Nephrotoxicity

About

The kidneys have important functions within organisms such as detoxification, regulation of extracellular fluids, homeostasis and excretion of toxic metabolites. [1] Impairment of normal kidney function can lead to severe diseases and, if untreated, to death. Such impairment can be caused by substances that interact with molecular mechanisms leading to nephrotoxicity, including renal tubular toxicity, inflammation, glomerular damage, crystal nephropathy and thrombic microangiopathy. [1] One typical mechanism is that the drug induces inflammatory responses and oxidative stress that lead to necrosis and apoptosis what results in tissue damage, reduced Glomerular Filtration Rates and acute kidney injury. (Figure1).

Figure1: Common mechanism that induces kidney dysfunction. Adapted and modified from Kristen Renee McSweeney et al. 2021 [2]

Therefore, especially during drug development and in the food industry, where exposure of substances to the kidney is high, assessment for neurotoxic risk of compounds is key to ensure the development of safe and sustainable products which customers can use without any concern. At SaferWorldbyDesign we provide solutions with which you can characterize your compounds and based on this make important decisions throughout the development of your products to ensure that your products are safe and sustainable.

References

[1] Nephrotoxicity: Role and significance of renal biomarkers in the early detection of acute renal injury by Marwa S. Al-Naimi, Huda A. Rasheed, Nawar R. Hussein, Hayder M. Al-Kuraishy and Ali I. Al-Gareeb in the Journal of Advanced Pharmaceutical Technology and Research – Wolters Kluwer – Medknow, 2019.

[2] Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions and Genetic Mitigations by Kristen Renee McSweeney, Laura Kate Gadanec, Tawar Qaradakhi, Benazir Ashiana Ali, Anthony Zulli and Vasso Apostolopoulos in Cancers, 13(7), 2021.

Solutions that we offer

With our Nephrotoxicity package we provide a wide variety of solutions adapted to your needs based on OECD guidelines. With our machine learning in silico approaches we characterize your compounds in concern of nephrotoxicity to offer you results with which you can make important decisions during product development for instance. Furthermore, together with our partners we offer a variety of different assays, which help in characterizing your compounds and offer a shop where you can purchase cell lines and tissues which you can use for your own research. Please have a look at our Partner contribution's subsection and the shop section, where you can have a look at what we offer.

Partner contribution

Biopredic

Beside primary hepatocytes and diverse liver tissue samples, Biopredic provides their most innovative and useful hepatic cell line «HepaRG» with which it is possible to produce early hepatic progenitor cells as well as completely mature human hepatocytes.

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InSphero

InSphero has a profound liver toxicity expertise and offers customized solutions for your needs in liver toxicity characterization. This includes the offering of 3D InSight Human Liver tissue models which can be used for confident Drug Induced Liver Injury (DILI) studies to predict possible side effects of compounds. Furthermore, InSphero offers diverse assays including Omics profiling, inflammation mediated toxicity, CYP-mediated toxicity, Cholestasis, Drug induced steatosis and apoptosis - assay to assist you in the development of your new safe and green product.

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Phenaris

Phenaris provides you with:

• Computational transporter models including data curation, model building and data analysis.
• ToxPHACTS including similarity search, data extraction and data analysis. A kinetics data.
• repository including data collection, data integration and data analysis.

With this you have an expertise which constantly challenges the status quo in computational drug design and in silico toxicology.

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TissUse

TissUse is a German based company which has developed a multi organ on a chip technique to replace animal experiments. Those chips can be used during drug development, in cosmetics, food, nutrition and consumer products to predict toxicity, ADME profiles and in vitro efficacy for example.

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Regulatory framework

To ensure integrity of experimental outcomes, the OECD has developed guidelines on Integrated Approaches on Testing and Assessment (IATA) where key events are identified for an Adverse Outcome Pathway initiated by Molecular Initiating Events (MOEs). Focusing on kidney injury, those MOEs include 1. inhibition of mitochondrial DNA polymerase γ (mtDNA Polγ), 2. receptor mediated endocytosis and lysosomal overload, and 3. covalent protein binding. [1] Those MOEs lead to key events downstream of their pathway all resulting in kidney toxicity. Figure 2 illustrates an example of nephrotoxicity induced by Acyclic Nucleoside Phosphatase.

References

[1] Mapping Adverse Outcome Pathways for Kidney Injury as a Basis for the Development of Mechanism-Based Animal-Sparing Approaches to Assessment of Nephrotoxicity by Angela Mally and Sebastian Jarzina in Frontiers in Toxicology, Volume 4, Article 863643, June 2022.