Hydrochlorothiazide Shows Lack of Effect on Prevention of Recurrent Kidney Stones

Daniel G. Fuster, MD

Treatment with hydrochlorothiazide did not appear to differ substantially from placebo in preventing the recurrence of kidney stones in patients at high risk for recurrence, according to results from the NOSTONE trial.¹

The data suggest the incidence of recurrence was similar across the 12.5-mg, 25-mg, and 50-mg hydrochlorothiazide groups and the placebo group in the double-blind trial enrolling approximately 400 patients from Switzerland.

“We were not able to confirm our hypothesis; we observed no relation between the hydrochlorothiazide dose and the primary endpoint, a composite of symptomatic or radiologic recurrence of kidney stones,” wrote the investigative team, led by Daniel G. Fuster, MD at the University of Bern.

Kidney stones recur frequently, and the prevalence and incidence are said to have increased worldwide in recent decades. Although thiazides are a cornerstone of pharmacologic prevention, there is a paucity of data on the efficacy of these agents compared with placebo, as well as limited dose-response data. The NOSTONE trial was a double-blind, randomized, placebo-controlled trial conducted to evaluate a range of hydrochlorothiazide doses for the prevention of the recurrence of kidney stones.

Patients with recurrent calcium-containing kidney stones were enrolled at 12 centers in Switzerland and randomly assigned to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The planned duration of treatment was 3 years, aside from patients enrolled during the final year of trial, for whom treatment was planned for 2 to 3 years, according to investigators.

The primary objective of the NOSTONE trial was to investigate the dose–response effect for the primary endpoint, a composite of symptomatic or radiologic recurrence of kidney stones. It defined symptomatic recurrence as the visible passage of a stone with or without accompanying typical symptoms. Meanwhile, radiologic recurrence was defined as the appearance of new stones on low-dose computed tomographic imaging or the enlargement of preexisting stones observed on the baseline image.

Between March 2017 and October 2019, a total of 1335 patients underwent screening and of this total, 416 met eligibility criteria. They were randomly assigned to receive 12.5-mg (n = 105), 25-mg (n = 108), or 50-mg (n = 101) doses of hydrochlorothiazide once daily or placebo once daily (n = 102). The median duration of follow-up was 2.9 years and 387 patients (93%) were reported to have completed follow-up as planned.

Upon analysis, in the placebo group, over half (59%) of patients had symptomatic or radiologic recurrence of kidney stones. A primary endpoint event occurred in 62 of 105 (29%) 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).

As such, investigators observed no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (rate ratio for trend, 0.98; 95% CI, 0.87 to 1.09; P = .66). Results on symptomatic recurrence were confirmed in various sensitivity analyses, including one restricted to patients without kidney stones at baseline, and analyses in which symptomatic events that had occurred within the first 6 or 12 months after randomization were excluded to allow for a washout period for preexisting stones.

Safety findings suggest new-onset diabetes mellitus, hypokalemia, gout, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients in the hydrochlorothiazide groups. However, the incidence of serious adverse events was not higher among patients receiving hydrochlorothiazide than among those receiving placebo.

“These results arouse concerns about the long-term use of hydrochlorothiazide for the prevention of kidney stones,” investigators wrote.

References

1. Dhayat NA, Bonny O, Roth B, et al. Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence. N Engl J Med. 2023;388(9):781-791. doi:10.1056/NEJMoa2209275