Hyperphosphatemia-induced neutrophil activation via fibroblast growth factor receptor 1 and gasdermin D drives immuno-calcification in chronic kidney disease.

Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD), with vascular calcification being a critical pathological feature. Despite the recognition of hyperphosphatemia as a key contributor to vascular intimal calcification, the precise mechanisms remain poorly understood. In this study, we demonstrate that hyperphosphatemia activates neutrophils through fibroblast growth factor receptor 1 (FGFR1) signaling, leading to the formation of neutrophil extracellular traps (NETs). During this process, the intracellular proteasome in activated neutrophils degrades fetuin-A, a critical inhibitor of phosphate-calcium binding, creating a microenvironment conducive to calcium-phosphate crystal formation. These crystals further induce NET formation via gasdermin D (GSDMD) signaling, resulting in massive calcification. NETs not only facilitate crystal aggregation but also aggravate vascular endothelial injury, forming a feedback loop that amplifies calcification. This process, which we coin "immuno-calcification," represents a novel immune-mediated mechanism of calcification that contributes to vascular injury in CKD. Furthermore, low-density granulocytes (LDGs), a subset of neutrophils with pro-inflammatory features, are increased in CKD patients and promote a pro-arteriosclerotic phenotype. Targeting the pathways involved in phosphate sensing, NET formation, and immune-driven calcification may offer novel therapeutic strategies to mitigate vascular calcification and reduce the cardiovascular burden in CKD patients.