Acute kidney injury (AKI) is a severe clinical syndrome associated with high morbidity and mortality, and it possesses high risk of progression to chronic kidney disease (CKD).  Renal infiltration of inflammatory cells, particularly macrophages, plays a key role in driving the progression from AKI to CKD.  Here, we utilized single-cell RNA sequencing and spatial transcriptomics profiling to investigate the heterogeneity and spatiotemporal dynamics of mononuclear phagocytes (MNPs) after unilateral ischemia-reperfusion injury (UIRI).  Six distinct MNP subpopulations were identified and each of them exhibited a unique set of gene expression pattern.  In particular, we uncovered a spatially distinct, injury-induced macrophage subset with specific profibrotic properties, termed as pro-fibrotic macrophages (PFMs).  During the progression of AKI to CKD, PFMs actively secreted thrombospondin-1 (THBS1), which induced the phosphorylation of LDL receptor-related protein 1 (LRP1) in the neighboring interstitial fibroblasts, thereby promoting fibroblast activation and proliferation.  In cultured kidney fibroblasts, THBS1 induced LRP1 phosphorylation and fibroblast activation, and blockade or knockdown of LRP1 abolished this effect.  Furthermore, THBS1 activated a cascade of LRP1 downstream mediators including focal adhesion kinase, protein kinase B, and extracellular signal-regulated kinase 1 and 2.  In humans, urinary THBS1 levels predicted the rate of CKD progression.  Collectively, these studies identify a unique subset of pro-fibrotic macrophages that drive fibroblast activation through THBS1/LRP1 signaling in a spatially confined setting.  Our findings suggest that PFMs-derived THBS1 plays a critical role in driving the progression from AKI to CKD.