Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity

Weber, Elijah; Lidberg, Kevin A.; Wang, Lu; Bammler, Theo K.; MacDonald, James W.; Li, Mavis J.; Redhair, Michelle; Atkins, William M.; Tran, Cecilia K.; Hines, Kelly M.; Herron, Josi; Xu, Libin; Monteiro, Maria Beatriz; Ramm, Susanne; Vaidya, Vishal S.; Vaara, Martti; Vaara, Timo; Himmelfarb, Jonathan; Kelly, Edward J.

doi:10.1172/jci.insight.123673

Cited by 67 publications

(59 citation statements)

References 52 publications

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“…Under the influence of many factors, such as unreasonable drug use and the interactions among drugs, drug-induced liver and kidney injuries, as the most important adverse drug reactions, have attracted increasing attention from clinicians. e ability to diagnose these conditions is also continually improving [8,9]. Drug-induced liver and kidney injuries are easily missed due to the lack of specific clinical manifestations and biochemical and pathological changes.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics of 162 Patients with Drug-Induced Liver and/or Kidney Injury

Wang

Chen

2020

BioMed Research International

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Context. Drug-induced liver and kidney injuries are the most common adverse drug reactions in the clinic, and they have similar pathogeneses. Aims. To analyze the clinical characteristics of patients with drug-induced liver and/or kidney injury. Settings and Design. This was a retrospective study. Methods and Materials. We analyzed data from 162 patients with drug-induced liver and/or kidney injury from 2008 to 2018 at the Chinese Rocket Force Characteristic Medical Center. Univariate and multivariate logistic analyses were performed on the drugs used, sex, age, weight, complications, and laboratory test results. Statistical analysis was performed using SPSS 25.0 statistical software. Results. (1) The most common drugs causing organ injury in this study were antineoplastic drugs, antibiotics, traditional Chinese medicine, lipid-lowering drugs, and nonsteroidal anti-inflammatory drugs. (2) Among 22 patients with drug-induced liver and kidney injuries, 68.18% had a hepatocellular pattern, 13.64% had a mixed pattern, and 18.18% had a cholestatic pattern. Among the three groups, the P value for creatinine was 0.002. (3) The P value for urinary protein between the isolated kidney injury group and the liver and kidney injury group was 0.028. (4) Multivariate analysis showed that, among the drug-induced renal injury patients and all injury patients, those with a higher neutrophil percentage had a lower risk of liver injury (OR = 0.574, 95% CI: 0.390–0.846; OR = 0.545, 95% CI: 0.396–0.749). Conclusions. (1) The serum creatinine level was higher in liver injury patients with the cholestatic pattern than in those with the hepatocellular or mixed pattern. (2) There was a significant difference in urinary protein between the isolated kidney and the liver and kidney injury groups. (3) Among patients with drug-induced organ injury, those with a higher neutrophils percentage had a lower risk of liver injury.

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Section: Discussionmentioning

confidence: 99%

Clinical Characteristics of 162 Patients with Drug-Induced Liver and/or Kidney Injury

Wang

Chen

2020

BioMed Research International

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“…Epithelial polarization has been confirmed in these chip systems by tight junction formation and the presence of primary cilia (Jang et al, 2013;Jansen et al, 2015;Weber et al, 2016;Vedula et al, 2017;Vormann et al, 2018;Vriend et al, 2018), as well as proof-of-concept studies indicating that transepithelial transport of anionic and cationic organic compounds is feasible (Weber et al, 2016;Jansen et al, 2019;van der Made et al, 2019;Stahl et al, 2020). Kidney-on-a-chip models have been used to study drug-induced toxicity (Jang et al, 2013;Sakolish et al, 2018;Suter-Dick et al, 2018;Weber et al, 2018;Vormann et al, 2018;Maass et al, 2019), but crucially have not previously been applied to study the implications of epithelial polarization and localization of drug transporters for replication of membrane-dependent drug toxicity in vitro.…”

Section: Introductionmentioning

confidence: 91%

A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization–Dependent Cisplatin Toxicity

et al. 2020

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“…The use of microphysiological systems (MPS) or “organs on chips” that are three-dimensional organ cultures might be a better predictor [20]. In the MPS utilizing primary proximal tubular epithelial cells from donors, polymyxin B elicited injury responses such as shedding of kidney injury molecule-1 (KIM-1) and induction of heme oxygenase-1 (HMOX-1) [94]. At equimolar concentration, NAB741 had no effect.…”

Section: Nab741/spr741mentioning

confidence: 99%

“…Furthermore, polymyxin B, but not NAB741, upregulated the biosynthesis of cholesterol. Finally, NAB741 was bound to cell membranes (POPC lipid nanodiscs) with an affinity eight-fold lower than that for polymyxin B [94].…”

Section: Nab741/spr741mentioning

confidence: 99%

Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics

Vaara

2019

Molecules

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134

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Polymyxins (polymyxin B (PMB) and polymyxin E (colistin)) are cyclic lipodecapeptide antibiotics, highly basic due to five free amino groups, and rapidly bactericidal against Gram-negative bacteria, such as the majority of Enterobacteriaceae as well as Acinetobacter baumannii and Pseudomonas aeruginosa. Their clinical use was abandoned in the 1960s because of nephrotoxicity and because better-tolerated drugs belonging to other antibiotic classes were introduced. Now, due to the global dissemination of extremely-drug resistant Gram-negative bacterial strains, polymyxins have resurged as the last-line drugs against those strains. Novel derivatives that are less toxic and/or more effective at tolerable doses are currently under preclinical development and their properties have recently been described in several extensive reviews. Other derivatives lack any direct bactericidal activity but damage the outermost permeability barrier, the outer membrane, of the target bacteria and make it more permeable to many other antibiotics. This review describes the properties of three thus far best-characterized “permeabilizer” derivatives, i.e., the classic permeabilizer polymyxin B nonapeptide (PMBN), NAB7061, and SPR741/NAB741, a compound that recently successfully passed the clinical phase 1. Also, a few other permeabilizer compounds are brought up.

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Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity

Cited by 67 publications

References 52 publications

Clinical Characteristics of 162 Patients with Drug-Induced Liver and/or Kidney Injury

Clinical Characteristics of 162 Patients with Drug-Induced Liver and/or Kidney Injury

A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization–Dependent Cisplatin Toxicity

Polymyxin Derivatives that Sensitize Gram-Negative Bacteria to Other Antibiotics

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