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ABSTRACT

  • Cystinuria (MIM 220200) is a disorder of amino acid transport affecting epithelial cells of the renal tubule and the gastrointestinal tract. The defective transport of cystine, lysine, arginine, and ornithine is transmitted as an autosomal recessive trait. According to the level of urinary excretion of cystine and dibasic amino acids in obligate heterozygotes, two types of cystinuria are envisaged: type I, the fully recessive form, and non-type I (type II, type III), the incomplete recessive form. In the latter type, the affected amino acids are excreted by heterozygotes in urine at levels greater than normal but less than in the homozygous state.

  • The only proven clinical manifestation of cystinuria is urolithiasis, due to the low solubility of cystine at low pH. Distinctive hexagonal cystine crystals appear in the urine and radiopaque cystine stones develop repeatedly in affected individuals. Cystinuria is diagnosed by demonstrating selective hyperexcretion of cystine and dibasic amino acids in urine. Stones generally form in acidic urine when urinary cystine concentration exceeds 300 mg cystine per liter (1200 μM). Prevention of urolithiasis is directed at high fluid intake and alkalinizing the urine to maximize cystine solubility. Oral sulfhydryl agents such as D-penicillamine and mercaptopropionylglycine may be used to form soluble mixed disulfides of cystine in the urine. Although effective, these agents are not risk-free and are usually reserved for patients who fail to respond to conservative therapy.

  • The corresponding small intestinal transport mechanism for absorption of cystine and dibasic amino acids is also defective in many cystinuria patients; oral loading tests and in vitro studies of jejunal biopsies demonstrate this. However, there are no gastrointestinal symptoms and, under conditions of normal protein intake, plasma amino acid levels are normal. This is presumably due to alternative absorptive mechanisms in the intestine, including direct uptake of dipeptides.

  • The renal clearance of cystine varies widely among affected individuals. In both humans and canine mutant phenotypes, fractional excretion of cystine may exceed the glomerular filtration rate, indicating net secretion, or back-leak, of cystine into the tubular fluid. This is particularly true in the first months of life when renal amino acid transport is immature. Thus, some heterozygous infants may initially appear to have homozygous cystinuria and should not be classified until at least 1 year of age.

  • In vitro studies of rat renal and intestinal brush-border membrane vesicles and renal tubular fragments show that cystine and dibasic amino acids share a high-affinity (low Km) transport mechanism. This transport system, also shared with neutral amino acids, is detected at the luminal surface of epithelial cells in the proximal straight tubule (S3 segment). A comparable system (bo,+-like) for cystine, dibasic, and neutral amino acids has been demonstrated in the apical membrane of an opossum kidney (OK) cell line. The bo,+-like system is an amino acid exchanger that normally mediates influx of cystine and dibasic amino acids and efflux of neutral amino acids. A separate low-affinity (high-Km) ...

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