The thiazide diuretic hydrochlorothiazide does not prevent kidney stone recurrence, regardless of dosage, investigators reported in the New England Journal of Medicine.

In the double-blind NOSTONE trial ( number: NCT03057431), investigators randomly assigned 416 patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. Patients also received dietary counseling. Over a median of 2.9 years, the rate of symptomatic or radiologic recurrence of kidney stones did not differ significantly between the hydrochlorothiazide and placebo groups: 59%, 56%, and 49% in the 12.5-mg, 25-mg, and 50-mg hydrochlorothiazide groups vs 59% in the placebo group, Daniel Fuster, MD, of the University of Bern in Switzerland, and colleagues reported. The rate of symptomatic kidney stone recurrence alone also was comparable among groups: 38%, 40%, and 28%, respectively, vs 34% with placebo. The rate of radiologic recurrence was significantly lower in the 25- and 50-mg hydrochlorothiazide groups compared with the placebo group: 32% and 34% vs 49%, respectively. 

At baseline, 63% of patients had hypercalciuria, defined as a urinary calcium excretion rate of more than 200 mg in 24 hours.

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“What is surprising, however, is that the current trial did not detect any protective effect of hydrochlorothiazide treatment on stone recurrence, even among patients who had hypercalciuria or who had only symptomatic recurrence of stones,” R. Todd Alexander, MD, PhD, of the University of Alberta in Canada, wrote in an accompanying editorial. He noted that the study sample size may have been too small to detect differences in efficacy in subgroups.

“These results call into question the use of what has become the standard medical treatment — thiazide and thiazide-like diuretic agents — to reduce the risk of recurrence of kidney stones; accordingly, these findings should lead to further and larger studies to examine the usefulness of thiazides for the prevention of recurrence of kidney stones,” Dr Alexander wrote. “However, these results may not bring about changes in clinical practice just yet.”

Urine relative supersaturation ratios for calcium oxalate and calcium phosphate did not differ among groups at the end of the study.

Adverse events of special interest, including new-onset diabetes, hypokalemia, gout, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level occurred more frequently in the hydrochlorothiazide than placebo groups. Serious adverse events occurred at a comparable frequency among groups.

According to Dr Alexander, “it is time for new, more effective medical therapies with fewer side effects to be developed for this common, costly medical problem.”


Dhayat NA, Bonny O, Roth B, et al. Hydrochlorothiazide and prevention of kidney-stone recurrence. N Engl J Med 388:781-791. Published online March 2, 2023. doi:10.1056/NEJMoa2209275

Alexander RT. Do thiazides reduce the risk of kidney-stone recurrence? N Engl J Med 388:841-842. Published online March 2, 2023. doi:10.1056/NEJMe2300120