Gelofusine ameliorates colistin-induced nephrotoxicity

Sivashangarie S. Sivanesan, Mohammad A. K. Azad, Elena K. Schneider, Maizbha U. Ahmed, Jiayuan Huang, Jiping Wang, Jian Li, Roger L. Nation, Tony Velkov

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

Colistin therapy is used as the last line of defense against life-threatening Gram-negative infections. Nephrotoxicity is the major dose-limiting side effect that impedes optimal dosing of patients. This study aims to examine the nephroprotective effect of the plasma volume expander gelofusine against colistin-induced nephrotoxicity. Renal protection was assessed in mice that were subcutaneously injected with colistin sulfate (14 mg/kg of body weight × 6 doses every 2 h; accumulated dose, 84 mg/kg) and simultaneously injected in the intraperitoneal region with gelofusine (75, 150, 300, or 600 mg/kg × 6). At 2 and 20 h after the last colistin dose, mice were euthanized, and the severity of renal alteration was examined histologi-cally. Histological findings in mice revealed that colistin-induced nephrotoxicity was ameliorated by gelofusine in a dose-dependent manner, whereas significant histological abnormalities were detected in the kidneys of mice in the colistin-only group. The impact of coadministered gelofusine on colistin pharmacokinetics was investigated in rats. Rats were administered a single intravenous dose of gelofusine at 400 mg/kg 15 min prior to the intravenous administration of colistin (1 mg/kg). Gelofusine codosing did not alter the pharmacokinetics of colistin in rats; however, gelofusine did significantly lower the accumulation of colistin in the kidney tissue of mice. This is the first study demonstrating the protective effect of gelofusine against colistin-induced nephrotoxicity. These findings highlight the clinical potential of gelofusine as a safe adjunct for ameliorating the nephrotoxicity and increasing the therapeutic index of polymyxins.

Original languageEnglish
Article numbere00985
Number of pages7
JournalAntimicrobial Agents and Chemotherapy
Volume61
Issue number12
DOIs
Publication statusPublished - 1 Dec 2017

Keywords

  • Colistin
  • Gelofusine
  • Nephrotoxicity

Cite this

Sivanesan, S. S., Azad, M. A. K., Schneider, E. K., Ahmed, M. U., Huang, J., Wang, J., ... Velkov, T. (2017). Gelofusine ameliorates colistin-induced nephrotoxicity. Antimicrobial Agents and Chemotherapy, 61(12), [e00985]. https://doi.org/10.1128/AAC.00985-17
Sivanesan, Sivashangarie S. ; Azad, Mohammad A. K. ; Schneider, Elena K. ; Ahmed, Maizbha U. ; Huang, Jiayuan ; Wang, Jiping ; Li, Jian ; Nation, Roger L. ; Velkov, Tony. / Gelofusine ameliorates colistin-induced nephrotoxicity. In: Antimicrobial Agents and Chemotherapy. 2017 ; Vol. 61, No. 12.
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Gelofusine ameliorates colistin-induced nephrotoxicity. / Sivanesan, Sivashangarie S.; Azad, Mohammad A. K.; Schneider, Elena K.; Ahmed, Maizbha U.; Huang, Jiayuan; Wang, Jiping; Li, Jian; Nation, Roger L.; Velkov, Tony.

In: Antimicrobial Agents and Chemotherapy, Vol. 61, No. 12, e00985, 01.12.2017.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Sivanesan, Sivashangarie S.

AU - Azad, Mohammad A. K.

AU - Schneider, Elena K.

AU - Ahmed, Maizbha U.

AU - Huang, Jiayuan

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AU - Nation, Roger L.

AU - Velkov, Tony

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AB - Colistin therapy is used as the last line of defense against life-threatening Gram-negative infections. Nephrotoxicity is the major dose-limiting side effect that impedes optimal dosing of patients. This study aims to examine the nephroprotective effect of the plasma volume expander gelofusine against colistin-induced nephrotoxicity. Renal protection was assessed in mice that were subcutaneously injected with colistin sulfate (14 mg/kg of body weight × 6 doses every 2 h; accumulated dose, 84 mg/kg) and simultaneously injected in the intraperitoneal region with gelofusine (75, 150, 300, or 600 mg/kg × 6). At 2 and 20 h after the last colistin dose, mice were euthanized, and the severity of renal alteration was examined histologi-cally. Histological findings in mice revealed that colistin-induced nephrotoxicity was ameliorated by gelofusine in a dose-dependent manner, whereas significant histological abnormalities were detected in the kidneys of mice in the colistin-only group. The impact of coadministered gelofusine on colistin pharmacokinetics was investigated in rats. Rats were administered a single intravenous dose of gelofusine at 400 mg/kg 15 min prior to the intravenous administration of colistin (1 mg/kg). Gelofusine codosing did not alter the pharmacokinetics of colistin in rats; however, gelofusine did significantly lower the accumulation of colistin in the kidney tissue of mice. This is the first study demonstrating the protective effect of gelofusine against colistin-induced nephrotoxicity. These findings highlight the clinical potential of gelofusine as a safe adjunct for ameliorating the nephrotoxicity and increasing the therapeutic index of polymyxins.

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