eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Xanthinuria

Sahar Fathallah-Shaykh, MD, Assistant Professor in Pediatric Nephrology, Northwestern University Feinberg School of Medicine; Consulting Staff, Division of Kidney Diseases, Children's Memorial Hospital
Steven C Diven, MD, Medical Director of Pediatric Dialysis Unit, Assistant Professor, Department of Pediatrics, University of Texas Medical Branch at Galveston

Updated: Jul 8, 2008

Introduction

Background

Xanthinuria is a descriptive term for excess urinary excretion of the purine base xanthine. Two inherited forms of xanthinuria principally result from a deficiency of the enzyme xanthine dehydrogenase, which is the enzyme responsible for degrading hypoxanthine and xanthine to uric acid. Deficiency of xanthine dehydrogenase results in plasma accumulation and excess urinary excretion of the highly insoluble xanthine, which may lead to arthropathy, myopathy, crystal nephropathy, urolithiasis, or renal failure. Hypoxanthine does not accumulate to an appreciable degree because it is recycled through a salvage pathway by the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT). Xanthine continues to accumulate, despite the recycling of hypoxanthine, because of the metabolism of guanine to xanthine by the enzyme guanase (see Media file 1).

Classic xanthinuria

Classic xanthinuria is one form of xanthinuria that is divided into 2 types based on the enzyme deficiency. Both types are inherited in an autosomal recessive manner.

Classic xanthinuria type I is the result of an isolated deficiency of xanthine dehydrogenase.
Type II xanthinuria is characterized by a deficiency of xanthine dehydrogenase and a related enzyme, aldehyde oxidase.

The distinction between the 2 types is based on the ability or inability to oxidize allopurinol, a substrate for xanthine dehydrogenase and aldehyde oxidase. Allopurinol is oxidized to oxypurinol by the normal function of aldehyde oxidase in patients with type I; however, allopurinol is not converted in patients with type II, who lack aldehyde oxidase activity. Other substrates that are oxidized by aldehyde oxidase, such as pyrazinamide and N -methylnicotinamide, can be used to distinguish between types I and II.

Molybdenum cofactor deficiency

The other inherited form of xanthinuria, termed molybdenum cofactor deficiency, presents in the neonatal period with microcephaly, hyperreflexia, and other CNS manifestations. Other reported manifestations include severe metabolic acidosis and intracranial hemorrhage. This condition is inherited recessively and is caused by a congenital defect of a molybdenum-containing cofactor essential for the function of 3 distinct enzymes (ie, xanthine dehydrogenase, aldehyde oxidase, sulfite oxidase). This defect is caused by the mutation of molybdenum cofactor genes (MOCS1 or MOCS2). Xanthinuria is only a marker in this setting because (1) the clinical presentation is overshadowed by neurologic manifestations and (2) death in the first year of life is caused by the deficiency of sulfite oxidase, which is the final step in cysteine metabolism.

Iatrogenic xanthinuria

Iatrogenic xanthinuria can occur during allopurinol therapy, which is used to reduce urine uric acid excretion in conditions with endogenous overproduction of uric acid. Inhibition of xanthine dehydrogenase by allopurinol may lead to accumulation and urinary excretion of xanthine. Patients with Lesch-Nyhan syndrome or patients with partial HGPRT deficiency have developed xanthine nephropathy, acute kidney failure, and stones following treatment with allopurinol.¹ A few incidents of xanthine nephropathy and renal failure have been reported in patients treated with allopurinol during chemotherapy for malignancy. The latter occurred either when large doses of allopurinol were used or during aggressive therapy for a large tumor cell burden with concomitant allopurinol therapy.

This discussion focuses on the classic and iatrogenic forms of xanthinuria in children.

Pathophysiology

The primary organs affected in xanthinuria are the kidney and, to a lesser extent, skeletal muscle and joints. Kidney complications are initiated by the formation of xanthine crystals in the tubules, leading to parenchymal deposition and/or radiolucent stone formation. Xanthine's high rate of renal clearance and low solubility in urine creates an environment in the urine favoring crystallization. Thus, patients with volume depletion who have xanthinuria are at particular risk of forming xanthine crystals. Irritation of the tubular epithelium by xanthine crystals results in hematuria, whereas renal tissue deposits induce an inflammatory reaction and consequent interstitial nephritis. Urolithiasis is the most common clinical manifestation of the xanthinuric states. Further renal complications include acute and chronic renal failure and even end-stage renal disease.

Myopathy and arthropathy are rare clinical manifestations of xanthinuria that have been described in older patients. Clinical manifestations of the myopathy (eg, muscle cramps, muscle pain, muscle stiffness) are believed to be the result of long-term accumulation of xanthine and hypoxanthine crystals in the muscle; this has been demonstrated in skeletal muscle biopsies in a few symptomatic patients. A form of myopathy has been described in one patient following vigorous exercise, which led to the postulate that heavy muscle use leads to an intracellular acid environment favoring xanthine and hypoxanthine crystal formation and deposition in muscle tissue. Hypoxanthine serum levels are also increased after vigorous exercise (eg, distance running) in healthy subjects and in patients with xanthinuria.

Arthropathy induced by xanthine crystal deposition has been demonstrated in animals. Although not clearly demonstrated in humans, arthritis and arthralgia are believed to be secondary to xanthine crystal deposition in the joints.

Frequency

United States

True incidence of classic xanthinuria is unknown because it is rarely reported. Surveys suggest a population incidence of 1 case per 6,000 population to 1 case per 69,000 population. Distribution of patients with type I and type II is approximately equal. The incidence of iatrogenic xanthinuria is unknown.

International

Most reported cases are from Mediterranean and Middle Eastern countries.

Mortality/Morbidity

Although the death rate is unknown and unexpected, death can result as a complication of unrecognized or untreated renal failure. Nearly 40% of patients with classic xanthinuria present with symptoms related to urolithiasis (eg, hematuria, renal colic, urinary tract infection, acute renal failure).

Race

Xanthinuria or xanthine dehydrogenase deficiency is reported in diverse ethnicities, although most reported incidents occur in Mediterranean and Middle Eastern countries. Consanguinity and an arid climate appear to have a significant role in the higher incidence in these populations.

Sex

Classic xanthinuria is more common in males than in females.

Age

Nephrotoxicity from classic xanthinuria can occur at any age, although more than one half of the incidents of urolithiasis occur in children younger than 10 years. Myopathy and arthropathy occur more often in older patients with xanthinuria.

Clinical

History

Symptoms are nonspecific and relate to the underlying pathophysiology and secondary complications. In young children, irritability, vomiting, and failure to thrive may be the presenting symptoms. At any age, the patient may present with gross or microscopic hematuria, pyuria, renal colic, dysuria, urinary frequency, urine incontinence, polyuria, abdominal pain, or symptoms of a urinary tract infection. Joint pain and muscle cramps or muscle pain are symptoms of the arthropathy and myopathy, respectively.

Renal system symptoms are not specific to xanthinuria and are typical of any cause of crystal nephropathy and stone formation.
Gross or microscopic hematuria may occur as a result of crystalluria or nephrolithiasis.
Renal colic is characterized by sudden onset of severe usually unilateral flank pain that may radiate toward the inguinal area.
- Nausea and vomiting may accompany the episode.
- In young children or infants, renal colic may present as irritability or unexplained abdominal pain.
Urinary tract infection is a frequent complication of any foreign body in the urinary system.
Acute renal failure may be the presenting feature of bilateral obstructing urolithiasis or crystal nephropathy.
Passing a urinary stone may be the initial clinical manifestation.
Myopathy usually occurs in older patients and is related to accumulation of xanthine. The symptoms may include muscle cramps, pain, or tightness in the hands, legs, or jaw. Muscle pain can follow vigorous exercise.
Joint pain and stiffness are features of arthropathy.

Physical

No specific physical examination findings lead to the diagnosis of xanthinuria.
Failure to thrive, recurrent emesis, and irritability are nonspecific findings in young children with renal failure or urolithiasis.
Fever, flank pain, dysuria, urinary frequency, and urinary urgency are features of a urinary tract infection, which can accompany xanthinuria.
Renal colic is a common presenting feature of urolithiasis.
Hematuria is a typical feature of urolithiasis and crystalluria.

Causes

Genetic causes
- Classic xanthinuria types I and II are autosomal recessive inherited conditions that result in dysfunction of the enzyme xanthine dehydrogenase.
- Xanthine dehydrogenase catalyzes 2 reactions, conversion of hypoxanthine to xanthine and conversion of xanthine to uric acid.
- The accumulation of xanthine is caused by the catabolism of guanine to xanthine by guanase and the lack of a salvage pathway for xanthine.
- Hypoxanthine does not accumulate appreciably because it is efficiently metabolized through a salvage pathway.
Iatrogenic causes
- Allopurinol is administered to block xanthine dehydrogenase and prevent uric acid overproduction, which leads to the accumulation of xanthine. Rarely, in the setting of aggressive chemotherapy with rapid tumor lysis and allopurinol therapy, patients can develop complications of renal failure from xanthine crystal nephropathy. Volume depletion may also be involved.
- In complete HGPRT deficiency (ie, Lesch-Nyhan syndrome) or in partial deficiency of HGPRT, an overproduction of uric acid occurs. Allopurinol is administered to reduce uric acid production, and this leads to xanthine and hypoxanthine accumulation. Hypoxanthine accumulates because HGPRT is the enzyme for the hypoxanthine salvage pathway.

Differential Diagnoses

Uric Acid Stones
Urolithiasis

Workup

Laboratory Studies

The laboratory evaluation should proceed in a manner to confirm the presence of urinary system disease due to crystal or stone formation. Initially, seek common etiologies because xanthinuria is an extremely rare cause of nephropathy and urolithiasis. Laboratory clues that may suggest the diagnosis of xanthinuria include a radiolucent stone, low serum and urine uric acid levels, or crystal nephropathy of undetermined etiology.
Obtain the following urine studies:
- Urinalysis can reveal evidence of crystal nephropathy or urolithiasis, including blood and possibly pyuria. Most laboratories should identify common types of urine crystals.
- Obtain urine culture.
- Obtain 24-hour urine collection to assess calcium, oxalate, uric acid, and creatinine levels. Uric acid levels are low or undetectable in the hereditary xanthinurias.
- If xanthinuria is suspected, identify a laboratory that can accurately measure urine xanthine and hypoxanthine. Determine the type of urine collection (ie, timed, spot) necessary. Xanthine and hypoxanthine levels in the urine in healthy individuals are less than 0.01 µmol per millimole of creatinine. In classic xanthinuria, xanthine and hypoxanthine levels are increased significantly, and the ratio of xanthine to hypoxanthine is approximately 4:1. Urine xanthine levels can approach 1 µmol per millimole of creatinine.
Stone analysis is the most direct method to assist the clinician in making the diagnosis of xanthinuria.
Obtain serum studies as follows:
- Serum electrolytes, creatinine, BUN, calcium, magnesium, phosphorus, and uric acid levels are appropriate studies in patients with suspected crystal nephropathy or urolithiasis.
- Serum uric acid levels are low or undetectable and suggest the possibility of xanthinuria. Note that xanthinuria is not the only disorder with low serum uric acid levels.
- Determine xanthine and hypoxanthine blood levels in patients with suspected xanthinuria. Identifying a laboratory capable of assaying the purines and receiving instructions to properly obtain the specimen is important. In general, plasma concentrations of xanthine and hypoxanthine in healthy individuals are less than 1 µmol and less than 5 µmol, respectively. The possible range of xanthine plasma levels is 10-40 µmol in classic xanthinuria.
Liver, duodenal, or jejunal mucosa biopsy material is used to determine tissue xanthine dehydrogenase deficiency; however, measurement of xanthine dehydrogenase activity is not usually necessary to make the diagnosis of classic xanthinuria.

Imaging Studies

Kidneys, ureters, and bladder testing
- Kidneys, ureters, and bladder (KUB) test with plain radiography of the abdomen is always performed in patients with suspected urolithiasis.
- Xanthine stones are radiolucent and are not routinely revealed on KUB testing. Further imaging of the urinary tract is necessary to determine the presence of a xanthine stone.
Intravenous pyelography: Intravenous pyelography may reveal recent stone passage or a filling defect in the renal pelvis or ureter, consistent with the presence of a radiolucent stone. The study is also helpful in identifying obstruction of urine flow by a stone.
Renal ultrasonography
- Sensitive enough to identify large radiolucent stones, this imaging study may miss smaller stones, generally less than 1 cm.
- The study can determine the presence of hydronephrosis or crystal nephropathy.
CT scanning and MRI
- CT scanning and MRI are very sensitive for identifying radiolucent stones throughout the urinary system.
- However, these studies are more expensive; reserve them for situations when nephrolithiasis is strongly suspected despite negative renal ultrasonography findings.

Other Tests

Allopurinol challenge
- Patients with classic xanthinuria type I are deficient in xanthine dehydrogenase, whereas patients with type II have a dual deficiency of xanthine dehydrogenase and aldehyde oxidase. Allopurinol is oxidized to oxypurinol by aldehyde oxidase. In patients with type I, allopurinol is metabolized to oxypurinol, whereas patients with type II do not metabolize allopurinol.
- No specific clinical guidelines specify how to perform the allopurinol challenge. Generally, oxypurinol is measured in a 24-hour urine specimen on a standard dose of allopurinol for 3-5 days.
- Before administering allopurinol, identifying a laboratory that is capable of measuring oxypurinol is important.
- Pyrazinamide and N -methylnicotinamide are also substrates for aldehyde oxidase and have been used to classify the type of classic xanthinuria.

Histologic Findings

Crystalline deposits of xanthine in the renal parenchyma may result in tubular epithelial cell damage, interstitial edema, inflammation, and fibrosis.

Treatment

Medical Care

Alkalinization of the urine has little effect on the solubility of xanthine.
No specific therapies are available for classic xanthinuria; however, some general measures are recommended as follows:
- High fluid intake: A reasonable goal for fluid intake is 1.5-2 times maintenance spaced over 24 hours. Drinking water at night is important to prevent the usual development of a concentrated morning urine.
- Dehydration prevention: Educate the patient about the importance of preventing dehydration.
- Low-purine diet: Sources of food with lower purine content include cheese and eggs, grains, fruits, nuts, and most vegetables. The foods that contain higher amounts of purines are beef, pork, poultry, seafood, liver, kidney, and heart as well as peas, beans, spinach, and lentils.
- Xanthine dehydrogenase and aldehyde oxidase metabolize certain medications, and the enzyme-deficient or inhibited state can lead to toxic accumulation of the parent drug. Xanthine dehydrogenase is involved in degradation of azathioprine or 6-mercaptopurine, and aldehyde oxidase metabolizes allopurinol, cyclophosphamide, methotrexate, and quinine.

Surgical Care

Xanthine stones are sensitive to extracorporeal shockwave lithotripsy. Consultation with a urologist is warranted because other techniques are available for stone removal.

Consultations

Nephrologist
Urologist

Diet

Advise a low-purine diet (see Medical Care).

Activity

Advise older patients with xanthine myopathy to avoid vigorous physical activity (eg, long-distance running).

Medication

No specific medication exists reduces xanthine production in the inherited forms of xanthinuria.

Follow-up

Further Inpatient Care

Inpatient care may be necessary for the secondary complications of pyelonephritis, obstructive urolithiasis, or acute renal failure.

Further Outpatient Care

Monitor frequency of symptoms, renal function, and passage of stones.
Ensure consistent high intake of fluid to maintain dilute urine.
Monitor purine intake.

Complications

Urolithiasis
Crystal nephropathy
Renal failure
Obstructive uropathy
Urinary tract infection
Hematuria
Myopathy
Arthropathy
Arthritis

Prognosis

Prognosis depends on the degree of renal injury from crystal nephropathy, urinary obstruction, and/or pyelonephritis.

Patient Education

Advise patients regarding the importance of the following:

Maintaining a dilute urine
Avoiding dehydration
Intervening early for conditions that may lead to dehydration
Avoiding high-purine foods
Providing proper home therapy for renal colic

Miscellaneous

Medicolegal Pitfalls

Failure to consider the diagnosis in a patient with renal colic and evidence of a radiolucent stone

Special Concerns

Infants and young children may have nonspecific symptoms related to the urinary system, including persistent emesis, irritability, anorexia, poor weight gain, or hematuria.
Older patients are more likely than children to have muscle symptoms from xanthine and hypoxanthine tissue deposits.

Multimedia

Media file 1: Purine metabolic pathway.

References

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Cameron JS, Moro F, Simmonds HA. Gout, uric acid and purine metabolism in paediatric nephrology. Pediatr Nephrol. Feb 1993;7(1):105-18. [Medline].
Carpenter TO, Lebowitz RL, Nelson D, Bauer S. Hereditary xanthinuria presenting in infancy with nephrolithiasis. J Pediatr. Aug 1986;109(2):307-9. [Medline].
Fildes RD. Hereditary xanthinuria with severe urolithiasis occurring in infancy as renal tubular acidosis and hypercalciuria. J Pediatr. Aug 1989;115(2):277-80. [Medline].
Gomez GA, Stutzman L, Chu TM. Xanthine nephropathy during chemotherapy in deficiency of hypoxanthine- guanine phosphoribosyltransferase. Arch Intern Med. Jun 1978;138(6):1017-9. [Medline].
Leimkuhler S, Charcosset M, Latour P, et al. Ten novel mutations in the molybdenum cofactor genes MOCS1 and MOCS2 and in vitro characterization of a MOCS2 mutation that abolishes the binding ability of molybdopterin synthase. Hum Genet. 2005;117(6):565-70. [Medline].
Macaya A, Brunso L, Fernandez-Castillo N, et al. Molybdenum cofactor deficiency presenting as neonatal hyperekplexia: a clinical, biochemical and genetic study. Neuropediatrics.Dec;. 2005;36(6):389-94. [Medline].
Reiter S, Simmonds HA, Zollner N, et al. Demonstration of a combined deficiency of xanthine oxidase and aldehyde oxidase in xanthinuric patients not forming oxipurinol. Clin Chim Acta. Mar 15 1990;187(3):221-34. [Medline].
Simmonds HA, Reiter S, Nishino T. Hereditary xanthinuria. In: The Metabolic and Molecular Bases of Inherited Disease. 1995:1781-97.
Teksam O, Yurdakok M, Coskun T. Molybdenum cofactor deficiency presenting with severe metabolic acidosis and intracranial hemorrhage. J Child Neurol. 2005;20(2):155-7. [Medline].
van Gennip AH, Mandel H, Stroomer LEM. Effects of allopurinol on the xanthinuria in a patient with molybdenum cofactor deficiency. In: Purine and Pyrimidine Metabolism in Man. Vol 8. 1995:375-8.
Zannolli R, Micheli V, Mazzei MA, et al. Hereditary xanthinuria type II associated with mental delay, autism, cortical renal cysts, nephrocalcinosis, osteopenia, and hair and teeth defects. J Med Genet. Nov 2003;40(11):e121. [Medline].

Keywords

xanthinuria, classic xanthinuria, hereditary xanthinuria, iatrogenic xanthinuria, xanthuria, xanthiuria, xanthine in the urine, arthropathy, myopathy, crystal nephropathy, urolithiasis, renal failure, microcephaly, hyperreflexia, Lesch-Nyhan syndrome, xanthine nephropathy, acute kidney failure, hematuria, interstitial nephritis, chronic renal failure, end-stage renal disease, arthritis, arthralgia, renal colic, urinary tract infection, urolithiasis

Contributor Information and Disclosures

Author

Sahar Fathallah-Shaykh, MD, Assistant Professor in Pediatric Nephrology, Northwestern University Feinberg School of Medicine; Consulting Staff, Division of Kidney Diseases, Children's Memorial Hospital
Sahar Fathallah-Shaykh, MD is a member of the following medical societies: American Society of Nephrology
Disclosure: emedecine Honoraria Other

Coauthor(s)

Steven C Diven, MD, Medical Director of Pediatric Dialysis Unit, Assistant Professor, Department of Pediatrics, University of Texas Medical Branch at Galveston
Steven C Diven, MD is a member of the following medical societies: National Kidney Foundation
Disclosure: Nothing to disclose.

Medical Editor

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 & Dental Society, 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, and Southwest Pediatric Nephrology Study Group
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Luther Travis, MD, William W Glauser Professor of Pediatrics and Pediatric Nephrology, Department of Pediatrics, Divisions of Nephrology and Diabetes, University of Texas Medical Branch and Children's Hospital
Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, and Texas Pediatric Society
Disclosure: Nothing to disclose.

CME Editor

Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine
Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD, The Isaac A Abt, MD, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University; Division Head of Kidney Diseases, Children's Memorial Hospital, Chicago
Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology
Disclosure: Amgen Grant/research funds None; Abbott Honoraria Speaking and teaching; Altus Pharmaceuticals Grant/research funds None; Genzyme Grant/research funds None; Merck Grant/research funds None; NIH Grant/research funds None

Further Reading