Vascular calcification contributes to the high risk of cardiovascular mortality in chronic kidney disease (CKD) patients. Dysregulation of calcium (Ca) and phosphate (P) metabolism is common in CKD patients and drives vascular calcification. In this article, we review the physiological regulatory mechanisms for Ca and P homeostasis and the basis for their dysregulation in CKD. In addition, we highlight recent findings indicating that elevated Ca and P have direct effects on vascular smooth muscle cells (VSMCs) that promote vascular calcification, including stimulation of osteogenic/chondrogenic differentiation, vesicle release, apoptosis, loss of inhibitors, and extracellular matrix degradation. These studies suggest a major role for elevated P in promoting osteogenic/chondrogenic differentiation of VSMC, whereas elevated Ca has a predominant role in promoting VSMC apoptosis and vesicle release. Furthermore, the effects of elevated Ca and P are synergistic, providing a major stimulus for vascular calcification in CKD. Unraveling the complex regulatory pathways that mediate the effects of both Ca and P on VSMCs will ultimately provide novel targets and therapies to limit the destructive effects of vascular calcification in CKD patients.

Arterial Calcification in Chronic Kidney Disease: Key Roles for Calcium and Phosphate

KDOQI Clinical Practice Guideline for Nutrition in CKD: 2020 Update

FGF-23 levels in the lowest tertile, those in the highest tertile had 2-fold greater risk for mortality (hazard ratio [HR], 2.15 [95% CI, 1.43 to 3.24]) and CVD events (HR, 1.83 [CI, 1.15 to 2.91]) after adjustment for traditional CVD risk factors, C-reactive protein levels, and kidney function. The highest ucMGP tertile was associated with lower mortality risk (HR, 0.48 [CI, 0.31 to 0.75]) and showed a nonsignificant trend toward lower CVD event risk by tertile analysis (HR, 0.65 [CI, 0.40 to 1.05])—an association that was significant when modeled continuously (P 0.029). No significant association of fetuin-A with mortality (HR, 0.84 [CI, 0.55 to 1.27]) or CVD events (HR, 0.99 [CI, 0.64 to 1.55]) was observed. Limitation: Participants had prevalent CAD. Conclusion: In outpatients with stable CAD, higher FGF23 and lower ucMGP levels are independently associated with mortality and CVD events.

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The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study

Vascular calcification is highly associated with cardiovascular disease mortality, particularly in high-risk patients with diabetes and chronic kidney diseases (CKD). In blood vessels, intimal calcification is associated with atherosclerosis, whereas medial calcification is a nonocclusive process which leads to increased vascular stiffness and reduced vascular compliance. In the valves, calcification of the leaflets can change the mechanical properties of the tissue and result in stenosis. For many decades, vascular calcification has been noted as a consequence of aging. Studies now confirm that vascular calcification is an actively regulated process and shares many features with bone development and metabolism. This review provides an update on the mechanisms of vascular calcification including the emerging roles of the RANK/RANKL/OPG triad, osteoclasts, and microRNAs. Potential treatments adapted from osteoporosis and CKD treatments that are under investigation for preventing and/or regressing vascular calcification are also reviewed.

/pdf/vascular-calcification-an-update-on-mechanisms-and-44ckkme73r.pdf

Vascular calcification: an update on mechanisms and challenges in treatment.

Masafumi Fukagawa, Keitaro Yokoyama, Fumihiko Koiwa, Masatomo Taniguchi, Tetsuo Shoji, Junichiro James Kazama, Hirotaka Komaba, Ryoichi Ando, Takatoshi Kakuta, Hideki Fujii, Msasaaki Nakayama, Yugo Shibagaki, Seiji Fukumoto, Naohiko Fujii, Motoshi Hattori, Akira Ashida, Kunitoshi Iseki, Takashi Shigematsu, Yusuke Tsukamoto, Yoshiharu Tsubakihara, Tadashi Tomo, Hideki Hirakata, and Tadao Akizawa for CKD-MBD Guideline Working Group, Japanese Society for Dialysis Therapy

https://onlinelibrary.wiley.com/doi/pdf/10.1111/1744-9987.12058

Clinical Practice Guideline for the Management of Chronic Kidney Disease-Mineral and Bone Disorder

Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. With the aid of conformation-specific antibodies MGP species in both tissue and the circulation have been detected in the healthy population, and significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.

Matrix Gla-protein: The calcification inhibitor in need of vitamin K

Effect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial

Vitamin K, discovered in the 1930s, functions as cofactor for the posttranslational carboxylation of glutamate residues. Gammacarboxy glutamic acid (Gla)-residues were first identified in prothrombin and coagulation factors in the 1970s; subsequently, extra-hepatic Gla proteins were described, including osteocalcin and matrix Gla protein (MGP). Impairment of the function of osteocalcin and MGP due to incomplete carboxylation results in an increased risk for developing osteoporosis and vascular calcification, respectively, and is an unexpected side effect of treatment with oral anticoagulants. It is conceivable that other side effects, possible involving growth-arrest-specific gene 6 (Gas6) protein will be identified in forthcoming years. In healthy individuals, substantial fractions of osteocalcin and MGP circulate as incompletely carboxylated species, indicating that the majority of these individuals is subclinically vitamin K-deficient. Potential new application areas for vitamin K are therefore its use in dietary supplements and functional foods for healthy individuals to prevent bone and vascular disease, as well as for patients on oral anticoagulant treatment to offer them protection against coumarin-induced side effects and to reduce diet-induced fluctuations in their INR values.

https://www.thieme-connect.com/products/ejournals/pdf/10.1160/TH07-04-0266.pdf

Vitamin K: the coagulation vitamin that became omnipotent.

Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.

Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species.

Objective: Matrix γ-carboxyglutamate (Gla) protein (MGP) is a vitamin K-dependent protein and a strong inhibitor of vascular calcification. Vitamin K deficiency leads to inactive un

Ellen C. M. Cranenburg

Papers

Matrix Gla-protein: The calcification inhibitor in need of vitamin K

Effect of Vitamin K2 Supplementation on Functional Vitamin K Deficiency in Hemodialysis Patients: A Randomized Trial

Vitamin K: the coagulation vitamin that became omnipotent.

Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species.

The Circulating Inactive Form of Matrix Gla Protein (ucMGP) as a Biomarker for Cardiovascular Calcification