Clinical Pearls & Morning Reports
Published March 1, 2023
Dhayat et al. conducted a double-blind trial in which patients with recurrent calcium-containing kidney stones were randomly assigned to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. Read the NEJM Original Article here.
Q: What agents have been used for the pharmacologic prevention of kidney-stone recurrence?
A: Most kidney stones are composed of calcium oxalate, calcium phosphate, or a mixture of these components; indeed, hypercalciuria is the most common metabolic abnormality among patients with kidney stones. Thiazide and thiazide-like diuretic agents (collectively referred to as thiazides) have been the cornerstone of pharmacologic prevention of recurrence for more than 50 years. Previous studies have suggested that thiazides effectively prevent the recurrence of stones.
Q: What was the motivation for this study, given the long-standing use of thiazides for the prevention of recurrent kidney stones?
A: Previous studies have had methodologic limitations such as inadequate concealment of treatment assignment, a lack of double-blinding, a lack of an intention-to-treat analysis, the use of outdated dietary recommendations, and the use of imaging methods with low sensitivity and specificity. Furthermore, only high doses of thiazides were studied; such dose levels are known to increase the risk of adverse effects. Thus, both the efficacy of thiazides in the prevention of recurrence of kidney stones and the dose–response effect remain unclear.
A: The authors observed no relation between the hydrochlorothiazide dose and the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. In the placebo group, 60 of 102 patients (59%) had symptomatic or radiologic recurrence of kidney stones. A primary end-point event occurred 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 hydrochlorothiazide group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg hydrochlorothiazide group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). 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 than among those in the placebo group.
A: This trial has limitations of importance for translating the results into clinical practice. The trial had an underrepresentation of women, and most of the patients were White. Still, the prevalence of kidney stones is by far the highest among White men. The median duration of the trial was close to 3 years, but the authors cannot rule out the possibility that hydrochlorothiazide has an effect on stone formation only after a longer treatment period. Whether the results also apply to longer-acting thiazides remains to be determined.