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

Keirstead ND, Wagoner MP, Bentley P, Blais M, Brown C, Cheatham L, Ciaccio P, Dragan Y, Ferguson D, Fikes J, Galvin M, Gupta A, Hale M, Johnson N, Luo W, McGrath F, Pietras M, Price S, Sathe AG, Sasaki JC, Snow D, Walsky RL, Kern G.
Journal   Toxicol Sci.
Species  
Analytes Measured   Albumin , Clusterin , HAVCR1 KIM-1 , Osteopontin , RPA-1
Matrix Tested   Urine
Year   2013
Volume  
Page Numbers  
Application   Toxicology
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.

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