This study found no evidence of renal toxicity that was attributable to the solubilizing agent, sulfobutylether-β-cyclodextrin (SBECD), in patients with impaired renal function (Clcr
50 mL/min) who were treated with an intravenous antifungal agent in clinical practice. The maximal increase in Scr
levels was less and calculated nadir Clcr
was higher for the SBECD-containing voriconazole group than those of fluconazole and caspofungin groups that did not contain SBECD. Importantly, SBECD was not associated with increased renal dysfunction during or at the end of therapy.
Voriconazole, a second-generation triazole, is a steric inhibitor of fungal cytochrome P450-dependent 14α-sterol demethylase, which is essential for the conversion of lanosterol to ergosterol required for building the cell membranes of fungal organisms [13
]. Like other triazoles, voriconazole has activity for this enzyme for both yeast and moulds, whereas fluconazole, the backbone structure of voriconazole, is only active against yeast. The early development plan for voriconazole incorporated the medical need for an intravenous formulation [written communication, Chris Hitchcock, PhD, Pfizer Inc]. Since voriconazole has a low aqueous solubility (0.7 mg/mL) [14
], its intravenous formulation includes SBECD as a solubilizing agent.
Naturally occurring cyclodextrins, notably α- and β-cyclodextrins, are reabsorbed and concentrated in the renal tubule, resulting in acute kidney injury at clinically-translatable doses in animal models [9
]. SBECD is a rationally-designed cyclodextrin which does not undergo significant tubular reabsorption, thus it was formulated to prevent injury to renal tubular cells. Animal studies with SBECD have not shown discrete changes in renal morphology at doses used clinically [11
]; moreover, SBECD is not nephrotoxic in these models when given at dose equivalents of naturally occurring cyclodextrins that are associated with nephrotoxicity and/or hepatotoxicity. However, at the time of FDA approval, a lack of information regarding the safety of SBECD in patients with impaired renal function led to warnings against the use of SBECD in patients with Clcr
50 mL/min for products including intravenous voriconazole [12
]. This study is important to clinicians because it provides evidence that SBECD-containing medications can be used to treat patients with serious fungal infections including those with impaired renal function without increased risk of nephrotoxicity.
Our main finding that treatment of a serious fungal infection for patients with impaired renal function with SBECD-containing voriconazole is not associated with worse renal outcomes than treatment with a non-SBECD containing alternative antifungal is consistent with recent smaller studies. A retrospective analysis of the Candida
Phase 3 trial database for nephrotoxic effects of intravenous voriconazole containing SBECD did not detect renal toxicity from voriconazole in contrast to the renal dysfunction associated with amphotericin B [10
]. Despite accumulation of SBECD in the plasma of patients with compromised renal function [16
], its lack of reabsorption in renal epithelial cells appears to prevent deleterious effects on renal function in this and other clinical reports [19
Targeting high risk patients may have increased the ability of our study of modest size to detect differences among agents with regard to renal toxicity. The association of fluconazole with worse renal function during therapy is consistent with its labeling: “In some patients, particularly those with serious underlying diseases such as AIDS and cancer, changes in renal and hematological function test results and hepatic abnormalities have been observed during treatment with fluconazole and comparative agents, but the clinical significance and relationship to treatment is uncertain [22
].” Our findings do not identify fluconazole as a direct nephrotoxin, rather they imply that the underlying disease state of which fluconazole is treating influences renal function. This is consistent with our identification of the organism as a significant predictor of renal outcome. The association was driven by worse renal function among those with systemic fungal infections, many of whom were treated with fluconazole for sensitive isolates of Candida albicans
. It is important to note that all cases of renal impairment were classified as mild-to-moderate according to the RIFLE criteria [23
]. We did not find evidence for other possible mechanisms of renal toxicity such as obstructive hydronephrosis [24
] or microangiopathy such as that which occurs with hemolytic uremic syndrome [32
This study has important limitations that should be taken into account when interpreting the data. It is a nonrandomized observational study of clinical practice at an academic medical center with policies that mandate the involvement of infectious disease experts for cases involving the administration of intravenous antifungals for nearly all patients. This leads to differences among the groups that are due to non-random factors that may be important. On the other hand, this approach may be more informative about the effects in clinical practice because cases are not excluded. We attempted to review patient cases with compromised renal function treated with amphotericin B but, despite our large database, we could not find a sufficient number of patients meeting this criteria. Similarly, the number of patients with compromised renal function treated with intravenous voriconazole is low and likely related to labeling that raises concerns about renal toxicity in this group.
Mortality was higher in the voriconazole group compared with the other two groups, likely as a result of the severity of the underlying fungal disease. A greater percentage of patients in the voriconazole group was infected with Aspergillus spp. A higher mortality rate is expected in this group because infection with Aspergillus spp. has been associated with higher mortality rates compared to yeast infections. In addition, a greater percentage of patients in the voriconazole group were treated with voriconazole prophylactically as part of a treatment plan for poor prognosis malignancies including acute myelogenous leukemia (AML). Importantly, differences among the indications for antifungal treatment did not appear to alter the validity of the association of the infecting organism that was isolated with the development of renal dysfunction. Nonetheless, there was a limited number of Candida and Aspergillus isolates identified in this study such that associations between the subspecies of yeast or mould with more severe renal disease could not be definitive.
Another limitation of this study is the lack of dosing information or therapeutic drug monitoring. At the time of data collection, there was no harmonization between pharmacy and medical records. However, there are defined guidelines for the dosing of the three IV antifungals established by the Food and Drug Administration which were reviewed by a UMass clinical pharmacist. Antifungal agent levels were not measured as part of this study and are not recommended by current therapeutic guidelines. The effects of SBECD on renal function that we observed do not suggest that measuring drug levels to prevent renal toxicity would be justified.