The Pathologic Actions of Phosphate in CKD.

CKD is associated with high serum levels of phosphate (also called hyperphosphatemia), which is a main driver of soft tissue calcifications and potentially other pathologic changes that are associated with CKD. However, it remains unclear in what form and through which mechanisms and targets elevated phosphate can damage cells and tissues. Rises in serum phosphate levels are accompanied by changes in the endocrine regulators of phosphate metabolism and result in the formation of calcium-phosphate crystals, and all three events can have pathologic actions on various tissues. Furthermore, tissues can accumulate phosphate from the circulation, and cells can generate free phosphate in their environment independently from circulating phosphate, which both result in local elevations of phosphate that could also contribute to tissue damage. It is important to better understand the various scenarios underlying the pathologic actions of hyperphosphatemia, as some of them suggest that measuring extracellular serum phosphate, which is the gold standard to estimate overall phosphate status of the body, is not sufficient to do so. Understanding the pathologic actions of phosphate on a conceptual level should not only help to design more efficient detection tools for phosphate but also to identify phosphate-induced pathomechanisms which could provide us with novel drug targets to tackle phosphate-driven pathologies in CKD. Here, we discuss the different concepts and scenarios that could underlie the widespread pathologic actions of hyperphosphatemia in CKD.