Background
Uric acid stones (see image below) are the most common cause of radiolucent kidney stones in children. Several products of purine metabolism are relatively insoluble and can precipitate when urinary pH is low. These include 2- or 8-dihydroxyadenine, adenine, xanthine, and uric acid. The crystals of uric acid may initiate calcium oxylate precipitation in metastable urine concentrates (see Xanthinuria).
The terms gouty nephropathy, urate nephropathy, and uric acid nephropathy are used to describe renal insufficiency due to uric acid precipitation within the renal tubules.
Uric acid urolithiasis or uric acid kidney stones refer to development of a stone or calculus composed of significant amounts of urate in the renal pelvis, ureter, or bladder.
Pathophysiology
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 [1] (Open Table in a new window)
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Neonates* |
Children |
Adults |
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29-33 wk |
34-37 wk |
38-40 wk |
3-4 y |
5-9 y |
10-14 y |
40-44 y |
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Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
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Serum uric acid (mg/dL) |
7.71±2.65 |
6.04±2.19 |
5.19±1.57 |
3.45±1.01 |
3.44±0.8 |
3.63±1.04 |
3.71±0.92 |
4.28±1.19 |
4.09±1.2 |
5.134±1.25 |
4.25±1.1 |
Uric acid excretion (mg/dL GFR†) |
4.8±2.23 |
2.81±0.93 |
1.69±0.84 |
0.34±0.11 |
0.403±0.095 |
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Uric acid excretion (mg/kg/d) |
N/A |
N/A |
19.6 |
13.5±3.75 (3 y) |
11.5±3.75 (7 y) |
9±3.75 (12 y) |
10 |
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Fractional excretion of uric acid (%) |
61.24±12.21 |
44.52±15.23 |
38.19±13.61 |
12±3.75 (3 y) |
10±3 (7 y) |
7.6±3.75 (12 y) |
7±1.6 |
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*Gestational ages † Glomerular filtration rate |
A printable version of this table is seen below.
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:
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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.
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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. [2, 3]
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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.
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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.
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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.
Epidemiology
Frequency
United States
The formation of uric acid stones in US children is infrequent. 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. [4]
International
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. [5]
Mortality/Morbidity
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.
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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.
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Children may experience frequent bouts of pain and gross hematuria due to frequent uric acid stones.
Race
Uric acid stones are more frequent 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.
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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.
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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.
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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.
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Uric acid stones.
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