Vascular calcification is common in chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients and is associated with increased cardiovascular and all-cause mortality. Vitamin K2 plays an important role in inhibiting vascular calcification by activating matrix Gla protein and other vitamin K-dependent proteins that prevent calcification. Studies have shown that CKD and ESRD patients have low vitamin K2 intake and status, resulting in increased levels of inactive vitamin K proteins and progression of vascular calcification. Intervention trials found that vitamin K2 supplementation was able to correct vitamin K2 deficiency and reduce markers of vascular calcification in these patient populations. Larger randomized controlled trials are still needed to confirm the long-

1. Vascular calcification and the role of
Vitamin K2 in CRF and ESRD
Salwa Ibrahim MD FRCP
Cairo University

2. Agenda
• Vascular Calcification in CKD
• Role of Vitamin K on VC
• Intervention studies

4. Atherosclerosis, arteriosclerosis, vascular
calcification, endothelial dysfunction

5. Vascular calcification in CKD
• Vascular calcification is frequent in CKD and predict CVS and
all cause mortality

7. IN CKD FACTORS PROMOTING CALCIFICATION
PREVAIL OVER FACTORS PROTECTING AGAINSI
CALCIFICATION

8. Causes of vascular calcification
• High phosphorus
• Vitamin D therapy
• Vitamin K deficiency
• warfarin
• DM
• Aging
• Dyslipidemia
Kidney Blood Press Res 2011

9. Several studies have shown that VC
resembles bone formation

10. Hyperphosphatemia

11. Increased serum phosphate play a key role in vascular
calcification
Hyperphosphatemia induces phenotypic change of VSMCs into
osteoblast like cells
Kidney Blood Press Res 2011

12. Vitamin D

13. Vitamin D in large dose induces phenotypic change of
VSMCs and promote vascular calcification
Kidney Blood Press Res 2011

14. Vitamin K

15. VK and VKDPs
• Vitamin K has important biological
actions mediated by the activation of
VKDPs
• There are 2 main forms of vitamin K
1. K1 is found in green vegetables
2. K2 (Menaquinone) found in specific
food (Natto Japan) or derived from the
metabolic activity of intestinal bacteria

16. Vitamin K dependent proteins (VKDPs)
• VKDPs require peripheral
carboxylation to become
active and is dependent on
vitamin K2
• MGP is an important VKDP
whose function to prevent
vascular calcification

17. Vitamin K2
• Vitamin K1 is essential for hepatic carboxylation of
VKDPs and production of coagulation factors
• Vitamin K2 is essential for peripheral activation of
MGP
• Vitamin K2 is not abundant in western diet

20. Vitamin K intake and status are low in
hemodialysis patients
Kidney Int 82: 605-610; 2012; d

21. • Vitamin K(1) and K(2) intake were low in a group of
HDx as compared to of healthy adults
• Non-carboxylated bone and coagulation proteins
were found to be elevated in a group hemodialysis
patients indicating vitamin K deficiency
• High non-carboxylated matrix Gla protein levels
confirmed vascular vitamin K deficiency

22. Low vitamin K in CKD promotes transformation of
VSMC into osteoblast and its apoptosis and
extracellular mineralization

23. Warfarin therapy

24. Warfarin and vascular calcification
• Warfarin inhibits
MGP and induces
widespread vascular
calcification in rats

26. • Subjects with long-term warfarin exposure were
more likely to have severe AV calcification
• There was an association between lifetime months of
warfarin exposure and severity of AV calcification
that was independent of dialysis vintage, calcium and
calcitriol intake

27. Interventional randomized trials

28. Effect of Vitamin K2 Supplementation
on Functional Vitamin K Deficiency in
Hemodialysis Patients
A Randomized Trial
Westenfeld et al, AJKD 2011

29. • 53 hemodialysis patients in stable conditions
• Vitamin K2 treatment at 45, 135, or 360 μg/d for 6 weeks
• Plasma levels of uncarboxylated MGP, uncarboxylated
osteocalcin
• Hemodialysis patients had 4.5-fold higher uncarboxylated
MGP and 8.4-fold higher uncarboxylated osteocalcin levels
compared with controls
• Vitamin K2 supplementation induced a dose- and time-
dependent decrease in circulating uncarboxylated MGP,
uncarboxylated osteocalcin,

30. • This study confirms that most hemodialysis
patients have a functional vitamin K deficiency
• It showed that inactive MGP levels can be
decreased markedly by daily vitamin K2
supplementation

32. Study Design
• The study included 42 CKD patients
• 270 days of supplementation with vitamin K2 at a
dose of 90 μg (menaquinone, MK-7) together with
10 μg of cholecalciferol (K+D group) or 10 μg of
cholecalciferol
• Common carotid intima-media thickness and
calcification modulators: matrix Gla protein (MGP)
and uncarboxylated MGP

34. The increase of CCA-IMT was
significantly lower in the K+D group
(P =0.003)
In the K+D
group, a significant decrease in
the level of ucMGP

36. • A 43-year-old female HDx
patient who developed
calciphylaxis
• 2 months prior to the diagnosis
she was found to have an
undetectable plasma vit K
concentration
• The calciphylaxis completely
resolved with vitamin K
supplementation and an
increase in haemodialysis
frequency

37. Ongoing studies

39. Evaluation of Vitamin K Supplementation for
Calcific Uremic Arteriolopathy (VitK-CUA)
• A pilot randomized controlled trial to examine the
effects of oral vitamin K supplementation on
circulating levels of anti-calcification factor
(carboxylated Matrix Gla Protein) and clinical
outcomes in patients with calcific uremic
arteriolopathy
• Study Start Date: March 2015
• Estimated Study Completion Date: March 2019

40. Conclusions
• VC is prevalent in CKD and links to increased morbidity and
mortality
• Vit K2 is important calcification inhibitor
• ESRD had low Vit K intake and that may contribute to VC
progression
• Intervention studies showed promising results in correcting
Vit K2 vasculopathy and larger intervention studies are
needed to confirm its effectiveness in improving long term
outcomes