Randomized Trial of Allopurinol in the Prevention of Calcium Oxalate Calculi

Abstract

In a double-blind study, we examined the efficacy of allopurinol in the prevention of recurrent calcium oxalate calculi of the kidney. Sixty patients with hyperuricosuria and normocalciuria who had a history of calculi were randomly assigned to receive either allopurinol (100 mg three times daily) or a placebo. After the study, the placebo group had 63.4 percent fewer calculi (P less than 0.001), whereas the allopurinol group had 81.2 percent fewer calculi (P less than 0.001). During the study period, the mean rate of calculous events was 0.26 per patient per year in the placebo group and 0.12 in the allopurinol group. When the treatment groups were compared by actuarial analysis, the allopurinol group was found to have a significantly longer time before recurrence of calculi (P less than 0.02). We conclude that allopurinol is effective in the prevention of calcium oxalate stones in patients with hyperuricosuria. The large reduction in the frequency of calculi in the placebo group underscores the positive treatment bias that regularly occurs in trials of prophylaxis against renal calculi when historical controls are used.

Modulation of Proliferating Renal Epithelial Cell Affinity for Calcium Oxalate Monohydrate Crystals

“…Intracellular MSU crystals were detected by electron microscopy, and release of cellular lactate dehydrogenase into the medium was demonstrated, which suggested cell injury. Increased COM crystal adhesion to cells that have "reacted" to UA crystals could in part explain the association between hyperuricosuria and calcium oxalate stone formation (28). It is interesting that Figure 8.…”

“…Given the association of hyperuricosuria and calcium oxalate stones (28) and the dramatic cellular response to UA crystals described by Emmerson and colleagues (22,29), we wondered what effect UA crystals might have on COM crystal binding to renal cells. The medium of confluent MDCKI monolayers was replaced with low-sodium, low-pH buffer to which 800 g/ml crystals was added.…”

Epidemiology and medical management of stone disease

“…Reports of an apparent relationship between hyperuricosuria and calcium stone formation led to the use of allopurinol as a means by which CaOx stone formation could be reduced [74]. The results obtained with allopurinol are conflicting and it is possible that an effect should be expected only when the urinary concentration of urate is high [75].…”

Potential Pharmacologic Treatments for Cystinuria and for Calcium Stones Associated with Hyperuricosuria

“…With many small and inadequately controlled trials in the literature suggesting that reducing uric acid excretion might reduce calcium stone recurrence, only one adequate randomized, controlled trial has dem-onstrated this effect (6). The hypothesis was that allopurinol, an inhibitor of xanthine oxidase (also known recently as xanthine dehydrogenase or xanthine oxidoreductase) would decrease the rate of recurrent calcium oxalate calculi in patients with hyperuricosuria (Ͼ800 mg/d in men, Ͼ750 mg/d in women) and normocalciuria (Ͻ300 mg/d in men, Ͻ250 mg/d in women).…”

“…Its title is "Febuxostat Versus Allopurinol or Placebo in Subjects with Hyperuricosuria and Calcium Oxalate Stones" (ClinicalTrials-.gov identifier NCT01077284). The preliminary design seeks essentially to replicate the allopurinol study of Ettinger et al (6). Patients with a history of calcium stones and at least one 3-mm stone in place and with hyperuricosuria (Ͼ700 mg/d) and normocalciuria (Ͻ4 mg/kg) will be randomly assigned to one of three groups: febuxostat 80 mg/d, allopurinol 200 or 300 mg/d (depending on GFR), or placebo.…”