ACMT Toxicology Visual Pearl | Substance-Induced Crystalluria: All That Glitters Is Not Gold

Answer: 4

Primidone, a medication used to treat epilepsy and essential tremor, has been associated with hexagonal crystals in the urine, typically when levels are very high such as following an overdose. Primidone crystalluria is depicted in the video below:

What is primidone?

• Used rarely for the treatment of essential tremors or seizure disorders
• Decreases central nervous system excitation
• Metabolized to 2 active metabolites: phenobarbital and phenylethylmalonamide (PEMA) [1]
  • Phenobarbital results in decreased CNS excitation by GABA receptor agonism
  • PEMA enhances phenobarbital activity at the receptor
• Common symptoms after exposure include crystalluria, sedation, ataxia, nystagmus, decreased deep tendon reflexes, hypotension, and coma [1,3,4,5]

Primidone crystalluria

• Has been described as white, shimmering, chalky urine or as “white paint” urine [1,4,6]
• Crystals are hexagonal in structure [1,3,7]
• Crystalluria is reported at serum concentrations of primidone >80 mg/L [3,4,7]; therapeutic concentration is typically 5-12 mg/L
• Primidone crystalluria is generally not associated with kidney injury [2,6] although there is a single case report [4]

What other substances can produce crystalluria?

• Ethylene glycol
  • Crystals associated with ethylene glycol toxicity are a result of the metabolite, oxalate [8]
  • Calcium oxalate monohydrate crystals are most often seen, however different morphologies including calcium oxalate dihydrate crystals have been reported [8]
  • Oxalate crystalluria has been reported with other disease states or ingestions as well [8]
• Acyclovir
  • Urine has been described as opaque, cloudy, or milky in color [9,10]
  • Crystals have been described as long and needle-shaped that are water soluble; however, crystals may not have a distinctly unique morphology [9,10]
• Sulfamethoxazole/trimethoprim
  • N-acetyl sulfamethoxazole, a metabolite of sulfamethoxazole, has been reported to produce crystals with various shapes including rectangular, spheroids, truncated lozenges, flowers, and more [11-13]
  • Crystals have been identified as a metabolite of sulfamethoxazole using infrared spectroscopy in multiple cases [11-13]
• Indinavir
  • Indinavir crystals are generally needles, flat rectangular plates, fan-shaped, or starburst-shaped in morphology [14]
  • Crystals should dissolve in an acidic environment [14]
• Other drugs that have been associated with crystalluria include: [15]
  • Sulfadiazine
  • Methotrexate
  • Atazanavir
  • Darunavir
  • Ciprofloxacin
  • Amoxicillin
  • Triamterene

Clinical Pearls

• Crystalluria can be seen with many different substances.
• Crystal morphology may help determine the etiology. Contacting the laboratory to assist with the identification of physical characteristics of the crystals may be beneficial.
• History is the most important determinant in diagnosing the etiology of crystalluria.