Thiazide diuretics lower urinary calcium excretion by acting directly at the distal renal tubule and indirectly at the proximal renal tubule to increase calcium reabsorption. Several studies have investigated the use of thiazides to reduce clinical and radiographic stone recurrence and symptomatic stone episodes.33, 34, 56, 171-173 The largest of these studies was the NOSTONE trial, which randomized adults with recurrent calcium-based kidney stones to hydrochlorothiazide at 12.5 mg, 25 mg, or 50 mg daily or placebo, with a primary composite endpoint of symptomatic stone recurrence or radiographic stone recurrence or growth.34 The study demonstrated no statistically significant reduction in the primary outcome across thiazide doses and no dose-response relationship. Hydrochlorothiazide did reduce urinary calcium slightly but without clear clinical benefit. Importantly, side effects were more common in the intervention group, including hypokalemia, gout, renal impairment, new-onset diabetes and metabolic effects, and allergic reactions. Important critiques of the trial included the finding of relatively high urinary sodium among participants, which may have blunted the response to thiazide; modest baseline hypercalciuria among participants, potentially diluting the therapeutic benefit among patients whose stones were primarily mediated by excessive calcium excretion; and use of a shorter-acting thiazide, compared to the longer-acting chlorthalidone or indapamide. While once-daily hydrochlorothiazide administered at 12.5 mg, 25 mg, or 50 mg doses did not improve stone recurrence compared to placebo, this may reflect in part, inadequate dosing frequency or trial design factors rather than definitively excluding a therapeutic effect.34 In addition, all study groups received substantial counseling about hydration, diet, and nonpharmacological stone prevention strategies, which may have lowered stone recurrence overall and reduced the potential to detect an incremental medication benefit. While no specific thresholds for hypercalciuria have been determined, patients with recurrent calcium-based kidney stones who have higher urinary calcium levels (i.e., ≥200 mg/24 hours in women and ≥250 mg/24 hours in men)174 may be considered at increased risk and thus candidates for therapy. There are no major contemporary trials comparing stone-specific outcome differences among hydrochlorothiazide and the thiazide-like diuretics, chlorthalidone and indapamide. Thus, clinicians may consider dosing-convenience and the frequency of administration when selecting an agent. Longer-acting agents suitable for once-daily administration such as chlorthalidone and indapamide may be preferable to hydrochlorothiazide, which when administered once daily may not achieve or sustain as robust a hypocalciuric effect.175 Typical total daily doses include 12.5-50 mg of hydrochlorothiazide administered twice daily, 12.5-50 mg of chlorthalidone administered once daily, and 1.25-2.5 mg of indapamide administered once daily.54, 173, 176-179 The hypocalciuric effect of these medications increases directly with total dose. Clinicians should consider a patient’s baseline blood pressure and age when selecting an initial dose due to the risk of symptomatic hypotension. Since the magnitude of change in urinary calcium is associated with reduced stone recurrence events, clinicians may titrate dosing based on response to achieve normal urinary calcium levels. Higher doses of indapamide (>2.5 mg/day) have not been studied for hypercalciuria but can increase the risk of dehydration, potassium depletion, and hyponatremia, and therefore not generally recommended. Clinicians should counsel patients taking thiazides to maintain a low-sodium diet, which decreases urinary calcium excretion and optimizes the hypocalciuric effects of the medication. Patients should also consume a moderate amount of dietary calcium, 1,000-1,200 mg daily. Because thiazides can increase urine output, patients should maintain adequate oral fluid intake to avoid the risk of dehydration. Although in some patients it may be advisable to try dietary measures first and assess the response of urinary calcium before initiating medications, in other patients in whom diet alone is unlikely to sufficiently lower urinary calcium, thiazides can be initiated in conjunction with dietary measures. Finally, clinicians may offer potassium supplementation (potassium citrate or potassium chloride based on urinary pH and citrate) to patients taking thiazides to avoid thiazide-induced hypokalemia and hypocitraturia.180 Potassium-sparing agents such as amiloride and spironolactone may reduce the hypokalemic effect, whereas triamterene is known to form drug metabolite stones and should not be used.181 In patients with significant thiazide-induced hypokalemia who cannot tolerate or do not respond to potassium supplementation, clinicians may use a potassium-sparing diuretic in combination with a thiazide (see Statement 38). No studies on the use of thiazides to reduce hypercalciuria in pediatric patients with calcium-based stones were included in the evidence report for this Guideline. The Panel acknowledges that thiazides are associated with significant side effects and recommends caution regarding their use in pediatric patients.