Xanthinuria

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.[1]

A study reported on the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor, to treat molybdenum cofactor deficiency (MoCD). The study concluded that cPMP substitution is the first effective therapy for patients with MoCD type A and has a favorable safety profile.[2]

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.[3] 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.

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.

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.

United States data

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 data

Most reported cases are from Mediterranean and Middle Eastern countries.

Race-, sex-, and age-related demographics

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.

Classic xanthinuria is more common in males than in females.

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.

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

Morbidity/mortality

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).

Complications

Complications of xanthinuria may include the following:

• Urolithiasis

• Crystal nephropathy

• Renal failure

• Obstructive uropathy

• Urinary tract infection

• Hematuria

• Myopathy

• Arthropathy

• Arthritis

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

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.

Moreover, about two thirds of patients are asymptomatic and present with an incidental finding of extremely low levels of uric acid in the blood.[4]  In nine cases of hereditary xanthinuria reported by Sebesta et al, all of the patients presented with profound hypouricemia and four were asymptomatic.[5]

• 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.

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.

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.

Kidneys, ureters, and bladder (KUB) testing 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 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 is sensitive enough to identify large radiolucent stones, though 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 are very sensitive for identifying radiolucent stones throughout the urinary system. However, these imaging studies are more expensive and should be reserved for situations when nephrolithiasis is strongly suspected despite negative renal ultrasonography findings.

An allopurinol challenge may be performed.

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.[6]

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.

Mraz et al suggested the following non-invasive approach to diagnose hereditary xanthinuria: (1) Documenting an extremely low serum/urinary uric acid and elevated urinary xanthine; (2) typing using urinary metabolomics; and (3) confirmation by molecular genetics.[6]

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

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.

Consultation with a nephrologist is helpful.

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

Diet

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

Activity

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

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

Monitor frequency of symptoms, renal function, and passage of stones.

Ensure consistent high intake of fluid to maintain dilute urine.

Monitor purine intake.

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