How do thiazides (thiazide diuretics) affect uric acid secretion?

Mechanism of Thiazide Diuretics' Effect on Uric Acid Secretion

Thiazide diuretics reduce uric acid secretion primarily by competing with uric acid for renal tubular secretion sites and causing volume contraction, leading to hyperuricemia.

Mechanisms of Thiazide-Induced Hyperuricemia

Thiazide diuretics affect uric acid handling through several mechanisms:

1. Competition for Renal Tubular Secretion:

   • Thiazides directly compete with uric acid for secretion at the organic anion transporter (OAT) in the proximal tubule 1
   • This competition reduces the ability of the kidney to secrete uric acid into the tubular lumen

2. Volume Contraction Effects:

   • Thiazides induce mild volume depletion, which enhances proximal sodium and water reabsorption 2
   • This volume contraction leads to increased uric acid reabsorption in the proximal tubule
   • The reduced effective circulating volume stimulates compensatory mechanisms that further impair uric acid excretion

3. Sex-Related Differences:

   • Women may experience more pronounced effects due to differences in the expression of organic anion transporters
   • Female patients have approximately 40% lower expression of OAT1 in renal tubular cells compared to males 2
   • This difference may explain why women are more susceptible to thiazide-induced hyperuricemia

Temporal Pattern of Uric Acid Changes

Interestingly, the effect of thiazides on uric acid handling is not uniform over time:

• Initial Phase: Acute reduction in uric acid excretion with corresponding rise in serum uric acid levels
• Long-Term Effects: Some studies suggest that during prolonged therapy (up to 3 years), there may actually be an enhancement of renal excretion of uric acid in some patients 3
  • In a study of 21 patients on hydrochlorothiazide (100 mg/day), 12 patients showed a transient or persistent rise in urinary uric acid excretion of more than 50 mg per day during treatment
  • This suggests thiazides may either increase uric acid production or decrease extrarenal disposal in some patients during long-term therapy

Clinical Implications

The hyperuricemic effect of thiazides has several important clinical implications:

• Metabolic Consequences: Thiazide-induced hyperuricemia may contribute to worsening of metabolic syndrome and increased risk of developing diabetes 1

• Renal Function: Despite lowering blood pressure, thiazide treatment has been associated with a decline in renal function in some patients, potentially related to hyperuricemia 1

• Management Options:

  • Combining losartan with thiazides can counteract the hyperuricemic effect, as losartan increases urinary uric acid excretion 4
  • In patients with recurrent calcium stones who have hyperuricosuria and normal urinary calcium, allopurinol should be considered 2

Monitoring and Prevention

For patients on thiazide therapy:

• Monitor serum uric acid levels periodically, especially in the early phase of treatment
• Consider potassium supplementation, as thiazide-induced hypokalemia is associated with increased blood glucose and may contribute to metabolic abnormalities 5
• For patients with gout or significant hyperuricemia, consider alternative antihypertensive agents or prophylactic measures

It's worth noting that despite the increase in serum uric acid levels, the HDPF study found that thiazide-induced hyperuricemia was not associated with significant renal injury, and there were few episodes of gout (only 15 recorded in five years among 3693 participants) 6.