Does Hydrochlorothiazide Cause Kidney Stones?
No, hydrochlorothiazide (HCTZ) does not cause kidney stones—it is actually a recommended treatment to prevent recurrent calcium kidney stones by reducing urinary calcium excretion. 1
HCTZ as Stone Prevention Therapy
HCTZ is specifically recommended by the American Urological Association for patients with high or relatively high urine calcium and recurrent calcium stones (Grade B evidence). 1
Mechanism of Action
- HCTZ reduces urinary calcium excretion, which is the primary mechanism by which it prevents calcium stone formation. 2
- The FDA label confirms that hydrochlorothiazide "decreases the excretion of calcium," which is the therapeutic effect that prevents stone formation. 3
- HCTZ may also reduce urine oxalate excretion and increase urine zinc and magnesium, all of which contribute to stone prevention. 4
Evidence for Effectiveness
- The American College of Physicians recommends thiazide diuretics as effective pharmacological monotherapy for preventing recurrent nephrolithiasis when increased fluid intake alone is insufficient. 1, 2
- Historical data from 346 patients showed that stone progression ceased in at least 90% of patients taking hydrochlorothiazide 50 mg twice daily regularly. 4
- However, a 2023 randomized controlled trial (the NOSTONE trial) found no significant difference in stone recurrence between HCTZ at doses of 12.5 mg, 25 mg, or 50 mg once daily compared to placebo over a median follow-up of 2.9 years. 5
Important Caveat: Recent Contradictory Evidence
The most recent high-quality evidence (2023 NOSTONE trial in NEJM) contradicts older guidelines and studies, showing HCTZ may not be effective when dosed once daily. 5
- This trial used once-daily dosing, whereas older successful studies used twice-daily dosing (50 mg twice daily). 4
- The guideline-recommended dosing includes hydrochlorothiazide 25 mg twice daily or 50 mg once daily. 1
- The discrepancy may be explained by dosing frequency—twice-daily dosing appears more effective than once-daily dosing for stone prevention. 4, 5
Practical Dosing Recommendations
If prescribing HCTZ for stone prevention, use 25 mg orally twice daily (or 50 mg once daily), not lower doses or once-daily regimens at lower strengths. 1
- Chlorthalidone 25 mg once daily produces greater reduction in urinary calcium (164 mg; 41% reduction) compared to HCTZ 25 mg once daily (85 mg; 21% reduction). 6
- Neither chlorthalidone nor HCTZ at 12.5 mg once daily significantly lowered urinary calcium. 6
- Consider chlorthalidone 25 mg once daily as an alternative to HCTZ if once-daily dosing is preferred. 1, 6
Essential Adjunctive Measures
- Dietary sodium restriction must be continued when thiazides are prescribed to maximize the hypocalciuric effect and limit potassium wasting. 1, 2
- Potassium supplementation (either potassium citrate or chloride) may be needed when thiazide therapy is employed. 1
- Maintain urine output of at least 2 liters daily regardless of pharmacological intervention. 2, 7
Monitoring Requirements
- Obtain a 24-hour urine specimen within six months of initiating treatment to assess response to therapy. 1, 2, 8
- Monitor for hypokalemia, which occurred more commonly with HCTZ than placebo in the NOSTONE trial. 5
- Periodic blood testing is required to assess for adverse effects including hypokalemia, glucose intolerance, gout, new-onset diabetes, and elevated creatinine. 1, 5
Metabolic Effects That Could Theoretically Increase Stone Risk
While HCTZ reduces urinary calcium (beneficial), it may increase urinary uric acid excretion in some patients, which could theoretically promote uric acid stone formation. 9
- Serum uric acid concentration increased during thiazide therapy in every patient in one study, with 12 of 21 patients showing increased urinary uric acid excretion. 9
- However, this effect does not outweigh the calcium-lowering benefit for calcium stone prevention, which represents 80% of all kidney stones. 1