A Path to Sustained Renoprotection in CKD?

Tejas P. Desai, MD


September 02, 2016

Uric Acid and CKD Progression

Uric acid is commonly thought of as a valueless substance in our bodies that, on occasion, reminds us of its presence with painful gouty attacks. These attacks are often temporary or infrequent—two qualities that contribute to our perception that uric acid is no more than an annoying member of our body's milieu. So it may come as a surprise that recent evidence suggests a greater deleterious role of uric acid than many of us had anticipated.

In the past few years, studies from Asia have suggested that uric acid plays a pathologic role in the development of chronic kidney disease (CKD). These studies suggest that drugs used to lower uric acid, such as allopurinol, may offer kidney protection against its negative effects. The investigations themselves are interesting, but are of limited clinical utility given their study design (prospective cohort or epidemiologic).

A study examining the effects of febuxostat on the decline in glomerular filtration rate (GFR) in patients with CKD[1] builds upon this early research and applies the gold standard of research design to determine whether uric acid is indeed harmful to the kidneys.

Febuxostat Shown to Slow the GFR Decline

In this double-blind, randomized, placebo-controlled trial, 108 patients with elevated uric acid levels (≥ 7 mg/dL) and CKD (estimated GFR [eGFR] 15-60 mL/min/1.73 m2, as per the four-variable Modification of Diet in Renal Disease Study equation) received febuxostat or placebo.

Febuxostat is a xanthine oxidase inhibitor that was the study drug of choice because of its dosing independence from existing kidney function. Patients were given either a 40-mg febuxostat tablet or placebo daily for 6 months and had their kidney function assessed. The primary endpoint was the percentage of patients in either arm with a 10% or greater decline in eGFR from the entry level at 18 months. Notably absent, as either a primary or secondary outcome, was the presence of or change in proteinuria.

The patients enrolled were from South Asia (specifically the eastern part of India). More men than women were enrolled in both arms (64% men in the febuxostat arm and 77% in the placebo arm). There was a relatively even split of patients with stage 3 and 4 CKD, with a mean creatinine level of 2.21 mg/dL.

Virtually all of the patients had concomitant hypertension, whereas less than one half of patients in the treatment arm and less than one third in the placebo arm had diabetes mellitus. Finally, approximately two thirds of patients in both arms were receiving an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Overall, the patients were nearly equally matched in age, comorbid conditions, most medications used, and biochemical lab values.

Although the study was conducted for 18 months, within the first 6 months the patients began to show marked differences in their kidney function. This is consistent with the administration of febuxostat (which was only given in the first 6 months). Patients in the placebo arm showed a decrease in eGFR from 32.6 ± 11.6 to 28.2 ± 11.5 mL/min/1.73 m2. After 6 months of medication administration and 18 months overall, a little more than one half of the patients in the placebo group had a 10% or more decline in eGFR. Patients receiving febuxostat, however, showed no statistical changes in their eGFRs within the first 6 months. At the conclusion of the study (18 months), only 38% of these patients met the primary endpoint.

Further Studies on Lowering Uric Acid Are Needed

The current investigation represents a natural and accretive progression of clinical research in the field of uric acid-induced CKD. Prior studies suggested a renoprotective effect when uric acid levels were lowered in patients with CKD and hyperuricemia, but these studies were not randomized trials. The current investigation is a necessary endeavor to both validate and incrementally build upon these initial findings.

Many questions still remain. Can lowering uric acid result in a sustained renoprotective effect (> 18 months)? Is febuxostat a better agent for this protection than allopurinol? Would clinicians be keen on using any xanthine oxidase inhibitor in patients with hypertensive CKD? Tell us what you think in the comments section below.

Follow Tejas P. Desai, MD, on Twitter @nephondemand
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