Can Vitamin K supplementation reduce vascular calcification risk in adults living with CKD?

A colleague of mine brought this question to my attention. She had a patient who was asking if they should take Vitamin K. I admit its not a supplement I freqently think of, so I had to do some digging.

Adults living with kidney disease are more likely to die from cardiovascular disease than start dialysis.  And while in the general population standard risk factors, such as diabetes, hypertension and dyslipidemia appear to be major predictors, in CKD there seems to be something more going on.  One area is vascular calcification.  The prevalence of vascular calcification among adults living with CKD is 45 times higher than the general population! 

So what’s going on?  And could Vitamin K help?

Today, I am summarizing this article on Vitamin K supplementation for prevention of Vascular Calcification in CKD.

A Vitamin K Refresher

Vitamin K is a fat soluble vitamin, that occurs in three forms:

1. K1 – Phylloquinone
2. K2 – Kenaquinone
3. K3 – Menadione

Vitamin K2 has several subtypes. The K2 subtype with the best bioavailability is Menaquinone-7 (MK-7) and considered the ideal Vitamin K supplement. Bacteria in our gut can also synthesize vitamin K2.  The main food sources of vitamin K occurs as K1 (phylloquinone) and comes from green leafy vegetables. 

There is no upper limit for Vitamin K. There has never been a reported adverse health effect from Vitamin K ingestion (either from food or supplements).

Why would Vitamin K help with vascular calcification?

Vitamin K dependent proteins are involved in the regulation of bone metabolism, blood coagulation (think warfarin interactions) and arterial calcification.  Vitamin K deficiency increases circulating levels of an unphosphorylated carboxylated vitamin K dependent protein.  Increased levels of this protein increase vascular calcification. 

In experimental models, vitamin K deficiencies accelerated calcification.  Vitamin K supplementation reduced calcification by 37%.  This suggests that vitamin K may prevent or even reverse vascular calcification.

Are my patients deficient in Vitamin K?

Adults living with kidney disease are at increased risk of vitamin K deficiency because:

1. Traditional renal diet restrict dietary sources of vitamin K (dairy products and green vegetables)
2. Uremic toxins decrease Vitamin K activity
3. Phosphorus binders may make vitamin K deficiency worse

Several observational studies have reported that adults with pre-dialysis CKD and on dialysis have sub-clinical Vitamin K deficiencies.  Measurement of Vitamin K dependent proteins can help diagnosis subclinical deficiencies. Circulating vitamin K is not an accurate marker of Vitamin K status. This is because circulating vitamin K is dependent on lipids and lipoprotein. Furthermore, circulating vitamin K only reflects Vitamin K1 levels and not Vitamin K2.

Is Vitamin K deficiency bad for my patients?

There is accumulating data arterial stiffness, cardiovascular events, mortality and transplant failure are association with a subclinical vitamin K deficiency. There is also a documented link between calciphylaxis and Vitamin K deficiency. However, a meta-analysis, that included over 220,000 patients, reported that while higher vitamin K intake was associated with a reduced risk of heart disease, there wasn’t an association between vitamin K intake and mortality.

Does Vitamin K supplementation help?

Several studies have attempted to determine if Vitamin K supplementation in adults with CKD or on dialysis will help.  Some studies report benefit but others don’t. There remains an inadequate evidence base to suggest that all adults living with CKD will benefit from vitamin K supplementation.

However, one identified challenge is in determining the correct dose to study.  Earlier studies were using doses between 200-500ug of Vitamin K.  The current thought is that doses under 460ug are sub-therapeutic.  Newer trials are using higher doses (1000ug/day or 2000ug three times per week). There is also a need to determine the optimal Vitamin K form to supplement, though most studies are using MK-7.

Are Vitamin K supplements harmful?

Interestingly, there has never been a documented adverse event from Vitamin K intake or supplementation, in the general population or the CKD population. Vitamin K has no upper limit.  This suggests that Vitamin K supplementation is safe. Vitamin K supplements are also well tolerated. Only a few studies have reported GI side effects and those reported were mild.

Take Aways

There is a good chance that our CKD patients are deficient in Vitamin K, related to our diet recommendations, phosphorus binders are uremia.  Unfortunately measuring vitamin K levels is challenging and seldom done in clinical practice. There is a link between Vitamin K deficiency and vascular calcification, though we don’t yet know if Vitamin K supplementation will improve outcomes for our patients.

So, for me, if I have a patient who is interested in this – I will tell them to go ahead.  But I am not yet convinced that “Vitamin K for all” is the way to go.