Higher Thiazide Doses Reduce Urine Calcium, Prevent Kidney Stone Recurrence

Ryan Hsi, MD

Credit: Vanderbilt University Medical Center

Findings from a recent study are providing clinicians with an overview of the benefit of thiazides for preventing kidney stone recurrence, suggesting greater thiazide doses are associated with increased reductions in urine calcium and fewer symptomatic kidney stone events.¹

The study, published in JAMA Network Open, offers a potential explanation for findings from the multicenter Hydrochlorothiazide for Kidney Stone Recurrence Prevention (NOSTONE) trial, which reported hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg did not reduce the recurrence of kidney stone events compared to placebo in a cohort of 416 patients with a history of kidney stone episodes at 12 centers in Switzerland.^1,2

“In light of our research, the calcium reductions in that [NOSTONE] were modest and likely insufficient to affect recurrence risk,” Ryan Hsi, MD, an associate professor in the department of urology at Vanderbilt University Medical Center, said in a press release.³

With the global incidence and prevalence of kidney stones on the rise, thiazides have served as a mainstay of pharmacologic prevention of kidney stone recurrence. However, the NOSTONE trial brought the efficacy of these agents for this indication into question, although Hsi and colleagues hypothesized this null finding may have been attributable to insufficient calcium reductions.^1,2

To assess the association between thiazide dose and calcium reduction and correlating calcium changes with symptomatic stone events, investigators analyzed data for adult patients with kidney stones in the Medicare-Litholink Database who underwent initial 24-hour urine collection for stone risk assessment between January 1, 2011, and December 31, 2018. Specifically, they identified and enrolled individuals who were prescribed thiazides, including hydrochlorothiazide, chlorthalidone, or indapamide, within the 6 months after urine collection as well as those who had follow-up collection between 30 and 180 days after their first prescription fill.¹

Investigators evaluated changes in calcium based on thiazide dosages applying the following low, medium, and high dosage criteria:

• Low: <12.5 mg/d chlorthalidone; <0.6125 mg/d indapamide; <25 mg/d hydrochlorothiazide
• Medium: 12.5 to <25 mg/d chlorthalidone; 0.6125 to <1.25 mg/d indapamide; 25 to <50 mg/d hydrochlorothiazide
• High: 25 mg/d chlorthalidone; 1.25 mg/d indapamide; 50 mg/d hydrochlorothiazide

Investigators then assigned participants into terciles based on the magnitude of the calcium change and assessed for the first occurrence of a symptomatic stone event, defined as an emergency department visit, hospitalization, or surgery for stones, 6 to 48 months after the initial prescription fill.¹

In total, the study included 634 participants. Among the cohort, the mean age was 67.6 years, 53.5% of participants were male, and 95.0% were White.¹

Investigators called attention to significant associations between increased thiazide doses and greater 24-hour mean and percentage calcium reductions:

• Low dose: −79.3 mg/d (95% CI, −94.1 to −64.4 mg/d) and −18.9% (95% CI, −23.9% to −14.0%), respectively
• Medium dose: −94.1 mg/d (95% CI, −106.7 to −81.5 mg/d) and −25.5% (95% CI, −29.6% to −21.3%), respectively
• High dose: −104.6 mg/d (95% CI, −117.0 to −92.3 mg/d) and −28.4% (95% CI, −32.6% to −24.4%), respectively (P = .04 for absolute difference and P = .02 for percentage difference)

The adjusted cumulative incidence of a symptomatic stone event at 4 years was 28.8% (95% CI, 21.1% to 35.7%), 19.5% (95% CI, 12.9% to 25.7%), and 18.0% (95% CI, 11.5% to 24.0%) for patients in the low (mean 24 mg/d), medium (mean −90 mg/d), and high (mean −216 mg/d) tercile of calcium change after thiazide prescription, respectively (P = .04).¹

Investigators acknowledged multiple limitations to these findings, including the possibility of omitted variable bias and unmeasured differences between participants prescribed different dosages as well as limited generalizability due to the sample being mostly older adults.¹

“What this means for patients is that thiazides remain an important option in the toolkit for preventing kidney stone recurrence,” Hsi concluded.³ “It may be beneficial to monitor calcium excretion while on thiazide therapy to adjust dose and diet to attain an adequate reduction in urine calcium.”

References

1. ^{Hsi RS, Yan PL, Maalouf NM, et al. Thiazide Dose, Urine Calcium, and Symptomatic Kidney Stone Events. JAMA Netw Open. doi:10.1001/jamanetworkopen.2024.28953}
2. ^{Dhayat NA, Bonny O, Roth B, et al. Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence. N Engl J Med. doi:10.1056/NEJMoa2209275}
3. ^{Vanderbilt University Medical Center. Higher thiazide doses shown to reduce kidney stone events. EurekAlert! August 22, 2024. Accessed August 22, 2024. https://www.eurekalert.org/news-releases/1055278}