Robert Terkeltaub, MD

Disclosures

April 17, 2001

Question

Certain textbooks/references suggest a maximum dose of allopurinol (Xyloprim, Lopurin) in patients with renal insufficiency.  Presumably, this is because of renal excretion of the metabolite, oxypurinol, and fear that overdosing of allopurinol in a patient with renal insufficiency may lead to toxic epidermal necrolysis. If these guidelines are followed, some patients are unable to reduce their serum uric acid level to an acceptable level, despite maximal control of other aggravating factors (eg, hypertension, medications, alcohol intake).  What should one do in this situation?  Are the "maximum dosing schedules of allopurinol in patients with renal insufficiency" justified?

Nikhil Chopra, MD

Response from Robert Terkeltaub, MD

The major active metabolite of allopurinol is oxypurinol, which is cleared quite slowly by renal elimination (giving oxypurinol a half-life of 24 hours in normal individuals). Clinicians run the risk of having insufficient respect for the toxicities of allopurinol. Some of the serious toxicities appear to be dose-dependent and increased in incidence by renal insufficiency. These clearly include full-blown allopurinol hypersensitivity syndrome, which has a mortality rate of approximately 20%, but also may include significant hepatic disease. I recommend general adherence to the recommended guidelines for allopurinol dosage in renal failure.

The standard dose of allopurinol is 300 mg a day for patients with a creatinine clearance of 90 mL/min or greater. I generally recommend giving a maximum of 100 mg a day of allopurinol to patients with a creatinine clearance of 30 mL/min or less, and I usually give no more than 200 mg a day to patients with a creatinine clearance of 60. In patients with normal renal function, the goal of the uric acid lowering therapy is to drop the serum uric acid to below 6.0 mg/dL, a point below which monosodium urate becomes supersaturated at physiologic pH in normal tissues. I carefully adjust the allopurinol dose upward if assured that the target uric acid level has not been achieved.

The strategy for uric acid lowering is different in the setting of renal insufficiency. Renal excretion is the predominant mechanism for clearing body stores of uric acid, which is normally done in a manner that directly adapts to increases in serum urate. But a decreased glomerular filtration rate (GFR) constrains the amount by which urate can be eliminated from the serum to lessen (or maintain) total body urate stores. Thus, increasing the allopurinol dose beyond the recommended maximum for marked renal insufficiency could decrease new formation of uric acid in cells but fail to efficiently decrease total body urate stores; the approach generally fails to reduce serum urate to below 6.0 mg/dL. For these reasons, adherence to the standard allopurinol dosing guidelines in renal failure is wise. This approach generally helps to stabilize the patient's gout despite a failure to achieve a marked reduction in serum uric acid.

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