Efficacy of Febuxostat for Slowing the GFR Decline in Patients With CKD and Asymptomatic Hyperuricemia

A 6-Month Double-Blind, Randomized, Placebo-Controlled Trial

Dipankar Sircar, MD, DM; Soumya Chatterjee, MD; Rajesh Waikhom, MD, DM; Vishal Golay, MD, DM; Arpita Raychaudhury, MD, DM; Suparna Chatterjee, MD; Rajendra Pandey, MD, DM

Disclosures

Am J Kidney Dis. 2015;66(6):945-950. 

In This Article

Abstract and Introduction

Abstract

Background: Hyperuricemia is a putative risk factor for the progression of chronic kidney disease (CKD). We hypothesized that control of asymptomatic hyperuricemia may slow disease progression in CKD.

Study Design: This was a single-center, double-blind, randomized, parallel-group, placebo-controlled study.

Setting & Participants: Eligible participants were adults from Eastern India aged 18 to 65 years with CKD stages 3 and 4, with asymptomatic hyperuricemia.

Intervention: The intervention group received febuxostat, 40 mg, once daily for 6 months, while the placebo group received placebo; both groups were followed up for 6 months.

Outcomes: The primary outcome was the proportion of patients showing a >10% decline in estimated glomerular filtration rate (eGFR) from baseline in the febuxostat and placebo groups. Secondary outcomes included changes in eGFRs in the 2 groups from baseline and at the end of the study period.

Results: 45 patients in the febuxostat group and 48 in the placebo group were analyzed. Mean eGFR in the febuxostat group showed a nonsignificant increase from 31.5 ± 13.6 (SD) to 34.7 ± 18.1 mL/min/1.73 m2 at 6 months. With placebo, mean eGFR decreased from a baseline of 32.6 ± 11.6 to 28.2 ± 11.5 mL/min/1.73 m2 (P = 0.003). The difference between groups was 6.5 (95% CI, 0.08–12.81) mL/min/1.73 m2 at 6 months (P = 0.05). 17 of 45 (38%) participants in the febuxostat group had a >10% decline in eGFR over baseline compared with 26 of 48 (54%) from the placebo group (P < 0.004).

Limitations: Limitations of this study included small numbers of patients and short follow-up, and ~10% of the randomly assigned population dropped out prior to completion.

Conclusions: Febuxostat slowed the decline in eGFR in CKD stages 3 and 4 compared to placebo.

Introduction

Chronic kidney disease (CKD) has traditionally been considered to be an irreversible process, and patients who have it are often expected to experience a progressively worsening course. The rate of disease progression varies with the cause, and various therapeutic interventions, such as control of hypertension and proteinuria, have been shown to decrease it.

Hyperuricemia has been associated with adverse outcomes in CKD. Hyperuricemia has been linked to macrovascular heart disease in diabetic CKD.[1] High uric acid levels have been reported to be associated with increased rates of decline in glomerular filtration rate (GFR) in cross-sectional studies.[2,3]

Febuxostat is a xanthine oxidase inhibitor shown to be efficacious in hyperuricemia and gout.[4] It does not require dose modification in patients with kidney failure. Therapy with febuxostat has been shown to prevent renal damage in 5/6 nephrectomized rats.[5] The xanthine reductase inhibitor allopurinol has been shown to be effective in reducing lipid accumulation and atherosclerosis in apolipoprotein E (ApoE) knockout mice.[6] One randomized controlled trial has demonstrated the efficacy of allopurinol in reducing the rate of decline in GFR in patients with CKD with estimated GFRs (eGFRs) < 60 mL/min/1.73 m2.[7] In this context, we hypothesized that febuxostat might retard the progression of kidney disease in patients with CKD and hyperuricemia.

The aims of the study were to determine the efficacy of febuxostat compared to placebo for slowing eGFR decline in patients with CKD stages 3 and 4 (eGFR, 15–60 mL/min/1.73 m2) and asymptomatic hyperuricemia (uric acid ≥ 7 mg/dL) and to compare the incidence of adverse cardiovascular events (myocardial infarction, cerebrovascular events, and heart failure), death, and hospitalization rates between the 2 groups. We also planned to compare treatment-associated emergent adverse events between the febuxostat and placebo groups and evaluate the reduction in serum uric acid levels in both groups.

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