Allopurinol for the treatment of chronic kidney disease: a systematic review

Nigel Fleeman, Gerlinde Pilkington, Yenal Dundar, Kerry Dwan, Angela Boland, Rumona Dickson, Hameed Anijeet, Tom Kennedy, Jason Pyatt
Health Technology Assessment: HTA 2014, 18 (40): 1-77, v-vi

BACKGROUND: The term chronic kidney disease (CKD) is used to describe abnormal kidney function (or structure). People with CKD have an increased prevalence of cardiovascular disease (CVD). Evidence is emerging that allopurinol may have a role to play in slowing down the progression of CKD and reducing the risk of CVD.

OBJECTIVES: This systematic review addresses the research question: does allopurinol reduce mortality, the progression of chronic kidney disease or cardiovascular risk in people with CKD?

DATA SOURCES: The following databases were searched on 7 January 2013: MEDLINE (1946 to 7 January 2013), EMBASE (1974 to 28 December 2012), The Cochrane Library (Issue 1, 2013) and Bibliographies of retrieved citations were also examined and two manufacturers of allopurinol were approached for data.

REVIEW METHODS: Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. Summary statistics were extracted for each outcome and, where possible, data were pooled. Meta-analysis was carried out using fixed-effects models.

RESULTS: Efficacy evidence was derived solely from four randomised controlled trials (RCTs). Adverse event (AE) data were derived from the RCTs and 21 observational studies. Progression of CKD was measured by estimated glomerular filtration rate (eGFR) in three trials and by changes in serum creatinine in the other. No significant differences in eGFR over time were reported. The only significant difference between groups was reported in one trial at 24 months favouring allopurinol [eGFR: 42.2 ml/minute/1.73 m(2), standard deviation (SD) 13.2 vs. 35.9 ml/minute/1.73 m(2), SD 12.3 ml/minute/1.73 m(2); p < 0.001]. In this same trial, there were twice as many cardiovascular events in the control arm (27%) as in the allopurinol arm (12%). Another trial reported an improvement in CKD progression as measured by serum creatinine in the allopurinol arm. No significant differences were reported in blood pressure between treatment groups in the meta-analyses. The incidence of AEs was estimated to be around 9% from all studies. The incidence of severe cutaneous adverse reactions (SCARs), which typically occurred within the first 2 months after allopurinol commencement, was reported to be 2% in two studies. Evidence for whether or not AEs and SCARs were dose related was conflicting. Not all patients had CKD in these studies.

LIMITATIONS: None of the included studies reported concealment of allocation, one of the greatest risks to study validity. Relatively few (< 115) patients were enrolled in any RCT. For studies reporting AEs, the main limitation is the heterogeneity across studies. No studies examining quality-of-life measures were identified.

CONCLUSIONS: There is limited evidence that allopurinol reduces CKD progression or cardiovascular events. It appears that AEs and in particular serious adverse events attributable to allopurinol are rare. However, the exact incidence of AEs in patients with CKD is unknown. Direct evidence for the impact of allopurinol on quality of life is lacking. Given the uncertainties in the evidence base, additional RCT evidence comparing allopurinol with usual care is required, accompanied by supporting data from observational studies of patients with CKD and using allopurinol.

STUDY REGISTRATION: The study is registered as PROSPERO CRD42013003642.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.

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