Vascular Calcification in Chronic Kidney Disease: The Role of Vitamin K- Dependent Matrix Gla Protein

Abstract

Arterial calcification is highly prevalent in chronic kidney disease (CKD) patients and is associated with cardiovascular (CV) morbidity and mortality. Patients at early CKD stages are more likely to suffer a fatal CV event than to develop end-stage renal disease and require hemodialysis treatment. The heavy CV burden of these patients cannot be solely explained by traditional calcification risk factors. Moreover, the pathophysiologic mechanisms underlying this association are complex and yet not fully understood. Although vascular calcification was regarded as a passive degenerative process for over a century, this theory changed by recent evidence that pointed toward an active process, where calcification promoters and inhibitors were involved. Matrix Gla Protein (MGP) has been established as a strong inhibitor of calcification both in vitro and in vivo. Not only it prevents mineralization of the arterial wall, but it is the only factor that can actually reverse it. To become fully active, MGP must undergo carboxylation of specific protein bound glutamate residues, a process fully dependent on the availability of vitamin K. Low vitamin K status leads to inactive, uncarboxylated forms of MGP and has been repeatedly associated with accelerated vascular calcification. Aim of this review is to present the pathophysiologic mechanisms underlying the activation and function of MGP and review the existing, accumulating data regarding the association between vitamin K, MGP and vascular calcification/CV disease in CKD patients.

The Association of dp-ucMGP with Cardiovascular Morbidity and Decreased Renal Function in Diabetic Chronic Kidney Disease

“…Circulating K1 and K2 levels do not necessarily reflect the vitamins’ bioavailability for MGP activation. This is why currently, the most reliable markers of vitamin K status are considered circulating dp-ucMGP and proteins induced by vitamin K absence or antagonism (PIVKA), which is a collective marker of all undercarboxylated, inactive vitamin K dependent proteins [ 53 ]. The prevalence of vitamin K deficiency (measured by PIVKA) augments in parallel with progression of CKD [ 54 ] and reaches 83–97% in HD patients [ 35 , 55 ].…”

The Role of Vitamin K in Humans: Implication in Aging and Age-Associated Diseases

“…Accumulating evidence describes the VC mechanism as an active process involving calcification promoters and inhibitors. The biologically active MGP, highly dependent on VK status, is viewed as a strong inhibitor of vascular elastic fiber damage and VC [87] and also the only factor that can actually reverse the process [88]. The inactive, uncarboxylated form of this protein reflected the deficiency of VK status and has been linked with VC and CV events.…”

Infection of Porphyromonas gingivalis Increases Phosphate-Induced Calcification of Vascular Smooth Muscle Cells

“…It is possible that the cytokines released by the P. gingivalis -stimulated VSMCs or P. gingivalis itself promote the Pi-induced vascular calcification. Down-regulation of the inhibitors of vascular mineralization, such as matrix Gla protein or fetuin-A, is associated with increased vascular calcification and consequent mortality due to cardiovascular dysfunction in patients with CKD [ 29 , 30 ]. Serum or salivary fetuin-A levels are known to decrease significantly with increasing severity of periodontal diseases [ 31 , 32 ].…”