Antifungal agents and the kidney: pharmacokinetics, clinical nephrotoxicity, and interactions

ABSTRACT

Introduction

Invasive fungal infections continue to be important causes of morbidity and mortality in severely ill and immunocompromised patient populations. The past three decades have seen a considerable expansion in antifungal drug research, resulting in the clinical development of different classes of antifungal agents with different pharmacologic properties. Among drug-specific characteristics of antifungal agents, renal disposition and nephrotoxicity are important clinical considerations as many patients requiring antifungal therapy have compromised organ functions or are receiving other potentially nephrotoxic medications.

Areas covered

The present article reviews incidence, severity and mechanisms of nephrotoxicity associated with antifungal agents used for prevention and treatment of invasive fungal diseases by discussing distribution, metabolism, elimination and drug-related adverse events in the context of safety data from phase II and III clinical studies.

Expert opinion

Based on the available data amphotericin B deoxycholate has the highest relative potential for nephrotoxicity, followed by the lipid formulations of amphotericin B, and, to a much lesser extent and by indirect mechanisms, the antifungal triazoles.

KEYWORDS:

• Amphotericin
• anidulafungin
• caspofungin
• fluconazole
• isavuconazole
• itraconazole
• micafungin
• nephrotoxicity
• posaconazole
• voriconazole

Article highlights

• Invasive fungal infections are important causes of morbidity and mortality in immunocompromised and severely ill patients

• The introduction of new antifungal agents and their incorporation into modern algorithms for prevention and management have led to substantial improvements in patient outcome

• Among drug-specific organ toxicities, nephrotoxicity has been reported mostly for amphotericin B in its various formulations

• Based on the available data, amphotericin B deoxycholate has the highest relative potential for nephrotoxicity, followed by the lipid formulations of amphotericin B, and, to a much lesser extent and by indirect mechanisms, the antifungal triazoles.

• In patients with preexisting renal impairment and those at risk of developing impaired renal function, pharmacokinetic properties, and the potential for nephrotoxicity are important considerations when selecting the appropriate agent for antifungal treatment and prophylaxis

This box summarizes key points contained in the article.

Declaration of interest

AH Groll has received grants from Gilead, Merck, Sharp & Dohme, Pfizer and Schering-Plough; is a consultant to Astellas, Basilea, Gilead, Merck, Sharp & Dohme, and Schering-Plough, and served at the speakers’ bureau of Astellas, Basilea, Gilead, Merck, Sharp & Dohme, Pfizer, Schering-Plough and Zeneus/Cephalon. A Tragiannidis has received grants from Merck, Sharp & Dohme, Gilead, GSK, and Sanofi Pasteur; is a consultant to Pfizer and served at the speakers’ bureau of Gilead, Merck, Sharp & Dohme. Apart from those disclosed, the authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.