Urate balance

INTRODUCTION — Uric acid is the end product of purine metabolism. Most uric acid circulates as the urate anion, and serum urate concentrations normally approach the theoretical limit of serum urate solubility. Human tissues have a very limited ability to metabolize urate; thus, uric acid must be eliminated by the kidney and the gut to maintain urate homeostasis. Factors affecting urate production and excretion that cause hyperuricemia result in an increased risk for asymptomatic hyperuricemia and gout, and for uric acid nephrolithiasis.

The processes that influence and maintain urate balance are described here. Asymptomatic hyperuricemia, the pathogenesis of gout, and the mechanisms that underlay uric acid renal diseases, including uric acid nephrolithiasis, are described in detail separately. (See "Asymptomatic hyperuricemia" and "Pathophysiology of gout" and "Uric acid kidney diseases" and "Kidney stones in adults: Uric acid nephrolithiasis".)

URIC ACID AND URATE — Uric acid, a weak organic acid, is the end product of the metabolism of purine compounds in humans and some other primate species. With a (functional) pKa of approximately 5.75 in blood (5.35 in urine), the reaction

is shifted far to the right at the normal arterial pH of 7.40. As a result, most uric acid, which is poorly soluble in its undissociated form, circulates as the substantially more soluble urate anion.

Urate is the end product of purine metabolism in humans because the human homolog of the mammalian uricase (urate oxidase) gene is structurally modified to an unexpressed (pseudogene) state. By contrast, the vast majority of other mammalian species have extremely low serum urate levels (approximately 1 mg/dL; 60 micromol/L) because urate in these species is converted by uricase to allantoin, a highly soluble excretory product. Normal humans have serum urate concentrations that approach the theoretical limit of urate solubility (6.8 mg/dL; 405 micromol/L) and regularly excrete urine that is supersaturated with respect to uric acid.

The typical adult male has a total body urate pool of approximately 1200 mg, approximately twice that of the normal adult female. This sex difference may be explained by an enhancement of renal urate excretion in women of childbearing age due to the effects of estrogenic compounds [1], which likely reduce the number of active renal reabsorptive urate transporters, resulting in less renal tubular uric acid reabsorption and consequently greater urate clearance [2,3]. Normally, all urate measured in the body pool is believed to be soluble urate. When insoluble urate crystal deposition occurs (in gout), body pool measurements underestimate the body urate pool. Under normal steady state conditions, daily turnover of approximately 60 percent of the urate pool is achieved by balanced production and elimination of urate.

The prevalence of hyperuricemia rose in the United States from the 1960s to the early 2000s but was stable from 2007 to 2016, as indicated by data from the National Health and Nutrition Examination Survey from 2007 to 2016, which found that hyperuricemia (defined in men in the study as a single urate determination exceeding 7 mg/dL) was present in up to 20.2 percent of adult males surveyed [4]. By contrast, the mean serum urate concentration had formerly been reported as between 5 and 6 mg/dL among healthy adult White men in the United States, and the prevalence of hyperuricemia as at least 5 to 8 percent. (See "Asymptomatic hyperuricemia".)

URATE PRODUCTION — Urate is not typically ingested; the major site of urate production is the liver, where it is produced by the degradation of dietary and endogenously synthesized purine compounds. Dietary intake appears to provide a significant source of urate precursors, as a purine-free formula diet reduces urinary excretion of uric acid by approximately 40 percent [5].

Urate production (ie, purine degradation) involves the breakdown of the purine mononucleotides, guanylic acid (guanosine monophosphate, GMP), inosinic acid (inosine monophosphate, IMP), and adenylic acid (adenosine monophosphate, AMP), ultimately into the purine bases guanine and hypoxanthine. These last two compounds are then metabolized to xanthine. In the final step, which is catalyzed by the enzyme xanthine oxidase, xanthine is irreversibly oxidized to produce urate (figure 1).

Defects in purine metabolism can cause hyperuricemia due to overproduction of urate, although these are very uncommon in the population compared with a range of medical conditions, medications, and other factors that can also cause increased purine biosynthesis or urate production (table 1). These rare monogenic disorders include:

●Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency – Purines can be salvaged through a pathway involving the enzyme HPRT; thus, genetic deficiency of HPRT in Lesch-Nyhan syndrome and related disorders is associated with hyperuricemia and gout, among other findings [6]. (See "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome'.)

●5'-phosphoribosyl 1-pyrophosphate (PRPP) synthetase overactivity – The de novo synthesis of purines involves the production of PRPP from adenosine triphosphate (ATP) and ribose 5'-phosphate. This step is catalyzed by PRPP synthetase; as a result, genetic overactivity of this enzyme is also associated with hyperuricemia and gout [7].

●Glucose-6-phosphatase deficiency (glycogen storage disease, type I) – ATP degradation leads to adenosine diphosphate (ADP) and AMP production, with subsequent metabolism to urate; thus, conditions associated with net degradation of ATP, such as glycogen storage disease, particularly type I, can also be associated with hyperuricemia and gout ("myogenic hyperuricemia") [8]. (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)

URIC ACID DISPOSAL — The excretion of intact urate by the gut and the kidney is required to maintain urate homeostasis because metabolism of urate is negligible in human tissues under normal physiologic circumstances, in which it is limited to minor nonspecific oxidation by peroxidases and catalases. Approximately one-third of daily urate disposal is by the gut, and two-thirds of the daily disposal of uric acid is by the kidneys.

Gastrointestinal tract — Urate efflux into the gut lumen is an active process mediated by urate transporters, rather than being a concentration-dependent passive process, as was historically thought. The best studied of these transporters is ABCG2 (also called the breast cancer resistance protein or BCRP) [9-11].

ABCG2 is a high-capacity urate transporter encoded by the ABCG2 gene on chromosome 4; it is expressed in intestinal epithelium and on the luminal surface of renal proximal tubule epithelial cells [12]. Intestinal tract bacteria are able to degrade urate, and this breakdown process (intestinal uricolysis) is responsible for approximately one-third of total urate disposal, which comprises nearly all the urate disposed of by extra-renal routes. Under normal conditions, urate in the gut is almost completely degraded by colonic bacteria, with little being found in the stool [13].

Urinary excretion — Urinary uric acid excretion normally accounts for the remaining two-thirds of the daily uric acid disposal that is not carried out in the gut. All or nearly all urate is readily available for filtration at the glomerulus. However, renal clearance of uric acid in normal adults is only 7 to 12 percent of the filtered load, indicating that, under usual circumstances, there is net tubular reabsorption of approximately 90 percent of filtered urate. Urate handling involves glomerular filtration and urinary excretion, with separate tubular reabsorptive and secretory processes mediated by completely separate sets of transport mechanisms [11]. (See 'Renal reabsorptive urate transport' below and 'Renal secretory urate transport' below.)

RENAL REABSORPTIVE URATE TRANSPORT — Urate reabsorption by the proximal tubule requires the cooperation of several apical and basolateral transporters. Filtered urate is absorbed at the apical membrane by the urate-anion exchangers URAT1 [14] and OAT10 (figure 2A-B) [15,16]. Both of these transporters are inhibited by uricosuric agents, including benzbromarone and probenecid. URAT1 is also inhibited by verinurad [17,18].

These transporters have the highest affinity for urate exchange with aromatic organic anions, such as nicotinate and pyrazinoate (PZA), followed by lactate, beta-hydroxybutyrate, and acetoacetate. The intracellular concentration of these monovalent anions is thus a key determinant of the activity of URAT1 and OAT10, with marked activation of urate transport when their intracellular concentration is increased [15]; this activation of urate-anion exchange by intracellular anionic substrates is referred to as "trans-activation." Similar trans-activation of urate-anion exchange can be seen in brush border membrane vesicles generated from renal cortex [19,20]. By contrast, higher concentrations of these anions can progressively compete with urate for absorption, leading eventually to "cis-inhibition." The intracellular concentrations of these anions in proximal tubular cells are largely determined by apical uptake via the Na⁺-dependent monocarboxylate transporters SMCT1 and SMCT2 [11], such that apical urate absorption by the proximal tubule has a secondary sodium dependency.

The various anions that participate in the SMCT1/SMCT2-URAT1/OAT10 interaction have potent anti-uricosuric effects in vivo. Increases in the plasma concentrations of these anti-uricosuric anions result in increased glomerular filtration, increased delivery to the proximal tubule, increased Na⁺-dependent uptake by SMCT1 or SMCT2, and increased intracellular concentration in tubular epithelial cells. The increases in intracellular activity of these anions in turn induce urate reabsorption and hyperuricemia, via "trans-stimulation" of URAT1 and OAT10 from inside the cell.

This "anti-uricosuric" physiology has several clinical correlates. For example, the increase in circulating beta-hydroxybutyrate and acetoacetate in diabetic ketoacidosis can cause initial hyperuricemia, which is lessened by treatment of the diabetic ketoacidosis with insulin [21,22]. Hyperuricemia is also a complication of a high-fat diet [23] and of starvation ketosis [24]. Increases in lactic acid, as seen in alcohol intoxication [25], can also result in hyperuricemia due to increased urate reabsorption; transient increases in lactate and/or keto acids may contribute to the association between gout and alcohol intake [26]. The effects of keto acids and lactate are not caused by their respective acidoses, given that the experimental infusion of these anions causes hyperuricemia [21,27,28].

The particularly potent interactions between nicotinate and PZA with URAT1 and OAT10 also have in vivo clinical counterparts. The treatment of hypercholesterolemia with nicotinic acid (niacin) is thus frequently complicated by hyperuricemia [29], as is the treatment of tuberculosis with pyrazinamide [30].

When uricosuric drugs are administered after pyrazinamide, there is a marked attenuation of their uricosuric effect [31]. The "trans-activation" model of the anti-uricosuric effect of PZA, via stimulation of urate reabsorption rather than inhibition of secretion, is viewed as the likely explanation for these observations, which is inconsistent with the older four-component model [31]. Physiologic studies in reabsorptive species typically indicate a co-existence of reabsorption and secretion along the entire length of the proximal tubule.

Certain drugs can cause a reduction in serum urate levels due to uricosuric effects. For example, losartan and fenofibrate inhibit URAT1, leading to uricosuria and reduced serum urate [32,33]. Additionally, the active metabolite of allopurinol, oxypurinol, is a substrate for URAT1, such that uricosurics such as benzbromarone and probenecid can increase the renal clearance of oxypurinol [34].

Following apical reabsorption of urate by URAT1 and OAT10, urate exits proximal tubular cells via the GLUT9 urate antiporter (figure 2A-B), encoded by the SLC2A9 gene. Variation in the SLC2A9 gene was initially identified in genome-wide association studies as a significant genetic factor in determination of serum urate levels [2,35], with no prior hints that the GLUT9 transporter played a role in urate homeostasis. The SLC2 gene family of GLUT transporters primarily functions in glucose and fructose transport, whereas GLUT9 is a uniquely potent urate transporter with minimal if any activity as a hexose transporter [36]. Urate transport mediated by GLUT9 is sensitive to uricosurics and is electrogenic, with a marked activation of transport in membrane-depolarized cells [15,37]; the interior-negative membrane potential of proximal tubule cells favors basolateral exit of urate from the cell via GLUT9.

RENAL SECRETORY URATE TRANSPORT — Urate secretion by the proximal tubule is mediated by multiple transporters that are distinct from the reabsorptive transporters (figure 2A-B). Urate enters the cell from the interstitium across the basolateral membrane, via the OAT1, OAT2, and OAT3 anion exchangers. Unlike OAT10 and URAT1 at the apical membrane, OAT1 and OAT3 exchange urate with divalent anions, primarily alpha-ketoglutarate [38,39]. Basolateral Na⁺-dependent uptake of alpha-ketoglutarate is mediated by the NADC-3 transporter [38,39]. This uptake, by increasing the intracellular concentration of alpha-ketoglutarate, results in trans-stimulation of basolateral urate-anion exchange, analogous to the interactions at the apical membrane between monovalent anti-uricosuric anions and urate uptake. OAT2, in contrast to OAT1 and OAT3, appears to interact with monovalent anions such as pyrazinoate (PZA) [40]; the relevant endogenous anion is not known.

At the apical membrane of proximal tubular cells, urate exits the cell by secretion through two adenosine triphosphate (ATP)-driven efflux pumps, ABCG2 and ABCC4. In addition, there are two electrogenic apical urate antiporters, NPT1 and NPT4, that also contribute to urate exit during secretion [41,42]. Like basolateral exit via GLUT9, the exit of urate at the apical membrane through NPT1 and NPT4 is thought to be driven in part by the cell-negative membrane potential.

REGULATION OF SERUM URATE LEVELS — Serum urate levels can be modulated by diverse physiologic conditions and neurohumoral factors. Volume status and salt balance, in particular, have potent effects on circulating serum urate.

Experimentally, salt restriction causes significant hyperuricemia, which is reversed by salt loading [11]. For example, in hypertensive subjects, there is a 1.8 to 2.0 mg/dL difference in serum urate between salt intakes of 29 to 38 milliequivalent/day and 258 milliequivalent/day [43].

Potential neurohumoral mediators include angiotensin-II and epinephrine, both of which can experimentally reduce the fractional excretion of urate in humans [44].

Clinically, volume depletion is associated with hyperuricemia, explaining in large part the association between diuretic use and gout [45]. The modest increase in extracellular fluid volume associated with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) is in turn associated with an increase in fractional excretion of urate, such that a low serum urate is an important key to the diagnosis of SIADH [46].

Hyperuricemia and gout are important concomitants of the metabolic syndrome [47], suggesting a role for hyperinsulinemia and insulin signaling in regulation of renal urate transport [48]. Insulin appears to reduce renal fractional excretion of urate [49,50]. A comprehensive survey of reabsorptive and secretory urate transporters has shown that multiple urate transporters are activated by insulin [51]. It has been proposed that the anti-uricosuric effect of insulin is primarily due to the enhanced expression and activation of GLUT9, given that the high-capacity urate transporter GLUT9a is the exclusive basolateral exit pathway for reabsorbed urate from the renal proximal tubule into the blood, that insulin stimulates both GLUT9 expression and urate transport activity more than other urate transporters, and that the SLC2A9 gene that encodes GLUT9 shows genetic interaction with urate-associated insulin-signaling loci [51]. Excess parathyroid hormone (PTH) activity also reduces urate excretion, in both primary hyperparathyroidism [52] and during pharmacologic therapy with teriparatide for osteoporosis [53].

Serum urate is typically depressed during gout flares compared with baseline levels, which has been postulated to occur due to cytokine-stimulated uricosuria [54,55]. The mediators and target urate transporters remain uncharacterized.

HYPERURICEMIA — Decreased efficiency of renal uric acid excretion is responsible for most primary or secondary hyperuricemia (table 2) [56,57]. This observation is not surprising given the complexity of renal uric acid handling and the sensitivity of the kidney to endogenous metabolites, alterations in volume status, and drugs. Volume depletion due to diuretics, for example, is a common cause of hyperuricemia. (See "Diuretic-induced hyperuricemia and gout".)

It is important to appreciate, however, that "underexcretors" actually have normal rates of urinary uric acid excretion since this is required to maintain the steady state in which urate production and disposal are relatively equal (see "General principles of disorders of water balance (hyponatremia and hypernatremia) and sodium balance (hypovolemia and edema)", section on 'The steady state'). It is the reduced efficiency of urate excretion that obligates a higher serum urate concentration in order to achieve the necessary rate of urinary uric acid excretion.

The remaining minority of patients with hyperuricemia ostensibly overproduce urate. Disorders that cause overproduction include inherited defects in regulation of purine nucleotide synthesis, disordered adenosine triphosphate (ATP) metabolism, or disorders that result in increased rates of cell turnover [6-8]. However, even among those whose daily excretion of uric acid is higher than normal, decreased efficiency of renal uric acid excretion may also play a role [57].

Several studies provide a likely mechanistic basis for the observed role of decreased efficiency of uric acid excretion [9,10]. In some gout patients with a hyperuricemia/gout risk allele (polymorphism) for the high-capacity urate transporter ABCG2, daily excretion of uric acid in the urine was paradoxically well within the normal range and often in a range (>800 mg/day) implying urate overproduction [9]. Since the gene product, Abcg2, is expressed in the gut as well as the renal proximal tubule, this paradox apparently results from the genetically determined underexcretion of urate in the gut, with consequent compensatory (but still relatively reduced) uric acid clearance at the kidney. This view was supported by the finding that patients with two risk alleles showed higher serum urate and urinary uric acid levels, implying that reduction of intestinal urate excretion directly correlated with increases in urate blood and urine burdens. Subsequent studies have indicated that subjects with a "urate-raising" allele of ABCG2 lose a substantial component of extrarenal urate excretion [58]. Excessive daily urinary uric acid excretion thus does not unequivocally imply urate overproduction. Rather, overexcretion of urinary uric acid may result from either "extra-renal urate underexcretion" or from genuine urate overproduction. (See "Asymptomatic hyperuricemia".)

Genetic variation in almost all the urate transporter genes involved in urate reabsorption and secretion has been implicated in serum urate variation; other implicated genes affect transcriptional and post-transcriptional regulation of urate transport [59]. Variation in >200 genes has been implicated in serum urate variation [60,61]. Notably, the relative balance of reabsorption and secretion is a major determinant of renal excretion of uric acid and thus of serum urate. For example, loss-of-function mutations in renal secretory urate transporters, such as NPT1 [62], NPT4, and ABCC4 [63], can contribute to an increase in serum urate by reducing the relative activity of renal urate secretion. Like the variation in ABCG2 mentioned above, genetic variation in the SLC2A9 gene encoding GLUT9 has been found to exert a particularly significant effect on serum urate levels [2,35]. Translational studies have utilized inosine loading to characterize the role of GLUT9 in human urate physiology, demonstrating a higher fractional excretion of urate in subjects with the protective (urate-lowering) C allele of SLC2A9 rs11942223 [58]. This indicates that the urate-lowering allele in SLC2A9 reduces GLUT9 function in urate reabsorption within the kidney.

Diet and lifestyle, particularly alcohol intake [26], can affect serum urate and the risk of gout. For example, higher consumption of purine-rich foods, particularly meat and seafood, is associated with an increased risk of gout, whereas a higher level of consumption of dairy products is associated with a decreased risk [64]. Notably, however, the effects of genetic variation in urate-determining genes on circulating serum urate may exceed the effects of diet [65]. (See "Nonpharmacologic strategies for the prevention and treatment of gout".)

HYPOURICEMIA — Hypouricemia can be induced by decreased production (primarily due to rare enzyme defects) or increased urinary excretion. The latter can result from a genetic defect in the urate-organic anion exchanger URAT1 in the proximal tubule (encoded by the SLC22A12 gene) [14,66], a loss-of-function genetic defect in the high-capacity renal urate transporter GLUT9 (encoded by SLC2A9) [67]. Thus, similar types of processes to those associated with hyperuricemia are involved in the pathogenesis of hypouricemia. (See "Hypouricemia: Causes and clinical significance".)

Careful characterization of patients with severe hypouricemia due to homozygous loss-of-function alleles in SLC2A9 provides important insight. These patients exhibit fractional excretions of urate that exceed 150 percent; since GLUT9 is the exclusive exit pathway for urate in reabsorption by the proximal tubule, renal urate reabsorption is abrogated completely and secretion predominates in these patients. Again, serum urate is to a large extent determined by the relative balance of urate reabsorption and secretion by the renal proximal tubule.

SUMMARY

●Uric acid is the end product of the metabolism of purine compounds. With a (functional) pKa of approximately 5.75 in blood (5.35 in urine), the reaction, uric acid  <> urate  +  H+, is shifted far to the right at the normal arterial pH of 7.40. As a result, most uric acid circulates as the urate anion. Normal humans have serum urate concentrations approaching the theoretical limit of solubility of urate in serum (6.8 mg/dL) and regularly excrete urine that is supersaturated with respect to uric acid. Normal adult males have a total body urate pool that averages approximately 1200 mg, nearly twice that of adult females. (See 'Uric acid and urate' above.)

●Urate is produced in the liver from the degradation of dietary and endogenously synthesized purine compounds. Urate is not typically ingested, although dietary intake provides a significant source of urate precursors. Urate production involves the breakdown of the purine mononucleotides, guanylic acid (guanosine monophosphate, GMP), inosinic acid (inosine monophosphate, IMP), and adenylic acid (adenosine monophosphate, AMP), ultimately into the purine bases guanine and hypoxanthine. These last two compounds are then metabolized to xanthine, which is irreversibly oxidized by xanthine oxidase to produce urate (figure 1). (See 'Urate production' above.)

●Human tissues have a very limited ability to metabolize urate, which must be eliminated by the kidney and the gut to maintain homeostasis. Uric acid disposal by the kidney involves glomerular filtration of nearly all urate from the blood and tubular reabsorption and secretion mechanisms that normally result in net reabsorption of approximately 90 percent of the uric acid filtered at the glomerulus. The entry of urate into the intestine is mediated at least in part by the high-capacity urate efflux transporter, ABCG2, the product of the ABCG2 gene, which is also expressed in proximal renal tubular epithelium. Intestinal tract bacteria degrade urate. This process (intestinal uricolysis) is responsible for approximately one-third of total urate disposal. Urinary uric acid excretion accounts for the remaining two-thirds of the daily uric acid disposal. (See 'Uric acid disposal' above.)

●In the renal proximal tubule, separate sets of transporters mediate urate reabsorption and urate secretion (figure 2A-B). Apical urate reabsorption by the proximal tubule has a secondary sodium dependency, with sodium-dependent uptake of "anti-uricosuric" anions driving apical urate-anion exchange via URAT1 and OAT10, followed by basolateral excretion via the GLUT9 urate transporter; these interactions explain the clinically relevant anti-uricosuric effects of pyrazinoate (PZA), nicotinate, and related anions. (See 'Renal reabsorptive urate transport' above and 'Renal secretory urate transport' above.)

Urate homeostasis is regulated by multiple hormones, most prominently insulin, angiotensin, adrenaline, and parathyroid hormone. (See 'Regulation of serum urate levels' above.)

●The relative balance of urate reabsorption and secretion by the proximal tubule determines renal excretion and thus circulating serum urate. Genetic variation in reabsorptive and secretory urate transporters and associated regulatory genes plays a major role in determining serum urate. (See 'Regulation of serum urate levels' above.)

●Decreased efficiency of renal uric acid excretion is responsible for most primary or secondary hyperuricemia (table 2). This results from a reduced efficiency of urate excretion that obligates a higher serum urate concentration to achieve the necessary rate of urinary uric acid excretion. "Underexcretors" actually have normal rates of urinary uric acid excretion since this is required to maintain the steady state in which urate production and disposal are relatively equal. The remaining 10 to 15 percent of patients with hyperuricemia overexcrete uric acid in the daily urine; in some instances, this reflects inherited defects in regulation of purine nucleotide synthesis, disordered adenosine triphosphate (ATP) metabolism, or disorders resulting in increased rates of cell turnover. In other instances, overexcretion of urinary urate results from extra-renal urate underexcretion due to genetically determined defects in ABCG2 urate efflux into the gut. (See 'Hyperuricemia' above.)

●Hypouricemia can be induced by decreased production (primarily due to rare enzyme defects) or to increased urinary excretion of uric acid. (See 'Hypouricemia' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael A Becker, MD, who contributed to an earlier version of this topic review.