ATTENUATION OF RENAL REPERFUSION INJURY IN RATS BY THE 21-AMINOSTEROID U74006F

Purpose: The 21-aminosteroids represent a new class of compounds that serve as potent inhibitors of iron-dependent lipid peroxidation, the latter being an important component of ischemia-reperfusion tissue injury. It is hypothesized that reperfusion injury accompanies renal ischemia, and postischemic administration of one of these steroids, U74006F, will reduce renal damage in a rodent model, as assessed by renal function (plasma creatinine), histologic evidence of renal injury, and animal survival during a 72-hour interval. Methods: Fifty-one rats subjected to 45 minutes of renal ischemia were treated on clamp release with 3 or 10 mg/kg U74006F intravenously (n = 5 and 19, respectively), an inactive vehicle (n = 23), or sham operation (n = 4). Results: Both doses of U74006F improved morphologic outcome compared with vehicle-treated animals. Statistically significant improvement in renal function was observed with the 10 mg/kg dose of U74006F (p = 0.029, 0.014, and 0.065 at 24, 48, and 72 hours, respectively) but not with the 3 mg/kg dose. Only one (5.2%) of 19 rats receiving high-dose U74006F (10 mg/kg) died within 72 hours after ischemia, compared with five deaths (29.4%) in 17 rats receiving citrate vehicle alone (p = 0.060). All sham-operated animals survived 72 hours with normal morphology and plasma creatinine levels. Conclusions: These data suggest that iron-dependent lipid peroxidation is a component of reperfusion injury and indicate that U74006F may be useful in reducing this form of renal ischemic damage.