S100A8/A9 in Kidney Diseases: Mechanisms, Spatiotemporal Regulation, Biomarker Potential, and Therapeutic Implications

Abstract

Abstract S100A8/A9 (calprotectin) is increasingly recognized as an inflammatory mediator and a potential biomarker and therapeutic target in kidney diseases. However, its roles appear to vary across different stages and contexts of renal injury and repair, yet these changes remain incompletely understood. This narrative review synthesizes evidence from PubMed, Web of Science, and Scopus, supplemented by manual reference screening. Current evidence indicates that S100A8/A9 promotes immune activation, tubular injury, and fibrotic remodeling in diverse renal disorders. Emerging findings further suggest that its effects vary according to disease stage, cellular source, receptor usage, and the local microenvironment, with S100A8/A9 predominantly amplifying early inflammatory injury while potentially contributing to inflammation resolution and tissue repair at later stages. We therefore propose a spatiotemporal framework that extends beyond previous disease- or pathway-centered perspectives by integrating the timing and cellular context of S100A8/A9 signaling. Altered S100A8/A9 levels in blood, urine, feces, and extracellular vesicles also show potential for disease detection, differential diagnosis, monitoring, and prognostic assessment, while pharmacological inhibition of this axis has produced renoprotective effects in preclinical models. Nevertheless, heterogeneous models, limited cell- and receptor-specific evidence, uncertain therapeutic windows, and insufficient prospective clinical validation hinder translation. Longitudinal clinical studies and spatial and single-cell analyses are needed to establish stage-specific biomarker and therapeutic strategies targeting S100A8/A9 in precision nephrology.