Continuing Education Activity

Hyperuricemia is a common disorder that affects patients of all ages and genders. The most common manifestation of hyperuricemia is gout, which can be very painful and is amenable to treatment. Hyperuricemia is also associated with uric acid and calcium nephrolithiasis. Hyperuricemia affects about 38 million Americans, over 11% of the population, and the incidence is increasing worldwide.

Most patients with hyperuricemia are asymptomatic, and the diagnosis requires a high degree of suspicion as serum uric acid levels are no longer routinely measured on serum blood panels. Patients with hyperuricemia who develop gout are usually best treated with a xanthine oxidase inhibitor like allopurinol. Depending on the urinary chemistry and stone type, allopurinol, potassium citrate, or both may be recommended in nephrolithiasis. 

This activity reviews the pathophysiology, presentation, evaluation, and treatment of hyperuricemia, as well as highlights the interprofessional team's role in caring for affected patients.

Objectives:

• Recognize individuals at risk of hyperuricemia by evaluating dietary habits, family history, and lifestyle factors, and regularly monitor serum uric acid levels.
• Initiate evidence-based management strategies, including lifestyle modifications, pharmacotherapy, and dietary interventions, to effectively control uric acid levels and reduce the risk of associated complications.
• Identify treatment modalities for both acute and chronic hyperuricemia.
• Facilitate coordinated care by ensuring seamless transitions among primary care, specialty care, and other healthcare providers, providing comprehensive management of hyperuricemia and its associated comorbidities.

Introduction

Hyperuricemia is defined as an elevated serum uric acid level, usually greater than 6 mg/dL in women and 7 mg/dL in men. Elevated serum uric acid is present in an estimated 38 million Americans, and the incidence is increasing worldwide as developing countries adopt more Western diets and lifestyles. Most people with this condition will not have obvious clinical manifestations, however, it is unclear what the long-term effects of hyperuricemia are on overall cardiovascular health, renal function, and overall morbidity.[1] Hyperuricemia results from increased uric acid production, decreased excretion, or a combination of both processes. 

Dietary purines are responsible for about one-third of the body's daily serum uric acid production; the rest is synthesized from endogenous sources. Elevated uric acid can also be seen with accelerated purine degradation in high cell turnover states (eg, hemolysis, rhabdomyolysis, tumor lysis) and decreased excretion (eg, genetic disorders, renal insufficiency, metabolic syndrome). About two-thirds of uric acid is excreted through the kidney and one-third through the gastrointestinal (GI) tract. However, these proportions can change depending on medications or dysfunction in the renal or GI systems.

Most people with hyperuricemia are asymptomatic (85% to 90%), but elevated uric acid levels in the blood or urine can lead to gout or nephrolithiasis. Hyperuricemia and hyperuricosuria have also been linked with other disorders such as metabolic syndrome, diabetes mellitus, cardiovascular disease, hypertension, atherosclerosis, obesity, and chronic renal disease.[2][3][4][5][6]

Etiology

Uric Acid Overproduction

• Purine-rich diet: alcohol (especially beer); bacon; beef; lamb; turkey; veal; venison; organ meats; and certain fish and shellfish (anchovies, cod, tuna, sardines, herring, mussels, shrimp, lobster, codfish, scallops, trout, and haddock)
• Fructose causes hyperuricemia as its hepatic metabolism through the aldolase reductase pathway produces uric acid. High-fructose corn syrup and full-sugar sodas are especially harmful and are associated with obesity in children and adolescents. [7][8]

• Errors of purine metabolism: hypoxanthine-guanine phosphoribosyltransferase (HPRT or HGPRT) deficiency, phosphoribosylpyrophosphate (PRPP) synthetase overactivity.
• High cell breakdown or turnover: lymphoproliferative diseases, myeloproliferative disease, polycythemia vera, Paget disease, psoriasis, tumor lysis, hemolysis, rhabdomyolysis, extreme exercise, chemotherapy.

Decreased Uric Acid Excretion

• Acute or chronic kidney disease, acidosis (eg, lactic acidosis, ketoacidosis), hypovolemia, medication/toxins (diuretics, niacin, pyrazinamide, ethambutol, cyclosporine, beryllium, salicylates, lead, alcohol), sarcoidosis, hyperparathyroidism, hypothyroidism, Bartter syndrome, Down syndrome.[9]

Diuretic-induced Hyperuricemia

• Thiazide and loop diuretics tend to cause a dose-dependent type of hyperuricemia and possibly even gout.[10][11][12] They tend to increase renal uric acid reabsorption either directly or indirectly through volume depletion.[10][12][13][14]

• The net increase in relative risk of gout by diuretics is almost 80%.[15]

• An alternate or concurrent antihypertensive, including an angiotensin II receptor blocker (especially losartan) or an angiotensin-converting enzyme inhibitor, is recommended in patients with gout flares.[16][17][18][19][20][21][22]

• Most patients with diuretic-induced gout are treated with a xanthine oxidase inhibitor, such as allopurinol. However, if the patient is asymptomatic, no treatment is needed. 

Epidemiology

Up to 21% of the general population and 25% of hospitalized patients are estimated to have asymptomatic hyperuricemia, and uric acid levels can be elevated 10 to 15 years before clinical manifestations of gout.[23][24] Hyperuricemia does not indicate a pathological state because it is extremely prevalent in the general population and is asymptomatic in 90% to 95% of people.[25] The worldwide incidence of hyperuricemia is increasing in economically advantaged countries and the developing world as they adopt a Western diet and lifestyle.[23][26] Hyperuricemia is particularly high in Pacific islanders.[27] Men have higher rates than women, as estrogen is protective against hyperuricemia, and women can develop hyperuricemia after menopause.[28][29] 

Pathophysiology

Clinical Manifestations

Gout is a metabolic disorder that allows for the accumulation of uric acid in the blood and tissues. This leads to the precipitation of urate monohydrate crystals within a joint. Crystal deposition is enhanced in acidic and cold environments, leading to gout manifestations in peripheral joints, such as the big toe. Gout has a male predominance in a 4:1 ratio of men to women.[24]

In uric acid nephrolithiasis, uric acid precipitates in the urine, most commonly due to acidic urine and metabolic syndrome. Acidic urine, hypovolemia, and hyperuricosuria are the most significant risk factors for uric acid nephrolithiasis. Hyperuricosuria is defined as uric acid levels that exceed 800 mg/day in men and 750 mg/day in women. Uric acid stones comprise 5% to 10% of all urinary stones and can also have calcium components.[30]

Hypertension is linked to hyperuricemia, even when adjusted for comorbidities of obesity and diabetes.[29][31][32] A large cross-sectional study showed that even at levels considered within the normal range (≥5.3 mg/dL in men, and ≥4.3 mg/dL in women), serum uric acid levels were directly related to hypertension after adjusting for other comorbidities. Mechanisms by which hyperuricemia may cause hypertension include activation of the renin-angiotensin system, oxidative stress, endothelial inflammation, endothelin-1 activation, and nitrous oxide reduction.[31][33]

Obesity and hyperuricemia are also highly linked, and some analyses suggest that obesity is a cause of hyperuricemia. Proposed mechanisms are (1) visceral adipose tissue providing free fatty acids to the liver, inducing uric acid production and (2) dysregulation of adipocytes causing decreased uric acid and sodium excretion by the renal tubules. Small clinical trials have shown that urate-lowering drugs may decrease the development of hypertension in adolescents; however, these drugs can have serious adverse effects, so this is not recommended as treatment.[31]

Hyperuricemia is also highly associated with cardiac and renal disease. However, given the significant overlap among the risk factors for all 3 disease states, it is difficult to determine cause and effect.[32][33] One prospective study found that urate-lowering therapy did not decrease the development of CKD and was actually associated with worse kidney outcomes, so urate-lowering drugs are not indicated for primary prevention of kidney disease.[34][35]

Mechanisms of Hyperuricemia

Uric acid (2,6,8 thiopurine-C5H4N4O3) is the result of purine breakdown. At the normal physiological pH of 7.4, uric acid circulates in the ionized form of urate. Purine metabolism mainly occurs in the liver but can also happen in any tissue containing xanthine oxidase, such as cardiac or pulmonary tissue. About two-thirds of the body's total production of uric acid is excreted in the kidneys, and a third is passed into the intestine. Urate is filtered and secreted in the kidneys, then 90% is reabsorbed in the proximal tubule. Other mammals have much lower uric acid levels due to the activity of uricase, which converts urate to the more water-soluble allantoin. However, in humans and higher primates, this enzyme is nonfunctional.[36]

Purine-rich diets, endogenous purine production, and high cell breakdown accelerate uric acid production. Beer, which is high in purines, especially increases uric acid levels.[37] Endogenous production of the purine production can be accelerated by phosphoribosylpyrophosphate (PRPP) synthetase activity and a defect in the regulatory enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT).[38][39] Accelerated cell breakdown or turnover conditions include rhabdomyolysis, hemolysis, psoriasis, myeloproliferative disorders, and tumor lysis.[40]

Urate Transport in the Kidney

Urate excretion occurs primarily in the kidneys, and impaired urinary excretion is responsible for hyperuricemia in 90% of individuals. Underexcretion is a combination of decreased glomerular filtration, reduced tubular secretion, and enhanced tubular reabsorption. 

Proximal tubular reabsorption of uric acid is controlled by uric acid transporter 1 (URAT1) located in the apical cell membrane.[41][42] This transporter can be stimulated by organic acids (lactate, acetoacetate, and beta-hydroxybutyrate), medications (niacin, pyrazinamide, ethambutol, cyclosporin, and chemotherapeutic agents), and reduced extracellular fluid volume resulting in hyperuricemia.[2] URAT1 inhibitors are the most effective class of uricosuric agents available to treat hyperuricemia.[41] Urate is then transported into the renal interstitium by the GLUT9 transporter.[42]

Histopathology

Hyperuricemia can be visualized when monosodium urate crystals precipitate. Joint precipitation appears as the classic "needle-shaped crystals" seen in aspirated synovial fluid. Urinary uric acid will form crystals if urine pH is acidic (<5.5). These yellowish-brown crystals can be rhomboid or cluster to create a rosette shape.

History and Physical

History

Hyperuricemia alone is not a specific indication for therapy (despite evidence linking it to the development of diabetes, hypertension, and cardiac disease). Most patients with elevated uric acid are asymptomatic and require no long-term therapy. The patient may give a history of a purine-rich diet or high alcohol consumption. Past medical history and current medications should be carefully reviewed for any correlation with poor renal excretion of urate or increased uric acid production.

Gout and uric acid nephrolithiasis are the 2 most common complaints associated with hyperuricemia. During a gout attack, the patient complains of red, hot, swollen joints, often including the big toe (podagra).[43] The presentation of nephrolithiasis includes renal colic or severe, acute flank, abdominal, or back pain, often radiating to the groin; hematuria or brownish-colored urine; dysuria; and nausea and vomiting. Urinary tract symptoms, including fever, cloudy urine, and frequent urination, may also be present.[44]

Physical Exam

No specific physical exam findings will indicate hyperuricemia unless the patient presents with symptoms of acute gout attack or uric acid nephrolithiasis. With gout, there is evidence of an erythematous, warm, and swollen joint, most commonly affecting the big toe, but it can be present in any joint. Usually, gout affects only one joint at a time. Classically, this presents as "pain out of proportion to exam." Nephrolithiasis has no specific physical exam findings but may have reproducible costovertebral angle tenderness. 

Evaluation

Laboratory Studies

• Elevated serum uric acid—normal values are typically less than 6.8 mg/dL and may vary by gender. Readings of 8 mg/dL or more are diagnostic of hyperuricemia.

• If nephrolithiasis is present, urinalysis may show microscopic hematuria, uric acid crystals, and low urinary pH (<5.5).

• A 24-hour urine uric acid collection should be optimally less than 600 mg/day on a low-purine diet. A level greater than 800 mg/d identifies hyperuricosuria but does not designate whether the cause is related to increased production or decreased excretion of uric acid.

• Other studies include a complete blood count (CBC) with differential, CMP, lipid profile, HgA1c, calcium, and phosphate levels. These laboratory studies are useful in assessing underlying diseases such as malignancy, sickle cell disease, diabetes, and metabolic syndrome.

• Consider joint x-rays to evaluate any unexplained swelling; however, x-ray findings are not required to diagnose gout.

• Renal ultrasounds or noncontrast CT scans are indicated in patients with suspected uric acid nephrolithiasis. The use of IV contrast can obscure the presence of stones.

Procedures

• Consider joint aspiration to evaluate for uric acid crystals, which are needle-shaped and negatively birefringent under polarized microscopy.

Treatment / Management

Most patients with hyperuricemia are asymptomatic and do not need medical therapy, except for patients undergoing cytolytic therapy for malignancy to prevent tumor lysis syndrome.[45][46][47][48] This recommendation is based on the cost of unnecessary medications and the potential for adverse effects, which generally outweigh the benefit of starting medication in asymptomatic patients.

The American College of Rheumatology recommends that patients with 2 or more gout attacks a year should be treated, but a lower threshold can be used based on the severity of the gout flares and patient preference.[49] Other indications for treatment include gouty bone erosion, structural joint injury, polyarticular disease, hyperuricosuric nephrolithiasis, and tophi.

Colchicine is frequently used to treat acute gout.[50][51] It binds the tubulin protein, preventing microtubule formation and polymerization. It also has anti-inflammatory and anti-fibrotic effects.[52] See our companion StatPearls reference article on "Colchicine."[50] Patients starting uric acid lowering therapy should be considered for prophylactic colchicine to minimize the risk of an acute gouty flare. Slowly introducing hyperuricemia medications can also decrease the risk of gout flare attacks.[53]

There are three types of uric acid-lowering medications: uricosuric agents, xanthine oxidase inhibitors, and recombinant uricases. Among these, only five are FDA-approved for use in the US: allopurinol, febuxostat, probenecid, rasburicase, and pegloticase.

Uricosuric agents work by increasing the renal and urinary excretion of uric acid. Normally, 10% of filtered uric acid is excreted in the urine. Uricosuric agents work by inhibiting the URAT1 anion-exchanging uric acid transporter system in the brush border of renal proximal tubular cells.[54] This causes increased urinary excretion with a corresponding drop in serum uric acid levels. These agents are not generally suitable for patients with hyperuricosuric nephrolithiasis and are most useful when urinary uric acid is less than 800 mg daily.

Losartan, atorvastatin, and fenofibrate have mild uricosuric effects and can be considered adjunctive agents in patients with hypertension (losartan) or hyperlipidemia (atorvastatin, fenofibrate).[16][55][56]

•  Probenecid inhibits URAT1 and several other anion transporters, increasing renal uric acid excretion by reducing reabsorption.[57] It is typically used as second-line therapy for gout as it is considered less potent than other uric acid-lowering medications.[58] Probenecid can be used in patients who cannot tolerate xanthine oxidase inhibitors and is often used with colchicine for gout prophylaxis. It has many drug interactions limiting its clinical use.[58][59] Probenecid can also increase the incidence of uric acid nephrolithiasis, so this should be closely monitored. It is also relatively contraindicated in patients with grade 3 or higher CKD.

• Benzbromarone is a URAT1 inhibitor type uricosuric drug used for gout and hyperuricemia in some countries but was unapproved in the US and Europe due to hepatotoxicity.[60][61] While it is a potent URAT1 inhibitor and a more effective uricosuric agent than probenecid, it has low selectivity.[60][62]

•  Dotinurad is a highly selective URAT1 inhibitor and effective uricosuric agent available only in Japan that appears to be equivalent to benzbromarone and febuxostat in overall uric acid-lowering ability.[63][64][65][66][67] It is being evaluated for possible approval in the US and Europe.

• Lesinurad is another uricosuric URAT1 inhibitor drug that significantly increases urinary uric acid excretion, thereby substantially lowering serum uric acid levels.[68][69][70] The manufacturers discontinued production of this drug in 2019 due to business considerations and concern for profit margins. 

Xanthine oxidase inhibitors block the hepatic oxidation of xanthine to uric acid.[71] Xanthine does not cause gout, is non-toxic until very high concentrations, and is much more soluble in urine than uric acid.[71] See our companion StatPearls reference article on "Biochemistry, Xanthine Oxidase."[72]

•  Allopurinol is a purine-based structural analog of hypoxanthine that acts as a xanthine oxidase inhibitor.[73] It is the preferred agent for patients with symptomatic hyperuricemia, gout, and hyperuricosuric nephrolithiasis.[71] It is also used as prophylaxis against gouty arthritis and chemotherapy-related hyperuricemia. It is effective and inexpensive, but treatment usually is lifelong. Compared to febuxostat, allopurinol appears to offer superior renal protection.[74] For tumor lysis syndrome prophylaxis, allopurinol should be started two or three days before initiating chemotherapy and continued for up to a week after the chemotherapy course.[71] See our companion StatPearls reference article on "Allopurinol."[71] The overall use of allopurinol is suboptimal, as many patients with gout either do not receive long-term treatment or are significantly underdosed.[75]

• Allergic reactions to allopurinol have been reported in up to 25% of patients. Such reactions include rashes, itching, hives, and blistering skin.[76][77] Allopurinol hypersensitivity syndrome, a much more severe allergic reaction, presents with Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, renal failure, hepatic injury, and eosinophilia.[78] The risk is 1:1,000 patients, and the reported mortality is 20% to 25%.[59] Individuals of Han Chinese, Thai, and Korean ethnicity and African Americans have a much greater risk of a specific genetic predisposition (HLA-B*58:01 allele) for this hypersensitivity response.[79] Genetic testing for HLA-B*58:01 should be considered for individuals of these ethnic groups before starting allopurinol therapy.[79]  Patients with pre-existing renal failure are also at higher risk of developing allopurinol hypersensitivity syndrome.[78][80] This can be minimized by starting patients on a very low dose of <50 mg (<1.5 mg per mL/min of creatinine clearance) and titrating it upwards very gradually (such as every two to four weeks).[80] 

•  Febuxostat is a non-purine-based xanthine oxidase inhibitor primarily used for patients who fail or cannot tolerate allopurinol. At standard dosages, febuxostat appears to have superior uric acid lowering ability than allopurinol and can be used in patients with a creatinine clearance as low as 15 mL/min.[81] However, compared to allopurinol, patients on febuxostat demonstrated a 34% higher risk of cardiovascular mortality and 22% higher overall mortality, prompting the FDA to issue a limited-use recommendation in 2019.[82] See our companion StatPearls reference article on "Febuxostat."[83]

• Topiroxostat is a xanthine oxidase inhibitor that, unlike allopurinol and febuxostat, is a non-purine agent. It is currently only approved for use in Japan. Unlike allopurinol, topiroxostat is unaffected by renal failure and can be used effectively in patients with chronic kidney disease. It was first approved for use in Japan in 2013. A post-marketing study of almost 4,500 patients over 5 years demonstrated efficacy and safety with no significant adverse drug reactions.[84] 

Recombinant uricase drugs are intended for chronic gout inadequately controlled by xanthine oxidase inhibitors or uricosuric agents alone. It is estimated that about 2% of all patients with gout may be refractory to standard therapy.[85] Such patients either have intractable hyperuricemia, two or more gout attacks while on therapy, or persistent subcutaneous tophi unresponsive to maximum dosages of conventional therapy.[86] 

Uricase drugs work by enzymatically converting uric acid to the water-soluble, non-toxic, purine metabolite allantoin, which is then readily excreted by the kidneys.[87] Other than humans and higher primates, most mammals naturally produce uricase and have much lower normal uric acid. Recombinant uricase drugs do not interfere with uric acid production or change its excretion. They are very effective in lowering uric acid in serum and urine.

•  Rasburicase was the first recombinant uricase to treat significant hyperuricemia from tumor lysis syndrome.[36] It was FDA-approved in 2002 for temporarily managing hyperuricemia in cancer patients with leukemia, lymphoma, and solid malignant lesions receiving chemotherapy likely to cause tumor lysis syndrome that would otherwise cause extremely high serum uric acid levels.[36]

• It works quickly (within 4 hours). It effectively controls uric acid levels in tumor lysis syndrome and avoids hemodialysis. Still, it is expensive, has a short half-life of 16 to 21 hours, and promotes the rapid development of antibodies to the drug.[88][89][90][91][92][93] See our companion StatPearls reference article on "Tumor Lysis Syndrome."[94]

• Pegloticase is a recombinant uricase (uric acid oxidase) that was FDA-approved in 2010 for chronic gout refractory to standard therapy.[87][95] (Its marketing authorization was discontinued in the European Union in 2016 due to business and commercial reasons.)

• To decrease immune reactivity and extend the half-life, an inert polyethylene glycol (PEG) was chemically attached to the rasburicase enzyme, making it "pegylated" and leading to pegloticase.[85][96][97][98] The half-life is longer than rasburicase at 8.5 days but remains highly immunogenic, requiring concomitant methotrexate as an immunosuppressive.[85]

• Pegloticase was created using a genetically altered variant of E. coli. Effectiveness was demonstrated in two multinational, six-month, randomized, double-blinded, placebo-controlled trials.[99][100] In addition to significantly lowering serum uric acid levels, pegloticase has been shown to shrink and resolve tophi, decrease joint pain, improve swelling, and even significantly reduce blood pressure in hyperuricemic patients without affecting kidney function.[85][100]  

• Patients on pegloticase can develop infusion reactions and antidrug antibodies that reduce its effectiveness.[85] These side effects can be eliminated by stopping the medication when it starts to lose efficacy or at the start of an adverse reaction, as well as by using immunosuppressive drugs such as methotrexate.[85][101] 

• The combination of pegloticase with methotrexate showed markedly increased response over pegloticase alone (71% vs. 38.5%) with similar adverse effects and much lower rates of infusion reactions and antidrug antibody production.[95][101][102] Gout flares are common (88%) when initiating pegloticase therapy.[100] Pegloticase is costly, and anaphylaxis has been reported.

• Folic acid supplementation should be started at least four weeks before beginning therapy. Other uric acid-lowering medications should be discontinued before starting pegloticase. Before every infusion, uric acid serum levels should be monitored, and patients should be premedicated with antihistamines and corticosteroids.[95] It is contraindicated in patients with glucose-6-phosphate deficiency and is not recommended for asymptomatic patients.[95] See our companion StatPearls reference article on "Pegloticase."[95]

Treatment Summary

• Allopurinol is the preferred initial treatment for hyperuricemia. If this is ineffective or not tolerated, then febuxostat is recommended. Dosage is adjusted until optimal serum (<6 mg/dL) or 24-hour urine (<600 mg/day) uric acid levels are achieved.[71][103][104]

• Febuxostat is recommended if allopurinol is not well tolerated, ineffective, or if there is a genetic risk of allopurinol hypersensitivity syndrome.

• In uric acid urolithiasis, treatment primarily reduces urinary acidity (to pH >6.5) with potassium citrate or sodium bicarbonate rather than just reducing hyperuricosuria.[103] Increasing urinary volume is also recommended. See our companion StatPearls reference article on "Uric Acid Nephrolithiasis" and "Hyperuricosuria."[103][105]

• In hyperuricosuric calcium nephrolithiasis, treatment is focused on optimizing urinary citrate with potassium citrate (urinary citrate goal is 500-600 mg/day) and reducing uric acid urinary excretion (usually with allopurinol).[104][106]

• Probenecid with or without colchicine can be used for gout prophylaxis but is not recommended for patients with uric acid nephrolithiasis or hyperuricosuria (>800 mg urinary uric acid/24 hours).

• Pegloticase can be used for otherwise intractable, symptomatic hyperuricemia in patients with ineffective or intolerable alternative treatments.[95]

• Rasburicase is recommended for temporary use in acute hyperuricemia due to tumor lysis syndrome but not for gout.[36]

Differential Diagnosis

Hyperuricemia alone does not cause clinical symptoms. However, other conditions can cause the symptoms of gout or nephrolithiasis often seen with elevated uric acid. Some of these conditions are rheumatoid arthritis, pseudogout (calcium pyrophosphate deposition disease), arthritis, hypothyroidism, alcoholic ketoacidosis, non-urate-based nephrolithiasis, hemolytic anemia, hyperparathyroidism, and malignancies.

Prognosis

Most patients with hyperuricemia are asymptomatic. Patients can be easily treated with several medication classes if they develop symptoms. There is evidence that hyperuricemia is a precursor to the development of hypertension, metabolic disease, diabetes, and cardiovascular and renal disease, but a definitive causal link has not been established. Urate-lowering therapy for asymptomatic patients is not yet standard.

Complications

Hyperuricemia primarily is known to have complications related to nephrolithiasis and gout. Some of the potential side effects include:

• Bone loss
• Chronic kidney disease 
• Gout
• Hypertension
• Joint damage and deformity
• Tophi deposits
• Loss of mobility
• Nephrolithiasis (uric acid and calcium oxalate)
• Restricted range of motion
• Skin rashes
• Allopurinol sensitivity syndrome

Deterrence and Patient Education

Patients with symptomatic hyperuricemia (gout, uric acid stones, or hyperuricosuric calcium nephrolithiasis) should be on prophylactic treatment, usually starting with allopurinol. Patients at risk for a flare, especially those with renal failure, should be started on a low dose of uric acid-lowering agents and gradually titrated upwards.[80] Dietary education should be prioritized regarding a low-purine, low-salt, and low-fructose diet. Many patients will benefit from seeing a dietician regularly.

Pearls and Other Issues

Key facts regarding hyperuricemia are listed below. 

• Most patients with gout are not on optimal doses of their uric acid-lowering medications.[75]  Many patients will need higher doses than the typical 300 mg daily to achieve optimal serum levels of 6 mg/dL or less.[75]

• Allopurinol hypersensitivity syndrome is a rare but potentially fatal reaction.[59] African Americans and individuals of Chinese, Korean, and Thai ancestry should be tested for the HLA-B*58:01 allele, which predisposes them to this dangerous hypersensitivity reaction, before starting allopurinol therapy.[79] Allopurinol should be avoided in those who test positive for this gene.

• Patients with chronic kidney disease are also at higher risk.[78][80] In these patients, use low doses of allopurinol initially and gradually titrate upwards only every 2-4 weeks.[80] 

• Pegloticase should generally only be used with methotrexate.[95] Stop all other uric acid-lowering drugs and start folic acid supplementation.[95] At every infusion, patients should be premedicated with steroids and antihistamines.[95]

• In patients with chronic kidney disease, xanthine oxidase inhibitors are generally preferred, but possibly at a lower starting dose.

• Among uricosuric agents, only benzbromarone  (not available in the United States and Europe)can be used in patients with significant chronic kidney disease.

• Patients with diuretic-induced hyperuricemia and gout can be treated with losartan or allopurinol but do not need any therapy if they are asymptomatic.

Enhancing Healthcare Team Outcomes

Because there are many causes of hyperuricemia, the condition is best managed by an interprofessional team that may include internists, primary care providers, endocrinologists, urologists, rheumatologists, and oncologists. Most patients are asymptomatic and do not need medical therapy for hyperuricemia.

The cost of unnecessary drugs and the potential for adverse effects outweigh the benefit of starting medication for most asymptomatic patients with hyperuricemia. Uric acid-lowering medications in such patients are only indicated in those undergoing cytolytic therapy for malignancy to prevent tumor lysis syndrome.[107][108]

The outlook for benign causes of hyperuricemia is good, but those with malignancy may develop complications like gout or renal 

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Yip K, Cohen RE, Pillinger MH. Asymptomatic hyperuricemia: is it really asymptomatic? Curr Opin Rheumatol. 2020 Jan;32(1):71-79. [PubMed: 31688126]

2.

Barkas F, Elisaf M, Liberopoulos E, Kalaitzidis R, Liamis G. Uric acid and incident chronic kidney disease in dyslipidemic individuals. Curr Med Res Opin. 2018 Jul;34(7):1193-1199. [PubMed: 28836857]

3.

Song D, Zhao X, Wang F, Wang G. A brief review of urate transporter 1 (URAT1) inhibitors for the treatment of hyperuricemia and gout: Current therapeutic options and potential applications. Eur J Pharmacol. 2021 Sep 15;907:174291. [PubMed: 34216576]

4.

Bhole V, Choi JW, Kim SW, de Vera M, Choi H. Serum uric acid levels and the risk of type 2 diabetes: a prospective study. Am J Med. 2010 Oct;123(10):957-61. [PMC free article: PMC3131180] [PubMed: 20920699]

5.

Borghi C, Rosei EA, Bardin T, Dawson J, Dominiczak A, Kielstein JT, Manolis AJ, Perez-Ruiz F, Mancia G. Serum uric acid and the risk of cardiovascular and renal disease. J Hypertens. 2015 Sep;33(9):1729-41; discussion 1741. [PubMed: 26136207]

6.

Borghi C. The role of uric acid in the development of cardiovascular disease. Curr Med Res Opin. 2015;31 Suppl 2:1-2. [PubMed: 26414729]

7.

Sanchez-Lozada LG, Andres-Hernando A, Garcia-Arroyo FE, Cicerchi C, Li N, Kuwabara M, Roncal-Jimenez CA, Johnson RJ, Lanaspa MA. Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats. J Biol Chem. 2019 Mar 15;294(11):4272-4281. [PMC free article: PMC6422088] [PubMed: 30651350]

8.

Russo E, Leoncini G, Esposito P, Garibotto G, Pontremoli R, Viazzi F. Fructose and Uric Acid: Major Mediators of Cardiovascular Disease Risk Starting at Pediatric Age. Int J Mol Sci. 2020 Jun 24;21(12) [PMC free article: PMC7352635] [PubMed: 32599713]

9.

Dong H, Xu Y, Zhang X, Tian S. Visceral adiposity index is strongly associated with hyperuricemia independently of metabolic health and obesity phenotypes. Sci Rep. 2017 Aug 18;7(1):8822. [PMC free article: PMC5562916] [PubMed: 28821853]

10.

Kahn AM. Effect of diuretics on the renal handling of urate. Semin Nephrol. 1988 Sep;8(3):305-14. [PubMed: 3059433]

11.

Carlsen JE, Køber L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ. 1990 Apr 14;300(6730):975-8. [PMC free article: PMC1662719] [PubMed: 2344503]

12.

Hagos Y, Stein D, Ugele B, Burckhardt G, Bahn A. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol. 2007 Feb;18(2):430-9. [PubMed: 17229912]

13.

Weinman EJ, Eknoyan G, Suki WN. The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. J Clin Invest. 1975 Feb;55(2):283-91. [PMC free article: PMC301746] [PubMed: 1127100]

14.

Steele TH, Oppenheimer S. Factors affecting urate excretion following diuretic administration in man. Am J Med. 1969 Oct;47(4):564-74. [PubMed: 4309843]

15.

Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med. 2005 Apr 11;165(7):742-8. [PubMed: 15824292]

16.

Würzner G, Gerster JC, Chiolero A, Maillard M, Fallab-Stubi CL, Brunner HR, Burnier M. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens. 2001 Oct;19(10):1855-60. [PubMed: 11593107]

17.

Weinberger MH. Influence of an angiotensin converting-enzyme inhibitor on diuretic-induced metabolic effects in hypertension. Hypertension. 1983 Sep-Oct;5(5 Pt 2):III132-8. [PubMed: 6313523]

18.

Shahinfar S, Simpson RL, Carides AD, Thiyagarajan B, Nakagawa Y, Umans JG, Parks JH, Coe FL. Safety of losartan in hypertensive patients with thiazide-induced hyperuricemia. Kidney Int. 1999 Nov;56(5):1879-85. [PubMed: 10571797]

19.

Soffer BA, Wright JT, Pratt JH, Wiens B, Goldberg AI, Sweet CS. Effects of losartan on a background of hydrochlorothiazide in patients with hypertension. Hypertension. 1995 Jul;26(1):112-7. [PubMed: 7607713]

20.

Manolis AJ, Grossman E, Jelakovic B, Jacovides A, Bernhardi DC, Cabrera WJ, Watanabe LA, Barragan J, Matadamas N, Mendiola A, Woo KS, Zhu JR, Mejia AD, Bunt T, Dumortier T, Smith RD. Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators. Clin Ther. 2000 Oct;22(10):1186-203. [PubMed: 11110230]

21.

Tikkanen I, Omvik P, Jensen HA. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. J Hypertens. 1995 Nov;13(11):1343-51. [PubMed: 8984133]

22.

Buscemi S, Buscemi C, Borzì AM, Cosentino L, Rosafio G, Randazzo C, Colomba D, Di Raimondo D, Pluchinotta FR, Parrinello G. Metabolic and Cardiovascular Effects of Switching Thiazides to Amlodipine in Hypertensive Patients With and Without Type 2 Diabetes (the Diuretics and Diabetes Control Study). Metab Syndr Relat Disord. 2020 Mar;18(2):110-118. [PubMed: 31976814]

23.

Li L, Zhang Y, Zeng C. Update on the epidemiology, genetics, and therapeutic options of hyperuricemia. Am J Transl Res. 2020;12(7):3167-3181. [PMC free article: PMC7407685] [PubMed: 32774692]

24.

Williams LA. The History, Symptoms, Causes, Risk Factors, Types, Diagnosis, Treatments, and Prevention of Gout, Part 2. Int J Pharm Compd. 2019 Jan-Feb;23(1):14-21. [PubMed: 30668531]

25.

Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med. 1987 Mar;82(3):421-6. [PubMed: 3826098]

26.

Singh G, Lingala B, Mithal A. Gout and hyperuricaemia in the USA: prevalence and trends. Rheumatology (Oxford). 2019 Dec 01;58(12):2177-2180. [PubMed: 31168609]

27.

Gosling AL, Matisoo-Smith E, Merriman TR. Hyperuricaemia in the Pacific: why the elevated serum urate levels? Rheumatol Int. 2014 Jun;34(6):743-57. [PubMed: 24378761]

28.

Wu X, You C. The biomarkers discovery of hyperuricemia and gout: proteomics and metabolomics. PeerJ. 2023;11:e14554. [PMC free article: PMC9828291] [PubMed: 36632144]

29.

Yokokawa H, Fukuda H, Suzuki A, Fujibayashi K, Naito T, Uehara Y, Nakayama A, Matsuo H, Sanada H, Jose PA, Miwa Y, Hisaoka T, Isonuma H. Association Between Serum Uric Acid Levels/Hyperuricemia and Hypertension Among 85,286 Japanese Workers. J Clin Hypertens (Greenwich). 2016 Jan;18(1):53-9. [PMC free article: PMC8031541] [PubMed: 26212524]

30.

Paquot N, Scheen AJ. [DPP-4 or SGLT2 inhibitor added to metformin alone in type 2 diabetes]. Rev Med Suisse. 2017 Aug 23;13(571):1410-1415. [PubMed: 28837277]

31.

Tian S, Liu Y, Xu Y, Feng A. Does obesity modify the epidemiological association between hyperuricemia and the prevalence of hypertension among Northern Chinese community-dwelling people? A Chinese population-based study. BMJ Open. 2019 Nov 21;9(11):e031803. [PMC free article: PMC6887063] [PubMed: 31753884]

32.

Borghi C, Agabiti-Rosei E, Johnson RJ, Kielstein JT, Lurbe E, Mancia G, Redon J, Stack AG, Tsioufis KP. Hyperuricaemia and gout in cardiovascular, metabolic and kidney disease. Eur J Intern Med. 2020 Oct;80:1-11. [PubMed: 32739239]

33.

Ejaz AA, Johnson RJ, Shimada M, Mohandas R, Alquadan KF, Beaver TM, Lapsia V, Dass B. The Role of Uric Acid in Acute Kidney Injury. Nephron. 2019;142(4):275-283. [PubMed: 30991383]

34.

Hassan W, Shrestha P, Sumida K, Thomas F, Sweeney PL, Potukuchi PK, Rhee CM, Streja E, Kalantar-Zadeh K, Kovesdy CP. Association of Uric Acid-Lowering Therapy With Incident Chronic Kidney Disease. JAMA Netw Open. 2022 Jun 01;5(6):e2215878. [PMC free article: PMC9166229] [PubMed: 35657621]

35.

Rincon-Choles H, Jolly SE, Arrigain S, Konig V, Schold JD, Nakhoul G, Navaneethan SD, Nally JV, Rothberg MB. Impact of Uric Acid Levels on Kidney Disease Progression. Am J Nephrol. 2017;46(4):315-322. [PubMed: 29032376]

36.

Yakupova SP. Gout. New opportunities of diagnosis and treatment. Ter Arkh. 2018 May 11;90(5):88-92. [PubMed: 30701896]

37.

Shiraishi H, Une H. The effect of the interaction between obesity and drinking on hyperuricemia in Japanese male office workers. J Epidemiol. 2009;19(1):12-6. [PMC free article: PMC3924090] [PubMed: 19164873]

38.

de Brouwer APM, Christodoulou J. Phosphoribosylpyrophosphate Synthetase Superactivity. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews^® [Internet]. University of Washington, Seattle; Seattle (WA): Sep 23, 2008. [PubMed: 20301734]

39.

Dewulf JP, Marie S, Nassogne MC. Disorders of purine biosynthesis metabolism. Mol Genet Metab. 2022 Jul;136(3):190-198. [PubMed: 34998670]

40.

Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet. 2021 May 15;397(10287):1843-1855. [PubMed: 33798500]

41.

Zhao Z, Liu J, Yuan L, Yang Z, Kuang P, Liao H, Luo J, Feng H, Zheng F, Chen Y, Wu T, Guo J, Cao Y, Yang Y, Lin C, Zhang Q, Chen J, Pang J. Discovery of novel benzbromarone analogs with improved pharmacokinetics and benign toxicity profiles as antihyperuricemic agents. Eur J Med Chem. 2022 Nov 15;242:114682. [PubMed: 36001935]

42.

Bobulescu IA, Moe OW. Renal transport of uric acid: evolving concepts and uncertainties. Adv Chronic Kidney Dis. 2012 Nov;19(6):358-71. [PMC free article: PMC3619397] [PubMed: 23089270]

43.

Fenando A, Rednam M, Gujarathi R, Widrich J. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 12, 2024. Gout. [PMC free article: PMC546606] [PubMed: 31536213]

44.

Patti L, Leslie SW. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 6, 2024. Acute Renal Colic. [PubMed: 28613743]

45.

Yang N, Yu Y, Zhang A, Estill J, Wang X, Zheng M, Zhou Q, Zhang J, Luo X, Qian C, Mao Y, Wang Q, Yang Y, Chen Y. Reporting, presentation and wording of recommendations in clinical practice guideline for gout: a systematic analysis. BMJ Open. 2019 Jan 29;9(1):e024315. [PMC free article: PMC6352818] [PubMed: 30700479]

46.

Alqarni NA, Hassan AH. Knowledge and practice in the management of asymptomatic hyperuricemia among primary health care physicians in Jeddah, Western Region of Saudi Arabia. Saudi Med J. 2018 Dec;39(12):1218-1225. [PMC free article: PMC6344656] [PubMed: 30520504]

47.

Engel B, Schacher S, Weckbecker K, Stausberg A, Gräff I. [Acute Gout in Emergency Admissions - Patient Characteristics and Adherence of Care Processes to Current Guidelines]. Z Orthop Unfall. 2018 Dec;156(6):653-661. [PubMed: 29986356]

48.

Buzas R, Tautu OF, Dorobantu M, Ivan V, Lighezan D. Serum uric acid and arterial hypertension-Data from Sephar III survey. PLoS One. 2018;13(7):e0199865. [PMC free article: PMC6028095] [PubMed: 29966019]

49.

FitzGerald JD, Dalbeth N, Mikuls T, Brignardello-Petersen R, Guyatt G, Abeles AM, Gelber AC, Harrold LR, Khanna D, King C, Levy G, Libbey C, Mount D, Pillinger MH, Rosenthal A, Singh JA, Sims JE, Smith BJ, Wenger NS, Bae SS, Danve A, Khanna PP, Kim SC, Lenert A, Poon S, Qasim A, Sehra ST, Sharma TSK, Toprover M, Turgunbaev M, Zeng L, Zhang MA, Turner AS, Neogi T. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Rheumatol. 2020 Jun;72(6):879-895. [PubMed: 32390306]

50.

Sadiq NM, Robinson KJ, Terrell JM. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 29, 2023. Colchicine. [PubMed: 28613754]

51.

Terkeltaub RA. Clinical practice. Gout. N Engl J Med. 2003 Oct 23;349(17):1647-55. [PubMed: 14573737]

52.

Leung YY, Yao Hui LL, Kraus VB. Colchicine--Update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015 Dec;45(3):341-50. [PMC free article: PMC4656054] [PubMed: 26228647]

53.

Doherty M, Jenkins W, Richardson H, Sarmanova A, Abhishek A, Ashton D, Barclay C, Doherty S, Duley L, Hatton R, Rees F, Stevenson M, Zhang W. Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial. Lancet. 2018 Oct 20;392(10156):1403-1412. [PMC free article: PMC6196879] [PubMed: 30343856]

54.

Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002 May 23;417(6887):447-52. [PubMed: 12024214]

55.

Milionis HJ, Kakafika AI, Tsouli SG, Athyros VG, Bairaktari ET, Seferiadis KI, Elisaf MS. Effects of statin treatment on uric acid homeostasis in patients with primary hyperlipidemia. Am Heart J. 2004 Oct;148(4):635-40. [PubMed: 15459594]

56.

Feher MD, Hepburn AL, Hogarth MB, Ball SG, Kaye SA. Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout. Rheumatology (Oxford). 2003 Feb;42(2):321-5. [PubMed: 12595630]

57.

Granados JC, Bhatnagar V, Nigam SK. Blockade of Organic Anion Transport in Humans After Treatment With the Drug Probenecid Leads to Major Metabolic Alterations in Plasma and Urine. Clin Pharmacol Ther. 2022 Sep;112(3):653-664. [PMC free article: PMC9398954] [PubMed: 35490380]

58.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jul 10, 2020. Probenecid. [PMC free article: PMC547852] [PubMed: 31643913]

59.

Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, Pillinger MH, Merill J, Lee S, Prakash S, Kaldas M, Gogia M, Perez-Ruiz F, Taylor W, Lioté F, Choi H, Singh JA, Dalbeth N, Kaplan S, Niyyar V, Jones D, Yarows SA, Roessler B, Kerr G, King C, Levy G, Furst DE, Edwards NL, Mandell B, Schumacher HR, Robbins M, Wenger N, Terkeltaub R., American College of Rheumatology. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken). 2012 Oct;64(10):1431-46. [PMC free article: PMC3683400] [PubMed: 23024028]

60.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Sep 5, 2017. Benzbromarone. [PMC free article: PMC547852] [PubMed: 31644041]

61.

Lee MH, Graham GG, Williams KM, Day RO. A benefit-risk assessment of benzbromarone in the treatment of gout. Was its withdrawal from the market in the best interest of patients? Drug Saf. 2008;31(8):643-65. [PubMed: 18636784]

62.

Reinders MK, van Roon EN, Jansen TL, Delsing J, Griep EN, Hoekstra M, van de Laar MA, Brouwers JR. Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis. 2009 Jan;68(1):51-6. [PubMed: 18250112]

63.

Hosoya T, Furuno K, Kanda S. A non-inferiority study of the novel selective urate reabsorption inhibitor dotinurad versus febuxostat in hyperuricemic patients with or without gout. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):71-79. [PMC free article: PMC7066279] [PubMed: 31970593]

64.

Hosoya T, Sano T, Sasaki T, Fushimi M, Ohashi T. Dotinurad versus benzbromarone in Japanese hyperuricemic patient with or without gout: a randomized, double-blind, parallel-group, phase 3 study. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):62-70. [PMC free article: PMC7066104] [PubMed: 31980978]

65.

Iqbal A, Iqbal K, Farid E, Ishaque A, Hasanain M, Bin Arif T, Arshad Ali S, Rathore SS, Malik M. Efficacy and Safety of Dotinurad in Hyperuricemic Patients With or Without Gout: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cureus. 2021 Apr 12;13(4):e14428. [PMC free article: PMC8114961] [PubMed: 33996294]

66.

Omura K, Miyata K, Kobashi S, Ito A, Fushimi M, Uda J, Sasaki T, Iwanaga T, Ohashi T. Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor. Drug Metab Pharmacokinet. 2020 Jun;35(3):313-320. [PubMed: 32327267]

67.

Kuriyama S. Dotinurad: a novel selective urate reabsorption inhibitor as a future therapeutic option for hyperuricemia. Clin Exp Nephrol. 2020 Mar;24(Suppl 1):1-5. [PMC free article: PMC7066308] [PubMed: 31754883]

68.

Wu JY, Chang YT, Lin YC, Lee CH, Loh EW, Wu MY, Chang YS, Tam KW. Efficacy and Safety of Lesinurad in Patients with Hyperuricemia Associated with Gout: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pharmacotherapy. 2018 Nov;38(11):1106-1119. [PubMed: 30246299]

69.

Cicero AFG, Fogacci F, Kuwabara M, Borghi C. Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update. Medicina (Kaunas). 2021 Jan 10;57(1) [PMC free article: PMC7827966] [PubMed: 33435164]

70.

Fam AG. Difficult gout and new approaches for control of hyperuricemia in the allopurinol-allergic patient. Curr Rheumatol Rep. 2001 Feb;3(1):29-35. [PubMed: 11177768]

71.

Qurie A, Preuss CV, Musa R. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jun 26, 2023. Allopurinol. [PubMed: 29763117]

72.

Aziz N, Jamil RT. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 25, 2023. Biochemistry, Xanthine Oxidase. [PubMed: 31424829]

73.

Rundles RW. The development of allopurinol. Arch Intern Med. 1985 Aug;145(8):1492-503. [PubMed: 3896181]

74.

Park S, Lee JP, Kim DK, Kim YS, Lim CS. Superior effect of allopurinol compared to febuxostat on the retardation of chronic kidney disease progression. PLoS One. 2022;17(2):e0264627. [PMC free article: PMC8884483] [PubMed: 35226683]

75.

Sarawate CA, Patel PA, Schumacher HR, Yang W, Brewer KK, Bakst AW. Serum urate levels and gout flares: analysis from managed care data. J Clin Rheumatol. 2006 Apr;12(2):61-5. [PubMed: 16601538]

76.

Singer JZ, Wallace SL. The allopurinol hypersensitivity syndrome. Unnecessary morbidity and mortality. Arthritis Rheum. 1986 Jan;29(1):82-7. [PubMed: 3947418]

77.

Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med. 1984 Jan;76(1):47-56. [PubMed: 6691361]

78.

Yaseen W, Auguste B, Zipursky J. Allopurinol hypersensitivity syndrome. CMAJ. 2023 Apr 03;195(13):E483. [PMC free article: PMC10069920] [PubMed: 37011932]

79.

Quach C, Galen BT. HLA-B*5801 Testing to Prevent Allopurinol Hypersensitivity Syndrome: A Teachable Moment. JAMA Intern Med. 2018 Sep 01;178(9):1260-1261. [PubMed: 30083702]

80.

Stamp LK, Taylor WJ, Jones PB, Dockerty JL, Drake J, Frampton C, Dalbeth N. Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum. 2012 Aug;64(8):2529-36. [PubMed: 22488501]

81.

Becker MA, Schumacher HR, Wortmann RL, MacDonald PA, Eustace D, Palo WA, Streit J, Joseph-Ridge N. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005 Dec 08;353(23):2450-61. [PubMed: 16339094]

82.

White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, Hunt B, Castillo M, Gunawardhana L., CARES Investigators. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018 Mar 29;378(13):1200-1210. [PubMed: 29527974]

83.

Gerriets V, Patel P, Jialal I. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 2, 2024. Febuxostat. [PubMed: 31334959]

84.

Ishikawa T, Maeda T, Hashimoto T, Nakagawa T, Ichikawa K, Sato Y, Kanno Y. Long-Term Safety and Effectiveness of the Xanthine Oxidoreductase Inhibitor, Topiroxostat in Japanese Hyperuricemic Patients with or Without Gout: A 54-week Open-label, Multicenter, Post-marketing Observational Study. Clin Drug Investig. 2020 Sep;40(9):847-859. [PMC free article: PMC7452866] [PubMed: 32621143]

85.

Schlesinger N, Lipsky PE. Pegloticase treatment of chronic refractory gout: Update on efficacy and safety. Semin Arthritis Rheum. 2020 Jun;50(3S):S31-S38. [PubMed: 32620200]

86.

Richette P, Doherty M, Pascual E, Barskova V, Becce F, Castañeda-Sanabria J, Coyfish M, Guillo S, Jansen TL, Janssens H, Lioté F, Mallen C, Nuki G, Perez-Ruiz F, Pimentao J, Punzi L, Pywell T, So A, Tausche AK, Uhlig T, Zavada J, Zhang W, Tubach F, Bardin T. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017 Jan;76(1):29-42. [PubMed: 27457514]

87.

Schlesinger N, Yasothan U, Kirkpatrick P. Pegloticase. Nat Rev Drug Discov. 2011 Jan;10(1):17-8. [PubMed: 21193861]

88.

Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci. 2007 Mar 02;4(2):83-93. [PMC free article: PMC1838823] [PubMed: 17396159]

89.

Ueng S. Rasburicase (Elitek): a novel agent for tumor lysis syndrome. Proc (Bayl Univ Med Cent). 2005 Jul;18(3):275-9. [PMC free article: PMC1200736] [PubMed: 16200184]

90.

Davidson MB, Thakkar S, Hix JK, Bhandarkar ND, Wong A, Schreiber MJ. Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome. Am J Med. 2004 Apr 15;116(8):546-54. [PubMed: 15063817]

91.

Pui CH, Mahmoud HH, Wiley JM, Woods GM, Leverger G, Camitta B, Hastings C, Blaney SM, Relling MV, Reaman GH. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol. 2001 Feb 01;19(3):697-704. [PubMed: 11157020]

92.

Majumdar S, Sharma N, Sengar M, Thorat J, Nayak L, Bonda A, Bagal B, Rajendra A, Sethi A, Jain H. A phase II study to evaluate the efficacy of low-dose rasburicase (1.5mg) in adolescent and adult acute leukemia and high-grade lymphomas with tumor lysis syndrome. Leuk Lymphoma. 2023 Mar;64(3):628-638. [PubMed: 36891578]

93.

Shaikh SA, Marini BL, Hough SM, Perissinotti AJ. Rational use of rasburicase for the treatment and management of tumor lysis syndrome. J Oncol Pharm Pract. 2018 Apr;24(3):176-184. [PubMed: 28077046]

94.

Adeyinka A, Bashir K. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Oct 31, 2022. Tumor Lysis Syndrome. [PubMed: 30085527]

95.

Padda IS, Bhatt R, Patel P, Parmar M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Feb 28, 2024. Pegloticase. [PubMed: 34283420]

96.

Sherman MR, Saifer MG, Perez-Ruiz F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv Drug Deliv Rev. 2008 Jan 03;60(1):59-68. [PubMed: 17826865]

97.

Sundy JS, Ganson NJ, Kelly SJ, Scarlett EL, Rehrig CD, Huang W, Hershfield MS. Pharmacokinetics and pharmacodynamics of intravenous PEGylated recombinant mammalian urate oxidase in patients with refractory gout. Arthritis Rheum. 2007 Mar;56(3):1021-8. [PubMed: 17328081]

98.

Hershfield MS, Ganson NJ, Kelly SJ, Scarlett EL, Jaggers DA, Sundy JS. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res Ther. 2014 Mar 07;16(2):R63. [PMC free article: PMC4060462] [PubMed: 24602182]

99.

Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, Vázquez-Mellado J, White WB, Lipsky PE, Horowitz Z, Huang W, Maroli AN, Waltrip RW, Hamburger SA, Becker MA. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011 Aug 17;306(7):711-20. [PubMed: 21846852]

100.

Sundy JS, Becker MA, Baraf HS, Barkhuizen A, Moreland LW, Huang W, Waltrip RW, Maroli AN, Horowitz Z., Pegloticase Phase 2 Study Investigators. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum. 2008 Sep;58(9):2882-91. [PubMed: 18759308]

101.

Botson JK, Saag K, Peterson J, Parikh N, Ong S, La D, LoCicero K, Obermeyer K, Xin Y, Chamberlain J, LaMoreaux B, Verma S, Sainati S, Grewal S, Majjhoo A, Tesser JRP, Weinblatt ME. A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings. Arthritis Rheumatol. 2023 Feb;75(2):293-304. [PMC free article: PMC10107774] [PubMed: 36099211]

102.

Botson JK, Obermeyer K, LaMoreaux B, Zhao L, Weinblatt ME, Peterson J. Improved joint and patient-reported health assessments with pegloticase plus methotrexate co-therapy in patients with uncontrolled gout: 12-month exploratory outcomes of the MIRROR open-label trial. Arthritis Res Ther. 2022 Dec 27;24(1):281. [PMC free article: PMC9793599] [PubMed: 36575505]

103.

KC M, Leslie SW. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Oct 15, 2023. Uric Acid Nephrolithiasis. [PubMed: 32809561]

104.

Leslie SW, Sajjad H, Bashir K. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Apr 30, 2024. 24-Hour Urine Testing for Nephrolithiasis: Interpretation and Treatment Guidelines. [PubMed: 29494055]

105.

Kaur P, Bhatt H. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): May 15, 2023. Hyperuricosuria. [PubMed: 32965872]

106.

Yu TF. Urolithiasis in hyperuricemia and gout. J Urol. 1981 Oct;126(4):424-30. [PubMed: 7288928]

107.

Yu KH, Chen DY, Chen JH, Chen SY, Chen SM, Cheng TT, Hsieh SC, Hsieh TY, Hsu PF, Kuo CF, Kuo MC, Lam HC, Lee IT, Liang TH, Lin HY, Lin SC, Tsai WP, Tsay GJ, Wei JC, Yang CH, Tsai WC. Management of gout and hyperuricemia: Multidisciplinary consensus in Taiwan. Int J Rheum Dis. 2018 Apr;21(4):772-787. [PubMed: 29363262]

108.

Janssen CA, Jansen TLTA, Oude Voshaar MAH, Vonkeman HE, van de Laar MAFJ. Quality of care in gout: a clinical audit on treating to the target with urate lowering therapy in real-world gout patients. Rheumatol Int. 2017 Sep;37(9):1435-1440. [PMC free article: PMC5570767] [PubMed: 28748426]

Disclosure: Christina George declares no relevant financial relationships with ineligible companies.

Disclosure: Stephen Leslie declares no relevant financial relationships with ineligible companies.

Disclosure: David Minter declares no relevant financial relationships with ineligible companies.