Cardiovascular Calcification Heterogeneity in Chronic Kidney Disease

Abstract

Patients with chronic kidney disease (CKD) exhibit tremendously elevated risk for cardiovascular disease, particularly ischemic heart disease, due to premature vascular and cardiac aging and accelerated ectopic calcification. The presence of cardiovascular calcification associates with increased risk in patients with CKD. Disturbed mineral homeostasis and diverse comorbidities in these patients drive increased systemic cardiovascular calcification in different manifestations with diverse clinical consequences, like plaque instability, vessel stiffening, and aortic stenosis. This review outlines the heterogeneity in calcification patterning, including mineral type and location and potential implications on clinical outcomes. The advent of therapeutics currently in clinical trials may reduce CKD-associated morbidity. Development of therapeutics for cardiovascular calcification begins with the premise that less mineral is better. While restoring diseased tissues to a noncalcified homeostasis remains the ultimate goal, in some cases, calcific mineral may play a protective role, such as in atherosclerotic plaques. Therefore, developing treatments for ectopic calcification may require a nuanced approach that considers individual patient risk factors. Here, we discuss the most common cardiac and vascular calcification pathologies observed in CKD, how mineral in these tissues affects function, and the potential outcomes and considerations for therapeutic strategies that seek to disrupt the nucleation and growth of mineral. Finally, we discuss future patient-specific considerations for treating cardiac and vascular calcification in patients with CKD-a population in need of anticalcification therapies.

Keywords: aortic valve stenosis; minerals; renal insufficiency, chronic; therapeutics; vascular calcification.

Figure 1.

Heterogeneity of cardiovascular calcification and its clinical consequences. Patients with chronic kidney disease experience accelerated cardiovascular calcification on various cardiovascular sites that are presented in different temporal patterns with diverse clinical consequences. Smaller microcalcifications in the tunica intima may increase plaque instability, promote local stress in the aortic valve leaflets, and trigger inflammation in all vascular beds and the aortic valve. Microcalcifications aggregate to form larger calcifications. Macro/sheet calcification alters gross tissue function: in the tunica intima, it may decrease plaque vulnerability, while it causes vessel stiffening when present in the tunica media and impaired aortic valve function when present in the valve leaflet. Illustration credit: Sceyence Studios.

Figure 2.

Contributing cellular and noncellular factors to the progression of cardiovascular (CV) calcification and potential therapeutic options for interference. CV calcification starts with changes in local and systemic factors, initiating the osteogenic differentiation of vascular cells to a calcifying phenotype capable of inserting minerals in the extracellular matrix. Calcification progresses with mineral nucleation and growth exponentially to form larger macrocalcification. Once the mineral is formed, hematopoietic lineage cells may differentiate into osteoclast-like cells, but there is no in vivo evidence of mineral-resorbing activity. The therapeutic window with the available medications might be before a point of no return—a time point in the calcification progression when mineralization cannot be halted and irreversible damages the vascular tissue. The indicated drugs are matched to the target mechanism, and the position does not indicate a possible treatment time related to the calcification progression. MGP indicates matrix Gla protein; RANKL, receptor activator of NF-κB ligand; and SGLT2, sodium-glucose cotransporter 2. Illustration credit: Sceyence Studios.