Advances in predictive in vitro models of drug-induced nephrotoxicity

Abstract

In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

Modeling acute kidney injury in kidney organoids with cisplatin

“…In recent years, kidney organoids differentiated from human pluripotent stem cells (hPSC) have been established to study various types of kidney disorders (5,8). Kidney organoids were reported to be susceptible to proximal tubule injury caused by nephrotoxins, such as cisplatin (2,9,16,17). However, a full characterization of the effects of cisplatin in this system has been lacking.…”

A Highly Sensitive Fluorogenic Assay for the Detection of Nephrotoxin-Induced Oxidative Stress in Live Cells and Renal Tissue

“…While monolayers of renal cells in culture serve as the current gold standard for screening nephrotoxins, the complexity of the renal system as a whole is not comprehensively represented by any single cell type in culture [1,25]. More physiologically relevant screening platforms are critical for improving safety profile predictability.…”

“…Drug-induced kidney injury, or nephrotoxicity, is a critical limiting factor in the development of new therapeutics. Existing preclinical screening processes are often unable to predict nephrotoxicity in humans, which results in failed clinical trials [1,2]. Currently used phenotypic preclinical screening assays measure alterations in cell viability, morphology and mitochondrial function [2].…”

“…However, the majority of these assays detect only severe forms of injury at high doses and/or after lengthy exposure to compounds. Therefore, these assays are insensitive to modest changes that can potentially generate a much greater magnitude of toxicity in vivo [1]. Recently a heme oxygenase-1-based nephrotoxicity screening assay has been reported [3,4,5].…”

Nephrotic syndrome in a dish: recent developments in modeling in vitro

“…Using either 2D or 3D culture approaches, and varying the choice and/or timing of growth factors, result in the induction of one renal cell type (e.g., podocyte-like cells) [15,21,55,56] or in self-organizing kidney organoids consisting of segmented nephrons [22,23,[57][58][59]. These protocols are extensively reviewed by Soo et al [60]. In brief, a combination of Wnt signaling agonist CHIR, fibroblast growth factors 2 and 9, bone morphogenic protein 2 or 4, as well as retinoic acid, vascular endothelial growth factor, and activin A are most commonly used as growth factors.…”