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Introduction

  1. Top of page
  2. Introduction
  3. Recent demographic and clinical trends in gout
  4. New directions for antihyperuricemic therapies
  5. Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?
  6. New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack
  7. Conclusion
  8. REFERENCES

Gout has been recognized since antiquity and is the best understood and most readily manageable of all common systemic rheumatic diseases (1–3). In this context, the direct diagnostic and pathogenic linkages of monosodium urate monohydrate (MSU) crystal deposition to inflammatory arthritis are well-established (1–4). The pathogenesis of hyperuricemia, the foundation for potential urate crystallization in tissues, has been illuminated by comprehensive studies of purine nucleotide metabolism and renal disposition of uric acid (1–3, 5). In addition, the cause of hyperuricemia via uric acid underexcretion or overproduction can be readily determined in most patients (for review, see refs. 1–3). Thus, practitioners can weigh the effects of iatrogenesis (e.g., diuretic therapy) on hyperuricemia and alter therapeutic regimens accordingly. The astute clinician uses the diagnosis of gout as a signal to search for the unrecognized significant comorbidities and underlying etiologies. These include metabolic syndrome, hypertension, nephropathy, alcohol abuse, and disorders that cause uric acid overproduction via a primary abnormality of purine metabolism or, secondarily, by increased cell turnover (1–3, 5).

Lifestyle modification, including dietary interventions and weight management, as well as a reduction in alcohol consumption, can significantly reduce hyperuricemia in many patients with gout (1–3, 6). Furthermore, xanthine oxidase inhibitory or uricosuric drugs can produce sustained lowering of serum urate levels that ultimately leads to stable disease control in the majority of patients with gout (for review, see refs. 1–3).

Low-dose oral colchicine prophylaxis for acute gouty attacks is effective and safe when dosing guidelines are adhered to, and nonselective cyclooxygenase (COX) inhibitors and colchicine provide effective options for treating most cases of gouty arthritis (for review, see refs. 1–4). The advent of selective inhibition of COX-2 (7, 8) and the validation of adrenocorticotropic hormone (ACTH) and intraarticular, oral, and parenteral glucocorticoids as effective treatment for many cases of acute gout have provided further options for primary treatment of gouty arthritis (1–4). However, polyarticular gouty inflammation can be both chronic and refractory to current therapeutics (4). Moreover, chronic gout can cause bone erosion and articular cartilage loss that may progress even after initiation of effective treatment for hyperuricemia (9).

An apparent increase in the prevalence of gout over the last 2–3 decades has been compounded by limitations in largely antiquated strategies for treating gouty inflammation and lowering serum urate levels. As a result, there remain substantial gaps in the capacity to manage subsets of refractory disease. In this review, we focus on how recent advances can pave the way to translational research targeted toward enriching current management options for gout.

Recent demographic and clinical trends in gout

  1. Top of page
  2. Introduction
  3. Recent demographic and clinical trends in gout
  4. New directions for antihyperuricemic therapies
  5. Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?
  6. New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack
  7. Conclusion
  8. REFERENCES

Gout is a common medical problem that affects at least 1% of adult men in Western countries (10–12). The episodic nature of the symptoms and signs in many patients with gout make the prevalence and incidence difficult to determine with precision. However, comparisons of epidemiologic data obtained at different periods over the last 4 decades (10–20) are consistent with an increasing prevalence (and annual incidence) of gout in Western industrialized countries (Table 1). In addition, gout has been observed to be increasing in prevalence and presenting earlier in life in less-industrialized Eastern countries (21, 22).

Table 1. Increased gout in the overall population (excluding children) in Western industrialized countries over the last 4 decades, as evaluated by different survey approaches
Author/study (ref.)YearPopulationFindings for gout
Lawrence (13)1960Western EuropePrevalence 3/1,000
Wyngaarden and Frederickson (14)1960USPrevalence 2.8/1,000
Kellgren (15)1964Europe and USPrevalence <3/1,000
O'Sullivan (16)1972Sudbury, MAPrevalence 3.7/1,000
Currie (17)1978Great BritainPrevalence 3/1,000
Harris et al (18)1995EnglandPrevalence 10/1,000
National Health Interview Survey (10, 11, 19, 20)1969USSelf-reported prevalence 5/1,000
 1988–1992USSelf-reported prevalence 8.4/1,000
 1996USSelf-reported prevalence 9.4/1,000
Arromdee et al (12)1977–1978Rochester, MNAnnual case incidence 45/100,000
Arromdee et al (12)1995–1996Rochester, MNAnnual case incidence 62.3/100,000

A retrospective analysis of newly diagnosed gout at Mayo Clinic between 1949 and 1972 demonstrated a progressive decline in tophaceous gout (from 14% to 3%) during a period in which the number of gout diagnoses was stable and novel urate-lowering therapies and antihypertensive agents were introduced (23). Studies to formally test for recent changes in the proportion of gout patients with tophaceous disease would be valuable, given the apparent increase in gout prevalence and our impression that the overall clinical complexity of the disease is increasing. Table 2 summarizes the proposed principal factors that underlie the increase in the prevalence of gout and subsets of refractory disease, which are discussed below.

Table 2. Proposed principal contributory factors to the increased prevalence of gout and subsets of refractory disease over the last 2 decades in the US
Increased longevity
Increased prevalence of hypertension
Dietary trends
Increased prevalence of obesity and metabolic syndrome
Changing demographic trends and high prevalence of hypertension or metabolic syndrome in specific racial and ethnic population subgroups
Increased prevalence of end-stage renal disease
Improved survival from congestive heart failure and coronary artery disease
Increased prevalence of diuretic and low-dose acetylsalicylic acid therapy
Limitations in the current armamentarium of antihyperuricemic agents, particularly in the allopurinol-hypersensitive patient with renal insufficiency
Increases in major organ transplantation linked with cyclosporine-induced gout

High alcohol intake, hypertension, thiazide and loop diuretic therapy, and obesity appear to contribute both independently and additively to the risk of developing gout in the hyperuricemic patient (24–26). Although overall alcohol consumption per capita in the US has declined over the last 2 decades (27), significant increases in the prevalence of hypertension, diuretic therapy, and obesity have occurred (28–30). Changes in dietary patterns, including increased consumption of meat and seafood, and possibly decreased consumption of dairy products, also may be contributing to an increased prevalence of gout in many societies (31, 32).

Gout prevalence increases in direct association with aging (11, 12, 20, 21). Sustained hyperuricemia results in tissue urate deposition in a minority of subjects (24, 25), but increasing longevity of the population in industrialized nations (33) can contribute to a higher prevalence of gout via disease associations with aging as well as more prolonged hyperuricemia.

Hypertension, thiazides, and gout.

The increased prevalence of hypertension (from 25.0% during 1988–1991 to 28.7% during 1999–2000) recently documented in the US has disproportionately affected African Americans (30). Hypertension, socioeconomic/lifestyle differences, and, possibly, environmental factors (34, 35) appear to be contributing synergistically to a higher frequency of gout and higher mean serum urate levels in African Americans relative to Caucasians (36, 37).

Hypertension alone promotes hyperuricemia (38), and diuretic therapy compounds this problem. But, the tangible benefits of thiazides in hypertension therapy include their low cost and convenient once-daily dosing schedule. Furthermore, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) of the late 1990s, the thiazide chlorthalidone was found to be superior to doxazosin and lisinopril with respect to the incidence of stroke (39, 40). However, in a recent Australian study, angiotensin-converting enzyme (ACE) inhibition demonstrated lower combined rates of cardiovascular events or all-cause mortality in elderly hypertensive patients compared with thiazide therapy, a benefit that was most evident in men (41). The ALLHAT analyses of first-line therapy for hypertension included younger patients and had more patients of African ancestry than did the Australian study. As such, it appears that subsets of patients with hypertension benefit differentially from treatment with thiazides versus ACE inhibitors. Clinicians have ample opportunity to develop individualized hypertension management regimens that also reduce the risk and severity of gout by avoiding the use of thiazides (42).

Obesity, metabolic syndrome, and gout.

An increased body mass index directly correlates with an increased serum urate level, apparently a multifactorial association (43). Importantly, ∼60% of Americans are overweight, and childhood obesity is rising at an alarming rate (44). Large subsets of obese subjects meet the criteria for metabolic syndrome (45), an entity centrally mediated by insulin resistance (IR) and associated with hyperuricemia accompanying the clinical features summarized in Table 3 (46). A significant impact of the metabolic syndrome on the apparent recent changes in the prevalence and clinical complexity of gout appears likely. However, the impact of the metabolic syndrome may not be uniform among all ethnic groups (47–49). For example, Mexican Americans, the most rapidly growing ethnic subgroup in America, have a significantly higher prevalence of metabolic syndrome than do Caucasians and African Americans, with an age-adjusted US prevalence of 31.9% (45), compared with 23.7% in the Third National Health and Nutrition Examination Survey (NHANES-III) (46).

Table 3. Principal features of the metabolic syndrome*
Elevated circulating levels of insulin and insulin resistance
Glucose intolerance or type 2 diabetes mellitus
Abdominal (visceral) obesity (defined as waist circumference >102 cm [40 inches] in men and >88 cm [35 inches] in women)
Dyslipidemia (hypertriglyceridemia and low levels of high-density lipoprotein cholesterol)
Hypertension
Hyperuricemia
Increased risk of atherosclerosis and coagulative arterial occlusion events

IR has been proposed to promote hyperuricemia, partly by enhancing renal urate reabsorption via overactivity of renal Na+/H+ exchange (50). But, Na+/H+ antiporter overactivity may be primarily a product of hypertension rather than IR, and the resorptive capacity of the antiporter for urate has not been defined (51). In our opinion, altered regulation of other mediators of intrarenal urate disposition (discussed below) is more likely to mediate hyperuricemia associated with IR. Altered urinary ammonium excretion associated with IR also promotes a more acidic urine (52), a central factor in increased susceptibility to uric acid nephrolithiasis. In association with IR, increased intracellular availability of the coenzyme A esters of long-chain fatty acids, acting on purine metabolism and cellular adenosine release, may also promote renal vasoconstriction, renal sodium and uric acid retention, and up-regulated uric acid production (53). However, disordered carbohydrate metabolism likely plays a greater role than dyslipidemia in promoting hyperuricemia in IR (54).

Gout in the elderly and gout after menopause.

Gout prevalence appears to be rising in the elderly, including elderly women (for review, see ref. 55). The prevalence of metabolic syndrome increases substantially in association with aging (46). For example, in the NHANES-III, the prevalence of metabolic syndrome increased from 6.7% among those ages 20–29 years to 43.4% for those ages 60–69 years (46). But, the higher prevalence of gout in the elderly reflects factors beyond an increased prevalence of the metabolic syndrome. Such factors likely include relatively high rates of diuretic treatment for hypertension and congestive heart failure, and could also include the use of low-dose acetylsalicylic acid (48) (Table 2). Survival post–myocardial infarction continues to improve (56). Gout in the elderly has a more equal sex distribution, partly reflecting loss of the uricosuric effect of estrogen (55). We predict that the declining use of estrogen replacement therapy postmenopause will promote a higher frequency of postmenopausal gout and an earlier age at onset.

Small observational studies have suggested that gout in the elderly, including postmenopausal gout, often presents differently from stereotypical gout seen in younger men (for review, see ref. 55). For example, gout in the aged commonly includes an initial presentation with acute polyarticular gout, fewer bouts of classic monarticular gout, a more indolent chronic clinical course, and increased tophi in the upper extremities (including tophaceous deposits in osteoarthritic distal and proximal interphalangeal joints) (for review, see ref. 55). Gouty inflammation also is more challenging to treat in the elderly, in part because of increased colchicine and nonsteroidal antiinflammatory drug toxicity (2, 55).

End-stage renal disease (ESRD).

Renal insufficiency promotes hyperuricemia and gout, and ESRD is particularly prevalent in industrialized countries (57). In the US, the incidence of ESRD nearly doubled in a single decade, from 156 new cases per million in 1987 to 303 per million in 1997, and concurrently, the point prevalence of ESRD more than doubled (57). Significantly, the prevalence of ESRD rises sharply in persons ages 65 years and older, and the prevalence of ESRD among African Americans is 4–5 times higher than the prevalence among Caucasians (57).

Renal and other major organ transplants associated with gout.

The increased prevalence of ESRD in industrialized countries has promoted a rise in the numbers of renal transplants (e.g., in the US, 8,874 renal transplants in 1988 and 14,775 in 2002) (58). Over the last 2 decades, expansion of the donor pool and advances in therapeutic immune tolerance that include cyclosporine regimens have resulted in significantly improved renal allograft survival rates and have allowed for more success with transplants of other major organs (59, 60). At the same time, cyclosporine-associated gout in recipients of major organ transplants has emerged as a particularly aggressive iatrogenic disease (61–63). Cyclosporine promotes decreased renal uric acid excretion via impaired tubular handling of uric acid (64), hypertension (65), interstitial nephropathy, and a decreased glomerular filtration rate (61–63). Hyperuricemia develops in 70–80% of cyclosporine-treated organ transplant recipients, with a markedly elevated mean serum urate level of ∼12 mg/dl in some cohorts studied. Gout typically develops in ∼8–13% of subjects within 2–3 years of cyclosporine initiation, and tophus development can be rapid and extensive, and polyarticular gouty arthritis refractory, in this setting (61–63). Significantly, cyclosporine-induced impairment of hepatobiliary colchicine disposition predisposes to colchicine toxicity, which can manifest as rapid-onset myopathy in patients receiving “low-dose” daily prophylactic oral colchicine treatment for gout (66).

An alternative calcineurin inhibitor FK-506 (tacrolimus) has a toxicity profile that is similar to that of cyclosporine, including reduction of renal fractional clearance of uric acid and stimulation of hyperuricemia (67, 68). Preliminary reports suggesting less hyperuricemia and hypertension with FK-506 compared with cyclosporine in kidney transplant recipients (69, 70) have yet to be verified in adequately powered studies. Fortunately, rapidly evolving therapeutic approaches should markedly reduce the prevalence of transplant-associated gout during the next decade (71–74). Current options include combinations of “lower-dose” cyclosporine (e.g., 25 mg of cyclosporine microemulsion twice a day) with other agents or expeditious substitution of non-nephropathic “uric acid–sparing” alternatives, such as rapamycin (sirolimus), for calcineurin inhibitors after transplantation (73, 74).

New directions for antihyperuricemic therapies

  1. Top of page
  2. Introduction
  3. Recent demographic and clinical trends in gout
  4. New directions for antihyperuricemic therapies
  5. Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?
  6. New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack
  7. Conclusion
  8. REFERENCES

Developments in diet modification.

In a recent small, open study in overweight or obese gouty men with limited alcohol intake, a low-carbohydrate, calorie-restricted diet generous in monounsaturated fatty acids and tailored for IR was shown to lower body weight by a mean of 7.7 kg and to diminish hyperuricemia by 17% at 16 weeks, without a flare of gout (75). Less palatable purine-restricted diets have been used in the past to lower serum urate levels (6, 76), apparently without greater efficacy than the customized and IR-tailored diet described in reference75. But, the effectiveness of tailored low-carbohydrate diets for IR and hyperuricemia has not yet been assessed in an adequately designed, controlled trial. It would also be valuable to formally evaluate the effects on gout of the recent surge in popularity of low-carbohydrate diets (e.g., the Atkins, Zone, and South Beach diets) (77), since there are concerns that ketosis and elevated intake of meat and seafood could lead to exacerbation of hyperuricemia and gout in persons changing to such diets.

A recent prospective study of more than 47,000 middle-aged male medical professionals (the Health Professionals Follow-up Study) revealed that regular, moderate consumption of beer, which has a high content of the purine guanosine, was associated with a high (and dose-dependent) risk of the development of gout (78). In contrast, moderate wine consumption was not associated with an elevated risk of developing gout (78). Nonetheless, dietary advice dispensed to most patients with existing gout should remain appropriately focused on limiting the consumption of all types of alcoholic beverages to moderate levels. Certain epidemiologic data and results of short-term dietary intervention studies also have suggested that the consumption of dairy products is linked to a diminished risk of gout and to lower serum uric acid levels, respectively, possibly mediated by uricosuric effects of the milk proteins casein and lactalbumin (31, 32, 79, 80). But, the recent association of low-fat dairy product consumption with a decreased incidence of gout development seen in the Health Professionals Follow-up Study (31) could have reflected ascertainment bias, since “health-oriented” study subjects would be expected to include more low-fat milk and yogurt products in their diet. It also is noted that a direct increase in dietary milk protein failed to induce sustained, therapeutically significant serum urate lowering in a controlled trial in postmenopausal nuns (80). Clearly, the therapeutic potential for increased dairy consumption remains to be directly established in gout patients.

Can we add substantively to the current armamentarium of uricosurics?

Most primary and secondary hyperuricemia states are mediated by renal uric acid underexcretion (1–3). As such, optimization of uricosuric therapy is a physiologically rational approach to limiting hyperuricemia in most patients with hypertension, congestive heart failure, and/or metabolic syndrome. Although uricosurics are safe and effective for serum urate lowering in many patients with gout, probenecid and sulfinpyrazone are generally ineffective and can be nephrotoxic when used to treat hyperuricemia associated with moderate chronic renal insufficiency (creatinine clearance 30–60 ml/minute) (for review, see ref. 2). Benzbromarone, which is not approved by the US Food and Drug Administration (FDA), is a more effective uricosuric than probenecid or sulfinpyrazone for patients with moderate renal insufficiency (81), but benzbromarone can cause fulminant hepatotoxicity, which recently prompted removal of the drug from the market in France (82).

At least 2 other drugs with moderately potent uricosuric effects, the angiotensin receptor blocker losartan (83, 84) and the triglyceride-lowering agent micronized fenofibrate (85, 86), can potentially be factored into the optimization of the overall medical management of patients with hypertension and metabolic syndrome, respectively. The uricosuric effect of losartan, which is unique among drugs that act directly on the renin–angiotensin axis, is associated with serum urate–lowering effects, typically 7–15% in magnitude (83, 84), in primary hypertension and in cyclosporine-induced hyperuricemia (87). The capacity of losartan to raise urinary pH may account for the apparently low incidence of losartan-induced uric acid urolithiasis. But, the serum urate–lowering effects of losartan generally decrease with time once a steady state is reached (83, 84), and losartan can worsen preexisting impairment of renal function. The serum urate–lowering activity of losartan may partly reflect nonspecific effects on the renal circulation related to its antihypertensive action. In this context, the calcium-channel blocker amlodipine, which lacks direct uricosuric activity, reduced serum urate levels by ∼10% in one study (65).

The maximal serum urate–lowering effects of fenofibrate, like losartan, appear to be substantially less than the effect achievable with standard dosing regimens of primary uricosuric drugs such as probenecid. Moreover, the safety and efficacy of fenofibrate (with respect to urolithiasis, nephrotoxicity, and serum urate lowering) in patients with moderate chronic renal insufficiency are unknown.

Implications of the recent molecular identification of mediators of renal urate disposition for uricosuric therapies.

Recently, distinct classes of plasma membrane ion-channel and ion-exchanger proteins that directly mediate transport of the anion urate have been identified (88, 89). These exciting developments provide an updated platform for developing and optimizing uricosuric therapeutics. Foremost among the recent discoveries is the elucidation of the role in urate transport of ion exchangers of the SLC22 organic anion transporter (OAT) family (90–95), and URAT1 in particular (88). URAT1 (Figure 1, top) exerts essential physiologic effects on urate transport in the proximal tubule (88). In this context, heritable defects in URAT1 have been identified in familial renal hypouricemia, a disorder featuring remarkably depressed basal serum urate levels and increased uricosuria, and the potential for clinical manifestation as episodes of exercise-induced renal failure (88, 96).

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Figure 1. Comparison of the putative structures and urate transport functions at the plasma membrane of the urate transporter URAT1 and the urate transport/channel protein UAT. While URAT1 expression is tissue-restricted, UAT expression is broad. Certain heritable defects of URAT1 are linked to severe hypouricemia, as discussed in the text. But, how significant the effects of UAT are on serum urate levels is not defined. The putative functions of URAT1 and UAT in renal proximal tubule epithelial cells are schematized in Figure 2 and discussed in the text. Top, The depicted, putative multiple-pass transmembrane protein structure of the organic anion transporter (OAT) family member URAT1 is based on the work of Endou and colleagues (88, 90). Illustrated here is the electroneutral exchange of the anion urate with anions via URAT1, although the precise locus within URAT1 where the anion exchange takes place is not known. Bottom, Illustrated here is ion channeling of urate through UAT1, whose depicted, putative transmembrane structure is based on the work of Abramson and colleagues (89, 97–99). Significantly, the UAT1 urate-channeling function is dependent on an electrochemical gradient. The process also is regulated by the depicted, putative extracellular sugar (β-galactoside) binding sites in UAT1, with lactose being a particularly potent, and glucose a less potent, stimulator of urate channeling by UAT1. The depicted adenosine A1/3 receptor homology domain also appears to mediate the capacity of adenosine to suppress urate channeling through UAT1. The illustrated urate (and oxonate) binding site in a UAT intracellular uricase–homologous domain mediates suppression of urate channeling by oxonate in this model.

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Figure 2. A, Reabsorption and B, secretion of the anion urate by renal proximal tubule epithelial cells. Urate movement in the proximal tubule is bidirectional, and the way in which urate secretory and reabsorptive activities are balanced there exerts a major influence on the ultimate quantity of uric acid that is eliminated in the urine. However, urate secretion and reabsorption distal to the proximal tubule, which are mediated partly by cotransport with inorganic ions, also regulate renal uric acid elimination, as discussed in the text. A, Organic anion transporter 3 (OAT3) stimulates urate reabsorption from the peritubular capillaries into the circulation at the basolateral membrane of the proximal renal tubule epithelial cell. Urate reabsorption at the lumen membrane is critically regulated by URAT1, which exchanges tubule lumen urate with intracellular anions. The most potent identified stimulators of the exchange process are the intracellular organic ions lactate, nicotinate, and the monocarboxylate metabolite of the antituberculous drug pyrazinamide. Certain intracellular inorganic ions, including chloride, also stimulate urate exchange by URAT, but less potently so than the aforementioned organic ions. As depicted, urate reabsorption is potently suppressed at the lumen membrane by the uricosurics benzbromarone, probenecid, losartan, and sulfinpyrazone, consistent with their uricosuric properties. Other moieties that affect urate reabsorption in the proximal tubule, including salicylates and furosemide, may act partly by regulating URAT1 function, as discussed in the text. B, In this model of urate secretion, movement of urate from the peritubular capillaries to the lumen through proximal tubular cells is mediated by OAT1 at the basolateral membrane. Urate movement into the lumen at the apical membrane is held to be mediated by the sodium-dependent phosphate cotransporter NPT1, in addition to electrogenic urate efflux channeled through UAT. Certain organic anions, including lactate and ketoacids, are believed to competitively inhibit urate secretion. But, stimulatory effects of organic anions (e.g., lactate) on urate reabsorption, a system with a substantially higher capacity for renal tubular urate-handling than for secretion, combines with the effects of impaired urate secretion in mediating hyperuricemia in response to enhanced lactate production and ketosis.

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URAT1 is an electroneutral transporter, and its expression is markedly tissue-restricted (88), unlike the ubiquitous expression of the electrogenic urate channeling protein UAT (also known as galectin 9) (89, 97–99) (Figure 1, bottom). UAT can carry out urate efflux from cells in the proximal tubule in a highly regulated process, as schematized in the bottom panel of Figure 1 (97–99). But, the potential roles of UAT in hyperuricemic conditions remain to be determined, and the comparative functions of the multiple isoforms of UAT and of the related UAT2 gene are unknown (89).

Intrinsic renal proteins that modulate renal urate disposition were recently shown to include glycosyl phosphatidylinositol–linked membrane protein uromodulin (Tamm-Horsfall protein), the most abundant protein in human urine (100). Although uromodulin does not have direct physiologic effects on urate disposition in the nephron, certain mutations in the UMOD gene have been linked to familial hyperuricemia and nephropathy by undefined mechanisms (100). It will be of interest to determine whether secondary alterations in UMOD expression contribute to renal uric acid disposition in primary nephropathic states.

Model of bidirectional urate movement in the proximal tubule and implications for uricosuric drugs.

The critical regulatory effects of URAT1 on urate reabsorption at the proximal tubule lumen membrane are schematized in Figure 2A. URAT1 exchanges proximal tubule lumen urate in a process stimulated by intracellular anions (Figure 2A), with potent effects exerted by the organic anions lactate, nicotinate, and the monocarboxylate metabolite of the antituberculous drug pyrazinamide (88, 96). These findings necessitate reevaluation of the long-held tenet of a pyrazinamide-suppressible postreabsorptive proximal tubule site serving as the primary urate secretory locus in a 4-compartment operational paradigm for renal urate handling (101).

Urate reabsorption by URAT1 appears to be potently suppressed at the proximal tubule lumen membrane by the uricosurics benzbromarone, probenecid, losartan, and sulfinpyrazone (Figure 2A), as well as by high tubule lumen concentrations of salicylate (88, 96). Conversely, furosemide may enhance urate reabsorption partly by direct effects on URAT1 (88). UAT and OAT3, which are expressed widely in the nephron, support urate reabsorption at the basolateral membrane of the renal tubule epithelial cells (Figure 2A) (89, 90). But, the proximal tubule also is one of the loci for urate secretion (101), putatively mediated by OAT1 at the basolateral membrane (90, 102) and by UAT (89) and the sodium-dependent phosphate cotransporter NPT1 (103) acting at the apical membrane (Figure 2B). The way in which urate secretory and reabsorptive activities are balanced in both the proximal tubule and more distal regions in the nephron regulates net urinary elimination of uric acid (89).

Development and optimization of effective uricosuric therapies would benefit from further advances in the identification of specific gene sequence variants, and patterns of expression and functionality of individual renal urate transport mediators in health and disease. Importantly, sex, sex hormones, aging, diuretic therapy, and experimental rat hyperuricemia modulate intrarenal expression patterns of certain OAT family members (92–95). A striking finding with pharmacogenomic implications is that pyrazinamide, benzbromarone, and probenecid failed to significantly affect urinary uric acid clearance in subjects with defective URAT1 (96). But, the lack of a complete picture, inclusive of inorganic ion antiporters that act as urate cotransporters and of anion exchangers and ion channels unrelated to the OAT family or UAT (89), is a current challenge to the development of new uricosuric therapeutics.

Xanthine oxidase inhibitors.

Given the increasing prevalence of advanced renal insufficiency cited above and the safety issues related to urolithiasis that may progress to renal tubulopathy, it is appropriate that novel xanthine oxidase inhibitors are in commercial development. The limitations of currently available antihyperuricemic drugs are most exposed in allopurinol-intolerant patients with tophaceous gout associated with renal insufficiency, urolithiasis, and/or uric acid overproduction (for review, see ref. 2). Importantly, severe allopurinol hypersensitivity syndrome is life-threatening (104), and to avoid this multiorgan disorder, a recommended strategy is to initiate allopurinol at a daily dose between 50 and 300 mg, in direct proportion to the creatinine clearance (104). However, the effectiveness of such dosing regimens in reducing allopurinol hypersensitivity reactions remains unclear (105). Furthermore, clinicians often undertreat gout patients on a long-term basis with such allopurinol dosing schedules, in a misguided attempt to lessen the very small risk of major allopurinol hypersensitivity syndrome.

Only about one-half of the patients with minor hypersensitivity reactions to allopurinol can be successfully desensitized and treated indefinitely with the drug (106). Alternatively, only about one-half of allopurinol-hypersensitive patients can tolerate oxypurinol, the major bioactive allopurinol metabolite, which has been available on a compassionate-use basis in the US (107). Nonpurine xanthine oxidase inhibitors, including compounds currently in clinical trials, have the potential to be particularly useful in medical management of such patients with refractory gout and renal insufficiency (108, 109). Because oxypurinol exerts its effects on pyrimidine metabolism, it will be of interest to learn whether nonpurine xanthine oxidase inhibitors that are selective for purine metabolism have an improved side-effects profile relative to allopurinol with respect to potential side effects other than allergic reactions, including hepatotoxicity.

Potential therapeutic role of uric acid oxidase (uricase).

Hominid evolution was associated with inactivation of the expression of uricase, which degrades relatively insoluble uric acid to more-soluble allantoin in the peroxisome (110) (Figure 3). As such, statistically “normal” serum urate levels in humans are much higher than those in other mammals and are close to the theoretical limits of solubility (∼7 mg/dl at 37°C) in physiologic solutions. The delicacy of physiologic uric acid balance imposed by this situation in humans is reinforced by the marked hyperuricemia and renal tubulopathy that occur via engineered uricase gene inactivation in the mouse, which elevates serum urate levels ∼10-fold (110).

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Figure 3. Degradation of uric acid by uric acid oxidase (uricase). Illustrated is the reaction catalyzed by uricase that converts relatively insoluble uric acid to highly soluble allantoin (which is ultimately eliminated by renal excretion). As shown, H2O2 is generated as a by-product of the catabolism of uric acid by uricase; the potential repercussions of this reaction are discussed in the text.

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Nonrecombinant uricase has been used in Europe to prevent severe hyperuricemia induced by chemotherapy in patients with a heavy burden of malignant cells, as well as for limited courses of treatment of hyperuricemia in highly selected patients with treatment-refractory gout (111–113). Recently, recombinant Aspergillus flavus uricase (rasburicase) was approved by the FDA for prevention of tumor lysis syndrome via a single, short-term course (111–114). Recombinant uricase therapy profoundly lowers serum levels and, unlike currently available urate-lowering therapeutics, has the theoretical potential to promote accelerated tophus dissolution when given in a therapeutic course limited to months in duration. As such, uricase preparations are currently under evaluation in gout clinical trials in the US. However, uricase is highly immunogenic, and in the treatment of tumor lysis syndrome, uricase can trigger severe and potentially lethal side effects, including anaphylaxis (111–113).

Catabolism of uric acid by uricase generates hydrogen peroxide as a reaction by-product (Figure 3), which can stimulate cell transformation in vitro (115), a significant concern with respect to potential long-term therapy. Uricase can trigger hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency and induce methemoglobinemia in vivo (111–114). Neutralizing antibodies also frequently develop in response to uricase treatment (116). Clearly, modification of uricase to reduce its antigenicity and to prolong its half-life (e.g., by PEGylation) (116) will be needed to move forward with clinical development for the reduction of tophus burden in carefully selected gout patients.

Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?

  1. Top of page
  2. Introduction
  3. Recent demographic and clinical trends in gout
  4. New directions for antihyperuricemic therapies
  5. Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?
  6. New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack
  7. Conclusion
  8. REFERENCES

The majority of patients with asymptomatic hyperuricemia do not go on to develop clinical gout (17, 18) or renal damage related to elevated serum urate levels (for review, see ref. 117). Asymptomatic hyperuricemia alone is not an indication for therapy, except in patients who overproduce uric acid or those who require prolonged calcineurin inhibitor treatment for posttransplant therapeutic immunosuppression (for review, see ref. 2). But, a growing body of data argues that treatment of asymptomatic hyperuricemia might directly improve the management of hypertension, hinder the development of atherosclerosis and its ischemic complications, and hinder the development of renal insufficiency.

Hyperuricemia is a powerful predictor of both ischemic cardiovascular diseases and poor outcome in these conditions (118). Recent studies also support hyperuricemia as an independent risk factor for cardiovascular disease, rather than simply an associated factor based on linked metabolic conditions (37, 119, 120). Serum urate levels were correlated directly with untreated high blood pressure in children and independently of renal function (121). Furthermore, direct, causal associations between hyperuricemia and rapid activation of the renin–angiotensin system, increased sodium reabsorption, and hypertension have been suggested by Johnson and colleagues in compelling experimentation in rats treated with the uricase inhibitor oxonic acid (for review, see ref. 122). Chronic development of afferent arteriolar arteriosclerotic glomerulopathy, interstitial inflammation, and further increases in salt retention, as well as aggravation of cyclosporine-induced nephropathy by hyperuricemia have been observed in the same model system (122). Furthermore, allopurinol treatment prevented these vascular changes (123). This body of work has principally employed a low-salt diet supplemented with the uricase inhibitor oxonic acid to induce a state of sustained hyperuricemia in rats (increasing serum urate levels to ∼1.8–3.2 mg/dl in animals with a typical baseline level of ∼1.1–1.4 mg/dl) (123).

The uricosuric benziodarone was less effective than allopurinol at lowering serum urate levels and preventing vascular lesions in the oxonic acid–treated rat (123). In vitro studies of isolated vascular smooth muscle cells treated with escalating concentrations of soluble uric acid suggested a mechanistic basis for these findings via uric acid induction of MAPK signaling, smooth muscle cell proliferation, and expression of COX-2, platelet-derived growth factor, and the chemokine monocyte chemoattractant protein 1 (124). Taken together, these observations have prompted the hypothesis that loss of uricase gene expression in hominid evolution conferred a survival advantage by promoting salt retention and blood pressure stabilization as the posture of primitive humans became increasingly upright (125).

In our opinion, the reported effects of hyperuricemia by itself in the pathogenesis of hypertension, renal dysfunction, and atherosclerosis (118, 120, 121) all remain in question. Direct uric acid infusion into healthy human adults did not alter selected hemodynamic or endothelial functions in a recent study (126). Our appraisal is that data for some of the reported adverse effects of water-soluble uric acid in vitro (118, 124) may reflect cell culture conditions. Given the relatively low solubility of uric acid in physiologic buffers, data on the proinflammatory effects of soluble uric acid would be more convincing if urate microcrystallization were ruled out (124). Questions also remain regarding the accordance of physiologic significance of the aforementioned in vivo findings to humans. Rats and humans must adapt to ∼5-fold different basal serum urate levels, and they likely possess distinct means of intrarenal uric acid handling. A central flaw in the aforementioned in vivo studies of hyperuricemia in oxonic acid–treated rats is that oxonate suppresses cellular urate efflux from the cytosol by inhibiting UAT, likely acting at the uricase–homologous urate/oxonate binding site of UAT (Figure 1B) (89, 97–99). As such, oxonate could be nephrotoxic in vivo, partly by inhibiting urate efflux out of renal tubular epithelial cells. On the whole, the aforementioned data in oxonic acid–treated rats would be more convincing if nephropathic effects associated with the hyperuricemia were reproduced via direct elevation of serum urate levels.

Excess uric acid is potentially modifiable by cells to a pro-oxidant, and uric acid can promote oxygen radical formation and either inhibit or promote proatherogenic low-density lipoprotein oxidation, depending on experimental conditions (118, 127, 128). But, the major physiologic function of uric acid appears to be as an antioxidant. Indeed, uric acid is ∼6-fold more abundant in human plasma than is the antioxidant ascorbic acid, and the capacity to generate ascorbic acid was lost in human evolution in roughly the same time frame as that in which uricase gene inactivation developed (118, 125, 129). The antioxidant activity of uric acid may promote human longevity, partly by protective effects against oxidative stress–induced cell transformation and hypoxia-induced and oxidant-induced cardiotoxicity and neurotoxicity (118, 129–134). Hence, soluble uric acid can exert beneficial or adverse effects that may depend on the health of the host, and this issue needs to be factored into the ongoing debate about the potential long-term therapeutic value of treating asymptomatic hyperuricemia.

New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack

  1. Top of page
  2. Introduction
  3. Recent demographic and clinical trends in gout
  4. New directions for antihyperuricemic therapies
  5. Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?
  6. New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack
  7. Conclusion
  8. REFERENCES

Acute gouty arthritis is largely neutrophil-dependent and driven by the capacity of MSU crystals to activate cells and induce numerous inflammatory mediators (4). Several of these mediators could provide novel targets for clinical trials in refractory gouty inflammation (4, 135–137) (Figure 4). The basic mechanisms by which MSU crystals activate cells (4) may be of broader importance in stimulating inflammation than previously appreciated, since urate crystals stimulate dendritic cell maturation and enhance the generation of CD8+ T cell immune responses (138). Furthermore, macrophage activation by seed crystals of MSU conceivably promotes granuloma-like foci of tophaceous urate deposits in some pericellular environments (139). Recent studies have elucidated that urate crystals induce the expression of interleukin-8 (IL-8) and certain other mediators through cell signaling pathways involving Src family kinases, Pyk-2, p38 and other MAPKs, and the transcription factors activator protein 1 and NF-κB (4, 140–143).

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Figure 4. Model showing the pathogenesis of the acute gouty attack. This model schematizes recent advances in understanding acute gouty arthritis, which is largely neutrophil-dependent and driven by the capacity of monosodium urate monohydrate crystals to activate complement and stimulate synovial lining cells and other resident cells in the joint, thereby inducing a variety of inflammatory mediators. Cellular signal transducers and several of the induced inflammatory mediators substantively involved in the acute gouty attack are listed at the bottom and are indexed numerically by their place in the sequence of events that culminates in full-blown gouty inflammation. As discussed in the text, CXC chemokine subfamily ligands that bind the receptor CXCR2, including interleukin-8 (IL-8; CXCL8) and growth-related oncogene (GRO) chemokines (e.g., GROα/CXCL1), play a central role in the initiation of the rapid, intense neutrophil ingress, and IL-8 alone is a major promoter of more sustained neutrophil accumulation. The roles of other mediators, including the calgranulin family proteins S100A8 and S100A9 that promote amplification of neutrophil ingress, are discussed in the text. AP-1 = activator protein 1; TNFα = tumor necrosis factor α.

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Fortunately, the development of therapeutics targeted to specific proinflammatory signal-transduction cascades and cytokines potentially applicable to gout therapy is rapidly advancing. Current availability of specific tumor necrosis factor α and IL-1 inhibitors and the ongoing drug development of complement and p38 MAPK offer compelling opportunities for clinical trials in refractory gouty inflammation. Selective chemokine inhibitors are of particular interest for gouty arthritis. Specifically, CXC chemokine subfamily ligands that bind the receptor CXCR2 play an essential role in the initiation of the rapid, intense neutrophil ingress that occurs within 4 hours at sites of experimental gouty inflammation, as illustrated in CXCR2-knockout mice (136). Neutralization of only one of these chemokines, IL-8, significantly diminishes the second phase of neutrophil accumulation between 9 and 24 hours after urate crystal injection into rabbit knee joints (137, 144). Recently, the calgranulin family proteins S100A8 and S100A9, which heterodimerize and are particularly abundant in the cytoplasm of resting neutrophils (145), were observed to be major amplifiers of experimental gouty inflammation (146). Release of S100A9 from activated neutrophils in the joint space could mediate IL-8–induced neutrophil adhesion and migration responses in acute gout (147), and S100A8 and S100A9 alone trigger acute neutrophilic inflammation in vivo (148).

Translational research opportunities have been revealed via elucidation of leukocyte melatonin receptor 3 activation as a factor in the peripheral antiinflammatory effects of ACTH (149), as well as collective observations revealing E-selectin to be a primary target of the colchicine antiinflammatory effects in gout (150, 151). New evidence also has underscored the importance of complement activation, including membrane attack complex assembly, in the gout inflammatory cascade, as reported elsewhere in this issue of Arthritis & Rheumatism (152).

Novel means of therapeutically harnessing the natural self-limitation of acute gout have been suggested by the delineation of the capacity of mature macrophage uptake of apoptotic neutrophils (153, 154) (or of urate crystals [155]) to limit acute inflammatory reactions. Furthermore, the capacity of peroxisome proliferator–activated receptor γ (PPARγ) ligands to limit macrophage-mediated inflammation (156) has now been linked partly to promotion of neutrophil and macrophage apoptosis (157) and has been implicated in self-limitation of gout (158). Hence, PPARγ-based strategies to concurrently treat type 2 diabetes and to suppress inflammation (159), including gouty arthritis, appear to merit investigation.

Conclusion

  1. Top of page
  2. Introduction
  3. Recent demographic and clinical trends in gout
  4. New directions for antihyperuricemic therapies
  5. Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?
  6. New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack
  7. Conclusion
  8. REFERENCES

The prevalence of gout appears to be increasing. This is partly a reflection of changes in diet, increases in longevity, hypertension, metabolic syndrome, and advanced renal disease, and the broad use of diuretics in clinical practice. Management of gout in the elderly, in organ transplant recipients, and in patients with renal insufficiency and allopurinol intolerance can be particularly challenging. As reinforced by a recent study (160), diagnosis and management could certainly be enriched in part by optimizing medical and patient education efforts related to the disease.

Treatment-refractory gout exposes deficiencies in the current venerable armamentarium of therapeutics for both hyperuricemia and gouty inflammation. Clinical development of novel xanthine oxidase inhibitors and of uricase could augment options for subsets of treatment-refractory gout. Recent advances in understanding the pathogenesis of renal uric acid disposition also should open new avenues for the development of drugs and pharmacogenomic approaches to optimizing the management of hyperuricemia, partly based on anticipated identification of disease associations with sequence polymorphisms in URAT1 and other renal proximal tubule urate transporter mediators.

The outcome of the ongoing debate concerning the direct pathologic significance of hyperuricemia for the human kidney and vasculature will have a substantial impact on future preventative and therapeutic approaches in patients with gout and medical conditions such as hypertension and metabolic syndrome associated with gout. Last, certain highly selective cytokine inhibitors, and signal transduction and gene transcription factor inhibitors under continuing development for other inflammatory joint diseases may provide novel management approaches for treatment-refractory arthritis and progressive joint destruction in gout.

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  4. New directions for antihyperuricemic therapies
  5. Is treatment of asymptomatic hyperuricemia advantageous for vascular and renal disease?
  6. New therapeutic directions for gouty inflammation: lessons learned from pathogenesis of the acute gouty attack
  7. Conclusion
  8. REFERENCES
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