Version May 2024
INTRODUCTION — Hypouricemia is arbitrarily defined as a serum urate concentration of less than 2 mg/dL (119 micromol/L). It occurs in approximately 2 percent of hospitalized patients and less than 0.5 percent of the normal population [1]. Hypouricemia may be caused by decreased uric acid production, uric acid oxidation due to treatment with uricase, or decreased renal tubular reabsorption due to inherited or acquired disorders [2]. There are no known abnormalities of intestinal uricolysis that produce hypouricemia. (See "Urate balance".)
Hypouricemia has been thought of as a biochemical disorder with no clinical significance other than as a marker of underlying disease [3]. However, individuals with renal tubular urate wasting may have an increased incidence of acute kidney injury (AKI; previously called acute renal failure). (See "Definition and staging criteria of acute kidney injury in adults".)
DECREASED PRODUCTION — Decreased uric acid production can be caused by several rare inherited disorders of purine synthesis and catabolism and, more commonly, by acquired deficiency of xanthine oxidase due to allopurinol therapy or liver disease.
Inherited disorders — Inherited disorders resulting in decreased uric acid production include hereditary xanthinuria and purine nucleosidase phosphorylase deficiency:
●Hereditary xanthinuria – Xanthine oxidase catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Deficiency of xanthine oxidase, which is inherited as an autosomal recessive trait, results in hereditary xanthinuria [4,5]. Striking hypouricemia is seen with levels usually below 1 mg/dL (59.5 micromol/L). Increased urinary excretion of relatively insoluble xanthine leads to the development of xanthine stones in approximately one-third of patients. Xanthine stones are managed with fluids to increase the urine output (which reduces the urine xanthine concentration) and with alkali administration (which modestly increases xanthine solubility) [6]. In a smaller number of patients, deposition of xanthine crystals in skeletal muscle produces myopathic symptoms.
The diagnosis is suspected by the finding of hypouricemia, reduced urinary uric acid excretion, and increased xanthine excretion; it is confirmed by liver or intestinal biopsy with measurement of enzyme activity.
●Purine nucleoside phosphorylase deficiency – Purine nucleoside phosphorylase (PNP) catalyzes the reaction in which inosine, deoxyinosine, and deoxyguanosine undergo phosphorylation to purine bases. PNP deficiency results in hypouricemia, developmental retardation, defective cellular immunity with lymphopenia, deceased T cells, and recurrent infections. (See "Purine nucleoside phosphorylase deficiency".)
Acquired disorders — Acquired deficiency of xanthine oxidase is considerably more common than inherited disorders of decreased production. The major acquired causes of xanthine oxidase deficiency are drugs (eg, allopurinol) and severe liver disease:
●Xanthine oxidase inhibitors – Allopurinol and febuxostat reduce the formation of uric acid by inhibiting xanthine oxidase activity and lowering intracellular phosphoribosyl pyrophosphate levels. This is the most common cause of hypouricemia, although it is unusual for the uric acid level to fall below 2.5 mg/dL (149 micromol/L).
●Liver disease – With severe hepatocellular injury, there may be sufficient loss of hepatic xanthine oxidase activity to produce hypouricemia. A renal tubular defect in urate reabsorption may also contribute [7].
URIC ACID OXIDATION — Unlike most animal species, humans lack urate oxidase (uricase). Thus, in humans, uric acid is an end product of metabolism. Derivatives of uricase (rasburicase), which catalyzes the oxidation of uric acid to allantoin, are widely used in the prevention and treatment of acute kidney injury (AKI) in tumor lysis syndrome. A "PEGylated" rasburicase may be used in the management of refractory gout [8], causing profound hypouricemia.
INCREASED URINARY EXCRETION — Increased urinary excretion of uric acid can be seen with familial hypouricemia (an inherited disorder) and in a variety of acquired conditions.
Familial renal hypouricemia — Familial hypouricemia, which is caused by a defect in renal tubular urate transport, is a rare syndrome transmitted as an autosomal trait [9-20]. The defect appears to be more common in non-Ashkenazi Jews and Japanese individuals. In a report of 3258 Japanese outpatients, for example, renal hyperuricosuria and persistent hypouricemia were found in 4 (0.12 percent) [11]. The mechanism for hyperuricosuria has been studied using the anti-uricosuric agent pyrazinamide and the uricosuric drugs benzbromarone and probenecid. Most patients exhibit attenuated responses to both pyrazinamide and uricosurics, while a minority have an attenuated response to uricosurics but a preserved anti-uricosuric response to pyrazinamide [20]. The basic aspects of renal urate handling are discussed elsewhere. (See "Urate balance", section on 'Urinary excretion'.)
The underlying defect in the great majority of patients is a mutation in a gene called SLC22A12 that encodes for a renal urate-anion exchanger named uric acid transporter 1(URAT1) [21,22]. URAT1 is expressed in the luminal membrane of the proximal tubular cells and is responsible for a large portion of proximal urate reabsorption (figure 1). The residual apical uptake of urate is likely mediated by the OAT10 (SLC22A13) urate-anion exchanger [23], in addition to GLUT9a (see below).
Familial renal hypouricemia has also been described in patients with mutations in the SLC2A9 gene, which encodes a high-capacity urate transporter called GLUT9. Two GLUT9 variants include the GLUT9a and GLUT9b forms [24-26]. Urate reabsorption from the tubular lumen into the cell is mediated by URAT1 and OAT10, as mentioned above. Uric acid efflux from the cell across the basolateral membrane appears to be mediated solely by basolateral GLUT9a (figure 1) [27]; the basolateral urate exchangers OAT1 and OAT3 function as the basolateral entry site for urate secretion [28], with no evident role in urate absorption across the proximal tubule (figure 2).
The severity of the hypouricemia varies with the genetic defect:
●Patients homozygous for URAT1 mutations typically have serum urate concentrations below 1.0 mg/dL (59.5 micromol/L) and a partial uric acid reabsorption defect with fractional excretion of urate that ranges between 40 and 90 percent. The uricosuric effect of benzbromarone and probenecid is abolished in these patients, as is the anti-uricosuric effect of pyrazinamide [22] (see "Urate balance", section on 'Urinary excretion'). Clinical abnormalities are unusual, although nephrolithiasis is three to four times more common than in the general population, and a few cases of exercise-induced acute kidney injury (AKI) have been described [29]. (See 'Acute kidney injury' below.)
●Loss-of-function mutations in GLUT9 cause more severe hypouricemia (close to zero) in homozygous individuals and are associated with a high incidence of renal calculi and exercise-induced AKI. In contrast to patients with mutations in URAT1, the loss of function of GLUT9 precludes uric acid reabsorption by all of the apical transporters (including URAT1) due to complete inhibition of basolateral uric acid efflux from the cell. The net effect is a fractional urate excretion of 100 to 150 percent; values above 100 percent reflect urate secretion. Urate secretion is mediated by a separate set of apical and basolateral urate transporters (figure 2) (see "Urate balance", section on 'Urinary excretion'). The anti-uricosuric effect of pyrazinamide is retained in these patients [25], unlike those with URAT1 deficiency. Patients heterozygous for a GLUT9 loss-of-function mutation have moderately reduced serum uric acid levels. (See 'Complications' below.)
Acquired disorders — Hypouricemia due to increased urinary excretion of uric acid results from a variety of conditions, as outlined below.
Fanconi syndrome — Uric acid reabsorption in the proximal tubule can be decreased in the Fanconi syndrome, along with defects in the reabsorption of phosphate, glucose, and amino acids [30]. This syndrome has multiple causes, including cystinosis, multiple myeloma, and various drugs [30]. (See "Cystinosis" and "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)
Volume expansion — Expansion of the extracellular fluid volume can be associated with hypouricemia by decreasing proximal tubular reabsorption of urate [31]. This is most commonly seen in patients receiving large volumes of intravenous fluids and in patients with primary polydipsia or the syndrome of inappropriate antidiuretic hormone (SIADH) [32-35]. (See "Diagnostic evaluation of adults with hyponatremia".)
Hypouricemia can develop in patients receiving large volumes of intravenous fluids because the reabsorption of urate by the proximal tubule parallels that of sodium [36]. Restriction of sodium intake reduces both sodium and urate excretion and can produce hyperuricemia; by contrast, excess sodium intake (as with large volumes of intravenous fluids) increases both sodium and urate excretion and can produce hypouricemia [37-40]. Several short-term studies have shown that serum urate on a high-sodium diet (170 to 260 mmol/day) was 1.0 to 2.0 mg/dL lower than on a low-sodium diet (20 to 50 mmol/day) [37-40].
Water restriction resolves both the hyponatremia and hypouricemia in the SIADH, suggesting a primary role for volume expansion [33]. Both the vasopressin 2 (V2) and vasopressin 1 (V1) receptors may be important in the hypouricemia associated with SIADH:
●Activation of the V2 receptor by either natively produced vasopressin or desmopressin (a vasopressin analog that only stimulates the V2 receptor) leads to sodium absorption by the principal cells of the connecting tubule and cortical collecting duct [41-43]. The ensuing sodium retention reduces the reabsorption of sodium by the proximal tubule. As just discussed, the reduction in proximal sodium reabsorption is associated with a similar reduction in proximal urate reabsorption, which can produce hypouricemia.
●However, stimulation of the V1 receptor may also contribute to the uric acid wasting via an uncertain mechanism. The importance of this receptor is suggested by the observation that the induction of hyponatremia by the administration of desmopressin produces a significantly smaller fall in the serum uric acid concentration (29 versus 53 percent) than seen in patients with a similar degree of hyponatremia due to the SIADH (in which the native hormone stimulates both the V1 and V2 receptors) [44]. Consistent with this hypothesis, lack of V1 receptor activity in patients with central diabetes insipidus has been associated with hyperuricemia that is not improved with desmopressin therapy [45].
Hypouricemia may also occur in a substantial number of patients with thiazide-induced hyponatremia, in whom SIADH-like physiology is the evident cause of hyponatremia [46]. (See "Diuretic-induced hyponatremia".)
Intracranial disease — Hypouricemia due to increased urate clearance has been described in patients with intracranial disease. One study, for example, evaluated 29 consecutive neurosurgical patients: 18 had an elevated fractional excretion of urate, and 7 had hypouricemia [47]. In some patients, the hypouricemia is associated with renal sodium wasting and hyponatremia, a disorder that has been called cerebral salt-wasting [2,35,48]. In contrast to the hypouricemia seen in the SIADH, the hypouricemia in cerebral salt-wasting should not be corrected by water restriction, because the primary problem appears to be a humoral substance released from the brain rather than volume expansion [45]. Alternatively, the apparent salt-wasting and increased urate clearance may reflect volume expansion due to saline, which is commonly administered to neurosurgical patients [49]. (See "Cerebral salt wasting" and "Diagnostic evaluation of adults with hyponatremia".)
Acquired immunodeficiency syndrome — Increased fractional excretion of urate and hypouricemia may be seen in patients with acquired immunodeficiency syndrome (AIDS) [50-52]. In a study of 96 patients, for example, hypouricemia was found in 21 (22 percent) and was associated with cerebral atrophy in 12 who underwent cranial computed tomography (CT) [50]. Risk factors for hypouricemia in these and other patients include disseminated disease, central nervous system infection, and high-dose therapy with trimethoprim-sulfamethoxazole [50-52]. The development of hypouricemia may be a poor prognostic factor [50,51].
Drugs — A number of drugs interfere with net renal tubular urate reabsorption and lower serum uric acid levels (table 1). Primary uricosurics such as probenecid and benzbromarone inhibit multiple urate transporters, whereas lesinurad is reportedly specific for OAT4 and URAT1 [53,54]. The most common other drugs with "off-target" uricosuria are high-dose trimethoprim-sulfamethoxazole and high-dose salicylate therapy [52,55,56]. Fenofibrate also inhibits URAT1 with a uricosuric and hypouricemic effect [57]. In most instances, the serum uric acid concentration does not fall below normal levels.
The uricosuric action of the angiotensin II receptor blocker (ARB) losartan has been used to treat the hyperuricemia associated with cyclosporine in heart transplant recipients; this effect appears to be more pronounced than that seen with an angiotensin-converting enzyme (ACE) inhibitor [58]. The uricosuria appears to occur via the inhibition of both URAT1 [59] and organic anion transporter 10 (OAT10) [60], the function of which is described above. (See 'Familial renal hypouricemia' above.)
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have a uricosuric effect, likely through the inhibitory effect of glycosuria on urate reabsorption rather than direct transporter inhibition [61]. Clinically, SGLT2 inhibitors reduce serum uric acid and appear to reduce the risk of gout [62].
Inflammation — Inflammatory cytokines appear to reduce net renal tubular reabsorption of urate, leading to hypouricemia. Urate levels are typically lower in the context of acute gout flares [63] due to an increase in urate excretion that has been linked to increases in cytokines and other inflammatory stimuli [64]. More severe renal hypouricemia has been described in sepsis. As an example, 16 out of 43 Taiwanese patients with severe acute respiratory syndrome (SARS) were shown to develop marked renal hypouricemia (mean serum uric acid, 1.7 mg/dL [100 micromol/L]), in association with elevated interleukin-8 levels [65].
Other — Several other causes have been associated with hypouricemia due to increased urate excretion:
●Pregnancy [66]
●Total parenteral nutrition [67]
●Malignancies, including Hodgkin lymphoma [68-70]
●Diabetes mellitus [71,72]; it is likely that decreased urate reabsorption is a function of glucosuria in these patients
●Amanita phalloides poisoning [73]
COMPLICATIONS — Although most patients with hypouricemia of any cause are asymptomatic, three complications related to renal hypouricemia can occur: acute kidney injury (AKI), nephrolithiasis, and reversible posterior leukoencephalopathy syndrome (also called posterior reversible encephalopathy syndrome, or PRES).
Acute kidney injury — An increased incidence of AKI, often following exercise, has been described in patients with familial renal hypouricemia [22,74-78]. The largest reported experience comes from a review of 54 patients with renal hypouricemia, approximately 90 percent of whom were male [74]. Episodes of AKI most often occurred after strenuous exercise, such as a short-distance race. The initial symptoms were severe loin or abdominal pain and nausea, which usually developed within 6 to 12 hours after exercise. At presentation to medical care, the mean serum creatinine was 5.5 mg/dL (486 mmol/L), and the mean serum uric acid concentration was normal (4.4 mg/dL [262 micromol/L]), which was felt to be at least in part due to the kidney failure. After recovery, the serum uric acid fell to 0.7 mg/dL (42 micromol/L). Recovery of kidney function occurred in all patients, although some required hemodialysis. At follow-up, 13 patients (24 percent) developed recurrent AKI. In some patients, repeated episodes of AKI may lead to chronic kidney disease [74].
Data are limited on the frequency of AKI following exercise in patients with renal hypouricemia. The increase in relative risk was assessed in a study of 13 patients presenting with AKI following exercise, three of whom (23 percent) had renal hypouricemia [75]. This rate exceeded the expected incidence of familial renal hypouricemia by 200-fold. (See 'Familial renal hypouricemia' above.)
Two major pathogenetic mechanisms have been proposed for exercise-associated AKI in renal hypouricemia:
●Oxidative stress from reactive oxygen species generated during exercise, leading to renal vasoconstriction, ischemia, oxidant injury [79], and acute tubular injury (also called acute tubular necrosis, or ATN).
●Increased uric acid production, leading to increased uric acid excretion and precipitation in the tubules, as occurs in tumor lysis syndrome and other causes of acute and marked tissue breakdown. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors", section on 'Pathogenesis' and "Uric acid kidney diseases", section on 'Acute uric acid nephropathy'.)
The majority of reported kidney biopsies in exercise-associated AKI in renal hypouricemia have demonstrated ATN without intratubular uric acid precipitation [74,80]. It is hypothesized that the reduction in circulating uric acid, which is a known antioxidant [81], impairs the ability of the kidney to cope with the increase in oxidative stress associated with strenuous exercise [82]. In a patient with renal hypouricemia and exercise-associated AKI, for example, both an acute increase in reactive oxygen species and a decreased antioxidant potential capacity were demonstrated soon after the initiation of exercise [83]. Consequently, many patients with a history of exercise-associated AKI are treated with oral vitamin C and vitamin E in an attempt to increase serum antioxidant capacity [74].
Prolonged or intense exercise is also associated with an elevation in uric acid production, most likely due to muscle adenosine triphosphate (ATP) utilization. The subsequent rise in adenosine diphosphate (ADP) leads to an increase in the production of hypoxanthine, which is then converted to uric acid in the liver, leading to increases in serum uric acid and uric acid excretion [84,85]. Volume depletion during exercise can lead to a reduction in urine volume, which might promote uric acid precipitation in the tubules. Uric acid precipitation in the tubules can also occur with other causes of an acute increase in uric acid excretion, including high-dose trimethoprim-sulfamethoxazole [52].
The theory of uric acid precipitation is supported by the kidney biopsy demonstration of renal tubular obstruction by uric acid crystals in a single case report of exercise-induced AKI [86] and by an increased prevalence of uric acid nephrolithiasis in patients with renal hypouricemia. (See 'Uric acid stone formation' below.)
Further evidence comes from two patients with recurrent exercise-induced AKI that could be prevented by allopurinol therapy [77,87]. As an example, a Pakistani patient with recurrent exercise-induced AKI and four normals were studied with and without allopurinol during a physical fitness test [77]. Uric acid excretion without allopurinol increased from 0.46 mg/min at baseline to 1.49 mg/min at four hours after exercise, and the patient developed AKI. Uric acid excretion in controls was also 0.46 mg/min at baseline but only increased to 0.59 mg/min at four hours after exercise. After five days of allopurinol, the patient underwent the same fitness test without experiencing an increase in urate excretion or AKI. However, allopurinol is also an antioxidant, which could have explained the protection against AKI [79].
Through potentially similar mechanisms (ie, uric acid precipitation), the potent URAT1/OAT4 inhibitor lesinurad has been reported to produce AKI in clinical trials [23]. In the Combining Lesinurad With Allopurinol in Inadequate Responders (CLEAR1) trial in patients with gout [88], creatinine elevations that were >1.5 times baseline occurred in 1.0 percent of those on allopurinol alone, in 6 percent of patients on lesinurad 200 mg/day plus allopurinol, and in 16 percent of those on lesinurad 400 mg/day plus allopurinol. Similar rates of renal adverse events were reported in two other trials of lesinurad [89,90]. The use of lesinurad in patients with gout is presented elsewhere. (See "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout".)
Uric acid stone formation — Patients with renal hypouricemia are at increased risk for nephrolithiasis [15-18,24,91]. In two series of 19 patients with familial renal hypouricemia, 5 (26 percent) had a history of kidney stones [24,91]. Most of these reports described uric acid stones and successful treatment with urinary alkalinization [15-18]. However, hyperuricosuria may predispose to calcium oxalate stones [92], which have also been described in patients with renal hypouricemia [93,94]. (See 'Familial renal hypouricemia' above and "Kidney stones in adults: Uric acid nephrolithiasis", section on 'Treatment'.)
Patients with renal hypouricemia have increased fractional excretion of urate but, in theory, should have normal 24-hour urinary excretion since urate production (which is unchanged in renal hypouricemia) and urate excretion are roughly equal in the steady state. Thus, an increased risk of uric acid stones would seem counterintuitive. However, many patients with familial renal hypouricemia have moderate or marked hyperuricosuria, possibly due to diversion of urate elimination from the intestine to the urine (ie, less gastrointestinal clearance of the daily uric acid load in favor of more urinary clearance) [20]. How this might occur is not known. In addition, some of these patients have hypercalciuria via an uncertain mechanism, which is another risk factor for stone formation [20].
Reversible posterior leukoencephalopathy syndrome (PRES) — Reversible posterior leukoencephalopathy syndrome (also called posterior reversible encephalopathy syndrome, or PRES) was described in two patients with exercise-associated AKI due to renal hypouricemia, one with loss-of-function mutations in SLC22A12/URAT1 [95], and the other with loss-of-function mutations in SLC2A9/GLUT9 [96]. One of these patients had recurrent episodes of PRES that occurred in absence of hypertension. The pathophysiology underlying the association of hypouricemia and PRES is unclear. (See "Reversible posterior leukoencephalopathy syndrome".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)
SUMMARY
●Hypouricemia is arbitrarily defined as a serum urate concentration of less than 2 mg/dL (119 micromol/L). It is a fairly uncommon disorder, occurring in approximately 2 percent of hospitalized patients and less than 0.5 percent of the normal population. (See 'Introduction' above.)
●Hypouricemia can be caused by decreased uric acid production, uric acid oxidation due to treatment with uricase, or enhanced urate excretion.
●Decreased uric acid production can be due to rare inherited disorders of purine synthesis and catabolism (hereditary xanthinuria or xanthine oxidase deficiency) or, more commonly, acquired deficiency of xanthine oxidase (as with allopurinol or severe liver disease). (See 'Decreased production' above.)
●Increased urinary uric acid excretion may be seen in the following disorders and with certain drugs (see 'Increased urinary excretion' above):
•Familial renal hypouricemia, due to mutations in URAT1 or GLUT9, which encode for proteins responsible for urate reabsorption in the proximal tubule (see 'Familial renal hypouricemia' above)
•Fanconi syndrome, in which uric acid reabsorption in the proximal tubule is decreased, along with reductions in the reabsorption of one or more of the following: phosphate, glucose, potassium, bicarbonate, and amino acids (see 'Fanconi syndrome' above)
•Expansion of the extracellular fluid volume, most commonly seen in patients receiving large volumes of intravenous fluids, those with primary polydipsia, and in the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (see 'Volume expansion' above)
•Intracranial disease in association with renal sodium wasting and hyponatremia (cerebral salt-wasting). (See 'Intracranial disease' above.)
•Acquired immunodeficiency syndrome (AIDS), which may be related to intracranial disease and tends to correlate with disseminated disease and a poor prognosis (see 'Acquired immunodeficiency syndrome' above)
•Drugs, such as high-dose trimethoprim-sulfamethoxazole, high-dose salicylate, lesinurad, and losartan (table 1) (see 'Drugs' above)
●Three complications related to renal hypouricemia can occur: acute kidney injury (AKI), nephrolithiasis, and posterior reversible leukoencephalopathy syndrome (also called posterior reversible encephalopathy syndrome, or PRES). (See 'Complications' above.)
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