Chronic Kidney Disease Increases Susceptibility to Escherichia coli Bacteremia in Mice via Decreased Bactericidal Activity by Kupffer Cells and Excessive TNF-α Production by Liver Monocyte-Derived Macrophages

Background: Patients with chronic kidney disease (CKD), particularly those undergoing hemodialysis, are highly susceptible to bacterial infections, which often progress to sepsis. Although the liver plays a crucial role in the host defense against sepsis, the precise mechanisms by which CKD alters systemic host defense, particularly the effects on liver immunity including Kupffer cells, remain elusive. Methods: We developed a mouse CKD model by administering a diet containing 0.2% adenine for 4 weeks. The mice were then intravenously challenged with Escherichia coli . Mouse survival rate and liver macrophage functions were examined. Results: CKD mice had significantly higher mortality after E. coli challenge as compared to control mice, which was accompanied by marked elevations of serum tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12 p70, and IL-18, a significant decrease in serum interferon-gamma levels, and significantly higher bacterial counts in the blood and liver 24 hours after the challenge. CKD mice also displayed an increased number of liver monocyte-derived macrophages and enhanced intracellular TNF-α production in response to bacterial challenge compared to control mice. In contrast, although the number of Kupffer cells remained unchanged, their bactericidal activity, assessed by pHrodo-labeled E. coli , was significantly reduced in CKD mice. Adoptive transfer of Kupffer cells from control mice to CKD mice significantly increased the survival rate of CKD mice after E. coli challenge. Conclusions: CKD increases susceptibility to E. coli infection in mice, potentially by reducing the antibacterial function of Kupffer cells while increasing the abundance of liver monocyte-derived macrophages and their TNF-α production.