American Journal of Kidney Diseases

Initiation Dose of Allopurinol and the Risk of Severe Cutaneous Reactions in Older Adults With CKD: A Population-Based Cohort Study

      Rationale & Objective

      Allopurinol should be started at lower doses in patients with chronic kidney disease (CKD) to avoid adverse effects. We examined the risk of severe cutaneous reactions in older adults with CKD who were newly prescribed allopurinol at varied doses.

      Study Design

      Population-based cohort study using linked health care databases.

      Setting & Participants

      Patients in Ontario, Canada (2008-2019) aged ≥66 years, with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, and who were new users of allopurinol.


      A new prescription for allopurinol >100 mg/d versus a dose ≤100 mg/d.


      The primary outcome was a hospital visit with a severe cutaneous reaction within 180 days of starting allopurinol. Secondary outcomes included all-cause hospitalization and all-cause mortality.

      Analytical Approach

      The exposure and referent groups were balanced on indicators of baseline health using inverse probability of treatment weighting on the propensity score. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression.


      Of 47,315 patients (median age, 76 years; median eGFR, 45 mL/min/1.73 m2), 55% started allopurinol at >100 mg/d. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of a severe cutaneous reaction: number of events (weighted), 103 of 25,802 (0.40%) versus 46 of 25,816 (0.18%), respectively (weighted RR, 2.25 [95% CI, 1.50-3.37]; weighted RD, 0.22% [95% CI, 0.12%-0.32%]. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of all-cause hospitalization but not with all-cause mortality.


      This study was underpowered to detect risk differences in the association of allopurinol dose with outcomes across eGFR categories (ie, 45-59, 30-44, and <30 mL/min/1.73 m2).


      Older patients with CKD who started allopurinol at >100 mg/d versus ≤100 mg/d were twice as likely to visit a hospital with a severe cutaneous reaction in the next 180 days.

      Index Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Cohen R.E.
        • Pillinger M.H.
        • Toprover M.
        Something old, something new: the ACR gout treatment guideline and its evolution from 2012 to 2020.
        Curr Rheumatol Rep. 2021; 23: 1-9
        • Qurie A.
        • Bansal P.
        • Goyal A.
        • Musa R.
        StatPearls Publishing, 2021
      1. ClinCalc DrugStats Database.
        Date accessed: November 22, 2020
      2. Allopurinol: Drug information. UpToDate.
        • Government of Canada
        The Drug and Health Product Register. Product Monograph: Allopurinol. 2017.
        • Stamp L.K.
        • Day R.O.
        • Yun J.
        Allopurinol hypersensitivity: investigating the cause and minimizing the risk.
        Nat Rev Rheumatol. 2016; 12: 235-242
        • Stamp L.K.
        • Barclay M.L.
        How to prevent allopurinol hypersensitivity reactions?.
        Rheumatology (Oxford). 2018; 57: i35-i41
        • Hande K.R.
        • Noone R.M.
        • Stone W.J.
        Severe allopurinol toxicity: description and guidelines for prevention in patients with renal insufficiency.
        Am J Med. 1984; 76: 47-56
        • FitzGerald J.D.
        • Dalbeth N.
        • Mikuls T.
        • et al.
        ACR gout guideline 2020.
        Arthritis Care Res (Hoboken). 2020; 72: 744-760
        • Yokose C.
        • Lu N.
        • Xie H.
        • et al.
        Heart disease and the risk of allopurinol-associated severe cutaneous adverse reactions: a general population-based cohort study.
        CMAJ. 2019; 191: E1070-E1077
        • Keller S.F.
        • Lu N.
        • Blumenthal K.G.
        • et al.
        Racial/ethnic variation and risk factors for allopurinol-associated severe cutaneous adverse reactions: a cohort study.
        Ann Rheum Dis. 2018; 77: 1188-1194
        • Stamp L.K.
        • Chapman P.T.
        Allopurinol hypersensitivity: pathogenesis and prevention.
        Best Pract Res Clin Rheumatol. 2020; 34101501
        • Stamp L.K.
        • Barclay M.L.
        • O’Donnell J.L.
        • et al.
        Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level.
        Clin Pharmacol Ther. 2011; 90: 392-398
        • US Food and Drug Administration
        Zyloprim (allopurinol) product information. December 2018.
        • Kim S.C.
        • Newcomb C.
        • Margolis D.
        • Roy J.
        • Hennessy S.
        Severe cutaneous reactions requiring hospitalization in allopurinol initiators: a population-based cohort study.
        Arthritis Care Res (Hoboken). 2013; 65: 578-584
        • Stamp L.K.
        • Taylor W.J.
        • Jones P.B.
        • et al.
        Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol.
        Arthritis Rheum. 2012; 64: 2529-2536
        • Yang C.Y.
        • Chen C.H.
        • Deng S.T.
        • et al.
        Allopurinol use and risk of fatal hypersensitivity reactions a nationwide population-based study in Taiwan.
        JAMA Intern Med. 2015; 175: 1550-1557
        • Statistics Canada
        Population by sex and age group, by province and territory (number, both sexes). Summary tables. 2016.
        • Benchimol E.I.
        • Smeeth L.
        • Guttmann A.
        • et al.
        The Reporting of studies conducted using observational routinely-collected health data (RECORD) statement.
        PLoS Med. 2015; 12e1001885
        • Institute for Clinical Evaluative Sciences
        ICES data and privacy.
        Date accessed: February 8, 2021
        • Levy A.R.
        • O’Brien B.J.
        • Sellors C.
        • Grootendorst P.
        • Willison D.
        Coding accuracy of administrative drug claims in the Ontario Drug Benefit database.
        Can J Clin Pharmacol. 2003; 10: 67-71
        • Statistics Canada
        Migration: interprovincial, 2011/2012.
        • Garg A.X.
        Identifying individuals with a reduced GFR using ambulatory laboratory database surveillance.
        J Am Soc Nephrol. 2005; 16: 1433-1439
        • Sato T.
        • Matsuyama Y.
        Marginal structural models as a tool for standardization.
        Epidemiology. 2003; 14: 680-686
        • Brookhart M.A.
        • Wyss R.
        • Layton J.B.
        • Stürmer T.
        Propensity score methods for confounding control in nonexperimental research.
        Circ Cardiovasc Qual Outcomes. 2013; 6: 604-611
        • Austin P.C.
        An introduction to propensity score methods for reducing the effects of confounding in observational studies.
        Multivariate Behav Res. 2011; 46: 399-424
        • Austin P.C.
        • Stuart E.A.
        Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies.
        Stat Med. 2015; 34: 3661-3679
        • Zou G.
        A modified poisson regression approach to prospective studies with binary data.
        Am J Epidemiol. 2004; 159: 702-706
        • Richette P.
        • Doherty M.
        • Pascual E.
        • et al.
        2016 Updated EULAR evidence-based recommendations for the management of gout.
        Ann Rheum Dis. 2017; 76: 29-42
        • Wei J.
        • Choi H.K.
        • Neogi T.
        • et al.
        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
        • Lu N.
        • Rai S.K.
        • Terkeltaub R.
        • Kim S.C.
        • Menendez M.E.
        • Choi H.K.
        Racial disparities in the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis as urate-lowering drug adverse events in the US HHS Public Access.
        Semin Arthritis Rheum. 2016; 46: 253-258
        • Saff R.R.
        • Li Y.
        • Santhanakrishnan N.
        • et al.
        Identification of inpatient allergic drug reactions using ICD-9-CM codes.
        J Allergy Clin Immunol Pract. 2019; 7: 259-264
        • Austin P.C.
        Using the standardized difference to compare the prevalence of a binary variable between two groups in observational research.
        Commun Stat Simul Comput. 2009; 38: 1228-1234
        • Hemmelgarn B.R.
        • Manns B.J.
        • Quan H.
        • Ghali W.A.
        Adapting the Charlson comorbidity index for use in patients with ESRD.
        Am J Kidney Dis. 2003; 42: 125-132
        • Levey A.S.
        • Stevens L.A.
        • Schmid C.H.
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Statistics Canada
        Population by selected ethnic origins, by province and territory (2006 Census). 2006 Census. 2006.