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Flucytosine and Amphotericin B Coadministration Induces Dose-Related Renal Injury
Alexandra Folk1, Cornel Balta2, Hildegard Herman2
1Faculty of Medicine, Department of Pathology, "Vasile Goldis" Western University of Arad, Arad, Romania.
Abstract:
Invasive fungal infections remain an important clinical problem, and despite recent approaches, they bring high morbidity and mortality. Combination therapies are the most effective; however, adverse effects need to be considered. In this study, we aimed to evaluate the nephrotoxicity induced by combined therapy of flucytosine (FL) and amphotericin B (AMF) at 3 different doses administered to mice for 14 days: 300 μg/kg AMF+50 mg/kg FL; 600 μg/kg AMF+100 mg/kg FL; 900 μg/kg AMF+150 mg/kg FL. Antifungal coadministration triggered nuclear translocation of NF-κB and upregulated nuclear factor kappa-light-chain-enhancer of activated B cells subunit p65 (NF-κB p65) messenger RNA mRNA level in dose-dependent manner. The immunopositivity of tumor necrosis factor-α and interleukin-6 (IL-6), together with IL-6 gene expression, increased both in tubular and glomerular cells. Amphotericin B-flucytosine cotreatment increased significantly the number of terminal deoxy-nucleotidyl transferase (TdT)-mediated dUTP nick end-labeling positive nuclei. Apoptotic cells in renal tubuli were confirmed by electron microscopy. Histopathological analysis revealed collagen accumulation at the glomerular level. Collagen was also evidenced in the glomeruli at the dose of 900 μg/kg AMF+150mg/kg FL by Masson-Goldner trichrome staining and electron microscopy. Moreover, antifungal cotherapy induced upregulation of transforming growth factor beta 1 (TGF-β1) gene expression in a dose-dependent manner. Inflammation and epithelial tubular apoptosis are associated with TGF-β1 activation and initiation of the early stage of glomerular fibrosis at higher doses, leading to tubule-interstitial fibrosis.
Insights
Combination antifungal therapy with flucytosine and amphotericin B causes dose-dependent kidney damage in mice. This study reveals inflammation, apoptosis, and fibrosis, highlighting the need to monitor nephrotoxicity during invasive fungal infection treatment.
Area of Science:
- * Pharmacology and Toxicology
- * Renal Pathology
- * Infectious Diseases
Background:
- * Invasive fungal infections present significant clinical challenges with high morbidity and mortality.
- * Combination antifungal therapies, while effective, require careful consideration of adverse effects, particularly nephrotoxicity.
- * Flucytosine (FL) and amphotericin B (AMF) are key antifungal agents used in combination therapy.
Purpose of the Study:
- * To evaluate the nephrotoxicity of combined flucytosine and amphotericin B therapy at varying doses in a murine model.
- * To investigate the molecular mechanisms underlying the observed kidney damage, including inflammatory markers and apoptotic pathways.
- * To assess the potential for fibrosis development in renal tissues following combination antifungal treatment.
Main Methods:
- * Murine model treated for 14 days with three different doses of AMF combined with FL.
- * Analysis of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway activation, inflammatory cytokine expression (TNF-α, IL-6), and apoptosis (TUNEL assay).
- * Histopathological examination including Masson-Goldner trichrome staining and electron microscopy to evaluate collagen deposition and fibrosis.
Main Results:
- * Combination therapy induced a dose-dependent increase in NF-κB p65 mRNA levels and inflammatory markers (TNF-α, IL-6) in renal cells.
- * Significant increase in apoptotic cells in renal tubules and evidence of glomerular collagen accumulation, particularly at higher doses.
- * Upregulation of transforming growth factor beta 1 (TGF-β1) gene expression correlated with inflammation, apoptosis, and the initiation of tubule-interstitial fibrosis.
Conclusions:
- * Combined flucytosine and amphotericin B therapy induces significant nephrotoxicity in mice, characterized by inflammation, apoptosis, and fibrosis.
- * The observed renal damage is dose-dependent and associated with the activation of NF-κB and TGF-β1 signaling pathways.
- * These findings underscore the importance of monitoring kidney function and potential adverse effects when using this combination therapy for invasive fungal infections.
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