New Data Examines Mortality Risk and Allopurinol Use in Patients with Gout and CKD

Contrary to recent research that indicated a higher risk of death associated with escalating doses of allopurinol for chronic kidney disease, investigators announce no association between allopurinol initiation and increased mortality among patients with gout and CKD.

A pair of recent randomized clinical trials examined escalating doses of allopurinol for the progression of chronic kidney disease (CKD) and reported no benefits. However, these studies did report a potential for increased risk of death.

Investigators, led by Jie Wei, PhD, Health Management Center, Xiangya Hospital, Central South University, conducted a cohort study to determine whether the risk could present in patients with gout and concurrent chronic kidney disease.

Investigators found no associations, in their population-based data, relating allopurinol initiation, achieving target serum urate level with allopurinol, nor allopurinol dose escalation to an increased mortality in patients with gout and concurrent chronic kidney disease.

The Motivation

In the past few decades, the prevalence of gout, the most common form of inflammatory arthritis, has increased. Urate-lowering therapy is the cornerstone to long-term management of this disease, according to investigators.

Rheumatology guidelines for the treatment of gout recommend lowering serum urate (SU) level to below 0.36 mmol/L, a treat-to-target approach, for patients with recurrent gout flares, tophi or radiographic joint damage due to gout.

Typically, the urate-lowering medication allopurinol is used, beginning with a low dose that’s increased over weeks to months. Inconclusive research has examined the medication’s relation to the risk of death in patients with gout.

In at least 20% of patients with gout, chronic kidney disease is a comorbidity. Previous studies have found that hyperuricemia is associated with an increased risk for incident chronic kidney disease and halting the progression could be targeted by serum urate therapy.

Recently, 2 randomized controlled trials revealed data indicating allopurinol has no renal function-preserving benefits in patients with renal disease, but without gout. Both trials indicated an association between allopurinol and a 2-fold increased risk for death in patients with renal disease.

The Study

Investigators aimed to determine if allopurinol use could increase mortality in patients with both gout and chronic kidney disease in this population-based cohort study.

“In addition, we conducted 2 cohort studies emulating randomized controlled trials to examine the effects of achieving target SU level with allopurinol and allopurinol dose escalation on mortality,” investigators wrote.

The association between allopurinol initiation and all-cause mortality was examined over a 5-year follow-up in propensity score-matched cohorts.

Patients were included if they had gout and concurrent moderate-to-severe chronic kidney disease and were between 40-89 years old from January 2000-January 2018 with at least 1 year of continuous enrollment with a general practitioner.

“The diagnosis of gout was based on the presence of at least 1 Read code for gout,” investigators wrote. “Moderate-to-severe CKD (≥stage 3) was identified by either estimated glomerular filtration rate (eGFR) less than 60 mL/min/ 1.73 m2 on at least 2 occasions more than 90 days apart within 1 year, with no intervening eGFR of 75 mL/min/ 1.73 m2 or greater, or at least 1 Read code for CKD stage 3 to 5, hemodialysis, or peritoneal dialysis.”

A propensity score-matched cohort study compared mortality in patients who were initiated on allopurinol and those who were not. Next, a cloning, censoring, and weighting approach assessed the effect of either achieving target serum urate levels or allopurinol dose escalation on mortality in initiated patients using observational data.

The Results

Patients who were initiated on allopurinol showed a higher serum urate level, a lower estimated glomerular filtration rate, a higher prevalence of prescriptions of diuretics, systemic corticosteroids, nonsteroidal anti-inflammatory drugs, and colchicine, as well as more general practitioner visits, compared with patients who were not initiated on allopurinol.

However, after propensity score matching, the characteristics between the 2 cohorts were balanced with all standardized differences appearing less than 0.10.

“In this large database of GP electronic health records from the United Kingdom, allopurinol initiation was associated with a modestly lower mortality compared with nonallopurinol use in participants with both gout and moderate-to-severe CKD. In addition, emulating a target randomized control trial in allopurinol initiators, we showed that a treat-to-target approach of lowering serum urate level with allopurinol does not seem to increase mortality in participants with both gout and CKD,” investigators concluded.

The study, “Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease”, was published in Annals of Internal Medicine.