INTRODUCTION — Hyperuricemia is a relatively common finding in people treated with a loop or thiazide diuretic and may, over a period of time, contribute to new-onset gout or recurrence of established gout [1-5]. Diuretics reduce urate excretion by both directly and indirectly increasing urate reabsorption and decreasing urate secretion [2,6-9]; the effect is dose dependent (figure 1). Treatment of asymptomatic hyperuricemia is not recommended in most countries. If diuretic-induced gout occurs, it is typically treated with a urate-lowering drug such as allopurinol.
The pathogenesis, epidemiology, and an overview of treatment of diuretic-induced hyperuricemia and gout are presented in this topic. The pathophysiology, clinical manifestations, diagnosis, and treatment of gout flares as well as the prevention of gout flares are discussed separately:
●(See "Pathophysiology of gout".)
●(See "Treatment of gout flares".)
PATHOGENESIS — The proximal tubule is the major site of urate handling; both secretion and reabsorption occur in this segment, with the net effect being reabsorption of most of the filtered urate (figure 2 and figure 3) [2,9-17]. Urate enters the proximal tubular cell from peritubular capillary blood through organic anion transporters 1 and 3 (OAT1 and OAT3) located on the basolateral membrane, and is secreted from the cell into the tubular fluid through solute carrier (SLC) family members SLC17A1 and SLC17A3, multidrug resistance protein 4 (MRP4), and ATP-binding cassette G2 (ABCG2) located on the luminal membrane. Urate reabsorption from the tubular fluid into the cell is mediated by urate transporter 1 (URAT1), OAT4, and OAT10, located on the luminal membrane, and from the cell back to the peritubular capillary blood through glucose transporter 9 (GLUT9) located on the basolateral membrane.
Loop and thiazide diuretics decrease urate excretion by increasing net urate reabsorption; this can occur either by enhanced reabsorption or by reduced secretion [2,6]. Two mechanisms have been proposed as contributing to diuretic-induced hyperuricemia [2,6-8]:
●A direct effect of diuretics on promoting urate reabsorption by the proximal tubule
●An indirect effect of diuretic-induced volume depletion on increasing urate reabsorption by the proximal tubule
The degree of urate retention caused by diuretics is dose dependent (figure 1) . This contrasts with the dose response relationship between diuretics and blood pressure, in which 12.5 mg of hydrochlorothiazide (or its equivalent) is often as effective as 50 mg (figure 4). (See "Use of thiazide diuretics in patients with primary (essential) hypertension".)
Direct effect of diuretics — Thiazide diuretics selectively enhance urate reabsorption by acting as a counter-ion for urate transport . First, the thiazide enters the proximal tubule cell from the peritubular capillary blood through the anion exchanger, OAT1, on the basolateral membrane. The diuretic is then released into the tubular fluid from the cell by the urate anion exchanger, OAT4, on the luminal membrane, driving reabsorption of urate. Thiazide diuretics also upregulate the sodium-hydrogen exchanger in the proximal tubule, thereby stimulating pH-dependent OAT4 activity . In addition, both thiazide and loop diuretics may inhibit MRP4 on the luminal membrane, reducing secretion of urate into the tubular fluid .
Indirect effect of diuretic-induced volume depletion — Volume depletion appears to play an important role in diuretic-induced hyperuricemia since urate retention does not occur if the diuretic-induced fluid losses are replaced . In addition, short- and long-term salt restriction produces significant hyperuricemia, which is reversed by salt loading [21-26]. In various studies, the difference in serum urate between salt restricted and salt loaded subjects was 1 to 1.4 mg/dL [22-26].
How volume depletion or salt restriction increases net urate reabsorption is unclear . One possible explanation is the parallel relationship between sodium and urate reabsorption in the proximal tubule [2,27]. Urate entry into the cell appears to occur by a variety of anion exchangers (figure 3), including urate-hydroxyl and urate-lactate exchangers . Both of these processes are dependent upon sodium transport.
As an example, sodium-hydrogen exchangers in the luminal membrane are responsible for most of proximal bicarbonate reabsorption. The secretion of hydrogen ions by these transporters makes the cell more alkaline than the tubular lumen. The higher hydroxyl concentration in the cell provides a favorable gradient for hydroxyl exit, which can then drive urate reabsorption. Similarly, sodium-lactate cotransporters in the luminal membrane mediate lactate entry into the cell; this lactate can then be secreted back into the lumen by urate-lactate exchange.
This indirect relationship between sodium and urate is clinically important because hypovolemia (in part via increased generation of angiotensin II) is associated with an appropriate increase in proximal sodium reabsorption . The rise in the activity of the sodium-hydrogen exchanger in this setting  can then lead to increased urate-hydroxyl exchange and therefore enhanced urate reabsorption [2,27].
EPIDEMIOLOGY — Thiazide diuretics are widely used in treatment of hypertension and are inexpensive and efficacious. (See "Use of thiazide diuretics in patients with primary (essential) hypertension".)
Thiazide and loop diuretics, but not potassium-sparing diuretics , are independent risk factors for incident [3,4] and, likely, recurrent  gout. In a large prospective cohort of men, for example, approximately 4700 participants without a prior history of gout used diuretics, and nearly 3 percent of these men subsequently developed gout . Compared with men who did not use diuretics, those who did had a 77 percent higher relative risk of developing gout, even after controlling for conventional risk factors for gout such as adiposity, alcohol intake, kidney function, and hypertension. While people with diuretic-induced gout present with similar clinical features as those with primary gout, they tend to be older and have a higher serum urate . In addition, genetic features such as the ABCG2 gout risk allele are less frequently present .
OVERVIEW OF TREATMENT AND BENEFITS OF ANGIOTENSIN INHIBITION — Treatment of diuretic-induced asymptomatic hyperuricemia is not routinely recommended in most countries, even though the serum urate concentration may exceed 15 mg/dL (0.89 mmol/L) with diuretic therapy (particularly in people with reduced kidney perfusion due to underlying advanced heart failure) [1,31]. These people are not at risk of uric acid precipitation in the tubules (uric acid nephropathy), since the elevation in the serum urate is due to an initial decrease in the rate of urate excretion. Prophylactic treatment with urate-lowering therapy is not warranted to treat an abnormal blood test . (See "Asymptomatic hyperuricemia".)
A diagnosis of gout is not necessarily an indication for discontinuation of the diuretic, particularly if diuretic therapy is required for management of edema. However, if blood pressure control can be effectively and affordably achieved with an appropriate alternative agent, such as an angiotensin inhibitor or a dihydropyridine calcium channel blocker, then the diuretic should be replaced by an alternative agent that is not associated with urate retention. Such an approach can lower urate levels and , theoretically, reduce gout risk. (See "Choice of drug therapy in primary (essential) hypertension".)
Most people with diuretic-induced gout are treated with a urate-lowering drug such as allopurinol (see "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout"). The concomitant use of a urate-lowering agent and a diuretic may require a higher dose of the former to achieve the goal range for serum urate of <6 mg/dL. This combination may impart a higher risk for allopurinol hypersensitivity reactions . However, subsequent studies suggest that carefully titrating the urate-lowering drug dose to achieve the goal urate level is likely not associated with a higher risk for this serious adverse event [34,35].
We agree with the 2020 American College of Rheumatology guidelines for treatment of hyperuricemia in gout that no one commence allopurinol at more than 100 mg daily and that the starting dose be reduced to 50 mg daily in people with stage 4 or 5 chronic kidney disease . The dose should be titrated in increments of 100 mg (or 50 mg) every two to four weeks until target serum urate is achieved (<6 mg/dL [0.36 mmol/L]). Gout flares are common in the early months of urate-lowering therapy, and flare prophylaxis, with colchicine, a nonsteroidal antiinflammatory drug (NSAID), or prednisone, is recommended as cotherapy with the urate-lowering therapy. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Approach to drug therapy' and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Prophylaxis during initiation of urate-lowering therapy'.)
People with gout who are receiving diuretics for comorbidities should be encouraged to adhere to the prescribed diuretic dose since many gout flares occur in the setting of changes in serum urate levels that accompany intermittent diuretic use .
Benefits of angiotensin inhibition and losartan — Among people with hypertension, the concurrent administration of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) can minimize the diuretic-induced rise in serum urate concentration [37-39]. This has been thought to be mediated by reversal of the stimulatory effect of angiotensin II on proximal sodium and urate reabsorption. (See 'Indirect effect of diuretic-induced volume depletion' above.)
In addition, losartan may have a more direct uricosuric effect, thereby inhibiting urate reabsorption and lowering the serum urate concentration. This hypothesis is supported by the following observations:
●In a randomized trial, 1161 people with mild to moderate hypertension were randomly assigned to losartan, candesartan, or losartan plus hydrochlorothiazide . At 12 weeks, serum urate levels had decreased, stayed the same, or increased in those administered losartan, losartan plus thiazide, and candesartan, respectively. The combination of losartan plus the thiazide also provided superior blood pressure control to monotherapy.
●In a small prospective study, four weeks of losartan decreased serum urate levels by 9 percent, while irbesartan had no effect . The effect of losartan was seen at a dose of 50 mg once daily with no further reduction at a dose of 50 mg twice daily.
Although uric acid excretion is initially increased, there appears to be little risk of uric acid nephropathy with losartan because of a concurrent elevation in urine pH due to reduced bicarbonate reabsorption . As a result, there is little or no increase in the urinary excretion of insoluble undissociated uric acid; urinary urate excretion rises but this is associated with little stone potential. A new steady state for uric acid is achieved within seven days as uric acid excretion returns to baseline levels. (See "Uric acid kidney diseases".)
The combination of losartan or an ACE inhibitor with a thiazide has the added advantages of a more potent antihypertensive effect than seen with either drug alone and of minimizing other metabolic effects of the diuretic, such as hypokalemia and hyperlipidemia [18,37]. (See "Renin-angiotensin system inhibition in the treatment of hypertension".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypertension in adults".)
SUMMARY AND RECOMMENDATIONS
●Hyperuricemia is a relatively common finding in people treated with a loop or thiazide diuretic and may lead, over time, to new-onset gout and, in people with already established gout, more frequent occurrence of gout flares. The degree of urate retention caused by diuretics is dose dependent (figure 1). (See 'Introduction' above.)
●Loop and thiazide diuretics decrease urate excretion by increasing net urate reabsorption; this can occur either by enhanced reabsorption or by reduced secretion. Two mechanisms have been proposed as contributing to diuretic-induced hyperuricemia (see 'Pathogenesis' above):
•A direct effect of diuretics on promoting urate reabsorption by the proximal tubule. (See 'Direct effect of diuretics' above.)
•An indirect effect of diuretic-induced volume depletion on increasing urate reabsorption by the proximal tubule. (See 'Indirect effect of diuretic-induced volume depletion' above.)
●Diuretics may increase the relative risk of gout by nearly 80 percent; the absolute incidence of gout in people taking diuretics may be close to 3 percent. (See 'Epidemiology' above.)
●A diagnosis of gout is not necessarily an indication for discontinuation of the diuretic. However, if blood pressure control can be effectively and affordably achieved with an appropriate alternative agent, such as an angiotensin inhibitor or a dihydropyridine calcium channel blocker, then the diuretic should be replaced with an alternate agent. (See 'Overview of treatment and benefits of angiotensin inhibition' above.)
●Most people with diuretic-induced gout are treated with a urate-lowering drug such as allopurinol. Treatment of diuretic-induced asymptomatic hyperuricemia is not recommended. (See 'Overview of treatment and benefits of angiotensin inhibition' above.)
●Among people with hypertension, the concurrent administration of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), particularly losartan, can minimize the diuretic-induced rise in serum urate concentration. The combination of losartan or an ACE inhibitor with a thiazide has the added advantages of a more potent antihypertensive effect than seen with either drug alone and of minimizing other metabolic effects of the diuretic, such as hypokalemia and hyperlipidemia. (See 'Benefits of angiotensin inhibition and losartan' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael A Becker, MD, who contributed to an earlier version of this topic review.
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