Frequently Prescribed Allopurinol No Better Than Placebo for CKD in Head-to-Head Trial

Allopurinol, often prescribed to reduce serum uric acid in patients with chronic kidney disease (CKD), fared no better than placebo in slowing renal decline in a new randomized clinical trial.

Investigators from the University of New South Wales (UNSW) published results for the CKD-FIX trial June 25, 2020, in the New England Journal of Medicine. They reported that up to 20% of patients with CKD take allopurinol for its urate-lowering effects, even though there was no evidence it would halt the decline in patients’ estimated glomerular filtration rate (eGFR).¹

“We found the kidney function declined at a similar rate in patients receiving allopurinol and those receiving placebo,” co-lead author Sunil Badve, MD, conjoint associate professor at UNSW Medicine and senior research fellow at The George Institute for Global Health, said in a statement.

The findings have “major implications,” Badve said, because unless CKD patients also have gout—which allopurinol can alleviate—there is no reason for them to take the drug. “Now we know that they are likely taking medication that is of no benefit to them, unless they have other conditions that allopurinol is effective against, like gout.”

Allopurinol, which was first developed in the 1950s to be used in as a therapy in patients with leukemia, was later found to have urate-lowering properties and came into use for this purpose in the 1960s. A 2018 retrospective cohort study in JAMA Internal Medicine found that in patients who had gout, the 300 mg dose of allopurinol was associated with a 13% lower risk of stage 3 CKD or higher compared with nonusers. Doses lower than 300 mg per day were not associated with renal decline.²

Findings

This time, however, allopurinol was tested in a head-to-head clinical trial. The study involved 363 patients with either stage 3 or 4 CKD but no history of gout. Patients had a urinary albmin:creatinine (A/C) ratio of 265 or above, or they had experienced an eGFR decrease of at 3.0 mL/min per 1.73 m² of body-surface area in the prior 12 months. They were randomized to receive 100 mg to 300 mg of allopurinol per day or placebo. Primary outcome was the change in eGFR through 104 weeks.

At enrollment, mean eGFR of the study population was 31.7 mL/min per 1.73 m², mean urine A/C ratio was 716.9, and mean serum urate level was 8.2 mg/dL. After 104 weeks, the mean eGFR did not change significantly between the 2 groups:

• In the allopurinal group, eGFR declined 3.33 mL/min per 1.73 m² per year (95% CI, —4.11 to –2.55),
• In the placebo group, eGFR declined 3.23 mL/min per 1.73 m² per year (95% CI, —3.98 to –2.47).
• The mean difference was —0.10 mL/min per 1.73 m² per year (95% CI, —1.18 to -0.97, P = .85).

Allopurinol is known to have side effects, including skin rashes. In CKD-FIX the allopurinol group had slightly more serious adverse events (AEs): 84 of 182 patients (46%), while the plabebo group saw serious AEs in 79 of 181 patients (44%).

The investigators warned that patients taking allopurinol to lower blood urate levels should not stop treatment on their own but should discuss the findings with their physician.

Badve said the study points out the need for better treatment options for slowing the progression of CKD are limited and only partially effective. “There is a huge need for new treatments for this condition,” he said.

References

1. Badve SV, Pascoe EM, Tiku A, et al, for the CKD-FIX Study Investigators. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020; 382:2504-2513. doi:10.1056/NEJMoa1915833

2. Vargas-Santos AB, Peloquin CE, Zhang Y, Neogi T. Association of chronic kidney disease with allopurinol use in gout treatment. JAMA Intern Med. 2018;178(11):1526-1533. doi:10.1001/jamainternmed.2018.4463