Hydrochlorothiazide Does Not Significantly Reduce Kidney Stone Recurrence, Research Suggests @MedPage Today

March 12th, 2023

Daily Thiazide No Help in Preventing Recurrent Kidney Stones

— Three different dosages of hydrochlorothiazide no better than placebo

A computer rendering of a cutaway kidney revealing kidney stones

A common diuretic wasn’t much help for staving off recurrent kidney stones, the NOSTONE trial showed.

Over a median follow-up of 2.9 years, symptomatic or radiologic recurrence of kidney stones occurred in 59% of patients who received hydrochlorothiazide (12.5 mg once daily) and 59% of those assigned placebo (rate ratio [RR] 1.33, 95% CI 0.92-1.93), reported Daniel Fuster, MD, of Bern University Hospital in Switzerland, and colleagues.

Moreover, patients who received higher doses of hydrochlorothiazide also experienced no significant reduction in kidney stone recurrence, with rates of 56% for those who received a 25-mg dose (RR 1.24, 95% CI 0.86-1.79) and 49% with a 50-mg dose (RR 0.92, 95% CI 0.63-1.36), they detailed in the New England Journal of Medicineopens in a new tab or window.

Overall, there was no relation between the hydrochlorothiazide dose and the occurrence of symptomatic or radiologic recurrence of kidney stones (P=0.66).

Fuster’s group also found no differences in the primary endpoint when broken down into specific subgroups, including by the number of stone events in the past 10 years, baseline hypercalciuria, stone composition, or any stone at baseline.

In an accompanying editorialopens in a new tab or window, R. Todd Alexander, MD, PhD, of the University of Alberta in Canada, noted that what was most surprising about the trial is that hydrochlorothiazide even failed to prevent kidney stones in patients with hypercalciuria and those who only had symptomatic recurrence of stones.

“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 wrote.

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

Fuster and colleagues explained that thiazide and thiazide-like diuretic agents “have been the cornerstone of pharmacologic prevention of recurrence for more than 50 years,” with hydrochlorothiazide being the “most widely prescribed and best studied thiazide.”

They expected the diuretic would reduce the incidence of kidney stones since these drugs reduce urinary calcium excretion. While participants taking hydrochlorothiazide did see decreased urinary calcium excretion, there was not a reduction in urine relative supersaturation ratios for calcium oxalate and calcium phosphate — the value used to predict risk of calcium-containing kidney stones.

Not only was the daily diuretic no help in preventing kidney stones, but patients taking hydrochlorothiazide also experienced a higher rate of several adverse events. Specifically, hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and plasma creatinine levels exceeding 150% of the baseline level were all more common in the hydrochlorothiazide group than the placebo group.

That being said, Alexander noted that it might be too soon to have these findings change clinical practice just yet. While he praised the trial for its large sample size — 416 patients — it may have still been underpowered to actually detect differences in stone recurrence between dosage groups. He also critiqued the study for not using urinary calcium excretion as part of the inclusion criteria.

Fuster’s group instead recruited adults who had at least two kidney stone episodes in the past decade or any previous kidney stone that contained at least 50% calcium oxalate, calcium phosphate, or both. Exclusion criteria included secondary causes of kidney stones and the receipt of drugs that could interfere with the formation of kidney stones.

The 1:1:1:1 trial stratified participants according to the number of kidney stone episodes in the patient’s history. Median age was 49, 80% were men, and 99% were white. Only a third of participants had four or more stone events in the past 10 years. At baseline, median urinary calcium excretion was 244 mg/24 hr, and 63% had hypercalciuria.