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The identification of novel urine biomarkers of chronic kidney disease that offer better prediction of progression than conventional clinical methods.

Abedin, Zainal (2016) The identification of novel urine biomarkers of chronic kidney disease that offer better prediction of progression than conventional clinical methods. PhD thesis, University of Sheffield.

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Chronic Kidney Disease (CKD) is a major public health problem. A major limitation of therapeutic interventions is failure of identification at early and intermediate stages. The current markers of CKD like albuminuria, proteinuria and estimated glomerular filtration rate (eGFR) are typically altered when the kidney has already experienced moderate to severe damage. Therefore, there is a requirement to search for new biomarkers for the better identification of CKD. The overall aim of this project was to look for new protein markers that could be assayed in patients’ urine. Potential new candidate markers of CKD progression were identified by reviewing recent literature and by exploring the cytokine contents of patient urine samples through array-based multiplex immunological assays. These literature searches identified KIM-1, MCP-1 and NGAL, which are already used as markers of acute kidney injury, as possible new markers of CKD. Additionally the results of array-based immunological assays (Proteome Profiler Arrays) identified CXCL-16, DPP-IV, leptin and IL-8 as potential biomarkers. Our hypothesis was that the urine levels of these proteins might reflect the extent of fibrosis and thus the rate of CKD progression. This was tested by performing ELISA assays of our candidates on urine samples from a cohort of 262 patients with various types of CKD and rate of progression and, for controls, from 47 healthy individuals. Patients were categorised as non-progressors or progressors based on loss of eGFR per year (≤ 2 and > 2ml/min/yr, respectively). The predictive potential of the candidate markers were then assessed through statistical analyses of the ELISA results. The results suggest that KIM-1 predicts the progression of CKD, though less accurately than the current clinical marker albumin: creatinine ratio (ACR). DPP-IV and CXCL-16 also appear to predict progression for diabetic patients and CXCL-16 also seem to be predictive for hypertensive patients. Finally, at the end of the project, a pilot quantitative analysis of urine proteomes by mass spectrometry was undertaken to identify new candidate markers using the iTRAQ methodology. While the power of this pilot study was limited, it identified 4 possible candidate markers (Apolipoprotein-A1, Cathepsin-D, Fibrinogen and haemoglobin β) and identified the technical requirements for planning more successful new attempts in the future. The predictive value of the candidates identified by iTRAQ remains to be assayed in future studies.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.694138
Depositing User: Dr Zainal Abedin
Date Deposited: 13 Sep 2016 15:06
Last Modified: 03 Oct 2016 13:19
URI: http://etheses.whiterose.ac.uk/id/eprint/13805

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