Allopurinol dosing in renal impairment: walking the tightrope between adequate urate lowering and adverse events

Allopurinol is the mainstay of urate-lowering therapy for patients with gout and impaired renal function. Although rare, a life-threatening hypersensitivity syndrome may occur with this drug. The risk of this allopurinol hypersensitivity syndrome (AHS) is increased in renal impairment. The recognition that AHS may be because of delayed-type hypersensitivity to oxypurinol, the main metabolite of allopurinol, and that oxypurinol concentrations are frequently elevated in patients with renal impairment prescribed standard doses of allopurinol has led to the widespread adoption of allopurinol-dosing guidelines. These guidelines advocate allopurinol dose reduction according to creatinine clearance in patients with renal impairment. However, recent studies have challenged the role of these guidelines, suggesting that AHS may occur even at low doses of allopurinol, and that these guidelines lead to under-treatment of hyperuricemia, a key therapeutic target in gout. Based on current data, we advocate gradual introduction of allopurinol according to current treatment guidelines, with close monitoring of serum uric acid concentrations. In patients with severe disease and persistent hyperuricemia, allopurinol dose escalation above those recommended by the guidelines should be considered, with careful evaluation of the benefits and risks of therapy. Further work is needed to clarify the safety and efficacy of allopurinol dose escalation, particularly in patients with renal impairment.