Urate balance

INTRODUCTION — Urate balance in the body depends both on its production, which is driven by purine metabolism, and its disposal, which primarily occurs through the gastrointestinal tract and kidneys. Most uric acid circulates as urate, and serum urate concentrations normally approach the theoretical limit of serum urate solubility. When factors affecting urate production and excretion cause hyperuricemia, patients are at risk of developing complications such as gout and uric acid nephrolithiasis.

The processes that influence and maintain urate balance are described here. Asymptomatic hyperuricemia, the pathogenesis of gout, and the mechanisms that underlie uric acid kidney 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".)

NORMAL URATE BALANCE — Most uric acid in the body is in the form of urate, which is an anion that is more soluble. Urate is produced through purine metabolism and is excreted primarily by the kidneys and gastrointestinal tract.

Physiologic levels of urate — Uric acid, a weak organic acid, is the end product of the metabolism of purine compounds in humans and some other primate species. In the blood, most uric acid circulates as the substantially more soluble urate anion. This is because the reaction:

is shifted far to the right at the normal arterial pH of 7.40, with a (functional) pKa of approximately 5.75 in blood (5.35 in urine).

Healthy people 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. This is in contrast to most other mammalian species that have extremely low serum urate levels (approximately 1 mg/dL; 60 micromol/L) due to the presence of mammalian uricase (urate oxidase); mammalian uricase converts urate to allantoin, which is a highly soluble excretory product. Uricase is sometimes used to treat people with advanced gout. (See 'Medications affecting urate balance' below and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Uricase'.)

The total body urate pool is approximately 1200 mg in males and 600 mg in females. The sex difference may be due to estrogenic compounds reducing the number of active reabsorptive urate transporters in the kidney, therefore decreasing urate reabsorption and increasing urate clearance [1-3]. 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.

Urate production — Urate is produced by the degradation of dietary and endogenously synthesized purine compounds, which primarily occurs in the liver. Dietary intake of purines accounts for a large amount of urate precursors; a purine-free formula diet reduces urinary excretion of uric acid by approximately 40 percent [4]. Urate itself is not typically ingested.

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

Urate excretion — Urate excretion by the gut and the kidney is required to maintain urate homeostasis. Metabolism of urate in other human tissues is negligible under normal physiologic circumstances, consisting of minor nonspecific oxidation by peroxidases and catalases.

Gastrointestinal tract — The gastrointestinal tract is responsible for approximately one-third of daily urate excretion, which occurs through active excretion of urate into the gut lumen and subsequent bacterial degradation:

●Active excretion into the gut lumen – Urate efflux into the gut lumen is an active process mediated by urate transporters; it is not a concentration-dependent passive process, as was historically thought. The best-studied urate transporter is ABCG2 (also called the breast cancer resistance protein or BCRP) [5-7]. 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 kidney proximal tubular epithelial cells [8].

●Bacterial degradation – Intestinal tract bacteria degrade urate once they are excreted into the gut lumen; this process is known as intestinal uricolysis. Under normal conditions, urate in the gut is almost completely degraded by colonic bacteria, with little being found in the stool [9].

Kidneys — 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. Nearly all urate is readily available for filtration at the glomerulus. However, in healthy adults, there is only clearance of 7 to 12 percent of the filtered urate load. This is due to reabsorption of approximately 90 percent of filtered urate in the proximal tubule, where urate is both reabsorbed and secreted through completely separate sets of transport mechanisms [7]. The relative balance of reabsorption and secretion by the proximal tubule determines the overall renal urate excretion and subsequent circulating serum urate; therefore, genetic variation in reabsorptive and secretory urate transporters and associated regulatory genes plays a major role in determining serum urate. (See 'Decreased urate excretion' below.)

Urate reabsorption — Urate reabsorption by the proximal tubule requires the cooperation of several apical and basolateral transporters.

●Uptake from the lumen – Filtered urate is reabsorbed at the apical membrane of proximal tubular cells by the urate-anion exchangers URAT1 [10] and OAT10 (figure 2A-B) [11,12]. URAT1 and OAT10 activity can be influenced by the concentration of certain intracellular, monovalent anions. These transporters have the highest affinity for urate exchange with aromatic organic anions, such as nicotinate (niacin) and pyrazinoate, followed by lactate, beta-hydroxybutyrate, and acetoacetate, and are a target of certain uricosuric therapies. (See 'Medications affecting urate balance' below.)

The concentration of anionic compounds that participate in urate exchange with URAT1 and OAT10 can increase or decrease urate-anion exchange, and therefore serum urate, through several mechanisms:

•Trans-activation – In "trans-activation" or "trans-stimulation," urate-anion exchange is increased when the intracellular concentration of certain monovalent anions is higher [11]. Ultimately, this leads to reduced urinary urate excretion and increased serum urate. Similar trans-activation of urate-anion exchange can be seen in brush border membrane vesicles generated from kidney cortex [13,14].

•Cis-inhibition – By contrast, "cis-inhibition" can occur when even higher concentrations of these anions progressively compete with urate for absorption, leading to increased urinary urate excretion and decreased serum urate.

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 [7]. Thus, apical urate absorption by the proximal tubule has a secondary sodium dependency.

●Resorption into the interstitium – 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 determining serum urate levels [2,15]. While the SLC2 gene family of GLUT transporters primarily functions in hexose (eg, glucose and fructose) transport, GLUT9 is a uniquely potent urate transporter with minimal if any activity as a hexose transporter [16]. Urate transport mediated by GLUT9 is electrogenic, with a marked activation of transport in membrane-depolarized cells [11,17]; the interior-negative membrane potential of proximal tubule cells favors basolateral exit of urate (ie, urate resorption) from the cell via GLUT9. GLUT9 is also sensitive to some uricosuric drugs (eg, probenecid), which decrease its activity and therefore decrease urate resorption. (See 'Medications affecting urate balance' below.)

Urate secretion — Urate secretion by the proximal tubule is mediated by multiple transporters that are distinct from the reabsorptive transporters (figure 2A-B).

●Uptake from the interstitium – Urate enters proximal tubular cells from the interstitium across the basolateral membrane via the OAT1, OAT2, and OAT3 anion exchangers. OAT1 and OAT3 exchange urate with divalent anions, primarily alpha-ketoglutarate [18,19]. Basolateral Na⁺-dependent uptake of alpha-ketoglutarate is mediated by the NADC-3 transporter [18,19]. The uptake of alpha-ketoglutarate results in trans-stimulation of basolateral urate-anion exchange, analogous to trans-stimulation of URAT1 and OAT10 by certain monovalent anions. OAT2, in contrast to OAT1 and OAT3, appears to interact with monovalent anions such as pyrazinoate (PZA) [20]. (See 'Medications affecting urate balance' below.)

●Secretion into the lumen – 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, two electrogenic apical urate antiporters (NPT1 and NPT4) also contribute to urate secretion [21,22]. 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. (See 'Urate reabsorption' above.)

Regulation of serum urate levels — Serum urate levels can be modulated by diverse physiologic conditions and neurohumoral factors. Sodium balance and volume status have particularly potent effects on circulating serum urate. Potential contributing factors include the following:

●Sodium intake – Experimentally, salt restriction causes significant hyperuricemia, which is reversed by salt loading [7]. As an 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, respectively [23].

●Volume status – Clinically, volume depletion is associated with hyperuricemia and partially explains the association between diuretic use and gout [24]. By contrast, increased extracellular fluid volume can increase the fractional excretion of urate and therefore lower serum urate, as is seen with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) [25]. (See "Diagnostic evaluation of adults with hyponatremia".)

●Neurohormonal mediators

•Insulin – Hyperuricemia and gout are associated with metabolic syndrome [26], suggesting that serum urate may be influenced by hyperinsulinemia and/or insulin signaling [27]. Insulin appears to reduce renal fractional excretion of urate [28,29] and activate multiple reabsorptive and secretory urate transporters [30]. It has been proposed that the anti-uricosuric effect of insulin is primarily due to the enhanced expression and activation of GLUT9 [30], since the high-capacity urate transporter GLUT9a is the only pathway to reabsorb urate from the renal proximal tubule, and insulin stimulates both GLUT9 expression and urate transport activity more than other urate transporters. In addition, the SLC2A9 gene that encodes GLUT9 shows genetic interaction with urate-associated insulin-signaling loci.

•Insulin-like growth factor – Insulin-like growth factor 1 (IGF-1) antagonizes the effects of insulin on urate transport and also inhibits multiple secretory transporters, thereby reducing serum urate [31].

•Parathyroid hormone – Excess parathyroid hormone (PTH) activity also reduces urate excretion, both in primary hyperparathyroidism [32] and during pharmacologic therapy with teriparatide for osteoporosis [33].

•Others – Potential neurohumoral mediators include angiotensin-II and epinephrine, both of which can experimentally reduce the fractional excretion of urate in humans [34].

●Cytokines – Serum urate is typically depressed during gout flares compared with baseline levels, which has been postulated to occur due to cytokine-stimulated uricosuria [35,36]. The mediators and target urate transporters remain uncharacterized.

CAUSES OF HYPERURICEMIA — In most cases, hyperuricemia is driven by the decreased efficiency of renal urate excretion. Less commonly, overproduction of urate can contribute to hyperuricemia (eg, conditions that increase the rate of cell turnover, rare monogenic disorders).

The pathophysiology of gout related to hyperuricemia is discussed separately. (See "Pathophysiology of gout".)

Decreased urate excretion — Hyperuricemia is frequently related to reduced efficiency of urinary uric acid excretion [6,37,38]; less commonly, there may be reduced gastrointestinal urate excretion. Decreased excretion may be related to a variety of clinical disorders, medications, and, less commonly, rare monogenic disorders (table 1):

●Clinical disorders – Excretion of uric acid is decreased in a variety of clinical disorders including chronic kidney disease, preeclampsia, volume depletion (eg, dehydration or diuretic use), conditions related to high circulating insulin (eg, diabetes, metabolic syndrome), laxative abuse (via alkalosis), and conditions that increase anti-uricosuric anions (eg, diabetic or starvation ketoacidosis, lactic acidosis). As an 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 [39,40]. Increases in lactic acid 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 [41,42]. The effects of keto acids and lactate are not caused by their respective acidoses, given that the experimental infusion of these anions causes hyperuricemia [39,43,44]. (See 'Urate reabsorption' above.)

●Medications – Multiple medications can decrease urate excretion, including loop and thiazide diuretics, calcineurin inhibitors (eg, cyclosporine, tacrolimus), salicylates (eg, aspirin), certain antimicrobials (eg, ethambutol, pyrazinamide), nicotinic acid (niacin), and levodopa. Due to particularly potent interactions with the urate transporters URAT1 and OAT10, the use of niacin to treat hypercholesterolemia is frequently complicated by hyperuricemia [45], as is the use of pyrazinamide to treat tuberculosis [46]. When uricosuric drugs are administered after pyrazinamide, there is a marked attenuation of their uricosuric effect [47]. Potential adjustment of medications that can contribute to hyperuricemia in patients with gout is discussed separately. (See 'Medications affecting urate balance' below and "Nonpharmacologic strategies for the prevention and treatment of gout", section on 'Addressing medications that affect urate balance'.)

●Diet – Salt restriction and alcohol use can also decrease urate excretion.

●Genetic factors – Rarely, decreased uric acid excretion may be related to monogenic disorders that affect the kidney, including autosomal dominant tubulointerstitial kidney disease (see "Asymptomatic hyperuricemia" and "Autosomal dominant tubulointerstitial kidney disease"). In addition, there are a number of genetic variants have been identified in transporters that regulate urate excretion in the kidneys and/or gastrointestinal tract, as well as in genes that affect transcriptional and post-transcriptional regulation of urate transport [48,49]. As an example, loss-of-function mutations in renal secretory urate transporters, such as NPT1 [50], NPT4, and ABCC4 [51], can cause hyperuricemia. Variants in urate transporters ABCG2 (encoded on ABCG2) and GLUT9 (encoded on SCL2A9) have been found to exert a particularly significant effect on serum urate levels [2,15]. These variants are not tested in clinical practice.

The total daily urinary excretion of uric acid may paradoxically be normal even when there is a defect in urinary acid excretion [38]. As an example, some patients with gout have a polymorphism in the urate transporter ABCG2, which is expressed in the gut and proximal tubule of the kidney. This reduces urate excretion in the gut and kidneys; however, the total daily urinary urate excretion is normal due to decreased gastrointestinal excretion causing hyperuricemia, with subsequently increased delivery of urate to the kidney [5]. Total daily urinary urate excretion is also increased when there is purine and/or urate overproduction; therefore, this measure is insufficient in isolation to identify the cause of hyperuricemia.

Purine and/or urate overproduction — A range of medical conditions, medications, and other factors can increase purine biosynthesis or urate production (table 2):

●Inherited enzyme defects (rare monogenic disorders) – Disorders that cause overproduction include inherited defects in regulation of purine nucleotide synthesis, disordered adenosine triphosphate (ATP) metabolism, and disorders that increase the rate of cell turnover [52-54]. Examples include the following:

•Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency – Normally, purines can be salvaged through a pathway involving the enzyme HPRT. Genetic deficiency of HPRT in Lesch-Nyhan syndrome and related disorders leads to an accumulation of purines, which are then metabolized into uric acid, causing subsequent hyperuricemia [52]. (See "Hyperkinetic movement disorders in children", section on 'Lesch-Nyhan syndrome'.)

•5'-phosphoribosyl 1-pyrophosphate (PRPP) synthetase overactivity – PRPP synthetase is a key catalyst for the de novo production of purines from ATP and ribose 5'-phosphate. Genetic overactivity of PRPP synthetase therefore leads to increased purine synthesis, ultimately leading to hyperuricemia and gout [53].

•Glucose-6-phosphatase deficiency (glycogen storage disease, type I) – ATP is ultimately metabolized into urate; thus, conditions associated with net degradation of ATP can also be associated with hyperuricemia and gout. As an example, glycogen storage disease, particularly type I, is associated with "myogenic hyperuricemia" [54]. (See "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)".)

●Clinical disorders – Multiple medical conditions are associated with an increase in purine and/or urate overproduction, including myelo- and lymphoproliferative disorders, hemolytic disorders, psoriasis, tissue hypoxia, Down syndrome, and certain types of glycogen storage diseases (types III, V, and VII). In many of these cases, hyperuricemia is caused by rapid cell turnover and subsequent metabolism of endogenous purines. Similarly, cytotoxic medications cause increased cell turnover and hyperuricemia.

●Diet – Certain foods increase the production of urate, including alcohol [42], fructose, and dietary purines (eg, red meat and seafood). Notably, however, the effects of genetic variation in urate-determining genes on circulating serum urate may exceed the effects of diet [55]. (See "Nonpharmacologic strategies for the prevention and treatment of gout", section on 'Modifying diet'.)

CAUSES OF 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) [10,56] or from a loss-of-function genetic defect in the high-capacity renal urate transporter GLUT9 (encoded by SLC2A9) [57]. More detail on the causes and clinical significance of hypouricemia is discussed separately. (See "Hypouricemia: Causes and clinical significance".)

MEDICATIONS AFFECTING URATE BALANCE — Multiple types of medications affect urate balance, including the following:

●Urate-lowering therapy for patients with gout – There are multiple types of treatment for gout that lower serum urate:

•Xanthine oxidase inhibitors (eg, allopurinol, febuxostat) decrease urate production. (See 'Urate production' above.)

•Uricosuric medications (eg, probenecid) increase urinary urate excretion, often through inhibition of urate transporters URAT1 and/or OAT10 [58,59]. (See 'Urate reabsorption' above.)

•Uricase (eg, pegloticase, rasburicase) metabolizes urate. (See 'Urate production' above.)

More detail on the mechanisms of urate lowering therapy is provided elsewhere. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout", section on 'Urate-lowering medications'.)

●Other medications that decrease serum urate – Losartan and fenofibrate both inhibit URAT1 and therefore decrease urate resorption in the kidney, leading to decreased serum urate [60,61] (see 'Urate reabsorption' above). Sodium-glucose cotransporter-2 (SGLT2) inhibitors likewise have uricosuric effects [62], although the responsible mechanisms are not yet clear.

●Medications that increase serum urate – Agents that are associated with decreased urinary urate secretion and subsequent hyperuricemia include loop and thiazide diuretics, calcineurin inhibitors (eg, cyclosporine, tacrolimus), and salicylates (eg, aspirin). (See 'Decreased urate excretion' above.)

A discussion of adjustment of medications that affect urate balance in patients with hyperuricemia and/or gout is provided elsewhere. (See "Nonpharmacologic strategies for the prevention and treatment of gout", section on 'Addressing medications that affect urate balance'.)

SUMMARY

●Normal urate balance – Uric acid is the end product of the metabolism of purine compounds. Most uric acid circulates in the blood 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. The total body urate pool is approximately 1200 mg in males and 600 mg in females. (See 'Physiologic levels of urate' above.)

•Urate production – Urate is produced by the degradation of dietary and endogenously synthesized purine compounds, which primarily occurs in the liver. Dietary intake of purines accounts for a large amount of urate precursors. During urate production (ie, purine degradation), purine mononucleotides are metabolized into purine bases and then into xanthine, which is irreversibly oxidized by xanthine oxidase to produce urate (figure 1). (See 'Urate production' above.)

•Urate excretion – Urate excretion by the gut and the kidney is required to maintain urate homeostasis. (See 'Urate excretion' above.)

-Gastrointestinal tract – Approximately one-third of daily urate disposal occurs through the gastrointestinal tract via intestinal uricolysis. Urate efflux into the gut lumen is an active process mediated by urate transporters, including the high-capacity urate efflux transporter ABCG2. Once urate is excreted into the gut lumen, it is degraded by intestinal tract bacteria. (See 'Gastrointestinal tract' above.)

-Kidneys – Urinary uric acid excretion accounts for the remaining two-thirds of the daily uric acid disposal. Nearly all of the serum urate is filtered at the glomerulus; however, there is net reabsorption of approximately 90 percent of filtered urate due to a combination of urate reabsorption and secretion in the proximal tubule. (See 'Kidneys' above.)

•Regulation of serum urate levels – Serum urate levels can be modulated by diverse physiologic conditions and neurohumoral factors, including insulin and parathyroid hormone. Sodium balance and volume status have particularly potent effects on circulating serum urate. (See 'Regulation of serum urate levels' above.)

●Causes of hyperuricemia

•Decreased urate excretion – In most cases, hyperuricemia is driven by the decreased efficiency of renal urate excretion (table 1). Related medical conditions include chronic kidney disease, preeclampsia, volume depletion, conditions related to high circulating insulin, laxative abuse, diabetic or starvation ketoacidosis, and lactic acidosis. Genetic variation in reabsorptive and secretory urate transporters and associated regulatory genes plays a major role in determining serum urate; however, these variants are not tested in clinical practice. (See 'Decreased urate excretion' above.)

•Purine and/or urate overproduction – Less commonly, overproduction of urate can contribute to hyperuricemia (table 2), as can be seen in rare monogenic disorders and conditions that increase the rate of cell turnover with subsequent metabolism of endogenous purines (eg, myelo- and lymphoproliferative disorders, psoriasis, tissue hypoxia). In addition, certain foods increase the production of urate, such as alcohol, fructose, and dietary purines (eg, red meat and seafood). (See 'Purine and/or urate overproduction' above.)

●Causes of hypouricemia – Hypouricemia can be induced by decreased production (primarily due to rare enzyme defects) or increased urinary excretion. (See 'Causes of hypouricemia' above and "Hypouricemia: Causes and clinical significance".)

●Medications affecting urate balance – There are multiple types of treatment for gout that lower serum urate; xanthine oxidase inhibitors (eg, allopurinol) decrease urate production, uricosuric medications (eg, probenecid) increase urinary urate excretion, and uricase (eg, pegloticase) increases urate metabolism. Other classes of medications can also affect urate balance, including ones that decrease urinary urate excretion and increase serum urate (eg, loop and thiazide diuretics, calcineurin inhibitors, salicylates) or decrease renal urate resorption and decrease serum urate (eg, losartan and fenofibrate). (See 'Medications affecting urate balance' above.)

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