title: 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.affiliation: * Drug Safety and Metabolism and.
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Keirstead
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Wagoner
authors.forename: Patricia
authors.initials: P
authors.lastname: Bentley
authors.forename: Marie
authors.initials: M
authors.lastname: Blais
authors.forename: Crystal
authors.initials: C
authors.lastname: Brown
authors.forename: Letitia
authors.initials: L
authors.lastname: Cheatham
authors.forename: Paul
authors.initials: P
authors.lastname: Ciaccio
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Dragan
authors.forename: Douglas
authors.initials: D
authors.lastname: Ferguson
authors.forename: Jim
authors.initials: J
authors.lastname: Fikes
authors.forename: Melanie
authors.initials: M
authors.lastname: Galvin
authors.forename: Anshul
authors.initials: A
authors.lastname: Gupta
authors.forename: Michael
authors.initials: M
authors.lastname: Hale
authors.forename: Nakpangi
authors.initials: N
authors.lastname: Johnson
authors.forename: Wenli
authors.initials: W
authors.lastname: Luo
authors.forename: Frank
authors.initials: F
authors.lastname: McGrath
authors.forename: Mark
authors.initials: M
authors.lastname: Pietras
authors.forename: Sally
authors.initials: S
authors.lastname: Price
authors.forename: Abhishek G
authors.initials: AG
authors.lastname: Sathe
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Sasaki
authors.forename: Debra
authors.initials: D
authors.lastname: Snow
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walsky
authors.forename: Gunther
authors.initials: G
authors.lastname: Kern
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D015415:Biomarkers / Q000652:urine; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003091:Colistin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D042241:Early Diagnosis; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000652:urine*; D008297:Male; D011112:Polymyxin B / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D011379:Prognosis; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000900:Anti-Bacterial Agents; D015415:Biomarkers; C038934:polymyxin B nonapeptide; D011112:Polymyxin B; D003091:Colistin
keywords: AKI; HK-2; Kim-1; RIFLE.; biomarkers; colistin; drug safety; histopathology; immunohistochemistry; infection; nephrotoxicity; polymyxin; toxicology; translation