Detecting nephrotoxic liabilities with Nephroscreen
Leiden, March 22, 2021 - Scientists from MIMETAS, Roche Innovation Center, Pfizer, GlaxoSmithKline (GSK), Utrecht Institute for Pharmaceutical Sciences, University of Applied Sciences Northwestern Switzerland, and the Swiss Centre for Applied Human Toxicology, developed a high throughput, 3D microfluidic platform (Nephroscreen) to detect drug-induced nephrotoxicity. The research is recently published in the journal Current Opinion in Toxicology.
Proximal tubule epithelial cells (PTEC) are the main driver of renal transport and secretion of xenobiotics, making them susceptible to drug-induced kidney injury (DIKI). Cell-based assays are a meaningful alternative to animal testing to detect nephrotoxicity and contribute to the 3Rs (Refine, Reduce, Replace animal experimentation). Here we report on a high throughput, 3D microfluidic platform (Nephroscreen) to detect drug-induced nephrotoxicity. Toxicologically relevant parameters were used to assess cell viability, functional epithelial barrier integrity, and interactions with specific transporters (P-glycoprotein: P-gp and multidrug resistance-associated protein 2/4: MRP2/4).
Nephroscreen allowed the combination of a variety of read-outs including imaging, extracellularly released markers, intracellular markers, and functional assays. Nephroscreen is compatible with automated pipetting, proved to be amenable to long-term experiments (at least eleven days) and was easily transferred between laboratories. The compelling data originates from several published reports on the development and implementation of this platform to detect nephrotoxicity and drug-transporter interactions. The reports demonstrate that Nephroscreen could be used to detect the nephrotoxic liabilities of the tested compounds. Future directions should include additional test compounds and thorough validation of its performance.
This project was supported under the Crack-it challenge 15 (Nephrotube) project no. 37497-25920, an initiative of the National Center for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs).