Cystinuria is an inherited defect of the renal tubules in which reabsorption of cystine (the homodimer of the amino acid cysteine) is impaired, urinary excretion is increased, and cystine stones form in the urinary tract. Symptoms are colic caused by stones and perhaps urinary infection or the sequela of chronic kidney disease. Diagnosis is by measurement of cystine excretion in the urine. Treatment is with increased fluid intake and alkalinization of the urine.
Cystinuria was originally classified according to urinary excretion of cystine and dibasic amino acids in obligate carriers. In this classification, parents of affected children were assessed as having either normal (type I), moderate (type III), or significant (type II) increases in cystine excretion.
A newer classification is based on genotype: Type A patients have homozygous mutations in the SLC3A1 gene, and type B patients have homozygous mutations in the SLC7A9 gene. These genes encode proteins that together form a heterodimer responsible for cystine and dibasic amino acid transport in the proximal tubule.
Cystinuria should not be confused with cystinosis (see Fanconi Syndrome).
Pathophysiology of Cystinuria
The primary defect results in diminished renal proximal tubular reabsorption of cystine and increased urinary cystine concentration. Cystine is poorly soluble in acidic urine, so when its urinary concentration exceeds its solubility, crystals precipitate and cystine kidney stones form. Males are generally affected more than females.
Resorption of other dibasic amino acids (lysine, ornithine, arginine) is also impaired but causes no problems because these amino acids have an alternative transport system separate from that shared with cystine. Furthermore, they are more soluble than cystine in urine, and their increased excretion does not result in crystal or stone formation. Their absorption (and that of cystine) is also decreased in the small bowel.
Symptoms and Signs of Cystinuria
Symptoms of cystinuria, most commonly renal colic, may occur in infants but usually appear between 10 and 30 years of age.
Urinary tract infection and chronic kidney disease due to urinary tract obstruction may develop.
Diagnosis of Cystinuria
Analysis of collected kidney stones
Microscopic examination of urinary sediment
Measurement of urinary cystine excretion
Radiopaque cystine stones form in the renal pelvis or bladder. Staghorn stones are common.
Cystine may appear in the urine as yellow-brown hexagonal crystals, which are diagnostic.
Excessive cystine in the urine may be detected with the nitroprusside cyanide test. Quantitative cystine excretion is typically > 400 mg/day in cystinuria (normal is < 30 mg/day).
Treatment of Cystinuria
High fluid intake
Alkalinization of the urine
Dietary sodium, animal protein, and methionine restriction (when possible)
Sometimes cystine-binding medications
End-stage kidney disease may develop. Decreasing urinary cystine concentration below about 250 to 300 mg/L (1 to 1.25 mmol/L) decreases kidney toxicity and can allow clearance of cystine in solution. This decrease is accomplished by increasing urine volume with fluid intake sufficient to provide a urine flow rate of 1.5 to 2 L/m2/day, which could require fluid intake as high as 2 to 4 L/day (1). Hydration is particularly important at night when urinary volume and pH drop.
Alkalinization of the urine to pH >
Mild restrictions of dietary sodium (100 mEq/day), animal protein (0.8 to 1.0 g/kg/day), and dietary methionine may help reduce cystine excretion. Because protein is essential for proper growth, protein intake should not be overly restricted in children.
penicillamine. About half of all patients develop some toxic manifestation, such as fever, rash, arthralgias, or, less commonly, nephrotic syndrome, pancytopenia, or a lupus-like reaction. Although a lower risk of toxicity has been suggested with use of tiopronin, this has not been confirmed (2). Close monitoring of response to therapy is very important.
Although medications may reduce stone burden, there is high risk that stones will recur.
Animal models have been helpful in the development of novel therapies for cystinuria (3tolvaptan in young patients with cystinuria (4).
(See also the multi-society 2021 clinical practice recommendation for cystinuria management.)
Treatment references
1. Claes DJ, Jackson E. Cystinuria: Mechanisms and management. Pediatr Nephrol. 2012;27(11):2031–2038. doi:10.1007/s00467-011-2092-6
2. Prot-Bertoye C, Lebbah S, Daudon M, et al. Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France. BJU Int. 2019;124(5):849-861. doi:10.1111/bju.14721
3. Sahota A, Tischfield JA, Goldfarb DS, et al. Cystinuria: Genetic aspects, mouse models, and a new approach to therapy. Urolithiasis. 2019;47(1):57–66. doi:10.1007/s00240-018-1101-7
4. Nelson CP, Kurtz MP, Venna A, Cilento BG Jr, Baum MA. Pharmacological Dilutional Therapy Using the Vasopressin Antagonist Tolvaptan for Young Patients With Cystinuria: A Pilot Investigation. Urology. 2020;144:65-70. doi:10.1016/j.urology.2020.07.002
Key Points
Defective urinary resorption of cystine increases urinary cystine levels, leading to cystine kidney stones and sometimes chronic kidney disease.
Yellow-brown hexagonal crystals in the urine are pathognomonic; quantitative cystine excretion is typically > 400 mg/day.
Restrict dietary sodium, animal protein, and methionine.
More Information
The following English-language resource may be useful. Please note that The Manual is not responsible for the content of this resource.
Multiple societies: Clinical practice recommendation for cystinuria management (2021)
