Anthony J. Tracey, MD, MPH
Raju Thomas, MD, MHA, FACS
BASICS
DESCRIPTION
• Cystinuria is caused by an autosomal recessive error of transepithelial transport involving the intestine and the kidneys. Cystine lithiasis is the clinical result of crystallization and stone formation in the urinary tract.
– Excessive urinary excretion secondary to reduced tubular absorption of cystine disulfate (1).
– There is a transport defect of dibasic amino acids including cystine, ornithine, lysine, and arginine (COLA). (See also Section I: “Urolithiasis, Pediatric.”) (1)
• Cystine stones form when concentrations rise above the saturation point (roughly 250 mg cystine per liter of urine)
• Cystinuria accounts for about 1–2% of adult and 6–8% of pediatric nephrolithiasis (1)
• Historically, three types of cystinuria have been recognized in humans—type I, type II, and type III—on the basis of levels of urinary cystine in obligate heterozygotes; however, this classification correlates poorly with molecular findings; newer genetic classification is available (see below).
• Cystinuria is distinct from cystinosis, which is intracellular cystine accumulation leading to the Fanconi syndrome and progressive renal failure
EPIDEMIOLOGY
Incidence
• For patients with cystinuria:
– One new stone formation per patient per year
– An average of one surgical procedure every 3 yr
– 7 surgical procedures for nephrolithiasis by middle age (2)
– Average age at first stone diagnosis was 12.2 yr
– Mean number of stone episodes of 0.42 and 0.21 per year occurring in men and women, respectively.
Prevalence
• Homozygous: 1 in 15,0000 in the United States
• Heterozygous: 1 in 20–200 in the United States
• Libyan Jews: 1 in 2,500 (3)
• Cystinuria is more common in Caucasians
• Cystine stones are common in the second or third decade of life
• 20% of these patients develop calculi in childhood
RISK FACTORS
Family history (See genetics)
Genetics
• Identification of genetic mutations that cause cystinuria have led to a new classification system based on genotype that is more accurate than the prior phenotypic one.
• Mutations in 2 genes, SLC3A1 and SLC7A9 (3)
• Recent classification by International Cystinuria Consortium (ICC) to account for the chromosomal localization of the mutation:
– Type A (SLC3A1 gene is located on chromosome 2p16.3-p21)
– Type B (SLC7A9 gene is located on chromosome 19q12-13.1)
– Type AB (both chromosomes)
• Homozygotes exhibit urinary cysteine levels as high as 2000 μmol/g of creatinine
• Heterozygotes do not form stones; urinary excretion <100 mg/d
• Autosomal recessive complete; urinary excretion 250–1,400 mg/d
• Autosomal recessive incomplete; urinary excretion 100–300 mg/d (1)
PATHOPHYSIOLOGY
• Cystine is a homodimer of the amino acid cysteine.
– Cystinurics have impaired renal cystine transport, with decreased proximal tubular reabsorption of filtered cystine resulting in increased urinary cystine excretion with the consequence of cystine urolithiasis.
• Clinical consequences present only when crystals precipitate (low cystine solubility at normal urinary pH values).
• Cystine stone formers have slightly lower creatinine clearance than other types of stone formers.
ASSOCIATED CONDITIONS
• Defective renal acidification
• Hypercalciuria 19%
• Hypertension
• Hyperuricosuria 22%
• Hypocitraturia 44%
• Urolithiasis
GENERAL PREVENTION
• Create high urine volume (>1.5 L/m2/d) to reduce the urinary concentration of cystine to below its solubility limit (200–300 mg/L)
• Alkalize urine to pH of >7.5 (3–4 mEq/kg/d potassium citrate/bicarbonate, in 3–4 divided doses. Alkaline urine increases solubility of cysteine) (1)
• Restrict sodium and protein.
DIAGNOSIS
HISTORY
• Stones in childhood (3)
• Family history of stones (3)
• The presentation of a large branched calculi
PHYSICAL EXAM
CVA tenderness may be present with active stone disease
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urine is screened for cystine using the cyanide-nitroprusside test (positive = purple hue) with cystine >75 mg/L)
– Cyanide converts cystine to cysteine; this binds nitroprusside then binds resulting in a purple color usually in <10 min.
• If positive, a 24-hr urine quantitative test is performed.
– Normal cystine excretion is 30 mg/d (0.13 mmol/d),
– Cystinurics >400 mg/d (1.7 mmol/d) (1).
• Heterozygotes for cystinuria and with the Fanconi syndrome, excrete <250 mg/d (1 mmol) and usually do not form stones.
• Urine microscopy: Hexagonal or benzene crystals, which are pathognomonic of cystinuria.
– Microscopic crystalluria is present in 26–83% of patients.
– Can also be seen in cystinosis
• Cystine capacity: A highly specialized assay that measures the ability of urine to take up additional cystine from a preformed solid phase reaction (under saturation, or “positive cystine capacity”) or to give it up to the solid phase (supersaturation, or “negative cystine capacity”)
– May help guide drug dosing and treatment
Imaging
• CT scan of abdomen without contrast
– Preferred imaging modality
• KUB may show stones with a fuzzy gray appearance (1)
– Stones are less radiopaque than calcium stones but usually well seen
• Renal ultrasonography
– More economical than CT scan for monitoring the growth of renal calculi
– Indicated for children and frequent stone formers to reduce radiation (2)
Diagnostic Procedures/Surgery
N/A
Pathologic Findings
Renal biopsy is not usually performed. However, renal pathology may include plugging of the Ducts of Bellini with cystine crystals, tubular dilation, and focal fibrosis.
DIFFERENTIAL DIAGNOSIS
• Other forms of urolithiasis (calcium oxylate, uric acid, etc.)
• Any of the following may be confused with pain related to urolithiasis:
– Vascular: Abdominal aortic aneurysm, mesenteric ischemia
– Gastrointestinal: Appendicitis, bowel obstruction, cholecystitis/biliary colic, constipation, diverticulosis/diverticulitis, gastritis, pancreatitis, peptic ulcer
– Gynecologic: Ectopic pregnancy, tubo-ovarian abscess, ovarian torsion/cyst rupture
– Musculoskelet al: Back pain
– Urologic: Pyelonephritis, urinary tract infection, sloughed renal papilla, ureteropelvic junction obstruction
TREATMENT
GENERAL MEASURES
• For existing calculi treatment is similar to other stones based on clinical indication
• Extracorporeal shockwave lithotripsy has been discouraged for stones >1 cm by some authors (2)
– Cysteine stones are often not well fragmented by ESWL (extracorporeal shock wave lithotripsy)
– Multiple treatments are usually required
• Algorithm for Patients with Renal cystine stones:
– Percutaneous nephrolithotripsy (PNL) for cystine renal calculi larger than 15 mm in diameter
– Ureteroscopy effective for cysteine ureteral stones and for select renal cystine calculi
– Laparoscopic pyelolithotomy may also be possible for stones in favorable locations of the ureter or renal pelvis.
– ESWL monotherapy for cystine renal calculi 15 mm or smaller (High failure rate)
MEDICATION
First Line
See general prevention
Second Line
• Use chelating agents (bind cystine) only if the conservative methods do not work
• These increase cystine solubility in urine via formation of a more soluble mixed-disulfide bond
• These medications have potentially serious side effects and must be monitored.
– α-Mercaptopropionylglycine (Thiola, Tiopronin)
Most frequently used cystine-binding agent
Dosage start at 100 mg, orally two times per day, doses titrated to achieve urinary concentrations of cystine less than 250 mg/L urine.
Side effects include asthenia, GI distress, rash, joint aches, and mental status changes
Better tolerated than d-penicillamine
– d-penicillamine (Cuprimine)
binds with cystine to yield a disulfide more soluble than cystine
Typically start therapy at 250 mg per day and titrate to effect
Significant side effects: nephrotic syndrome, dermatitis, and pancytopenia.
– Captopril: Potential alternative
More favorable side effect profile: Fatigue, hypotension, and chronic cough
No long-term clinical trials demonstrate the effectiveness of captopril in preventing recurrent cystine stone formation
SURGERY/OTHER PROCEDURES
See General Measures above
ADDITIONAL TREATMENT
Radiation Therapy
NA
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• One study reported 1.22 stone episodes per year (2)
• The medical compliance of patients with cystinuria can be poor.
• A few patients are able to achieve and maintain targeted goals of medical intervention
– 15% achieved and maintained therapeutic success, as defined by urine cystine concentration less than 300 mg/L.
– 42% achieved therapeutic success but subsequently had failure at an average of 16 mo
• Rare Kidney Stone Consortium has developed a registry and will lead further efforts in managing cystinuria
COMPLICATIONS
• Studies report 1.22 stone episodes per year
• Chronic pyelonephritis—19%
• Renal impairment—Approximately 70%
• Risk for nephrectomy—10–20%
• End-stage renal failure—5%
• Hypertension—10%
• Mental illness and mental retardation (2)
FOLLOW-UP
Patient Monitoring
• Patients should have frequent clinical, radiologic, and laboratory surveillance
– Patients should follow a diet low in protein and sodium chloride
– Urinary pH level, and check first-morning urine for cystine crystals (2)
– Regularly check renal function
– RBC counts, WBC counts, and platelet counts should be monitored for patients on d-penicillamine and tiopronin (2).
– KUB and renal ultrasound should be routine
• Surveillance:
– Annually perform 24-hr urine testing and imaging for patients with stable disease (2)
– Multidisciplinary approach early in disease
Nephrologists
Renal dietitians
Patient Resources
• http://www.cystinuria.com/
• http://www.cystinuria.org/index.php
• Urology Care Foundation http://www.urologyhealth.org/content/moreinfo/kidneystone05.pdf
REFERENCES
1. Vella M, Karydi M, Coraci G, et al. Pathophysiology and clinical aspects of urinary lithiasis. Urol Int. 2007;79(Suppl I):26–31.
2. Biyani CS, Cartledge J. “Cystinuria” Medscape Article 2012; emedicine.medscape.com/article/435678
3. Eggermann T, Venghaus A, Zerres K. et al. Cystinuria: an inborn cause of urolithiasis. Orphanet J Rare Dis. 2012;7:19–29.
ADDITIONAL READING
Sumorok N, Goldfarb DS. Update on cystinuria. Curr Opin Nephrol Hypertens. 2013;22(4):427–431.
See Also (Topic, Algorithm, Media)
• Cystinosis
• Metabolic Stone Evaluation (24 Hour Urine Studies)
• Sodium Cyanide-Nitroprusside Test
• Urolithiasis, Adult, General
• Urolithiasis, Calcium Oxalate/Phosphate
• Urolithiasis, Cystine and Cystinuria (Hypercystinuria) Image 
• Urolithiasis, Pediatric, General
• Urolithiasis, Staghorn
• Urolithiasis, Ureteral Calculi Algorithm 
CODES
ICD9
• 270.0 Disturbances of amino-acid transport
• 592.9 Urinary calculus, unspecified
ICD10
• E72.01 Cystinuria
• N20.9 Urinary calculus, unspecified
CLINICAL/SURGICAL PEARLS
• Cystine stones are often not well fragmented by ESWL and may be considered for cystine renal calculi < 15 mm.
• Consider PCNL for cystine renal calculi larger than 15 mm in diameter.
• Ureteroscopy effective for cystine ureteral stones and for select renal cystine calculi.