Chronic kidney disease (CKD) is a serious health condition that significantly elevates the risk of cardiovascular disease (CVD). This risk increases as kidney function deteriorates, making CKD patients particularly vulnerable to cardiovascular complications. Emerging factors such as inflammation, oxidative stress, and vascular calcification (VC) are now recognized for their critical roles in CVD and reduced patient survival in CKD contexts.
VC is an early and progressively worsening condition in CKD. It encompasses four types: intimal and medial calcification in arteries, heart valve calcification, and calciphylaxis, a severe form specific to dialysis patients. Calciphylaxis involves calcium deposits in small arteries, leading to skin and fat tissue necrosis, which causes painful ulcers. Each type of VC independently increases the risk of cardiovascular morbidity and mortality among CKD patients. For instance, arterial microcalcification is found 45 times more frequently in CKD patients compared to age- and gender-matched controls from the general population. The prevalence of intimal and medial calcification ranges from 50% to 90% in pre-dialysis CKD patients, and heart valve calcification is reported in over 80% of patients after five years on dialysis.
The imbalance between activators and inhibitors of VC is severely disrupted in CKD and end-stage kidney disease (ESKD). This disruption is primarily due to the pronounced upregulation of VC activators and suppression or reduction of circulating inhibitors by the uremic environment and dialysis-related factors. Interestingly, even after years of hemodialysis, 10-20% of patients do not develop VC due to naturally occurring defense inhibitors. In healthy individuals, VC is a degenerative process that accelerates with aging. CKD, therefore, can be viewed as a model of premature and abnormally increased aging, leading to arterial aging.
Matrix Gla protein (MGP) is a critical inhibitor protein in this context. Initially discovered in bone tissue, MGP has emerged as a significant factor in preventing VC. Research has shown that MGP can delay or even reverse VC by scavenging free reactive calcium ions, phosphorus ions, and hydroxyapatite crystals from the arterial wall and disposing of them in circulation. MGP also downregulates the promoter of VC, bone morphogenetic protein-2 (BMP-2). These actions depend heavily on vitamin K for MGP activation, which involves γ-carboxylation of glutamate and phosphorylation of serine residues.
Vitamin K status is crucial for CKD patients due to its role in activating MGP and other vitamin K-dependent proteins (VKDPs). Inadequate vitamin K status, reflected by the levels of inactive VKDPs such as dp-ucMGP, is strongly associated with VC and CVD in CKD patients. Research shows that dp-ucMGP levels increase as kidney function deteriorates, indicating uremia as a state of pronounced vitamin K deficiency.
The measurement of circulating vitamin K levels has limitations, as it represents only a small fraction of total body stores and varies with recent dietary intake. Therefore, VKDPs such as dp-ucMGP and protein induced in the absence of vitamin K or antagonism factor II (PIVKA-II) are used as more reliable biomarkers for vitamin K status. Elevated dp-ucMGP levels are strongly associated with arterial calcification and stiffness, CVD, and mortality in CKD patients. Elevated PIVKA-II levels, indicating vitamin K deficiency, are also associated with increased cardiovascular risk in CKD patients.
The actual recommended daily intake of vitamin K, particularly for CKD patients, remains a subject of ongoing research. The current recommended daily intake focuses on preventing coagulation abnormalities and does not account for the higher needs of CKD patients to prevent VC. Many CKD patients consume less than the recommended daily vitamin K intake due to dietary restrictions, leading to subclinical vitamin K deficiency and its long-term consequences.
Clinical studies have shown that vitamin K deficiency in CKD patients is linked to worse cardiovascular outcomes and bone health complications. Observational studies like the Rotterdam Study and the PREVEND study have demonstrated that low vitamin K intake is associated with higher risks of aortic calcification, CVD, and increased all-cause mortality. CKD patients with poor vitamin K status also exhibit impaired bone remodeling, leading to conditions like CKD-mineral and bone disease (CKD-MBD).
Vitamin K2, in particular, plays a crucial role in bone health by inhibiting bone resorption and promoting bone formation through the activation of osteocalcin. Clinical research has shown that poor vitamin K status is associated with reduced bone mass, increased fracture risk, and aortic calcification in CKD patients.
Despite the growing evidence of the importance of vitamin K in CKD, its measurement, function, and supplementation are often underutilized in clinical practice. Millions of patients continue to be prescribed vitamin K antagonists, which can exacerbate VC and cardiovascular complications. There is a critical need for further research and clinical trials to establish the optimal vitamin K intake and supplementation strategies for CKD patients to improve their cardiovascular and bone health outcomes.
REFERENCE LINK : https://www.mdpi.com/2072-6643/16/12/1798
