Viral Priming Enhances Kidney Injury at Early Time Points in Lipopolysaccharide (LPS)-Induced Sepsis-Associated AKI

Background: Sepsis-associated acute kidney injury (SA-AKI) is a heterogenous syndrome inflicted by the sepsis inflammatory cascade and phenotype-specific mechanisms. Viral priming followed by bacterial sepsis causes exaggerated inflammation and is associated with higher mortality than bacterial sepsis alone. We generated a novel murine SA-AKI model that recapitulates the viral primed bacterial sepsis phenotype using polyinosinic-polycytidylic (poly(IC)) acid, a synthetic viral double-stranded DNA analog, followed by low-dose lipopolysaccharide (LPS). Methods: Using 8-week-old male C57BL/6J mice, we induced viral priming at 0h via poly(IC) intraperitoneal (IP) injection (10 mg/kg) vs. saline control. At 24h post-poly(IC), we administered low-dose LPS (0.5 mg/kg via) by IP injection vs. PBS control. We measured glomerular filtration rate (GFR) at 28h via FITC-sinistrin and sacrificed mice at 32h for collection of blood and urine. Analysis employed 2-way ANOVA; p<0.05 deemed significant. Results: GFR was significantly reduced by 28h in poly(IC)+LPS (IC:LPS, 12.9±8.0 uL/min) mice compared to poly(IC)+PBS (IC, 223.3± 7.9 uL/min, p<0.001), saline+LPS (LPS, 117.4±31.4 uL/min, p=0.014) or control (Veh, 221.3±35.8 ml/min, p<0.001) mice. This corresponded to increased serum creatinine in IC:LPS mice at 32h compared to normal creatinine in other cohorts. At 32h, IC:LPS mice had significantly increased IL6 along with leukopenia and thrombocytopenia compared to LPS or Veh mice. Urine kidney injury molecule-1 was elevated in IC:LPS mice, but not in IC mice. Conclusion: We generated a novel murine model to study mechanisms of viral primed SA-AKI. Poly(IC) alone does not cause kidney injury. Poly(IC)+LPS leads to early and significant kidney injury despite low dose LPS that has modest reduction in GFR with no changes in creatinine. Viral priming imparts a synergistic injurious response and warrants further investigation.