Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities

Abstract

Patients with chronic kidney disease (CKD) are highly susceptible to cardiovascular (CV) complications, thus suffering from clinical manifestations such as heart failure and stroke. CV calcification greatly contributes to the increased CV risk in CKD patients. However, no clinically viable therapies towards treatment and prevention of CV calcification or early biomarkers have been approved to date, which is largely attributed to the asymptomatic progression of calcification and the dearth of high-resolution imaging techniques to detect early calcification prior to the ‘point of no return’. Clearly, new intervention and management strategies are essential to reduce CV risk factors in CKD patients. In experimental rodent models, novel promising therapeutic interventions demonstrate decreased CKD-induced calcification and prevent CV complications. Potential diagnostic markers such as the serum T50 assay, which demonstrates an association of serum calcification propensity with all-cause mortality and CV death in CKD patients, have been developed. This review provides an overview of the latest observations and evaluates the potential of these new interventions in relation to CV calcification in CKD patients. To this end, potential therapeutics have been analyzed, and their properties compared via experimental rodent models, human clinical trials, and meta-analyses.

Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall

“…Maintaining a calcium phosphate product of less than 60 is imperative in preventing the rapid progression of VC and complications such as calciphylaxis. Phosphate binders are recommended in all patients in CKD to lower phosphate levels [ 123 ]. There are two types of phosphate binders, calcium-based and non-calcium-based.…”

“…Denosumab is a monoclonal antibody that inhibits NFkB-ligand (RANKL), which blocks its osteoclastic and resorptive properties. Few studies have been performed on the effect on VC in vivo and mortality benefits of both bisphosphonates and denosumab in CKD patients; therefore, their clinical benefit is still unclear, and they are not routinely recommended in these patients [ 123 ]. Other options also include magnesium supplementation, which has been shown to decrease phosphate-induced calcification in vitro; however, there are very few studies that have shown a statistically significant impact on reducing VC in CKD patients in vivo [ 123 , 129 ].…”

Editorial on the Special Issue “Comorbidities in Chronic Kidney Disease”

“…Although vascular calcification has been associated with increased cardiovascular risk, there are currently no therapies available that adequately tackle this pathological axis. This is being discussed by Himmelsbach et al [ 31 ]: a detailed overview of new potential therapeutic strategies to reduce cardiovascular calcification in CKD is provided, covering findings from in vitro molecular studies and animal models to observational and interventional studies in CKD patients.…”

Effects of Chronic Kidney Disease and Uremic Toxins on Extracellular Vesicle Biology

“…In a CKD setting, VC leads to a decrease in blood vessel elasticity, an increase in blood pressure and therefore to serious cardiovascular complications. VC is a complex pathological process caused by an imbalance between activators of calcification (phosphorus and calcium) and inhibitors of calcification (matrix Gla protein, fetuin-A, osteoprotegerin and osteopontin) [ 8 ]. This dysregulation prompts vascular smooth muscle cells (VSMCs) found in the media layer of blood vessels to turn into osteoblast-like cells; this switching may have an important role in the onset of VC [ 9 ].…”