Dear Editor,
Tragiannidis et al. has published an article titled ‘Antifungal agents and the kidney: pharmacokinetics, clinical nephrotoxicity, and interactions’ in 2021 [Citation1], but we found his reviews about voriconazole and renal function has some limitations. Therefore, we aimed to complete it with a short review of the relevant literature.
In the review, Tragiannidis et al. considered that sulphobutylether-β-cyclodextrin (SBECD) is eliminated by glomerular filtration and may accumulate in kidney cells [Citation1]. However, recent studies have shown that SBECD does not accumulate in renal epithelial cells and therefore does not lead to deterioration of renal function [Citation2–6]. There was no association between SBECD exposure and deterioration of renal function in patients with impaired renal function [Citation5–9]. Although SBECD accumulates in the plasma of patients with impaired renal function [Citation6,Citation10–13], it is not reabsorbed in renal epithelial cells and thus has little harmful effect on renal function [Citation7,Citation9]. Intravenous SBECD induced renal tubule vacuolation is dose-dependent in animal models, but SBECD-induced tubular vacuoles were not associated with changes in renal function and were reversible after discontinuation of treatment [Citation2]. Alvarez-Lerma et al. also confirmed that there was no related toxicity of SBECD accumulation in patients with severe renal impairment (Initial serum creatinine concentration >2.5 mg/dL) [Citation8]. Using intravenous voriconazole in critically ill patients with impaired renal function was not associated with renal deterioration or an increase in ICU mortality. However, it is still recommended that the serum creatinine level should be monitored in patients with renal impairment when using multiple doses of voriconazole containing SBECD [Citation2].
Current studies suggest that intravenous voriconazole formulated with SBECD is relatively safe in patients with renal insufficiency. Kim et al. showed that intravenous voriconazole containing SBECD applied in renal injured patients (CrCl <50 mL/min) was tolerable and safe and would not lead to significant deterioration of renal function [Citation3]. Although voriconazole trough concentration was significantly higher in the renal injury group (5.84 mg/L) than in the control group (2.28 mg/L), there were no significant differences in the proportion of patients within the target therapeutic concentration range and the incidence of adverse reactions between the two groups (P = 0.658; P = 0.355) [Citation3]. There was also no significant deterioration of renal function in patients with renal injury treated with intravenous voriconazole. This study showed that intravenous voriconazole containing SBECD did not cause an increased incidence of adverse reactions, such as nephrotoxicity in patients with renal impairment. The conclusions of Verena et al. [Citation11] and Alvarez-Lerma [Citation14] were also consistent with it, both of which described that patients with chronic renal failure were well tolerated during the treatment of intravenous voriconazole and were not discontinued due to adverse events. Dionissios et al. evaluated patients with baseline CrCl <50 mL/min for 3 or 7 consecutive days of intravenous voriconazole treatment, and no deterioration of renal function was observed in these patients [Citation7]. A small number of patients with moderate injured renal had higher plasma concentrations of voriconazole, but no difference was observed in the pharmacokinetic parameters after dose normalization, and did not observe any deterioration of renal functions [Citation4]. Generally, patients with moderate renal impairment could tolerate intravenous voriconazole treatment for up to 7 days [Citation9].
Voriconazole intravenous injection was also not found to increase the risk of nephrotoxicity in patients with renal insufficiency compared with other antifungal agents. Kullberg et al. included 41 patients with moderate (CrCl 30–50 mL/min) or severe (CrCl <30 mL/min) renal insufficiency, and the results showed that intravenous voriconazole has well tolerated, better survival rate and less renal toxicity compared with amphotericin B and fluconazole [Citation13]. Prague Luke et al. and Oude et al. also have the similar findings [Citation6]. Intravenous voriconazole containing SBECD can be used to treat patients with impaired renal function with severe fungal infection without an increased risk of nephrotoxicity, similar to caspofennet and fluconazole injections [Citation5].
Intravenous voriconazole is also considered safe in children with impaired renal function based on a number of case reports. A case report described a preterm infant with reduced renal function and developed a disseminated fluconazole-resistant Candida albicans infection. The report showed that administered intravenous voriconazole 6 mg/kg every 8 hours was safely [Citation15]. Durre et al. reported that a 2-year-old child with acute renal failure was successfully treated for primary renal aspergillosis with intravenous voriconazole, and renal function did not deteriorate during treatment [Citation16].
Voriconazole dosage forms are less likely to cause renal function deterioration. Dionissios et al. compared the effects of intravenous and oral voriconazole on renal deterioration in patients with impaired renal function, administration route did not cause further damage to renal function after 3 or 7 days of continuous administration and at the end of treatment [Citation7].
In practical clinical practice, voriconazole has no serious adverse effects in patients with renal impairment after intravenous administration for a short period of time. However, the short-time treatment may result in insufficient treatment for invasive fungal disease [Citation8].
Most studies have shown that intravenous voriconazole formulated with SBECD is safe in patients with renal impairment. SBECD does not accumulate in renal epithelial cells and therefore does not lead to deterioration of renal function.
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The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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References
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