Diuretic-Related Side Effects: Development and Treatment

Domenic A. Sica, MD

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In This Article

Hyperuricemia

Thiazide diuretic therapy increases serum urate concentrations by as much as 35%; an effect related to decreased renal clearance of urate, and one that is most prominent in those with the highest pretherapy urate clearance values.[47] Decreased urate clearance may be linked to increased reabsorption secondary to diuretic-related extracellular fluid volume depletion and/or competition for tubular secretion, since both thiazide diuretics and urate undergo tubular secretion by the same organic anion transporter pathway.[48,49] Diuretic-related hyperuricemia is dose-dependent and is pertinent for two reasons: first, as a precipitant of gout and second, relative to its effect on CVR event rate.

First, diuretic-related hyperuricemia does not typically precipitate a gouty attack unless the patient has an underlying gouty tendency or serum urate concentrations routinely exceed 12 mg/dL.[48] To this end, in the MRC trial, patients receiving high-dose thiazide diuretics had significantly more withdrawals for gout than did placebo-treated patients (4.4 vs. 0.1/1000 patient years).[50] Second, in the SHEP,[51] those with a serum uric acid increase ≥0.06 mmol/L (median change) in the active treatment group had a similar risk of coronary events as the placebo group, suggesting that diuretic-related hyperuricemia offsets the positive CVR benefits otherwise seen with diuretic therapy. This difference was not explained by BP effects.

Allopurinol should not be routinely started (as often is the case) for asymptomatic diuretic-related hyperuricemia. If a gouty attack occurs in a diuretic-treated patient, the diuretic in use should be temporarily discontinued. Oftentimes, a diuretic can be restarted at a lower and sometimes still effective dose. In the process, careful attention should be paid to avoidance of excessive volume contraction. In the patient with preexisting gout and with a need for diuretic therapy, the xanthine oxidase inhibitor, allopurinol, can be considered. However, allopurinol (a renally-cleared compound) should be used cautiously (dose-adjusted according to level of renal function) in patients receiving a thiazide-type diuretic, since allopurinol hypersensitivity reactions are more common with this combination.[52] A final consideration is what steps to take in a patient with diuretic-related hyperuricemia who is intolerant of allopurinol. In such subjects, the ARB losartan, which is a uricosuric compound, can be safely given with a reduction in serum uric acid and no risk of acute urate nephropathy and/or uric acid stones.[53]

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