A major clinical trial from the University of New South Wales (UNSW) reports that a medication called allopurinol, which is prescribed to about 20% of patients with chronic kidney disease (CKD), doesn’t work as expected. The results are published in the New England Journal of Medicine on June 25, 2020.
There are more than 1.7 million Australians aged 18 or older with CKD. Over 3,000 individuals develop kidney failure serious enough to require dialysis every year. At present, there are over 13,000 patients in Australia who are on dialysis.
Study: Effects of Allopurinol on the Progression of Chronic Kidney Disease. Image Credit: Bluebay / Shutterstock
What Does Allopurinol Do?
The medication in question is allopurinol, which is prescribed in patients who have gout, high uric acid due to some cancer treatments, and kidney stones composed of uric acid, to help prevent further growth of the stones. The trial was conducted by researchers from UNSW, The George Institute for Global Health, and the Australasian Kidney Trials Network.
Purines are molecules found in nucleic acid and are released from cells being broken down during digestion of food as well as during normal cell turnover in various body tissues. Hypoxanthine is a chemical generated during the metabolism of purines. Hypoxanthine is converted to xanthine via the enzyme xanthine oxidase, and then xanthine is broken down to the waste product uric acid.
Allopurinol is a xanthine oxidase enzyme inhibitor. This drug is metabolized to another chemical called oxypurinol, which is similar to the natural purine breakdown product hypoxanthine. This similarity causes it to bind to and block the enzyme that converts hypoxanthine to xanthine. Since xanthine is the precursor of uric acid, this inhibition reduces the blood levels of uric acid.
Using Allopurinol to Stabilize Kidney Function
Involving 31 hospitals in Australia and New Zealand, the trial lasted 2 years and examined results from 369 patients enrolled with chronic kidney disease (CKD) who were thought to be at risk of developing more severe disease. The researchers put the patients on either allopurinol or a placebo and then analyzed the rate of decline in kidney function over time.
Earlier studies concluded that allopurinol treatment reduces the rate of progression of CKD. About three-fourths of people with CKD have high uric acid levels in the blood, and researchers have therefore thought that high urate levels correlate with a higher risk of CKD. However, the evidence was lacking that lowering urate levels through allopurinol delayed the progression of the disease.
The Study: Allopurinol and Kidney Function
The current study was aimed at exploring this connection. The researchers looked at how fast kidney function deteriorated in the group of patients on allopurinol and those without it.
Says co-leader of the study, Sunil Badve, “We found the kidney function declined at a similar rate in patients receiving allopurinol and those receiving placebo.” In other words, the theory that raised blood levels of urate cause a faster deterioration of kidney function is probably not correct. Instead, says Badve, they probably indicate impaired kidney function.
This would mean, he says, that these patients “are likely taking medication that is of no benefit to them, unless they have other conditions that allopurinol is effective against, like gout.” Allopurinol has its own side effects such as allergic reactions and skin rashes, and therefore should not be taken without evidence of benefit.
However, the researchers cautioned that people already on allopurinol should not simply stop taking the drug but discuss its use with their physician. The finding is a discouraging one in some ways, as there are few effective treatments for CKD progression. Thus, says Badve, “There is a huge need for new treatments for this condition.”
This type of evidence-seeking study is crucial to improve the practice of medicine. According to Professor Sean Emory of UNSW Medicine, “Independent, academic research through coordinated networks is critical to changing health outcomes. e now know that a routine intervention in nephrology can no longer be justified. Clinical practice will now change globally.”
- Sunil V. Badve, Ph.D., Elaine M. Pascoe, M.Biostat., Anushree Tiku, M.B., B.S., Neil Boudville, D.Med., Fiona G. Brown, Ph.D., Alan Cass, Ph.D., Philip Clarke, Ph.D., Nicola Dalbeth, M.D., Richard O. Day, M.D., Janak R. de Zoysa, M.B., Ch.B., Bettina Douglas, M.N., Randall Faull, Ph.D., et al., , Effects of Allopurinol on the Progression of Chronic Kidney Disease, N Engl J Med 2020; 382:2504-2513, DOI: 10.1056/NEJMoa1915833, https://www.nejm.org/doi/10.1056/NEJMoa1915833