Vitamin k1 and Its Relation to Vascular Calcification in Hemodialysis Patients

Vascular calcification (VC) represents one of the major complications associated with progressive renal impairment. Matrix Gla-protein (MGP) is a vitamin K-dependent protein that acts as a powerful inhibitor of vascular calcification. Despite this fact, it remains unknown whether supplementation with vitamin K can lead to reduction or reversal of vascular and heart valve calcification. Our study aims primarily to investigate the effect of intravenous vitamin K1 three times weekly for a total duration of 6 months on the serum levels of dephosphorylated-uncarboxylated MGP (dp-ucMGP) as well as aortic calcification score and severity of aortic and mitral valve lesions.

Vascular calcification (VC) represents one of the major complications associated with progressive renal impairment. In addition, VC has been regarded as one of the major predictors of cardiovascular risk, the most common cause of mortality in chronic kidney disease patients (CKD).

65% of end-stage kidney disease (ESKD) patients on regular peritoneal dialysis (PD) and 80-85% of ESKD patients on regular hemodialysis (HD) showed coronary or aortic calcification. These calcifications were associated with the total time on dialysis, with a yearly-increase of vascular calcification by 15% . Traditional risk factors for vascular calcification include age, male gender, smoking, diabetes, hypertension, and dyslipidemia.

VC, the pathological deposition of mineral in the vascular system, can manifest as intimal, medial, or heart valve calcification. Whereas intimal calcification, taking place within atherosclerotic plaque in aorta and coronary arteries, indicates advanced atherosclerosis, media calcification, which is often found in patients with diabetes and/or CKD, is characterized by diffuse mineral deposition along elastic fibers in both low resistance elastic-type as well as high resistance muscle-type arteries. Calciphylaxis, or calcific uremic arteriolopathy, represents a special form of ectopic, extraosseous calcification, that is characteristically observed in CKD patients, particularly those with ESKD with additional secondary hyperparathyroidism or those receiving warfarin. A study on hemodialysis patients showed more than two-fold higher odds of aortic and iliac calcifications in patients receiving warfarin than those who do not . VC results from an imbalance of promoters and inhibitors. Matrix Gla-protein (MGP) is a vitamin K-dependent protein and has been found to be expressed by medial vascular smooth muscles of arteries, endothelial cells, chondroblasts, and fibroblasts. Moreover, it is also expressed in the heart, kidneys, and lungs . MGP acts as a powerful inhibitor of vascular calcification. Loss-of-function mutations of MGP was associated with vascular calcification in animal models. In the setting of progressive vascular calcification, MGP transcription increases, giving rise to dephosphorylated-uncarboxylated MGP (dp-ucMGP). This molecule represents the inactive form of MGP, which later undergoes a γ- glutamate carboxylation and serine phosphorylation to produce the active form, phosphorylated carboxylated MGP (p- cMGP). Vitamin K acts as a cofactor for the enzyme γ-glutamylcarboxylase that is responsible for activating dp-ucGMP into dp-cMGP. Despite its key role in activation of dp-ucMGP, it remains unknown whether supplementation with vitamin K can lead to reduction or reversal of vascular and heart valve calcification in hemodialysis patients.

Eligibility Criteria:
Inclusion Criteria:

* Males or females ≥18 years of age,
* Not less than 6 months on HD,
* High level of serum dephosphorylated uc-MGP
* Signed informed consent,

Exclusion Criteria:

* Patients with normal level of dp-ucMGP
* History of thrombosis,
* Intake of vitamin K antagonists (warfarin) at baseline or in the 3 months prior to baseline,
* Inflammatory bowel disease,
* Liver dysfunction,