Neutrophils in Kidney Disease: Linking Neutrophil Function and Microenvironment to Therapeutic Targets

Neutrophils are central mediators of kidney immunity and injury, exerting both protective and pathogenic functions on tissue compartment, inflammatory response, and disease state. During urinary tract infection and pyelonephritis, neutrophils protect the host through phagocytosis, granule release, reactive oxygen species (ROS) production, and neutrophil extracellular trap (NET) formation. In contrast, dysregulated neutrophil activation contributes to sterile and autoimmune kidney disease, including cholesterol crystal embolism, anti-neutrophil cytoplasmic antibody -associated vasculitis (AAV), ischemic acute kidney injury, and progression to chronic kidney disease. Emerging evidence indicates that neutrophil function in the kidney is highly compartment-specific and shaped by local metabolic and inflammatory cues. Persistent neutrophil activation promotes thromboinflammation, endothelial injury, autoimmunity, and fibrogenic remodeling through release of cytokines, S100A8/A9, proteases, ROS, and NET-associated mediators. In chronic kidney disease, uremic toxins and metabolites, such as uric acid, further alter neutrophil function by impairing antimicrobial responses while sustaining inflammatory activation. This review summarizes current insights into neutrophil biology across infection, sterile, and autoimmune kidney diseases, with focus on complement-specific neutrophil functions and effector mechanisms. In addition, we discuss emerging therapeutic strategies targeting neutrophil activation pathways and highlight recent advances in spatial transcriptomics, single-cell technologies, and intravital imaging that are reshaping our understanding of neutrophil-mediated kidney injury.