Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease: A Population-Based Cohort Study
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Visual Abstract. Allopurinol and All-Cause Mortality.
Allopurinol is a commonly used medication to lower uric acid levels among patients with gout. However, in 2 recent randomized clinical trials, allopurinol was reported to potentially increase mortality in patients with chronic kidney disease (CKD). This study investigated whether allopurinol use was associated with an increased risk for death in patients with gout and concurrent CKD. The results of the study provide population-based evidence that will help providers weigh the risk–benefit tradeoff of prescribing allopurinol in patients with gout and CKD.
Abstract
Background:
Two recent randomized clinical trials of escalating doses of allopurinol for the progression of chronic kidney disease (CKD) reported no benefits but potentially increased risk for death. Whether the risk could occur in patients with gout and concurrent CKD remains unknown.
Objective:
To examine the relation of allopurinol initiation, allopurinol dose escalation, and achieving target serum urate (SU) level after allopurinol initiation to all-cause mortality in patients with both gout and CKD.
Design:
Cohort study.
Setting:
The Health Improvement Network U.K. primary care database (2000 to 2019).
Participants:
Patients aged 40 years or older who had gout and concurrent moderate-to-severe CKD.
Measurements:
The association between allopurinol initiation and all-cause mortality over 5-year follow-up in propensity score (PS)–matched cohorts was examined. Analysis of hypothetical trials were emulated: achieving target SU level (<0.36 mmol/L) versus not achieving target SU level and dose escalation versus no dose escalation for mortality over 5-year follow-up in allopurinol initiators.
Results:
Mortality was 4.9 and 5.8 per 100 person-years in 5277 allopurinol initiators and 5277 PS-matched noninitiators, respectively (hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.93]). In the target trial emulation analysis, the HR of mortality for the achieving target SU level group compared with the not achieving target SU level group was 0.87 (CI, 0.75 to 1.01); the HR of mortality for allopurinol in the dose escalation group versus the no dose escalation group was 0.88 (CI, 0.73 to 1.07).
Limitation:
Residual confounding cannot be ruled out.
Conclusion:
In this population-based data, neither allopurinol initiation, nor achieving target SU level with allopurinol, nor allopurinol dose escalation was associated with increased mortality in patients with gout and concurrent CKD.
Primary Funding Source:
Project Program of National Clinical Research Center for Geriatric Disorders.
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Published In
Annals of Internal Medicine
Volume 175 • Number 4 • April 2022
Pages: 461 - 470
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Published online: 25 January 2022
Published in issue: April 2022
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© 2022 American College of Physicians.
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Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease: A Population-Based Cohort Study. Ann Intern Med.2022;175:461-470. [Epub 25 January 2022]. doi:10.7326/M21-2347
Allopurinol Initiation and All-Cause Mortality Among Patients With Gout and Concurrent Chronic Kidney Disease: A Population-Based Cohort Study. Ann Intern Med.2022;175:461-470. [Epub 25 January 2022]. doi:10.7326/M21-2347
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Concern about the progression of kidney function in chronic kidney disease with gout
We read the article by Wei and colleagues with great interest, and appreciate the authors’ efforts to assess the safety of allopurinol to chronic kidney disease (CKD) patients (1). However, we would like to point out our concern.
The study did not investigate the serious complications after allopurinol initiation in CKD patients with gout. The progression of kidney disease is a major problem in CKD patients and has many negative health impacts, including cardiovascular disease (CVD), chronic respiratory disease, and diabetes (2). Allopurinol has been reported to reduce the progression of kidney disease (3). Therefore, the authors should provide the information regarding the progression of renal disease, including the initiation of renal replacement therapy. These data would provide readers with clinically important information.
References
Concerns about the definition and inclusion criteria of patients with gout and chronic kidney disease.
We read the article by Jie Wei with great interest that investigated the relationship between allopurinol and mortality in patients with chronic kidney disease (CKD) (1); However, we would like to raise several concerns regarding the included participants.
First, the diagnosis of gout based on the Read code (1) may cause misclassification. We are concerned that patients with other causes of arthritis such as septic arthritis or acute calcium pyrophosphate crystal arthritis (pseudogout) might be included in a situation where the diagnosis of gout was dependent upon the electronic health records database that the study used (2). It is not feasible for all patients with suspected gout to perform the arthrocentesis in the primary care setting, but we suggest the authors use the validated diagnostic rule (3) to define gout.
Second, the definition of CKD in the study was not considered the amount of proteinuria. Prior studies have shown that higher proteinuria was associated with a faster rate of decline in estimated glomerular filtration rate (eGFR), regardless of gender, age, or baseline eGFR (4). The degree of proteinuria is crucial to investigate mortality in patients with CKD; hence, we encourage the authors to analyze the mortality rate stratified by the presence or absence of proteinuria.
Third, the inclusion criteria of this study may miss out on patients who did not receive nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine for gout. In clinical practice, patients with CKD Stage 4-5 are treated with a short-term course of steroids and avoid using NSAIDs to prevent further decline of kidney function. Although the study only included less than 5% of patients with CKD Stage 4-5 who have an increased risk of mortality (5). Our concern is that the inclusion criteria may not cover the vulnerable group of patients we mentioned above, which may affect the interpretation of analyses.
References
Disclosures:
None.
Author Response to Imai et al.
We appreciate the interest of Imia et al. in our manuscript (1). Vargas-Santos and colleagues previously examined the association between allopurinol use and progression of chronic kidney disease among patients with gout using the THIN. Their study showed that allopurinol initiation of at least 300mg/d was associated with a lower risk of renal function deterioration (2).
Reference
Disclosures:
None
Author Response to Yamamoto et al.
Yamamoto et al. raised a concern of the definitions we used to define gout and chronic renal diseases (CKD) (1). The diagnosis of gout in our primary analysis was based on the presence of at least 1 Read code for gout. This definition has been used in several previous studies (2-4). In addition, in our sensitivity analysis, we defined a gout diagnosis using Read code plus use of gout medication. This definition had a positive predictive value of 90% in the General Practice Research Database, in which 60% of participants overlap with THIN (5). As mentioned above, we took the same approach to define CKD as a present study did (2). We did not consider proteinuria as one of the criteria to define CKD. It may be interesting to assess whether the degree of proteinuria could modify the association between allopurinol initiation and mortality.
Reference
Disclosures:
None