Cystinuria is an autosomal recessive disorder of proximal tubular transport of dibasic amino acids—cystine, ornithine, arginine, and lysine (COAL or COLA amino acids). However, only impaired transport of cystine is clinically significant because cystine is poorly soluble in the urine, resulting in recurrent stone formation. In normal individuals, 100 % of filtered cystine is reabsorbed in the proximal tubule.

Cystinuria accounts for approximately 1 % of all stones in adults and 6–10 % in children with the average age of presentation of 12–13 years old [1–4]. Cystinuria results from mutations in one of two components of the proximal tubular cystine transporter system, composed of two subunits linked by a disulfide bridge [5, 6]. The heavy subunit (rBAT) is encoded by gene SLC3A1 gene on chromosome 2 and the light subunit (B^0,+AT) is encoded by SLC7A9 on chromosome 19. B^0,+AT is the transporter for neutral (cystine) and dibasic (ornithine, arginine and lysine) amino acids. rBAT modulates trafficking of B^0,+AT to the apical membrane of the proximal tubular epithelial cell. Although cystinuria is an autosomal recessive disorder, heterozygote carriers of mutated SLC7A9 alleles have the pattern of autosomal dominance with incomplete penetrance and have elevated, but not usually clinically significant cystine excretion and rarely form stones.

Prior to the genetic understanding of cystinuria, patients were classified as type I and non-type 1 (type II or III) based on urinary excretion of cystine of their heterozygote parents. Non-type 1 carriers may also have elevated cystine without stone formation. Since the understanding of the genetics of cystinuria, the classification has changed to describe the genetic mutations. Two defective genes for SLC3A1 result in type A cystinuria and all of these carriers have no detectable cystine in the urine. Two defective genes for SLC7A9 have Type B cystinuria, and 14 % of heterozygote carriers have no detectable cystine while the remainder have elevated cystine levels but generally do not make stones. One mutated gene in each allele does not cause disease, as two mutations are required of each allele to cause disease. Although very rare (1.6 % of study population in one report), a mutation in one allele of one gene and one allele of the other gene, or more than two mutated alleles (Type AB) can also occur [1, 5, 7]. Although patients now may be classified by their genetic abnormalities in cystinuria, genetic testing is not usually performed as part of day to day clinical care, as there is no difference clinically between the two defects as far as presentation, stone disease, or management. Thus, genetic screening is not routinely performed outside of research protocols.

Clinical suspicion for cystinuria should be high if the patient presents with very large or multiple large stones (staghorn), family history of stones, or refractory recurrent stone disease without a clinical diagnosis. The diagnosis of cystinuria can be made when urinalysis with microscopy demonstrates the classic, pathognomonic hexagonal cystine crystals. Ideally, this should be performed on a first morning urine as it is the most concentrated and will increase the likelihood of observing the crystals. Diagnosis can often be made after a stone analysis following passage of a stone or a procedure. A cyanide-nitroprusside test is also utilized (cyanide reduces cystine to cysteine leading to a color change). False positives occur in those with other tubular disorders leading to aminoaciduria such as Fanconi syndrome or homocystinuria as well as acetonuria, and patients on certain medications. As previously mentioned, type B heterozygotes (carrier) may also have increased cystine excretion and also a positive cyanide-nitroprusside test. Premature babies and children under age 2 may also have tubular immaturity resulting in increased amino acid excretion and a false positive test [1, 3, 4, 7]. Routine random amino acid analysis can also be sent and will demonstrate elevations in COAL amino acids and random urine cystine to creatinine ratios can be assessed. Ideally, 24-h analysis of cystine excretion should be assessed (commercially available). Normal cystine excretion is 30 mg/day or 0.1 mmol/day (conversion for cystine is 1 mmol = 250 mg). These 24-h tests also provide information on 24-h urine volume, pH, citrate excretion as well as cystine supersaturation and a newer measure called cystine capacity, which will be discussed further. These studies are helpful to get baseline characteristics about the patients and to guide initial therapy as well as assess efficacy of therapy [8, 9].