Key role of oxidative stress in animal models of aminoglycoside nephrotoxicity revealed by a systematic analysis of the antioxidant-to-nephroprotective correlation

The clinical utility of aminoglycoside antibiotics is partly limited by their nephrotoxicity. Co-administration of a variety of candidate nephroprotectants has been tested at the preclinical level. According to a recent meta-analytic study, antioxidants are the only family of compounds with enough preclinical documentation to draw solid conclusions on their class nephroprotective capacity in animal models. In this study a systematic analysis of the relation between the level of antioxidation and the level of nephroprotection was performed. A regression model is presented which crosses the y-axis (i.e. the axis representing the level of nephroprotection) very nearly the zero value, meaning that maximal prevention of the oxidative stress induced by aminoglycosides results in almost maximal nephroprotection. This indicates that oxidative stress plays a central role in the hierarchy of pathophysiological mechanisms underlying aminoglycoside nephrotoxicity. In addition, this model may potentially serve: i) as a standard to evaluate the role of the antioxidant effect of candidate nephroprotectants; ii) to reveal additional, antioxidant-independent effects among those compounds providing more nephroprotection than that expected from its antioxidant activity; and thus iii) to discriminate and focus most effective nephroprotectants on clinical usage.