Abstract
Chronic kidney disease (CKD) is one of the most powerful predictors of premature cardiovascular disease (CVD), with heightened susceptibility to vascular intimal and medial calcification associated with a high cardiovascular mortality. Abnormal mineral metabolism of calcium (Ca) and phosphate (P) and underlying (dys)regulated hormonal control in CKD-mineral and bone disorder (MBD) is often accompanied by bone loss and increased vascular calcification (VC). While VC is known to be a multifactorial process and a major risk factor for CVD, the view of primary triggers and molecular mechanisms complexity has been shifting with novel scientific knowledge over the last years. In this review we highlight the importance of calcium-phosphate (CaP) mineral crystals in VC with an integrated view over the complexity of CKD, while discuss past and recent literature aiming to highlight novel horizons on this major health burden. Exacerbated VC in CKD patients might result from several interconnected mechanisms involving abnormal mineral metabolism, dysregulation of endogenous calcification inhibitors and inflammatory pathways, which function in a feedback loop driving disease progression and cardiovascular outcomes. We propose that novel approaches targeting simultaneously VC and inflammation might represent valuable new prognostic tools and targets for therapeutics and management of cardiovascular risk in the CKD population.
Highlights
Cardiovascular disease (CVD) and chronic kidney disease (CKD), known as chronic or noncommunicable diseases, are leading causes of disability and death all over the world
Cardiovascular diseases continue to be the leading cause of death in all Chronic kidney disease (CKD) stages, despite all research efforts to improve our knowledge on the molecular mechanisms and processes involved on its development and progression
Traditional risk factors are widely accepted as insufficient to predict and prevent cardiovascular disease (CVD) events in CKD, and great attention is focused on the benefits of additional nontraditional risk factors, such as vascular calcification (VC) and inflammation, which are considered potentially valuable prognostic tools and targets for therapeutics and management of cardiovascular risk
Summary
Cardiovascular disease (CVD) and chronic kidney disease (CKD), known as chronic or noncommunicable diseases, are leading causes of disability and death all over the world. In vitro studies have shown that only γcarboxylated GRP display anti-mineralization capacity [92, 93] This is in line with the widely demonstrated role of vitamin K in cardiovascular calcification, which has been consistently associated to its function as cofactor for γ-carboxylation reaction of VKDPs. Low concentrations of vitamin K in CKD patients have been associated with (i) dietary restrictions; (ii) storage exhaustion due to a high demand on VKDP activity involved in the regulation of VC related processes; (iii) the use of anticoagulant therapy with vitamin K antagonists such as warfarin; (iv) the use of phosphate binders that can bind vitamin K inducing vitamin K-deficiency [112,113,114,115,116]. It is clear that several biomolecules, includeing mineralization inhibitors such as GRP, act in a highly complex and coordinated network between inflammation and calcification processes, and that a deeper knowledge of this complex crosstalk is crucial to the development of new therapies and biomarkers that will benefit the populations at high risk for cardiovascular diseases
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