Vitamin K2: A little known nutrient with big potential benefits for CKD
Compared to the general population, people with chronic kidney disease are at marked increased risk for cardiovascular disease and bone fracture. Standard in-center hemodialysis itself can cause organ stunning. Vitamin K2, a long misunderstood fat-soluble vitamin holds great potential for treating and preventing these conditions. In fact, a lack of vitamin K2 among CKD patients is likely a major risk factor leaving people vulnerable to these diseases. Understanding this overlooked nutrient provides a key, missing piece to the health puzzle for people with CKD.
Vitamin K is not a single nutrient, but a family of related vitamins. Vitamin K1 is found primarily in green leafy vegetables and plays a major role in coagulation by activating several clotting proteins in the liver. This form of vitamin K is easy to obtain in the diet, but its role in coagulation is so important levels are not left to the whims of dietary intake. The body has a mechanism to recycle vitamin K1 so deficiency is very rare and, when it occurs, is usually secondary to liver disease rather than inadequate intake.
Vitamin K2 is a different story – although for decades it and vitamin K1 were assume to be practically one and the same. K2 does not participate in coagulation under normal circumstances and instead activates a number of extra hepatic proteins that, among other things, channel calcium into the skeleton and away from soft tissues. For this reason vitamin K2 plays newly recognized, pivotal role in building bone density and reducing arterial calcifications and cardiovascular mortality1 - major health concerns for the CKD population. Vitamin K2 also activates other proteins that influence cell growth regulation, making it a key player in cancer prevention and even treatment.2
Humans can obtain small amounts of vitamin K2 by converting K1 from food, but this conversion is limited, and does not meet our intake requirements. Vitamin K2 is found in some foods of animal origin, such as eggs and butter as well as in certain fermented foods, such as cheese and the infamous Japanese fermented soy breakfast food, natto.
Given the limited known food sources of vitamin K2 and the decades long (although now debunked) advice to avoid many of these food for heart health, it should come as no surprise that vitamin K2 deficiency is common in the general population, but it is even more common among the CKD population.3 Experts in this area postulate that most HD patients have a functional vitamin K deficiency, with up to 97% of patients having insufficient levels, depending on the method of sufficiency testing.4 This has several potentially serious implications, contributing to the risk of many health concerns, including heart disease, osteoporosis and cancer.
The risk of cardiovascular mortality among CKD patients is several times higher than general population; it is the first cause of death in this group. CKD patients have a disproportionately high prevalence of atherosclerosis and arterial calcification that can’t be fully explained by traditional risk factors such as diabetes, hypertension and advanced age, and treatment of elevated cholesterol with statins fails to lower arterial calcification burden.5 Even young adults who have been on hemodialysis for a long period of time have a prevalence of coronary artery calcification (CAC) that is at least ten times higher than those of the same age whose kidney function is normal. A recent clinical trial 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.6
Arterial calcification leads to an increase in arterial stiffness and a decrease in coronary perfusion, resulting in myocardial ischemia. While this is a concern for the general population, arterial stiffness is a highly prevalent condition for kidney patients and it predicts decline in renal function as well as cardiovascular events.7 A 2015 clinical trial published showed vitamin K2 supplements (180 mcg of MK-7 daily) improved arterial stiffness in healthy postmenopausal women, especially in those with high arterial stiffness.8
Osteoporosis is another common comorbidity in the CKD community. Patients with CKD requiring dialysis have a 4-fold increased risk of hip fracture compared with the general population. 9 Bone health has been related to vitamin K status in adult HD patients as far back as the late 1990s and recent studies confirm that relationship. While evidence mounts for the benefits of vitamin K2 on bone health in the general population, clinical trials on vitamin K2 for osteoporosis management among CKD patients are lagging. However, two trials to date have shown high dose vitamin K2 to have a positive impact on markers of bone health in CKD patients. 10
Vitamin D deficiency is exceptionally common among CKD patients and the reduced ability to convert the nutrient to its active form further complicates this situation. For that reason, as well as to treat hyperparathyroidism and low bone density, vitamin D supplements are routinely prescribed to CKD patents. However, since vitamin D stimulates calcium absorption in the intestine, this can worsen calcium burden and vascular calcifications – the proverbial double-edged sword. By channeling calcium away from soft tissues and towards the skeleton, vitamin K2 buffers the potential toxicity of vitamin D. 11 12
While vitamin K2 is being established as a critically important nutrient for people with CKD, it also shows great promise in mitigating the potential organ damage associated with HD, namely organ stunning. Although the pathogenesis of organ stunning is not definitively established, it is thought to be caused either by an accumulation of free radicals due to ischemia and/or a transient calcium overload on reperfusion. Vitamin K has been shown to completely block free radical accumulation and cell death due to ischemia.13 Given the potential benefit here, calls for clinical research in this area should be loud and clear from the CKD community.
Finally, since blood clotting is a concern for some HD patients, I’d like to clarify the potential effect of vitamin K2 supplements on coagulation, as this remains an area of confusion for many. Under normal circumstances clotting proteins are all or almost all occupied by vitamin K1, so no amount of vitamin K2 (or K1, for that matter) from diet or supplements will affect blood clotting. The exception to this is for patients on Warfarin/Coumadin or coumarin-type blood thinners. Drugs in this class - prescribed to approximately 20% of dialysis patients in North America - work by inhibiting the recycling of vitamin K, effectively creating a vitamin K deficiency. [Not surprisingly these drugs exacerbate the soft tissue calcifications that already plague CKD patients.14]
Interference with this mechanism is why intake of green leafy vegetables and other vitamin K1-rich foods is strictly limited in patients on Warfarin. Likewise, vitamin K2 from food or supplements will counteract the action of the drug, making them contraindicated, technically. In fact, maintaining a consistent daily intake of K vitamins - rather than trying to avoid them altogether - helps to stabilize INR, but this needs to be managed carefully. The relative contraindication for vitamin K2 supplements and oral anticoagulants does not extend to aspirin, platelet inhibitors such as Plavix, or blood thinners that works by other mechanisms, such as Effient, Xarelto, etc. These can safely be taken with vitamin K2. K2 is also well-established to be non-toxic, carrying none of the concerns sometimes associated with fat-soluble vitamins.15
Kate Rhéaume-Bleue N.D. is the author of Vitamin K2 and the Calcium Paradox: How A Little Known Vitamin Could Save Your Life (HarperCollins).
Geleijnse JM, Vermeer C, Grobbee DE, et al. Dietary Intake of Menaquinone Is Associated with a Reduced Risk of Coronary Heart Disease: The Rotterdam Study. J Nutr. 2004;134(11):3100-3105↩
Samykutty A, Shetty AV, Dakshinamoorthy G, et al. Vitamin K2, a Naturally Occurring Menaquinone, Exerts Therapeutic Effects on Both Hormone-Dependent and Hormone-Independent Prostate Cancer Cells. Evid-based Compl Alt. 2013;2013:287358. doi:10.1155/2013/287358.↩
Cranenburg EC, Schurgers LJ, Uiterwijk HH et al. Vitamin K intake and status are low in hemodialysis patients. Kidney Int. 2012;82:605–610.↩
McCabe KM, Adams MA, Holden RM. Vitamin K Status in Chronic Kidney Disease. Nutrients. 2013;5(11):4390-4398. doi:10.3390/nu5114390.↩
Vo T-M, Disthabanchong S. Are there ways to attenuate arterial calcification and improve cardiovascular outcomes in chronic kidney disease? World J Cardio. 2014;6(5):216-226. doi:10.4330/wjc.v6.i5.216.↩
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.↩
Yoon HE, Shin DI, Kim SJ, et al. Brachial-Ankle Pulse Wave Velocity Predicts Decline in Renal Function and Cardiovascular Events in Early Stages of Chronic Kidney Disease. Int J of Med Sci. 2013;10(11):1430-1436. doi:10.7150/ijms.6645.↩
Knapen MH, Braam LA, Drummen NE, et al. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial. Thromb Haemost. 2015;19:113↩
Jadoul M., Albert J.M., Akiba T., et al. Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the dialysis outcomes and practice patterns study. Kidney Int. 2006;70:1358–1366. doi: 10.1038/sj.ki.5001754.↩
Masterjohn, C. Vitamin D toxicity redefined: Vitamin K and the molecular mechanism. Med Hyp 2007,68(5):1026–1034↩
Fu X, Wang XD, Mernitz H, et al. 9-Cis Retinoic Acid Reduces 1α,25-Dihydroxycholecalciferol-Induced Renal Calcification by Altering Vitamin K-Dependent γ-Carboxylation of Matrix γ-Carboxyglutamic Acid Protein in A/J Male Mice J. Nutr. 2008;138(12):2337-2341; doi:10.3945/jn.108.093724↩
Li J1, Lin JC, Wang H et al. Novel role of vitamin K in preventing oxidative injury to developing oligodendrocytes and neurons. J Neurosci. 2003;23(13):5816-26.↩
Holden R.M., Sanfilippo A.S., Hopman W.M., et al. Warfarin and aortic valve calcification in hemodialysis patients. J. Nephrol. 2007;20:417–422.↩
Pucaj K, Rasmussen H, Moller M, Preston T. Safety and toxicological evaluation of a synthetic vitamin K2, menaquinone-7. Tox Mech Meth. 2011;21(7):520-532. doi:10.3109/15376516.2011.568983.↩
Comments
Dori Schatell
Dec 13, 2023 9:21 PM
Clin Kidney J
. 2023 Oct 14;16(12):2738-2749. doi: 10.1093/ckj/sfad255. eCollection 2023 Dec.
Vitamin K supplementation impact in dialysis patients: a systematic review and meta-analysis of randomized trials
Titus Andrian 1 2 , Anca Stefan 2 , Ionut Nistor 1 2 , Adrian Covic 1 2
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PMID: 38046003 PMCID: PMC10689161 DOI: 10.1093/ckj/sfad255
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Abstract
Vitamin K supplementation has been considered recently as a potential treatment for addressing vascular calcification in chronic kidney disease patients. We conducted a systematic review and meta-analysis to summarize the impact of vitamin K supplementation in dialysis patients. Electronic databases were searched for clinical randomized trials among patients treated with vitamin K. Random effects models were performed and risk of bias was evaluated with Cochrane tools and the search was conducted until 15 of September 2023. Eleven trials comprising 830 patients (both adult and pediatric, mainly hemodialysis) compared vitamin K with different controls: lower doses of vitamin K, standard care or placebo. Vitamin K supplementation had no effect on mortality. Vitamin K administration improved vitamin K levels and led to lower levels of dp-uc-MGP and moderately increased calcium levels [0.18 (0.04-0.32)]. Vitamin K1 proved more potency in reducing dp-uc-MGP [SMD -1.64 (-2.05, -1.23) vs. -0.56 (-0.82, -0.31)] and also raised serum vitamin K levels in comparison with vitamin K2 [5.69 (3.43, 7.94) vs. 2.25 (-2.36, 6.87)]. While it did not have a proved benefit in changing calcification scores [-0.14 (-0.37 ± 0.09)], vitamin K proved to be a safe product. There was some concern with bias. Vitamin K supplementation has no impact on mortality and did not show significant benefit in reversing calcification scores. Vitamin K1 improved vitamin K deposits and lowered dp-uc-MGP, which is a calcification biomarker more than vitamin K2. As it proved to be a safe product, additional randomized well-powered studies with improved treatment regimens are needed to establish the true impact of vitamin K in dialysis patients.
Stephen M Arrington
Sep 16, 2022 6:57 PM
Glenda J Seese
May 09, 2022 6:49 PM
Dori Schatell
Feb 11, 2019 4:14 PM
Dori
Feb 11, 2019 4:01 PM
Dori
Dec 19, 2018 5:03 PM
J Bone Miner Res. 2018 Nov 14. doi: 10.1002/jbmr.3608. [Epub ahead of print]
Poor Vitamin K Status Is Associated With Low Bone Mineral Density and Increased Fracture Risk in End-Stage Renal Disease.
Evenepoel P1,2, Claes K1,2, Meijers B1,2, Laurent M3, Bammens B1,2, Naesens M1,2, Sprangers B1,2, Pottel H4, Cavalier E5, Kuypers D1,2.
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Abstract
Chronic kidney disease and osteoporosis are major public health problems associated with an aging population. Vitamin K insufficiency is prevalent among patients with end-stage renal disease (ESRD). Preliminary data indicate that poor vitamin K status may compromise bone health and that increased inflammation may be in the causal pathway. We performed an ancillary analysis of data collected in the frame of prospective observational cohort studies exploring various aspects of bone health in de novo renal transplant recipients to investigate the association between vitamin K status, inflammation, bone mineral density, and incident clinical fractures. Parameters of mineral metabolism (including biointact PTH and FGF23, sclerostin, calcidiol, calcitriol) and inflammation (CRP and IL-6), osteoprotegerin, bone turnover markers (P1NP, BsAP, and TRAP5B), and dephosphorylated-uncarboxylated Matrix Gla Protein (dp-ucMGP) were assessed on blood samples collected immediately prior to kidney transplantation in 468 patients. Areal bone mineral density (aBMD) was measured at the lumbar spine and femoral neck by dual-energy X-ray absorptiometry within 14 days posttransplant. Poor vitamin K status, defined by dp-ucMGP >500 nmol/L, was highly prevalent (90%). High dp-ucMGP levels independently associated with elevated inflammatory markers and low aBMD. No associations were observed between vitamin K status and bone turnover markers. During a median follow-up of 5.1 years, 33 patients sustained a fragility fracture. In Cox-proportional hazards analysis, a dp-ucMGP above median associated with incident fractures, independent of classical determinants, including age, gender, history of fracture, and aBMD (HR 2.21; 95% CI, 1.00 to 4.91; p < 0.05). In conclusion, poor vitamin K status associates with inflammation and low aBMD in patients with ESRD and confers an increased risk of incident fractures in de novo renal transplant recipients.
© 2018 American Society for Bone and Mineral Research.
liz
Jul 11, 2015 8:50 AM
You answered my concern regarding heparin. THANK U :)
Here is a study you may find interesting: K2 and hemodialysis
http://ndt.oxfordjournals.org/content/early/2013/11/26/ndt.gft464.full
John Agar
May 06, 2015 2:28 AM
One of the useful things about blogs like this is that they can bring novel research ideas and concepts to the fore - concepts that would otherwise remain submerged in the noise of countless papers and publications on any number of issues. Written in lay-terms, they can synthesise topics and provide food for thought.
But, it seems to me that while there are still a number of leaps of faith within the blog text that still need to be confirmed and further researched before it can be said that vitamin K2 is 'a golden bullet' to improved vascular and bone health. That said, there is certainly enough to say that this under-researched and under-appreciated (indeed, by me, till now, un-met) vitamin deserves a lot more attention and interest.
While I found the data in the Caluwe paper in NDT (2014) particularly interesting [= reference 6 of this blog], I think it may still be too early in the K2 research cycle to extrapolate the moderate K2 dose-dependent reductions these researchers found in the matrix Gla protein (dp-u-MGP) ... a protein thought to be 'one of the strongest local inhibitors of vascular calcification acting in the vessel wall' ... into a clinical benefit, particularly as the 'mechanisms of the inhibitory effect of MGP on calcification have not yet been entirely elucidated' [NB: the quotations are taken from the NDT paper].
Nevertheless, it is certainly now an area of research that deserves careful watching and additional work, and I am grateful to Kate for bringing this forward and to attention.
I was also rather shocked to read that 20% of US dialysis patients are on warfarin or warfarin-like medication! [second last paragraph]. Is this so? If so, why so? This is particularly of concern when considering:
1. Bill Bennett's excellent assessment "Should Dialysis Patients Ever Receive Warfarin and for What Reasons?" CJASN 2006: http://cjasn.asnjournals.org/content/1/6/1357.full)
2. The excellent review by Kruger from Juergen Floege's group 'Sailing Between Scylla and Charybdis: Oral Long-term Anticoagulation in Dialysis Patients' Nephrol Dial Transplant. 2013;28(3):534-541 and reproduced in Medscape 2014 http://www.medscape.com/viewarticle/780707_10 ... a review that concluded "Physicians caring for patients with advanced CKD or ESRD and atrial fibrillation cannot rely on evidence-based guidelines in their decisions about OAT. Observational studies in dialysis patients with atrial fibrillation provide very little evidence to encourage the use of coumarins in such patients. It must be stressed that recommendations developed for the non-CKD population cannot be simply transferred to HD patients. Moreover, avoiding treatment with coumarins might reduce the burden of vascular calcification and the risk of calciphylaxis in ESRD––a population cohort at special risk of these cardiovascular complications. Considering the current absence of suitable alternatives to coumarins in advanced CKD, we still see some indications for their use in this population, but we discourage using coumarins for the prevention of thromboembolic events in ESRD patients with atrial fibrillation."
All in all, a thought-provoking blog on a subject and substance unknown to many of us - myself included ... one that warrants greater attention and awareness than has currently been accorded to it.
Kate
May 06, 2015 7:54 PM
I found the 20% of dialysis patients on warfarin number to be shocking as well. This was from the McCabe, Adams paper (reference #4).
Vitamin K2 research is in it infancy - probably 20 years behind vitamin D, for example. Hopefully raising awareness of it in blogs like this one will encourage more studies to confirm its potential benefits. Thanks for your thoughtful comments on the blog.
Gearold Batson
Mar 11, 2020 6:33 AM
Allan Goodson
Mar 09, 2021 1:48 AM
How is the k2 working? Me and my wife have been taking it for a few years. My wife has 1 kidney, and is stage 3 right now...history of kidney stones.
John Agar
May 07, 2015 12:18 AM
On the anticoagulation aspect another paper has just appeared in the BMJ (350:h246 - 2015) that shows that the incidence of major bleeding rises as eGFR declines and is 10 fold the risk compared to people with normal renal function ... reaffirming that we should have second thoughts before using coumadin derivatives for routine AF management in advanced CKD and dialysis patients. Although anticoagulation clearly reduces the risk of stroke in the general population, this may not be the case in the advanced CKD and dialysis cohort where the risk of major anticoagulation-induced haemorrhage is 10 fold greater but the risk of stroke is not. There are now a number of papers that all say the same thing - the latest being this BMJ paper from Min Jun and the Alberta group on an assessment of the risks of coumadin anticoagulation vs. eGFR in 12,403 Canadian adults >66 yrs old.
Kate
May 08, 2015 3:51 PM
Here are a couple of recent papers from Medical Hypothesis on vitamin K2 that might be of interest to you:
http://www.medical-hypotheses.com/article/S0306-9877(15)00011-0/abstract
http://www.medical-hypotheses.com/article/S0306-9877(15)00032-8/abstract
Amanda Wilson
May 05, 2015 2:43 AM
John Agar
May 06, 2015 2:30 AM
John Agar
May 05, 2015 10:50 PM