Abstract 3365: Sitaxsentan Sodium, an Endothelin-1 Receptor Antagonist, Prevents Post-Cardiopulmonary Bypass Acute Kidney Injury in a Novel Pre-Clinical Recovery Model
Background Acute kidney injury (AKI) post cardiac surgery is associated with mortality rates approaching 20%.
Aim To characterise post cardiopulmonary bypass (CPB) AKI in an animal model with significant homology to cardiac surgery patients and to assess the effect of Sitaxsentan Sodium, an endothelin-1 A receptor antagonist on these changes.
Methods Adult White-Landrace pigs (50 –70kg, n=20) were randomised to undergo either:
2.5 hours of CPB, or
2.5 hours of CPB + sitaxsentan sodium (0.5 mg/kg). Perfusion pressure and hydration were standardised.
Endpoints included serial functional and biochemical measures of AKI. All pigs were recovered for 24 hours prior to nephrectomy and histological assessment.
Results CPB caused significant renal dysfunction and an increase in urinary IL-18 excretion when compared to sham controls at 24 hours, similar to cardiac surgical patients. CPB resulted in significant changes in renal tubular morphology with marked tubular dilatation as well as a reduction in intra-renal high energy phosphates (ATP/ADP ratio). This was associated with endothelial injury characterised by a reduction in nitric oxide bioavailability and dBA lectin staining (disruption of the endothelial glycocalyx), and an increase in endothelin-1 and VCAM staining and the vasoconstrictor adenosine. When compared to CPB, Sitaxsentan prevented AKI by preserving creatinine clearance and reducing the urinary protein:creatinine ratio and IL-18 excretion. Sitaxsentan also preserved nitric oxide bioavailability and intra-renal high energy phosphates. Absolute mean differences are presented in the table⇓.
Conclusions This novel porcine model of post-CPB AKI links functional, biochemical and histological measures of kidney injury and demonstrates significant homology to AKI in cardiac surgical patients. Sitaxsentan sodium represents a novel renoprotective intervention and warrants evaluation in a randomised controlled trial.