A Randomized Controlled Trial of the Effects of Febuxostat Therapy on Adipokines and Markers of Kidney Fibrosis in Asymptomatic Hyperuricemic Patients With Diabetic Nephropathy

Srinivasan Beddhu, Rebecca Filipowicz, Bin Wang, Guo Wei, Xiaorui Chen, Abinash C Roy, Scott L DuVall, Hanadi Farrukh, Arsalan N Habib, Terrence Bjordahl, Debra L Simmons, Mark Munger, Greg Stoddard, Donald E Kohan, Tom Greene, Yufeng Huang
Canadian Journal of Kidney Health and Disease 2016, 3: 2054358116675343

BACKGROUND: In observational studies, higher uric acid levels are associated with metabolic syndrome, diabetes, and kidney disease.

OBJECTIVE: The objective of this study is to examine whether reduction of plasma uric acid with febuxostat, a xanthine oxido reductase inhibitor, impacts adipose tissue oxidative stress, adipokines, and markers of systemic inflammation or kidney fibrosis.

DESIGN: This was a double-blinded randomized controlled trial.

SETTING: Academic university setting was used.

PATIENTS: Overweight or obese adults with hyperuricemia and type 2 diabetic nephropathy were included.

MEASUREMENTS: Adipose tissue thiobarbituric acid reducing substances (TBARS) and adiponectin concentrations and urinary transforming growth factor-β (TGF-β) were primary endpoints. Plasma C-reactive protein, high molecular weight-adiponectin, interleukin-6, tumor necrosis factor-α, and TBARS and albuminuria were among predefined secondary endpoints.

METHODS: Participants were randomly assigned to febuxostat (n = 40) or matching placebo (n = 40) and followed for 24 weeks.

RESULTS: Baseline plasma uric acid levels were 426 ± 83 µmol/L; 95% completed the study. Estimated glomerular filtration rate (eGFR) declined from 54 ± 17 mL/min/1.73 m2 at baseline to 51 ± 17 mL/min/1.73 m2 at 24 weeks ( P = .05). In separate mixed-effects models, compared with placebo, febuxostat reduced uric acid by 50% ( P < .001) but had no significant effects on subcutaneous adipose tissue TBARS (-7.4%, 95% confidence interval [CI], 57.4%-101.4%) or adiponectin (6.7%, 95% CI, 26.0%-53.8%) levels or urinary TGF-β/creatinine ratio (18.0%, 95% CI, 10.0%-54.8%) or secondary endpoints.

LIMITATIONS: Relatively modest sample size and short duration of follow-up.

CONCLUSIONS: In this population with progressive diabetic nephropathy, febuxostat effectively reduced plasma uric acid. However, no detectable effects were observed for the prespecified primary or secondary endpoints.

TRIAL REGISTRATION: The study was registered in (NCT01350388).

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