Chlorthalidone Is Superior to Potassium Citrate in Reducing Calcium Phosphate Stones and Increasing Bone Quality in Hypercalciuric Stone-Forming Rats

Significance Statement Genetic hypercalciuric stone-forming rats, which universally and spontaneously form calcium phosphate stones, have a pathophysiology resembling that of human idiopathic hypercalciuria. The authors previously demonstrated that chlorthalidone, but not potassium citrate, decreased stone formation in this rat model. In this study, they investigated whether chlorthalidone and potassium citrate combined would reduce calcium phosphate stone formation more than either medication alone. They found that chlorthalidone was more effective than potassium citrate alone or combined with chlorthalidone in reducing stone formation and increasing mechanical strength and bone quality. However, replication of these findings in patients with nephrolithiasis is needed before concluding that chlorthalidone alone is more efficacious in this regard than potassium citrate alone or in combination with chlorthalidone. Background The pathophysiology of genetic hypercalciuric stone-forming rats parallels that of human idiopathic hypercalciuria. In this model, all animals form calcium phosphate stones. We previously found that chlorthalidone, but not potassium citrate, decreased stone formation in these rats. Methods To test whether chlorthalidone and potassium citrate combined would reduce calcium phosphate stone formation more than either medication alone, four groups of rats were fed a fixed amount of a normal calcium and phosphorus diet, supplemented with potassium chloride (as control), potassium citrate, chlorthalidone (with potassium chloride to equalize potassium intake), or potassium citrate plus chlorthalidone. We measured urine every 6 weeks and assessed stone formation and bone quality at 18 weeks. Results Potassium citrate reduced urine calcium compared with controls, chlorthalidone reduced it further, and potassium citrate plus chlorthalidone reduced it even more. Chlorthalidone increased urine citrate and potassium citrate increased it even more; the combination did not increase it further. Potassium citrate, alone or with chlorthalidone, increased urine calcium phosphate supersaturation, but chlorthalidone did not. All control rats formed stones. Potassium citrate did not alter stone formation. No stones formed with chlorthalidone, and rats given potassium citrate plus chlorthalidone had some stones but fewer than controls. Rats given chlorthalidone with or without potassium citrate had higher bone mineral density and better mechanical properties than controls, whereas those given potassium citrate did not. Conclusions In genetic hypercalciuric stone-forming rats, chlorthalidone is superior to potassium citrate alone or combined with chlorthalidone in reducing calcium phosphate stone formation and improving bone quality.