The possible protective effect of solute and water diuresis on the development of acute failure (ARF) following administration of gentamicin, 40 mg/kg body wt per day for 14 days, was studied in unanesthetized rats. Adult female Sprague-Dawley rats with streptozotocin-induced diabetes mellitus (DM) and rats with hereditary diabetes insipidus (DI) were used as models of chronic solute and water diursis, respectively. Aged-matched Sprague-Dawley (C) and heterozygous Brattleboro (BC) rats were the respective controls. Because of higher creatinine clearance (C(Cr)) in the DM rats, another DM group received a higher dose of gentamicin (DM-H), 70 mg/kg/day for 14 days. C and DM animals injected in Ringer's were SHAM-C and SHAM-DM groups. Following gentamicin, C rats developed ARF (maximal decrease in C(Cr) from baseline was 85 ± 6(SEM)%; P < 0.001), severe lysozymuria, and tubular necrosis. In marked contrast, all DM and DMH rats exhibited complete functional and morphologic integrity with undetectable lysozymuria; no differences were observed between the two diabetic groups. BC and DI rats exhibted a 56 ± 7% (P < 0.001) and 38 ± 8% (P < 0.01) maximal decrease in C(Cr), lysozymuria, and tubular necrosis. SHAM-C and DM rats maintained unchanged renal function throughout. The kidney content of gentamicin analyzed on day 15 of the study was significantly lower in the DM and DM-H rats than in C, while no differences were found between BC and DI rats. In a separate group of Sprague-Dawley C and DM rats, renal cortical gentamicin content was measured 3, 6, and 9 days after beginning gentamicin administration at 40 mg/kg/day. By day 3 the DM rats had a cortical gentamicin content that was three-fold lower (164 ± 18 μg/g wet tissue) than that of C animals (523 ± 55; P < 0.005). The latter group subsequently developed acute renal failure and lysozymuria. We conclude that in contast to the development of gentamicin-induced ARF in C and BC rats, complete protection was afforded in the DM and DM-H animals. Partial protection was observed in the DI group. Protection in the DM animals was associated with lower renal cortical gentamicin content, suggesting that factors influencing the early cellular uptake of gentamicin may have determined the protection exhibited by these animals. The mechanism(s) whereby this occurred remain(s) to be elucidated but cannot be ascribed solely to enhanced solute excretion in the diabetic rats. The rat with streptozotocin-induced diabetes millitus is a useful model for the study of gentamicin-induced nephrotoxicity.
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