An Open‐Label Dose‐Finding Study of Allopurinol to Target Defined Reduction in Urate Levels in Hemodialysis Patients

Allopurinol is a xanthine oxidase inhibitor mainly used to reduce circulating urate (also known as uric acid) levels. This helps to prevent recurrent urate crystal deposition in the form of gout.1 Gout is relatively common in patients with renal failure. Although routine dose reduction of allopurinol is recommended in the hemodialysis (HD) population this is not based on evidence from robust clinical trials.2 Guidelines generally recommend aiming to reduce urate levels by 50% to protect against future gout episodes.3 This study aimed to determine the optimal dose of allopurinol to achieve this in the HD population. Determining an optimal dose of allopurinol to use in the HD population will first help to guide clinicians in their treatment of their HD patients who develop gout. Second, patients with end-stage renal disease are at greatly increased risk of cardiovascular disease and death.4 Urate levels are known to be higher in the chronic kidney disease (CKD) population than in the general population.5 We know from large observational studies that increased urate levels are strongly associated with an increased cardiovascular risk, in both the general and CKD populations.6–9 In addition to its urate-lowering abilities, allopurinol itself has some specific properties that make it a potentially attractive drug to use in the HD population. Allopurinol has been shown to improve endothelial function in several population groups— including CKD patients—who are prone to endothelial dysfunction.10–12 In a large observational study the use of allopurinol was associated with reduced cardiovascular and all-cause mortality in patients undergoing HD who had no history of cardiovascular disease.13 In addition to this, allopurinol has also been demonstrated to regress left ventricular hypertrophy (LVH) in CKD, diabetic patients and in those with ischemic heart disease.10,11,14 Given that reduction in left ventricular mass is a common therapeutic target in the HD population,15–18 it is a natural question whether allopurinol might also regress LVH in this population. Until now this had not been investigated in a robust prospective clinical trial. We therefore designed a clinical trial to investigate this, the ALTERED (Does ALlopurinol regress lefT ventricular hypertrophy in End stage REnal Disease) study. This study looked to address this question through a multicenter randomized, placebo-controlled, double-blind trial of allopurinol. The primary outcome of the ALTERED study is change in left ventricular mass measured by cardiac magnetic resonance imaging at follow-up from baseline after 1 year of therapy. For the reasons described above, defining the optimal dose of allopurinol to use in this study was a priority. The first stage of the ALTERED study was therefore an open-label dose-escalation study to determine the