Hyperuricosuria and Gouty Diathesis 

Updated: Jan 17, 2019
Author: Bijan Shekarriz, MD; Chief Editor: Bradley Fields Schwartz, DO, FACS 

Overview

Practice Essentials

Hyperuricosuria is defined as urinary excretion of uric acid greater than 800 mg/day in men and greater than 750 mg/day in women. Uric acid, the major end-product of purine metabolism, is relatively insoluble in water. This excess uric acid leads to the formation of uric acid calculi. Such high levels may be due to either excess dietary intake of purine-rich foods or endogenous uric acid overproduction. Hyperuricosuria may be associated with hyperuricemia. In contrast, the term gouty diathesis describes the formation of urinary stones in persons with primary gout. These patients may present with other manifestations of gout (eg, gouty arthritis).

Uric acid–related nephrolithiasis may involve pure calcium stones, uric acid stones, or a combination of both. Furthermore, uric acid stones may develop in persons with normal urinary and serum levels of uric acid. Unlike most other forms of urolithiasis, medical therapy is an integral part of management of uric acid stones. Therefore, an understanding of the pathophysiology of uric acid–related nephrolithiasis is important for a cost-effective treatment approach.

In patients with hyperuricosuria, dietary purine restriction is the initial treatment. If that proves insufficient, pharmacologic intervention with allopurinol may be considered, especially in patients with primary gout.[1]  

Pathophysiology

The urinary solubility of uric acid depends on its concentration in urine and the urinary pH. At a pH below 5.5, nearly 100% of uric acid exists in an undissociated form. The 3 mechanisms responsible for uric acid related stone formation include (1) an acidic urinary milieu, (2) dehydration, and (3) hyperuricosuria. One or more of these factors may be found in patients with uric acid–related calculi. However, persistently acidic urine (ie, pH < 5.5) is the most important factor observed in patients with uric acid stones. Patients with gouty diathesis have consistently acidic urine (pH < 5.5) and elevated levels of serum uric acid. Urine uric acid levels in these patients may be elevated or within the reference range.

Although the mechanism of low urinary pH in many patients may not be completely clear and can be multifactorial, studies suggest an association between diabetes and insulin resistance in patients with normal urinary uric acid levels and acidic urine.[2] Therefore, a subset of patients with idiopathic uric acid stones may have a broader systemic disorder of insulin resistance. A manifestation of insulin resistance is a mild defect in ammonium excretion that can result in stone formation. Acidic urine and uric acid stones have been reported as more common in patients with non–insulin-dependent diabetes than in patients with stones who do not have diabetes. The loss of diurnal variation in urinary pH and dietary content are other factors that contribute to acidity of the urine.

Hyperuricosuria is defined as urinary uric acid levels that exceed 800 mg/day in men and 750 mg/day in women. The most common cause of hyperuricosuria is increased dietary purine intake, but many other hereditary or acquired factors (eg, gout) may result in this condition. Individuals with hyperuricosuria may develop uric acid or calcium oxalate stones due to supersaturation of urine with monosodium urate. Monosodium urate may initiate calcium oxalate stone formation by the induction of heterogeneous nucleation or by absorption of certain inhibitors. Patients with calcium oxalate stones have a urinary pH of greater than 5.5.

Finally, all conditions that contribute to low urinary volume may increase uric acid supersaturation in urine and result in uric acid stone formation.

Etiology

Hyperuricosuric calcium nephrolithiasis is characterized by calcium oxalate or calcium phosphate stones in persons with hyperuricosuria. The hyperuricosuria is most commonly due to an excessively purine-rich diet; however, hyperuricosuria may be related to overproduction of uric acid in as many as 30% of these patients. This may represent a latent form of gout. In contrast to calcium-based stones, uric acid stones form in an acidic environment with a urinary pH that is always below 5.5.

The solubility of uric acid depends on three factors: urinary pH, uric acid concentration, and urinary volume. The causes of uric acid stones can be categorized according to those three factors.

Acidic urine may result from any of the following:

  • Gouty diathesis
  • Chronic diarrhea
  • Inflammatory bowel disease
  • Exercise/dehydration
  • Familial
  • Obesity, diabetes, and the metabolic syndrome - Strong association with low urinary pH [3]

Hyperuricosuria may result from any of the following:

  • Gouty diathesis
  • An excessively purine-rich diet
  • Inborn errors of metabolism (ie, hypoxanthine-guanine phosphoribosyl-transferase deficiency, phosphoribosylpyrophosphate synthetase overactivity, glucose-6-phosphatase synthetase deficiency
  • Myeloproliferative disorders (eg, leukemia, hemolytic anemia, neoplasia)
  • Medications
  • Chemotherapy

Low urinary volume may result from any of the following:

  • GI disorders
  • Strenuous exercise/dehydration

Epidemiology

In the United States, uric acid stones account for 5-10% of urinary stones. Approximately 15-20% of patients with calcium stones have hyperuricosuria. Up to 20% of patients with gout develop uric acid stones.[4]

The frequency of uric acid–related stones in other Western countries is similar to that in the United States; however, the proportion of uric acid stones varies between countries and accounts for 5% to 40% of all urinary calculi. For example, an analysis of stones in gout patients in Japan showed that the incidence of uric acid stones was 30%.[4]

In a retrospective study of 260 returning patients at a tertiary center in Israel, the prevalence of hyperuricosuria was 16.5%. Other metabolic abnormalities detected were hypocitraturia (60%), low urine volume (LUV) (60%), hypercalciuria (40.8%), hyperoxaluria (24.2%), and hyperuricemia (13.5%). Stone compositions was calcium-oxalate (81%), calcium-phosphate (11.9%) and uric acid (7.1%).[5]

In a cross-sectional study of 2,861 patients with kidney stones in the United Kingdom (2,016 male), the prevalence of hyperuricosuria was 18%. The prevalence of other risk factors included low urine volume, 5.6%; hypercalciuria, 38%; hyperoxaluria, 7.9%; and hypocitraturia, 38%. Most stones were mixed in composition, with around 90% containing some proportion of calcium salts.[6]

Approximately 80-90% of persons with hyperuricosuric calcium nephrolithiasis are men. Similarly, most individuals (70%) with calcium stones who do not have hyperuricosuria are also men. Uric acid stones are more common in men than in women. Most uric acid stones are not associated with gout. Dehydration and urine acidity predispose patients to uric acid stones. Gout is mainly a disorder of men; only 5% of cases occur in women.

Hyperuricosuric calcium nephrolithiasis and gouty diathesis usually manifest in middle-aged individuals. In men, the peak age of onset of clinical gout is approximately 45 years.

Prognosis

The prognoses of the familial and genetic forms depend on the primary disease and associated abnormalities. With appropriate diagnosis and treatment, most patients survive with minimal long-term morbidity. In the chronic phase, recurrent obstruction and infections rarely lead to loss of renal function.

Untreated urinary stones may result in urinary obstruction (with or without pain) and subsequent urinary tract infection. If severe, this may result in life-threatening urosepsis. This condition requires immediate resolution of obstruction.

Severe hyperuricemia may result in acute urate nephropathy in patients with myeloproliferative or lymphoproliferative disorders. The mechanism of urate nephropathy involves precipitation of urate within the renal tubules, with subsequent intratubular obstruction and severe azotemia.

Patient Education

With appropriate diet and medical therapy, uric acid–related urolithiasis is a preventable disease. Patients should be instructed to maintain a daily fluid intake sufficient to generate a urinary output of at least 1.5-2 L, to avoid an excessively purine-rich diet (eg, red meat, solid-organ meats), and to limit the sodium content of their diet.

Patients with uric acid stones should be instructed to measure their urinary pH at home with the aid of nitrazine pH paper and to adjust their dosage of the alkalinizing agent accordingly. Generally, achieving and maintaining a urinary pH in the range of 6.5-7.0 requires a motivated and compliant patient. 

UriDynamics, Inc offers an improved urinary dipstick (Stone Guard 2) specifically designed for patient use to monitor urine pH. The authors usually recommend checking urine pH 3 times per day and then adjusting oral alkalinization and retesting until the daily urinary pH is in the desired range. Testing can then be reduced to once per day or even less depending on the individual’s daily variation.

For patient education information, see Gout.

 

Presentation

History

Acute phase

Hyperuricosuria that results in stone formation can present as pain, gastrointestinal signs and symptoms, and urinary signs and symptoms.

Pain 

As with many other stone types, patients with uric acid–related urinary calculi may present with acute renal or ureteral colic. A typical episode occurs suddenly during the night. The pain is abrupt in onset and does not resolve with rest or change in position. In contrast to someone with an acute abdomen who is stationary, patients experiencing acute renal colic frequently move in unusual positions in an effort to relieve their severe pain.

Some patients may experience a gradual onset of pain, resulting in a dull chronic ache in the flank region. The location of pain varies depending on stone location and may shift from the flank to the anterior abdominal wall, groin, and, eventually, to the ipsilateral testicle or labia.

The severity of pain is often inversely proportional to the size of the stone. Large renal staghorn calculi rarely result in acute renal colic, as is observed with smaller ureteral stones. The degree and type of pain is not specific to any particular stone composition.

Gastrointestinal manifestations

Nausea and vomiting are frequently associated with urolithiasis. Patients may report altered bowel habits, including diarrhea or constipation.

Urinary manifestations

Patients with ureteral stones lodged near the bladder often report dysuria, frequency, and urgency. Furthermore, gross hematuria may be observed. Eighty-five percent of patients present with either gross or microscopic hematuria. Some patients may present with an associated urinary tract infection. Rare, severe, gas-forming infections may result in pneumaturia.

The vast majority of ureteral stones that pass into the bladder transit the urethra uneventfully. A ureteral stone passed into the bladder rarely causes urinary obstruction; these persons usually report an interrupted stream. Unlike in cats, in whom stones frequently become inspissated in the urethra, resulting in renal failure and/or death, stones rarely become obstructed in the human urethra.

Chronic phase

A history of gout and associated joint disease are important clues in discerning the etiology. The use of probenecid (a known uricosuric agent) in patients with gout may result in hyperuricosuria and increase the risk of uric acid stone formation. Uricosuric agents such as probenecid specifically increase urinary uric acid levels to help decrease hyperuricemia and to reduce gout attacks. When they cause hyperuricosuria or uric acid calculi, alternate therapies for the hyperuricemia should be used.

Myeloproliferative disorders, especially in children, may result in hyperuricosuria and associated urinary stones. Furthermore, chemotherapy for myeloproliferative disorders can lead to tumor necrosis and a massive increase in the endogenous purine pool, which may result in severe hyperuricosuria, crystalluria, and acute urinary obstruction. In these patients, the rate of uric acid stone formation is approximately 40%, which is much higher than in patients with gout.

Obtaining a dietary history is important to help elucidate iatrogenic causes of hyperuricosuria, including an excessive intake of purine-rich foods and excessive weight loss, which result in a catabolic state and increased uric acid production.[7]

A hereditary form of hyperuricemia and hyperuricosuria is Lesch-Nyhan syndrome, which may be associated with urinary calculi. These patients have a deficiency in the enzyme hypoxanthine-guanine phosphoribosyl-transferase. This enzyme catalyzes the salvage pathway of purines and is responsible for the conversion of hypoxanthine to inosinic acid and guanine to guanylic acid. If the enzyme is deficient, low levels of guanylic and inosinic acid occur with a subsequent increase in de novo purine synthesis because these nucleotides modulate purine synthesis by feedback inhibition.

Long-standing malaise and lethargy may be associated symptoms of urinary obstruction with or without infection.

Physical Examination

Costovertebral angle tenderness is common during acute renal colic. Abdominal distention and tenderness secondary to ileus may also occur. In cases with associated urinary tract infection, fever is common.

After resolution of the acute stone event, patients may be asymptomatic or may present with physical findings related to the underlying disease. For example, patients with gout may present with chronic joint changes (ie, tophi) due to gouty arthritis.

 

DDx

Diagnostic Considerations

Other problems to be considered in the differential diagnosis include the following:

  • Musculoskeletal disorders

  • Herniated disc

  • Renal artery embolism

Differential Diagnoses

 

Workup

Laboratory Studies

Laboratory evaluation should include urinalysis and urine culture. In patients with known uric acid stones, urinary pH should be recorded using pH paper. Blood chemistry tests should include the following:

  • Calcium

  • Phosphorus

  • Electrolytes

  • Creatinine

  • Uric acid

  • Parathyroid hormone levels

Perform a 24-hour urine collection for volume, pH, calcium, uric acid, oxalate, citrate, phosphorus, sodium, and creatinine analysis after the acute stone event has resolved. This test should help elucidate the metabolic abnormality associated with stone formation. The most common urinary abnormalities in patients with uric acid stones are persistently acidic urine (< 5.5), low volume, and hyperuricosuria.

Imaging Studies

All patients with questionable urinary calculi should undergo a baseline radiologic evaluation, including a scout film (ie, kidneys, ureters, bladder [KUB]). The scout film is useful not only as a baseline for tracking radiopaque calculi, but also for establishing radiolucency of possible uric acid stones.

Pure uric acid stones are relatively radiolucent but produce a bright-white signal on noncontrast CT scans. The diagnosis of uric acid stones can be suggested by a persistent urinary pH of less than 5.5, uric acid crystals visible on microscopic urinalysis, hyperuricemia, a KUB study that fails to show a calcific stone, or a history of gout or previous uric acid calculi.

CT scan demonstrating right partial staghorn uric CT scan demonstrating right partial staghorn uric acid calculus. Uric acid stones appear dense on CT scan and radiolucent on kidneys, ureters, and bladder (KUB) imaging (not shown).
Follow-up CT scan of patient in the image above (i Follow-up CT scan of patient in the image above (ie, with partial staghorn uric acid calculus) 1 year later. This patient was treated with oral urinary alkalinization with sodium bicarbonate. Note only a small residual fragment is present (right image).

Intravenous urography (ie, intravenous pyelography [IVP]) or renal ultrasonography may be useful. Contrast is used for IVP, which can make a uric acid stone appear as a filling defect, especially in the renal pelvis. Ultrasonography is a very good tool for identifying and tracking larger uric acid calculi, especially in the renal pelvis, because their radiolucency does not affect sonograms. This modality is less useful for ureteral calculi.

Noncontrast CT scanning is the imaging modality of choice for the differential diagnoses of urinary calculi. With noncontrast CT scanning, uric acid calculi, despite being radiolucent on conventional radiographs, appear as bright-white images, as do other calculi. The average density readings of uric acid stones on CT scans are substantially less than calcium-containing stones but are still well above the threshold of optical visualization as anything but a bright-white spot. In these cases, performing KUB imaging at the same time as CT scanning is essential to help indicate that the stone is relatively radiolucent and therefore likely to be composed of uric acid. If the stone is located in the kidney, ultrasonography can be particularly useful for tracking the progress or dissolution of the stone.

Uric acid and non-uric acid renal stones can be differentiated using two consecutive spatially registered low- and high-energy scans acquired on a conventional CT scanning system. In a study of 33 patients who underwent clinically indicated dual-source dual-energy CT followed by two consecutive scans (at 80 kV and 140 kV) on a conventional CT scanner over the region identified on the initial scan, the overall sensitivity, specificity, and accuracy for identifying uric acid stones were 73.1%, 90.1%, and 89.1%, respectively. For stones 3 mm or larger, the sensitivity, specificity, and accuracy were 94.7%, 96.9%, and 96.8%, respectively.[8]

In rare circumstances (eg, intravenous contrast allergy, unavailability of CT scanning), retrograde pyelography may help to confirm the diagnosis.

 

Treatment

Medical Care

In the acute phase, the primary goals are symptomatic relief with hydration for the euvolemic state and adequate pain management. When the acute stone episode has resolved, the cornerstones of medical treatment are urinary alkalinization (ie, pH 6.5-7.0), hydration (ie, urinary output 1500-2000 mL/d), and allopurinol (ie, patients with hyperuricosuric calcium nephrolithiasis) to decrease serum and urinary uric acid levels. The authors have observed impressive dissolution of large uric acid stones (staghorn) with oral alkalinization (see the images below). These measures are effective for dissolving existing uric acid stones and for stone prophylaxis.

CT scan demonstrating right partial staghorn uric CT scan demonstrating right partial staghorn uric acid calculus. Uric acid stones appear dense on CT scan and radiolucent on kidneys, ureters, and bladder (KUB) imaging (not shown).
Follow-up CT scan of patient in the image above (i Follow-up CT scan of patient in the image above (ie, with partial staghorn uric acid calculus) 1 year later. This patient was treated with oral urinary alkalinization with sodium bicarbonate. Note only a small residual fragment is present (right image).

Febuxostat, an xanthine oxidase inhibitor, has been shown to decrease urinary uric acid excretion in calcium stone formers with hyperuricosuria. However, its role in preventing calcium or even uric acid stones remains to be defined and warrants future investigations.[1]

Surgical Care

In the acute phase, surgical intervention may be indicated to relieve urinary obstruction associated with infection or to relieve pain in patients who are not responding to medical treatment. Furthermore, a complete or high-grade ureteral obstruction may require intervention irrespective of the clinical symptoms. In all these circumstances, the urinary obstruction should be relieved. This may be achieved by retrograde insertion of a ureteral stent or a percutaneous nephrostomy tube.

Once the acute stone event has subsided, urinary alkalinization is the treatment of choice for dissolution of uric acid stones. Percutaneous or retrograde irrigation with alkalinizing agents was a common practice in the past. It was mainly used for dissolution of residual stone fragments after percutaneous or retrograde manipulations or in patients who did not tolerate systemic alkalinization. The most commonly used solutions are sodium bicarbonate (pH 7.0-8.0), tromethamine (THAM, pH 8.6), and 0.3 M tromethamine E (THAM-E, pH 10.5). These procedures require prolonged hospitalization and are currently not cost-effective compared with modern endourological modalities.

Surgical intervention (eg, percutaneous nephrolithotomy) may be necessary for treating large uric acid stones that do not dissolve with medical management.

Hyperuricosuric calcium stones are not amenable to chemolysis; surgical intervention may be indicated based on stone size.

Extracorporeal shockwave lithotripsy (ESWL) is the primary mode of treatment for renal and proximal ureteral stones up to 2.5 cm in maximal diameter. Uric acid stones fragment easily with ESWL, and this modality may improve oral chemolysis by increasing the stone surface. Larger stones may require percutaneous nephrolithotripsy. Intravenous or retrograde contrast via ureteral catheters or double-J stents may be necessary for visualization of the uric acid calculi during ESWL.

Ureteroscopy and intracorporeal lithotripsy are the treatments of choice for most large or impacted distal ureteral stones. All intracorporeal lithotripsy modalities, such as electrohydraulic, ultrasonic, or laser, are effective for uric acid stone fragmentation.

Consultations

Consultation with an internal medicine specialist may be helpful for gout. An oncologist may be consulted for management of myeloproliferative disease.

Diet

A diet with high fluid intake, low sodium intake, and moderate protein intake is recommended. Low sodium intake reduces sodium urinary excretion, which reduces monosodium urates that are catalysts for hyperuricosuric calcium nephrolithiasis. Additionally, decreased sodium intake reduces sodium urinary excretion, which reduces urinary calcium excretion.

Activity

Individuals with sedentary and white-collar occupations are at an increased risk for urinary stones; therefore, regular physical exercise may be beneficial in all persons who form stones. Physical activity may facilitate stone passage during acute renal colic.

Long-Term Monitoring

All patients should undergo regular follow-up imaging studies with KUB imaging, renal ultrasonography, or unenhanced CT scanning, as indicated. Measuring urinary pH is important to monitor the efficacy of urinary alkalinization and to adjust medications accordingly. A repeat 24-hour urinary collection after initiation of medical therapy is beneficial. Furthermore, with any significant change in medication or diet, a repeat 24-hour urinary collection is indicated.

Patients may titrate their own urinary alkalinization program with the aid of Nitrazine pH paper or other available pH monitoring systems. One should strive to maintain a urinary pH of 6.5-7.0. Medications may need to be adjusted during certain periods of the day.

 

Guidelines

Guidelines Summary

The American Urological Association (AUA) guidelines for medical management of kidney stones include the following treatment recommendations relevant to hyperuricosuria[9] :

  • Fluid intake should be sufficient to achieve a urine volume of at least 2.5 liters daily. 
  • Patients with uric acid stones or calcium stones and relatively high urinary uric acid should limit intake of non-dairy animal protein. 
  • Allopurinol should be offered to to patients with recurrent calcium oxalate stones who have hyperuricosuria and normal urinary calcium, but should not routinely be offered as first-line therapy for uric acid stones. 

 

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Allopurinol has been associated with the development of hemorrhagic skin lesions, exfoliation, and a rare fatal systemic vasculitis. Pruritus often precedes the development of rash and should prompt patients to discontinue the medication. Alterations in hepatic function and jaundice have been reported with allopurinol use; these complications require monitoring of serum liver function test results soon after the institution of therapy. Allopurinol may result in an acute gouty attack in patients with hyperuricemia.

Urinary alkalinizing agents

Class Summary

The most important medications used for the dissolution or prevention of uric acid urinary stones are alkalinizing agents (eg, potassium citrate) to increase the urinary pH to 6.5-7.0. Balanced citrate alkali (eg, potassium citrate; Urocit-K, Polycitra-K) are the most commonly used medications. Sodium and potassium bicarbonate are also used frequently. One disadvantage of sodium alkali is that the increased sodium and fluid load may be detrimental to patients with renal failure, liver failure, or congestive heart failure.

Alternatively, citrate supplementation may be given. Citrate inhibits calcium oxalate crystallization directly and by complexing with calcium in solution to reduce its concentration and availability. Potassium citrate is preferred over sodium citrate because it is not associated with a sodium load. Potassium citrate comes in a slow-release wax-based tablet, which may be seen as an intact tablet in the stool; however, the citrate has been absorbed. Patients should be warned that this may occur.

For patients who are not tolerant of or compliant with a frequent dosing schedule, a single evening dose may be quite beneficial to increase the urinary pH (alkaline tide) overnight.

Potassium citrate can also be given as a crystal preparation. The advantage of this preparation is that it forces patients to increase their fluid intake. Potassium citrate may be given in liquid preparations, with and without glucose additives. Finally, lemonade has been shown to increase urinary citrate levels and is an alternative or supplement to pharmacologic formulations.

The primary treatment for uric acid stones is urinary alkalinization. Surprisingly, it is not associated with hypocitraturia. Allopurinol should be added to the therapeutic regimen in the presence of associated hyperuricemia, hyperuricosuric calcium stone disease, intolerance of alkali, or continuing uric acid stone production despite alkalinization therapy. Initial dosing should be 300 mg/d.

Potassium citrate (Urocit-K, Polycitra-K)

Available as tab, syr, and crystals. All forms should be taken with water or juice according to directions.

Potassium bicarbonate/potassium citrate (Effer-K, K-Ide, Klor-Con/EF, K-Lyte)

Needed for conduction of nerve impulses in heart, brain, and skeletal muscle. Helps maintain normal renal function. Plays role in contraction of cardiac, skeletal, and smooth muscles. All PO forms of potassium bicarbonate should be taken with adequate fluids according to directions.

Sodium bicarbonate (Neut)

Excellent urinary alkalinization agent. Dissociates to provide bicarbonate ion, which neutralizes hydrogen ion concentration and raises blood and urinary pH.

Antihyperuricemic agents

Class Summary

In cases of hyperuricemia or significant hyperuricosuria, allopurinol is effective. This drug inhibits the conversion of hypoxanthine and xanthine to uric acid. In patients with hyperuricosuric calcium stones, treatment involves reducing the monosodium urate–induced calcium oxalate crystallization. This is accomplished by decreasing urinary uric acid excretion and limiting dietary sodium intake (< 150 mEq/d). Patients should initially be treated with dietary purine and sodium restriction. In approximately 30% of patients, hyperuricosuria is due to uric acid overproduction and does not improve with dietary restriction. In this situation and in patients intolerant of diet restriction, allopurinol is the medication of choice.

Allopurinol (Zyloprim)

Inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. Reduces the synthesis of uric acid without disrupting the biosynthesis of vital purines.