INTRODUCTION	Section 2 of 11
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Background: Uric acid is the major end-product of purine metabolism. Uric acid is relatively insoluble in water, which leads to the formation of uric acid calculi. Hyperuricosuria is defined as urinary excretion of uric acid greater than 800 mg/d in men and greater than 750 mg/d in women. This 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 patients with primary gout. These patients may be otherwise asymptomatic or 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 occur in patients 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.

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 are (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. Persistently acidic urine (ie, pH <5.5) is the most important factor predisposing patients with gout to the formation of uric acid stones. Monosodium urate may initiate calcium oxalate stone formation by the induction of heterogeneous nucleation or by absorption of certain inhibitors. Patients with hyperuricosuric calcium stones have a urinary pH of greater than 5.5.

Frequency:

• In the US: 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.

• Internationally: Other Western countries have a similar frequency of uric acid–related stones; however, the incidence varies in other countries and some geographic differences may exist. In Israel, for example, uric acid stones have been found in approximately 40% of individuals who form stones. Uric acid bladder stones are a common problem in children in rural Southeast Asia.

Mortality/Morbidity:

• With appropriate diagnosis and treatment, most patients survive with minimal long-term morbidity. The prognosis of the familial and genetic forms is dependent on the primary disease and associated abnormalities.

Race:

• A familial form of uric acid lithiasis, with an ethnic predilection for individuals of Jewish and Italian descent, has been described.

Sex:

• Between 80-90% of patients with hyperuricosuric calcium nephrolithiasis are men, compared to approximately 70% of patients with calcium stones and not hyperuricosuria.

• Gout is mainly a disorder of men, and only 5% of cases occur in women.

• Uric acid stones occur more commonly in men than in women. Most uric acid stones are not associated with gout. Dehydration and urine acidity predispose patients to uric acid stones.

Age:

• 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.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History:

• Acute phase

• Pain symptoms are discussed as follows:
  • Similar to patients 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 episode is abrupt 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.

  • When the stone is lodged in the ureterovesical junction, patients frequently complain of marked urinary frequency and urgency.

  • 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.

• GI symptoms include the following:
  • Nausea and vomiting are frequently associated with urolithiasis.

  • Patients may complain of altered bowel habits, including diarrhea or constipation.

• Urinary symptoms include the following:
  • When ureteral stones are near the bladder, patients often complain of 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, ie, with patients complaining of an interrupted stream. Unlike our feline friends, 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 an increased risk of uric acid stone formation. Uricosuric agents such as probenecid specifically increase urinary uric acid levels to help decrease hyperuricemia and 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, a massive increase in the endogenous purine pool due to tumor necrosis may result in severe hyperuricosuria, crystalluria, and acute urinary obstruction during chemotherapy for myeloproliferative disorders. In these patients, the rate of uric acid stone formation is approximately 40%, which is much higher compared to 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.

• A hereditary form of hyperuricemia and hyperuricosuria is the 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 an associated symptom of urinary obstruction with or without infection.

Physical:

• Costovertebral angle tenderness is common during acute renal colic. Abdominal distention and tenderness secondary to ileus may also be observed.

• In cases with associated urinary tract infection, fever is commonly present.

• After resolution of the acute stone event, patients may be asymptomatic, or they 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.

Causes: Hyperuricosuric calcium nephrolithiasis is characterized by calcium oxalate or calcium phosphate stones in patients with hyperuricosuria. The hyperuricosuria most commonly is due to excessive intake of a 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 3 factors: (1) urinary pH, (2) uric acid concentration, and (3) urinary volume. Based on these factors, the causes of uric acid stones can be categorized as follows:

• Acidic urine

• Gouty diathesis

• Chronic diarrhea

• Inflammatory bowel disease

• Exercise/dehydration

• Familial

• Hyperuricosuria

• Gouty diathesis

• Excessive intake of a purine-rich diet

• Inborn errors of metabolism
  • Hypoxanthine-guanine phosphoribosyl-transferase deficiency

  • Phosphoribosylpyrophosphate synthetase overactivity

  • Glucose-6-phosphatase synthetase deficiency

• Myeloproliferative disorders
  • Leukemia

  • Hemolytic anemia

  • Neoplasia

• Medications

• Chemotherapy

• Low urinary volume

• GI disorders

• Strenuous exercise/dehydration