#1116 Hyperuricemia worsens bacterial sepsis by suppressing neutrophil functions in CKD

Abstract

Abstract Background and Aims Patients with kidney disease, especially those on dialysis, are more susceptible to infections such as peritonitis, sepsis, pneumonia, and are at a higher risk for infection-related mortality. Pathogenic mechanisms underlying the secondary immunodeficiency in kidney disease include gut dysbiosis and barrier dysfunction, persistent inflammation, immune paralysis due to increased levels of immunoregulatory metabolites (e.g. uric acid) and proteins (e.g. FGF23) [1]. Currently, it is unknown whether CKD-related hyperuricemia may contribute to the immune paralysis in this context. We hypothesized that hyperuricemia (HU) may aggravate the innate immune response to infection in CKD in mice. Method Mono- and polybacterial sepsis was induced by LPS injection or cecal ligation and puncture in Alb-creERT2;Glut9lox/lox mice with HU and/or CKD, and in Glut9lox/lox (healthy) control mice. After 24 hours, systemic inflammation was evaluated by measuring serum cytokine levels, immune cell activation and recruitment, and neutrophil extracellular trap release. Tissue injury in liver, heart, and kidney was assessed by performing RT-qPCR and immunohistochemistry. In addition, kidney function was determined by measuring the glomerular filtration rate (GFR). Additionally, mice were treated with urate-lowering therapy to reduce serum uric acid levels and the immune response and functional outcomes after sepsis is quantified. Results We found that both mono- and polybacterial sepsis caused systemic inflammation as indicated by an increased number of blood neutrophils (see Figure), neutrophil activation and pro-inflammatory cytokine levels as compared to the PBS-treated or sham-operated control groups in Glut9lox/lox healthy mice, respectively. Mice with sepsis also displayed a slightly worsened kidney function. Interestingly, HU significantly increased neutrophil numbers but decreased their activation status and the ability of neutrophils to form neutrophil extracellular traps in Alb-creERT2;Glut9lox/lox mice with sepsis as compared to the control groups, which was further aggravated in mice with CKD-related HU (CKD+HU). This impaired inflammatory response was partially reversible by lowering serum uric acid with febuxostat. Conclusion Our results identify hyperuricemia related or unrelated to kidney disease as immune regulator in bacterial infection by suppressing neutrophil functions in mice. Specifically targeting uric acid may help to overcome the secondary immunodeficiency related to kidney disease during infection but enhances sterile inflammation [2].