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Hydrochlorothiazide for Prevention of Kidney-Stone Recurrence

In a randomized trial, 3 doses of hydrochlorothiazide and placebo produced similar outcomes in patients with recurrent kidney stones, and the diuretic was associated with adverse effects. “Whether our results also apply to longer-acting thiazides remains to be determined,” the authors write.

Participants with recurrent calcium-containing kidney stones were assigned to hydrochlorothiazide 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. Seeking to determine the dose–response effect of the drug on a composite outcome of symptomatic or radiologic recurrence of kidney stones, the researchers determined: “In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo.”

Editorial: “Recent molecular insights gleaned from studies of proximal tubular calcium reabsorption (e.g., the role that the claudin family of tight-junction proteins plays in permitting paracellular reabsorption of calcium in this nephron segment) should be used to confirm [the] mechanism [of action]; such molecules should then be targeted to facilitate the lowering of urinary calcium excretion to prevent kidney-stone formation,” concludes an editorialist. “Claudin 2 is of particular interest because it contributes to substantial calcium reabsorption from the proximal tubules. Moreover, deletion of the claudin 2 gene Cldn2 in mice and a pathogenic variant of CLDN2 in humans results in hypercalciuria as well as nephrolithiasis. Furthermore, this gene has been linked to kidney-stone formation in a genomewide association study. Regardless of the effectiveness of thiazides in the treatment of kidney stones, thiazide therapy clearly confers an array of frequent side effects, including hypokalemia, hyponatremia, hypercalcemia, hyperuricemia, dysglycemia, and dyslipidemia; the risk of such conditions prevents many patients from taking them. Thus, it is time for new, more effective medical therapies with fewer side effects to be developed for this common, costly medical problem.”

Source: New England Journal of Medicine