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.