Enzymuria in Gentamicin-Induced Kidney Damage

The nephrotoxic potentials of the new aminoglycoside SCH 21420 and amikacin were compared in a rat model. Groups of rats received 100, 200, 300, or 600 mg of either drug per kg per day for 14 days. Enzymuria, urine osmolality, protein excretion, and blood urea nitrogen were monitored at periodic intervals, whereas creatinine clearance and pathological changes were determined at sacrifice. Amikacin caused more enzymuria at the two lower doses as well as greater proteinuria and blood urea nitrogen elevations at the highest dose than did SCH 21420 (P < 0.05). Pathological changes were more severe with amikacin than with SCH 21420 at the three lower doses (P < 0.05); however, at the 600 mg/kg per day dose, the pathological scores and creatinine clearances of animals receiving either drug were not significantly different (P > 0.05).

Section: Methodsmentioning

confidence: 99%

Comparative nephrotoxicity of SCH 21420 and amikacin in rats

Rankin¹,

Luft²,

Yum³

et al. 1979

“…NAG in urine was measured by the technique of Patel et al (12), BUN was measured by the method of March et al (10), and creatinine was measured by the method of Martinez and Doolan (11). The urine osmolality was determined by freezing-point depression (Advanced Instruments, Newton Highlands, Mass.…”

Section: Methodsmentioning

confidence: 99%

Recovery from Aminoglycoside Nephrotoxicity with Continued Drug Administration

Luft

Rankin

Sloan

et al. 1978

Self Cite

To examine the nephrotoxicity of prolonged gentamicin administration compared to the effect obtained when a less toxic aminoglycoside is substituted during the course of treatment, we gave gentamicin (67.5 mg/kg per day) to rats for 21 days, gentamicin for 14 days followed by either netilmicin or tobramycin for 7 days, or gentamicin for 14 days followed by saline diluent. After initial tubular, necrosis, the animals recovered from renal injury whether the drug was continued or discontinued or another drug was substituted. These data are consistent with the observation that regenerating renal epithelium is resistant to continued or additional nephrotoxic insults. These findings suggest that improvement in renal function during aminoglycoside therapy cannot necessarily be attributed to the substitution of another aminoglycoside or other therapeutic interventions.Aminoglycoside antibiotics differ in their propensity to cause renal damage in experimental animals. Previous studies have shown that tobramycin and netilmicin are less nephrotoxic than gentamicin in rats (1, 3, 7). Should nephrotoxicity occur during gentamicin therapy in humans, clinicians have the option of changing their therapy to an aminoglycoside purported to be less nephrotoxic. In all likelihood any improvement in renal function would be attributed to the drug substitution. We studied the course of prolonged gentamicin administration in rats with or without substitution of another aminoglycoside late in the course of treatment. After 2 weeks, renal function and structure recovered whether the gentamicin, was continued or another drug was substituted. These studies indicate that, in rats, recovery from aminoglycoside nephrotoxicity may occur despite continued administration of the same, or a different, aminoglycoside. MATERIALS AND METHODSAdult, male Sprague-Dawley rats (Cox Laboratories, Indianapolis, Ind.), weighing 225 to 250 g, were housed and fed as described elsewhere (4). Ten groups of 12 rats each were studied. Four groups were given gentamicin, 67.5 mg/kg per day, as a daily subcutaneous injection in 1 ml of saline diluent for 14 days. Thereafter, group 1 received saline diluent, group 2 received netilmicin (90 mg/kg per day), group 3 received tobramycin (67.5 mg/kg per day), and group 4 received gentamicin (67.5 mg/kg per day) for an additional 7 days, after which the animals were sacrificed.

“…The need for more sensitive renal monitoring techniques has increased interest in proxiinal tubular tests such as urinary enzymes (6,7) and urinary ,B2-microglobulin (8,10). These tests clearly are more sensitive than is serum creatinine.…”

mentioning

confidence: 99%

Urinary casts as an indicator of renal tubular damage in patients receiving aminoglycosides

Schentag¹,

Gengo²,

Plaut³

et al. 1979

We assessed the value of quantitative cast excretion as an early marker of renal tubular damage in 154 seriously ill patients. One hundred twenty-four of these received aminoglycoside antibiotics, and 30 of the 124 experienced a rise in serum creatinine of 0.5 mg/dl or more during therapy. The remaining 30 of the 154 patients were treated with other antibiotics and served as controls. Casts were quantitated in random urines collected before morning diuretic doses. Cast counts in control patients averaged 44 ± 51 casts during the intensive care unit admission. Patients given aminoglycosides without a significant rise in serum creatinine of 0.5 mg/dl or more excreted 153 ± 196 casts, significantly more than controls. In comparison to both the control and nontoxic patients, the 30 nephrotoxic patients excreted significantly more casts (625 ± 364) and were significantly higher as early as 9 days before serum creatinine first rose. Daily urinary cast counts are a rapid and inexpensive means of identifying early renal tubular damage in critically ill patients given aminoglycosides.Aminoglycoside antibiotics such as gentamicin, tobramycin, amikacin, and netilmicin are highly effective in the treatment of serious gramnegative infections. However, their use in critically ill patients may be associated with acute, nonoliguric renal insufficiency. Although serum creatinine and creatinine clearance are commonly employed to monitor the renal function of treated patients, both are tests of glomerular filtration rate rather than renal tubular function, the location of aminoglycoside-related damage. Because of considerable lag time between tubular injury and creatinine clearance rise, measurement of serum creatinine and creatinine clearance provides essentially no early warning of proximal tubular damage. Moreover, aminoglycosides accumulate rapidly in renal tissue, produce damage, and persist in the kidney long after treatment ends, so stopping therapy only after glomerular filtration rate falls will not prevent further progression of the renal failure (9).The need for more sensitive renal monitoring techniques has increased interest in proxiinal tubular tests such as urinary enzymes (6, 7) and urinary ,B2-microglobulin (8, 10). These tests clearly are more sensitive than is serum creatinine. However, in addition to aminoglycosides, many clinical tubular insults alter the excretion of urinary enzymes (14) and unrnary fi2-microglobulin (3), thus diminishg their diagnostic value.Although it appears unlikely that an aminoglycoside-specific renal tubular marker will be discovered, tests of renal tubular function, if frequently employed, may give early warning of tubular damage before a decline in glomerular filtration rate occurs. However, daily measurement of f)2-microglobulin and most urinary enzymes is limited in availability and is expensive and time consuming. Therefore, we explored the measurement of urinary cast excretion as an early marker of renal tubular damage, because the identification of a renal tubular marker with a...