Uric Acid Stones

Uric acid is a weak acid, with an ionization constant of acid (pK) of 5.8. At pH levels below the pK, uric acid is predominately found in a nonionized form. The urate ion is more soluble than the nonionized molecule. Urate ions (predominate form at a pH level of 7.4) are about 5% protein bound. Urate is filtered at the glomerulus. The renal tubule can reabsorb (movement of urate from tubule lumen to peritubular fluid) or secrete (movement of urate from peritubular fluid into tubular lumen) urate. Typically, net reabsorption occurs in infants and children. The fractional excretion of urate in infants and children ranges from about 0.1-0.6 (see the table below).

Table 1. Serum Uric Acid levels and Urinary Acid Excretion in Neonates, Children, and Adults ^[3] (Open Table in a new window)

A printable version of this table is seen below.

Printer friendly version of the table.

The fractional excretion of urate can exceed 1, indicating net urate secretion.

When the concentration of uric acid in urine exceeds its solubility at the urine pH, uric acid changes from a compound dissolved in solution to an insoluble precipitate. Urate stones are formed by 1 of 3 general mechanisms: overproduction, increased tubular secretion, or decreased tubular reabsorption.

Uric acid results as a relatively insoluble end-product of purine metabolism. The concentration of uric acid in plasma depends on dietary ingestion, de novo purine synthesis, and uric acid elimination by the kidneys and intestine. Normal uric acid excretion is shown in the table above.

Diseases that produce uric acid nephropathy or pure uric acid stones in children are rare. They may be considered in 5 basic groups. The evaluation should be directed at identifying one of the following:

• Group 1: The patient may have deficiencies in hypoxanthine-guanine phosphoribosyltransferase (HGPRT), adenine phosphoribosyltransferase, or xanthine dehydrogenase enzymes. Mutations for these gene products occur as autosomal recessive, spontaneous, or X-linked. Assess for a history of deficiency of these enzymes, family history of gout at a young age, renal stones with uric acid in other family members, or glycogen-storage disease. A previous history of painful gross hematuria is requested in the proband.

• Group 2: The patient may have tissue breakdown, which can produce large amounts of uric acid that precipitate in the nephron. This group includes children with primary leukemia and lymphoma. Other malignancies may produce uric acid nephropathy such as lung cancer, breast cancer, and pancreatic cancer; however, these conditions are very rare in children. Rotavirus-associated gastroenteritis can result in uric acid stones. This is thought to be mainly due to the hyperuricemia caused by tissue breakdown in the infected GI tract of the infants who are vulnerable to human rotavirus and to dehydration.[4, 5]

• Group 3: These children have genetic defects in renal tubular urate reabsorption. The defects are X-linked or sporadic, and these patients have hyperuricosuria with hypouricemia. The high urinary urate concentration in the scenario of low urine volume and low urine pH tends to promote crystallization. Uricosuric drugs (eg, cellulose sodium phosphate, colchicine, probenecid, sulfinpyrazone) inhibit renal tubular urate reabsorption, producing hyperuricosuria.

• Group 4: These children have hyperuricemia and hypouricosuria secondary to decreased renal excretion. This is due to decreased tubular secretion of uric acid rather than decreased filtered load. Children with familial juvenile gouty nephropathy are in this group. This condition is inherited in an autosomal dominant fashion. Several other children with similar pathology, which occurs in an isolated sporadic fashion, are reported. Glycogen-storage disease type I is also in this category.

• Group 5: These children develop hyperuricosuria with or without hyperuricemia secondary to oral purine intake. Although unusual, this may occur with a diet rich in purines (eg, children with cystic fibrosis who take enzymes rich in purines). It may occur in children on ketogenic diets because the increase in ketoacids probably competes with uric acid via organic anion secretory transporters. Several drugs, such as hydrochlorothiazide (HCTZ), inhibit uric acid excretion in a similar manner.

Uric acid stones are produced when the urinary uric acid concentration is increased secondary to overproduction, increased renal tubular urinary uric acid secretion, decreased renal tubular urinary uric acid reabsorption, decreased urinary water content, or increased hydrogen ion concentration.

Specific causes include the following purine enzyme defects, which lead to overproduction and increased urinary uric acid concentration:

• HGPRT deficiency

• PRPP synthetase overactivity

• Glucose-6-phosphatase deficiency

Other causes include increased nucleotide turnover secondary to cell death.

• Myeloproliferative and lymphoproliferative disorders

• Hemolytic anemia

• Cytotoxic drugs

Other causes include the following:

• Excessive dietary purine intake producing increased urinary uric acid concentration

• Hyperuricemia related to rotavirus gastroenteritis likely caused by tissue breakdown in the infected GI tract and dehydration in infants.[4, 5]

• Decreased glomerular filtration, renal tubular uric acid reabsorption, or both producing increased uric acid concentration in urine (eg, renal failure, acidosis, drugs, lead nephropathy)

• Dehydration produces decreased urine water content (ie, increased urine solute concentration) and increases urinary uric acid concentration.

United States statistics

The formation of uric acid stones in US children is infrequent. Studies suggest that fewer than 5% of renal stones detected in children are composed of uric acid.[6] No population-based studies are available. A review of several reports shows the incidence of uric acid stones to be between 4 per 100 children and 4 per 1000 children with renal stones presenting to academic medical centers.[7]

International statistics

The incidence of uric acid stones in most parts of the world is not known. Uric acid stones tend to be more frequently reported in urban societies than rural societies. Persons with higher dietary protein intake are more likely to develop uric acid stones. Variation in incidence among different parts of the world is likely.

In countries with a hot climate such as Pakistan, poor nutritionn and diarrheal diseases are the major causative factors of kidney stones and uric acid stones are present in 3-6% of stone formers.[8]

Race-, sex-, and age-related demographics

Race

Uric acid stones are more common in White children.

Sex

Uric acid stones are more frequent in boys than in girls.

Age

With Lesch-Nyhan syndrome, the HGPRT defect is greater than 95%. A severe disease occurs. Numerous individuals have been reported with 20-50% of normal HGPRT function who develop uric acid stones as their primary manifestation.

• Uric acid nephropathy (precipitation of urate crystals in renal tubules) and uric acid stones develop in people of any age (even infants or children). Occasionally, acute renal failure occurs secondary to crystal nephropathy in infants or children with inherited abnormalities of purine salvage enzymes. Renal failure produced by uric acid also occurs in children with leukemia and lymphoma as a component of tumor lysis disease. Children with Lesch-Nyhan disease may develop uric acid stones or nephropathy.

• Remember that prepubertal children have relatively high uric acid clearance; therefore, hyperuricosuria rather than hyperuricemia may be the primary manifestation of uric acid overproduction in high-risk children.

• Specific enzyme defects (ie, xanthine oxidase, phosphoribosyl pyrophosphate [PRPP] synthetase, adenine phosphoribosyltransferase, HGPRT) should be suspected if gout develops at an early age, if a family history of early gout is present, and if uric acid lithiasis is the first sign of excessive uric acid production.

The prognosis depends on the primary disease process. Children with cancer and Lesch-Nyhan syndrome tend to do worse than children with isolated HGPRT defects.

Morbidity/mortality

Complications of renal stone diseases include renal failure, infection, pain, urinary tract obstruction, renal colic, gross hematuria, pallor, vomiting, sweating, nausea, and insomnia. In addition, if surgical intervention is necessary, surgical complications may occur.

Mortality and morbidity are not increased with uric acid stones compared with other stones; however, the process that leads to excess uric acid production (eg, malignancy, Lesch-Nyhan syndrome) may cause death.

Children may experience frequent bouts of pain and gross hematuria due to frequent uric acid stones.

Complications

Complications of renal stone disease include the following:

• Bleeding

• Obstruction

• Infection

• Pain

• Complications of acute renal failure (ie, hypertension, hyperkalemia, pulmonary edema)

Inform patients about the specific disease process when possible.

Discuss the importance of diet, medication, and fluid intake in preventing new stone formation.

Indicate the importance of physician reevaluation if the child develops fever, pain, vomiting, dehydration, renal colic, or gross hematuria.

When obtaining the history, attempt to identify factors associated with hyperuricosuria such as the following:

• Lesch-Nyhan syndrome

• Familial gout

• Uricosuric medications

• Renal insufficiency

• Malignancy

• Polycythemia

• Hemolysis

• Lead exposure

• Purine disorders

• Sarcoidosis

• Glycogen-storage disease type I

• Congestive heart failure

• Dehydration

• Laxative abuse in females with anorexia nervosa[9]

• Rotavirus-associated gastroenteritis

• Vesicourethral reflux[10]

Infants with urate crystalluria may have pink-to-orange areas in their diapers after urination. If Serratia marcescens is also present, the diaper may appear red.

Renal stones, particularly in the upper urinary tract, cause pain, costovertebral angle tenderness, or both. The manifestations of pain are expressed differently in infants than in teenagers. Hematuria is most often present. Fever, nausea, and vomiting occur. Urinary tract infection may be present.

No physical findings are sensitive or specific for uric acid urolithiasis.

Children with inherited disorders such as trisomy 21, glycogen-storage disease, or Lesch-Nyhan syndrome may have physical findings consistent with their inherited disease.

Children with malignancy may have findings such as lymphadenopathy, hepatosplenomegaly, or paleness secondary to anemia.

Tophi (urate deposits) may be present.

Any child with a stone should have a 24-hour urine sample collected for analysis of calcium, magnesium, uric acid, citrate, sodium, and urine volume.[2] A spot urine pH level should be obtained.

Serum uric acid, 24-hour acid excretion, urine uric acid, creatinine, and serum creatinine can be used to assess uric acid production and excretion.

Blood should be obtained for measurement of blood urea nitrogen (BUN), creatinine, calcium, phosphorus, bicarbonate, uric acid, and parathyroid hormone levels.

• These test results are used to estimate the fractional excretion of uric acid.

• Reference range values for uric acid excretion by children and infants are shown in the table above.

• Results are used to determine if the elevated urinary uric acid concentration is caused by uric acid overproduction, decreased net renal tubular uric acid reabsorption, or increased net renal tubular uric acid secretion.

• Overproduction is indicated by high uric acid excretion for 24 hours with high or reference range serum uric acid levels and reference range or increased fractional excretion of uric acid.

• Decreased net renal tubular reabsorption or increased net tubular secretion is indicated by reference range or low uric acid excretion with low or low-normal serum uric acid and high fractional excretion of uric acid.

Once the problem is recognized as overproduction or increased tubular secretion or decreased net tubular reabsorption, specific testing for the primary cause can be undertaken.

Other tests

Any stones collected should be sent for crystallographic analysis.

For children, renal ultrasonography and abdominal flat plate radiography are as effective as intravenous pyelography (IVP) for identifying stones and do not expose the child to the risk of contrast agents. In addition, the radiation exposure is less. Renal ultrasonography is nonpainful, noninvasive, and creates no radiation exposure.[7] Ultrasonography can reveal hydronephrosis and, frequently, acoustic shadowing produced by a renal stone. Although the stone position can be identified, its composition cannot be determined using ultrasonography.

Noncontrast CT scanning (spiral CT scanning) is the most sensitive and specific study to search for uric acid stones.[7, 11] . A combination of stone size, attenuation intensity, and attenuation pattern from conventional computerized tomography can distinguish uric acid stones from calcium oxalate stones with high sensitivity and specificity.[12]  A meta-analysis by McGrath et al found that the use of dual-energy CT to detect uric acid–dominant stones had a sensitivity of 88% and a specificity of 98%; for uric acid–containing stones, dual-energy CT had a mean sensitivity of 82% and a specificity of 97%.[13]

Retrograde pyelography may be necessary to delineate upper tract anatomy and localize small or radiolucent calculi.

The primary treatments are to alkalinize (citrate or bicarbonate) and dilute (large water intake) the urine. Sodium urate is 15 times more soluble than uric acid. At a urine pH level of 6.8, 10 times as much sodium urate as uric acid is present. At a urine pH level of 7.8, 100 times as much urate as uric acid is present.

A systematic review showed that complete or partial dissolution of uric acid stones was achieved in 80.5% of patients who received medical therapy; of those patients, 61.7% had complete and 19.8% had partial dissolution.[14]  A study by Nevo et al, in which complete and partial dissolution of uric acid stones occurred in 33% and 22% of patients, respectively, demonstrated that successful medical therapy is more cost-effective than surgical management.[15]

Children with uric acid stones tend to have 1 of 3 types of presentations: (1) renal colic, gross hematuria, and infection; (2) renal colic with or without hematuria with one or more large stones or renal colic with or without hematuria with one or more small stones; and (3) one or more stones found incidentally.

• A child with severe acute pain and the likelihood of infection should be admitted to the hospital. Pain should be managed with analgesics and narcotics if necessary. A urine Gram stain may guide in the selection of antibiotic coverage. Consultation with a pediatric urologist should be obtained because surgery may be necessary to provide drainage.

• A child with acute pain and large stones (>0.3 cm) is likely to require lithotripsy or surgical stone removal. Analgesics and adequate hydration should be provided.

• For smaller stones or incidental stones, allowing time for the stone to pass is appropriate. The primary treatment for uric acid stones includes increased hydration (urine output increased to 30 mL/kg/24h) and alkalinization (urine pH level >7) of the urine. If uric acid overproduction is the problem, allopurinol may be indicated. In Lesch-Nyhan syndrome, uric acid stones may respond to hydration and urine alkalinization.[16] If increased urinary uric acid concentration is secondary to medication, substitution to another agent that is less uricosuric is suggested.

• In an infant or child with acute renal failure secondary to uric acid crystals, allopurinol and dialysis may be indicated in addition to supportive care for renal failure.

• Most children with uric acid calculi do not have hyperuricemia. Elevated serum uric acid levels are frequently due to dehydration and excessive purine intake. Consistently low urine pH is a risk factor for stone formation. As the urine pH level increases above the pK (5.8), uric acid forms the more soluble urate ion.

• Children with uric acid stones frequently describe passing gravel. With persistent urinary alkalinization and large urine output, urinary uric acid stones can dissolve with time.

Surgical treatments may include ureteroscopic stone extraction, percutaneous nephrolithotomy, open stone surgery, and extracorporal shock wave lithotripsy.

Stones may need to be removed by a pediatric urologist. The technique used depends on stone size and location.

The diagnosis of uric acid stones in a child mandates consultation with a pediatric nephrologist and urologist.

• Consulting a pediatric nephrologist is necessary to perform a metabolic evaluation and provide follow-up care for children with uric acid nephropathy or uric acid stones.

• Consultation with a pediatric urologist may be necessary for removal of uric acid stones.

Diet

Hydration is one of the most important dietary issues. The child should be encouraged to drink enough water to maintain a urine output of 30 mL/kg/d.[7]  The urine should be collected and measured until the quantity of water needed each day is understood. Most children have nocturia on this regimen. Water intake may need to be greater in the summer and in warm climates.

A diet low in purine (ie, limited quantities of liver, kidney, brains, sweetbreads, fish, poultry, asparagus, spinach, peas, and beans) may aid in lowering the total-body burden of uric acid and other purine metabolites. Children do not generally have problems with limiting the above items.

Activity

No change in activity is necessary.

Further outpatient care

The child should continue a low-purine diet if prescribed.

• Continue Bicitra (2-6 mEq/kg/d) for urinary alkalinization.

• Parents can be provided urine dipsticks to monitor urine pH level and specific gravity to assess the adequacy of treatment. Urine pH levels should be maintained above 7. Urine specific gravity should be maintained below 1.01.

• Fluid intake should be sufficient to maintain urine output of 30 mL/kg/24h or more.

• Allopurinol is continued to lower uric acid production if prescribed.

Children with urinary tract uric acid stones and/or urinary tract anatomic abnormalities or a previous urinary tract infection may require urinary tract infection uroprophylaxis.

A low-purine diet, allopurinol, Bicitra, and aggressive hydration should be continued. The goals are to dissolve present stones and to prevent new stones.

Further inpatient care

Inpatient care is indicated for management of renal failure, urologic surgery, severe pain, infection, or obstruction.

Prevention

A low-purine diet, urinary alkalinization, and large fluid intake may prevent new stones from forming.

The overall goal of medical treatment is to dissolve formed stones and prevent new stones from forming.

Citrate or bicarbonate is used to alkalinize the urine. Uric acid has 4 ionizable hydrogen ions (positions 1, 3, 7, and 9). Only the hydrogen ion on position 9 (pKa = 5.8) is ionizable at physiologic pH. Sodium urate is 15 times more soluble than uric acid. When pH levels equal the pKa (5.8), uric acid and sodium urate are present in equal quantities. As pH levels increase, the ratio of sodium urate to uric acid increases. At a pH level of 6.8, 10 times more sodium urate is present than uric acid; whereas, at a pH level of 7.8, 100 times more sodium urate is present than uric acid.

Class Summary

These agents are used to decrease the production of uric acid, thus lowering the serum and urine concentration of uric acid.

Allopurinol (Zyloprim)

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

Class Summary

These agents are used to alkalinize the urine and increase the solubility of uric acid.

Sodium citrate and citric acid (Bicitra)

Citrate is metabolized to bicarbonate. Several mixtures of citrate with sodium or potassium or both are available as alkalinizing agents. With normal hepatic function, 1 mEq of citrate is converted to 1 mEq of bicarbonate.