Macrophage fate decisions during AKI-CKD transition insights from single-cell and spatial transcriptomics.

Acute kidney injury (AKI) is an established risk factor for chronic kidney disease (CKD), but the cellular events that determine recovery or maladaptive repair remain incompletely defined. Macrophages are central regulators of this transition because their functional states change with time and tissue context. Recent single-cell RNA sequencing and spatial transcriptomic studies show that renal macrophages cannot be adequately described by a simple M1/M2 scheme. Instead, inflammatory, cycling, reparative and profibrotic programs emerge in a model- and niche-dependent manner. Experimental studies identify early S100A8/A9-associated inflammatory macrophages, cycling states and repair-associated programs involving TREM2, MRC1/IGF1 and efferocytosis. Together, these changes define a transient reparative phase in which inflammation can resolve and tubular repair can proceed. Failure to sustain this phase is associated with persistent inflammation, fibro-inflammatory niches, CD38-high and scar-associated macrophages, and progression towards fibrosis. Spatial transcriptomics further shows that interactions with injured tubular cells, fibroblasts, endothelial cells, immune cells and platelets shape macrophage function. Although the timing and dominant populations differ across experimental models, several pathway-level programs recur. Human datasets support selected inflammatory and fibrotic macrophage states but show limited one-to-one conservation of cell subsets across species. Clinical translation will therefore require conserved macrophage programs, treatment windows and biomarkers that distinguish reparative from maladaptive responses.