New Research Finds Commonly Used Gout Drug Not Useful for Slowing the Progression of Chronic Kidney Disease

For most patients suffering from gout, allopurinol (LOPURIN, ZYLOPRIM) is a first-line therapy: By reducing high uric acid levels in the blood, the drug prevents sudden attacks of disabling joint pain and swelling, progressive joint damage and other gout complications. The drug also is a cornerstone of treatment for patients with kidney stones caused by high levels of uric acid in the urine.

High blood uric acid levels also have been linked to an increased risk of the development and progression of chronic kidney disease. This has led some doctors to prescribe allopurinol to patients with chronic kidney disease — but not gout or kidney stones — with the intent of slowing their loss of kidney function and delaying the need for dialysis or kidney transplantation.

However, the Food and Drug Administration has not approved allopurinol for the prevention or treatment of chronic kidney disease[1] — a so-called “off-label” use — and eight randomized clinical trials published from 1982 to 2012 that tested whether allopurinol treatment slowed the progression of chronic kidney disease were small, poorly designed and produced inconclusive results.[2]

Results of two large, well-designed, randomized clinical trials published in the June 25, 2020, issue of the New England Journal of Medicine (NEJM) provide important new evidence against using allopurinol to slow the rate of kidney function decline in patients with chronic kidney disease.

Facts About Chronic Kidney Disease

• Chronic kidney disease means the kidneys are damaged and are unable to filter the blood and remove the body’s waste products normally.
• In many patients, chronic kidney disease gradually progresses, eventually leading to end-stage kidney disease and the need for dialysis or kidney transplantation.
• The leading causes of chronic kidney disease in the U.S. are diabetes and hypertension.
• Chronic kidney disease can be diagnosed only through simple blood and urine tests.
• Approximately 37 million people in the U.S. have chronic kidney disease, but most do not know they have it.[3]
• In 2016, nearly 125,000 people in the U.S. started treatment for end-stage kidney disease, and more than 726,000 (two in every 1,000 people) were on dialysis or were living with a kidney transplant.[4]

The NEJM trials

The first trial, called the CKD-FIX study, was conducted at 31 hospitals in Australia and New Zealand and funded by government medical research agencies in those countries.[5] For the trial, researchers randomly assigned adults with moderate-to-severe chronic kidney disease to receive either allopurinol (100 to 300 milligrams [mg]; 182 subjects) or a placebo (181 subjects) daily. The subjects’ kidney function was then monitored for two years.

To be eligible for the CKD-FIX study, subjects had to have a high risk of chronic kidney disease progression based on either high urine protein levels or significant kidney function decline during the year preceding enrollment. Forty-five percent of the subjects had diabetic kidney disease, and 95% had hypertension.

The CKD-FIX study showed no difference in the rate of kidney function decline between the two groups, despite a significant decline in blood uric acid levels in allopurinol group subjects. In addition, for subjects in the allopurinol group, 63 (35%) experienced either a 40% decline in kidney function, progression to end-stage kidney disease or death, whereas such events occurred in 51 (28%) of placebo-group subjects, a difference that was not statistically significant. The rate of serious adverse events was similar in both groups.

The second trial, called the PERL study, was conducted at 16 sites in the U.S., Canada and Denmark, and was funded in part by the U.S. National Institutes of Health.[6] For the trial, researchers randomly assigned patients with type 1 diabetes and evidence of diabetic kidney disease to receive either allopurinol (100 to 400 mg; 267 subjects) or a placebo (263 subjects) daily. The subjects’ kidney function was then measured after three years.

Like the CKD-FIX study, the PERL study showed no difference in the rate of kidney function decline between the two groups, despite a significant decline in blood uric acid levels in allopurinol group subjects. The rate of serious adverse events was similar in both groups.

In conclusion, these well-designed clinical trials demonstrated that treatment with allopurinol to lower blood uric acid levels does not slow the progression of chronic kidney disease in patients with chronic kidney disease at high risk for progression or in type 1 diabetes patients with evidence of diabetic kidney disease.

What You Can Do

Given the findings of the CKD-FIX and PERL studies and the fact that allopurinol rarely can cause dangerous hypersensitivity (allergic-like) reactions involving the skin, mouth and other organs, if you have chronic kidney disease, you should not take allopurinol to slow the rate of kidney function decline.
 

References

[1] Casper Pharma. Label: allopurinol (ZYLOPRIM). December 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016084s044lbl.pdf. Accessed October 26, 2020.

[2] Bose B, Badve SV, Hiremath SS, et al. Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2014;29(2):406-413.

[3] Centers for Disease Control and Prevention. Chronic kidney disease in the United States, 2019. March 5, 2019. https://www.cdc.gov/kidneydisease/pdf/2019_National-Chronic-Kidney-Disease-Fact-Sheet.pdf. Accessed October 26, 2020.

[4] Ibid.

[5] Badve SV, Pascoe EM, Tiku A, et al. Effects of allopurinol on the progression of chronic kidney disease. N Engl J Med. 2020;382(26):2504-2513.

[6] Doria A, Galecki AT, Spino C, et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med. 2020;382(26):2493-2503.