Quiz Page June 2009: Worsening Kidney Function With a History of Urolithiasis

What does the kidney biopsy specimen show in Figure 1, Figure 2? 

Light microscopy identifies large crystals within the lumen of a distended atrophied urinary tubule, with reactive interstitial nephritis (Fig 1). The crystals were shaped like cogwheels or sea urchins, negative for von Kossa stain, and doubly refractile (Fig 2). Electron microscopy showed a lancet-shaped crystal penetrating into the tubular cell (Fig 3).

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Figure 3. Electron micrograph.

What is the differential diagnosis? 

Virtually any disease that causes urolithiasis can cause crystal nephropathy. The histochemical reaction known as von Kossa stain is specific for phosphates. Absence of reaction with the von Kossa stain indicates that the crystals do not contain calcium phosphate salts, but there are several different potential causes of von Kossa–negative stones.

Adult-onset congenital metabolic defects cannot be ruled out as a primary cause. Primary hyperoxaluria and cystinuria are frequently associated with kidney stones. Although stones from primary hyperoxaluria are sometimes von Kossa positive, stones formed of most pure oxalates are negative by means of von Kossa stain. Stones associated with disorders of purine metabolism are phosphate free and have a characteristic shape. Stones associated with acute hyperoxaluria caused by ethylene glycol or ascorbic acid intoxication also are possibly negative by means of von Kossa stain.1 An increased incidence of kidney stones and renal failure in infants has been reported in China, believed to be associated with the ingestion of infant formula contaminated with melamine.2 To the best of our knowledge, no biopsy specimens have been obtained from human cases, but melamine and cyanuric acid intoxication was found to cause rather circular von Kossa–negative crystal formation in animals.3 Drugs, such as acyclovir or protease inhibitors, as well as infection, also can cause crystals.4

What is needed to confirm the diagnosis? 

In addition to patient history, stone analysis is necessary for the diagnosis; however, enough urinary stones were not obtained from our patient. Instead we performed urinary analysis by using gas chromatography and mass spectrometry for a broad screening of congenital metabolic defects.5 Urine samples from our patient showed marked increases in adenine and its metabolite, 2,8-dihydroxyadenine (2,8-DHA). Subsequent genetic examination showed that the patient was homozygous for the APRT*Q0 allele, that is, the null allele of the adenine phosphoribosyltransferase gene. The patient therefore was identified as having a type I APRT deficiency.6

APRT deficiency is an autosomal recessive inherited disorder of purine metabolism.6 Age at diagnosis has ranged from 5 months to 74 years, and this disease affects only the kidney and urinary tract.6 Two types of APRT deficiency have been described. Patients with type I, predominantly white, feature undetectable enzyme activity in erythrocyte lysate and are either homozygotes or compound heterozygotes for a variety of null alleles, collectively referred to as APRT*Q0.6 The inability to salvage adenine in APRT deficiency results in the accumulation of its alternative metabolite, 2,8-DHA, by means of xanthine dehydrogenase. This extremely insoluble and nephrotoxic product generates crystals in affected individuals. In addition to adenine restriction and hydration, allopurinol is used as treatment for this condition.6

Tubular crystal deposition in patients with APRT deficiency is not a well-known cause of acute kidney injury or chronic kidney disease.7, 8 APRT deficiency usually is identified by detection of urinary stones, whereas urinary stones have not been detected in some patients with chronic kidney disease, possibly because of diminished clearance of 2,8-DHA.7