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 gene SLC3A1 and type B patients have homozygous mutations in SLC7A9. 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 : Hereditary Fanconi syndrome).
Pathophysiology
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
Symptoms of cystinuria, most commonly renal colic, may occur in infants but usually appear between ages 10 and 30. Urinary tract infection and chronic kidney disease due to urinary tract obstruction may develop.
Diagnosis
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
End-stage renal disease may develop. Decreasing urinary cystine concentration below about 250 to 300 mg/L (1 to 1.25 mmol/L) decreases renal toxicity and can allow clearance of cystine in solution. This 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 pH drops. Alkalinization of the urine to pH > 7.0 with potassium citrate or potassium bicarbonate 1 mEq/kg orally 3 to 4 times a day and in some cases acetazolamide 5 mg/kg (up to 250 mg) orally at bedtime increases the solubility of cystine significantly. Mild restrictions of dietary sodium (100 mEq/day) and protein (0.8 to 1.0 g/kg/day) may help reduce cystine excretion.
When high fluid intake and alkalinization do not reduce stone formation, other oral drugs may be tried. Penicillamine (7.5 mg/kg 4 times a day in young children and 125 mg to 0.5 g 4 times a day in older children) improves cystine solubility, but toxicity limits its usefulness. About half of all patients develop some toxic manifestation, such as fever, rash, arthralgias, or, less commonly, nephrotic syndrome, pancytopenia, or lupus-like reaction. Pyridoxine supplements (50 mg once/day) should be given with penicillamine. Tiopronin (100 to 300 mg 4 times a day) can be used instead of penicillamine to treat some children because it has a lower frequency of adverse effects. Captopril (0.3 mg/kg 3 times a day) is not as effective as penicillamine but is less toxic. Close monitoring of response to therapy is very important.
Animal models (eg, gene knockout mice) are currently being used toward the development of novel therapies for cystinosis (2).
Treatment references
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1. Claes DJ, Jackson E: Cystinuria: Mechanisms and management. Pediatr Nephrol 27(11):2031–2038, 2012. doi: 10.1007/s00467-011-2092-6
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2. Sahota A, Tischfield JA, Goldfarb DS, et al: Cystinuria: Genetic aspects, mouse models, and a new approach to therapy. Urolithiasis 47(1):57–66, 2019. doi: 10.1007/s00240-018-1101-7
Key Points
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Defective urinary resorption of cystine increases urinary cystine levels, leading to cystine kidney stones and sometimes chronic kidney disease.
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Yellow-brown hexagonal crystals in the urine are pathognomonic; quantitative cystine excretion is typically > 400 mg/day.
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Treat with increased fluid intake to give urine output of 1.5 to 2 L/m2/day, and alkalinize urine with potassium citrate or potassium bicarbonate.
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Restrict dietary sodium and protein.
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Drugs such as penicillamine, tiopronin, or captopril may be necessary, but adverse effects are a concern.
