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Summary  Despite advances in our understanding of the mechanisms underlying the progression of chronic kidney disease and the development of fibrosis, only limited efficacious therapies exist. The calcium binding protein S100A8/A9 is a damage‐associated molecular pattern which can activate Toll‐like receptor (TLR)‐4 or receptor for advanced glycation end‐products (RAGE). Activation of these receptors is involved in the progression of renal fibrosis; however, the role of S100A8/A9 herein remains unknown. Therefore, we analysed S100A8/A9 expression in patients and mice with obstructive nephropathy and subjected wild‐type and S100A9 knock‐out mice lacking the heterodimer S100A8/A9 to unilateral ureteral obstruction (UUO). We found profound S100A8/A9 expression in granulocytes that infiltrated human and murine kidney, together with enhanced renal expression over time, following UUO. S100A9 KO mice were protected from UUO‐induced renal fibrosis, independently of leucocyte infiltration and inflammation. Loss of S100A8/A9 protected tubular epithelial cells from UUO‐induced apoptosis and critical epithelial–mesenchymal transition steps.  In‐vitro  studies revealed S100A8/A9 as a novel mediator of epithelial cell injury through loss of cell polarity, cell cycle arrest and subsequent cell death. In conclusion, we demonstrate that S100A8/A9 mediates renal damage and fibrosis, presumably through loss of tubular epithelial cell contacts and irreversible damage. Suppression of S100A8/A9 could be a therapeutic strategy to halt renal fibrosis in patients with chronic kidney disease.

S100A8/A9 promotes parenchymal damage and renal fibrosis in obstructive nephropathy