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Uric Acid Stones

  • Author: Sahar Fathallah-Shaykh, MD; Chief Editor: Craig B Langman, MD  more...
 
Updated: Oct 07, 2015
 

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).

Uric acid stones. Uric acid stones.

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.

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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)

  Neonates* Children Adults
29-33 wk 34-37 wk 38-40 wk 3-4 y 5-9 y 10-14 y 40-44 y
Male Female Male Female Male Female Male Female
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
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
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
*Gestational ages



Glomerular filtration rate



A printable version of this table is seen below.

Printer friendly version of the table. 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. [2, 3]
  • 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.
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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.

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.

  • 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.

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.

  • 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.
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Contributor Information and Disclosures
Author

Sahar Fathallah-Shaykh, MD Associate Professor of Pediatric Nephrology, University of Alabama at Birmingham School of Medicine; Consulting Staff, Division of Pediatric Nephrology, Medical Director of Pediatric Dialysis Unit, Children's of Alabama

Sahar Fathallah-Shaykh, MD is a member of the following medical societies: American Society of Nephrology, American Society of Pediatric Nephrology

Disclosure: Nothing to disclose.

Coauthor(s)

Richard Neiberger, MD, PhD Director of Pediatric Renal Stone Disease Clinic, Associate Professor, Department of Pediatrics, Division of Nephrology, University of Florida College of Medicine and Shands Hospital

Richard Neiberger, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Medical Association, American Society of Nephrology, American Society of Pediatric Nephrology, Christian Medical and Dental Associations, Florida Medical Association, International Society for Peritoneal Dialysis, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Shock Society, Sigma Xi, Southern Medical Association, Southern Society for Pediatric Research, Southwest Pediatric Nephrology Study Group

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Frederick J Kaskel, MD, PhD Director of the Division and Training Program in Pediatric Nephrology, Vice Chair, Department of Pediatrics, Montefiore Medical Center and Albert Einstein School of Medicine

Frederick J Kaskel, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, Eastern Society for Pediatric Research, Renal Physicians Association, American Academy of Pediatrics, American Pediatric Society, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, American Society of Transplantation, Federation of American Societies for Experimental Biology, International Society of Nephrology, National Kidney Foundation, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, The Ann and Robert H Lurie Children's Hospital of Chicago

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, International Society of Nephrology

Disclosure: Received income in an amount equal to or greater than $250 from: Alexion Pharmaceuticals; Raptor Pharmaceuticals; Eli Lilly and Company; Dicerna<br/>Received grant/research funds from NIH for none; Received grant/research funds from Raptor Pharmaceuticals, Inc for none; Received grant/research funds from Alexion Pharmaceuticals, Inc. for none; Received consulting fee from DiCerna Pharmaceutical Inc. for none.

Additional Contributors

Uri S Alon, MD Director of Bone and Mineral Disorders Clinic and Renal Research Laboratory, Children's Mercy Hospital of Kansas City; Professor, Department of Pediatrics, Division of Pediatric Nephrology, University of Missouri-Kansas City School of Medicine

Uri S Alon, MD is a member of the following medical societies: American Federation for Medical Research

Disclosure: Nothing to disclose.

References
  1. Baldree LA, Stapleton FB. Uric acid metabolism in children. Pediatr Clin North Am. 1990 Apr. 37(2):391-418. [Medline].

  2. Fujita T, Shimooka T, Teraoka Y, Sugita Y, Kaito H, Iijima K, et al. Acute renal failure due to obstructive uric acid stones associated with acute gastroenteritis. Pediatr Nephrol. 2009 Dec. 24(12):2467-9. [Medline].

  3. Kaneko K, Shimo T, Hirabayashi M, Ito T, Okazaki H, Harada Y. Cause of uric acid stones in rotavirus-associated gastroenteritis. Pediatr Nephrol. 2010 Oct. 25(10):2187-8. [Medline].

  4. Tasian GE, Copelovitch L. Evaluation and medical management of kidney stones in children. J Urol. 2014 Nov. 192 (5):1329-36. [Medline].

  5. Kato K, Sai S, Hirata T, et al. Two cases of ammonium acid urate urinary stones related to anorexia nervosa and laxative abuse. Hinyokika Kiyo.Mar. 2004. 50(3):181-5. [Medline].

  6. Madani A, Kermani N, Ataei N, Esfahani ST, Hajizadeh N, Khazaeipour Z. Urinary calcium and uric acid excretion in children with vesicoureteral reflux. Pediatr Nephrol. 2012 Jan. 27(1):95-9. [Medline].

  7. Torricelli FC, De S, Liu X, Calle J, Gebreselassie S, Monga M. Can 24-hour urine stone risk profiles predict urinary stone composition?. J Endourol. 2014 Jun. 28 (6):735-8. [Medline].

  8. Leng S, Shiung M, Ai S, Qu M, Vrtiska TJ, Grant KL, et al. Feasibility of discriminating uric acid from non-uric acid renal stones using consecutive spatially registered low- and high-energy scans obtained on a conventional CT scanner. AJR Am J Roentgenol. 2015 Jan. 204 (1):92-7. [Medline]. [Full Text].

  9. Oh MM, Ham BK, Kang SH, Bae JH, Kim JJ, Yoo KH, et al. Urine alkalinization may be enough for the treatment of bilateral renal pelvis stones associated with Lesch-Nyhan syndrome. Urol Res. 2011 Oct. 39(5):417-9. [Medline].

  10. Sakhaee K, Maalouf NM. Metabolic syndrome and uric acid nephrolithiasis. Semin Nephrol. 2008 Mar. 28(2):174-80. [Medline].

  11. Raj GV, Auge BK, Assimos D, Preminger GM. Metabolic abnormalities associated with renal calculi in patients with horseshoe kidneys. J Endourol. 2004 Mar. 18(2):157-61. [Medline].

  12. Undefined. [Medline].

  13. Barrat TM, PG Duffy. Nephrocalcinosis and Urolithiasis. Pediatric Nephrology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999. 933-46.

  14. Camron JS, F Moro. Gout, Uric Acid, and Purine Metabolism in Pediatric Nephrology. Pediatric Nephrology. 1993. Vol 7: 105-18.

  15. Johnson RJ, Kivlighn SD, Kim YG, et al. Reappraisal of the pathogenesis and consequences of hyperuricemia in hypertension, cardiovascular disease, and renal disease. Am J Kidney Dis. 1999 Feb. 33(2):225-34. [Medline].

 
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Uric acid stones.
Printer friendly version of the table.
Table 1. Serum Uric Acid levels and Urinary Acid Excretion in Neonates, Children, and Adults [1]
  Neonates* Children Adults
29-33 wk 34-37 wk 38-40 wk 3-4 y 5-9 y 10-14 y 40-44 y
Male Female Male Female Male Female Male Female
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
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
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
*Gestational ages



Glomerular filtration rate



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