The mechanism by which high urinary uric acid promotes calcium oxalate stone formation is unclear. Possible theories include epitaxy, urate-induced reduction in the inhibitory activity of urinary glycosaminoglycans, and decreased solubility of calcium oxalate by way of a “salting out” phenomenon.190 Allopurinol, presumably by its reduction in urinary uric acid, has been shown in two RCTs (n=143) to reduce stone recurrence or stone regrowth at 6 months to 3 years in patients with recurrent calcium oxalate stones (minimum of two prior stone episodes) and high urinary uric acid compared to placebo (pooled RR: 0.59; 95% CI: 0.43 to 0.82), corresponding to an absolute risk difference per 1,000 participants of 265 fewer recurrent stone episodes (95% CI: from 371 fewer to 119 fewer).55, 63 In the first RCT, in patients with isolated hyperuricosuria, Ettinger et al. (n=60) reported stone recurrences in 9 of 29 participants in the allopurinol group (31.0%) versus 18 of 31 participants in the placebo group (58.1%) at 3 years follow-up (calculated RR: 0.53; 95% CI: 0.29 to 0.99).55 In addition, they found a significantly longer time to stone recurrence in the allopurinol group compared to the placebo group (33.3 months versus 27.4 months; p<0.05).55 In the second RCT, Smith et al. (n=92) observed stone recurrences in 21 of 49 participants in the allopurinol group (42.9%) versus 30 of 43 participants in the placebo group (69.8%) at 6 months follow-up (calculated RR: 0.61; 95% CI: 0.42 to 0.90).63 Of note, hyperuricemia was not required for allopurinol therapy in these studies. It should also be noted that there was insufficient data to recommend the use of febuxostat, another xanthine oxidase inhibitor, in this clinical setting.66 Allopurinol is generally well-tolerated and associated with a low risk of adverse effects. Two RCTs showed minimal to no difference in the overall risk of adverse effects associated with allopurinol versus placebo (pooled estimate RR: 0.98; 95% CI: 0.66 to 1.44).55, 66 As indicated in Statement 28, allopurinol should not be used as first-line therapy for uric acid stones. Please refer to Statement 38 for guidance on monitoring for adverse effects of allopurinol. In addition, it is recommended by the American College of Rheumatology to test African American and Southeast Asian patients for HLA-B*58:01 allele prior to starting allopurinol due to the high risk of severe cutaneous adverse reactions, and use of allopurinol is contraindicated in those who test positive.191