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Fenofibrate Toxicity and Impact on Clinical Biomarkers in Patients with Dyslipidaemia

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Fenofibrate Toxicity and Impact on Clinical Biomarkers in Patients with Dyslipidaemia Fenofibrate toxicity and impact on clinical biomarkers in patients with dyslipidaemia Ivo Sama Fombon Department of Applied Sciences University of the West of England, Bristol May 2020 A thesis submitted in partial fulfilment of the requirements of the University of the West of England, Bristol for the degree of Professional Doctorate in Biomedical Sciences Fombon, I.S. (2020) Copyright Disclaimer This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without appropriate acknowledgement. i Fombon, I.S. (2020) ACKNOWLEDGEMENTS This thesis and the entire project could not have been achieved without the support of my supervisors, colleagues, family and friends. I would like to thank them immensely for their support. Firstly, I would like to thank my director of studies, Prof Myra Conway, for her guidance, support and encouragement. I am extremely grateful for her valuable time, expertise and advice on the design and conduct of the studies described in this thesis. I have learnt an incredible amount from her teachings, patience and hard work. I would like to thank Dr David James for making it possible for this project to be carried out at the laboratories of the Southwest Pathology Services, Taunton. Thank you too, Prof. Tim Reynolds for accepting to take part in this project and for helping to obtain the ethics approval for this project. Prof Tim Reynolds and Dr David James also recruited the participants for this project. To the staff of Southwest Pathology Services, Taunton, and Queen’s Hospital, Burton-on-Trent, I say thank you for helping with the collection and storage of patient samples. Your continuous encouragement and enquiry on the progress of the project also helped to keep me going. I am also thankful to the staff and students at the CRIB laboratory for their support during my lab sessions at UWE, particularly to Team Conway – Jon, Matt, Tom, Chris, Grace, Fred, Marcela and Mai. It was a pleasure working with you all. I would also like to say thank you to my wife, Irine, for having to listen about fenofibrate toxicity for the last six years, and to the entire Fombon family. I am thankful to the families of Chief and Rev. Mrs Anayo, Rudolf Dobdinga, Akin Ojo, Eric Ndifor and other friends who have been there with me on my journey. I am also thankful to all the participants of this project without whom this work would not have been realised. And to all, whose names have not been mentioned, I am not guilty of any omission, your names are engraved deep in my heart and I will forever remember you. ii Fombon, I.S. (2020) ABSTRACT Introduction and aims: Fenofibrate (FF) is the most widely used fibric acid derivative for managing mixed dyslipidaemia, characterised by elevated levels of cholesterol, triglycerides and low-density lipoprotein cholesterol and low levels of high-density lipoprotein cholesterol. It is linked with various adverse effects, notably FF-associated creatininaemia (or inferred nephrotoxicity), but also injury to liver and muscle cells. However, the mechanism and clinical significance of FF toxicity in these tissues remain unclear. Monitoring of kidney function is recommended in patients receiving FF therapy. However, due to limitations of measuring serum creatinine (a routinely used marker of kidney function), cystatin C, a low molecular weight protein has been proposed as a better marker of kidney function. The impact of FF on cystatin C clearance and its clinical utility for monitoring kidney function in patients receiving FF therapy have not been fully elucidated, a main aim of this study. The overall focus was to investigate the impact of FF on routine clinical biomarkers in patients with dyslipidaemia, evaluate the utility of cystatin C for monitoring kidney function in patients receiving FF therapy and investigate underlying mechanisms of FF toxicity to kidney and muscle cells. Methods: The impact of FF therapy on routine clinical biomarkers was examined in 19 adult (14 male, 5 female) patients with mixed dyslipidaemia, aged 34 – 70 years. All the particpants were administered FF at 160 mg/day and clinical biomarkers including kidney function test, liver function tests, lipid profile, markers of inflammation and muscle damage, and thyroid function tests were measured at baseline and after 3, 6 and 12 months after starting treatment. The impact of FF therapy on serum cystatin C level and cystatin C-based estimates of glomerular filtration rate (eGFR) was compared with serum creatinine level and creatinine- based eGFR. Furthermore, FF cytotoxicity was assessed in kidney (NRK52E and HEK293) and skeletal muscle (L6) cell lines using the MTS assay and the potential mechanisms investigated using the reactive oxygen species (ROS) assay and western blot analysis to determine changes in related apoptotic protein markers. Results: FF therapy reduced serum triglyceride concentrations and increased HDL cholesterol levels in patients with dyslipidaemia. A moderate increase in iii Fombon, I.S. (2020) serum creatinine, urea and cystatin C levels were observed after 3 months of treatment. These were accompanied by a decrease in eGFR using creatinine- based and cystatin C-based equations. Interestingly, this effect was reversed even when treatment was continued (after 12 months). Fenofibrate therapy also reduced serum uric acid concentration via increased urinary excretion. Serum liver enzymes were also reduced, with a much greater impact on serum ALP and GGT. The impact on liver enzymes was greater in individuals with higher pre-treatment values. Cystatin C-based eGFRs were higher than creatinine-based eGFRs suggesting underestimation of kidney function by the creatinine-based equations. Data from in vitro studies showed a dose- and cell line-dependent anti-proliferation impact of fenofibrate on the kidney and skeletal muscle cell lines, associated with oxidative stress due to intracellular ROS accumulation. Results from the western blot analysis of apoptosis-related proteins (Bax and Bcl-2) and the NFκB and MAPK signalling pathways did not indicate apoptosis as a potential mechanism of FF toxicity. Conclusion: This study confirms the association of fenofibrate therapy with increased serum creatinine levels, which is shown to be partially reversible even with long-term fenofibrate administration. Fenofibrate therapy is also shown to reduce serum uric acid and liver function tests. The clinical significance of the impact of FF therapy on serum uric acid and liver function tests is unclear. This study also suggests that fenofibrate is safe when administered within the therapeutic range. However, increased doses may be toxic to kidney and muscle cells via a mechanism that involves increased intracellular oxidative stress. iv Fombon, I.S. (2020) PRESENTATIONS AND PUBLISHED WORKS Poster presentation Fenofibrate induces apoptosis of normal muscle cells via accumulation of intracellular reactive oxygen species, Postgraduate Research Forum 2017, University of the West of England. v Fombon, I.S. (2020) TABLE OF CONTENTS ACKNOWLEDGEMENTS ...................................................................................... ii ABSTRACT ........................................................................................................... iii PRESENTATIONS AND PUBLISHED WORKS .................................................... v Poster presentation .............................................................................................. v TABLE OF CONTENTS ........................................................................................ vi LIST OF FIGURES AND TABLES ........................................................................ xi List of Figures ......................................................................................................... xi List of Tables ........................................................................................................ xiv ABBREVIATIONS ............................................................................................. xviii Chapter 1................................................................................................................ 1 Introduction and main aims ................................................................................. 1 1.1 DYSLIPIDAEMIA .............................................................................................. 1 1.2 CLASSIFICATION OF DYSLIPIDAEMIA.......................................................... 2 1.2.1 Familial (or primary) hyperlipidaemia ...................................................... 2 1.2.2 Acquired (or secondary) hyperlipidaemia ................................................ 3 1.3 MANAGEMENT OF DYSLIPIDAEMIA ............................................................. 4 1.3.1 Guidelines for managing dyslipidaemia .................................................. 5 1.3.2 Therapeutic lifestyle changes ................................................................. 7 1.3.3 Pharmacological management of dyslipidaemia ..................................... 9 1.3.4 Role of Fenofibrate in managing dyslipidaemia .................................... 25 1.3.5 Pleiotropic effects of FF therapy ........................................................... 27 1.3.6 Limitations of FF in the management of dyslipidaemia ......................... 28 1.4 IMPACT OF FF ON KIDNEY FUNCTION ...................................................... 30 1.5 MONITORING KIDNEY FUNCTION IN FF THERAPY..................................
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