Response to Letter Regarding Article, “High-Dose Allopurinol Improves Endothelial Function by Profoundly Reducing Vascular Oxidative Stress and Not by Lowering Uric Acid”
We agree entirely that great caution would be required if high-dose allopurinol were ever to be given to patients with impaired renal function. In fact, we specifically devote a whole paragraph in our discussion1 to cautions about the dose used, the risk of allopurinol toxicity, and the importance of patient selection regarding renal dysfunction.
Although our study was performed before estimated glomerular filtration rate became routine practice in the United Kingdom, we now have calculated the creatinine clearance of our patients. The mean creatinine clearance for patients on placebo was 63.35 mL/min; for patients on 300 mg of allopurinol, it was 62.68 mL/min; and for patients on 600 mg of allopurinol, it was 63.04 mL/min. There was no significant difference between the treatment groups (P=0.59).
On the other hand, a recent consensus conference found that oxidative stress was a particular cause of atherosclerosis in renal patients.2 This is confirmed by the fact that the only disease in which exogenous antioxidant vitamins produced cardiovascular benefits was renal impairment.3 These 2 observations make oxidative stress a potential therapeutic target in patients with renal impairment. Our work shows that allopurinol can be exceptionally potent at ameliorating this key therapeutic target.
Therefore, as in our article, we suggest that very cautious dose–response studies should be undertaken to explore this potential benefit of allopurinol in patients with renal dysfunction, and we are currently undertaking such studies. The example given by Dr Kielstein and colleagues of spironolactone in the Randomized Aldactone Evaluation Study is a good example of how many lives can be saved in a population at very high risk, if cautious use and appropriate monitoring are undertaken to minimize toxicity. We hope that the same may turn out to be true if allopurinol is very cautiously prescribed to patients with renal dysfunction, once the correct dose is established for each level of renal dysfunction.
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.
Locatelli F, Canaud B, Eckardt KU, Stenvinkel P, Wanner C, Zoccali C. Oxidative stress in end-stage renal disease: an emerging threat to patient outcome. Nephrol Dial Transplant. 2003; 18: 1272–1280.
Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green MS. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet. 2000; 356: 1213–1218.