Persistent acute tubular toxicity after switch from conventional amphotericin B to liposomal amphotericin B (Ambisome)

Edouard Gerbaud1, Fabienne Tamion1,*, Christophe Girault1, Karine Clabault1, Stephane Lepretre2, Jacques Leroy1 and Guy Bonmarchand1

1 Medical Intensive Care Unit and 2 Department of Haematology, Charles Nicolle University Hospital, Rouen 76031, France

Keywords: amphotericin B, nephrotoxicity, antifungal therapy

Sir,

Invasive fungal infections are a major cause of morbidity and mortality in neutropenic patients. The diagnosis is often difficult, thus patients with persistent fever and neutropenia frequently receive empirical antifungal therapy. Unfortunately, empirical treatment with amphotericin B may be limited by dose-dependent nephrotoxicity.1 The lipid formulations of amphotericin B, such as liposomal amphotericin B (Ambisome) and amphotericin B in a lipid complex (ABLC; Abelcet) have been developed in attempts to improve tolerability.1

We report a case of amphotericin B-related renal toxicity suspected to be sustained after switch to liposomal amphotericin B. A 30-year-old man with acute monoblastic leukaemia (AML5) was referred to the haematology department in August 2000. AML5 relapse was diagnosed in December 2001 requiring a new chemotherapy. Empirical antimicrobial therapy combining cefepime (2 g), netilmicin (5 mg/kg) and amphotericin B (1 mg/kg) was initiated due to persistent fever with severe watery diarrhoea. Despite rehydration, the patient became confused. He was transferred to our medical Intensive Care Unit (ICU) for coma and severe metabolic disorders. On admission, clinical examination showed coma (Glasgow Coma Score 7), fever (40°C), tachypnoea (35 breaths/min) and tachycardia (150 beats/min) with normal systolic arterial blood pressure (100 mmHg). There was no evidence of extracellular dehydration. A computerized tomographic cerebral scan and electroencephalogram were normal. Baseline biological data found severe neutropenia, acute renal failure, metabolic acidosis (pHa 7.25; base excess 15.1 mmol/L; CO2 arterial pressure 37 mmHg) and normal anion gap (12 mequiv./L). We observed hypernatraemia (166 mmol/L) and hypokalaemia (3.4 mmol/L). Diuresis sharply increased (5000 mL/day) with low natriuresis (6 mmol/24 h) and increased kaliuresis (64 mmol/24 h). Plasma and urine osmolality was altered (358 and 434 mosm/L, respectively). The clinical presentation was attributed to metabolic disorders with high variations in natraemia before ICU admission (135–166 mmol/L on two consecutive days). This disorder could be dependent on diarrhoeic enteritis, fever and insufficient hydration, and aggravated by amphotericin B. The renal toxicity consisted of mild acute renal failure, nephrogenic diabetes insipidus documented by high serum anti-diuretic hormone (ADH) level (17.9 ng/L), polyuria, negative desmopressin test and type 1 renal tubular acidosis (urinary pH > 5.5 with base excess <15 mmol/L, normal anion gap, hypokalaemia 3.4 mmol/L). We stopped amphotericin B for liposomal amphotericin B (3 mg/kg). Nephrogenic diabetes insipidus and distal tubulopathy persisted despite the switch to liposomal amphotericin B (Figure 1). We therefore stopped liposomal amphotericin B administration 1 week later. Five days following liposomal amphotericin B discontinuation an improvement in renal function, metabolic acidosis and kalaemia was observed. The serum ADH level then rapidly decreased and polyuria resolved with concomitant normalization of natraemia (Figure 1). The patient was referred to the haematology department with no neurological sequelae.



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Figure 1. Time course of natraemia, base excess and serum ADH in the patient. L-amB, liposomal amphotericin B.

 
Amphotericin B has been used extensively in clinical practice for more than 40 years and remains the most widely used drug for the treatment of serious fungal infections. Nephrotoxic manifestations are common, and this is the major factor limiting the clinical use of this drug. Amphotericin B alters cell membrane permeability and consequently alters tubular and vascular smooth muscle cell function, leading to various tubular transport defects and vasoconstriction.2,3 Lipid formulations of amphotericin B have been developed to improve both efficacy and tolerability. Liposomal amphotericin B may provide a protective effect based on altering the affinity of amphotericin B for mammalian cell membranes while preserving high efficacy against fungal cells.2 This preservation of glomerular function by lipid formulations of amphotericin B is related to several possible mechanisms.4 Mammalian cytotoxicity is reduced by complexing amphotericin B to a mixture of phospholipids. This alters the affinity of amphotericin B and decreases its selective transfer from the complex to cholesterol-containing mammalian cells. To our knowledge, this is the first reported observation involving nephrogenic diabetes insipidus and distal type 1 tubulopathy with liposomal amphotericin B administration. However, nephrotoxicity may be observed with liposomal amphotericin B.3 This renal toxicity appears to be similar whatever the liposomal amphotericin B dose (3 or 5 mg/kg/day) used, and remains lower than conventional amphotericin B regardless of the number of concomitant nephrotoxic drugs used.3,5 A higher frequency of hypokalaemia in patients receiving higher dosages of liposomal amphotericin B (12.5 or 15 mg/kg) than in those receiving lower dosages (7.5 or 10 mg/kg) has been demonstrated.6 These findings suggest that tubular cell function may be more sensitive to high dosages of liposomal amphotericin B than glomerular cell function. Tubular nephrotoxicity observed in our patient could be related to the total accumulation of amphotericin B in tubular cells. Although a delayed renal toxicity of amphotericin B was not formally excluded, the clinical and biological improvement 5 days after liposomal amphotericin B discontinuation support this role in persistent renal toxicity. This report suggests that caution should be exercised in the use of liposomal amphotericin B in patients who have developed tubular abnormalities with amphotericin B.1,7 Recently licensed antifungal agents, such as voriconazole or caspofungin, could be suitable alternatives to standard antifungal therapies and useful in this complex clinical situation.

Acknowledgements

We thank Richard Medeiros for his valuable advice in editing the manuscript.

Footnotes

* Corresponding author. Tel: +33-232-888-261; Fax: +33-232-888-314; E-mail: Fabienne.Tamion{at}chu-rouen.fr Back

References

1 . Deray, G. (2002). Amphotericin B nephrotoxicity. Journal of Antimicrobial Chemotherapy 49, 37–41.[Abstract/Free Full Text]

2 . Sawaya, B. P., Briggs, J. P. & Schnermann, J. (1995). Amphotericin B nephrotoxicity: the adverse consequences of altered membrane properties. Journal of the American Society of Nephrology 6, 154–64.[Abstract]

3 . Wingard, J. R., White, M. H., Anaissie, E., Affali, J., Goodman, J., Arrieta, A. et al. (2000). A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clinical Infectious Diseases 31, 1155–63.[CrossRef][ISI][Medline]

4 . Luke, R. G. & Boyle, J. A. (1998). Renal effects of amphotericin B lipid complex. American Journal of Kidney Diseases 31, 780–5.[ISI][Medline]

5 . Walsh, T. J., Finberg, R. W., Arndt, C., Hiemenz, J., Schwartz, C., Bodensteiner, D. et al. (1999). Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. New England Journal of Medicine 340, 764–71.[Abstract/Free Full Text]

6 . Walsh, T. J., Goodman, J., Pappas, P., Bekersky, I., Buell, D. N., Roden, M. et al. (2001). Safety, tolerance and pharmacokinetics of high dose liposomal amphotericin B (Ambisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrobial Agents and Chemotherapy 45, 3487–96.[Abstract/Free Full Text]

7 . Boswell, G. W., Buell, P. D. & Bekersky, I. (1998). Ambisome (liposomal amphotericin B): a comparative review. Journal of Clinical Pharmacology 38, 583–92.[Abstract/Free Full Text]