Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence

N Engl J Med. 2023 Mar 2;388(9):781-791. doi: 10.1056/NEJMoa2209275.


Background: Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited.

Methods: In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed.

Results: 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.

Conclusions: Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Diuretics* / administration & dosage
  • Diuretics* / adverse effects
  • Diuretics* / therapeutic use
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Humans
  • Hydrochlorothiazide* / administration & dosage
  • Hydrochlorothiazide* / adverse effects
  • Hydrochlorothiazide* / therapeutic use
  • Kidney / diagnostic imaging
  • Kidney Calculi* / diagnostic imaging
  • Kidney Calculi* / prevention & control
  • Recurrence
  • Sodium Chloride Symporter Inhibitors / administration & dosage
  • Sodium Chloride Symporter Inhibitors / adverse effects
  • Sodium Chloride Symporter Inhibitors / therapeutic use


  • Hydrochlorothiazide
  • Sodium Chloride Symporter Inhibitors
  • Diuretics

Associated data

  • ClinicalTrials.gov/NCT03057431