Ethyl pyruvate decreases sepsis-induced acute renal failure and multiple organ damage in aged mice

Background. Sepsis is a common cause of acute renal failure (ARF). The incidence of sepsis increases dramatically after 50 years of age; however, most ARF studies are performed in young mice. Methods. We performed two common sepsis models, lipopolysaccharide (LPS) administration and cecal ligation puncture (CLP) in aged mice. We developed a fully treated CLP model in aged mice by treating mice with fluid resuscitation and antibiotics. Results. LPS induced renal injury in aged but not young mice. However, volume resuscitation starting within 6 hours decreased renal injury. We then used this fluid resuscitation scheme, along with antibiotics, to develop a fully treated CLP model in aged mice. Mice subjected to CLP developed functional and histologic ARF and multiple organ damage. Treatment with ethyl pyruvate, even when started 12 hours after surgery, decreased serum creatinine, tubular damage, and multiple organ injury at 24 hours. Ethyl pyruvate decreased plasma tumor necrosis factor-alpha (TNF-alpha), and kidney mRNA for TNFalpha, tissue factor, and plasminogen activator inhibitor-1 (PAI-1), and increased mRNA for urokinase-like plasminogen activator. Conclusion. CLP in aged mice causes functional and histologic changes consistent with human ARF. A single dose of ethyl pyruvate inhibits renal and multiple organ damage, and is still effective when given 12 hours after surgery.