Renal damage caused by gentamicin: A study of the effects on renal morphology and urinary enzyme excretion

Wellwood, J. M.; Lovell, D.; Thompson, A. E.; Tighe, J. R.

doi:10.1002/path.1711180307

Cited by 130 publications

(33 citation statements)

References 22 publications

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“…As detailed in previous studies by ourselves and others (11,13,29,32), renal tubular epithelial cells of the gentamicin-treated rats displayed progressive light and electron microscopic changes, which resulted in nearly total ( ) light and electron microscopic changes were essentially the same as those at the same intervals in animals treated with 40 mg of tobramycin per kg per day. After 10 days of treatment, foci of acute necrosis were identified in approximately 5% of proximal tubules.…”

supporting

confidence: 65%

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Gilbert

Plamp

Starr

et al. 1978

Antimicrob Agents Chemother

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A rat model was utilized to compare the nephrotoxic potential of gentamicin and tobramycin. Gentamicin, 40 mg/kg per day, predictably produced renal failure and morphological evidence of proximal tubular necrosis over 14 days of treatment. An identical dosage of tobramycin was associated with only minimal morphological changes and normal concentrations of serum creatinine and blood urea nitrogen. Similar results were obtained even after the tobramycin dosage was tripled to 120 mg/kg per day. A decrease in urine osmolality, mechanism unknown, was observed in all aminoglycoside-treated rats, but the lowest osmolalities were found in the gentamicin-treated rats. According to both histological criteria and renal function measurements, gentamicin was more nephrotoxic than tobramycin in this animal model. This study was undertaken as a result of our interest in determining whether there were any important differences between the aminoglycoside antibiotics gentamicin and tobramycin. A review of the literature indicated only minor differences in in vitro antibacterial activity (1,6,8,14,20,31). Gentamicin is slightly more active against Serratia species, and tobramycin is slightly more active against isolates of Pseudomonas aeruginosa. In vivo animal studies of antibacterial activity again show similar degrees of activity, except that tobramycin is more active against P. aeruginosa infections (5,30). The pharmacokinetics of the two drugs in humans are felt to be virtually identical (9,12,22,28). Comparative toxicity studies of the effects of these two drugs in humans have not been reported.In a rat model, tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to have a lower lethal dose than gentamicin (5). Tobramycin was found to be less ototoxic than gentamicin in guinea pigs (2). Tobramycin was considered less nephrotoxic than gentamicin in rats on the basis of subtle but consistent histological changes and differences in drug-induced urinary lysosomal enzymes (12, 21). Since a clear difference in nephrotoxic potential would have clinical importance, studies were designed to more precisely detect any abnormalities in renal structure or function.Initially, a prospective randomized doubleblind study in humans was considered. A recent report describes such a study comparing gentamicin and amikacin (26). However, it appears virtually impossible to determine the incidence of aminoglycoside-induced nephrotoxicity in humans. There is no way for the investigator to separate disease-induced toxicity from drug-induced toxicity. Also, preillness measurements of renal structure and function are rarely available. Because of these concerns, we chose to use a rat model of aminoglycoside nephrotoxicity. Nephrotoxicity was quantitated by histological changes and alterations in renal fimction. The results demonstrate that, in this model, tobramycin is less nephrotoxic than gentamicin.MATERIALS AND METHODS Animals. Adult male Fischer 344 rats, weighing 175 to 275 g, were used. The rats were kept sing...

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supporting

confidence: 65%

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Gilbert

Plamp

Starr

et al. 1978

Antimicrob Agents Chemother

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“…It is interesting that the localization of the aminoglycoside coincides with the site of histological damage to the kidneys as described by others (2,5,6,8,10,12,14). Thus, it seems likely that the accumulation and retention-of aminoglycosides by the proximal renal tubules is related to the morphological damage to those tubules.…”

supporting

confidence: 53%

Autoradiographic Localization of [ ³ H]Gentamicin in the Proximal Renal Tubules of Mice

Kuhar

Mak

Lietman

1979

Antimicrob Agents Chemother

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The site of localization of [3H]gentamicin within mouse kidney is shown to be the proximal renal tubule by coincidence of the radioactivity, as visualized by autoradiography, and the mucopolysaccharide-rich microvilli characteristic of proximal convoluted tubules, as visualized by histochemical staining.The extensive accumulation and avid retention of aminoglycoside antibiotics by the kidneys of both experimental animals (4, 9, 13) and humans (1, 3) may be related to the nephrotoxicity associated with these drugs. If these processes are related, then an understanding of the precise anatomic localization of aminoglycoside accumulation and retention may be fundamental to the prevention and treatment ofaminoglycosideinduced nephrotoxicity. We have investigated the intrarenal localization of the aminoglycoside gentamicin in the mouse kidney.Three ,uCi/mg with gentamicin sulfate from Sigma) in 0.2% ethanol. Three control male mice were injected with 5 ml of 0.2% ethanol per kg, and both kidneys from each of these mice were prepared and examined in the same manner as for the treated mice. Twenty-four hours later, both kidneys from each mouse were removed under pentobarbital anesthesia, and sections of the medial parts of the kidneys (both axes were sampled in different kidneys) were mounted on a copper microtome chuck and frozen in liquid nitrogen slush. Four-micrometer sections of these tissues were either thaw-mounted or drymounted onto emulsion-coated (Kodak NTB-3) slides and stored for approximately 1 month. This autoradiographic procedure has been developed to prevent or minimize the diffusion of small molecules from tissue sites (11). After development of the emulsion, the tissues were stained either with pyronine-y or by the periodic acid-Schiff technique, which visualizes mucopolysaccharide-rich microvilli characteristic of cells in the proximal convoluted tubules.A representative photograph of the resultant autoradiograph and histochemical staining is shown in Fig. 1. All kidney preparations from treated animals showed similar findings. Dense clusters of autoradiographic grains (ARG) were restricted to cortical regions of the kidney, where they were associated with most, but not all, tubule profiles. The ARG were strikingly absent over glomeruli and over structures in the medulla including the thin limbs, collecting ducts, and blood vessels. A very slight enrichment of ARG was observed over the straight parts of the tubules below the cortical layers containing the glomeruli. In periodic acid-stained sections, the ARG were found exclusively over tubules that stained positively for mucopolysaccharides near the lumen. Furthermore, the convoluted tubules with the dense cluster of ARG had larger cells when compared with the tubules with no ARG. Control slides prepared for positive and negative chemography showed no spurious generation of or fading of latent images. The same localization has also been visualized in rat kidney preparations (data not shown).From these data it is concluded that [3H]gentamicin is very ...

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“…These enzymes include aminotransferases, isocitric dehydrogenase, lactic dehydrogenase, alkaline phosphatase, f-glucuronidase, leucine, alanine and glutamyl aminopeptidases, glucosidases and Nacetyl-,(-glucosaminidase (NAG) (Balazs et al, 1963;Ono et al, 1968;Raab & Hohenegger, 1968;Prescott & Ansari, 1969;Leathwood & Plummer, 1969;Raab, 1972;Wright & Plummer, 1974;Wellwood et al, 1975Wellwood et al, , 1976Stroo & Hook, 1977;Mondorf et al, 1978;Procter & Kunin, 1978;Merle et al, 1980;Jones et al, 1980: and others). Depending on the severity of the injury there is an initial delay of 12-48 h after administration of the nephrotoxic agent before the rise in urine enzyme activity.…”

Section: Enzymuriamentioning

confidence: 99%

Assessment of nephrotoxicity.

Prescott¹

1982

Brit J Clinical Pharma

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Renal damage caused by gentamicin: A study of the effects on renal morphology and urinary enzyme excretion

Cited by 130 publications

References 22 publications

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Autoradiographic Localization of [ ³ H]Gentamicin in the Proximal Renal Tubules of Mice

Assessment of nephrotoxicity.

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Renal damage caused by gentamicin: A study of the effects on renal morphology and urinary enzyme excretion

Cited by 130 publications

References 22 publications

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Comparative Nephrotoxicity of Gentamicin and Tobramycin in Rats

Autoradiographic Localization of [ 3 H]Gentamicin in the Proximal Renal Tubules of Mice

Assessment of nephrotoxicity.

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Autoradiographic Localization of [ ³ H]Gentamicin in the Proximal Renal Tubules of Mice