Abstract
Background: The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) chiefly in patients with diabetes. It has been recently reported that the change ratio in TNFR1 by SGLT2 inhibitor treatment is also related with future GFR decline in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline chiefly in chronic kidney disease (CKD) patients without diabetes.Methods: We conducted a post-hoc analysis of the FEATHER study on patients with asymptomatic hyperuricemia and CKD stage 3, who were randomly assigned febuxostat 40 mg/day or matched placebo. This analysis included 426 patients in whom baseline stored samples were available. Serum TNFR levels at baseline were measured using enzyme-linked immunosorbent assay. Those levels were also measured using 12-week stored samples from 197 randomly selected patients.Results: Compared with placebo, short-term febuxostat treatment significantly decreased the median percent change from baseline in serum uric acid (−45.05, 95% CI −48.90 to −41.24 mg/dL), TNFR1 (1.10, 95% CI−2.25 to 4.40), and TNFR2 (1.66, 95% CI −1.72 to 4.93), but not TNFR levels. Over a median follow-up of 105 weeks, 30 patients (7.0%) experienced 30% eGFR decline from baseline. In the Cox multivariate model, high levels of baseline TNFR predicted a 30% eGFR decline, even after adjusting for age, sex, systolic blood pressure, high sensitivity C-reactive protein, uric acid, and presence or absence of febuxostat treatment and diabetes, in addition to baseline albumin to creatinine ratio and eGFR.Conclusion: Early change in circulating TNFR levels failed to predict future eGFR decline; however, regardless of febuxostat treatment, the elevated baseline level of TNFR was a strong predictor of 30% eGFR decline even in chiefly non-diabetic CKD patients with asymptomatic hyperuricemia.
Highlights
Hyperuricemia was previously considered to occur because of reduced renal clearance of uric acid in patients with decreased renal function; treatment of asymptomatic hyperuricemia has received less attention from researchers
Age, body mass index (BMI), diastolic blood pressure (BP), glycated hemoglobin (HbA1c), high sensitivity C-reactive protein (hsCRP), presence of diabetes, and febuxostat treatment did not differ between both groups
Compared with patients on placebo treatment at week 12, those on febuxostat treatment had a more pronounced reduction in median uric acid level (−45.05, 95% confidence interval (CI) −48.90 to −41.24 mg/dL) but had similar serum tumor necrosis factor receptor (TNFR) levels (Table 2)
Summary
Hyperuricemia was previously considered to occur because of reduced renal clearance of uric acid in patients with decreased renal function; treatment of asymptomatic hyperuricemia has received less attention from researchers. In patients with type 1 diabetes, high-normal serum uric acid was reported to predict estimated future decline in glomerular filtration rate (eGFR) [3]. Recent randomized controlled clinical trials (RCTs) demonstrated that the reduction of serum uric acid with allopurinol did not prevent renal function decline in patients with type 1 diabetes and mild to moderate diabetic kidney disease (DKD) or stage 3 and 4 chronic kidney disease (CKD), both of which are high risk factors for eGFR decline [4, 5]. The levels of circulating tumor necrosis factor receptor (TNFR) 1 and 2 help predict the future decline of estimated glomerular filtration rate (eGFR) in patients with diabetes. The aims of this study are to investigate the association between baseline TNFR levels and early change in TNFR levels by the non-purine selective xanthine oxidase inhibitor, febuxostat, and future eGFR decline in chronic kidney disease (CKD) patients without diabetes
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