Aoun M, Makki M, Azar H, Matta H, Chelala DN. High dephosphorylated-uncarboxylated MGP in hemodialysis patients: risk factors and response to vitamin K2, a pre-post intervention clinical trial. BMC Nephrology. 2017;18(1):191.
To assess the effects of vitamin K2 treatment on levels of dephosphorylated-uncarboxylated matrix gla protein (dp-ucMGP) and vascular calcification scores
Prospective, pre-post intervention clinical trial
Fifty patients in a Lebanese hemodialysis center; 60% of the participants were men and all were aged 18 or older (median age 56.75) and had been receiving hemodialysis for more than 1 month.
Participants received 360 mcg vitamin K2 per day for 4 weeks. Vitamin K2 was provided in the form of menaquinone-7 (MK-7).
Study Parameters Assessed
Dephosphorylated-uncarboxylated matrix gla protein (dp-ucMGP) was measured at baseline and at 4 weeks. The Aortic Calcification Severity (AC-24) test was used to estimate the extent of abdominal aortic calcification for each patient. The AC-24 test was calculated by 2 independent physicians; if their scores differed the higher score was recorded.
Additional variables collected included demographic information, medical history, and results of recent laboratory testing.
The primary outcome measured was the percentage drop of dp-ucMGP from baseline after 4 weeks of vitamin K2 supplementation. Secondary endpoints included the following:
- Correlation between AC-24 score and baseline dp-ucMGP
- Correlation between baseline dp-ucMGP and other variables such as age, BMI, diabetes, smoking, and fracture within the last 6 months
- Correlation between dp-ucMGP drop and other collected variables (eg, serum levels of albumin)
After 4 weeks of MK-7 supplementation, median dp-ucMGP levels decreased by 86%. In 88% of the patients, dp-ucMGP levels fell to less than 500 pM.
There was also a correlation between high dp-ucMGP and increased AC-24 scores. Because dp-ucMGP levels increase gradually with age, levels were significantly higher in patients who were 65 years old or older.
The majority of patients with CKD die of a cardiovascular event before they can get a kidney transplant. Thus, finding effective solutions to mitigate cardiovascular disease risk in patients on hemodialysis is vitally important.
Patients with a longer duration of hemodialysis also had a tendency toward high dp-ucMGP levels, but it was not statistically significant (P=0.18). Women overall had a tendency toward lower vitamin K levels and consequently higher dp-ucMGP levels.
MK-7 was well-tolerated; none of the participants withdrew from treatment and there were no reports of adverse effects.
Vascular calcification increases risk of mortality, and most hemodialysis patients experience increased vascular calcifications.1 Matrix gla protein is a vitamin K-dependent protein that inhibits cardiovascular calcification.2 Elevated plasma levels of dp-ucMGP, the precursor of MGP, is correlated with vascular calcification and predictive of vitamin K status.3 It is now known that individuals with vascular calcification are 3 to 4 times more likely to experience a cardiovascular event or die prematurely compared to those who do not have vascular calcification.4,5
Theoretically, physiologically, and clinically it makes sense that correcting a vitamin K deficiency will help reduce risk of vascular calcification. This is especially important with patients who have chronic kidney disease (CKD) because vitamin K deficiency is common in this population.6
The majority of patients with CKD die of a cardiovascular event before they can get a kidney transplant.7 Thus, finding effective solutions to mitigate cardiovascular disease risk in patients on hemodialysis is vitally important.
The present study is promising because it shows supplementation with 360 mcg MK-7 can reduce dp-ucMGP, but unfortunately the researchers didn’t evaluate whether MK-7 alters the progression of arterial calcifications.
Kernatowka and colleagues did test the effects of MK-7 on calcification in their 2015 study. They gave 90 mcg MK-7 to 42 nondialyzed patients with chronic kidney disease (CKD) for 270 days.8 They concluded that while MK-7 significantly reduced dp-ucMGP levels, it did not significantly affect calcification progression. However, it’s possible that a dose-response effect exists with MK-7. Perhaps a higher dose could have helped slow the progression or even reverse arterial calcifications. A second study is currently underway to evaluate the effect of 360 mcg MK-7 on aortic calcifications in patients with coronary artery disease; results of that clinical trial are pending.9
As a vitamin K-dependent protein, dp-ucMGP can be viewed as marker for functional vitamin K deficiency. Supplementing with vitamin K when dp-ucMGP is elevated reduces dp-ucMGP; however, whether vitamin K supplementation also improves clinical outcomes in this patient population remains to be demonstrated in clinical trials.
Most integrative practitioners are well-versed in identifying and correcting nutrient deficiencies. This study further illustrates the potential positive health benefits that can be gained when we do that, especially in specific patient populations. Since vitamin K is safe even in very high doses, clinicians may decide that the higher dose used in this study may be appropriate to help their patients while we await the outcomes of additional studies that may show direct clinical benefit.
Conflict of Interest Disclosure
The author of this commentary is the founder and President of Nutritional Biochemistry, Inc. (NBI) and NBI Pharmaceuticals. NBI is a supplement manufacturer that sells vitamin K2 dietary supplements, and NBI Pharmaceuticals has received US FDA Orphan Drug Designations for a specific form of vitamin K2 to potentially treat rare cancers.
- Jean G, Bresson E, Terrat JC, et al. Peripheral vascular calcification in long-hemodialysis patients: associated factors and survival consequences. Nephrol Dial Transplant. 2009;24(3):948-955.
- Schurgers LJ, Barreto DV, Barreto FC, et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol. 2010;5(4):568-575.
- Delanaye P, Krzesinski JM, Warling X, et al. Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrology. 2014;15:145.
- Rennenberg R, Kessels A, Schurgers L, et al. Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis. Vasc Health Risk Manag. 2009;5(1):185-197.
- Nasir K, Rubin J, Blaha MJ, et al. Interplay of coronary artery calcification and traditional risk factors for the prediction of all-cause mortality in asymptomatic individuals. Circ Cardiovasc Imaging. 2012;5(4):467-473.
- McCabe KM, Adams MA, Holden RM. Vitamin K status in chronic kidney disease. Nutrients. 2013;5(11):4390-4398.
- 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):590-597.
- Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, et al. 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):631-640.
- Vossen LM, Schurgers LJ, van Varik BJ, et al. Menaquinone-7 supplementation to reduce vascular calcification in patients with coronary artery disease: rationale and study protocol (VitaK-CAC trial). Nutrients. 2015;7(11):8905-8915.