Risk Factors for Vascular Calcifications in Hemodialysis Patients: to What Extent is Vitamin K2 Deficiency Involved?

Background The majority of patients reaching end-stage renal disease (ESRD) and dialysis have vascular calcifications. Those vascular calcifications tend to increase mortality in this specific population. It has been shown that high scores of vascular calcifications in a healthy patient with no cardiovascular risk factors lead to a higher mortality rate compared with someone with ≥3 risk factors without calcification. In hemodialysis (HD) patients, cardiovascular risk factors are numerous and they include the traditional ones such as age, smoking, diabetes, hypertension, hyperlipidemia and those specific to chronic kidney disease (CKD) as for instance hyperparathyroidism. All those facts are compelling arguments to look seriously for a treatment against vascular calcifications. Therefore the 2009 Kidney disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD) has suggested to measure those vascular calcifications scores by a lateral abdominal radiograph that is a cost-effective alternative to the standard computed tomography-based imaging.

In order to lower or prevent vascular calcifications in chronic kidney disease (CKD) patients, many interventions have been studied in the past. They have included treatments such as statins, non-calcium-based phosphate binders and cinacalcet. So far, the non-calcium-based phosphate binders showed significant benefit on mortality but none of the studies manifested a solid beneficial effect on vascular calcifications.

In the last years, remarkable data emerged concerning the association between vascular calcifications and plasmatic levels of dephosphorylated-undercarboxylated MGP (dp-ucMGP). dp-ucMGP is the inactive form of Matrix gla protein (MGP). MGP is a small protein known to act locally in the tissues as a calcification inhibitor and it is vitamin K dependent. High dp-ucMGP levels reflect low activity of MGP. Vitamin K2 deficiency is one of the factors that increase dp-ucMGP. There have been several reports also showing that dp-ucMGP levels increase gradually after the age of 40 and are significantly higher in those older than 65, in patients with diabetes, aortic stenosis, heart failure and on vitamin K antagonists (VKA). They are also extremely high in ESRD patients on dialysis. Moreover the combination of VKA and dialysis increases the incidence of calciphylaxis.

Since high dp-ucMGP levels suggest vitamin k2 deficiency and are associated with vascular calcification, supplementing high-risk patients especially CKD patients with vitamin k2 (menaquinone) seems very promising. Vitamin k2 can be provided to the patient as a pill or through a specific food diet. Food that seems to affect dp-ucMGP levels includes natto and fermented cheese such as camembert, goat cheese or gouda.

Vitamin K2 supplementation was analyzed in several European HD cohorts. In 2012, Westenfeld et al. demonstrated that vitamin k2 supplements in hemodialysis patients lead to a dose-dependent decrease in plasma dp-ucMGP levels. This was reproduced by Caluwé at al in 2014 and they both showed that a dose of 360 μg /d lower the dp-ucMGP by 30-33%.