eMedicine Specialties > Urology > Stones

Cystinuria: Differential Diagnoses & Workup

Author: Chandra Shekhar Biyani, MBBS, MS, DUrol, FRCS(Urol), FEBU, Consulting Urologist, Department of Urology, Pinderfields General Hospital, UK
Coauthor(s): Jon Cartledge, MD, FRCS (Urol), Consulting Urologist, Pyrah Department of Urology, St James's University Hospital, UK
Contributor Information and Disclosures

Updated: Jun 23, 2009

Differential Diagnoses

Wilson Disease

Other Problems to Be Considered

Renal tubular immaturity in infants, Wilson disease, and Fanconi syndrome are other causes of elevated urinary cystine levels.

Workup

Laboratory Studies

  • Urinalysis
    • Cystine is one of the sulfur-containing amino acids; therefore, the urine may have the characteristic odor of rotten eggs.
    • Urinalysis may show typical hexagonal or benzene crystals, which are essentially pathognomonic of cystinuria. Microscopic crystalluria is present in 26%-83% of patients.
    • Disappearance of cystine crystals in the first morning urine is a good index of treatment efficacy.
    • Daudon et al calculated the cystine crystal volume (Vcys) from microscopic analysis of early-morning urine to predict stone recurrence.25
      • Patients who formed stones recurrently had an average Vcys of 8173 µ3/mm3, versus 233 µ3/mm3 in those who did not form stones. The absence of cystine crystals or a Vcys of less than 3000 µ3/mm3 was associated with the absence of cystine stone formation. The presence of multiple crystals (>20/mm3) and a Vcys of more than 3000 µ3/mm3 was predictive of stone recurrence.
      • The measurement of Vcys is helpful in assessing the effect of any treatment schedule. Daudon et al reported an average Vcys of 12,000 µ3/mm3 in untreated patients, 2600 µ3/mm3 associated with conservative therapy, 1141 µ3/mm3 in patients with high fluid intake receiving mercaptopropionyl-glycine therapy, and 791 µ3/mm3 in patients with high fluid intake receiving penicillamine therapy.
    • Measurement of urine cystine capacity: Assessments of cystine excretion or solubility in the presence of cystine-binding thiol drugs are difficult. Coe et al (2001) have developed an assay for determining cystine capacity, a measure of the ability of urine either to take up additional cystine from a preformed solid phase (undersaturation, or positive cystine capacity) or to give it up to the solid phase (supersaturation, or negative cystine capacity).26 Cystine capacity can be used to monitor the response to the drug therapy and can help the clinician to prescribe minimal effective dose.27 It is slightly difficult to differentiate between cystine and cysteine-drug complex when thiol drugs are used. Coe et al reported that a solid-phase assay for cystine supersaturation could distinguish between cystine and the cysteine-drug complex to guide the treatment and drug dosing.26
  • Sodium cyanide–nitroprusside test
    • This is a rapid, simple, and qualitative determination of cystine concentrations.
    • Cyanide converts cystine to cysteine. Nitroprusside then binds, causing a purple hue in 2-10 minutes.
    • The test detects cystine levels of higher than 75 mg/g of creatinine.
    • False-positive test results occur in some individuals with homocystinuria or acetonuria and in people taking sulfa drugs, ampicillin, or N -acetylcysteine. In persons with Fanconi syndrome, a false-positive test result can result from generalized aminoaciduria.
    • For individuals with positive cyanide-nitroprusside test findings, perform ion-exchange chromatographic quantitative analysis of a 24-hour collected urine sample.
      • The normal excretion rate is 40-80 mg/d (0.166-0.333 mmol/d).
      • Heterozygotes excrete 200-400 mg/d (0.8-1.7 mmol/d).
      • Homozygotes always excrete 600-1400 mg/d (2.5-5.8 mmol/d).
  • Twenty-four–hour urine collection for other metabolic abnormalities
    • Results indicate the presence of hypercalciuria, hypocitraturia, and hyperuricosuria.
    • Results may help define a subgroup of patients at risk for failure of medical therapy due to the formation of noncystine or mixed calculi.
  • Routine monitoring of renal function: Patients can self-monitor urine pH with Nitrazine paper.
  • Proton nuclear magnetic resonance spectroscopy of urine
    • Urine proton nuclear magnetic resonance spectroscopy is a very powerful technique that allows multicomponent analysis useful in both diagnosis and follow-up.
    • As reported by Pontoni et al in 2000, the relevant amino acids can be detected in the urine of patients with cystinuria.28 The most abundant amino acid in these patients is lysine (>5 mmol), whose typical signals become very high. Cystine, arginine, and ornithine are usually detectable, although pathologic concentrations are lower (<2 mmol).
    • The nuclear magnetic resonance spectroscopy technique is also suitable in the follow-up of therapy with alpha-mercaptopropionylglycine (alpha-MPG) because it provides quantitation of cystine, citrates, and creatinine, thus allowing better monitoring.
    • Heterozygotes show a high level of lysine, and spectroscopy provides a very easy preliminary identification of this group.

Imaging Studies

Calculi are frequently multiple and bilateral, and they often form staghorns.

  • Plain radiography of the abdomen and pelvis and intravenous pyelography
    • Images from these studies may show faintly radiopaque calculi that become radiolucent with intravenous contrast materials.
    • Cystine stones have a homogeneous or ground-glass appearance on radiographs (see Images 3-5). Although radiopaque, they are often less dense than calcium-containing stones.

      Plain radiograph of the abdomen showing cystine s...

      Plain radiograph of the abdomen showing cystine staghorn stones.

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      Plain radiograph of the abdomen showing cystine s...

      Plain radiograph of the abdomen showing cystine staghorn stones.


      Faintly opaque (ground-glass appearance) left low...

      Faintly opaque (ground-glass appearance) left lower ureteric stone.

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      Faintly opaque (ground-glass appearance) left low...

      Faintly opaque (ground-glass appearance) left lower ureteric stone.


      Intravenous urogram showing left ureterohydroneph...

      Intravenous urogram showing left ureterohydronephrosis.

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      Intravenous urogram showing left ureterohydroneph...

      Intravenous urogram showing left ureterohydronephrosis.

    • Intravenous pyelography is essential for defining calyceal anatomy prior to extracorporeal shockwave lithotripsy (ESWL).
  • Helical CT scan without intravenous contrast
    • The stone burden, including calculi, is difficult to accurately visualize and assess on plain radiography.
    • Helical CT scans are ideal for patients with contrast allergy or renal insufficiency.
  • Renal ultrasonography
    • This study is more economical than CT scan for monitoring the growth of renal calculi (see Image 6).

      Renal sonogram demonstrating renal calculi in the...

      Renal sonogram demonstrating renal calculi in the lower pole.

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      Renal sonogram demonstrating renal calculi in the...

      Renal sonogram demonstrating renal calculi in the lower pole.

    • The lack of radiation exposure makes this test ideal for children and patients with frequent recurrences, who would otherwise accumulate relatively large radiation doses over a lifetime.

Other Tests

  • Stone analysis
    • Cystine stones are pale yellow. Electron microscopic evaluation coupled with x-ray diffraction crystallography has been useful in identifying stone components and specific spatial relationships of stone components (see Image 2). Pure cystine stones are observed in 60%-80% of cases.

      Electron microscopic picture showing cystine crys...

      Electron microscopic picture showing cystine crystals.

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      Electron microscopic picture showing cystine crys...

      Electron microscopic picture showing cystine crystals.

    • Two subtypes of cystine calculi have been identified by electron microscopic evaluation of stones removed from persons with cystinuria, rough and smooth. Smooth calculi have an irregular, interlacing crystal structure, making them more resistant to ESWL fragmentation than the more homogenous hexagonal crystal structure of the rough subtype. Unfortunately, clinically differentiating the 2 types before ESWL is not possible.
    • Of patients, 20%-40% have cystine mixed with calcium oxalate, calcium phosphate, or magnesium ammonium calcium phosphate.

Procedures

  • Jejunal biopsy was once used to distinguish among 3 subtypes of cystinuria. This procedure is not recommended as part of routine workup and is primarily a research tool.

More on Cystinuria

Overview: Cystinuria
Differential Diagnoses & Workup: Cystinuria
Treatment & Medication: Cystinuria
Follow-up: Cystinuria
Multimedia: Cystinuria
References
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Further Reading

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Keywords

cystinuria, urolithiasis, cystine urolithiasis, urinary calculi, stone formation, amino acids, cystine, cysteine, SLC3A1, SLC7A9, rBAT, urinary alkalinization, hydration, D-penicillamine, tiopronin, Thiola, captopril, extracorporeal shockwave lithotripsy, ESWL, extracorporeal shock wave lithotripsy, retrograde endoscopic lithotripsy, percutaneous nephrolithotomy, PCNL, stone removal, urinary tract stone, kidney stone, recurrent stone formation, stone recurrence, urinary calculus, cystic oxide, cystine stones, cystine stone formers, ornithine, arginine, lysine

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Contributor Information and Disclosures

Author

Chandra Shekhar Biyani, MBBS, MS, DUrol, FRCS(Urol), FEBU, Consulting Urologist, Department of Urology, Pinderfields General Hospital, UK
Chandra Shekhar Biyani, MBBS, MS, DUrol, FRCS(Urol), FEBU is a member of the following medical societies: British Association of Urological Surgeons, British Medical Association, European Association of Urology, and International College of Surgeons
Disclosure: Nothing to disclose.

Coauthor(s)

Jon Cartledge, MD, FRCS (Urol), Consulting Urologist, Pyrah Department of Urology, St James's University Hospital, UK
Jon Cartledge, MD, FRCS (Urol) is a member of the following medical societies: British Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Direct of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Omeros Corporation Consulting fee Consulting

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoendoscopic Surgeons, and Society of University Urologists
Disclosure: Nothing to disclose.

 
 
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