Exaggerated response to gentamicin-induced nephrotoxicity in Sprague-Dawley rats: Identification of a highly sensitive outlier population

Abstract

A number of factors have been shown to predispose patients treated with aminoglycosides to nephrotoxicity. In a previous study in our laboratory investigating the interaction of prior renal dysfunction with gentamicin toxicokinetics, 9.4% of rats in all treatment groups were relatively more sensitive to gentamicin-induced nephrotoxicity. To determine if these outliers had an underlying disease or physiological abnormality, serum was collected from 99 Sprague-Dawley rats prior to daily treatment with 75 mg/kg gentamicin for seven days. urea nitrogen, creatinine, Na, K, Ca, Mg, P, total protein, albumin, aspartate transaminase, serum osmolality, total white and red blood cell count, hematocrit, hemoglobin, blood gases, and thyroxine were measured. Blood was collected one and four hours after the first dose of gentamicin for pharmacokinetic analysis. Elevations in post-treatment creatinine and nitrogen were significantly greater in the outliers (4.10 ± 0.24 mg/dl (n = 12) vs 1.92 ± 0.06 mg/dl (n = 87) and 146.4 ± 7.2 mg/dl (n = 12) vs 71.5 ± 2.0 mg/dl (n = 87); both p = 0.0001) and served as criteria for identifying this subgroup. Post-treatment creatinine and urea nitrogen were not normally distributed in the entire study population. However, when the population was divided into normal and sensitive subgroups, both subgroup values were normally distributed. The gentamicin pharmacokinetic profiles were similar in both groups. Postmortem histopathology showed significant increases in tubular casts and tubular necrosis (p = 0.01) in the sensitive rats, compared to the normally responding subgroup. Clinical tests on pre-treatment serum revealed significant differences only in serum osmolality (p = 0.04), total protein (p = 0.02), and oxygen tension (p = 0.01). The pre-treatment creatinine/urea nitrogen ratio was marginally decreased in the sensitive rats (p = 0.057).