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Cystinuria is an inherited defect of the renal tubules in which resorption of the amino acid cystine 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 renal failure. Diagnosis is by measurement of cystine excretion in the urine. Treatment is with increased fluid intake and alkalinization of the urine.
Cystinuria is inherited as an autosomal recessive trait. Heterozygotes may excrete increased quantities of cystine in the urine but seldom enough to form stones. Cystinuria should not be confused with cystinosis (see Renal Transport Abnormalities: Hereditary Fanconi syndrome).
Pathophysiology
The primary defect is in one of several genes responsible for cystine transport in the kidneys and intestine. Diminished renal tubular resorption of cystine increases cystine concentration in the urine. Cystine is poorly soluble in acidic urine, so that when its urinary concentration exceeds its solubility, crystals precipitate and stones form.
Resorption of 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, most commonly renal colic, may occur in infants but usually appear between ages 10 and 30. UTI and renal failure due to 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. Excessive cystine in the urine may be detected with the nitroprusside cyanide test. Diagnosis is confirmed by observing a cystine excretion of > 400 mg/day (normal is < 30 mg/day).
Treatment
Eventually, end-stage renal disease usually develops. Decreasing the urinary concentration of cystine decreases renal toxicity. This decrease is accomplished by increasing urine volume. Fluid intake must be sufficient to provide a urine flow rate of 3 to 4 L/day. Hydration is particularly important at night when urinary pH drops. Alkalinization of the urine to pH > 7.0 with K citrate or KHCO3 1 mEq/kg po tid to qid and perhaps acetazolamide 5 mg/kg (up to 250 mg) po at bedtime increases the solubility of cystine significantly. Mild restrictions of dietary Na (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 drugs may be tried. Penicillamine (7.5 mg/kg po qid in young children and 125 mg to 0.5 g po qid in older children) is effective, 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 SLE-like reaction. Pyridoxine supplements (50 mg po once/day) should be given with penicillamine. Tiopronin (100 mg to 300 mg po qid) is being used instead of penicillamine to treat some children. Captopril (0.3 mg/kg po tid) is not as effective as penicillamine but is much less toxic. Close monitoring of response to therapy is very important.
Last full review/revision September 2009 by Peter C. Brazy, MD
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