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Kidney Week

Abstract: SA-PO162

Continuous Antithrombin III Infusion in a Clinically Relevant Sepsis Model

Session Information

  • AKI: Mechanisms - III
    November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Hayase, Naoki, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Chari, Rohit R., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Aragao Carneiro dos Santos, Alef, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Naito, Yoshitaka, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Hu, Xuzhen, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Yuen, Peter S.T., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
  • Star, Robert A., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background

Despite unacceptably high mortality and economic burden, effective therapeutic strategies for sepsis remain elusive. Discrepancies between septic patients and animal models may be caused by drug pharmacokinetics, route, and timing of drug administration. Antithrombin III (AT) is an anticoagulant that might ameliorate sepsis-induced multiorgan dysfunction, though clinical trial results are conflicting due to variation in patient selection and drug regimens. AT has not been tested in clinically relevant sepsis models. AT has a short half-life, so we devised a method to continuously infuse drugs starting 6-12 h after cecal ligation and puncture (CLP). We asked, “Is AT effective in a clinically translatable sepsis model, and does the route of administration matter?”

Methods

We catheterized the mouse jugular vein, then connected the catheter to an osmotic minipump containing saline. After 1 wk stabilization, we performed CLP and replaced the minipump with one containing AT or saline. We set a 6-12-h time delay between sepsis induction and treatment by incorporating a 4 cm saline-filled catheter in the circuit. We measured the actual time lag with FITC-sinistrin and measured its systemic appearance with a transdermal fluorescence detector. Survival studies were conducted. In separate experiments, we collected blood, kidney, liver, and lung at 48 h for biochemical and histological tests. To examine the effect of administration route, we compared continuous AT infusion with saline infusion, and a conventional bolus AT injection.

Results

First, we detected a sustained fluorescence signal in the systemic circulation 5–6 hours after adding FITC-sinistrin to our drug administration system. Second, delayed, continuous AT infusion significantly improved 7-day survival compared to saline-infusion (65% vs. 29%, n = 21 /group, p = 0.018). Continuous AT infusion markedly improved survival vs. a single injection of AT (65% vs. 19%, n = 21 /group, p = 0.003). Continuous AT attenuated liver injury but not renal or lung injury in the histology and biochemistry analyses.

Conclusion

We created a clinically relevant murine sepsis model with both a continuous infusion and time lag. Survival was higher in continuous AT infusion than either single bolus injection or vehicle. Future studies will elucidate the mechanism of the survival benefit.

Funding

  • NIDDK Support