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

Abstract

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 clinicaltrials.gov (NCT01350388).

Xanthine Oxidase Inhibitors for Improving Renal Function in Chronic Kidney Disease Patients: An Updated Systematic Review and Meta-Analysis

“…The number of participants ranged from 40 [ 14 , 16 ] to 179 [ 18 ]. All trials reviewed [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 22 , 23 , 24 , 25 , 26 , 27 ] enrolled hyperuricemic (uric acid ≥ 6 mg/dL) CKD patients. Baseline uric acid levels ranged from ~6.2 [ 14 ] to 10.5 mg/dL [ 27 ].…”

“…One study [ 27 ] enrolled individuals with moderate-to-severe (stage 4–5) CKD. The prevalence of diabetes was available in eight studies [ 13 , 14 , 17 , 22 , 24 , 25 , 26 , 27 ], ranging from 21.5% [ 17 ] to 100% [ 14 , 26 ]. The mean age of patients ranged from ~40 [ 16 ] to 72.2 years [ 15 ].…”

“…The type of XOi employed was Allopurinol in nine studies [ 13 , 14 , 15 , 16 , 18 , 19 , 20 , 22 , 23 ], Febuxostat in six [ 18 , 23 , 24 , 25 , 26 , 27 ] and Topiroxostat in one [ 17 ]. Drug intervention was compared to a placebo [ 14 , 15 , 17 , 18 , 24 , 26 , 27 ] or standard therapy [ 13 , 16 , 19 , 20 , 22 , 23 , 25 ]. Two RCTs [ 18 , 23 ] tested the effect of both Allopurinol and Febuxostat vs. the control.…”

“…In the study conducted by Hosoya et al [ 17 ], patients received Topiroxostat at a daily dose of 160 mg/day. End-of treatment uric acid levels ranged from 3.9 [ 26 ] to 6.6 mg/dL [ 20 ].…”

Independent links between plasma xanthine oxidoreductase activity and levels of adipokines

“…It has also been reported that unexpected high plasma XOR activities possibly associated with liver dysfunction and insulin resistance are found in some women with a relatively low level of uric acid in a general population. There have been some interventional investigations on the effects of XOR inhibitors, including allopurinol, febuxostat and topiroxostat, on adipokine levels in humans, but results showed that XOR inhibitors did not significantly change levels of adipokines. Possible interventions for adipokines, including adiponectin receptor agonists, FABP4 inhibitors and FGF21 analogs, have been postulated in metabolic and cardiovascular diseases.…”