Comparative studies on the action of aminoglycosides and cephalosporins on the proximal tubule of the human kidney

Zegelman, M.; Klose, Johannes; Hendus, J; Breier, Joseph M.

doi:10.1093/jac/4.suppl_a.53

Cited by 40 publications

(17 citation statements)

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“…We studied a large number of critically ill patients who received aminoglycoside antibiotics by appropriate dosing schedules, and we (10,12,20,21) in humans, although in rats, netilmicin is consistently less nephrotoxic (1,9,11). Third, our nephrotoxic patients showed abnormal tissue uptake early in treatment, before changes in serum creatinine occurred.…”

Section: Discussionmentioning

confidence: 99%

“…Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P < 0.05). Two major conclusions of this study are at variance with those of previous investigators: (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients.We and others have previously shown that the various aminoglycosides differ in their intrinsic nephrotoxic potential in animals (1, 9, 11, 13) and humans (10,17,18,19). In such studies, both nontoxic and nephrotoxic patients must have precise control of the serum concentrations before the population can be analyzed for the factors predisposing to nephrotoxicity.…”

mentioning

confidence: 99%

“…We and others have previously shown that the various aminoglycosides differ in their intrinsic nephrotoxic potential in animals (1,9,11,13) and humans (10,17,18,19). In such studies, both nontoxic and nephrotoxic patients must have precise control of the serum concentrations before the population can be analyzed for the factors predisposing to nephrotoxicity.…”

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confidence: 99%

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Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients

Schentag¹,

Cerra²,

Plaut³

1982

Antimicrob Agents Chemother

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We studied 201 critically ill patients during 267 courses of gentamicin (139 courses) or tobramycin (128 courses) therapy. Clinical and pharmacokinetic data were obtained on 240 of 267 courses (120 courses each of gentamicin and tobramycin). Two judgments of nephrotoxicity and its cause were made independently in this study, using a clinical and a pharmacokinetic definition of nephrotoxicity. The two sets of criteria were generally in good agreement, as all but 10 of 41 patients who were judged nephrotoxic by pharmacokinetic criteria were independently judged nephrotoxic by the clinical definition. Groups of patients judged nontoxic did not differ from groups judged nephrotoxic in age, sex, weight, initial creatinine clearance, total dose given, duration of treatment, initial aminoglycoside trough serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Prior aminoglycosides (usually gentamicin) had been used more frequently in the nontoxic group (P < 0.05). Two major conclusions of this study are at variance with those of previous investigators: (i) we found no clinical parameters of value in predicting nephrotoxicity in critically ill patients; and (ii) aminoglycoside serum concentrations, once in the therapeutic range, were of limited value in prevention of aminoglycoside nephrotoxicity in our patients.We and others have previously shown that the various aminoglycosides differ in their intrinsic nephrotoxic potential in animals (1, 9, 11, 13) and humans (10,17,18,19). In such studies, both nontoxic and nephrotoxic patients must have precise control of the serum concentrations before the population can be analyzed for the factors predisposing to nephrotoxicity. We have treated 201 critically ill patients with suspected or proven infections, with aminoglycosides administered in regimens that were closely monitored by measured blood levels (17). Dosing adjustments were made as required to maintain the recommended concentration range. The judgment of nephrotoxicity was made independently by both clinical and pharmacokinetic criteria. Gentamicin was more frequently (24%) nephrotoxic than was tobramycin (12%). In this analysis, we compared all nontoxic patients with all nephrotoxic patients so as to use our large groups of nephrotoxic patients to define the characteristics of those who experienced renal damage when appropriately dosed with aminoglycosides. METHODSPatients. We gave 201 acutely ill patients 267 courses of aminoglycoside therapy. Pharmacokinetic and clinical data were available on 240 courses, which were used for analysis. The patients were older adults in critical care units, with serious infections complicating either major medical or surgical disorders. Most infections were intra-abdominal or pneumonic. Patients were entered into this study at the time of request for dosing and pharmacokinetic monitoring.Dosing and sample collection. Aminoglycosides were administered by intravenous infusion over 30 to 60 min. Dosing rates were determined initially by n...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients

Schentag¹,

Cerra²,

Plaut³

1982

Antimicrob Agents Chemother

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“…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.…”

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

Schentag¹,

Gengo²,

Plaut³

et al. 1979

Antimicrob Agents Chemother

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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...

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“…Aminoglycoside treatment leads to an increased excretion of brush border enzymes (22), lysosomal enzymes (23) and LMWP such as P2-microglobulin and lysozyme (16). Aminoglycoside-induced functional alterations were detected by measuring the urinary excretion of the LMWP lysozyme, the lysosomal enzyme N-acetyl-,3-D-glucosaminidase and total proteins in intact rats (Table 2).…”

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Renal ultrastructural and biochemical injuries induced by aminoglycosides.

Cojocel¹,

Docius²,

Maita³

et al. 1984

Environ Health Perspect

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Aminoglycoside-induced proteinuria may result from general renal damage or may reflect alterations in specific steps in the renal handling of proteins. To differentiate between the two possibilities, experiments were designed to quantify the effects of nephrotoxic doses of gentamicin, tobramycin and netilmicin in the intact rat, isolated perfused rat kidney (IPK) and kidney slices using the cationic low molecular weight protein lysozyme as a model protein. Each aminoglycoside was administered IP to male Wistar rats (15 or 30 mg/kg/day) for 5 or 7 days.Scanning and transmission electron microscopy indicated that gentamicin and tobramycin induced a decrease in the number and diameter of endothelial fenestrae and degranulation of the myoepithelioid cells of the juxtaglomerular apparatus. Concurrently, gentamicin and tobramycin decreased the glomerular sieving coefficient of lysozyme from 0.8 to 0.6 and 0.5, respectively. Netilmicin did not affect the percentage reabsorption of lysozyme whereas gentamicin and tobramycin induced a 50% decrease in lysozyme reabsorption by the IPK. Gentamicin and tobramycin decreased equally lysozyme degradation by the IPK; this decrease was time-and dose-dependent when evaluated in slices from renal cortex. Perfusion of rat kidneys with gentamicin induced a dose-dependent decrease in reabsorption and catabolism of lysozyme.In conclusion, these studies demonstrate that polycationic aminoglycosides alter ultrastructure and glomerular permeability, tubular reabsorption and intracellular digestion of proteins.Aminoglycoside antibiotics are valuable therapeutic agents which are employed frequently in clinical management of gram-negative bacterial infections. Nephrotoxicity, a major side effect of aminoglycoside treatment, is usually characterized by a fall in glomerular filtration rate (GFR), decreased urinary concentrating capacity, proteinuria, enzymuria and ultrastructural alteration of proximal tubular cells. For several years, efforts of various research groups have focused on detection and assessment of the mechanisms of aminoglycoside nephrotoxicity. Luminal uptake is the major route of aminoglycoside tubular reabsorption and subsequent intracellular accumulation (1-3). Contraluminal uptake of aminoglycosides (4,5) also appears to contribrute to the accumulation of aminoglycosides. Although aminoglycosides inhibit Na, K-ATPase activity, it is unlikely that this is the primary mechanism of aminoglycoside nephrotoxicity (6). The effects of aminoglycosides on mitochondrial, (7) and lysosomal function (8-11) appear to play the

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Comparative studies on the action of aminoglycosides and cephalosporins on the proximal tubule of the human kidney

Cited by 40 publications

References 1 publication

Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients

Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients

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

Renal ultrastructural and biochemical injuries induced by aminoglycosides.

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