Vitamin K2 and D3: A little known nutrient with big potential benefits for chronic kidney disease (CKD) patients
People with chronic kidney disease (CKD) are at marked increased risk for cardiovascular disease and bone fracture compared to the general population. Among those with end-stage renal disease, 50% of all deaths are due to cardiovascular disease, and the risk is 10 – 20 times higher than in the general population (1). Whilst the risk of skeletal fracture is up to five times higher in individuals with CKD, as well as a 3.7-fold increased risk of death (2). Accumulating evidence has demonstrated that CKD patients suffer from subclinical vitamins deficiency, which may hold great potential for treating and preventing these conditions. Vitamins play crucial role in multiple key metabolic pathways.
Lack of Vitamin K2 and D3 among CKD patients is likely a major risk factor leaving people vulnerable to these diseases. Thus, understanding this overlooked nutrient may provide the key to unlock the health puzzle for people with CKD.
Vitamin K2D3 and CKD
Although it has been long assumed that vitamin K1 is similar to vitamin K2, but actually it’s not. Vitamin K2 does not participate in coagulation under normal circumstances and instead activates an essential number of hepatic proteins that channel calcium into the skeleton and away from soft tissue. Vitamin K2 helps in building bone density and reducing arterial calcifications and cardiovascular mortality(3). Vitamin K2 is commonly found in foods of animal origin, including eggs and butter, as well as in certain fermented food, such as cheese and natto. As such food sources were known to be avoided for heart health, thus, vitamin K2 deficiency is common in the general population, even more common among the CKD population. Study has showed up to 97% of CKD patients have a functional vitamin K deficiency(4). Vitamin K2 is a shortfall nutrient among older adults that has been implicated in arterial calcification. Vitamin K2 functions as an enzyme cofactor for the carboxylation of vitamin K-dependent proteins involved in various physiological process, such as vascular calcification. Matrix gla protein (MGP) is the most studied protein in vascular calcification. MGP in its uncarboxylated (UC) form needs to be synthesized into the carboxylated (C) form by vitamin K2 and inhibits abnormal calcification in the vasculature. It has been proposed that vitamin K2 has a role in the complications of CKD as arterial calcification and stiffening developed when kidney function declines(5). A recent clinical trial has demonstrated supplementation with vitamin K2 in CKD patients reduced markers of calcification(6).
Vitamin D deficiency is also common among CKD patients and the reduced ability to convert the nutrient to its active form further complicates this situation. Vitamin D deficiency is a common complication in CKD patients because of proteinuria, decline in the glomerular filtrate rate and tubulointerstitial injury. Vitamin K2 works synergistically with vitamin D by channelling calcium away from soft tissues and towards the skeleton, buffering the potential toxicity of vitamin D. Vitamin D3 activates the expression of the calcium binding proteins osteocalcin and MGP, however these proteins are synthesized in an inactive form. Vitamin K2 activates osteocalcin and MGP through carboxylation and thus, if intakes of vitamin K2 are inadequate, osteocalcin and MGP will remain inactive. This affects both calcium integration to build bones, and its deposition into the vascular system, which can have harmful effects. Without K2 and D3, calcium cannot do its job effectively. Fraser et al have reported that the protein and mRNA expression of MGP increased after vitamin D3 treatment. Besides that, vitamin D3 could directly stimulate vitamin K-dependent MGP production, alleviate vascular calcification. Gigantes et al. has shown that co-supplementation of vitamin D3 and K2 is helpful for osteogenesis because vitamin K enhances the vitamin D gene induction of osteocalcin in mesenchumal stem cells. Moreover, vitamin K enhances osteogenesis and further mineralization, as well as alleviate the formation of advanced glycoxidated end products in osteoblasts (7).
Thus, supplementation of vitamin K2D3 can be a therapeutic target for CKD patients in restoring matrix gamma-carboxylation, alleviating vascular calcification and improving bone remodeling process.
References:
1. Major RW, Cheng MRI, Grant RA, Shantikumar S, Xu G, Oozeerally I, Brunskill NJ, Gray LJ. Cardiovascular disease risk factors in chronic kidney disease: A systematic review and meta-analysis. PLoS One. 2018 Mar 21;13(3):e0192895. doi: 10.1371/journal.pone.0192895. PMID: 29561894; PMCID: PMC5862400.
2. Cohen-Solal M, Funch-Brentano T, Urena P. Bone fragility in patients with chronic kidney diseases. Endocr Connect. 2020 Mar 1;9(4):R93–R101. doi: 10.1530/EC-20-0039. Epub ahead of print. PMID: 32168473; PMCID: PMC7219138.
3. 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
4. McCabe KM, Adams MA, Holden RM. Vitamin K Status in Chronic Kidney Disease. Nutrients. 2013;5(11):4390-4398. doi:10.3390/nu5114390
5. Sedaghat S, Mattace-Raso FU, Hoorn EJ, Uitterlinden AG, Hofman A, Ikram MA, Franco OH, Dehghan A. Arterial Stiffness and Decline in Kidney Function. Clin J Am Soc Nephrol. 2015 Dec 7;10(12):2190-7. doi: 10.2215/CJN.03000315. Epub 2015 Nov 12. PMID: 26563380; PMCID: PMC4670762.
6. 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
7. Hou YC, Lu CL, Zheng CM, Chen RM, Lin YF, Liu WC, Yen TH, Chen R, Lu KC. Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification. Nutrients. 2019 Jan 12;11(1):152. doi: 10.3390/nu11010152. Erratum in: Nutrients. 2019 Mar 06;11(3): PMID: 30642029; PMCID: PMC6356797.