IL-18 function is neutralized in IL-18 binding protein transgenic (IL-18BP Tg) mice. First we determined whether IL-18BP Tg mice are protected against ischemic AKI. Ischemic AKI was induced by bilateral renal pedicle clamping. IL-18BP Tg mice were functionally and histologically protected against ischemic AKI as determined by BUN, serum creatinine and ATN score. We have demonstrated that the injurious effect of IL-18 in the kidney is independent of neutrophils and lymphocytes. Thus the effect of IL-18 inhibition on renal macrophage infiltration was determined. The number of macrophages was significantly reduced in IL-18BP Tg kidneys compared to wild type kidneys. To determine the cytokines and chemokines that are dependent on IL-18, flow cytometry based assays were performed. Multiple chemokines/cytokines (IL-6, IL-3, GM-CSF, MCP-1, IL-15, IL-18, LIF, M-CSF and MIP-2) were significantly increased in AKI vs. sham kidneys. Only CXCL1 (also known as KC or IL-8) was significantly reduced in IL-18BP Tg vs. wild type AKI kidneys. To determine whether macrophages are the source of CXCL1 in the kidney, macrophages were depleted with liposomal encapsulated clodronate (LEC). CXCL1 was significantly decreased in macrophage depleted vs. control AKI mice. In summary, in ischemic AKI in mice, 1) IL-18BP Tg mice are functionally and histologically protected, 2) macrophage infiltration in the kidney and CXCL1 are significantly reduced in IL-18BP Tg mice, 3) macrophage depletion significantly reduces CXCL1 in the kidney. In conclusion, protection against ischemic AKI in IL-18BP Tg mice is associated with less macrophage infiltration and less production of CXCL1 in the kidney.