Development of urinary exosomes as biomarkers of drug-induced kidney injury

Aims

This project aims to develop the use of urinary exosomes as a non-invasive approach to assessing renal toxicity.

Background

Renal toxicity is estimated to account for around 2% of drug attrition in preclinical development and 19% in phase III clinical trials. Improving the identification of kidney toxicity and to ensuring better translation of biomarkers has the potential to reduce and refine the use of animals.

Damage to the kidneys as a result of drug toxicity is assessed as part of preclinical studies in animals. They tend not to be standalone studies unless a specific toxicity has been identified which requires further investigation. Assessment typically focuses on circulating biomarkers of kidney damage such as serum creatinine levels and post-mortem tissue analysis, however, these provide little information on the cellular site of injury or the underlying pathophysiology.

The use of urinary exosomes provides an opportunity to non-invasively investigate renal toxicity. This has a number of 3Rs advantages; early signs of renal toxicity should allow decisions to be made to terminate studies before animals suffer, and longitudinal studies in the same animal should be possible allowing animals to be used as their own control. Importantly, improved biomarkers which translate to the clinic should allow drugs to be dropped earlier in the pipeline before the extensive animal testing required to support late stage clinical trials.

Research details and methods

Exosomes are nanoparticle-sized vesicles which transport a range of molecules including microRNAs. They are derived from derived from a range of cells and released into blood and urine. This research aims to investigate whether rat urinary exosomes can be used as a non-invasive marker of renal toxicity.

Urinary exosomes have been shown to capsulate microRNA originating from the glomerulus and nephron. Recent evidence suggests that microRNAs are mediators of drug toxicity and therefore may provide potential biomarkers of cell injury. The research will explore the utility and reproducibility of urinary exosomes for analysis of kidney toxicity. It will employ nanoparticle tracking analysis technology and antibody labelling to identify exosome concentration and cellular origin.

Th'ng F et al. (2018). Evaluation of plasma microRNA-122, high-mobility group box 1 and keratin-18 concentrations to stratify acute gallstone disease: a pilot observational cohort study in an emergency general surgery unit. BMJ Open 8(4):e020061. doi: 10.1136/bmjopen-2017-020061

Rivoli L et al. (2017). The effect of renal dysfunction and haemodialysis on circulating liver specific miR-122. British Journal of Clinical Pharmacology 83(3):584-92. doi: 10.1111/bcp.13136

Rissin DM et al. (2017). Polymerase-free measurement of microRNA-122 with single base specificity using single molecule arrays: Detection of drug-induced liver injury. PloS One 12(7):e0179669. doi: 10.1371/journal.pone.0179669

Vliegenthart A et al. (2017). Circulating acetaminophen metabolites are toxicokinetic biomarkers of acute liver injury. Clinical Pharmacology and Therapeutics 101(4):531-40. doi: 10.1002/cpt.541

Vliegenthart ADB et al. (2017). Characterization of Triptolide-Induced Hepatotoxicity by Imaging and Transcriptomics in a Novel Zebrafish Model. Toxicological Sciences 159(2):280-91. doi: 10.1093/toxsci/kfx144

Vliegenthart ADB et al. (2017). MicroRNA-122 can be measured in capillary blood which facilitates point-of-care testing for drug-induced liver injury. British Journal of Clinical Pharmacology 83(9):2027-33. doi: 10.1111/bcp.13282

McCrae JC et al. (2016). Ethanol consumption produces a small increase in circulating miR-122 in healthy individuals. Clinical Toxicology 54(1):53-5. doi: 10.3109/15563650.2015.1112015

Vliegenthart AD et al. (2015). Comprehensive microRNA profiling in acetaminophen toxicity identifies novel circulating biomarkers for human liver and kidney injury. Scientific Reports 5:15501. doi: 10.1038/srep15501

Liga A et al. (2015). Exosome isolation: a microfluidic road-map. Lab on a Chip 15(11):2388-94. doi: 10.1039/c5lc00240k

Vliegenthart AD et al. (2015). Target biomarker profile for the clinical management of paracetamol overdose. British Journal of Clinical Pharmacology 80(3):351-362. doi: 10.1111/bcp.12699

Vliegenthart AD et al. (2014). Retro-orbital blood acquisition facilitates circulating microRNA measurement in zebrafish with paracetamol hepatotoxicity. Zebrafish 11(3):219-26. doi: 10.1089/zeb.2013.0912

Vliegenthart AD et al. (2014). Zebrafish as model organisms for studying drug-induced liver injury. British Journal of Clinical Pharmacology 78(6):1217-27. doi: 10.1111/bcp.12408

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PhD Studentship

Status:

Closed

Principal investigator

Dr James Dear

Institution

University of Edinburgh

Co-Investigator

Dr Matthew Bailey
Professor David John Webb

Grant reference number

NC/K001485/1

Award date:

Oct 2013 - Sep 2016

Grant amount

£90,000