Cystinuria is an autosomal recessive defect in transport of the amino acids cystine, ornithine, arginine and lysine in the intestinal epithelium and proximal renal tubule. Its major morbidity, urolithiasis, results from profoundly decreased cystine resorption in the proximal renal tubule, causing the urinary cystine concentration to exceed its solubility threshold of 1200 μM1
. In addition to episodic renal colic, patients are at long-term risk for loss of renal function. Cystinuria has a worldwide incidence of approximately 1:7000, and is a major metabolic cause of pediatric urolithiasis, causing 8% of all pediatric stones2, 3
At the molecular level, cystinuria results from dysfunction of the b0,+
heteromeric amino acid transporter, which is composed of heavy and light subunits. Type I (fully recessive) cystinuria is caused by mutations in SLC3A1
, the gene encoding rBAT, a heavy subunit, while non-Type I (incompletely recessive) cystinuria is usually caused by mutations in SLC7A9
, encoding a light subunit3
. Both types cause urolithiasis but differ in heterozygote cystine excretion (elevated in non-Type I; normal in Type I).
A variety of treatment options have been proposed to treat cystinuria. Increasing fluid intake increases urinary volume and reduces cystine crystallization somewhat4
. However, the urinary volume needed to reduce cystine concentration below the solubility threshold is high, and consequently fluid therapy alone is not feasible for very young patients. A second option is to alkalinize the urine with oral agents (e.g. potassium citrate), because cystine solubility increases when urine pH exceeds 7.5. However, alkalinization therapy, even in conjunction with increased fluid intake, is insufficient to eliminate formation of new stones in most patients5, 6
The most effective therapy for cystinuria is oral administration of thiol-containing compounds like penicillamine (β,β-dimethylcystine), which form mixed-disulfides with urinary cystine, reducing crystallization. Penicillamine's effectiveness in reducing stone formation and dissolving pre-existing stones in cystinuria has been well-documented5-8
. Compliance with a medical regimen that includes penicillamine or other thiol-containing compounds has been found to protect against the formation of new stones and the need for urological interventions to remove stones9, 10
. However, penicillamine's toxicities, including marrow suppression, proteinuria, arthralgias, febrile reactions, loss of taste, liver dysfunction and skin eruptions require interruption or termination of treatment in many patients. In a series of 39 adult patients, 50% of penicillamine-treated patients had rash or proteinuria8
, while in another series, a variety of toxicities (especially febrile reactions, skin eruptions and proteinuria) forced discontinuation in 40% of patients11
Although penicillamine has been used in pediatric patients for some forty years, little information exists about either its safety or efficacy in this age group. In a series of fifteen Japanese children, 85% had a side effect to the medication12
. We are not aware of a similar study in an American population, and our experience has been that most children and adolescents tolerate the medication if monitored closely. We present our eighteen years’ experience in treating pediatric cystinuria with penicillamine. We employed a treatment plan featuring gradual introduction of the drug and close monitoring of side effects. In these children, penicillamine was well-tolerated and decreased urinary cystine concentration, and patients who adhered to the dosing schedule did not have acute stone crises.