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Otto C Boerman - One of the best experts on this subject based on the ideXlab platform.
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Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention
2015Co-Authors: Erik Vegt, Marion De Jong, Jack F M Wetzels, Rosalinde Masereeuw, Marleen Melis, Wim J G Oyen, Martin Gotthardt, Otto C BoermanAbstract:Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-lim-iting Nephrotoxicity. An overview of renal handling of radiola-beled peptides and resulting Nephrotoxicity is presented, and strategies to reduce Nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of com-petitive inhibitors of reabsorption also interferes with the interac-tion of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clin-ical PRRT. Furthermore, Nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of Nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT. Key Words: kidney; peptide; antibody fragment; radionuclide therapy; PRR
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renal toxicity of radiolabeled peptides and antibody fragments mechanisms impact on radionuclide therapy and strategies for prevention
The Journal of Nuclear Medicine, 2010Co-Authors: Erik Vegt, Marion De Jong, Jack F M Wetzels, Rosalinde Masereeuw, Marleen Melis, Wim J G Oyen, Martin Gotthardt, Otto C BoermanAbstract:Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting Nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting Nephrotoxicity is presented, and strategies to reduce Nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, Nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of Nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.
Yann Guéguen - One of the best experts on this subject based on the ideXlab platform.
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In vivo comparison between two nephrotoxic agents, sodium fluoride and uranyl nitrate: phenotypic aspects and molecular mechanisms involved
2019Co-Authors: Alice Bontemps, Laurine Conquet, Christelle Elie, Victor Magneron, Céline Gloaguen, Dimitri Kereselidze, Karine Tack, Olivier Barbier, Yann GuéguenAbstract:1 Background Humans can be exposed at low concentrations to toxic agents with anthropogenic and natural origins such as uranium and fluoride. Because of its functions of filtration, transport and reabsorption the kidney is a primary target organ of toxicity to foreign compounds. Uranium and fluoride are both known to be nephrotoxic, nevertheless there is a lack of knowledge of their mechanisms of Nephrotoxicity and of the underlying molecular pathways involved [1, 2]. This study aims to compare these agents to identify the cellular and molecular pathways of Nephrotoxicity in mouse. 2 Methods and results C57Bl6 mice are exposed to uranyl nitrate (UN) (0, 2, 4, 5 mg/kg) or sodium fluoride (NaF) (0, 2, 5, 7.5, 10 mg/kg) by intraperitoneal injection and put into metabolism cages for 24 hours before and directly after injection. Collected urines are used to quantify uranium or fluoride, to measure specific and sensitive biomarkers of Nephrotoxicity levels and to assess clinical bioassays. Finally, animals are euthanized 48h and 72h after exposure, chosen as the peak of Nephrotoxicity is observed after intraperitoneal injection [3]. The protocol is shown in figure 1. Renal phenotypic aspects and biological mechanisms are evaluated by urinary biochemistry, gene and protein expressions, enzyme activity, and histological analyses. Exposure to UN and NaF induces Nephrotoxicity in a dose-dependent manner. A 5 mg/kg injection of UN induces mild histopathological alterations and respectively 44 and 6-fold increase in gene expressions of Nephrotoxicity markers KIM1 and osteopontin. In comparison, 10 mg/kg of NaF induces high Nephrotoxicity with histopathological alterations scored as severe and late appearing parameters of toxicity whereas 7.5 mg/kg induces mild histopathological scoring and gene expressions of KIM1 and clusterin enhanced respectively by 70 and 4-fold compared to control. No signs of Nephrotoxicity are observed below 5 mg/kg of NaF. Clusterin is respectively increased by 2.4 and 4.4-fold in urines after 7.5 and 10 mg/kg injection of NaF, whereas 4 and 5 mg/kg of UN induce respectively a 2.2 and 2.7-fold increase of clusterin in urines. Apoptosis is evaluated through caspases 3/7 activity which is increased by 210% after UN treatment (5mg/kg) whereas NaF does not induce apoptosis significantly. Inflammation is implied in UN and NaF acute Nephrotoxicity as shown by gene and in situ overexpressions of ICAM and VCAM measurement by immunohistochemical staining. 3 Conclusions UN and NaF acute exposures resulted in dose and time-dependent Nephrotoxicity with a higher Nephrotoxicity after 72h. Inflammation and apoptosis are both involved in UN or NaF toxicity. These observations allow us to identify the mechanisms that will be studied in a low-dose exposure protocol after a chronic exposure.
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In Vivo Comparison of the Phenotypic Aspects and Molecular Mechanisms of Two Nephrotoxic Agents, Sodium Fluoride and Uranyl Nitrate
MDPI AG, 2019Co-Authors: Alice Bontemps, Laurine Conquet, Christelle Elie, Victor Magneron, Céline Gloaguen, Dimitri Kereselidze, Karine Tack, Olivier C. Barbier, Yann GuéguenAbstract:Because of their Nephrotoxicity and presence in the environment, uranium (U) and fluoride (F) represent risks to the global population. There is a general lack of knowledge regarding the mechanisms of U and F Nephrotoxicity and the underlying molecular pathways. The present study aims to compare the threshold of the appearance of renal impairment and to study apoptosis and inflammation as mechanisms of Nephrotoxicity. C57BL/6J male mice were intraperitoneally treated with a single dose of U (0, 2, 4 and 5 mg/kg) or F (0, 2, 5, 7.5 and 10 mg/kg) and euthanized 72 h after. Renal phenotypic characteristics and biological mechanisms were evaluated by urine biochemistry, gene/protein expression, enzyme activity, and (immuno)histological analyses. U and F exposures induced Nephrotoxicity in a dose-dependent manner, and the highest concentrations induced severe histopathological alterations as well as increased gene expression and urinary excretion of Nephrotoxicity biomarkers. KIM-1 gene expression was induced starting at 2 mg/kg U and 7.5 mg/kg F, and this increase in expression was confirmed through in situ detection of this biomarker of Nephrotoxicity. Both treatments induced inflammation as evidenced by cell adhesion molecule expression and in situ levels, whereas caspase 3/7-dependent apoptosis was increased only after U treatment. Overall, a single dose of F or U induced histopathologic evidence of Nephrotoxicity renal impairment and inflammation in mice with thresholds under 7.5 mg/kg and 4 mg/kg, respectively
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In vivo comparison of the phenotypic aspects and molecular mechanisms of two nephrotoxic agents, sodium fluoride and uranyl nitrate
International Journal of Environmental Research and Public Health, 2019Co-Authors: Alice Bontemps, Laurine Conquet, Christelle Elie, Victor Magneron, Céline Gloaguen, Dimitri Kereselidze, Karine Tack, Olivier C. Barbier, Yann GuéguenAbstract:Because of their Nephrotoxicity and presence in the environment, uranium (U) and fluoride (F) represent risks to the global population. There is a general lack of knowledge regarding the mechanisms of U and F Nephrotoxicity and the underlying molecular pathways. The present study aims to compare the threshold of the appearance of renal impairment and to study apoptosis and inflammation as mechanisms of Nephrotoxicity. C57BL/6J male mice were intraperitoneally treated with a single dose of U (0, 2, 4 and 5 mg/kg) or F (0, 2, 5, 7.5 and 10 mg/kg) and euthanized 72 h after. Renal phenotypic characteristics and biological mechanisms were evaluated by urine biochemistry, gene/protein expression, enzyme activity, and (immuno)histological analyses. U and F exposures induced Nephrotoxicity in a dose-dependent manner, and the highest concentrations induced severe histopathological alterations as well as increased gene expression and urinary excretion of Nephrotoxicity biomarkers. KIM-1 gene expression was induced starting at 2 mg/kg U and 7.5 mg/kg F, and this increase in expression was confirmed through in situ detection of this biomarker of Nephrotoxicity. Both treatments induced inflammation as evidenced by cell adhesion molecule expression and in situ levels, whereas caspase 3/7-dependent apoptosis was increased only after U treatment. Overall, a single dose of F or U induced histopathologic evidence of Nephrotoxicity renal impairment and inflammation in mice with thresholds under 7.5 mg/kg and 4 mg/kg, respectively. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
Erik Vegt - One of the best experts on this subject based on the ideXlab platform.
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Renal Toxicity of Radiolabeled Peptides and Antibody Fragments: Mechanisms, Impact on Radionuclide Therapy, and Strategies for Prevention
2015Co-Authors: Erik Vegt, Marion De Jong, Jack F M Wetzels, Rosalinde Masereeuw, Marleen Melis, Wim J G Oyen, Martin Gotthardt, Otto C BoermanAbstract:Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-lim-iting Nephrotoxicity. An overview of renal handling of radiola-beled peptides and resulting Nephrotoxicity is presented, and strategies to reduce Nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of com-petitive inhibitors of reabsorption also interferes with the interac-tion of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clin-ical PRRT. Furthermore, Nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of Nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT. Key Words: kidney; peptide; antibody fragment; radionuclide therapy; PRR
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renal toxicity of radiolabeled peptides and antibody fragments mechanisms impact on radionuclide therapy and strategies for prevention
The Journal of Nuclear Medicine, 2010Co-Authors: Erik Vegt, Marion De Jong, Jack F M Wetzels, Rosalinde Masereeuw, Marleen Melis, Wim J G Oyen, Martin Gotthardt, Otto C BoermanAbstract:Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting Nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting Nephrotoxicity is presented, and strategies to reduce Nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, Nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of Nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.
Richard H Drew - One of the best experts on this subject based on the ideXlab platform.
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comparison of the incidence of vancomycin induced Nephrotoxicity in hospitalized patients with and without concomitant piperacillin tazobactam
Pharmacotherapy, 2014Co-Authors: Lindsey D Burgess, Richard H DrewAbstract:tudy Objectives To determine whether the addition of piperacillin-tazobactam leads to an increased incidence of Nephrotoxicity in patients receiving vancomycin and to explore potential confounding factors that may increase the risk of vancomycin-induced Nephrotoxicity. Design Single-center, retrospective cohort study. Setting Large, academic, tertiary-care hospital. Patients One hundred ninety-one adults hospitalized between July 1, 2009, and July 1, 2012, with normal baseline renal function who received a minimum of 48 hours of vancomycin for any indication were included in the analysis. Of these patients, 92 received a minimum of 48 hours of intravenous piperacillin-tazobactam concurrently with vancomycin, with piperacillin-tazobactam being initiated within 48 hours of the initiation of vancomycin (combination group); 99 received vancomycin without piperacillin-tazobactam (vancomycin group). Measurements and Main Results A univariate analysis was performed to assess the effect of the following risk factors on the incidence of Nephrotoxicity within the first 7 days of vancomycin treatment: concomitant nephrotoxic agents, advanced age, steady-state vancomycin trough concentration of 15 μg/ml or greater, elevated Charlson Comorbidity Index, and a total daily vancomycin dose of 4 g or greater. A multivariate model was constructed to compare the incidence of the primary end point of Nephrotoxicity, defined as a minimum 1.5-fold increase in serum creatinine concentration, between groups. Nephrotoxicity developed in 8 (8.1%) of 99 patients in the vancomycin group and in 15 (16.3%) of 92 patients in the combination group (1-sided χ2 test, p=0.041). In the univariate analysis, only vancomycin trough concentration of 15 μg/ml or greater (odds ratio 3.67) was associated with an increased risk of developing Nephrotoxicity. In the multivariate analysis, patients with piperacillin-tazobactam added to vancomycin exhibited an increased incidence of Nephrotoxicity, with an odds ratio of 2.48 (1-sided χ2 test, p=0.032). Conclusion We observed an increased incidence of Nephrotoxicity in vancomycin-treated patients who received concomitant piperacillin-tazobactam. A steady-state vancomycin trough concentration of 15 μg/ml or greater was also associated with an increased risk of the development of Nephrotoxicity. These findings should be confirmed in larger, randomized studies.
Alice Bontemps - One of the best experts on this subject based on the ideXlab platform.
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In vivo comparison between two nephrotoxic agents, sodium fluoride and uranyl nitrate: phenotypic aspects and molecular mechanisms involved
2019Co-Authors: Alice Bontemps, Laurine Conquet, Christelle Elie, Victor Magneron, Céline Gloaguen, Dimitri Kereselidze, Karine Tack, Olivier Barbier, Yann GuéguenAbstract:1 Background Humans can be exposed at low concentrations to toxic agents with anthropogenic and natural origins such as uranium and fluoride. Because of its functions of filtration, transport and reabsorption the kidney is a primary target organ of toxicity to foreign compounds. Uranium and fluoride are both known to be nephrotoxic, nevertheless there is a lack of knowledge of their mechanisms of Nephrotoxicity and of the underlying molecular pathways involved [1, 2]. This study aims to compare these agents to identify the cellular and molecular pathways of Nephrotoxicity in mouse. 2 Methods and results C57Bl6 mice are exposed to uranyl nitrate (UN) (0, 2, 4, 5 mg/kg) or sodium fluoride (NaF) (0, 2, 5, 7.5, 10 mg/kg) by intraperitoneal injection and put into metabolism cages for 24 hours before and directly after injection. Collected urines are used to quantify uranium or fluoride, to measure specific and sensitive biomarkers of Nephrotoxicity levels and to assess clinical bioassays. Finally, animals are euthanized 48h and 72h after exposure, chosen as the peak of Nephrotoxicity is observed after intraperitoneal injection [3]. The protocol is shown in figure 1. Renal phenotypic aspects and biological mechanisms are evaluated by urinary biochemistry, gene and protein expressions, enzyme activity, and histological analyses. Exposure to UN and NaF induces Nephrotoxicity in a dose-dependent manner. A 5 mg/kg injection of UN induces mild histopathological alterations and respectively 44 and 6-fold increase in gene expressions of Nephrotoxicity markers KIM1 and osteopontin. In comparison, 10 mg/kg of NaF induces high Nephrotoxicity with histopathological alterations scored as severe and late appearing parameters of toxicity whereas 7.5 mg/kg induces mild histopathological scoring and gene expressions of KIM1 and clusterin enhanced respectively by 70 and 4-fold compared to control. No signs of Nephrotoxicity are observed below 5 mg/kg of NaF. Clusterin is respectively increased by 2.4 and 4.4-fold in urines after 7.5 and 10 mg/kg injection of NaF, whereas 4 and 5 mg/kg of UN induce respectively a 2.2 and 2.7-fold increase of clusterin in urines. Apoptosis is evaluated through caspases 3/7 activity which is increased by 210% after UN treatment (5mg/kg) whereas NaF does not induce apoptosis significantly. Inflammation is implied in UN and NaF acute Nephrotoxicity as shown by gene and in situ overexpressions of ICAM and VCAM measurement by immunohistochemical staining. 3 Conclusions UN and NaF acute exposures resulted in dose and time-dependent Nephrotoxicity with a higher Nephrotoxicity after 72h. Inflammation and apoptosis are both involved in UN or NaF toxicity. These observations allow us to identify the mechanisms that will be studied in a low-dose exposure protocol after a chronic exposure.
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In Vivo Comparison of the Phenotypic Aspects and Molecular Mechanisms of Two Nephrotoxic Agents, Sodium Fluoride and Uranyl Nitrate
MDPI AG, 2019Co-Authors: Alice Bontemps, Laurine Conquet, Christelle Elie, Victor Magneron, Céline Gloaguen, Dimitri Kereselidze, Karine Tack, Olivier C. Barbier, Yann GuéguenAbstract:Because of their Nephrotoxicity and presence in the environment, uranium (U) and fluoride (F) represent risks to the global population. There is a general lack of knowledge regarding the mechanisms of U and F Nephrotoxicity and the underlying molecular pathways. The present study aims to compare the threshold of the appearance of renal impairment and to study apoptosis and inflammation as mechanisms of Nephrotoxicity. C57BL/6J male mice were intraperitoneally treated with a single dose of U (0, 2, 4 and 5 mg/kg) or F (0, 2, 5, 7.5 and 10 mg/kg) and euthanized 72 h after. Renal phenotypic characteristics and biological mechanisms were evaluated by urine biochemistry, gene/protein expression, enzyme activity, and (immuno)histological analyses. U and F exposures induced Nephrotoxicity in a dose-dependent manner, and the highest concentrations induced severe histopathological alterations as well as increased gene expression and urinary excretion of Nephrotoxicity biomarkers. KIM-1 gene expression was induced starting at 2 mg/kg U and 7.5 mg/kg F, and this increase in expression was confirmed through in situ detection of this biomarker of Nephrotoxicity. Both treatments induced inflammation as evidenced by cell adhesion molecule expression and in situ levels, whereas caspase 3/7-dependent apoptosis was increased only after U treatment. Overall, a single dose of F or U induced histopathologic evidence of Nephrotoxicity renal impairment and inflammation in mice with thresholds under 7.5 mg/kg and 4 mg/kg, respectively
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In vivo comparison of the phenotypic aspects and molecular mechanisms of two nephrotoxic agents, sodium fluoride and uranyl nitrate
International Journal of Environmental Research and Public Health, 2019Co-Authors: Alice Bontemps, Laurine Conquet, Christelle Elie, Victor Magneron, Céline Gloaguen, Dimitri Kereselidze, Karine Tack, Olivier C. Barbier, Yann GuéguenAbstract:Because of their Nephrotoxicity and presence in the environment, uranium (U) and fluoride (F) represent risks to the global population. There is a general lack of knowledge regarding the mechanisms of U and F Nephrotoxicity and the underlying molecular pathways. The present study aims to compare the threshold of the appearance of renal impairment and to study apoptosis and inflammation as mechanisms of Nephrotoxicity. C57BL/6J male mice were intraperitoneally treated with a single dose of U (0, 2, 4 and 5 mg/kg) or F (0, 2, 5, 7.5 and 10 mg/kg) and euthanized 72 h after. Renal phenotypic characteristics and biological mechanisms were evaluated by urine biochemistry, gene/protein expression, enzyme activity, and (immuno)histological analyses. U and F exposures induced Nephrotoxicity in a dose-dependent manner, and the highest concentrations induced severe histopathological alterations as well as increased gene expression and urinary excretion of Nephrotoxicity biomarkers. KIM-1 gene expression was induced starting at 2 mg/kg U and 7.5 mg/kg F, and this increase in expression was confirmed through in situ detection of this biomarker of Nephrotoxicity. Both treatments induced inflammation as evidenced by cell adhesion molecule expression and in situ levels, whereas caspase 3/7-dependent apoptosis was increased only after U treatment. Overall, a single dose of F or U induced histopathologic evidence of Nephrotoxicity renal impairment and inflammation in mice with thresholds under 7.5 mg/kg and 4 mg/kg, respectively. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.
