Can hydrochlorothiazide and losartan cause kidney stones?

Can Hydrochlorothiazide and Losartan Cause Kidney Stones?

No, neither hydrochlorothiazide nor losartan cause kidney stones; in fact, hydrochlorothiazide is specifically prescribed to prevent calcium stone recurrence, and losartan (an ARB) has been associated with a reduced risk of stone formation compared to other antihypertensives.

Hydrochlorothiazide and Kidney Stone Prevention

Evidence for Stone Prevention

• Thiazide diuretics, including hydrochlorothiazide, are traditionally prescribed to prevent recurrent calcium-containing kidney stones by reducing urinary calcium excretion 1
• In a large retrospective cohort study of 542,581 older adults, thiazide diuretics were associated with a 24% lower risk of kidney stones compared to beta-blockers (HR 0.76; 95% CI 0.68-0.84) 2

Recent Contradictory Evidence: The NOSTONE Trial

• The 2023 NOSTONE trial challenged conventional practice by showing that hydrochlorothiazide at doses of 12.5 mg, 25 mg, or 50 mg daily did not significantly reduce stone recurrence compared to placebo over a median follow-up of 2.9 years 3
• Stone recurrence occurred in 59% of placebo patients versus 59%, 56%, and 49% in the 12.5 mg, 25 mg, and 50 mg hydrochlorothiazide groups, respectively, with no dose-response relationship (P = 0.66) 3
• A 2024 meta-analysis of all randomized placebo-controlled trials concluded that current evidence does not indicate thiazide monotherapy is significantly better than placebo for preventing kidney stone recurrence 4

Important Safety Considerations

• Hydrochlorothiazide was associated with increased adverse events including hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and elevated creatinine levels compared to placebo 3
• The drug does not appear to preserve bone mineral density in stone formers, with similar BMD loss observed across all treatment groups over 3 years 5

Losartan and Kidney Stone Risk

Protective Effect of ARBs

• Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) like losartan were associated with a borderline decreased risk of kidney stones compared to beta-blockers (HR 0.90; 95% CI 0.83-0.98) in older adults 2
• Laboratory studies demonstrate that losartan ameliorates calcium oxalate-induced elevation of stone-related proteins in renal tubular cells by inhibiting NADPH oxidase and oxidative stress 6
• Losartan reduced renal crystallization in hyperoxaluric rat models by blocking the angiotensin II/AT1 receptor signaling pathway 6

FDA Drug Label Confirmation

• The FDA drug label for losartan explicitly states: "No clinically significant drug interactions have been found in studies of losartan potassium with hydrochlorothiazide" 7
• This confirms that the combination of losartan and hydrochlorothiazide does not create any interaction that would promote stone formation 7

Clinical Algorithm for Stone Prevention

First-Line Approach

• Increase fluid intake to achieve at least 2 liters of urine output daily as the primary intervention 1, 8
• Restrict sodium intake to ≤2300 mg/day, as high sodium increases urinary calcium excretion 1
• Maintain adequate dietary calcium intake of 1000-1200 mg/day 1

Pharmacologic Therapy When Stones Recur

• For calcium stones with low urinary citrate or low pH: Potassium citrate is the preferred first-line pharmacologic agent, targeting urinary pH of 6.0-6.5 1, 8
• For uric acid stones: Potassium citrate is the cornerstone of treatment 8
• Thiazide diuretics: Given the NOSTONE trial results showing no benefit over placebo and increased adverse events, advocate for restrictive use of thiazides for stone prevention 4

Monitoring

• Obtain a 24-hour urine specimen within six months of initiating or changing treatment to assess response 1, 8

Critical Pitfalls to Avoid

• Do not discontinue losartan due to stone concerns: ARBs may actually provide modest protection against stone formation 2, 6
• Do not use sodium citrate: It increases urinary calcium excretion through sodium loading, potentially promoting stone formation 1, 8
• Do not raise urinary pH above 7.0: This increases the risk of calcium phosphate stone formation 1, 8
• Recognize thiazide limitations: The combination of limited efficacy demonstrated in recent trials and significant adverse effects (diabetes, gout, hypokalemia) argues against routine use 3, 4