Cidofovir-induced end-stage renal failure
Pascal Meier,
Sandrine Dautheville-Guibal,
Pierre M. Ronco and
Jérôme Rossert
Service of Nephrology B, Hôpital Tenon (AP-HP), Paris, France
Keywords: cidofovir; Fanconi syndrome; end-stage renal failure; AIDS; nephrotoxicity
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Introduction
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Cidofovir ((S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine) is an antiviral nucleotide analogue with significant activity against almost all types of DNA viruses [1]. It has been approved for treatment of cytomegalovirus (CMV) retinitis and for infections by other herpes viruses, in patients with acquired immunodeficiency syndrome (AIDS) [2,3]. We report the second case of cidofovir-induced acute renal failure that led to end-stage renal failure (ESRF) in a few months.
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Case
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A 34-year-old man with AIDS was admitted to our nephrology unit in December 1999 because of non-oliguric acute renal failure after cidofovir administration. The patient had a long history of HIV-positive disease, and he had developed AIDS in 1992. From 1992 to 1999, his medical history included oropharyngeal candidosis bouts, herpes genitalis, and resistant cutaneous Kaposi's sarcoma. Since 1990 many anti-retroviral treatments had been introduced, including highly active anti-retroviral therapies (HAART), with few effects on CD4+ cell counts and HIV RNA load. Since March 1999, HAART consisted of a combination of amphonavir, abacavir and lamivudine. The patient was also treated with trimethoprim-sulfamethoxazole (80/400 mg/qd), rifabutine (150 mg/qd) and oral ganciclovir (250 mg/bid). Cidofovir treatment was introduced in March 1999 in order to be active against human herpes virus-8 (HHV-8) and against resistant HIV (K103N mutation), and to prevent CMV retinitis. It was administered intravenously at a dose of 5 mg/kg once every 2 weeks, and each injection was associated with administration of 2 l of i.v. normal saline. Four grams of probenecid were also given during cidofovir injections, in March and April 1999, but this drug was then stopped because of severe erythrodermia. Between March and November 1999, serum creatinine was 8085 µmol/l (i.e. glomerular filtration rate estimated according to the Cockcroft and Gault formula was 8287 ml/min) and urinary dipstick analysis was negative for proteins, but glycosuria appeared in May 1999.
On 20 November 1999, 2 weeks after the last injection of cidofovir, serum creatinine was 155 µmol/l despite the absence of any concomitant event or treatment modification. This led us to discontinue administration of cidofovir. Nevertheless, serum creatinine continued to rise in a symptom-free patient, and 2 weeks later it was 266 µmol/l. At the end of December, the patient experienced a transient episode of nausea and vomiting, which led to a new measurement of serum creatinine, which showed that it was 368 µmol/l. On admis sion, 1 week later, blood pressure was 100/60 mmHg, serum creatinine was 426 µmol/l, proteinuria was 2.5 g/d (with 57% of albumin), and urinary sediment was bland with one red cell/mm3, one white cell/mm3, no cast and no crystal. The daily urine output was more than 1 l. Renal ultrasound examination was normal, but this test is known to have a low predictive value. Proximal tubular functions were impaired, with decreased maximal transport of bicarbonate (19 mmol/l of glomerular filtrate), impaired glucose reabsorption (glycosuria despite normal fasting glycaemia) and decreased maximal transport of phosphate (0.3 mmol/l of glomerular filtrate). Renal biopsy showed extensive necrosis of proximal tubular epithelial cells associated with diffuse interstitial fibrosis and with interstitial oedema. There was almost no interstitial infiltrate by inflammatory cells. There were no glomerular or vascular lesions. The evolution was marked by rapidly progressive deterioration of renal function, and chronic haemodialysis was started 3 months after the last injection of cidofovir.
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Discussion
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In this case, cidofovir is very likely to have been responsible for ESRF. There was a close temporal relationship between the onset of renal failure and cidofovir administration. Renal biopsy showed severe tubular lesions, which are reminiscent of histological lesions described in animals receiving high doses of cidofovir [4] and also in some case reports [5,6]. The patient presented signs of proximal tubular cell dysfunction, which correspond to the spectrum of adverse effects reported with cidofovir [6]. Besides cidofovir, the patient had been taking trimethoprim-sulfamethoxazole and rifabutine, but these drugs have been implicated only in acute interstitial nephritis, a diagnosis that was ruled out by the renal biopsy. Similarly, the biopsy showed no sign of HIV- or CMV-associated nephropathy or of thrombotic microangiopathy. Proteinuria and increased serum creatinine levels have been reported in 24% and 12%, respectively, of patients treated with cidofovir [7]. Nevertheless, in all but one reported case, renal failure was mild and at least partially reversible after cidofovir withdrawal [8].
This case report points out that the spectrum of cidofovir side effects also includes rapidly progressive renal insufficiency leading to ESRF. Factors predisposing to potential irreversible renal damage in patients treated with cidofovir, include high doses (>5 mg/kg), impaired renal function, concomitant administration of nephrotoxic drugs, and dehydration [3]. The use of probenecid protects against renal damage by decreasing cidofovir accumulation in proximal tubular cells. In this case report, probenecid co-administration was limited to the first two doses, which may have favoured cidofovir nephrotoxicity. Furthermore, vomiting may have been responsible for dehydration and have favoured the occurrence of acute tubular damage. Nevertheless, the occurrence of cidofovir-induced chronic interstitial nephritis may also be dependent on individual factors that are still unknown. Other drugs such as five amino-salicylic acid derivatives have been shown to induce chronic interstitial nephritis in few individuals, even in the absence of identified predisposing factor [9].
Retrospective analysis of the patient's file showed that glycosuria was present 7 months before admission, while serum creatinine was still normal (82 µmol/l). This suggests that patients with cidofovir-induced proximal tubular dysfunction may be at risk of developing a sudden and irreversible renal failure and that, in these patients, discontinuing administration of the drug should be considered. This also points out the usefulness of monitoring early markers of tubular damage, such as of urinary excretion
-1 microglobulin or retinol-binding protein, which may be more sensitive than glycosuria.
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Notes
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Correspondence and offprint requests to: Pascal Meier, Service of Nephrology B, Hôpital Tenon, 4 Rue de la Chine, F-75020 Paris, France. Email: meierpascal{at}usa.net 
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References
|
---|
-
Hitchcock MJM, Jaffe JS, Martin JC, Stagg RJ. Cidofovir, a new agent with potent anti-herpesvirus activity. Antiviral Chem Chemother1996; 7: 115127[ISI]
-
Lalezari JP. Cidofovir: a new therapy for cytomegalovirus retinitis. J Acquir Immune Defic Syndr Hum Retrovirol1997; 14 [Suppl 1]: S22S26
-
Safrin S, Cherrington J, Jaffe HS. Cidofovir. Review of current and potential clinical uses. Adv Exp Med Biol1999; 458: 111120[ISI][Medline]
-
Lalezari JP, Stagg RJ, Jaffe HS, Hitchcock MJ, Drew WL. A preclinical and clinical overview of the nucleotide-based antiviral agent cidofovir (HPMPC). Adv Exp Med Biol1996; 394: 105115[Medline]
-
Vandercam B, Moreau M, Goffin E, Marot JC, Cosyns JP, Jadoul M. Cidofovir-induced end-stage renal failure. Clin Infect Dis1999; 29: 948949[ISI][Medline]
-
Vittecoq D, Dumitrescu L, Beaufils H, Deray G. Fanconi syndrome associated with cidofovir therapy. Antimicrob Agents Chemother1997; 41: 1846[Free Full Text]
-
Lalezari JP, Stagg RJ, Kuppermann BD et al. Intravenous cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS. A randomized, controlled trial. Ann Intern Med1997; 126: 257263[Abstract/Free Full Text]
-
Lalezari JP, Holland GN, Kramer F et al. Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS. J Acquir Immune Defic Syndr Hum Retrovirol1998; 17: 339344[Medline]
-
Rocha GM, Michea LF, Peters EM et al. Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells. Proc Natl Acad Sci USA2001; 98: 53175322[Abstract/Free Full Text]
Received for publication: 26. 3.01
Accepted in revised form: 9. 7.01