An in vitro method for the prediction of renal proximal tubular toxicity in humans

Yao, Li; Oo, Zay Yar; Chang, Shu Yung; Huang, Peng; Eng, Kim Guan; Zeng, Jialiu; Kaestli, Alicia J.; Gopalan, Began; Kandasamy, Karthikeyan; Tasnim, Farah; Zink, Daniele

doi:10.1039/c3tx50042j

Cited by 57 publications

(119 citation statements)

References 52 publications

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“…20 We did not observe KIM-1 upregulation in HPTECs cultured in 2D consistent with a previous study, 10 or even consistently when HPTECs were cultured in the microphysiological 3D kidney system ( Figure 4B), highlighting the need for new biomarkers applicable to in vitro as well as in vivo and human studies.…”

Section: Discussionsupporting

confidence: 71%

“…Immortalized kidney epithelial cell lines, derived from human kidney (HK-2), 7 pig kidney (LLC-PK1), or dog kidney (MDCK), 8 frequently used for nephrotoxicity studies, do not fully express all the differentiated functions found in their in vivo counterparts due to loss of polar architecture and changes in drug transporter expression. 9,10 Primary proximal tubular epithelial cells of human origin, being the predominant target of most toxicants in the kidney, 11 are characterized by polarity and junctional assembly of epithelia, brush border enzyme activity, and metabolic and transport capacity. 10,[12][13][14] Among the currently available two-dimensional (2D) models, they are the model that comes closest to the ideal with respect to kidney physiology and toxicology studies.…”

mentioning

confidence: 99%

“…9,10 Primary proximal tubular epithelial cells of human origin, being the predominant target of most toxicants in the kidney, 11 are characterized by polarity and junctional assembly of epithelia, brush border enzyme activity, and metabolic and transport capacity. 10,[12][13][14] Among the currently available two-dimensional (2D) models, they are the model that comes closest to the ideal with respect to kidney physiology and toxicology studies.…”

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confidence: 99%

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A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

105

102

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Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality and morbidity, but there is no high throughput in vitro method for predictive nephrotoxicity assessment. We show that primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated epithelial cells rendering them desirable to use in such in vitro systems. To identify a reliable biomarker of nephrotoxicity, we conducted multiplexed gene expression profiling of HPTECs after exposure to six different concentrations of nine human nephrotoxicants. Only overexpression of the gene encoding heme oxygenase-1 (HO-1) significantly correlated with increasing dose for six of the compounds, and significant HO-1 protein deregulation was confirmed with each of the nine nephrotoxicants. Translatability of HO-1 increase across species and platforms was demonstrated by computationally mining two large rat toxicogenomic databases for kidney tubular toxicity and by observing a significant increase in HO-1 after toxicity using an ex vivo three-dimensional microphysiologic system (kidneyon-a-chip). The predictive potential of HO-1 was tested using an additional panel of 39 mechanistically distinct nephrotoxic compounds. Although HO-1 performed better (area under the curve receiver-operator characteristic curve [AUC-ROC]=0.89) than traditional endpoints of cell viability (AUC-ROC for ATP=0.78; AUC-ROC for cell count=0.88), the combination of HO-1 and cell count further improved the predictive ability (AUC-ROC=0.92). We also developed and optimized a homogenous time-resolved fluorescence assay to allow high throughput quantitative screening of nephrotoxic compounds using HO-1 as a sensitive biomarker. This cell-based approach may facilitate rapid assessment of potential nephrotoxic therapeutics and environmental chemicals. Drugs and environmental chemicals, such as aminoglycoside antibiotics, analgesics, chemotherapeutic agents, and heavy metals, as well as endemic toxins like aristolochic acid are a common cause of AKI or CKD. 1,2 Current approaches to conduct safety and risk assessment of compounds rely predominantly on animal studies, and these results are extrapolated to dose effects in humans despite knowledge that the typical responses of animal models and humans can differ greatly. 3 The lack of adequate models to accurately predict human toxicity contributes to an underestimation of the kidney toxic potential of new therapeutic candidates, which also explains why nephrotoxic effects in patients are often only detected during late phase

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Section: Discussionsupporting

confidence: 71%

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confidence: 99%

mentioning

confidence: 99%

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A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

105

102

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“…Induction of these three CYP forms, HO-1, and IL-8 are seen in both acute (1-day) and chronic (13-day) exposure conditions. Supporting the U133 GeneChip data, Li et al (2013) observed that expression of IL-6, and IL-8 in human primary renal proximal tubular cells were increased after Cd exposure. Only a few previous studies have examined CYP expression in primary culture of human proximal tubular cells (PTCs).…”

Section: Cadmium and The Pathogenesis Of Hypertension In Humanssupporting

confidence: 51%

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

Satarug

Vesey

Gobé

2017

Tohoku J. Exp. Med.

104

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“…Most of these predictors have only been tested in around ten or less compounds [2]. Recently, Li et al have developed an in vitro predictor based on the expression levels of two inflammatory markers, interleukin (IL)-6 and -8, in human primary renal proximal tubular cells (HPTCs) [14] and human embryonic stem cell-derived HPTC-like cells [15]. These markers were tested in a larger number of 41 compounds, and gave higher prediction accuracy than many previous predictors [2].…”

Section: Introductionmentioning

confidence: 99%

Supervised prediction of drug-induced nephrotoxicity based on interleukin-6 and -8 expression levels

Zink

et al. 2014

BMC Bioinformatics

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BackgroundDrug-induced nephrotoxicity causes acute kidney injury and chronic kidney diseases, and is a major reason for late-stage failures in the clinical trials of new drugs. Therefore, early, pre-clinical prediction of nephrotoxicity could help to prioritize drug candidates for further evaluations, and increase the success rates of clinical trials. Recently, an in vitro model for predicting renal-proximal-tubular-cell (PTC) toxicity based on the expression levels of two inflammatory markers, interleukin (IL)-6 and -8, has been described. However, this and other existing models usually use linear and manually determined thresholds to predict nephrotoxicity. Automated machine learning algorithms may improve these models, and produce more accurate and unbiased predictions.ResultsHere, we report a systematic comparison of the performances of four supervised classifiers, namely random forest, support vector machine, k-nearest-neighbor and naive Bayes classifiers, in predicting PTC toxicity based on IL-6 and -8 expression levels. Using a dataset of human primary PTCs treated with 41 well-characterized compounds that are toxic or not toxic to PTC, we found that random forest classifiers have the highest cross-validated classification performance (mean balanced accuracy = 87.8%, sensitivity = 89.4%, and specificity = 85.9%). Furthermore, we also found that IL-8 is more predictive than IL-6, but a combination of both markers gives higher classification accuracy. Finally, we also show that random forest classifiers trained automatically on the whole dataset have higher mean balanced accuracy than a previous threshold-based classifier constructed for the same dataset (99.3% vs. 80.7%).ConclusionsOur results suggest that a random forest classifier can be used to automatically predict drug-induced PTC toxicity based on the expression levels of IL-6 and -8.

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An in vitro method for the prediction of renal proximal tubular toxicity in humans

Cited by 57 publications

References 52 publications

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Kidney Cadmium Toxicity, Diabetes and High Blood Pressure: The Perfect Storm

Supervised prediction of drug-induced nephrotoxicity based on interleukin-6 and -8 expression levels

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