It is reported that approximately 25% of cases of renal failure are related to drug-induced nephrotoxicity. This is an alarming statistic, especially when considering the high mortality rate associated with renal failure. Therefore, having reliable in vitro methods that are capable of detecting human nephrotoxicity during drug discovery and early drug development would be of value in preventing these safety issues in the future.
Cyprotex is pioneering research in this field through its expertise in 2D and 3D cell-based models, confocal high content screening and in vitro drug transporter science. Primary cells such as human renal proximal tubule epithelial cells (RPTEC) exhibit renal drug transporter activity. This characteristic is an important aspect of drug accumulation and associated toxicity in the kidney, making these cells an ideal cell choice when developing models for assessing nephrotoxicity.
Recent research performed by Cyprotex evaluated three different in vitro kidney models including a:
- 2D kidney model using human primary RPTEC alone
- 3D kidney model using human primary RPTEC alone
- 3D kidney model using human primary RPTEC in co-culture with human primary renal cortical epithelial cells and human primary renal fibroblasts
In the study, reference compounds from a range of chemical classes were dosed over 3 days, 9 days or 14 days. Markers of toxicity were assessed including glutathione depletion, accumulation of phospholipids, mitochondrial disruption and cellular ATP content. Confocal high content imaging techniques were used to analyse the cells.
The research demonstrates that both 2D and 3D in vitro kidney models are capable of detecting drug-induced nephrotoxicity. Using sophisticated high content imaging techniques, it is also possible to gain an in-depth analysis of the cellular responses behind the nephrotoxicity.
This research was presented at SOT in Baltimore in March 2017.