crystalluria primidone

Which of the substances below causes crystalluria with hexagonal crystals that shimmer on macroscopic urine examination?

  1. Acyclovir
  2. Ethylene glycol
  3. Indinavir
  4. Primidone
  5. Sulfamethoxazole/trimethoprim

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.


  1. Bailey DN, Jatlow PI. Chemical analysis of massive crystalluria following primidone overdose. Am J Clin Pathol. 1972 Nov;58(5): 583-9. PMID: 4642162.
  2. Sigg T. Leikin JB. Massive crystalluria in a patient taking primidone. Ann Emerg Med. 1999 Jun;33(6):726-7. PMID: 10339696.
  3. Lehmann DF. Primidone crystalluria following overdose a report of a case and an analysis of the literature. Med Toxicol Adverse Drug Exp. Sep-Oct 1987;2(5):383-7. PMID: 3312932.
  4. VanHeijst ANP, Dejong W, Seldenrijk R, Vankijk A. Coma and crystalluria: a massive primidone intoxication treated with haemoperfusion. J Toxicol Clin Toxicol. 1983 Jun;20(4):307-18. PMID: 6655772.
  5. Brillman J, Gallagher BB, Mattson RH. Acute primidone intoxication. Arch Neurol. 1974 Mar;30(3):255-8. PMID: 4812959.
  6. Turner CR. Primidone intoxication and massive crystalluria. Clin Pediatr (Phila). 1980 Oct;19(10):706-7. PMID: 7408374.
  7. Lane GP, Lewis CJ, Zall SC. Macroscopic crystalluria after primidone overdosage. Med J Aust. 1987 Dec7-12;147(11-12):625-5. PMID: 3696053.
  8. Gaddam M, Velagapudi RK, Sitta EA, Kanzy A. Two gaps too many, three clues too few? Do elevated osmolal and anion gaps with crystalluria always mean ethylene glycol poisoning. BMJ Case Rep. 2017 Oct 15;2017bcr2017221739. PMID: 29038192.
  9. Andrews AR, Yu D, Lyons AW. Diagnostic Challenges with Acyclovir Crystalluria – A Case Study. EJIFCC. 2020 Jun 2;31(2):157-63. PMID: 32549883.
  10. Lyons AW, Mansoor A, Trotter MJ. Urinary gems: acyclovir crystalluria. Arch Pathol Lab Med. 2002 Jun;126(6):753-4. PMID: 12087974.
  11. Castiglione V, Cavalier E, Gadisseur. Case report: Uncommon Sulfamethoxazole crystlluria. Clin Biochem. 2018 Aug;48: 116-117. PMID: 29777658.
  12. Castiglione V, Cavalier E, Gadisseur. Clinical data on rare Sulfamethoxazole crystalluria assessed by Fourier transform inftrared spectrophotometry. Data Brief. 2018 Nov 6;2033-6. PMID: 30510989.
  13. Shrishrimal K, Wesson J. Sulfamethoxazole Crystalluria. Am J Kidney Dis. 2011 Sep;48(3):492-3. PMID: 21856494.
  14. Famularo G, Toro SD, Moretti S, De Simone C. Symptomatic crystalluria associated with indinavir. Ann Pharmacother. 2000 Dec;34(12):1414-18. PMID: 11144699.
  15. The Crystalline Nephropathies. Kidney Int Rep. 2021 Sep 17;6(12):2942-57. PMID: 34901567.
Alex Ponce, PharmD

Alex Ponce, PharmD

Pharmacy Toxicology Fellow
Indiana Poison Center
Kris Nañagas, MD

Kris Nañagas, MD

Associate Professor of Clinical Emergency Medicine
Medical Toxicology Faculty
Indiana University School of Medicine