Role of vitamin K in controlling atherosclerosis and vascular calcification in CKD patients: Review

Published On 2020-12-01 07:15 GMT   |   Update On 2020-12-01 10:08 GMT

Chronic kidney disease (CKD) is recognized as a major health problem across the world with Global Burden of Disease (GBD) study 2015 ranking chronic kidney disease as the eighth leading cause of death in India. (1)

Simply put, CKD is defined as the presence of kidney damage, manifested by abnormal albumin excretion or decreased kidney function, quantified by measured or estimated glomerular filtration rate (GFR) that persists for more than three months. (2).

As the disease progresses, complications of atherosclerosis and vascular calcification are commonly noted in the patients of chronic kidney disease. Understanding the pathophysiology behind these complications and the risk factors helps in its prevention and in halting its progression.
Atherosclerosis, often regarded to be a complication of CKD, is a disease in which fatty deposits called atheromatous plaques appear in the inner layers of arteries. Formation of these plaques starts with the deposition of small cholesterol crystals in the intima and its underlying smooth muscle(3)
The current understanding of atherosclerosis in CKD is that it parallels bone mineralization and occurs in a highly regulated fashion that can be modulated at multiple levels(4). The progression of mineralization depends on the balance of pro-calcific factors such as the calcium-phosphorus product, parathyroid hormone, and bone morphogenetic protein-2 and inhibitory factors such as the protein fetuin-A, pyrophosphate, osteopontin, osteoprotegerin, and γ-carboxyglutamic acid protein as well as calcification modulators like matrix Gla protein (MGP),desphosphorylated- uncarboxylated MGP (dp-ucMGP) , osteocalcin (OC),and fibroblast growth factor 23.(5)
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Vascular calcification is also common in chronic kidney disease and associated with increased morbidity and mortality. Its mechanism is multifactorial and incompletely understood. Patients with chronic kidney disease are at risk for vascular calcification because of multiple risk factors that induce vascular smooth muscle cells to change into a chondrocyte or osteoblast-like cell. (6)
It is well documented that Vitamin K2 is required as a co-factor in the process of gamma-carboxylation of several vitamin K-dependent proteins like Matrix GLA protein (MGP) and osteocalcin (OC), turning inactive uncarboxylated proteins into active carboxylated forms to confer functioning. These proteins act as a potent inhibitor of vascular calcification. (7)
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A growing body of evidence supports that Vitamin K2 deficiency may result in the synthesis of under-carboxylated, biologically inactive gla proteins—a risk factor for vascular calcification, atherosclerosis and cardiovascular disease, especially in highly susceptible patients of CKD. (8)
Previous studies have shown that in experimental CKD models, vitamin K is key to the susceptibility of vascular calcification. It has also been noted that Vitamin K deficiency is highly prevalent among CKD populations [9, 10].
A clinical trial, in 2014, demonstrated that an 8–week supplementation with vitamin K2 in HD patients reduced markers of calcification in a linear and dose-dependent fashion, with the greatest benefits being seen at doses of roughly 360 mcg MK-7 daily (11).
While evidence mounts for the benefits of vitamin K2 in the general population, clinical trials on vitamin K2 for managing cardiac effects among CKD patients had been lagging since long.
With this background, in 2015, Ilona Kurnatowska et al, at the Department of Nephrology, Hypertension and Kidney Transplantation, Medical University of Lodz, Poland sought to carry out a study with an aim to assess the effect of vitamin K2 substitution on the progression of atherosclerosis and calcification in non dialyzed patients with CKD stages 3–5. (12)
METHODOLOGY
The study was designed as a prospective, randomized, and double-blind study conducted between 2009 and 2012.
The sample population included 42 (22 men; mean age, 60 ±3.0 years, and 20 women, mean age, 56 ±1.5 years) non dialyzed patients with CKD stages 3–5 from a single nephrology outpatient clinic whose age ranged from 18 to 70 years old, had a history of stable estimated glomerular filtration rate (eGFR <60 ml/min/1.73 m 2 ) over at least 6 months, not requiring dialysis.
Two groups were prepared and supplementation with vitamin K2 at a dose of 90 μg (menaquinone, MK-7) together with 10 μg of cholecalciferol or Vitamin D (K+D group) or 10 μg of cholecalciferol (group D) was done.
The outcome parameters assessed were -common carotid intima-media thickness (CCA-IMT), coronary artery calcification score (CACS), basic biochemical parameters, lipids, and calcification modulators: matrix Gla protein (MGP), dephosphorylated-uncarboxylated MGP (dp-ucMGP), osteoprotegerin (OPG), fetuin-A, osteocalcin (OC), and fibroblast growth factor 23. All the measurements were taken at baseline and after 270 ±12 days of supplementation.
Within 7 days after the end of active treatment, the CACS level was assessed by a multiscan CT and CCA-IMT—by ultrasonography.
Results
The following key facts emerged on analysis.
• The increase of CCA-IMT was significantly lower in the K+D group compared with the D group,from 0.95 ±0.2 mm to 1.01 ±0.3, P = 0.003 vs from 1.02 ±0.2 mm to 1.16
±0.3, P = 0.003
• The increase in CACS was slightly lower in the K+D group than in the D group
•  In the K+D group, a significant decrease in the level of dp-ucMGP and total OC was observed. A borderline increase in the FGF-23 level in K+D patients during the treatment was observed, while in the vitamin D group, it did not change.
Based on the results, researchers made some observations.
1. A tendency to slow the progression of CAC in patients who received both vitamins K2 and D was observed in the study. A 270-day course of vitamin K2 administration in patients with CKD stages 3–5 may reduce the progression of atherosclerosis, but does not significantly affect the progression of calcification.
2. It was also noted that Vitamin K2 significantly changes the levels of calcification promoters and inhibitors: dp-ucMGP, OC, and OPG.
The authors further noted that the progression of CCA-IMT was significantly slower in patients treated with both vitamin K2 and cholecalciferol compared to patients receiving vitamin D alone. Therefore, since all patients received the same dose of vitamin D, but only in one of the arms vitamin K2 was administered, by comparing the treatment results from both groups, one could assume that the differences between the groups were dependent mainly on the effects of vitamin K2.
Further noting that Deficiency of carboxylated MGP may contribute substantially to the development and progression of arterial calcification, the researchers suspected that supplementing vitamin K2 for a longer time could result in a more distinct inhibition of calcification process.
The authors acknowledged that due to the small sample size of their study, larger studies are needed to confirm whether vitamin K2 needs to be supplemented in CKD patients for the prevention of atherosclerosis as well as calcification.
" In conclusion, a 270-day course of vitamin K2 administration (90 μg) may reduce the progression of atherosclerosis in non-dialysis subjects with CKD stages 3–5, but does not have a significant effect on CAC progression," the authors stated

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REFERENCES

1. GBD 2015 Mortality and Causes of Death CollaboratorsGlobal, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of Disease Study 2015.Lancet. 2016; 388: 1459-1544
2. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Levey AS, Eckardt KU, Tsukamoto Y, Levin A, Coresh J, Rossert J, De Zeeuw D, Hostetter TH, Lameire Eknoyan G Kidney Int. 2005 Jun; 67(6):2089-100.
3. Rafieian-Kopaei, M., Setorki, M., Doudi, M., Baradaran, A., & Nasri, H. (2014). Atherosclerosis: process, indicators, risk factors and new hopes. International journal of preventive medicine, 5(8), 927–946.
4. The Scope of Coronary Heart Disease in Patients With Chronic Kidney Disease Fadi G. Hage, Rajesh Venkataraman, Gilbert J. Zoghbi, Gilbert J. Perry, Angelo M. DeMattos, Ami E. Iskandrian J Am Coll Cardiol. 2009 Jun, 53 (23) 2129-2140
5. McCullough P.A., Agrawal V., Danielewicz E., Abela G.S. (2008) Accelerated atherosclerotic calcification and Monckeberg's sclerosis: a continuum of advanced vascular pathology in chronic kidney disease. Clin J Am Soc Nephrol
3:1585–1598.6. Moe, S. M., & Chen, N. X. (2008). Mechanisms of Vascular Calcification in Chronic Kidney Disease. Journal of the American Society of Nephrology, 19(2), 213–216. doi:10.1681/asn.200708085.
7. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, et al.Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997;386(6620):78–81. doi: 10.1038/386078a0.
8. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species.Cranenburg EC, Koos R, Schurgers LJ, Magdeleyns EJ, Schoonbrood TH, Landewé RB, Brandenburg VM, Bekers O, Vermeer C Thromb Haemost. 2010 Oct; 104(4):811-22
9. 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.
10. Schurgers LJ. Vitamin K: key vitamin in controlling vascular calcification in chronic kidney disease. Kidney Int. 2013;83(5):782–4.
11. Caluwé R, Vandecasteele S, Van Vlem B et al. Vitamin K2 supplementation in haemodialysis patients: a randomized dose-finding study. Nephrol Dial Transplant. 2014;29(7):1385-90. doi: 10.1093/ndt/gft464. Epub 2013 Nov 26.
12. Kurnatowska I, Grzelak P, Masajtis-Zagajewska A, Kaczmarska M, Stefanczyk L, Vermeer C, 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):631–40.
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