Project Details
Projekt
Integrative assessment of kidney tissue toxicity
Subject Area
Nephrology
Term
since 2025
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 445703531
As an excretory organ, the kidney is challenged by numerous toxic substances, which can transition to nephrotoxicity. Nephrotoxicity is a relatively common finding in kidney biopsies, but markers indicating the causative agent are missing. Despite the frequency and importance of renal side effects of many drugs, understanding of the mechanisms of nephrotoxicity is limited. In our previous and preliminary work, we have established animal models to test nephrotoxins, a reverse toxicogenomic pipeline to identify toxins from tissue molecular signatures, and a prospective observational study with pharmacogenetic data and a biobank of emergency visits due to adverse drug reactions in patients with polypharmacy. We hypothesize that integrating tissue morphometric and (spatial) molecular expression data with existing toxicological and pharmacological knowledge will uncover novel features of nephrotoxicity and enhance pathomechanistic insight, diagnostics and toxicity predictions. To tackle this, we will combine complementary expertise in clinical pharmacology (Stingl) with experimental nephrology and environmental science (Vervaet), and methods from multiple CRU projects. In WP1, to identify tissue-based patterns of nephrotoxicity, we will characterize kidney morphological and molecular alterations in animals exposed to nephrotoxic drugs, like calcineurin inhibitors, or environmental substances, like pesticides. We will use detailed histopathological assessment, pathomics (with P4), multiplex imaging, spatial transcriptomics (with P2), and their integration (with P8). In WP2, we will create similar maps in patients' kidney biopsies with drug and environmental toxin-induced injury. We will also establish humanized in vitro models, including organoids (with P1 and P10), to facilitate translational testing. In WP3, we will develop a computational approach aimed at identifying nephrotoxic substrates based on the kidney morpho-molecular alterations. For validation, we will use animal and human tissues from well-recognized entities, e.g., calcineurin inhibitor nephropathy, and apply it to diseases likely caused by environmental toxin(s), e.g., chronic interstitial nephritis in agricultural communities. Hereto, we will extend our reverse toxico- and pharmacogenomics framework, which uses public toxicological and pharmacological databases, with own molecular tissue profiles (with P2) and morphometric findings (with P4). In WP4, nephrotoxicity will be assessed in Real-World conditions analyzing the burden of nephrotoxic drugs in polypharmacy patients (taking >5 drugs) in a reverse pharmaco-genomic approach. In conclusion, using a comprehensive integration of methods, we will set the basis for a novel approach to study nephrotoxicity. The long-term vision is to identify and validate a panel of morpho-molecular markers reflecting specific nephrotoxins, potentially facilitating screening of new drug candidates or (tissue) diagnostics of nephrotoxicity.
DFG Programme
Clinical Research Units
