Despite many advances in the care of patients with chronic kidney disease (CKD) and ESKD, cardiovascular (CV) disease remains the leading cause of death in the kidney disease patient population. One of the factors explaining this excess mortality risk is vascular calcification, which predisposes patients to myocardial ischemia, left ventricular hypertrophy, and stroke (1).
The pathophysiology of vascular calcification in patients with CKD and ESKD is distinct from that in the general population. In the general population, vascular calcifications form in the intima of vessels and are linked to traditionally modifiable risk factors, including smoking, age, obesity, diabetes, hypertension, and hypercholesterolemia. By contrast, in CKD and ESKD, vascular calcifications form in the intima and media of medium and large arteries. Whereas the pathogenesis of intimal vascular calcification in CKD and ESKD mirrors that of the general population, the pathogenesis of medial vascular calcification is not well understood.
Medial vascular calcification occurs early in the course of CKD (2) and strongly predicts cardiovascular (CV) events and mortality. Mineral–bone disorder is a major factor involved in the development of medial vascular calcification (3, 4). Other involved factors include vascular smooth muscle cell osteochondrogenic shift (4), decreased levels of calcification inhibitors (5, 6), and increased levels of oxidative stress, all of which contribute to the progression of vascular calcification. Medial vascular calcification is a highly regulated multipathway process (4), but there are not yet any proven preventative treatments. Vitamin K supplementation is one potential therapy that is currently being investigated in clinical trials.
The role of vitamin K in vascular calcification
Matrix Gla protein (MGP) plays an important role in vascular biology. It is present in soft tissue, where it functions as a calcification inhibitor. MGP requires vitamin K to undergo γ carboxylation, an important step for MGP activity. In states of vitamin K deficiency, MGP remains decarboxylated and inactive, therefore increasing soft tissue propensity for calcification (Figure 1). Calcified vessels have higher concentrations of the dephosphorylated uncarboxylated form of MGP (dp-ucMGP), whereas normal vessels have higher concentrations of the carboxylated form of MGP (cMGP).
Hepatic and peripheral carboxylation of vitamin K–dependent proteins
Citation: Kidney News 11, 12
Vitamin K–dependent proteins undergo carboxylation to become biologically active, requiring vitamin K as a cofactor in the conversion. Abbreviation: MGP = matrix Gla protein. Adapted from Danziger J. Vitamin K–dependent proteins, warfarin, and vascular calcification. Clin J Am Soc Nephrol 2008; 3:1504–1510.Vitamin K in CKD and ESKD
Patients with CKD and ESKD have vitamin K deficiency, which stems from multifactorial causes. The Western diet does not provide enough vitamin K to activate MGP in all tissues. The poor oral intake and the dietary restrictions of patients with advanced CKD and ESKD further contribute to vitamin K deficiency. Additionally, it is suggested that some phosphate binders can sequester vitamin K in the gut, therefore compounding the deficiency. Finally, the use of vitamin K antagonists such as warfarin inhibits vitamin K–dependent carboxylation of MGP. These agents have historically been associated with the progression of vascular calcification in patients with kidney disease.
With the discovery of the role of MGP in vascular calcification, vitamin K was proposed as a treatment to modify the development of vascular calcification and the risk of CV disease in CKD. Circulating MGP is used as a surrogate of vitamin K status: dp-ucMGP level inversely correlates with vitamin K level. Multiple observational studies have shown significant associations between higher levels of dp-ucMGP and lower levels of cMGP with vascular calcification in patients with CKD and ESKD (Table 1). These studies were cross-sectional; therefore, causal inferences could not be made. Subsequent studies evaluated the effect of vitamin K supplementation on vascular calcification. In patients with ESKD, supplementation with vitamin K resulted in a decrease of dp-ucMGP levels (Table 2). However, we cannot make any conclusions with certainty based on these studies because they were limited to 6 to 8 weeks of follow-up and did not measure vascular calcification scores. Clinical trials evaluating the effect of long-term vitamin K supplementation on vascular calcification, cardiovascular events, and mortality are currently ongoing.
Association between vitamin K level and vascular calcification in CKD and ESKD
Effect of vitamin K supplementation on dephosphorylated-uncarboxylated MGP level in ESKD
What can we do now?
While we await the ongoing vitamin K supplementation clinical trials that will give us a more definite answer to the question whether vitamin K supplementation can improve CV outcomes in patients with kidney disease, should we be giving all our CKD and ESKD patients vitamin K supplements?
There is no known toxicity of vitamin K, nor is there an upper level of intake. Additionally, vitamin K supplementation does not seem to increase the risk of thrombosis or stroke. Therefore, it seems to be a treatment with relatively little harm but with potentially significant benefit—a treatment that we may be justified to use more liberally.
Furthermore, should we be actively switching our patients from vitamin K antagonists such as warfarin to the novel anticoagulants when possible? This is currently recommended in patients with calciphylaxis, but we should perhaps be more liberal in prescribing novel anticoagulant agents for our patients with CKD and ESKD. This effort may decrease CV events and improve outcomes in these patients.
In conclusion, vitamin K is one piece of the puzzle of vascular calcification—a process that is unlikely to be reversed by targeting one pathway only. Targeting several pathways, including vitamin K deficiency, mineral–bone disorders, and the bone–vascular axis could improve vascular calcification development and progression. Further research into the mechanisms of vascular disease in CKD will ultimately lead to the development of therapeutic agents that can improve the risk of CV disease in kidney disease.
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