Recent developments in our understanding of the renal basis of hyperuricemia and the development of novel antihyperuricemic therapeutics
© BioMed Central Ltd 2006
Published: 12 April 2006
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© BioMed Central Ltd 2006
Published: 12 April 2006
Although dietary, genetic, or disease-related excesses in urate production may contribute to hyperuricemia, impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout. The aims of this review are to highlight exciting and clinically pertinent advances in our understanding of how uric acid is reabsorbed by the kidney under the regulation of urate transporter (URAT)1 and other recently identified urate transporters; to discuss urate-lowering agents in clinical development; and to summarize the limitations of currently available antihyperuricemic drugs. The use of uricosuric drugs to treat hyperuricemia in patients with gout is limited by prior urolothiasis or renal dysfunction. For this reason, our discussion focuses on the development of the novel xanthine oxidase inhibitor febuxostat and modified recombinant uricase preparations.
Gout is a crystal deposition disease with clinical manifestations that include acute gouty arthritis, chronic gouty arthropathy, tophi, and renal functional impairment due to monosodium urate (MSU) crystal deposition; and urolithiasis and obstructive uropathy due to uric acid crystal deposition . Gout ultimately results from inflammatory and/or degenerative responses to one or more derangements in the metabolism or physiology of urate, the obligatory end-product of human purine degradation . In all untreated patients with gout, the body pool of urate exceeds normal, the level of serum urate is elevated, and the accompanying state of urate supersaturation predisposes to clinical events . Persistent hyperuricemia (defined as a serum urate level >6.8 mg/dl) reflects extracellular fluid supersaturation for urate; it is simple to measure and is the primary risk factor for symptomatic gout. Although dietary, genetic, or disease-related excesses in urate production underlie hyperuricemia in some affected individuals , impaired renal excretion of uric acid is the dominant cause of hyperuricemia in the majority of patients with gout [1–3].
A weak organic acid with a pKa1 of 5.75, uric acid is the final product of human purine metabolism. At the physiologic pH of 7.4 in extracellular fluid, the concentration of urate ion is approximately 50-fold that of the less soluble un-ionized uric acid. Because of the high concentration of sodium in extracellular fluid, urate is largely present as MSU; a consequence of this is that the appreciable solubility of urate ion (120 mg/dl at 37°C) is replaced by the much lower solubility of MSU (approximately 6.8 mg/dl). As urate concentrations increasingly exceed 6.8 mg/dl, the risk for urate crystal formation and precipitation increases. At pH 5.0 (often found in urine), undissociated uric acid predominates, with a solubility of approximately 10–15 mg/dl .
The human diet contains little urate. Urate is synthesized endogenously in the liver and, to a lesser extent, in the small intestine and circulates relatively free of protein binding (<4%), so that all, or nearly all, urate is filtered at the glomerulus before undergoing extensive net renal tubular reabsorption (see below). Purine ingestion, endogenous synthesis of purines from nonpurine precursors, and reutilization of preformed purine compounds are the sources of urate production, an overall process that under steady state conditions is balanced by uric acid disposal . Daily renal uric acid excretion is equivalent to about two-thirds of daily production, and urate secretion into the small intestine, with breakdown of urate by gut bacteria (intestinal uricolysis), accounts for nearly all of the remainder of urate disposal .
Humans and certain other primate species lack expression of uricase , the enzyme that catalyzes conversion of urate to allantoin, which is a substantially more soluble product than urate and that is easily eliminated by renal excretion. Consequently, serum urate levels are several fold higher in normal humans than in rodents, for example. The body pool of urate in humans is normally composed entirely of soluble urate. In normal men and women the urate pools range from about 800 to 1500 mg and from about 500 to 1000 mg, respectively, with a daily turnover (the balanced production and disposal of urate) of about 0.6–0.7 pools/day [3, 4]. Imbalance between the production and disposal of urate may result in expansion and supersaturation of the urate pool [3, 4], sometimes resulting in urate crystal deposition and, ultimately, the formation of tophi, which may or may not be measurable in estimates of the miscible urate pool .
In about 90% of individuals with sustained hyperuricemia, impaired renal uric acid excretion is the dominant mechanism underlying expansion of the urate pool [1–3]. Important advances in our understanding of renal uric acid excretion are discussed below. Xanthine oxidase, the enzyme that catalyzes the terminal steps in urate production, namely oxidation of the purine bases hypoxanthine to xanthine and xanthine to uric acid, is a critical target of drug action in the treatment of hyperuricemia; this is also discussed below. Hyperuricemia may also be caused by excessive urate production alone or in combination with impaired renal uric acid excretion [1–3, 7]. The pathways of purine metabolism , their normal regulation [8, 9], and regulatory aberrations that lead to urate overproduction [2, 3, 8, 9] are reviewed in detail elsewhere.
Most individuals with hyperuricemia and impaired renal uric acid excretion have normal amounts of uric acid in their daily urine. However, excretion of normal amounts of uric acid in these individuals is accomplished only when serum urate levels are, on average, 2–3 mg/dl higher than in normal persons excreting comparable amounts of uric acid . Renal hyperuricemia may be primary (idiopathic) and unassociated with an identifiable disorder or drug regimen, or it may be secondary to any of the broad array of disorders, treatments, or toxic states that disrupt the mechanisms involved in renal uric acid excretion . Although some patients with primary hyperuricemia and gout may have impaired tubular urate secretory capacity , it seems unlikely that there is a unitary mechanism for hyperuricemia due to decreased renal uric acid excretion. In fact, the weight of evidence supports the view that, as in secondary gout, multiple renal processes for handling uric acid can be targets for disruption in patients with primary hyperuricemia.
Despite nearly complete filtration of urate at the glomerulus, uric acid clearance averages only 8–12% that of inulin or creatinine, reflecting the net reabsorption of about 90% of filtered urate. Over several decades, the multiple processes that mediate proximal convoluted tubule handling of filtered urate were operationally defined by studying the effects of inherited mutations and pharmacologic agents on renal uric acid excretion and by applying classic methods of renal physiology .
A multicompartmental model for renal uric acid handling, generated using the above approaches, included glomerular filtration; proximal tubule (S1 segment) reabsorption of virtually all filtered urate; secretion of 45–50% of reabsorbed urate (S1 and S2 segments of the proximal tubule); and postsecretory reabsorption of secreted urate (S3 segment of the proximal tubule). Thus, net excretion of uric acid is composed almost entirely of secreted rather than filtered urate. This model did not achieve consensus , however; in part this was because the compounds used to evaluate the components were not entirely specific in their sites of action, especially the use of drugs such as pyrazinamide and probenecid. Fortunately, the application of newer methodologies has begun to clarify the dynamics and molecular bases of renal uric acid excretion.
That affected individuals in families with 'loss of function' mutations in the gene encoding URAT1 (SLC22A12) demonstrate hypouricemia and hyperuricosuria as well as functional renal impairment supports the suggestion that URAT1 is the most potent regulator of serum urate levels [13, 14]. Additional studies support a role of URAT1 and possibly other urate transport/exchange molecules in hyperuricemia and gout. A specific URAT1 gene sequence variant is associated, when carried in the heterozygous state, with less frequent gout and substantially lower serum uric acid levels among Japanese individuals . Pyrazinamide, benzbromarone, and probenecid do not significantly affect urinary uric acid clearance in subjects with defective URAT1 transport function . Finally, sex, sex hormones, aging, diuretic therapy, and experimentally induced hyperuricemia (in rats) have been observed to modulate the intrarenal expression patterns of certain OAT family members [17–20]. For example, estrogen suppresses proximal tubule epithelial cell OAT expression , a finding that may explain the higher renal urate clearances, lower serum urate levels, and much reduced incidence of gout in premenopausal women as opposed to men and postmenopausal women.
A second candidate renal urate transporter, urate transporter/channel 1 (UAT-1), mediates voltage-dependent urate channeling in transfected cells and artificial membranes . UAT-1 is more widely distributed in tissues than is URAT1, and it has been identified as galectin-9, one of a family of proteins with a number of nontransport functions including modulation of cell adhesion and differentiation [21, 22]. The role of UAT-1 in the physiologic renal tubular transport or intestinal transport (specifically secretion) of urate remains to be established . A number of other organic acid transporters and additional candidate exchangers may also participate in urate handling, particularly at the basolateral membrane of proximal tubule epithelial cells [23–25].
Further insight into the mechanisms that affect renal uric acid excretion has been provided by studies of familial juvenile hyperuricemic nephropathy (FJHN), an autosomal dominantly inherited disorder that is characterized by early onset of hyperuricemia (with or without gout), hypertension, and progressive renal failure culminating in end-stage renal disease by age 40 years . Severely impaired renal uric acid clearance is present early, and the ensuing progressive nephropathy does not appear to be dependent on urate/uric acid crystal deposition . Most affected families harbor a mutation in the chromosome 16p-linked UMOD gene, usually in a base that is involved in specifying a cysteine residue [28, 29]. This gene encodes uromodulin (the Tamm–Horsfall glycoprotein), a disulfide bond-rich molecule that is normally the most abundant protein in human urine . Among several mechanisms proposed to explain the relationship of altered uromodulin expression and the FJHN phenotype  is the hypothesis that uromodulin promotes maintenance of the structural and functional integrity of the ascending limb of the loop of Henle by providing a gel-like protective lattice. Compromise of uromodulin structure and function is believed to impair distal nephron sodium chloride reabsorption, with an ensuing fluid volume depletion that activates voltage-dependent sodium/urate cotransport at the proximal tubule. Mutations in UMOD also characterize variant forms of medullary cystic kidney disease (MCKD type 2) and glomerulocystic kidney disease (GCKD) as well as FJHN , which are thus allelic disorders with FJHN. These hyperuricemia-associated disorders are characterized by tubulointerstitial nephropathy and fibrosis, although glomerulocystic kidney disease is also associated with dilation of Bowman's space and glomerular tuft collapse. The possibility that other more subtle defects in uromodulin structure and expression may also explain gout in additional patients is under investigation.
Uricosuric agents have long been used in the treatment of hyperuricemia associated with gout . Probenecid, the only uricosuric agent currently used for this purpose in the USA, remains useful in patients with primary gout who have decreased renal uric acid excretion in the setting of well preserved renal function (creatinine clearance ≥60 ml/min) [1, 34]. Unfortunately, all uricosuric agents currently available in the USA are generally ineffective and potentially nephrotoxic when used to treat hyperuricemia associated with moderate chronic kidney disease (creatinine clearance 30–60 ml/min) [33, 34]. Given the marked rise in prevalence of both renal insufficiency and gout during the past 2 decades , therapy for hyperuricemia in complicated gout is likely to require approaches other than uricosuric drugs, such as safer and more effective xanthine oxidase inhibitors or modified recombinant uricase preparations.
Allopurinol is the most commonly used antihyperuricemic agent and is the only xanthine oxidase inhibitor approved to date by the US Food and Drug Administration. This drug inhibits xanthine oxidase by a competitive mechanism with respect to the natural purine base substrates [3, 37, 38]. Allopurinol binds to the oxidized form of xanthine oxidase at the active site Mo6+-pterin coenzyme, and, in the process of reducing it, generates the oxidized form of allopurinol, namely oxypurinol. Advantages of allopurinol are a once-daily dosing regimen and urate-lowering efficacy regardless of the cause of hyperuricemia.
Major limitations of allopurinol therapy
Rash in about 2% of treated patients
Additional intolerance in up to 10% of patients (includes hepatic enzyme, gastrointestinal, and central nervous system effects)
Allopurinol hypersensitivity syndrome: <1/1000 treated patients, but 20% fatality rate
Prolonged renal elimination of active oxypurinol metabolite necessitates reduced dose in renal disease with impaired function
Contraindicated in patients receiving azathioprine or 6-mercaptopurine
Other allopurinol side effects, including hepatic toxicity with serum transaminase elevation, render approximately 10% of treated persons unable to tolerate this agent. Furthermore, for patients with chronic kidney disease  the prolonged half-life of renal elimination of oxypurinol limits the recommended maximum allopurinol dosage because of concerns about an increased incidence of hypersensitivity reactions. A major issue currently limiting effective allopurinol use is patient compliance. In one study , for example, compliance with allopurinol over 2 years of treatment was only about 20%. It seems likely that insufficient patient education regarding the long-term aims of urate-lowering therapy contributes to this problem, which is shared by therapies for other treatable disorders that may be asymptomatic for substantial periods of time.
Oxypurinol  is currently only available on a compassionate-use basis in the USA and Canada, and may be useful and effective in most (but not all) patients with mild-to-moderate allopurinol intolerance.
Like allopurinol, oxypurinol is a competitive inhibitor of xanthine oxidase. In contrast to allopurinol, oxypurinol binds to the reduced form of the enzyme with very high affinity but is released from xanthine oxidase when the enzyme is reoxidized. Oral absorption of oxypurinol is poor relative to allopurinol, and oxypurinol doses may require extended titration to achieve satisfactory lowering of serum urate.
In a recently reported 1-year phase III randomized controlled trial comparing 80 mg/day and 120 mg/day doses of febuxostat with allopurinol at 300 mg/day in patients with gout and serum urate levels of 8.0 mg/dl or greater , both doses of febuxostat resulted in sustained and superior (to allopurinol) urate-lowering efficacy. Nevertheless, after 1 year of treatment, the secondary outcomes of reduction in gout flares and tophus area were not different in the febuxostat and allopurinol group, and the overall incidence of treatment-related adverse events-most of which were mild and moderate in severity- was similar for all treatment groups. However, a significantly greater number of patients in the febuxostat 120/day group discontinued therapy (P = 0.003).
Neutralizing antibodies frequently develop in the course of treatment with purified native or unmodified recombinant uricase [55, 57–59]. In order to reduce antigenicity and prolong the half-life of uricase activity, polyethyleneglycol modified forms of recombinant uricase have been developed, and two such biologic agents are currently in clinical trials [63, 64]. It is likely that the therapeutic niches for modified uricases in the treatment of gout will be for short-term acceleration of tophus dissolution ('debulking') in carefully selected patients with large tophus burdens and perhaps for more long-term use in patients intolerant of or unresponsive to all other forms of urate-lowering therapy.
Gout is among the oldest recognized rheumatic diseases. Current research into the physiologic mechanisms and molecular processes that underlie hyperuricemia and gout has identified a range of targets for pharmacotherapy and is fostering the development of new drugs and biologic agents for reversing hyperuricemia. The future promises more effective treatments for patients with difficult-to-manage gout, including those with renal insufficiency, allopurinol intolerance, and extensive tophi.
familial juvenile hyperuricemic nephropathy
organic anion transporter
urate transporter/channel 1