Aminoglycoside Nephrotoxicity Research Articles

Pathogenic factors in aminoglycoside-induced nephrotoxicity

Aminoglycoside antibiotics play an integral role in antimicrobial chemotherapy. Unfortunately, these drugs are known to cause nephrotoxicity in man and experimental animals. In fact, the incidence of renal dysfunction during the course of clinical treatment with aminoglycoside antibiotics is approximately 10%. Over the past two decades the elucidation of the pathogenesis of aminoglycoside-induced nephrotoxicity has been the subject of numerous investigations. This review describes the recent theories postulated to play a role in the pathogenesis of antibiotic-induced renal damage. In particular, the importance of aminoglycoside levels in the renal cortex or at the membrane binding site is examined in detail. The relevance of antibiotic tissue levels is reflected in the ability of other drugs to modify nephrotoxicity through an alteration in renal aminoglycoside content. The role of factors including age and diet in drug-induced nephrotoxicity is described. In clinical practice, aminoglycoside antibiotics may often be administered in conjunction with other agents. The influence of aminoglycoside interaction with other drugs including vancomycin, cephalosporins and cytotoxic drugs is examined in the light of reports that nephrotoxicity is potentiated in these situations. In addition, this review focuses on the role of infection (pyelonephritis and septicemia) and bacterial endotoxin as pathogenic factors involved in aminoglycoside nephrotoxicity. Both the direct influence of endotoxin and the indirect effects of vasoactive mediators and inflammatory processes will be discussed. A multiplicity of factors is involved in the pathogenesis of aminoglycoside-induced nephrotoxicity and these are further amplified in the presence of infection.

Aminoglycoside nephrotoxicity

The high incidence of associated nephrotoxicity represents an important concern in the use of aminoglycoside antibiotics, which have been implicated as one of the primary causes of drug-induced acute renal failure. Several factors, including the underlying health of the patient, criteria used to define nephrotoxicity, and the specific aminoglycoside administered, may contribute to the nephrotoxic potential of these agents. The development of aminoglycoside-induced nephrotoxicity is a complex problem. These drugs appear to be only minimally metabolized within the body and undergo nearly exclusive renal excretion, primarily by glomerular filtration. Ultimately, reabsorption and accumulation within the kidney results in proximal tubular cell damage; several possible mechanisms have been proposed, both for the development of such cell damage and for its subsequent role in the evolution of nephrotoxicity. The pathology and the clinical pattern of aminoglycoside-induced kidney damage have been extensively studied in animal models and in humans. Although the data often conflict, many of these studies have attempted to identify some of the factors associated with a higher risk for aminoglycoside nephrotoxicity. Of the factors generally agreed upon to influence risk, correction of volume depletion and diminished renal perfusion, as well as dose adjustment for level of renal function, have been identified as critical measures for prevention of renal damage by aminoglycosides. Recent studies have indicated that newer agents, such as third-generation cephalosporins and aztreonam, often may be as therapeutic and cost-effective as the aminoglycosides without the nephrotoxicity associated with the latter agents. Clearly, such a safe and effective alternative, if confirmed, would be preferable to aminoglycoside therapy in patients at high risk for nephrotoxicity.

INFLUENCE OF HYDROCORTISONE ON GENTAMICIN-INDUCED NEPHROTOXICITY IN RATS

Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans and experimental animals. They include an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of therapy, liver disease, and renal infection. The concomitant administration of steroids has never been investigated. We evaluated the role of hydrocortisone on gentamicin-induced nephroxicity in a model of infused rats. We showed that hydrocortisone given over 3 days after the infusion did not modify the gentamicin half-life in the renal cortex, gentamicin-induced lysosomal phospholipidosis, or histopathology but did reduce significantly the 3H/DNA ratio on day 4 after gentamicin infusion. We concluded that hydrocortisone interferes with the postnecrotic cellular regeneration process, an important step that is responsible for the recovery of normal kidney structure following toxic injuries associated with aminoglycoside therapy.

Polyaspartic Acid Prevents Experimental Aminoglycoside Nephrotoxicity

The influence of the polyamino acid polyaspartic acid (PAA) on experimental aminoglycoside nephrotoxicity was determined. PAA prevented all measured functional and pathologic evidence of gentamicin nephrotoxicity for less than or equal to 27 d of study. All the animals given PAA, either alone or with gentamicin, developed prominent cytoplasmic vacuoles in the cells of the renal proximal convoluted tubules; the vacuoles in rats given just PAA differed from those observed in rats given PAA plus gentamicin. Rats given PAA plus gentamicin accumulated roughly 10 times more renal aminoglycoside as did rats given gentamicin alone. Immunohistochemical localization studies confirmed the presence of increased amounts of gentamicin in the cytoplasm of the tubular cells of animals given gentamicin plus PAA. PAA did not alter the in vitro antimicrobial activity of gentamicin versus Escherichia coli or Pseudomonas aeruginosa. These studies demonstrate the ability of PAA to prevent experimental gentamicin nephrotoxicity.

Amylase-Creatinine Clearance Ratio: A Simple Test to Predict Gentamicin Nephrotoxicity

• The initial target of aminoglycoside nephrotoxicity is the proximal tubule. Yet, no simple test is available to predict such toxicity. Taking advantage of the fact that amylase is filtered in the glomerulus and reabsorbed by the proximal tubules, we prospectively examined in 23 patients if changes in renal amylase creatinine clearance ratio (ACCR) can predict gentamicin nephrotoxicity. Eighteen of these patients had an initial creatinine clearance (rCcr) above 30 mL/min. Eleven of them (group A) had an ACCR above 3.5% (control 3% ±1.03%) and all exhibited an average reduction of 32.2%±11.6% in rCcr following one week of gentamicin therapy. In contrast, only one of seven patients (group B) with an initial ACCR below 3.5% had a reduction, albeit transient, in rCcr. During gentamicin therapy, group A patients had a further increase in ACCR which was proportional to the reduction observed in rCcr (r= -.54). Our preliminary data suggest that ACCR may prove a simple and possibly a reliable predictor of kidney function deterioration during gentamicin therapy in patients with rCcr above 30 mL/mi n: patients with pretherapy ACCR above 3.5% may exhibit a deterioration in the creatinine clearance during the first week of therapy. For patients with pretherapy renal failure (rCcr ( Arch Intern Med 1988;148:1093-1096)

Clinical assessment of a published model to predict aminoglycoside-induced nephrotoxicity.

During the past decade, several patient risk factors have been identified as contributing to the development of aminoglycoside nephrotoxicity. Sawyers et al. recently published a method for estimating the probability of aminoglycoside nephrotoxicity on an individual patient basis. The present work represents a refinement of previous publications and has not been tested with the common variations used in aminoglycoside dosing. The purpose of this study was to determine both the qualitative and quantitative value of this method in predicting aminoglycoside induced nephrotoxicity. Eighty-three patients (47 male, 36 female) meeting the inclusion criteria of Sawyers et al. were entered into the study. Patient risk factors (age, sex, initial 1-h postinfusion aminoglycoside serum level, initial calculated creatinine clearance, duration of therapy, and presence of liver disease) were entered into a logistic regression analysis to determine the individual patient's risk of developing nephrotoxicity. These calculated probability scores were then compared with the observed nephrotoxicity in specific groups within our patient sample to see how effectively the model quantitatively performed. Twelve patients (14.5%) developed nephrotoxicity. The model predicted only 5 of the 12 patients developing nephrotoxicity (sensitivity or true positive = 42%). In the nonnephrotoxic group, the model accurately predicted only 38 of 71 patients (specificity or true negative = 54%). These data suggest that the model may accurately quantitate the number of patients likely to develop nephrotoxicity from a specific group but is unable to discriminate specific patients at risk of developing aminoglycoside-induced nephrotoxicity.

Diltiazem enhances gentamicin nephrotoxicity in rats.

The effect of the calcium antagonist, diltiazem, was examined in gentamicin-induced nephrotoxicity states in rats. Animals were injected for 5 days with diltiazem intraperitoneally (40 mg/kg/day), or gentamicin subcutaneously (100 mg/kg/day) or simultaneously with both preparations using the same doses. At the time of sacrifice, the urea and creatinine clearances, as well as urine osmolality were determined and the renal tissues were processed for examination by light microscopy. Gentamicin-injected rats demonstrated the typical pattern of aminoglycoside nephrotoxicity characterized by poliuric renal failure and necrosis of the proximal tubular epithelium. Rats injected with diltiazem revealed only mild depression of urine osmolality. There was no elevation of blood urea nitrogen and serum creatinine or depression of urea and creatinine clearances, and no focal tubular cell necrosis was detected. However, concomitant administration of both compounds considerably increased nephrotoxicity by according both histological indications and renal function measurements. Thus, we conclude that the combination of diltiazem and gentamicin must be used carefully in human clinical practice.

Aminoglycoside nephrotoxicity in obstructive jaundice: Possible contribution by con-comitantly administered corticosteroids

Aminoglycoside nephrotoxicity in obstructive jaundice: Possible contribution by con-comitantly administered corticosteroids

Aminoglycoside nephrotoxicity: mechanism and prevention.

Nephrotoxicity limits the clinical utility of aminoglycosides (Lietman, 1985). Therefore, the identification of factors associated with a greater incidence of renal damage is critical. These factors can be classified in those related to the drug and its administration and those related to the clinical condition of the patient (Table 1).

Once-daily dosing decreases renal accumulation of gentamicin and netilmicin.

The pathogenesis of aminoglycoside nephrotoxicity is intimately related to the extent of drug accumulated in the renal cortex. In the framework of searching for preventive measures of aminoglycoside-induced nephrotoxicity, we investigated the influence of dosage regimen on the renal cortical accumulation of gentamicin and netilmicin in humans. Patients with a tumor partly involving one kidney, with normal renal function, and scheduled for nephrectomy received one dose of either gentamicin (4.5 mg/kg) or netilmicin (5 mg/kg) as a single short-term infusion or as 24-hour continuous infusion. Treatment started 24 hours before surgery. Serum aminoglycoside pharmacokinetics were examined during treatment and renal cortical tissue was sampled at the moment of operation for drug determination. The short-term infusion schedule yielded cortical concentrations of 103.2 +/- 36.3 and 137.4 +/- 34.6 micrograms/gm for gentamicin and netilmicin, respectively. Tissue levels after continuous infusion were 158.1 +/- 52.9 and 178.5 +/- 21.8 micrograms/gm for gentamicin and netilmicin, respectively. For each aminoglycoside, a single short-term infusion resulted in significantly lower renal drug levels than did a continuous infusion of the same dose. From the nephrotoxicity point of view, these data support the administration of gentamicin and netilmicin as once-daily injections. This also supports the appropriateness of further studies to determine clinical efficacy of once-a-day dosing for aminoglycosides.

Analysis of Urinary Sediment by Transmission Electron Microscopy: An Innovative Approach to Diagnosis and Prognosis in Renal Disease

Urinary sediment TEM is capable of unequivocally demonstrating renal tubule cells and distinguishing them from urinary tract epithelial cells. The renal tubule cells and the accompaniments including myeloid bodies, inflammatory cells, or fibrin permit, in a particular clinical setting, synthesis of a meaningful renal diagnosis. Sequential TEM sediment studies can clarify ambiguities in diagnosis. Precisely, when much difficulty is experienced in distinguishing ATN from aminoglycoside nephrotoxicity in a patient with sepsis who has received aminoglycoside, urinary sediment TEM can facilitate the differential diagnosis with confidence. In another clinical setting, such as hypersensitivity acute interstitial nephritis, TEM urinary sediment has an irrevocable place by exhibiting the characteristic eosinophil granules that will confirm the above diagnosis, or deny it when they are absent. The morphologic features in the renal tubule cells in the sediment reflect similar changes in the tubular cells in renal tissue. Therefore, the severity of tubular changes are commensurate with the clinical outcome in terms of renal function recovery, need of dialysis, and mortality. The degree of correlation is significant. Thus, slight or no TEM sediment tubular changes signifies a good prospect for renal function recovery and low or no mortality. Conversely, severe tubular changes in the TEM sediment denote persistent renal failure accompanied by high mortality. Furthermore, the most severe tubular changes, found in hepatorenal syndrome, are consistent with its dismal prognosis.

Liver disease, aminoglycoside antibiotics and renal dysfunction.

HepatologyVolume 8, Issue 4 p. 966-968 EditorialFree Access Liver disease, aminoglycoside antibiotics and renal dysfunction Paul S. Lietman M.D., Ph.D., Corresponding Author Paul S. Lietman M.D., Ph.D. The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205Osler 527, Johns Hopkins Hospital, Baltimore, Maryland 21205===Search for more papers by this author Paul S. Lietman M.D., Ph.D., Corresponding Author Paul S. Lietman M.D., Ph.D. The Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205Osler 527, Johns Hopkins Hospital, Baltimore, Maryland 21205===Search for more papers by this author First published: July/August 1988 https://doi.org/10.1002/hep.1840080442Citations: 19AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References 1 Camps J, Sola X, Rimola A. et al. Comparative study of aminogly-coside nephrotoxicity in normal rats and rats with experimental cirrhosis. Hepatology 1988; 8: 837– 844. 2 Moore RD, Smith CR, Lipsky JJ. et al. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100: 352– 357. 3 Moore RD, Smith CR, Lietman PS. Increased risk of renal dysfunction due to interaction of liver disease and aminoglycosides. Am J Med 1986; 80: 1093– 1097. 4 Smith CR, Moore RD, Lietman PS. Studies of risk factors for aminoglycoside nephrotoxicity. Am J Kidney Dis 1986; 8: 308– 313. 5 Sawyers CL, Moore RD, Lerner SA. et al. A model for predicting nephrotoxicity in patients treated with aminoglycosides. J Infect Dis 1986; 153: 1062– 1068. 6 Wade JC, Smith CR, Petty BG. et al. Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside. Lancet 1978; 2: 604– 606. 7 Smith CR, Lipsky JJ, Laskin OL. et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med 1980; 302: 1106– 1109. 8 Moore RD, Smith CR, Lietman PS. Risk factors for the development of auditory toxicity in patients receiving aminoglycosides. J Infect Dis 1984; 149: 23– 30. 9 Cabrera J, Arroyo V, Ballesta AM. et al. Aminoglycoside nephrotoxicity in cirrhosis. Gastroenterology 1982; 82: 97– 105. 10 Felisart J, Rimola A, Arroyo V. et al. Cefotaxime is more effective than is ampicillin-tobramycin in cirrhotics with severe infections. Hepatology 1985; 5: 457– 462. 11 Vree TB, Zweens K, Huige PJ, et al. Interaction between the renal excretion rates of beta 2-microglobulin and tobramycin in man. Clin Chim Acta 1984; 138: 49– 57. 12 Smith CR, Lietman PS. Enzymuria and controlled trials of aminoglycosides in healthy human volunteers. In: K Solez, A Whelton, eds. Acute renal failure: correlations between morphology and function. New York: Marcel Dekker, Inc., 1984: 273– 279. 13 Luft FC, Aronoff GR, Evan AP. et al. The effect of aminoglycosides on glomerular endothelium: a comparative study. Res Commun Chem Pathol Pharmacol 1981; 34: 89– 95. 14 Wood AS, Sawyers CL, Smith CR. et al. The effect of bile duct ligation on gentamicin nephrotoxicity in rats (Abstract). Clin Pharmacol Ther 1986; 39: 236. 15 Wood AS, Smith CR, Sawyers CL. et al. The effect of bile duct ligation on gentamicin nephrotoxicity in rats (Abstract). Clin Pharmacol Ther 1988; 43: 198. 16 Desai TK, Tsang T-K. Aminoglycoside nephrotoxicity in obstructive jaundice. Am J Med (in press). 17 Lipsky JJ, Lefkowith J, Lietman PS. Cytoplasmic and membrane effects of aminoglycosides: a hypothesis for the mechanism of aminoglycoside toxicity. In: K Solez, A Whelton, eds. Acute renal failure: correlations between morphology and function. New York: Marcel Dekker, Inc., 1984: 261– 271. Citing Literature Volume8, Issue4July/August 1988Pages 966-968 ReferencesRelatedInformation

Aminoglycoside nephrotoxicity in obstructive jaundice

Purpose: Although it is known that liver disease predisposes to aminoglycoside nephrotoxicity, specific features of such disease that may predispose to aminoglycoside-induced renal injury have not been identified. We sought to identify such features. Patients and methods: We undertook a retrospective review of the charts of 42 consecutive patients with biliary obstruction and/or cholangitis who had received more than three doses of an aminoglycoside. Results: Comparison of patients in whom aminoglycoside nephrotoxicity did and did not develop revealed no differences in age, race, sex, dose, and duration of aminoglycoside therapy; mean peak and trough aminoglycoside levels; initial pre-treatment levels of serum creatinine, aspartate transaminase, alkaline phosphatase, or albumin; or prothrombin time. The initial pre-treatment serum bilirubin level was higher in the patients in whom aminoglycoside nephrotoxicity developed (12.2 ± 8.8 mg/dl versus 3.4 ± 3.2 mg/dl, p <0.01). Aminoglycoside nephrotoxicity occurred in eight patients (19 percent): in seven of 15 patients (47 percent) with an initial bilirubin value greater than 5.0 mg/dl, but in only one of 27 patients (4 percent) with an initial bilirubin value below 5.0 mg/dl (p <0.01). The pre-treatment bilirubin level correlated with the change in creatinine during aminoglycoside therapy (n = 42, r = 0.66, p <0.01). Conclusion: Aminoglycosides should probably be avoided in patients with biliary obstruction and a high serum bilirubin level.

Influence of hydrocortisone on gentamicin-induced nephrotoxicity in rats.

Many risk factors associated with aminoglycoside nephrotoxicity have been identified in humans and experimental animals. They include an initial high rate of creatinine clearance, high initial peak levels in serum, age, sex, duration of therapy, liver disease, and renal infection. The concomitant administration of steroids has never been investigated. We evaluated the role of hydrocortisone on gentamicin-induced nephroxicity in a model of infused rats. We showed that hydrocortisone given over 3 days after the infusion did not modify the gentamicin half-life in the renal cortex, gentamicin-induced lysosomal phospholipidosis, or histopathology but did reduce significantly the 3H/DNA ratio on day 4 after gentamicin infusion. We concluded that hydrocortisone interferes with the postnecrotic cellular regeneration process, an important step that is responsible for the recovery of normal kidney structure following toxic injuries associated with aminoglycoside therapy.

Light and electron microscopic characterization of the proliferative response induced by tobramycin in rat kidney cortex

Administration of aminoglycoside antibiotics is frequently associated with tubular necrosis which can eventually lead to renal dysfunction. Previously, we have shown that renal tissue injury due to aminoglycoside nephrotoxicity elicits a process of tissue repair characterized by stimulation of cell proliferation. The present study was undertaken to examine both quantitatively and qualitatively the cell proliferation associated with renal tissue repair. Female Sprague-Dawley rats (180–200 g body weight) were treated ip for 10 days with various doses of tobramycin (10, 20, or 50 mg/kg twice daily). Each animal received 200 μCi [ 3H]thymidine 1 hr before sacrifice to evaluate the extent of cell proliferation in renal cortex. The rate of DNA synthesis in renal cortex was estimated by measuring the specific radio-activity of the nucleic acid. The frequency and localization of S-phase cells in cortex tissue were determined on paraffin and plastic tissue sections processed for histoautoradiography. In addition, the ultrastructure of proliferating cells was characterized by electron microscopic examination of consecutive ultrathin sections. An excellent correlation ( r = 0.993) was found between the rate of DNA synthesis and the frequency of S-phase cells evaluated in rats receiving various doses of tobramycin. The stimulation of cell proliferation involved mostly proximal tubular cells and interstitial cells. The latter cells had the ultrastructural appearance of fibroblasts at various stages of differentiation. Similarly, S-phase cells in proximal tubules were either fully differentiated epithelial cells or immature elements. Taken together, the present experimental data illustrate the capacity of the kidney to trigger complex tissue reactions in response to nephrotoxic injury.

Amylase-creatinine clearance ratio. A simple test to predict gentamicin nephrotoxicity

The initial target of aminoglycoside nephrotoxicity is the proximal tubule. Yet, no simple test is available to predict such toxicity. Taking advantage of the fact that amylase is filtered in the glomerulus and reabsorbed by the proximal tubules, we prospectively examined in 23 patients if changes in renal amylase creatinine clearance ratio (ACCR) can predict gentamicin nephrotoxicity. Eighteen of these patients had an initial creatinine clearance (rCcr) above 30 mL/min. Eleven of them (group A) had an ACCR above 3.5% (control 3% +/- 1.03%) and all exhibited an average reduction of 32.2% +/- 11.6% in rCcr following one week of gentamicin therapy. In contrast, only one of seven patients (group B) with an initial ACCR below 3.5% had a reduction, albeit transient, in rCcr. During gentamicin therapy, group A patients had a further increase in ACCR which was proportional to the reduction observed in rCcr (r = -.54). Our preliminary data suggest that ACCR may prove a simple and possibly a reliable predictor of kidney function deterioration during gentamicin therapy in patients with rCcr above 30 mL/min: patients with pretherapy ACCR above 3.5% may exhibit a deterioration in the creatinine clearance during the first week of therapy. For patients with pretherapy renal failure (rCcr less than 30 mL/min) the creatinine levels (but not the ACCR) seem to retain their significance in predicting and monitoring further renal function deterioration during aminoglycoside therapy.

Amylase—Creatinine Clearance Ratio

• The initial target of aminoglycoside nephrotoxicity is the proximal tubule. Yet, no simple test is available to predict such toxicity. Taking advantage of the fact that amylase is filtered in the glomerulus and reabsorbed by the proximal tubules, we prospectively examined in 23 patients if changes in renal amylase creatinine clearance ratio (ACCR) can predict gentamicin nephrotoxicity. Eighteen of these patients had an initial creatinine clearance (rCcr) above 30 mL/min. Eleven of them (group A) had an ACCR above 3.5% (control 3% ±1.03%) and all exhibited an average reduction of 32.2%±11.6% in rCcr following one week of gentamicin therapy. In contrast, only one of seven patients (group B) with an initial ACCR below 3.5% had a reduction, albeit transient, in rCcr. During gentamicin therapy, group A patients had a further increase in ACCR which was proportional to the reduction observed in rCcr (r= -.54). Our preliminary data suggest that ACCR may prove a simple and possibly a reliable predictor of kidney function deterioration during gentamicin therapy<i>in patients with rCcr above 30 mL/mi</i>n: patients with pretherapy ACCR above 3.5% may exhibit a deterioration in the creatinine clearance during the first week of therapy. For patients with pretherapy renal failure (rCcr&lt;30 mL/min) the creatinine levels (but not the ACCR) seem to retain their significance in predicting and monitoring further renal function deterioration during aminoglycoside therapy. (<i>Arch Intern Med</i>1988;148:1093-1096)

Gentamicin nephrotoxicity in the setting of acute renal hypoperfusion

The purpose of this study is to assess interactions between acute renal hypoperfusion and aminoglycoside nephrotoxicity. One hour of renal hypoperfusion (55-60 mmHg; renal blood flow 1.6 +/- 0.13 ml/min) was created in rats by suprarenal partial aortic constriction. Gentamicin, 120 mg/kg, was given at the start of the hypoperfusion period. Rats that either received gentamicin alone or were subjected to hypoperfusion alone served as controls. Hypoperfusion alone induced mild S3 proximal tubular brush-border membrane blebbing, but it caused no enzymuria, azotemia, or tubular necrosis. Gentamicin alone induced no azotemia or tubular necrosis. However, gentamicin injected during hypoperfusion caused severe azotemia (blood urea nitrogen 94 +/- 16; creatinine 1.74 +/- 0.22 mg/dl) and extensive S3 proximal tubular necrosis without affecting renal perfusion. S1 and S2 tubular segments, the major targets of gentamicin toxicity, showed minimal damage. Hypoperfusion increased renal gentamicin uptake, but matching it in control rats induced no renal damage. In conclusion, gentamicin can precipitate hypoperfusion-induced acute renal failure. This effect appears to be due to an S3 cytotoxic effect, which converts sublethal ischemic S3 tubular injury into overt cell necrosis.

The dissociation between aminoglycoside serum concentrations and nephrotoxicity

Using newborn and adult rats we tested the correlation between aminoglycoside dose, resultant serum and renal cortical concentrations and nephrotoxicity evidenced by creatinine in serum and urine, N-acetylglucosaminidase and β 2 microglobulins in urine and sphingomyelinase in renal cortical tissue. Our data reveal that aminoglycoside nephrotoxicity is clearly more evident in adult rats despite significantly lower drug serum concentrations and in the presence of substantially higher renal cortical concentrations. These data indicate that high aminoglycoside serum concentrations are not causing nephrotoxicity but rather reflect secondary body accumulation of the drug associated with renal damage.

Aminoglycoside nephrotoxicity and urinary excretion of N-acetyl-beta-D-glucosaminidase.

The purpose of this paper is to discuss briefly the mechanism of aminoglycosides nephrotoxicity. This kind of antibiotic seems to act preferentially on the phospholipid metabolism of the proximal tubular cell. A lysosomal enzyme, N-acetyl-beta-D-glucosaminidase, could be of interest in assessing this renal interference.