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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 in the NOSTONE randomized controlled trial.

The rate of stone recurrence within 3 years was similar among 416 patients randomly assigned to receive hydrochlorothiazide 12.5 mg, 25 mg, or 50 mg daily or placebo. Side effects were more common with hydrochlorothiazide.

The study by Nasser A. Dhayat, MD, and colleagues was published March 2 in The New England Journal of Medicine.

The findings call into question the use of this standard treatment, according to the study’s senior author and an accompanying editorialist.

Similarly, nephrologist F. Perry Wilson, MD, is chlorpromazine a narcotic of Yale University School of Medicine, who is a columnist for Medscape and was not involved with this study, commented: “This strikes me as 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,” the study’s senior author, Daniel G. Fuster, MD, explained to Medscape Medical News in an email.

“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,” explained Fuster, of the Department of Nephrology and Hypertension, Bern University Hospital, Switzerland.

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 [that are used to prevent calcium-containing kidney stones], such as chlorthalidone or indapamide,” he added, “remains to be seen. My personal opinion: They are more potent, ie, will probably lower urine calcium more efficiently, but will likely also produce a more pronounced reduction in urine citrate.

“We need more outcome trials for kidney stone prevention,” Fuster concluded.

“Most current recommendations are not supported by high-quality, randomized evidence. And we need innovation — new pharmacologic treatment options,” he stressed.

“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,” R. Todd Alexander, MD, PhD, writes in his 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 that received the two higher doses of hydrochlorothiazide than among the other two groups, Alexander, professor in the Division of Pediatric Nephrology, University of Alberta, Edmonton, Canada, noted.

“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,” he summarized. “Accordingly, these findings should lead to further and larger studies to examine the usefulness of thiazides for the prevention of recurrence of kidney stones.”

Moreover, Alexander noted, “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.”

Like Fuster, he urges: “It is time for new, more effective medical therapies with fewer side effects to be developed for this common, costly medical problem.”

New Trial to Replace Outdated Evidence

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 100 mg, which is larger than is used today.

The NOSTONE trial enrolled 416 eligible patients from March 2017 to October 2019. Participants were aged 18 years 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 they 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 hematuria 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.

The study was supported by the Swiss National Science Foundation and Inselspital, Bern University Hospital, University of Bern, Switzerland. Fuster is a consultant for Anylam Pharmaceuticals, Kyowa Hakko Kirin, and Otsuka America Pharmaceutical and receives grants from Boehringer Ingelheim and Otsuka America Pharmaceutical. The disclosures of the other authors are listed with the original article. Alexander is a consultant for Ardelyx and Ultragenyx Pharmaceutical and has received travel reimbursement from Advicenne and a grant from Ardelyx. Wilson is a columnist for Medscape.

N Engl J Med. Published online March 2, 2023. Abstract, Editorial

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