Early Prediction of Polymyxin-Induced Nephrotoxicity With Next-Generation Urinary Kidney Injury Biomarkers

Keirstead, Natalie D.; Wagoner, Matthew P.; Bentley, Patricia; Blais, Marie; Brown, Crystal; Cheatham, Letitia; Ciaccio, Paul J.; Dragan, Yvonne P.; Ferguson, Douglas; Fikes, Jim; Galvin, Melanie; Gupta, Anshul; Hale, Michael R.; Johnson, Nakpangi; Luo, Wei; McGrath, Frank P.; Pietras, Mark; Price, Sally; Sathe, Abhishek G.; Sasaki, Jennifer C.; Snow, Debra; Walsky, Robert L.; Kern, Günther

doi:10.1093/toxsci/kft247

Cited by 77 publications

(63 citation statements)

References 43 publications

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“…Lycopene has been shown to interact with ROS and thereby to prevent ROSinduced tissue and cellular damage (35). Consistent with previous studies, we revealed that colistin-induced nephrotoxicity is associated with significantly increased MDA levels and a concomitant decrease in the levels of antioxidant enzymes CAT, SOD, and GSH (Table 2) (16,18,60,61). In the present study, lycopene treatment restored the levels of all of these biomarkers to the normal range observed in the untreated control group (Table 2), confirming its nephroprotective effect.…”

Section: Discussionsupporting

confidence: 92%

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Dai

Tang

Deng

et al. 2015

Antimicrob Agents Chemother

103

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bNephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-B mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

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Section: Discussionsupporting

confidence: 92%

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Dai

Tang

Deng

et al. 2015

Antimicrob Agents Chemother

103

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“…6,7 Polymyxin B has well-documented toxicity in humans. 18 Protamine has demonstrated toxicity as well, including anticoagulant effects in the absence of heparin 19,20 and the ability to precipitate fibrinogen at high concentrations. 21 Cationic PAMAM dendrimers also interact with and precipitate fibrinogen in solution, 9 which was confirmed in this study.…”

Section: Discussionmentioning

confidence: 99%

Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis

Travers

Shenoi²,

Kalathottukaren³

et al. 2014

Blood

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“…However, the clinical use of polymyxins was considerably reduced in the early 1970s due to concerns about nephrotoxicity (2)(3)(4). Despite being available for decades, the correlation between the pharmacokinetics and toxicodynamic profiles of polymyxin B is still not thoroughly understood.…”

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confidence: 99%

Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

Manchandani

Zhou

Babic

et al. 2017

Antimicrob Agents Chemother

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Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 Ϯ 0.4 g/g, 9.9 Ϯ 1.5 g/g, and 21.7 Ϯ 4.8 g/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. KEYWORDS Polymyxin B, renal drug concentration, megalin, polymyxins T here is a renewed interest in the clinical use of polymyxins due to the increased prevalence of infections caused by multidrug-resistant Gram-negative bacteria (1). Many currently available antibiotics are no longer effective against these resistant bacterial strains. Additionally, the situation is further exacerbated by the limited number of new antibacterial agents in the advanced drug development pipeline. Consequently, the polymyxins have emerged as the last treatment resort against these life-threatening infections.Polymyxins (polymyxin B and polymyxin E [colistin]) are cyclic polypeptide antibiotics which were available for clinical use in the 1950s. However, the clinical use of polymyxins was considerably reduced in the early 1970s due to concerns about nephrotoxicity (2-4). Despite being available for decades, the correlation between the pharmacokinetics and toxicodynamic profiles of polymyxin B is still not thoroughly understood. This knowledge gap often hinders the optimal clinical use of polymyxin B. There is evidence suggesting that polymyxin B is not eliminated through the renal route (5, 6). However, pharmacokinetic studies have reported preferential accumulation and prolonged residence of polymyxin B in rat kidneys (7,8). Several studies have also reported a daily dose of polymyxin B as an independent risk factor associated with...

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Early Prediction of Polymyxin-Induced Nephrotoxicity With Next-Generation Urinary Kidney Injury Biomarkers

Cited by 77 publications

References 43 publications

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway

Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis

Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

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