A novel therapeutic agent to prevent sepsis-induced acute kidney injury and mortality

Background

Acute kidney injury (AKI) occurs in about one-half of the patients who develop septic shock, and the mortality of AKI with sepsis is extremely high. An effective therapeutic intervention is urgently needed. In the present study we tested the ability of a novel tetrapeptide, EA-230, to improve survival and attenuate loss of kidney function in a clinically relevant model of sepsis – cecal ligation and puncture (CLP) in mice.

Methods

Sepsis was induced in C57BL/6 mice by CLP. Four hours postoperatively, EA-230 was administered. Subsequently, animals were treated twice daily for four consecutive days intraperitoneally. The effects of 20, 30, 40, or 50 mg/kg were compared with those of saline. Survival and renal function were monitored. Inulin clearance and para-aminohippuric acid clearance were used to measure the glomerular filtration rate and renal blood flow.

Results

All saline-treated control animals died within 5 days of CLP, whereas EA-230 treatment improved survival significantly in a dose-dependent manner. The best result was obtained with 50 mg/kg EA-230 (43.8% survival after 2 weeks). Serum creatinine and blood urea nitrogen increased markedly 24 hours after CLP. EA-230 attenuated the increases in creatinine and blood urea nitrogen significantly in the 30 to 50 mg/kg treatment groups. Furthermore, the glomerular filtration rate and renal blood flow were significantly higher (P < 0.05) 36 hours post CLP in EA-230-treated mice versus those treated with saline.

Conclusion

EA-230 is a novel and promising therapeutic agent for preventing AKI in sepsis. Its beneficial effect is associated with an improvement in renal hemodynamics.