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Abstract: PO0443

Comparison of Inflammatory Responses in Sepsis-Induced AKI Mouse Models and Response to Dexamethasone

Session Information

  • AKI: Novel Insights
    November 04, 2021 | Location: On-Demand, Virtual Only
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Rankin, Matthew M., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Ho, George, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Meng, Rong, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Skrypnyk, Nataliya, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Lewis, Gavin, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Rajoria, Rohit, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Nawrocki, Andrea R., Janssen Research and Development LLC, Spring House, Pennsylvania, United States
  • Camacho, Raul, Janssen Research and Development LLC, Spring House, Pennsylvania, United States
Background

AKI occurs in the majority of patients with severe sepsis and contributes to high morbidity and mortality. Despite the frequency of AKI, the underlying mechanisms of renal injury during sepsis are not fully understood, and no approved therapies to prevent or reverse this condition. Systemic and local inflammatory responses play a large role in the development of sepsis induced acute kidney injury (S-AKI).

Methods

To develop novel treatments for patients with S-AKI, animal models of polymicrobial sepsis are used; the most widely reported models being cecal ligation puncture (CLP) and cecal slurry (CS). We compared the acute (24h) renal function and inflammatory response of these two models, as well as the ability of dexamethasone (dexa) to prevent the development of S-AKI.

Results

CLP significantly reduced renal function, with increased plasma creatinine (0.18±0.11 mg/dL), blood urea nitrogen (BUN, 81.11±12.88 mg/dL), and increased inflammatory markers IL-6 (127±73 ng/mL), TNF-α (176±33 pg/mL), and IL-1β (164±141 pg/mL) compared to sham animals. Dexa (8 mg/kg) significantly decreased BUN but did not significantly decrease plasma creatinine or the inflammatory markers. Dexa (2.5mg/kg) had no significant effects on renal functional markers or circulating cytokines. CS significantly increased plasma creatinine (0.7±0.1 mg/dL), BUN (103±20 mg/dL), cystatin C (2443±947 ng/mL), IL-6 (124±63 ng/mL), TNF-α (134±39 pg/mL) compared to basal levels. Dexa treatment (2.5 mg/kg) significantly decreased creatinine, cystatin C, IL-6, TNF-α, and IL-1β. In this study, we have shown the CS model elicits a more robust increase in AKI and inflammatory measurements than the CLP model, with reduced variability. It also responds to a greater extent to the same dose of dexa. Our results suggest that the CS model may be provide a better window with less variability compared to the CLP model, to test novel treatments for S-AKI.

Conclusion

We have shown the CS model elicits a more robust increase in AKI and inflammatory measurements than the CLP model, with reduced variability. It also responds to a greater extent to the same dose of dexamethasone. Our results suggest that the CS model may be provide a better window with less variability compared to the CLP model, to test novel treatments for S-AKI.