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Drug – induced nephrotoxicity is a serious adverse reaction that can have deleterious effects on a patient’s health and well-being. Acyclovir is an example of such an agent that causes the aforesaid effects. The drug induces severe nephrotoxicity in patients. The etiology of acyclovir – induced nephrotoxicity has not been fully elucidated. The overall objective of this thesis is to gain new insight into the pathogenesis of acyclovir – induced nephrotoxicity. Cytotoxicity studies showed that acyclovir induced human renal proximal tubular (HK-2) cell death, in vitro, and that the degree of this toxicity was significantly reduced by co-exposure to 4-methylpyrazole. The results suggest that acyclovir induces direct insult to human renal proximal tubular cells and the toxicity may be caused by the parent drug’s noxious acyclovir aldehyde metabolite. Transepithelial transport studies illustrated that acyclovir does not inhibit the transport of creatinine across porcine renal proximal tubular (LLC-PK1) or HK-2 cell monolayers. The results suggest that acyclovir does not inhibit the tubular secretion of creatinine in vitro, and possibly, in vivo, as well. Therefore, the abrupt, pronounced and transient elevations in the levels of plasma creatinine observed in patients may be solely and genuinely due to reduced GFR as a result of acyclovir – induced nephrotoxicity, and not to a tubular interaction between creatinine and acyclovir. Employing human embryonic kidney cells (HEK293) containing the full-length human ABCG2 gene encoding the wildtype ABCG2 amino acid sequence; cell accumulation studies showed that in the presence of the human breast cancer resistance protein (BCRP) inhibitor, fumitremorgin C (FTC), there was significant intracellular accumulation of acyclovir. The results suggest that acyclovir is a substrate for the efflux transporter and bears several potential implications with respect to the renal transport mechanisms and pathogenesis of the direct tubular damage induced by the drug. Synthesizing all the data, the results contribute to a better understanding of the pathogenesis of acyclovir – induced nephrotoxicity. Moreover, the research highlights the need for future studies that will aid in further elucidation of the underlying cell and molecular mechanism(s) of this toxicity and potential therapies for prevention of the direct renal tubular injury induced by the drug.

Drug – induced nephrotoxicity is a serious adverse reaction that can have deleterious effects on a patient’s health and well-being. Acyclovir is an example of such an agent that causes the aforesaid effects. The drug induces severe nephrotoxicity in patients. The etiology of acyclovir – induced nephrotoxicity has not been fully elucidated. The overall objective of this thesis is to gain new insight into the pathogenesis of acyclovir – induced nephrotoxicity. Cytotoxicity studies showed that acyclovir induced human renal proximal tubular (HK-2) cell death, in vitro, and that the degree of this toxicity was significantly reduced by co-exposure to 4-methylpyrazole. The results suggest that acyclovir induces direct insult to human renal proximal tubular cells and the toxicity may be caused by the parent drug’s noxious acyclovir aldehyde metabolite. Transepithelial transport studies illustrated that acyclovir does not inhibit the transport of creatinine across porcine renal proximal tubular (LLC-PK1) or HK-2 cell monolayers. The results suggest that acyclovir does not inhibit the tubular secretion of creatinine in vitro, and possibly, in vivo, as well. Therefore, the abrupt, pronounced and transient elevations in the levels of plasma creatinine observed in patients may be solely and genuinely due to reduced GFR as a result of acyclovir – induced nephrotoxicity, and not to a tubular interaction between creatinine and acyclovir. Employing human embryonic kidney cells (HEK293) containing the full-length human ABCG2 gene encoding the wildtype ABCG2 amino acid sequence; cell accumulation studies showed that in the presence of the human breast cancer resistance protein (BCRP) inhibitor, fumitremorgin C (FTC), there was significant intracellular accumulation of acyclovir. The results suggest that acyclovir is a substrate for the efflux transporter and bears several potential implications with respect to the renal transport mechanisms and pathogenesis of the direct tubular damage induced by the drug. Synthesizing all the data, the results contribute to a better understanding of the pathogenesis of acyclovir – induced nephrotoxicity. Moreover, the research highlights the need for future studies that will aid in further elucidation of the underlying cell and molecular mechanism(s) of this toxicity and potential therapies for prevention of the direct renal tubular injury induced by the drug.

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Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Aneta Pražáková Supervisor: RNDr. Jana Maixnerová, Ph.D. Title of diploma thesis: Determination of selected biomarkers of nephrotoxicity in urine and Plasma The discovery and development of novel biomarkers, that can be used for diagnosis of kidney damage earlier and more accurately, are needed for the effective prediction of drug-induced nephrotoxicity. Mechanisms of drug-induced nephrotoxicity include changes in glomerular hemodynamics, tubular cell cytotoxicity, inflammation, crystalline nephropathy, etc. Detection at initial stage of damage using sensitive and specific biomarkers belongs between one of the most important strategies in the treatment of acute kidney injury and renal failure. Although some these biomarkers do not show specificity and sensitivity, several promising biomarker candidates have been established recently to evaluate nephrotoxicity, e.g. selected KIM-1, cystatin C and NGAL. The advantages of these biomarkers compared to traditionally used biomarkers are higher sensitivity, specificity, just mentioned early diagnosis and non-invasiveness (the possibility of determination levels of the biomarkers from blood or urine). The aim of this diploma thesis was to determine...

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O resveratrol (Res), um polifenol presente no vinho tinto, é conhecido por possuir potente atividade antioxidante. O efeito do resveratrol (Res) frente à nefrotoxicidade do antineoplásico cisplatina (cDDP) foi avaliado em ratos neste estudo. Os animais foram tratados com Res (25 mg/Kg de peso copóreo, ip., dose única) 30 minutos antes da administração de cisplatina (5 mg/Kg de peso copóreo, ip., dose única) e foram sacrificados depois de 2 ou 5 dias do tratamento. Após 5 dias, o aumento da creatinina sérica, volume urinário e proteinúria, que são marcadores de alterações renais, apresentaram significativa redução (p < 0,05) com a administração de resveratrol. Os ratos tratados com cisplatina apresentaram necrose tubular aguda e maior marcação imuno-histoquímica para células ED1 e linfócitos T no córtex e medula externa renal. Estas alterações foram menos intensas nos animais tratados com resveratrol. Após 2 dias, a administração de cisplatina aos ratos induziu aumento na concentração de malonaldeído (MDA) e reduziu nos níveis de glutationa (GSH) no tecido renal, que não foram amenizadas pelo resveratrol. Os resultados desse estudo indicam que o tratamento com resveratrol atenuou as alterações renais funcionais, histológicas e imuno-histoquímicas induzidas pela cisplatina. O efeito protetor provavelmente está relacionado à diminuição de infiltrado de células inflamatórias no tecido renal / Resveratrol (Res), a polyphenolic present in red wine, is known to possess potent antioxidant properties. The ability of resveratrol to protect against the nephrotoxicity of the antineoplastic agent cisplatin (cDDP) was evaluated in rats. The animals were treated with Res (25 mg/Kg body weight, ip., single dose) 30 minutes before administration of cDDP (5 mg/Kg body weight, ip., single dose) and then, sacrificed in 2 or 5 days followed by the treatment. After 5 days with resveratrol administration, the enhanced serum creatinine levels, urinary volume and urinary protein, which are indicative of renal injury, shown a significant reduction (p < 0.05). The cisplatintreated rats presented a tubular cell necrosis and increase immunostaining for ED1 and T-lymphocytes in the renal cortex and outer medulla. Those alterations were less intense in animals treated with resveratrol. After 2 days, administration of cisplatin to rats induced a higher malondialdehyde levels (MDA), and reduction in glutathione (GSH) concentrations in kidney tissue that were not prevented by resveratrol. In this study, the results indicate that resveratrol treatment attenuated the functional, histological and immunohistochemical renal alterations induced by cisplatin. The protect effect is relatated to the decrease of cells infiltrated at kidney tissue.

O resveratrol (Res), um polifenol presente no vinho tinto, é conhecido por possuir potente atividade antioxidante. O efeito do resveratrol (Res) frente à nefrotoxicidade do antineoplásico cisplatina (cDDP) foi avaliado em ratos neste estudo. Os animais foram tratados com Res (25 mg/Kg de peso copóreo, ip., dose única) 30 minutos antes da administração de cisplatina (5 mg/Kg de peso copóreo, ip., dose única) e foram sacrificados depois de 2 ou 5 dias do tratamento. Após 5 dias, o aumento da creatinina sérica, volume urinário e proteinúria, que são marcadores de alterações renais, apresentaram significativa redução (p < 0,05) com a administração de resveratrol. Os ratos tratados com cisplatina apresentaram necrose tubular aguda e maior marcação imuno-histoquímica para células ED1 e linfócitos T no córtex e medula externa renal. Estas alterações foram menos intensas nos animais tratados com resveratrol. Após 2 dias, a administração de cisplatina aos ratos induziu aumento na concentração de malonaldeído (MDA) e reduziu nos níveis de glutationa (GSH) no tecido renal, que não foram amenizadas pelo resveratrol. Os resultados desse estudo indicam que o tratamento com resveratrol atenuou as alterações renais funcionais, histológicas e imuno-histoquímicas induzidas pela cisplatina. O efeito protetor provavelmente está relacionado à diminuição de infiltrado de células inflamatórias no tecido renal / Resveratrol (Res), a polyphenolic present in red wine, is known to possess potent antioxidant properties. The ability of resveratrol to protect against the nephrotoxicity of the antineoplastic agent cisplatin (cDDP) was evaluated in rats. The animals were treated with Res (25 mg/Kg body weight, ip., single dose) 30 minutes before administration of cDDP (5 mg/Kg body weight, ip., single dose) and then, sacrificed in 2 or 5 days followed by the treatment. After 5 days with resveratrol administration, the enhanced serum creatinine levels, urinary volume and urinary protein, which are indicative of renal injury, shown a significant reduction (p < 0.05). The cisplatintreated rats presented a tubular cell necrosis and increase immunostaining for ED1 and T-lymphocytes in the renal cortex and outer medulla. Those alterations were less intense in animals treated with resveratrol. After 2 days, administration of cisplatin to rats induced a higher malondialdehyde levels (MDA), and reduction in glutathione (GSH) concentrations in kidney tissue that were not prevented by resveratrol. In this study, the results indicate that resveratrol treatment attenuated the functional, histological and immunohistochemical renal alterations induced by cisplatin. The protect effect is relatated to the decrease of cells infiltrated at kidney tissue.