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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.
Objective
To evaluate the effects of vitamin K2 treatment on dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) levels and vascular calcification scores
Draft
Prospective clinical study before and after intervention
Study population
Fifty patients in a Lebanese hemodialysis center; 60% of participants were men and all were 18 years or older (mean age 56.75) and had been receiving hemodialysis for more than 1 month.
intervention
Participants received 360 mcg of vitamin K2 daily 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 after 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 there were different scores, the higher score was noted.
Additional variables collected included demographic information, medical history, and results of recent laboratory tests.
Target parameters
The primary outcome measured was the percentage decrease from baseline in dp-ucMGP after 4 weeks of vitamin K2 supplementation. Secondary endpoints included:
- Korrelation zwischen AC-24-Score und Baseline-dp-ucMGP
- Korrelation zwischen dp-ucMGP zu Studienbeginn und anderen Variablen wie Alter, BMI, Diabetes, Rauchen und Fraktur innerhalb der letzten 6 Monate
- Korrelation zwischen dp-ucMGP-Abfall und anderen erhobenen Variablen (z. B. Serumspiegel von Albumin)
Key insights
After 4 weeks of MK-7 supplementation, mean dp-ucMGP levels decreased by 86%. In 88% of 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 gradually increase with age, levels were significantly higher in patients 65 years of age or older.
The majority of CKD patients die from a cardiovascular event before they can receive a kidney transplant. Therefore, it is crucial to find effective solutions to reduce the risk of cardiovascular disease in hemodialysis patients.
Patients with longer duration of hemodialysis also had a tendency toward high dp-ucMGP levels, but this was not statistically significant (P=0.18). Women had an overall trend toward lower vitamin K levels and consequently higher dp-ucMGP levels.
MK-7 was well tolerated; None of the participants discontinued treatment and there were no reports of side effects.
Clinical implications
Vascular calcification increases the risk of mortality and most hemodialysis patients suffer from increased vascular calcification.1Matrix Gla protein is a vitamin K-dependent protein that inhibits cardiovascular calcification.2Elevated plasma levels of dp-ucMGP, the precursor of MGP, correlate with vascular calcification and are predictive of vitamin K status.3It is now known that individuals with vascular calcification are 3 to 4 times more likely to suffer a cardiovascular event or die prematurely than those without vascular calcification.4.5
Theoretically, physiologically and clinically, it makes sense that correcting vitamin K deficiency will help reduce the risk of vascular calcification. This is particularly important in patients with chronic kidney disease (CKD), as vitamin K deficiency is common in this population.6
The majority of CKD patients die from a cardiovascular event before they can receive a kidney transplant.7Therefore, it is crucial to find effective solutions to reduce the risk of cardiovascular disease in hemodialysis patients.
The present study is promising because it shows that supplementation with 360 mcg MK-7 can reduce dp-ucMGP, but unfortunately researchers have not examined whether MK-7 alters the progression of arterial calcifications.
Kernatowka and colleagues tested the effects of MK-7 on calcification in their 2015 study. They gave 90 micrograms of MK-7 for 270 days to 42 non-dialyzed chronic kidney disease (CKD) patients.8They concluded that although MK-7 significantly reduced dp-ucMGP levels, it did not significantly affect calcification progression. However, it is possible that there is a dose-response effect with MK-7. Perhaps a higher dose could have helped slow progression or even reverse hardening of the arteries. A second study is currently underway to evaluate the effect of 360 mcg MK-7 on aortic calcifications in patients with coronary artery disease; the results of this clinical trial are still pending.9
As a vitamin K-dependent protein, dp-ucMGP can be viewed as a marker for functional vitamin K deficiency. Vitamin K supplementation with elevated dp-ucMGP 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 adept at identifying and correcting nutritional deficiencies. This study further illustrates the potential positive health benefits that can be achieved, particularly in certain patient populations. Because vitamin K is safe even at 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 results of additional studies that may show direct clinical benefit.
Disclosure of Conflicts of Interest
The author of this commentary is the founder and president of Nutritional Biochemistry, Inc. (NBI) and NBI Pharmaceuticals. NBI is a dietary supplement manufacturer that sells vitamin K2 supplements, and NBI Pharmaceuticals has received Orphan Drug Designations from the U.S. FDA for a specific form of vitamin K2 for the potential treatment of rare cancers.