Soft tissue calcifications in chronic kidney disease-beyond the vasculature

Inappropriate mineralization of soft tissues, also called ectopic calcification, is a well-known pathology in chronic kidney disease (CKD) that is associated with increases in systemic phosphate levels. Vascular calcification is a major contributor to cardiovascular injury and high mortality rates in CKD patients. Therefore, most animal and human studies have focused on the vasculature when describing ectopic calcifications and on the pathologic actions of elevated phosphate on vascular smooth muscle cells in this process. The extent of calcifications within soft tissues beyond the vasculature is not well described, and the involvement of cell types other than vascular smooth muscle cells is not clear. Here we provide a summary of CKD-associated extravascular calcifications in various tissues, which includes the lung, the gastrointestinal system, the liver, the skin, and the brain. Since phosphate elevations and widespread ectopic calcifications do not only occur in the context of CKD, but also in rare genetic disorders that affect the regulators of phosphate metabolism, the cellular transporters of phosphate and the factors protecting from mineral depositions outside of bone, we also discuss these pathologic scenarios. We describe different types of ectopic calcification to flesh out common aspects as well as differences in the potential mechanisms and target cell types. We postulate that phosphate elevations might act in various ways and on various tissues, which together causes a wide spectrum of phosphate-induced pathologies in CKD.