Cl-Amidine Improves Survival and Attenuates Kidney Injury in a Rabbit Model of Endotoxic Shock

Ali Z. Siddiqui, Umar F. Bhatti, Qiufang Deng, Ben E. Biesterveld, Yuzi Tian, Zhenyu Wu, Julia Dahl, Baoling Liu, Jie Xu, Yui Koike, Jun Song, Jifeng Zhang, Yongqing Li, Hasan B. Alam, Aaron M. Williams*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Objective: Sepsis causes millions of deaths on a global scale annually. Activation of peptidylarginine deiminase (PAD) enzymes in sepsis causes citrullination of histones, which results in neutrophil extracellular trap formation and sepsis progression. This study evaluates pan-PAD inhibitor, Cl-amidine, in a model of lipopolysaccharide (LPS)-induced endotoxic shock in rabbits. We hypothesized that Cl-amidine would improve survival and attenuate kidney injury. Methods: In the survival model, rabbits were injected injected intravenously with 1 mg/kg of LPS, and then randomly assigned either to receive dimethyl sulfoxide (DMSO; 1 mcL/g) or Cl-amidine (10 mg/kg diluted in 1 mcL/g DMSO). They were then monitored for 14 days to evaluate survival. In the non-survival experiment, the same insult and treatment were administered, however; the animals were euthanized 12 hours after LPS injection for kidney harvest. Acute kidney injury (AKI) scoring was performed by a histopathologist who was blinded to the group assignment. Serial blood samples were also collected and compared. Results: Rabbits that received Cl-amidine had a higher survival (72%) compared with the rabbits that received DMSO (14%; p < 0.05). Cl-amidine-treated rabbits had lower (p < 0.05) histopathologic AKI scores, as well as plasma creatinine and blood urea nitrogen (BUN) levels 12 hours after insult. Conclusions: Pan-PAD inhibitor Cl-amidine improves survival and attenuates kidney injury in LPS-induced endotoxic shock in rabbits.

Original languageEnglish (US)
Pages (from-to)421-426
Number of pages6
JournalSurgical Infections
Issue number4
StatePublished - May 2021
Externally publishedYes


  • acute kidney injury
  • Cl-amidine
  • lipopolysaccharide
  • peptidylarginine deiminase

ASJC Scopus subject areas

  • Surgery
  • Microbiology (medical)
  • Infectious Diseases


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