Molecular biomarkers and regulators of susceptibility to drug induced kidney injury

Sharkey, Jack
Molecular biomarkers and regulators of susceptibility to drug induced kidney injury. PhD thesis, University of Liverpool.

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Adverse drug reactions (ADRs) are undesirable effects of any therapeutic compound beyond its desired pharmacological effect. They are not only a serious issue for the sufferer but also bear a large societal cost and are one of the main reasons for the withdrawal of drugs from the market. Nephrotoxicity is the toxic affect of any exogenous compound on the kidney. The kidney is particularly susceptible to adverse effects of drugs due to its adaptations which allow it to carry out its physiological role efficiently. The kidney receives approximately 25 % of the cardiac output so is exposed to any blood borne toxin at high levels. The kidney also concentrates the filtrate as it passes through the nephron which exposes the epithelial cells of the nephron to much greater concentrations of any toxin present. The fact that the cells of the nephron are metabolically active and have active transport mechanisms also contribute towards the susceptibility of the kidney to ADRs. Adverse events which affect the kidney are often initially very subtle but can rapidly progress into more serious events if not detected early. A biomarker is any quantifiable change in an endogenous protein or molecule which can be indicative of a disease process or state. Current gold standard biomarkers of kidney injury include Serum Creatinine and blood urea nitrogen. Both of these are suboptimal biomarkers of kidney injury in terms of sensitivity and specificity so there is a real need for the development of more specific, translational biomarkers of kidney injury. Ideally these next generation biomarkers would also provide information on the location of the injury or the extent of the injury. MicroRNAs (miRNAs) are short ribonucleic acid sequences which are the smallest functional non-coding RNA units in plants and animals. Recent research has implicated miRNAs in many disease states, particularly cancers where many miRNA species have been shown to be aberrantly expressed. MiRNAs have also been shown to have potential as biomarkers of drug induced liver injury (DILI). This thesis focuses on the potential of miRNAs to serve as translational biomarkers of kidney injury. Techniques used to isolate, purify and quantify miRNA species were validated to determine the suitability of them for routine quantification in any laboratory. The qPCR technique was shown to be highly precise and sensitive for miRNA quantification. Intra-assay and inter-assay variation was low (

Item Type: Thesis (PhD)
Additional Information: Date: 2013-09 (completed)
Uncontrolled Keywords: Biomarkers, microRNA, miRNA, kidney, kidney injury, translational medicine, toxicity
Depositing User: Symplectic Admin
Date Deposited: 23 Feb 2015 15:13
Last Modified: 17 Dec 2022 01:13
DOI: 10.17638/00015213