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 which results in tissue damage, reduced Glomerular Filtration Rates and acute kidney injury. (Figure 1).

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 nephrotoxic 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.

Our services

With our Nephrotoxicity package we provide a wide variety of solutions adapted to your needs. With our machine learning in silico approaches we characterize your compounds in a in concern of nephrotoxicity to offer you results with which you can make important decisions during product development.

Our services are based on a tiered strategy where we provide in silico machine learning solutions in a first phase. Thereby, we apply a variety of algorithms on already existing data from verified datasets. Based on feature extraction and ontology characterization, we evaluate your compounds and provide you with a detailed report as base to discuss on how you can proceed to improve your products, ensuring consumer safety and sustainability.

In a second tier approach we further evaluate your compounds by next generation in vitro assays that are specific for endocrine disruption endpoints. Resulting data can be implemented into the in silico tools to confirm outcomes of the first tier.

Data management is key for successful and efficient risk assessment. At SaferWorldbyDesign, we manage data under FAIR principles so that it is easy Findable, Accessible, Interoperable and Reusable. Thereby, our data is harmonized and managed through premium customer accounts on a secure cloud.

Partner contribution

Biobide

Biobide is a leader in zebrafish testing, committed to quality and customer service efficiency. Biobide has expertise in nephrotoxicity risk assessment. With their zebrafish embryo model they can study the morphology (development) of the pronephric tubules and evaluate impact on kidney function.

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TissUse

TissUse is a German based company which has developed a multi organ on a chip system to replace animal experiments. These 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. Compounds can be evaluated with an established TissUse Liver - Kidney interaction model.

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Vrije Universiteit Amsterdam

The Vrije Universiteit Amsterdam has the expertise in toxicology risk assessment and offers assay to evaluate:

• Biokinetics
• Cellular impedence
• HCL
• Lactate
• Mitochondrial respiration
• Resazurin
• Toxicogenomics
• custom nephrotox service
• Evercyte cell line

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Edelweiss Connect

Edelweiss Connect leverages its data expertise to assist in the modeling of nephrotoxicity. Using machine learning techniques, Edelweiss Connect can help identify key markers and patterns that may show a substance’s potential to cause toxic effects to the kidneys, allowing for better-informed decision-making in the drug development and risk assessment process.

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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 (MIEs).

• OECD Guidelines for the testing of chemicals