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Fenofibrate toxicity and impact on clinical biomarkers in patients with dyslipidaemia

Fombon, Ivo

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Authors

Ivo Fombon



Abstract

Introduction and aims: Fenofibrate is the most widely used fibric acid derivative for managing mixed dyslipidaemia, characterised by elevated levels of cholesterol, triglycerides and LDL cholesterol and low levels of HDL cholesterol. Fenofibrate is associated with various adverse effects, notably fenofibrate-associated creatininaemia (or inferred nephrotoxicity), but also injury to liver and muscle cells. However, the mechanism and clinical significance of fenofibrate toxicity in these tissues remain unclear. Monitoring of kidney function is recommended in patients receiving fenofibrate 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 touted as a better marker of kidney function. The impact of fenofibrate on cystatin C clearance and its clinical utility for monitoring kidney function in patients receiving fenofibrate therapy have not been fully elucidated, a main aim of this study. The overall focus was to investigate the impact of fenofibrate on routine clinical biomarkers in patients with dyslipidaemia, evaluate the utility of cystatin C for monitoring kidney function in patients receiving fenofibrate therapy and investigate underlying mechanisms of fenofibrate toxicity to kidney and muscle cells.
Methods: The impact of fenofibrate (160 mg/day) on routine clinical biomarkers was evaluated in 15 adult patients with dyslipidaemia. The 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 of fenofibrate (160 mg/day) therapy. We also assessed the impact of fenofibrate on serum cystatin C level and compared cystatin C-based eGFR with creatinine-based eGFR for monitoring kidney function in patients administered fenofibrate. Furthermore, fenofibrate 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 ROS assay and Western blot analysis to determine changes in related apoptotic protein markers.
Results: Fenofibrate therapy reduced serum triglyceride concentrations and increased HDL cholesterol levels in patients with dyslipidaemia. A moderate increase in 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 ALP was also significantly reduced, the greatest impact observed 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, which caused an imbalance in the pro- and anti-apoptosis protein leading to modulation of the NFκB and MAPK signalling pathways of apoptosis.
Conclusion: Our results have confirmed the association of fenofibrate with kidney function impairment, which is shown to be partially reversible even with long-term fenofibrate administration. We have demonstrated other beneficial effects of fenofibrate therapy, including the reduction of serum uric acid and liver function tests. Our study has also shown that fenofibrate is a safe drug compared to 5-FU (anticancer drug used in the clinics). However, increased doses of fenofibrate may be toxic to kidney and muscle cells via a mechanism that involves oxidative stress and modulation of NFκB and MAPK apoptosis signalling pathways.

Citation

Fombon, I. Fenofibrate toxicity and impact on clinical biomarkers in patients with dyslipidaemia. (Thesis). University of the West of England. Retrieved from https://uwe-repository.worktribe.com/output/3829730

Thesis Type Thesis
Deposit Date Oct 16, 2019
Publicly Available Date Mar 29, 2024
Public URL https://uwe-repository.worktribe.com/output/3829730
Award Date Jul 14, 2020

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