A randomised controlled trial has shown that hydrochlorothiazide, which for decades has been a standard treatment to prevent the recurrence of calcium-containing kidney stones, did not lower the rate of stone recurrence, and side effects, compared with placebo, actually increased with the medication.
The research also showed that the rate of stone recurrence within three years was similar among 416 patients randomly assigned to receive hydrochlorothiazide 12.5mg, 25mg, or 50mg daily or placebo in the NOSTONE trial, led by Dr Nasser Dhayat of Bern University Hospital and published in the New England Journal of Medicine.
The findings call into question the use of this standard treatment, according to senior author Dr Daniel Fuster.
Similarly, nephrologist Dr Perry Wilson of Yale University School of Medicine who was not involved with this study, said: “This is important. Thiazides are standard of care for calcium-containing stone formers, so this has significant potential to upset that apple cart.”
“Guidelines recommend 25 or 50 mg hydrochlorothiazide daily,” Fuster, from the Department of Nephrology and Hypertension, Bern University Hospital, told Medscape Medical News.
“Our study is the first state-of-the-art study for kidney stone recurrence prevention with thiazides and shows that hydrochlorothiazide is not effectively preventing recurrence, but it puts patients at risk of side effects,” he said.
Compared to the patients who received placebo, those treated with hydrochlorothiazide had lower levels of urine calcium, which promotes stone formation, but they also had lower levels of urine citrate, which is protective, he noted.
“Whether these results also apply to other thiazides used to prevent calcium-containing kidney stones), such as chlorthalidone or indapamide, remains to be seen,” he added. “My personal opinion: they are more potent, i.e, will probably lower urine calcium more efficiently, but will probably also produce a more pronounced reduction in urine citrate.
“We need more outcome trials for kidney stone prevention. Most current recommendations are not supported by high-quality, randomised evidence, so we need innovation – new pharmacologic treatment options.”
The NOSTONE trial enrolled 416 eligible patients from March 2017 to October 2019.
Participants were aged 18 or older and had had a kidney stone during the previous 10
years that contained at least 50% calcium oxalate, calcium phosphate, or both.
Patients were randomly assigned in a 1:1:1:1 ratio to receive placebo or 12.5 mg, 25 mg, or 50 mg hydrochlorothiazide once daily, and were followed for a median of 2.9 years.
The primary endpoint was a composite of symptomatic kidney stone recurrence (visible passage of a stone with or without flank or loin pain and haematuria or the presence of a stone that needed surgical removal) or radiologic kidney stone recurrence (using CT).
In the 12.5-mg, 25-mg, 50-mg daily hydrochlorothiazide and placebo groups:
A composite primary endpoint event occurred in 59%, 56%, 49%, and 59% of patients, respectively.
Symptomatic kidney stone recurrence occurred in 38%, 40%, 28%, and 34% of patients, respectively.
Radiologic kidney stone recurrence occurred in 45%, 32%, 34%, and 49% of patients, respectively.
New-onset type 2 diabetes, hypokalemia, gout, skin allergy, and plasma creatinine level >150% of the baseline level were more common among patients in the hydrochlorothiazide groups than among the placebo group.
Results call into question thiazide treatment
“These results are consistent with health administrative data from a much larger number of patients, which also failed to show an effect of hydrochlorothiazide dose on the prevention of recurrence of stones,” Dr Todd Alexander wrote in an accompanying editorial.
“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, although the incidence of radiographic recurrence was lower among the groups receiving the two higher doses of hydrochlorothiazide than among the other two groups,” said Alexander, professor in the Division of Paediatric Nephrology, University of Alberta, Edmonton, Canada.
“These results call into question the use of the standard medical treatment – thiazide and thiazide-like diuretic agents – to reduce the risk of recurrence of kidney stones.”
He said it was time for new, more effective medical therapies with fewer side effects to be developed for this common, costly medical problem.
Thiazides have been the cornerstone pharmacotherapy to prevent kidney stone recurrence for more than 50 years, but previous studies used outdated diets or imaging or had flaws, such as lack of double blinding.
In addition, the daily dose of hydrochlorothiazide, the agent most widely studied, was 50 or 100mg, which is larger than is used today.
Study details
Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence
Nasser Dhayat, Olivier Bonny, Beat Roth, Andreas Christe, Alexander Ritter, Nilufar Mohebbi, Nicolas Faller, Lisa Pellegrini, Giulia Bedino, Reto Venzin, Philipp Grosse, Carina Hüsler, et al.
Published in NEJM on 2 March 2023
Abstract
Background
Nephrolithiasis is one of the most common conditions affecting the kidney and is characterised 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.
NEJM article – Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence (Open access)
NEJM accompanying editorial – Do Thiazides Reduce the Risk of Kidney-Stone Recurrence? (Open access)
Medscape article – Stop giving thiazides to prevent recurrent kidney stones (Open access)
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