Macrophage Plasticity and Functional Dynamics in Acute Kidney Injury and Its Progression to Chronic Kidney Disease

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are increasingly recognized as interconnected syndromes with overlapping pathophysiological mechanisms. A growing body of evidence suggests that macrophages are central regulators of the AKI-to-CKD transition, influencing both injury and repair through dynamic, microenvironment-dependent phenotypic shifts. M1-like macrophages dominate early injury responses in AKI, while M2-like macrophages can adopt a pro-fibrotic phenotype potentially contributing to the progression of CKD. Beyond this classical dichotomy, single-cell and spatial transcriptomic studies reveal a complex spectrum of macrophage states shaped by origin, tissue niche, temporal dynamics, and intercellular signaling. This review summarizes the current understanding of macrophage ontogeny, heterogeneity, and functional specialization in AKI and progression to CKD. We highlight how macrophages respond to local cues, engage in crosstalk with other cell types, and mediate phase-specific effects on inflammation and tissue remodeling. We also evaluate the consequences of macrophage depletion in AKI and the progression of AKI to CKD, highlighting divergent outcomes. Advancing our understanding of macrophage complexity is essential for developing precise immunomodulatory strategies for treating AKI and preventing CKD progression. By disentangling the context-specific roles of macrophages, future therapies can be tailored to attenuate pathogenic responses without compromising essential reparative functions, ultimately improving long-term renal outcomes.