Abstract: TH-PO343

Renal Cholesterol Rafts Blockade Ameliorates Septic Multiorganic Failure

Session Information

Category: Acute Kidney Injury

  • 002 AKI: Repair and Regeneration

Authors

  • Lazaro Fernandez, Alberto, Renal Physiopathology Lab, Instituto de Investigación Sanitaria Gregorio Marañón,Hospital G.U. Gregorio Marañón, Madrid, Spain, Madrid, Spain
  • GONZALEZ-NICOLAS GONZALEZ, Maria angeles, Renal Physiopathology Lab, Instituto de Investigación Sanitaria Gregorio Marañón,Hospital G.U. Gregorio Marañón, Madrid, Spain, Madrid, Spain
  • Humanes, Blanca, Renal Physiopathology Lab, Instituto de Investigación Sanitaria Gregorio Marañón,Hospital G.U. Gregorio Marañón, Madrid, Spain, Madrid, Spain
  • Herrero, Raquel, Critical Care Department, Hospital Universitario de Getafe, Madrid, Spain, Getafe, Madrid, Spain
  • Arenillas, Mario, Hospital Universitario de Getafe, Madrid, Spain, Getafe, Spain
  • Ferruelo, Antonio, Critical Care Department, Hospital Universitario de Getafe, Madrid, Spain, Getafe, Madrid, Spain
  • Lorente, José Ángel, Critical Care Department, Hospital Universitario de Getafe, Madrid, Spain, Getafe, Madrid, Spain
  • Tejedor jorge, Alberto, Renal Physiopathology Lab, Instituto de Investigación Sanitaria Gregorio Marañón,Hospital G.U. Gregorio Marañón, Madrid, Spain, Madrid, Spain
Background

Sepsis is a potentially life-threatening condition that occurs due to systemic inflammatory response to infection that leads to organ failure and death. Acute kidney injury (AKI) has been reported as a particularly serious complication in patients with severe sepsis, where it is the leading cause of death among critically ill patients. In fact, the mortality of septic patients with AKI is about 75%, while those with severe sepsis without AKI ranges between 27 and 32%. Cilastatin, a renal dehydropeptidase-I inhibitor has shown its usefulness in the protection of AKI induced by nephrotoxic drugs due to disruption of lipid rafts cycling. Here, we evaluated the utility of cilastatin as a protector against renal damage induced by sepsis and its effect on survival.

Methods

Sepsis was developed on male Sprague-Dawley rats by cecal ligation puncture model (CLP). The animals were divided into 4 groups: SHAM, CLP, SHAM+cilastatin and CLP+cilastatin. Cilastatin (150 mg/kg bw, i.p.) was administered immediately and at 24h after induction of sepsis. Renal damage was evaluated 48h after surgery by measuring serum creatinine, BUN, glomerular filtration rate (GFR), proteinuria, renal injury biomarker KIM-1 and renal morphology. Survival was evaluated in another CLP model with greater perforation thickness, in the presence and absence of cilastatin.

Results

Sepsis increased serum creatinine, BUN and proteinuria levels and decreased the GFR in comparison with the sham groups. These renal effects of sepsis were confirmed by the increased of the acute kidney injury biomarker KIM-1 at protein level and the presence of severe morphological changes such as swelling of tubular cells, and hyaline cast in the tubular lumen. Treatment with cilastatin completely prevented renal dysfunction, restored KIM-1 into control levels, and reduced many of the histologic symptoms of renal damage. Importantly, these protective effects of cilastatin at the renal levels caused a decrease in mortality by 33%.

Conclusion

Our findings support the potential use of cilastatin as a useful drug in the treatment of sepsis, improving the AKI induced by it and preventing its lethality. Therefore, it could be a very beneficial therapeutic strategy for septic patients susceptible to renal damage in clinical practice.

Funding

  • Government Support - Non-U.S.