Letter by Kielstein et al Regarding Article, “High-Dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid”
To the Editor:
We read with interest the paper by George and colleagues1 about the benefit of high-dose allopurinol on endothelial dysfunction in patients with class II or III heart failure. The authors suggest that on the basis of the steep dose–response relationship between allopurinol and endothelial function, a dose of 600 mg/d yields the most improvement in endothelial function. We are concerned about the implications of this report in patients with impaired renal function. It is difficult to ascertain renal function from the data presented, because only the serum creatinine levels are provided. The glomerular filtration rate was neither measured nor estimated. In accordance with recent American Heart Association recommendations to use the Modification of Diet in Renal Disease formula,2 we estimate a mean glomerular filtration rate of less than 60 mL/min for the patients in this study.
The clearance of oxipurinol, the main active metabolite of allopurinol, is directly proportional to the renal clearance of creatinine. Hande and colleagues3 have reported 78 patients with renal impairment and life-threatening allopurinol toxicity. On the basis of their report, it was recommended that a patient with an estimated glomerular filtration rate of 60 to 80 mL/min should receive a maximal dose of 200 mg of allopurinol per day.3 In the study by Dr George and colleagues,1 the dose of allopurinol used was 3-fold higher than that. Others have suggested that the drug should be avoided altogether in patients with renal insufficiency.4 It has been estimated that 17% of the adult US population suffers from chronic kidney disease. Novel, promising treatment strategies may be safe in the general population, but they could cause substantial toxicity in patients with chronic kidney disease—a lesson we should have learned from the high incidence of life-threatening hyperkalemia following the publication of the Randomized Aldactone Evaluation Study.5 The present study raises the interesting possibility of a novel treatment strategy; however, in our opinion, caution is needed because of the concern of substantial toxicity in patients with chronic kidney disease.
George J, Carr E, Davies J, Belch JJ, Struthers A. High-dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation. 2006; 114: 2508–2516.
Brosius FC 3rd, Hostetter TH, Kelepouris E, Mitsnefes MM, Moe SM, Moore MA, Pennathur S, Smith GL, Wilson PW; American Heart Association Kidney and Cardiovascular Disease Council; Council on High Blood Pressure Research; Council on Cardiovascular Disease in the Young; Council on Epidemiology and Prevention; Quality of Care and Outcomes Research Interdisciplinary Working Group. Detection of chronic kidney disease in patients with or at increased risk of cardiovascular disease: a science advisory from the American Heart Association Kidney And Cardiovascular Disease Council; the Councils on High Blood Pressure Research, Cardiovascular Disease in the Young, and Epidemiology and Prevention; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: developed in collaboration with the National Kidney Foundation. Circulation. 2006; 114: 1083–1087.
Kumar A, Edward N, White MI, Johnston PW, Catto GR. Allopurinol, erythema multiforme, and renal insufficiency. BMJ. 1996; 312: 173–174.