Kidney-based in vitro models for drug-induced toxicity testing

Abstract

The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs' microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.

Drug‐target‐ADR Network and Possible Implications of Structural Variants in Adverse Events

“…If we remove the cytochrome enzymes, proteins such as ALB, SLC22 A6, PTGS1, UGT2B7, UGT1 A9, and PTGS2 are highly related to ‘Acute kidney injury’ (Figure 3). Some of these proteins have been associated with this adverse effect in studies [39–41] . ‘Somnolence’ is highly related to ADRA1 A, but so far, no clear relationship has been reported in the literature.…”

“…Some of these proteins have been associated with this adverse effect in studies. [39][40][41] 'Somnolence' is highly related to ADRA1 A, but so far, no clear relationship has been reported in the literature. Finally, 'Toxicity to various agents' is highly associated with the human H1 receptor (HRH1).…”

Human Organs-on-Chips for Virology

“…Conventional in vitro kidney models with primary cells have limited growth capacity and, just like liver, tend to lose their phenotype over time [ 51 ]. While kidney organoids cultured from human induced pluripotent stem cells (hiPSCs) can contain cell types from different nephron segments, they do not accurately reflect the kidney in vivo , in part due to the lack of fluid flow and the correct kidney vasculature [ 52 ]. However, advances in kidney chip models are providing new options that overcome many of these hurdles and more closely resemble the physiological environment and anatomy of the human kidney.…”

“…While this model proved successful in demonstrating virus-related pathogenesis and symptoms, further developments are still needed to better reflect in vivo physiological and functional changes in response to infection. Namely, the incorporation of spatial features of kidney, ECM components, heterogeneous composition of (human) cell types and fluid shear stress, as well as the coordination of microvilli, cilia, and glycocalyx with each other in response to flow [ 52 ].…”

Drug Toxicity Evaluation Based on Organ-on-a-chip Technology: A Review

“…To simulate the toxic effects of drug candidates on different cells, tissues, or organs of the human body, scientists have constructed many organ-on-a-chip models that simulate single or multiple organs, e.g., the liver [13]-, kidney [14]-, heart [15]-, nerves [16]-, and multi-organs-on-chips [17]. These models have been proven to have the potential to develop into new platforms for drug toxicity detection [18].…”