Which diuretics are most commonly associated with increased serum uric acid levels?

Diuretics and Uric Acid: Which Increase and Which Do Not

Loop diuretics (furosemide, bumetanide) and thiazide/thiazide-like diuretics (hydrochlorothiazide, chlorthalidone, bendroflumethiazide) consistently increase serum uric acid levels, while potassium-sparing diuretics (spironolactone, amiloride, triamterene) do not significantly affect uric acid levels. 1

Diuretics That INCREASE Uric Acid

Loop Diuretics (Highest Risk)

• Loop diuretics carry the highest risk for hyperuricemia and gout development, with a 2.64-fold increased risk of incident gout compared to past use 1
• Furosemide and bumetanide both elevate serum uric acid by increasing net uric acid reabsorption in the proximal tubule 2
• The mechanism involves fluid and sodium loss, which appears to be the main driver of diuretic-induced hyperuricemia 3

Thiazide and Thiazide-Like Diuretics (Moderate-High Risk)

• Thiazide diuretics increase gout risk 1.70-fold, while thiazide-like diuretics (such as chlorthalidone) increase risk 2.30-fold 1
• Hydrochlorothiazide elevates uric acid even at low doses of 12.5 mg daily, with dose-dependent increases 2
• The FDA label for hydrochlorothiazide explicitly warns that "hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics" 4
• Doses ≥25 mg/day of hydrochlorothiazide (or equivalent) significantly increase the risk for requiring anti-gout therapy 5
• The JNC 7 guidelines note that gout occurrence is uncommon with doses ≤50 mg/day hydrochlorothiazide or ≤25 mg chlorthalidone, though uric acid levels still rise 6

Combined Diuretic Therapy (Highest Risk)

• The combination of loop and thiazide diuretics produces the highest risk, with a 4.65-fold increased risk of gout 1
• This represents a synergistic rather than additive effect on uric acid elevation 1

Diuretics That DO NOT Increase Uric Acid

Potassium-Sparing Diuretics (No Significant Effect)

• Potassium-sparing diuretics (spironolactone, amiloride, triamterene) do not significantly increase gout risk, with an odds ratio of only 1.06 (not statistically significant) 1
• These agents should be considered when a diuretic is absolutely necessary in patients at high risk for gout 7
• Monitoring for hyperkalemia is required with these agents, particularly in patients with CKD or those taking ACE inhibitors/ARBs 6

Clinical Monitoring Recommendations

When to Monitor

• Periodic serum electrolyte determination should be performed in all patients receiving thiazide or loop diuretics, particularly those at risk for hypokalemia 4
• Thiazide and thiazide-like diuretics require monitoring for hyponatremia, hypokalemia, uric acid, and calcium 6
• The greatest electrolyte shifts occur within the first 3 days of diuretic administration, when maximal diuretic effect is achieved 6

Key Warning Signs

• Watch for signs of fluid/electrolyte imbalance: dryness of mouth, thirst, weakness, lethargy, muscle cramps, hypotension, oliguria, tachycardia, nausea, and vomiting 4
• These symptoms may indicate the need for dose adjustment or alternative therapy 4

Preferred Alternatives for Patients at Gout Risk

First-Line Alternatives

• Losartan is the preferred alternative for hypertension in patients with or at risk of gout, as it has unique uricosuric properties that increase urinary uric acid excretion by approximately 25% and reduce serum uric acid by 20-47 μmol/L 7
• Calcium channel blockers do not increase uric acid and may slightly attenuate gout risk when combined with diuretics 1, 7

ACE Inhibitors

• ACE inhibitors (captopril, enalapril, ramipril, lisinopril) can mildly increase uricosuria and blunt the rise in uric acid provoked by diuretics when used at sufficiently high doses relative to the diuretic dose 2
• These agents lower net uric acid reabsorption in the proximal tubule 2

Common Pitfalls to Avoid

• Do not continue hydrochlorothiazide in gout patients when alternatives exist, as the American College of Rheumatology conditionally recommends switching to alternative antihypertensives regardless of current gout disease activity 7
• Avoid treating asymptomatic hyperuricemia in patients on diuretics, as baseline uric acid level does not appear to injure the kidney and pharmacologic lowering of uric acid in non-gouty hypertensive patients is not indicated 8
• Do not abruptly stop diuretics in patients with compelling indications (heart failure, severe volume overload) without carefully weighing cardiovascular benefits against gout risk 7
• When diuretics cannot be discontinued, optimize urate-lowering therapy and closely monitor serum uric acid levels 7