From the Journals

Allopurinol reduces risk of renal decline in gout patients

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Observational studies require skepticism

Physicians should consider the inherent limitations of observational studies before altering clinical decisions, according to Jonathan Zipursky, MD, and David N. Juurlink, MD, PhD. This is particularly important since the findings in this paper challenge the American College of Rheumatology, which recommends lower allopurinol doses in patients with chronic kidney disease (CKD).

On one hand, they noted, observational studies have some advantages over randomized trials.

“Observational studies frequently include patients who are ineligible for RCTs, and extended follow-up enables examination of outcomes that might not have arisen earlier in treatment,” Dr. Zipursky and Dr. Juurlink wrote in an editorial. “Moreover, sample sizes often greatly exceed those of RCTs, facilitating detection of less common adverse events. Consequently, population-based observational studies are critical to postmarketing surveillance and, increasingly, evidence-based prescribing recommendations.”

On the other hand, observational studies are less tightly controlled than randomized trials.

As “treatment allocation is nonrandom, it raises the possibilities of selection bias and confounding by indication,” Dr. Zipursky and Dr. Juurlink wrote. “Perhaps the drugs were preferentially prescribed to patients destined to tolerate them, or fare better in some other way apparent to prescribers but beyond the resolution of large databases. For example, of the nearly 43,000 patients in the study by Vargos-Santos et al, only 10% were started on 300 mg or more per day of allopurinol. This leaves readers to wonder what motivated practitioners to start such doses, or, conversely, what it was about the remaining 90% of patients that led them to receive lower doses of allopurinol or none at all.”

Along with these unanswered questions, the study compared treated patients to untreated ones, but “it is generally desirable to compare 1 drug with another used for the same indication, which can help mitigate the effect of unmeasured factors that might have influenced the decision to treat in the first place.”

Familiarity with observational studies is essential for clinicians, as Dr. Zipursky and Dr. Juurlink expect such trials will become more common in the future, and they provide useful insight if clinicians maintain an appropriate viewpoint.

“The findings will need to be contextualized and viewed with more skepticism than RCTs,” they wrote, “but in some instances, they can be thoughtfully integrated into our treatment decisions.”

Dr. Zipursky and Dr. Juurlink are with the department of medicine at Sunnybrook Health Sciences Centre, Toronto. These comments are adapted from their accompanying editorial (JAMA Intern Med. 2018 Oct 8. doi: 10.1001/jamainternmed.2018.5766).



In patients with gout, at least 300 mg of allopurinol daily may reduce the risk of renal function decline, according to a new study.


Since no evidence supports allopurinol nephrotoxicity and usage does not appear to worsen chronic kidney disease (CKD), clinicians should consider other causes of declining renal function, according to lead author Ana Beatriz Vargas-Santos, MD, of the rheumatology unit at the State University of Rio de Janeiro and her colleagues.

These findings reinforce the American College of Rheumatology’s 2012 treatment recommendation that the dose of allopurinol, a urate-lowering therapy (ULT), “can be raised above 300 mg daily, even with renal impairment, as long as it is accompanied by adequate patient education and monitoring for drug toxicity may worsen renal function.”*

“Renal-dosing of allopurinol compounds the poor management of gout and adds to the perception that allopurinol may be detrimental for renal function,” the investigators wrote in JAMA Internal Medicine. “In contrast, recent studies provide support for starting allopurinol at a low dose with gradual dose escalation to serum urate target with close monitoring, even among patients with renal insufficiency, without increased risk of allopurinol hypersensitivity syndrome (AHS). Further, there is emerging evidence that ULT may be beneficial for kidney dysfunction.”

Building upon these developments, the investigators “aimed to assess the relation of allopurinol initiation to the risk of developing CKD stage 3 or higher among people with newly diagnosed gout.”

Patients for the cohort study were drawn from the Health Improvement Network (THIN), a database of records from general practitioners in the United Kingdom. Included patients were recently diagnosed with gout but did not have stage 3 or higher chronic kidney disease or ULT usage within a year prior to diagnosis. After screening, 4,760 allopurinol users were matched with 4,760 allopurinol nonusers. Overall, 71% of patients had CKD stage 2, while the remaining 29% had CKD stage 1 or normal kidney function.

The primary outcome of CKD stage 3 or higher was defined as glomerular filtration rate below 60 mL/min (recorded at least twice in 1 year with a 3-month interval between readings and GFR never exceeding 75 mL/min during the intervening period), kidney transplant, or dialysis. The mean follow-up time was 5 years for allopurinol users and 4 years for nonusers.

The investigators found that 579 allopurinol users developed CKD stage 3 or higher, compared with 623 nonusers, suggesting that allopurinol reduced risk of CKD stage 3 or higher by 13%. Allopurinol doses of at least 300 mg/day were associated with a hazard ratio of 0.87, but lower doses did not share this association (HR = 1.02).

In defense of their findings, Dr. Vargas-Santos and her associates evaluated the relevance of their study, compared with previous allopurinol studies.

“This study is one of few that have evaluated the relation of allopurinol to renal function among patients with gout and normal or near-normal kidney function at baseline,” the authors wrote, noting that most gout patients do not have severe kidney disease.

Previous studies have suggested that allopurinol worsens kidney function, but these studies were often conducted in nongout populations, with patients exhibiting CKD stage 3 or higher, they noted. Instead of allopurinol-induced kidney damage, renal decline in gout patients is likely multifactorial.

“Because people with gout have intrinsic differences compared with those with asymptomatic hyperuricemia, including higher mortality, more comorbidities, and more NSAID use, these studies’ results are not directly applicable to gout patients,” the investigators wrote.

“At minimum, allopurinol does not seem to have a detrimental effect on renal function in individuals with gout,” Dr. Vargas-Santos and her associates concluded. “Clinicians should consider evaluating other factors when faced with renal function decline in their patients with gout rather than lowering the dose of or discontinuing allopurinol, a strategy that has contributed to the ongoing suboptimal treatment of gout.”
The authors reported funding from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq); Ministry of Science, Technology and Innovation of Brazil; and National Institutes of Health. Dr Vargas-Santos has received speaking fees and support for international medical events from Grünenthal. No other disclosures were reported.

*Correction, 11/5/2018: An earlier version of this story incorrectly stated the American College of Rheumatology’s 2012 gout treatment recommendation for using allopurinol in patients with renal impairment.

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