Early prediction of polymyxin-induced nephrotoxicity with next-generation urinary kidney injury biomarkers.

Abstract

Despite six decades of clinical experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of standard of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) derivative with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathological and biomarker analysis of PMBN, an important test of the hypothesis that fatty acid modifications and charge reductions in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathological injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clinical standards of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathological evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.

• Authors: Natalie D Keirstead, Matthew P Wagoner, Patricia Bentley, Marie Blais, Crystal Brown, Letitia Cheatham, Paul Ciaccio, Yvonne Dragan, Douglas Ferguson, Jim Fikes, Melanie Galvin, Anshul Gupta, Michael Hale, Nakpangi Johnson, Wenli Luo, Frank McGrath, Mark Pietras, Sally Price, Abhishek G Sathe, Jennifer C Sasaki, Debra Snow, Robert L Walsky, Gunther Kern
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 137 Issue 2 Pg. 278-91 (Feb 2014) ISSN: 1096-0929 [Electronic] United States
• PMID: 24189134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Bacterial Agents
• Biomarkers
• polymyxin B nonapeptide
• Polymyxin B
• Colistin

Topics

• Animals
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics, toxicity)
• Biomarkers (urine)
• Cell Line
• Cell Survival (drug effects)
• Colistin (administration & dosage, pharmacokinetics, toxicity)
• Data Interpretation, Statistical
• Dose-Response Relationship, Drug
• Early Diagnosis
• Kidney Diseases (chemically induced, metabolism, pathology, urine)
• Male
• Polymyxin B (administration & dosage, analogs & derivatives, pharmacokinetics, toxicity)
• Prognosis
• Rats
• Rats, Wistar