dietary potassium and phosphate restrictions8. Whilst both forms of vitamin K have been shown to have epidemiological links with adverse cardiovascular outcomes, vitamin K2 has been hypothesized to play a more substantial role in inhibition of calcification due to the longer half-life and greater levels of carboxylation of MGP compared to vitamin K1s12, s13. However, despite these differences, vitamin K1 supplementation in the general population was shown to slow down the progression of coronary artery calcifications14. In this issue, Haroon and colleagues report findings from the Treatment to Reduce Vascular Calcification in Hemodialysis Patients Using Vitamin K, Trevasc-HDK studys15. This well-executed, open-label randomized controlled trial (RCT) aimed to assess whether vitamin K2 supplementation reduces progression of vascular calcification assessed by coronary artery calcification, aortic valve calcification, carotid-femoral pulse wave velocity, aortic augmentation index and cardiovascular events. They randomized 178 patients undergoing maintenance hemodialysis to receive either oral vitamin K2 supplementation at a fixed dose of 360 μg thrice weekly on dialysis or matching placebo, of whom 138 completed the 18-months follow-up and were included in the analysis. Despite effective reduction in the plasma levels of the inactive form of MGP, vitamin K2 supplementation did not result in a change in coronary artery or aortic valve calcification, vascular stiffness or clinical outcomes including death, major adverse cardiac events, and vascular access events. Whilst being a single centre study that fell-short of the required sample size for the primary outcome analysis, Trevasc-HDK has several important learning points. Trevasc-HDK is the largest RCT to date using vitamin K2 in the dialysis population that was well-designed to capture patients with pre-existing high coronary calcification burden and had a comprehensive 18 months follow-up. The recruitment in a predominant Asian population further enriches and diversifies the literature on the effects of vitamin K. The secondary outcomes were relevant here as they further demonstrate minimal ‘signals’ of the benefits of vitamin K2 on vascular calcification. Overall, the data aligns with previously published smaller RCTs of Vitamin K supplementation in the hemodialysis populations16, s17 and more broadly with other interventions in the field of vascular calcification in the CKD population. Despite the convincing pre-clinical and epidemiology data for the role vitamin K in vascular calcifications18, there is currently insufficient high-certainty evidence to justify the routine use of vitamin K supplementation in CKD. Many questions are yet to be answered: It is unclear if both forms of vitamin K can be used interchangeably and if the clinical benefits might sway towards one form of vitamin K more than the other. In addition, given the complexity of the pathogenesis of vascular calcification with many vitamin K independent factors in play, a multipronged approach or more potent novel targeted biologic therapy may be the future for vascular health. Another consideration is vascular calcification likely reflects a state of irreversibility that may no longer be amenable to intervention especially for patients on dialysis and intervention at early stages of CKD may be required to prevent the occurrence of vascular calcification. Finally, vascular calcification has proven to be a challenging surrogate endpoint in CKD research and further studies should therefore focus on the effect of vitamin K supplementation on hard clinical endpoints. Until then, vitamin K lurks as another by-stander for CVD management in CKD. Download .pdf (.06 MB) Help with pdf files