NDT Advance Access originally published online on October 7, 2008
Nephrology Dialysis Transplantation 2009 24(3):763-768; doi:10.1093/ndt/gfn540
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Characterization of a novel model for investigation of radiocontrast nephrotoxicity
1 Department of Internal Medicine, University of Virginia Health Systems, Charlottesville, VA 22908, USA 2 Department of Cardiovascular Services 3 Department of Pharmacology, Marshall University, Joan C. Edwards School of Medicine, 1700 3rd AVE Huntington, WV 25755-9388, USA
Correspondence and offprint requests to: Monica A. Valentovic, Department of Pharmacology, Marshall University School of Medicine, 1700 3rd AVE Huntington, WV 25755-9388, USA. Tel: +1-304-696-7332; Fax: +1-304-696-7391; E-mail: valentov{at}marshall.edu
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Abstract |
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Objectives. Radiocontrast agents are one of the most common causes of acute renal failure in the world. These agents are required for both diagnostic and therapeutic modalities of medical intervention, including computed tomography (CT), angiography and cardiac catheterization. Publications over the past 40 years support three potential mechanisms of toxicity: oxidative stress, haemodynamics and hyperosmolar effects. An in vitro model provides a rapid evaluation of cellular toxicity without the complications of haemodynamics. This study evaluated the renal toxicity of radiocontrast agents at clinically relevant concentrations.
Methods. This study investigated the toxicity of two radiocontrast agents, diatrizoic acid (DA) and iothalamic acid (IA), using an in vitro model. Renal cortical slices isolated from F344 rats were incubated with 0–111 mg I/ml DA or IA.
Results. Renal slices exposed to DA and IA showed toxicity as measured by increased lactate dehydrogenase (LDH) leakage at concentrations lower than previously published using isolated cell models. These data indicate that DA and IA are toxic to renal cortical slices, and this is a more sensitive model than previously used cell culture systems. DA and IA treatment failed to cause a significant decrease in total cellular glutathione or increase in percent glutathione disulphide (GSSG), implying that oxidative stress may not be an initial mechanism of toxicity. Finally, the addition of exogenous glutathione did provide complete protection from DA- and IA-induced LDH leakage.
Conclusion. These data validate the renal cortical slice in vitro model for investigation of radiocontrast nephrotoxicity. These studies further showed that glutathione was cytoprotective. Future research using this model is aimed at further characterization of radiocontrast nephrotoxicity, which may allow for improved prevention and treatment of radiocontrast-induced acute renal failure.
Keywords: glutathione; nephrotoxicity; radiocontrast; rat cortical model
Received for publication: 10. 3.08
Accepted in revised form: 3. 9.08