Uricosuric Therapy of Hyperuricemia in Gout

Key Points

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Inefficient renal excretion of uric acid is the most common cause of hyperuricemia in gout patients.
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Uricosuric drugs tend to normalize renal excretion of uric acid through inhibiting renal tubular reabsorption of uric acid, thus reducing serum urate levels.
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Availability, potency, and safety profile vary greatly among uricosuric drugs, most of them lacking well-designed clinical trials. Some drugs that are not labeled for gout show mild uricosuric effects.
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Patients suitable for uricosuric treatment should be selected based on renal handling of uric acid, preferably with clearance of uric acid.
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The assessment of efficacy and safety can be accomplished with first morning spot blood and urine samples and glomerular filtration rate prediction equations.
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The risk of urolithiasis can be minimized with proper selection of patients and adequate monitoring during follow-up.
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The combination of xanthine oxidase inhibitors and uricosurics is a promising approach in patients failing to reach target serum urate concentration levels with monotherapy with xanthine oxidase inhibitors.

Introduction: Concepts and Historical Background

Uricosuric drugs were the first agents used to control hyperuricemia in patients with gout. Any drug that increases renal excretion of uric acid, independently of the mechanism through which it exerts its effect, may be considered a uricosuric drug. Salicylates were the first drugs to be used to correct hyperuricemia of gout, as they showed a paradoxical effect on renal handling of uric acid: they reduce renal excretion at low doses and increase renal excretion at high doses.

The concept that underlines the term “uricosuric” may be misleading, if one considers that these drugs will exert an effect on the renal handling of urate that will induce what could be considered a hyperuricosuric state. However, it may certainly occur in subjects who show normal renal excretion of uric acid in the hyperuricemic state.

The most actual concept would be to consider uricosuric drugs as drugs to be used to correct hyperuricemia derived from “inefficient renal excretion” (IRE) of uric acid, lately known as “underexcretion,” that conceptually means that renal excretion of uric acid is not found to the amount expected based on serum urate concentration (SUR) levels and glomerular filtration, that is to say to the filtered load. Thus, our clinical approach to the use of uricosurics will be to recognize them as means to normalize renal excretion of uric acid in patients with IRE of uric acid.

In this chapter, we will further discuss the concept, targets, and clinical assessment of IRE; drugs that increase renal excretion of uric acid, either approved, not approved, or in development; and clinical management of uricosuric therapy, including combination of xanthine oxidase inhibitors (XOIs) and uricosurics.

Inefficient Renal Excretion of Uric Acid as a Target for Urate-Lowering Therapy

Most patients with gout in the hyperuricemic state will show IRE of uric acid; that is, they show less urinary excretion of uric acid than that expected in relation to the amount of urate that is filtered in the glomerulus. This can be either a primary or secondary (acquired) defect, but overall IRE of uric acid may be present in 90% of the patients with gout and over 80% of patients with primary gout.

In the very early clinical studies of uricosuric drugs, most agents possessing uricosuric properties, such as probenecid, sulfinpyrazone, or salicylates, were found to be organic acids. Investigators empirically proposed that these drugs shared with uric acid a common renal tubular transport system and then would compete with uric acid as substrates for this transporter system, thus inducing renal uric acid leakage through inhibition of tubular reabsorption of uric acid.

Recent investigation has recognized an organic anion transporter (OAT) family mainly located in the proximal renal tubules. Although multiple transporters have been identified, molecular cloning approaches have been used to identify two major tubular transporters of urate: URAT1 and GLUT9 (as reviewed in detail in Chapter 4 ).

URAT1 (uric acid transporter 1) is the product of the SCL22A12 gene. URAT1 is expressed only in the kidney and it is located in the epithelium of the proximal, but not of distal renal tubules at the apical membrane (luminal side), with deficient mice and humans showing complete loss of the capacity of reabsorbing uric acid.

Interestingly, most of the drugs well known to exert a uricosuric effect show an inhibitory effect on URAT1, thus enhancing renal excretion of uric acid. On the other hand, diuretics such as furosemide increase uric acid URAT1-mediated transport, favoring the increase in SUR levels. In addition, the most effective uricosuric drug ever tested in clinical practice, benzbromarone, was shown to be the most potent inhibitor of URAT1, completely inhibiting the uric acid uptake in the renal proximal tubule epithelial cell.

A member of the facilitated glucose transporter named GLUT9 has been recently shown to be a uric acid transporter located mainly in the kidney and in the liver. GLUT9 is encoded by the SCL2A9 gene and is present both in the apical and basolateral membranes of the proximal tubule epithelial cells. It shows different affinities compared to that of URAT1, as it is not influenced by organic anions, suggesting that uric acid may be the only or the primary substrate for GLUT9. Benzbromarone, a strong inhibitor of URAT, only shows a moderate inhibition of uric acid transport through GLUT9. Probenecid and losartan also inhibit GLUT9 moderately. In addition to uric acid, hexoses, such as glucose and fructose, strongly inhibit the uric acid transport via GLUT9.

Assessment of Renal Excretion of Uric Acid in Clinical Practice

A debate has taken place over the past decades regarding whether renal excretion of uric acid assessment should be implemented as a standard in clinical practice. The argument against such procedure is that if patients are to be treated with XOIs estimation of renal excretion of uric acid is less relevant for therapy choice, although still potentially useful to determine the etiology of hyperuricemia.

From a clinical point of view, identifying patients with IRE of uric acid would separate patients with normal excretion and so classify them as showing an overproduction mechanism leading to hyperuricemia and can help in selecting patients suitable for uricosuric therapy. It may also be helpful for differential diagnosis of causes inducing hyperuricemia, with the limitation that the presence of underexcretion in subjects with renal insufficiency cannot exclude the concomitant presence of uric acid overproduction. In addition, identification and correction of the underlying mechanisms leading to hyperuricemia are attractive from a physiopathologic point of view, especially to select patients with IRE of uric acid if they are to be considered candidates for uricosuric therapy.

Several methods have been proposed to be useful to identify subjects with IRE of uric acid, including the 24-hour urinary uric acid (24-UUR) excretion, the clearance (CUR) of uric acid, the urine uric acid–to–creatinine ratio, the uric acid excretion per glomerular filtration volume or Simkin’s index (SI), and fractional excretion of uric acid. Some authors even suggested a composite method to “simplify” this assessment. The first two require 24-hour urine collection, while the latter three may be calculated using spot urine and blood samples. Calculations for the different methods and pros and cons for all of them are cited in Table 12-1 .

Table 12-1

Methods Most Commonly Used in Clinical Practice to Evaluate Real Handling of Urate

Method	Urine Sample	Calculation (UNL)	Pros and Cons
24-hr UUR (mg/day)	24-Hour	UVOL ^∗UUR (880 mg/1.73 m ²)	Useful in the hyperuricemic state Good correlation with clearance Not reliable with borderline hyperuricemia or patients treated with XOIs
CLUR (ml/min)	24-Hour	UVOL ^∗UUR/SUR (6 mL/min/1.73 m ²)	Conceptually shows renal capacity Useful despite XOIs Associated with risk of urolithiasis
FE _UA(%)	Spot	[UUR ^∗SCR]/[SUR ^∗UCR] (7%)	Dependent on renal function False normal results in patients with chronic kidney disease Useful for follow-up
Simkin´s Index (mg/dL glomerular filtration)	Spot	UUR ^∗[UCR/CR] (0.6)	Dependent on renal function False normal results in patients with chronic kidney disease Useful for follow-up

CLUR, Clearance of uric acid; FE _UA, fractional excretion of uric acid; SCR, serum creatinine concentration; SUR, serum urate concentration (mg/dL); UCR, urinary creatinine concentration (mg/dL); UNL , upper normal limit; UUR, urinary uric acid concentration (mg/dL); 24-hr UUR , 24-hour urinary uric acid; UVOL, urinary volume (dL); XOI, xanthine oxidase inhibitor.

From an academic point of view, clearance of uric acid seems to give a sense of the renal capacity to clear blood of such a substance, and clearance of creatinine (ClCr) is a paradigm of the widespread use of this concept. In addition, CUR shows a good correlation with 24-hour UUR ; unlike the other methods, CUR shows no change in patients treated with XOI and may be used to estimate IRE of uric acid in patients taking XOIs; and, finally, high baseline CUR was associated with increased risk for development of renal colic in patients with ongoing uricosuric therapy.

Following a practical clinical approach, SI may be a simple, cheap, and feasible method to estimate the IRE of uric acid. Subjects showing SI less than 0.6 mg/dL will probably suffer from IRE of uric acid. On the other hand, SI greater than 0.6 mg/dL may be associated with normal renal uric acid excretion (overproduction) or with renal function impairment, as the plasma creatinine–to–urinary creatinine (SCR/UCR) ratio will increase in patients with renal dysfunction, leading to high false-positive SI results. If the latter is the case, glomerular filtration (ClCr) should be estimated with any method to ascertain whether patients show normal renal function.

Uricosuric Drugs: Pharmacokinetics, Pharmacodynamics, and Clinical Applicability

Drugs Labeled for the Treatment of Hyperuricemia of Gout

Probenecid

Probenecid, a drug first used to avoid renal excretion of penicillin, was shown to have urate-lowering effects by increasing renal uric acid excretion. Moderate inhibition of both URAT1 and GLUT9 transporter in the renal tubule has been reported, and so probenecid efficacy may be blunted in patients with mild to moderate renal function impairment. However, the GFR level at which probenecid is no longer effective as a uricosuric, although held to be at a GFR less than 50, is not entirely clear from data in the literature.

Probenecid is well absorbed after oral administration, despite being sparingly soluble in water. Peak plasma levels are reached close to 4 hours after oral intake, it is highly bound to proteins, and it has a dose-dependent effect, ranging from 6 to 12 hours, so it is orally administered in a twice-daily prescription but might ideally be suited to three-times-daily dosing.

Dosing is usually started at 500 mg twice daily and increased in a stepwise fashion to reach target SUR levels or up to 2 g/day if tolerated, with an absolute maximum dose of 3 g/day.

Probenecid is mainly metabolized in the liver to glucuronide but it is also hydroxylated and carboxylated derivatives are produced, with all of them excreted renally. Low-dose aspirin seems to not have a significant impact on renal uric acid excretion in patients on probenecid.

The initial reports of the efficacy of probenecid suggested that dosing equal to or greater than 2 g/day in divided doses would not succeed in achieving a reduction over half the baseline levels. Results from a small-population, open-label, randomized, actively controlled 2-month trial in patients failing therapy with allopurinol (85% in first stage of the study) have been reported. Probenecid 2 g/day in divided doses showed a reduction of mean baseline SUR from 9.0 mg/dL to 4.5 mg/dL, with 65% of the patients reaching outcome SUR target of less than 5 mg/dL. Despite adequate efficacy, withdrawals due to intolerance rose up to 15% in this study during the 2-month exposure period.

Severe side effects due to probenecid are not frequent. Cutaneous rash and gastrointestinal complaints are reported in up to 20% of patients, with intolerance being a limitation to this therapy.

Sulfinpyrazone

Sulfinpyrazone was initially used as a uricosuric agent because uricosuric activity was noted during its development as an analog of phenylbutazone.

The tubular target of sulfinpyrazone is URAT1. It is rapidly and well absorbed after oral administration, with its half-life ranging from reaching peak levels and showing a short half-life, close to 3 hours. It is highly bound to plasma proteins. Although sulfinpyrazone is metabolized in the liver, up to one third of the dose is excreted unaltered through the kidneys.

It has been withdrawn from most countries due to a bunch of limitations: the loss of its efficacy in the presence of low GFR, its antiaggregating effect on platelets, and poor tolerability.

Benzbromarone

Benzbromarone is to date the most potent uricosuric drug ever tested in clinical practice, being able to totally suppress URAT1-mediated reabsorption of uric acid. Unfortunately, it is not universally available. It is a benzofuran derivative, and after oral intake, it reaches peak plasma concentration in 2 to 4 hours, with its bioavailability being close to 50%. Benzbromarone undergoes liver metabolism and is excreted primarily through the bile, no dose adjustment needed in patients with nonterminal renal dysfunction. Although the half-life of benzbromarone is short, 6-hydroxibenzbromarone is a major metabolite with uricosuric properties and a half-life exceeding 24 hours.

As with other potent urate-lowering drugs, benzbromarone prescription is started at low dose, 50 mg/day, to avoid mobilization flares due to sharp and sudden reduction of SUR levels. Doses may be increased up to the maximum labeled dose of 200 mg/day. The efficacy in reducing SUR levels of benzbromarone 100 mg/day has been shown to be superior to allopurinol 300 mg/day or probenecid 1000 mg/day, its efficacy being close to that of allopurinol 400 mg/day in patients with normal renal function. Recent blinded, randomized, controlled trials have shown that the effectiveness of benzbromarone 200 mg/day to reach target SUR levels lower than 5 mg/dL is superior to allopurinol 2 g/day and that benzbromarone 200 mg/day is comparable to allopurinol 600 mg/day. Limitations inherent to these two recent trials are the short exposure period, limiting any conclusion on safety, and the prescriptions being twice daily for allopurinol but once daily for benzbromarone.

Adding low-dose benzbromarone to standard allopurinol doses has shown an additive effect on SUR level reduction similar to that observed with standard doses of benzbromarone. Contrary to other available uricosuric drugs, which may lose at GFR lower than 50 ml/min, benzbromarone has been shown to maintain its uricosuric properties in patients with mild to moderate reduction of GFR down to 20 mL/min, despite concomitant treatment with drugs that induce hyperuricemia, such as diuretics and cyclosporine, as occurs with renal transplant recipients.

Severe hepatic toxicity has been infrequently reported in patients on benzbromarone. This issue has led the European Medicine Agency to limit the use of benzbromarone.

Drugs With Uricosuric Properties Not Approved for Gout

In addition to the uricosuric drugs labeled for the treatment of hyperuricemia of gout, some other compounds have shown mild uricosuric properties. These drugs could be considered as “adjuvant” urate-lowering treatment that could be useful to control SUR levels in patients not reaching target SUR provided the presence of comorbidities for which their prescription is labeled.

Fenofibrate is a drug labeled for the treatment of type IV hyperlipidemia. At a dose of 200 mg once daily, it was shown to reduce SUR levels by 20% in an open study in patients on stable doses of allopurinol in an open, noncomparative, short-term study. In another short-term open study, fenofibrate 200 mg/day was added to allopurinol 200 mg twice a day, showing a reduction of SUR from 6.2 to 5.2 mg/dL (16% reduction). If added to benzbromarone 50 mg/day, SUR was lowered from 5.9 to 5.1 mg/dL (13% reduction).

Losartan is an antagonist of angiotensin II receptor (ARA-II) labeled for the treatment of hypertension. In a twin study with fenofibrate, patients were to also receive losartan 50 mg once daily. SUR levels were lowered from 6.1 to 5.5 mg/dL (9%) in patients on allopurinol and from 4.8 to 4.4 mg/dL (8%) in patients on benzbromarone. In a small randomized clinical trial in patients with asymptomatic hyperuricemia, losartan 50 mg/day showed a mild uricosuric effect. Interestingly, losartan antagonized the effect of hydrochlorothiazide on SUR levels when given in combination, a clinical applicability that deserves further investigation. In a short-term, small, double-blind, randomized study in patients with gout, losartan 50 mg/day, but not ibesartan 150 mg/day, showed a mild reduction of SUR, from 9.1 to 8.3 mg/dL (9%) but obviously not enough to reduce average SUR to target for urate-lowering therapy.

Atorvastatin , a drug labeled for the treatment of hypercholesterolemia, was shown to mildly reduce SUR levels in patients showing or not showing features of the metabolic syndrome in a post-hoc analysis of the GREACE trial, but the highest benefit was observed in patients with the metabolic syndrome compared with patients without features of the metabolic syndrome. SUR differences between the groups were 1.0 mg/dL versus 0.6 mg/dL, respectively. In a randomized trial comparing atorvastatin 40 mg/day with simvastatin 40 mg/day in patients with primary hyperlipidemia, a significant reduction of SUR from 5.6 to 4.9 mg/dL (12% reduction) was observed in patients treated with atorvastatin, but no change in SUR levels was observed in patients treated with simvastatin. Baseline SUR levels were associated with a greater urate-lowering effect.

Leflunomide is a drug labeled for the treatment of rheumatoid arthritis and psoriatic arthritis with peripheral joint involvement. In patients with rheumatoid arthritis, leflunomide 20 mg/day reduced baseline SUR by 30% and increased fractional excretion of uric acid by 67%. This effect was associated with a decrease of renal tubular reabsorption of phosphate by 5%, suggesting that leflunomide interacts with transporters involved in uric acid and phosphate handling.

Overall, the evaluation of the urate-lowering effect of “adjuvant drugs” is limited by design and external applicability. Data suggest that adding uricosurics to allopurinol is better than adding uricosurics to uricosurics. Despite this, these drugs could be useful in patients with (1) presence of a concomitant disease for which the drug is labeled and (2) borderline SUR levels at baseline or SUR levels close to the target for urate-lowering therapy. In addition, some of these drugs, such as statins or fenofibrate, have drug-drug interaction risks with colchicine that specifically raise the risk for myopathy with or without rhabdomyolysis, which should be taken into consideration for dose prescription and monitoring.

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