Risk factors for amphotericin B- induced nephrotoxicity

Andrew D. Luber, Lucy Maa, Minh Lam and B. Joseph Guglielmo*

University of California, San Francisco, Department of Clinical Pharmacy/School of Pharmacy, 521 Parnassus Avenue, Room C-152, San Francisco, CA 94143-0622, USA


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The association of amphotericin B with nephrotoxicity is well known, but risk factors for this complication are not well characterized. One hundred and seventy-eight patients who received >3 days of intravenous amphotericin B and a minimal total cumulative dose >100 mg were reviewed retrospectively. The mean age, average cumulative dose of amphotericin B and duration of therapy were 46 ± 22 years, 536 ± 547 mg and 16.6 ± 8.2 days, respectively. Eighty-six percent of patients received amphotericin B for empirical therapy of febrile neutropenia. Various definitions of nephrotoxicity were used; these were as follows (the incidence of nephrotoxicity as determined by the given definition is given in parentheses): definition 1, a change in creatinine of >46 µmol/L over baseline (50%); definition 2, a doubling of creatinine over baseline (49%); definition 3, a change in creatinine of >92 µmol/L (29%); definition 4, a doubling and/or a change in creatinine of >92 µmol/L (49%); definition 5, an increase in creatinine to >230 µmol/L (8%). Multivariate analysis showed that nephrotoxicity was associated with a greater cumulative dose of amphotericin B and receipt of concomitant nephrotoxic drugs for all definitions (P < 0.05). In those patients who experienced severe nephrotoxicity (creatinine increased to >230 µmol/L), cyclosporin therapy was the most significant risk factor (odds ratio 18.8, P= 0.022). Haemodialysis was necessary in one patient, but multiple concomitant risk factors for renal dysfunction were present. No patient experienced irreversible nephrotoxicity. These findings allow for stratification of patients at risk for amphotericin B-induced nephrotoxicity and rational use of alternative agents.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Amphotericin B is considered the drug of choice for many fungal infections. Despite its broad spectrum of activity and wide clinical use, there is often drug-induced nephrotoxicity. Up to 80% of patients receiving amphotericin B will experience an episode of altered renal function during treatment. 1,2,3,4 However, varying definitions, differing patient populations and concomitant administration of other medications complicate the identification of risk factors. 1,2,3,4,5 Identification of risk factors for amphotericin B toxicity would optimize the use of this antifungal agent. The purpose of this study was to identify the incidence and risk factors for amphotericin B-induced nephrotoxicity.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study was approved by the Committee on Human Research at the University of California, San Francisco. All patients at the Medical Center treated with amphotericin B between 1 July 1995 and 31 December 1996 were identified via pharmacy computer records. Patients were excluded if they received <3 days of therapy, a total cumulative dose <100 mg, had a calculated creatinine clearance <10 mL/min at initiation of therapy or received inadequate follow-up (defined as 2 months following completion of amphotericin B therapy).

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 {chi}2 or Fisher's exact test. Logistic regression analysis and likelihood ratio {chi}2 testing were performed to determine multivariate risk factors.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
A total of 178 patients met the inclusion criteria. Baseline demographic data are listed in Table I. Using the definitions of nephrotoxicity given in Materials and methods, the following incidences were observed: definition 1, 50%; definition 2, 49%; definition 3, 29%; definition 4, 49%; definition 5, 8%. The mean increase in creatinine from baseline was 65 ± 83 µmol/L, occurring 12.1 ± 8.4 days into therapy.


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Table I. Patient demographics (n = 178)
 
Severe renal insufficiency was rare, occurring in 8% of patients. These patients were noted to have higher baseline creatinine values (83 ± 64 µmol/L), received larger cumulative doses of amphotericin B (1430 ± 1364 mg) and had a longer duration of therapy (23.9 ± 15.2 days) than patients with mild to moderate toxicity.

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 2–69 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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Table II. Risk factors for amphotericin B-induced nephrotoxicitya
 
In no instance did irreversible nephrotoxicity occur; however, one patient required haemodialysis. This 74 year old patient received amphotericin B for invasive pulmonary aspergillosis and required long-term intensive care therapy. The hospital course was complicated by Pseudomonas aeruginosa and Staphylococcus epidermidis bacteraemias and associated hypotension, arrhythmias and hypovolaemia. The nephrology consult concluded that the renal dysfunction was due to acute tubular necrosis secondary to haemodynamic instability, embolic event and/or the administration of amphotericin B. The patient died 40 days after initiation of amphotericin B therapy.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this analysis of amphotericin B-induced nephrotoxicity, the incidence of mild to moderate nephrotoxicity (definitions 1–4) was common (50%), but the rate of severe toxicity (definition 5) was low (8%). The severe nephrotoxicity was reversible and was rarely associated with dialysis. The one patient requiring haemodialysis had numerous other risk factors for renal dysfunction. Previous studies have suggested that the incidence of amphotericin B-induced nephrotoxicity may be as high as 80%. 1,2,3,4 Our results, as well as those of others, 5 suggest that this risk may be substantially lower. One of our findings documented that the primary indication for amphotericin B was febrile neutropenia. Considering that febrile neutropenic patients tend to be younger than most hospitalized patients, the incidence may be lower than that expected for older patients.

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.


    Acknowledgments
 
This study was presented in part at the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, 28 September-1 October 1997 (Abstract A93). This study was funded through an unrestricted educational grant from the Liposome Company.


    Notes
 
* Corresponding author. Tel: +1-415-476-1927; Fax: +1-415-476-6632; E-mail: bjg{at}itsa.ucsf.edu Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Butler, W. T., Bennett, J. E., Alling, D. W., Wertlake, P. T., Utz, J. P. & Hill, G. J. (1964). Nephrotoxicity of amphotericin B: early and late effects in 81 patients. Annals of Internal Medicine 61, 175–87.[ISI]

2 . Pathak, A., Pien, F. D. & Carvalho, L. (1998). Amphotericin B use in a community hospital, with special emphasis on side effects. Clinical Infectious Diseases 26,334 –8.[ISI][Medline]

3 . Larsen, R. A., Leal, M. E. & Chan, L. S. (1990). Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. Annals of Internal Medicine 113, 183–7.[ISI][Medline]

4 . Clements, J. S. & Peacock, J. E. (1990). Amphotericin B revisited: reassessment of toxicity. American Journal of Medicine 88 , Suppl. 5N , 22N–7N.[Medline]

5 . Stein, R. S., Albridge, K., Lenox, R. K., Ray, W. & Flexner, J. M. (1988). Nephrotoxicity in leukemic patients receiving empirical amphotericin B and aminoglycosides. Southern Medical Journal 81, 1095–9.[ISI][Medline]

6 . White, M. H., Anaissie, E. J., Kusne, S., Wingard, J. R., Hiemenz, J. W., Cantor, A. et al. (1997). Amphotericin B colloidal dispersion vs amphotericin B as therapy for invasive aspergillosis. Clinical Infectious Diseases 24, 635–42.[ISI][Medline]

7 . McCormack, J. P. & Jewesson, P. J. (1992). A critical reevaluation of the `therapeutic range' of aminoglycosides. Clinical Infectious Diseases 14,320 –9.[ISI][Medline]

8 . Gallis, H. A., Drew, R. H. & Pickard, W. W. (1990). Amphotericin B: 30 years of clinical experience. Review of Infectious Diseases 12, 308–29.[ISI][Medline]

9 . Sabra, R. & Branch, R. A. (1990). Amphotericin B nephrotoxicity. Drug Safety 5, 94–108.[ISI][Medline]

Received 23 March 1998; returned 3 August 1998; revised 26 August 1998; accepted 17 September 1998





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