Vormann MK(1), Vriend J(2), Lanz HL(1), Gijzen L(1), van den Heuvel A(1), Hutter S(3), Joore J(1), Trietsch SJ(1), Stuut C(2), Nieskens TTG(2), Peters JGP(2), Ramp D(4), Caj M(4), Russel FGM(2), Jacobsen B(5), Roth A(5), Lu S(6), Polli JW(7), Naidoo AA(8), Vulto P(1), Masereeuw R(9), Wilmer MJ(2), Suter-Dick L(10). Author information:
(1)MIMETAS B.V., Leiden, the Netherlands.
(2)Department of Pharmacology and Toxicology, Radboud Institute for Molecular
Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
(3)MIMETAS B.V., Leiden, the Netherlands; School of Life Sciences, University of
Applied Sciences Northwestern Switzerland, Muttenz, Switzerland.
(4)School of Life Sciences, University of Applied Sciences Northwestern
Switzerland, Muttenz, Switzerland.
(5)F. Hoffmann-La Roche Ltd., Roche Innovation Center Basel, Switzerland.
(6)Pfizer Inc., San Diego, USA.
(7)Mechanistic Safety and Disposition, GlaxoSmithKline, Upper Merion, PA, USA.
(8)Mechanistic Safety and Disposition, GlaxoSmithKline, Ware, UK.
(9)Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences,
Utrecht, the Netherlands.
(10)School of Life Sciences, University of Applied Sciences Northwestern
Switzerland, Muttenz, Switzerland; Swiss Centre for Applied Human Toxicology
(SCAHT), Basel, Switzerland. Electronic address: [Email]
Proximal tubule epithelial cells (PTEC) are susceptible to drug-induced kidney injury (DIKI). Cell-based, two-dimensional (2D) in vitro PTEC models are often poor predictors of DIKI, probably due to the lack of physiological architecture and flow. Here, we assessed a high throughput, 3D microfluidic platform (Nephroscreen) for the detection of DIKI in pharmaceutical development. This system was established with four model nephrotoxic drugs (cisplatin, tenofovir, tobramycin and cyclosporin A) and tested with eight pharmaceutical compounds. Measured parameters included cell viability, release of lactate dehydrogenase (LDH) and N-acetyl-β-d-glucosaminidase (NAG), barrier integrity, release of specific miRNAs, and gene expression of toxicity markers. Drug-transporter interactions for P-gp and MRP2/4 were also determined. The most predictive read outs for DIKI were a combination of cell viability, LDH and miRNA release. In conclusion, Nephroscreen detected DIKI in a robust manner, is compatible with automated pipetting, proved to be amenable to long-term experiments, and was easily transferred between laboratories. This proof-of-concept-study demonstrated the usability and reproducibility of Nephroscreen for the detection of DIKI and drug-transporter interactions. Nephroscreen it represents a valuable tool towards replacing animal testing and supporting the 3Rs (Reduce, Refine and Replace animal experimentation).
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