University of California, San Francisco, Department of Clinical Pharmacy/School of Pharmacy, 521 Parnassus Avenue, Room C-152, San Francisco, CA 94143-0622, USA
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Abstract |
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Introduction |
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Materials and methods |
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The following information was obtained: age, weight, primary medical service, clinical indication, culture data (where applicable), daily serum creatinine measurements, concomitant disease states, hospital location (e.g. intensive care unit (ICU) or non-ICU), day of amphotericin B therapy and concomitant nephrotoxins. Potential nephrotoxins included acyclovir, aminoglycosides, carboplatin, cisplatin, cyclosporin, foscarnet, frusemide, non-steroidal anti-inflammatory agents, radio-contrast dye, rifampicin, intravenous co-trimoxazole, tacrolimus and vancomycin.
Various definitions of nephrotoxicity were used, as follows.2,4,6,7 Definition 1: an increase in serum creatinine of >46 µmol/L from baseline; definition 2: a doubling of serum creatinine over the baseline; definition 3: an increase in serum creatinine of >92 µmol/L from baseline; definition 4: a doubling in serum creatinine over the baseline and/or an increase in serum creatinine >92 µmol/L from baseline; and definition 5: an increase in creatinine to >230 µmol/L. Nephrotoxicity that met any of definitions 1-4 was considered mild to moderate, whereas definition 5 was considered severe. Peak creatinine levels were defined as the maximum creatinine value during the study evaluation period. In those cases in which nephrotoxicity occurred, patients were followed for an additional 2 months to determine whether their nephroptoxicity was reversible (defined as a serum creatinine value returning to within 20% of baseline value).
All data were entered into a computer spreadsheet. Univariate analysis of the possible risk
factors was performed using 2 or Fisher's exact test. Logistic
regression analysis and likelihood ratio
2 testing were performed to
determine multivariate risk factors.
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Results |
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The time taken to reach peak creatinine levels did not differ significantly between groups, although in patients with severe renal insufficiency these times were longer than for other groups (mean 21.5 ± 8.4 days; range 269 days). In addition, no clear trends were observed in time to rise in creatinine levels with some patients experiencing a change within the first few days of therapy, whereas in others it took place much later in the course of therapy.
Univariate analysis consistently demonstrated that nephrotoxicity was associated with a greater cumulative dose, longer duration of therapy, and greater mean number of concomitant nephrotoxins for all definitions (Table II). Underlying disease states, including diabetes and hypertension, were not found to be risk factors. Multivariate analysis (Table II) identified increased cumulative doses of amphotericin B and greater mean number of concomitant nephrotoxic agents as risk factors for nephrotoxicity for most definitions. In those patients in whom creatinine values increased to >230 µmol/L, concomitant therapy with cyclosporin was the most significant risk factor associated with amphotericin B-induced nephrotoxicity (odds ratio 18.8; P= 0.022). The combined effect of increased cumulative amphotericin B dose, concurrent number of nephrotoxins and concomitant cyclosporin therapy did not further increase the risk for toxicity over that observed with cyclosporin alone.
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Discussion |
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When severe nephrotoxicity occurred, it was usually associated with multiple other risk factors such as increased cumulative dose of amphotericin B or a greater number of concomitant nephrotoxic agents. In particular, those patients receiving concomitant cyclosporin therapy were at greatest risk. While increased cumulative dose was a significant risk factor, the time to onset of severe renal dysfunction varied substantially among patients. In some instances, the rise in creatinine occurred during the first few days of therapy, whereas in others, it took place much later. This finding may reflect the two distinct mechanisms of nephrotoxicity associated with amphotericin B, namely an early acute vasoconstriction and a later acute tubular effect. 8,9
In conclusion, our results demonstrate that amphotericin B-induced mild to moderate nephrotoxicity was common, with an overall incidence of 50%. Severe nephrotoxicity, however, was uncommon and reversible in our patient population. As a result, amphotericin B can safely be administered in most febrile neutropenic patients. Risk factors for the development of severe nephrotoxicity include an increased cumulative dose of amphotericin B and concomitant number of nephrotoxins (especially cyclosporin). These findings will aid in the identification of those patients at risk for this complication. Patients at risk for severe amphotericin B-induced nephrotoxicity should be considered candidates for the early administration of alternative antifungal therapy.
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Acknowledgments |
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Notes |
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References |
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Received 23 March 1998; returned 3 August 1998; revised 26 August 1998; accepted 17 September 1998