Background and purpose: Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD progression is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney injury, repair, and fibrosis. Here, we aim to investigate whether and how macrophage ITGAM contributes to hyperuricemia-related CKD. Experimental approach: In vivo, we explored dynamic characteristics of renal tissue in hyperuricemia-related CKD. By incorporating mRNA and protein sequencing data, we analyzed gene expression profile, hub genes and potential pathways responsible for disease development, which was further confirmed using qPCR, western blotting, and immunofluorescent stainings. In vitro, we validated bioinformatic findings under different conditions of macrophages with interventions corresponding to core nodes in pathway. Key Results: Hyperuricemia-related CKD was characterized by the rise in serum uric acid, decline in renal function, macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed ITGAM as the potential core gene mediating disease progression which was associated with FAK/Akt1/β-catenin signaling. Notably, we confirmed the upregulated macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys and macrophages. In vitro, we verified ITGAM/FAK/Akt1/β-catenin pathway participated in promoting macrophage M2 polarization through silencing Itgam and inhibiting FAK or Akt1 phosphorylation, where the expression of M2 phenotype macrophage markers and downstream molecules in pathway were down-regulated. Conclusion and implications: In hyperuricemia-related CKD, ITGAM promotes macrophage M2 polarization contributing to renal fibrosis through FAK/Akt1/β-catenin pathway. Targeting macrophage ITGAM might be a promising therapeutic approach for preventing or delaying CKD.