In advanced-stage chronic kidney disease (CKD), allopurinol didn’t slow decline in kidney function, the CKD-FIX study found.
During the 104-week randomized controlled trial, daily allopurinol treatment did not slow down the yearly decline in eGFR versus placebo (mean difference -0.10 mL/min/1.73 m2 per year, 95% CI -1.18 to 0.97, P=0.85), reported Sunil Badve, MBBS, MD, PhD, of the George Institute for Global Health in Newtown, Australia, and colleagues in the New England Journal of Medicine.
Those on allopurinol treatment had a yearly decline in eGFR of -3.33 mL/min/1.73 m2 (95% CI -4.11 to -2.55), while those on placebo saw an average annual decline in eGFR of -3.23 mL/min/1.73 m2 (95% CI -3.98 to -2.47).
Badve told MedPage Today that his group was surprised to find that the observed yearly mean difference of -0.10 mL/min/1.73 m2 in eGFR decline between the allopurinol and placebo groups was “appreciably smaller” than the prespecified clinically meaningful difference, -0.6 mL/min/1.73 m2 per year.
“Based on preclinical and observational studies, nephrologists have long believed that uric acid plays a causative role in CKD progression and 20% of all CKD patients are prescribed a urate-lowering medication even in the absence of a clinical indication, such as gout,” Badve pointed out. “Our results do not appear to support the view that circulating urate levels play a causal role in the progression of CKD.”
And based on these findings, he noted that urate-lowering treatments should instead only be used for specific conditions, such as gout, and not CKD.
These findings are also in line with another recent NEJM study — the Preventing Early Renal Loss in Diabetes (PERL) trial — from Alessandro Doria, MD, PhD, MPH, of Joslin Diabetes Center in Boston, and colleagues, that found allopurinol didn’t have any clinically meaningful benefit on progression of early-stage diabetic kidney disease in people with type 1 diabetes.
For the CKD-FIX study, a total of 185 adults received between 100 mg to 300 mg of daily allopurinol, while 184 individuals received placebo. For inclusion, all participants had stage 3 or 4 CKD — eGFR from 15 to 59 mL/min/1.73 m2 — as well as no history of gout. All individuals also had a urinary albumin to creatinine ratio of 265 or higher or an eGFR decrease of at least 3.0 mL/min/1.73 m2 of body-surface area the year prior.
There was an initial 12-week dose-escalation phase upon study entry, then a 92-week follow-up period.
For the secondary composite outcome of a 40% decrease in eGFR, end-stage kidney disease, or death, there were no significant differences between the treatment and placebo groups (occurred in 35% of the allopurinol group vs 28% of the placebo group).
However, average serum urate levels did significantly drop with allopurinol as expected — decreasing to 5.1 mg/dL at 12 weeks and remaining at 5.3 mg/dL through follow-up — whereas the placebo group remained at 8.2 mg/dL.
Calling this an “impressive finding,” Badve noted this 35% sustained mean in serum urate levels in the allopurinol group was achieved “despite not titrating the dose of the study medication against serum urate levels.”
In regards to safety, there was a similar rate of serious adverse events in each group: 46% in the allopurinol group versus 44% in the placebo group.
“The potential role of uric acid in the progression of kidney disease has been argued about for decades,” noted Daniel Feig, MD, PhD, MPH, of the University of Alabama at Birmingham, in an accompanying editorial.
Feig wrote that although this trial and the PERL trial both showed that allopurinol is not beneficial for CKD control, neither addressed urate-lowering therapy, either pharmacologic or dietary, in young patients or those in earlier stages of kidney disease progression.
“As is often the conclusion in clinical research, more high-quality randomized, controlled trials are needed,” he concluded.
The trial was supported by grants from the National Health and Medical Research Council of Australia and the Health Research Council of New Zealand.
Badve reported relationships with Amgen and Bayer Healthcare. Other study authors also reported disclosures.
Feig reported no disclosures.