Dietary protein level alters gentamicin-induced nephrotoxicity in rats N. Zeeni a , B. Selmaoui b , D. Beauchamp c , G. Labrecque d , L. Thibault a, ⁎ a School of Dietetics and Human Nutrition, Macdonald Campus of McGill University, Montréal, Québec, Canada H9X 3V9 b Centre de Recherche en Sciences de la Santé de l'Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Québec, Canada H4J 1C5 c Centre de Recherche en Infectiologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Sainte-Foy, Québec, Canada G1V 4G2 d Faculté de Pharmacie, Université Laval, Sainte-Foy, Québec, Canada G1V 4G2 Received 2 May 2006; received in revised form 5 December 2006; accepted 19 December 2006 Abstract Aminoglycosides (AG) such as gentamicin are antimicrobial drugs widely used in the hospital setting due to their efficacy in the treatment of severe gram-negative bacterial infections. However, all AG have the potential to cause nephrotoxicity. Two studies have been conducted (1) to assess the protein level of a diet that would give the best renal outcome with gentamicin administration, and (2) to get a better idea about the rhythms of food ingestion associated with the different protein levels. Adult female Sprague–Dawley rats fully adapted to a standard chow diet, the standard chow with 20% or 55% added casein were chronically treated for 10 days with a nephrotoxic dose of gentamicin sulfate (40 mg/kg/ day, i.p.) or a saline solution. Food ingestion patterns of rats were recorded every hour using a Diet Scan system and gentamicin nephrotoxicity indices were measured. The second study used rats that were fed the same diets and given a sham injection. Corticosterone was assayed to quantify the stress of the animals. Results showed that chronic gentamicin treatment leads to a decrease in food intake and flattening of the rhythms of food ingestion. Also, chow feeding and the 20% casein diet were found to be more protective against gentamicin-induced nephrotoxicity than the 55% casein diet. Therefore, while a protein-rich diet can be protective against gentamicin-induced nephrotoxicity, the present study demonstrates that a diet too high in protein might rather be harmful to the kidneys. © 2007 Elsevier Inc. All rights reserved. Keywords: Gentamicin; Nephrotoxicity; Temporal variation; Food intake; Protein; Rat 1. Introduction Aminoglycosides (AG) are antimicrobial drugs widely used in the hospital settings due to their efficacy in the treatment of severe gram-negative bacterial infections [1]. However, all AG have the potential to cause nephrotoxicity. The incidence of aminoglycoside-induced nephrotoxicity was estimated to range between 15 and 30% [2]. Also, in a study conducted in 2216 patients admitted at the Tufts-New England Medical center, it was found that 7% of the cases of hospital-acquired renal insufficiency could be attributed to the administration of ami- noglycosides [3]. Many studies have been conducted with this class of anti- biotics in order to assess the circumstances that would limit its detrimental consequences. First, it was shown in animal models that a single daily dosage instead of the traditional multiple dosage of AG may be used to reduce renal toxicity [4]. In addition, it was found in rodents and humans that nephrotox- icity caused by AG varies temporally with a peak observed when the drug is administered during the resting period and a trough when it is given during the activity period [5–9]. The relationship between food intake and AG nephrotoxicity was also investigated. The studies conducted were based on the assumption that since minimal toxicity occurred when the drug was administered during the activity period, this also meant that it occurred during the period of maximal food intake. In a study conducted in fasted or chow-fed adult female Sprague–Dawley rats treated with gentamicin (150 mg/kg of body weight) at 1400h or 0200h, no temporal variations of nephrotoxicity were observed in the fasted rats [10]. Indeed, in these animals gen- tamicin was as toxic when administered in the middle of the activity period (0200h) as in the resting period (1400h). This demonstrates that the time-dependent nephrotoxicity variations Physiology & Behavior 90 (2007) 760 – 770 ⁎ Corresponding author. School of Dietetics and Human Nutrition, Macdonald Campus of McGill University, 21,111 Lakeshore Road, Ste. Anne de Bellevue, QC, Canada H9X3V9. Tel.: +1 514 398 7848; fax: +1 514 398 7739. E-mail address: louise.thibault@mcgill.ca (L. Thibault). 0031-9384/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.physbeh.2006.12.018