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 was previously phenotypically classified according to the pattern of excretion of urinary cystine in parents and siblings of affected children. Patients were classified as type I if their parents had normal urine cystine excretion; patients were classified as type II or III depending on the degree of increased urinary cystine. Identification of responsible gene mutations has led to a genotypic classification. Type I cystinuria is inherited as an autosomal recessive trait, whereas non-type I is inherited as an autosomal dominant trait with incomplete penetrance in which heterozygotes may excrete increased quantities of cystine in the urine but seldom enough to form stones. Cystinuria should not be confused with cystinosis (see Hereditary Fanconi syndrome).
The primary defect results in diminished renal proximal tubular resorption 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.
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, 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.
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).
End-stage renal disease may develop. Decreasing urinary cystine excretion decreases renal toxicity and is accomplished by increasing urine volume with fluid intake 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 in some cases 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) 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 SLE-like reaction. Pyridoxine supplements (50 mg po once/day) should be given with penicillamine. Tiopronin (100 mg to 300 mg po qid) can be used instead of penicillamine to treat some children because it has a lower frequency of adverse effects. Captopril (0.3 mg/kg po tid) is not as effective as penicillamine but is less toxic. Close monitoring of response to therapy is very important.
Last full review/revision July 2013 by Christopher J. LaRosa, MD
Content last modified July 2013