Vitamin K2 in hemodialysis patients- Review
Vascular calcification has been emerging as a leading cause of cardiovascular complications in patients on hemodialysis. (1) Cardiovascular deaths have seen a global rise among dialysis patients in the last decade. (2)
Matrix Gla protein has taken a central role in determining the vessel wall plaque conditions. It has been widely documented that high circulating levels of uncarboxylated MGP is associated with increased tendencies of developing intimal and medial arterial wall calcifications. (3,4)
Vitamin K2 plays an important role in the process of gamma-carboxylation of MGPs, which in turn helps directly in the inhibition of vascular calcification. Research has repeatedly shown that deficiency of vitamin K2 leads to an inactivation of the vitamin K-dependent proteins which include MPGs and osteocalcin, and may aggravate the vascular calcification process. (5,6)
Addressing the fact that patients on hemodialysis are very often deficient in vitamin K1 and K2 (7), it has been suggested that one reason behind this may be the low sodium and phosphorus diets that they are recommended. This restricts the daily intake of green vegetables and dairy products which are regarded to be essential sources of vitamin K1 and K2. As vitamin K1 can be converted to vitamin K2 in the human body (8), deficiency of both can affect the risk of developing CV in such patients.
Though, previous studies have suggested that regularly high dietary intake of vitamin K2 is associated with 50% decreased coronary artery calcification and cardiovascular death in humans with normal kidney function, (9,10) the precise effect of vitamin K2 on dialysis patients was scantily investigated.
Progressing with the hypothesis that vitamin K2 deficiency in hemodialysis patients may lead to impaired MGP carboxylation (as shown by increased plasma uncarboxylated MGP levels), which subsequently contributes to the aggravated vascular calcification in this population; in 2012, a first of its kind study report was published in the American Journal of Kidney Diseases by Westenfeld et. al, attached to the Division of Cardiology, Pulmonary Diseases, Vascular Medicine, University Hospital Düsseldorf (11).
The main aim of the study was to investigate whether daily vitamin K supplementation improves the bioactivity of vitamin K–dependent proteins in hemodialysis patients, assessed by circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and uncarboxylated prothrombin (PIVKA-II [protein induced by vitamin K absence II]).
The study was a prospective randomized blinded intervention study. Of the 75 patients consecutively screened for the study participation, 55 were eligible, included, and randomly assigned.
Inclusion criteria involved long-term hemodialysis patients in stable condition and 18 years or older were eligible irrespective of sex, underlying primary kidney disease, and the presence of cardiovascular disease or traditional atherogenic risk factors.
Fifty healthy age-matched participants were recruited from the general population to serve as a reference population. In both groups, MGP, osteocalcin, and PIVKA-II were measured.
After a 1-week baseline period, patients received daily oral administration of 45 (group 1), 135 (group 2), or 360 g (group 3) of vitamin K2 for 6 consecutive weeks. The 6-week supplementation period was followed by a washout period of 3 weeks (Fig 2B). During the baseline period, blood samples were obtained on days 1, 3, and 5. During the supplementation and washout periods, blood samples were obtained once weekly after the long interval (days 14, 21, 28, 35, 42, and 49 and during washout period days 56, 63, and 70). Plasma levels were assessed using enzyme-linked immunosorbent assays.
On data analysis, some interesting facts emerged.
• At baseline, hemodialysis patients had 4.5-fold higher dephosphorylated-uncarboxylated MGP and 8.4-fold higher uncarboxylated osteocalcin levels compared with controls.
• PIVKA-II levels were elevated in 49 hemodialysis patients.
• Vitamin K2 supplementation induced a dose- and time-dependent decrease in circulating dephosphorylated-uncarboxylated MGP, uncarboxylated osteocalcin, and PIVKA-II levels.
• Response rates in the reduction in dephosphorylated-uncarboxylated MGP levels were 77% and 93% in the groups receiving 135 g and 360 g of menaquinone-7, respectively.
• Serum parameters associated with the progression of vascular calcification, such as calcium, phosphate, alkaline phosphatase, and triglycerides, were not altered by vitamin K2 supplementation. Likewise, blood pressure measurements were unchanged during vitamin K2 supplementation.
"We show for the first time that oral supplementation with vitamin K2 can significantly improve the carboxylation status (activity) of vitamin K–dependent proteins in hemodialysis patients in a dose-dependent manner. We selected menaquinone-7 instead of menaquinone-4 as the therapy due to its longer half-life (72 vs 1 hour)." the authors explained.
Based on the results, the researchers made some interesting observations.
• The significantly high levels of inactive vitamin K dependent proteins in the patients strongly support the dose and time dependency of vitamin K supplementation in them.
• Dietary Vitamin K2 supplementation significantly decreased dephosphorylated- uncarboxylated MGP levels, suggesting the restoration of MGP functionality, thus linking the potential benefit of vitamin K supplementation directly to the risk of mortality in such patients.
This study specifically highlights the indispensable role of dietary vitamin K2 supplementation for the optimum carboxylation of MGPs, thus inhibiting cardiovascular events in hemodialysis patients.
Addressing the novelty of their study, the team concluded "Our data provide the rationale for upcoming prospective trials assessing the potential of vitamin K2 supplementation to counteract the devastating and rapidly progressing vascular calcification in hemodialysis patients."
The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Vitamin K, click here
References
1. Cozzolino M, Gallieni M, Brancaccio D. Vascular calcification in uremic conditions: new insights into pathogenesis. Semin Nephrol. 2006 Jan;26(1):33-7. DOI: 10.1016/j.semnephrol.2005.06.008. PMID: 16412823.
2. Wang A. Y. (2011). Vascular and valvular calcification in chronic peritoneal dialysis patients. International journal of nephrology, 2011, 198045. https://doi.org/10.4061/2011/198045
3. Barrett, H., O'Keeffe, M., Kavanagh, E., Walsh, M., & O'Connor, E. M. (2018). Is Matrix Gla Protein Associated with Vascular Calcification? A Systematic Review. Nutrients, 10(4), 415. https://doi.org/10.3390/nu10040415
4. Roumeliotis, S., Dounousi, E., Salmas, M., Eleftheriadis, T., & Liakopoulos, V. (2020). Vascular Calcification in Chronic Kidney Disease: The Role of Vitamin K- Dependent Matrix Gla Protein. Frontiers in medicine, 7, 154. https://doi.org/10.3389/fmed.2020.00154
5. El Asmar, M. S., Naoum, J. J., & Arbid, E. J. (2014). Vitamin k dependent proteins and the role of vitamin k2 in the modulation of vascular calcification: a review. Oman medical journal, 29(3), 172–177. https://doi.org/10.5001/omj.2014.44
6. Silaghi, C. N., Ilyés, T., Filip, V. P., Farcaș, M., van Ballegooijen, A. J., & Crăciun, A. M. (2019). Vitamin K Dependent Proteins in Kidney Disease. International journal of molecular sciences, 20(7), 1571. https://doi.org/10.3390/ijms20071571
7. Cases, A., Cigarrán-Guldrís, S., Mas, S., & Gonzalez-Parra, E. (2019). Vegetable-Based Diets for Chronic Kidney Disease? It Is Time to Reconsider. Nutrients, 11(6), 1263. https://doi.org/10.3390/nu11061263.
8. Schwalfenberg G. K. (2017). Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health. Journal of nutrition and metabolism, 2017, 6254836. https://doi.org/10.1155/2017/6254836
9. Beulens JW, Bots ML, Atsma F, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009;203:489-493.
10. Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134:3100-3105.
11. Westenfeld, R., Krueger, T., Schlieper, G., Cranenburg, E. C. M., Magdeleyns, E. J., Heidenreich, S., … Schurgers, L. J. (2012). Effect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial. American Journal of Kidney Diseases, 59(2), 186–195. doi:10.1053/j.ajkd.2011.10.041
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