Effects of Febuxostat on Adipokines and Kidney Disease in Diabetic Chronic Kidney Disease

Hyperuricemia is emerging as a risk factor for development of diabetes and metabolic syndrome. Recently, it was shown in in-vitro cell culture experiments that hyperuricemia induces redox-dependent signaling and oxidative stress in adipocytes. By targeting levels of uric acid with febuxostat it is hypothesized that the levels of oxidative stress in adipose tissue (obtained by fat biopsy) will decrease. Primary aims of the study are to determine whether febuxostat therapy in overweight or obese, diabetic patients with stage 3 Chronic Kidney Disease (CKD) and high serum uric acid levels will affect adipose tissue concentrations of thiobarbituric acid reactive substance (TBARS), a marker of oxidative stress will affect adipose tissue expression and concentrations of adiponectin; and will affect urinary concentrations of transforming growth factor (TGF)- B1.

Hyperuricemia is highly prevalent in the US population and commonly clusters with obesity and metabolic syndrome. It remains controversial whether this reflects an epiphenomenon or connotes a causal role of hyperuricemia in metabolic syndrome. If indeed hyperuricemia plays a causal role in metabolic syndrome, it would be expected that hyperuricemia will impact on the molecular signals that mediate the effects of adiposity on inflammation and insulin resistance. Adipokines, the protein hormones produced by the adipocytes, serve as the signals for the effects of adipocytes on insulin resistance, dyslipidemia, hypertension, inflammation and atherosclerosis. Adipokines include tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), plasminogen activator inhibitor (PAI-1), leptin, angiotensinogen and adiponectin. In obesity, the production of TNF-α, IL-6, PAI-1, leptin and angiotensinogen increases whereas the production of adiponectin decreases. Increased expression of pro-inflammatory TNF-α and IL-6 and decreased expression of anti-inflammatory adiponectin by adipocytes results in insulin resistance and inflammation. As oxidative stress in adipose tissue is considered to play a critical role in dysregulation of adipokines production in obesity and that hyperuricemia induces oxidative stress in adipocytes, it is hypothesized that hyperuricemia alters adipose tissue production of adipokines; therefore, febuxostat therapy will decrease hyperuricemia and thereby, have beneficial effects on adipokine production by adipose tissue; the favorable effects on adipokine production by febuxostat therapy will result in decrease in plasma levels of markers of inflammation; and as a result of the above, urinary markers of kidney disease will improve. Chronic Kidney Disease (CKD) patients with type 2 diabetes will be studies because this population has a high prevalence of hyperuricemia and likely represents a target population which might benefit from reduction of uric acid levels. This is a placebo-controlled, double-blinded, randomized controlled trial to examine the effects of uric acid lowering with oral febuxostat on adipokines and markers of inflammation.

Change in Thiobarbituric Acid Reactive Substance (TBARS) Concentration in Adipose Tissue From Baseline to 24 Weeks

The percent difference in thiobarbituric acid reactive substance (TBARS) concentration geometric mean values from baseline to 24 weeks was calculated for each arm

The percent difference in adiponectin concentration geometric mean values from baseline to 24 weeks was calculated for each arm

Change in Urinary Concentrations of Transforming Growth Factor-beta1 (TGF-beta1) From Baseline to 24 Weeks

The percent difference in TGF-beta1 concentration geometric mean values from baseline to 24 weeks was calculated for each arm

The percent difference in plasma TNF-α concentration geometric mean values from baseline to 24 weeks was calculated for each arm

The percent difference in plasma IL-6 concentration geometric mean values from baseline to 24 weeks was calculated for each arm

Change in High Sensitivity C-Reactive Protein (hsCRP) Concentration in Plasma From Baseline to 24 Weeks

The percent difference in plasma hsCRP concentration geometric mean values from baseline to 24 weeks was calculated for each arm

Inclusion Criteria: Age > 18 years BMI > 25 kg/m2 type 2 diabetes serum uric acid ≥ 5.5 mg/dl in men and ≥ 4.6 mg/dl in women eGFR 30-60 mL/min/1.73m2 Exclusion Criteria: History of gout concurrent use of azathioprine, mercaptopurine, theophylline, allopurinol, thiazolidinediones or warfarin concurrent use of metformin current antibiotic therapy pregnant women prisoners

Beddhu S, Filipowicz R, Wang B, Wei G, Chen X, Roy AC, DuVall SL, Farrukh H, Habib AN, Bjordahl T, Simmons DL, Munger M, Stoddard G, Kohan DE, Greene T, Huang Y. A Randomized Controlled Trial of the Effects of Febuxostat Therapy on Adipokines and Markers of Kidney Fibrosis in Asymptomatic Hyperuricemic Patients With Diabetic Nephropathy. Can J Kidney Health Dis. 2016 Dec 5;3:2054358116675343. doi: 10.1177/2054358116675343. eCollection 2016.