In Vitro Models for Nephrotoxiciry Screening and Risk Assessment

Bach, Peter H.; Obatomi, David K.; Brant, Stephen

doi:10.1016/b978-012163390-5.50005-3

In Vitro Methods in Pharmaceutical Research 1997

DOI: 10.1016/b978-012163390-5.50005-3

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In Vitro Models for Nephrotoxiciry Screening and Risk Assessment

Peter H. Bach¹,

David K. Obatomi²,

Stephen Brant³

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Cited by 4 publications

References 205 publications

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Identification of Nephrotoxic Compounds with Embryonic Stem-Cell-Derived Human Renal Proximal Tubular-Like Cells

et al. 2014

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The kidney is a major target for drug-induced toxicity, and the renal proximal tubule is frequently affected. Nephrotoxicity is typically detected only late during drug development, and the nephrotoxic potential of newly approved drugs is often underestimated. A central problem is the lack of preclinical models with high predictivity. Validated in vitro models for the prediction of nephrotoxicity are not available. Major problems are related to the identification of appropriate cell models and end points. As drug-induced kidney injury is associated with inflammatory reactions, we explored the expression of inflammatory markers as end point for renal in vitro models. In parallel, we developed a new cell model. Here, we combined these approaches and developed an in vitro model with embryonic stem-cell-derived human renal proximal tubular-like cells that uses the expression of interleukin (IL)-6 and IL-8 as end points. The predictivity of the model was evaluated with 41 well-characterized compounds. The results revealed that the model predicts proximal tubular toxicity in humans with high accuracy. In contrast, the predictivity was low when well-established standard in vitro assays were used. Together, the results show that high predictivity can be obtained with in vitro models employing pluripotent stem cell-derived human renal proximal tubular-like cells.

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Identification of Nephrotoxic Compounds with Embryonic Stem-Cell-Derived Human Renal Proximal Tubular-Like Cells

et al. 2014

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Cross talk between primary human renal tubular cells and endothelial cells in cocultures

Tasnim

Zink

2012

American Journal of Physiology-Renal Physiology

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Interactions between renal tubular epithelial cells and adjacent endothelial cells are essential for normal renal functions but also play important roles in renal disease and repair. Here, we investigated cocultures of human primary renal proximal tubular cells (HPTC) and human primary endothelial cells to address the cross talk between these cell types. HPTC showed improved proliferation, marker gene expression, and enzyme activity in cocultures. Also, the long-term maintenance of epithelia formed by HPTC was improved, which was due to the secretion of transforming growth factor-β1 and its antagonist α2-macroglobulin. HPTC induced endothelial cells to secrete increased amounts of these factors, which balanced each other functionally and only displayed in combination the observed positive effects. In addition, in the presence of HPTC endothelial cells expressed increased amounts of hepatocyte growth factor and vascular endothelial growth factor, which have well-characterized effects on renal tubular epithelial cells as well as on endothelial cells. Together, the results showed that HPTC stimulated endothelial cells to express a functionally balanced combination of various factors, which in turn improved the performance of HPTC. The results give new insights into the cross talk between renal epithelial and endothelial cells and suggest that cocultures could be also useful models for the analysis of cellular communication in renal disease and repair. Furthermore, the characterization of defined microenvironments, which positively affect HPTC, will be helpful for improving the performance of this cell type in in vitro applications including in vitro toxicology and kidney tissue engineering.

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Achievements and challenges in bioartificial kidney development

Tasnim

Deng

et al. 2010

Fibrogenesis Tissue Repair

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Bioartificial kidneys (BAKs) combine a conventional hemofilter in series with a bioreactor unit containing renal epithelial cells. The epithelial cells derived from the renal tubule should provide transport, metabolic, endocrinologic and immunomodulatory functions. Currently, primary human renal proximal tubule cells are most relevant for clinical applications. However, the use of human primary cells is associated with many obstacles, and the development of alternatives and an unlimited cell source is one of the most urgent challenges. BAKs have been applied in Phase I/II and Phase II clinical trials for the treatment of critically ill patients with acute renal failure. Significant effects on cytokine concentrations and long-term survival were observed. A subsequent Phase IIb clinical trial was discontinued after an interim analysis, and these results showed that further intense research on BAK-based therapies for acute renal failure was required. Development of BAK-based therapies for the treatment of patients suffering from end-stage renal disease is even more challenging, and related problems and research approaches are discussed herein, along with the development of mobile, portable, wearable and implantable devices.

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In Vitro Models for Nephrotoxiciry Screening and Risk Assessment

Cited by 4 publications

References 205 publications

Identification of Nephrotoxic Compounds with Embryonic Stem-Cell-Derived Human Renal Proximal Tubular-Like Cells

Identification of Nephrotoxic Compounds with Embryonic Stem-Cell-Derived Human Renal Proximal Tubular-Like Cells

Cross talk between primary human renal tubular cells and endothelial cells in cocultures

Achievements and challenges in bioartificial kidney development

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