Cystinuria

AbstractCystinuria accounts for 1% of kidney stones in adults and up to 5–7% of stones in children. The two genes responsible for the disorder,SLC3A1andSLC7A9. The genes code, respectively, for proteins called rBAT and b0,+AT, both of which are necessary for the proximal tubule of the nephron to reabsorb cystine filtered by the glomerulus. The identification ofSLC3A1made cystinuria the first disorder of amino acid transport with an identified gene. Most patients are affected by autosomal recessive inheritance, but a mutation in one allele ofSLC7A9may sometimes be sufficient to form stones, constituting autosomal dominant inheritance with variable penetrance.l‐Cystine is poorly soluble and precipitates in the urinary tract to form stones which are often large and recurrent. Stone removal with urologic interventions such as ureteroscopy may be required. Prevention of stone recurrence is directed at increasing the solubility of cystine. New inhibitors of cystine crystal growth have been identified and may be effectivein vitroandin vivoin a knock‐out mouse model.Key ConceptsCystinuria accounts for 1% of kidney stones in adults and up to 5–7% of stones in children.The genes responsible for cystinuria,SLC3A1andSLC7A9, code, respectively, for proteins called rBAT and b0,+AT, both of which are necessary for the proximal tubule of the nephron to reabsorb cystine filtered by the glomerulus.The amino acidl‐cystine is a homodimer of two molecules of the amino acid cysteine, linked by a disulfide bond.Amino acids are present in the plasma, filtered by the glomerulus and reabsorbed by the proximal tubule. Normally, the amount of cystine in the urine is <1% of filtered cystine but in cystinuria, there may be more than 100% of filtered cystine.Most patients are affected by autosomal recessive inheritance, but a mutation in one allele ofSLC7A9may sometimes be sufficient to form stones, constituting autosomal dominant inheritance with variable penetrance.The only clinical manifestation of cystinuria is kidney stones. Cystine is poorly soluble and precipitates in the urinary tract to form stones which are often large and recurrent.Stone removal with urologic interventions such as ureteroscopy may be required.Prevention of stone recurrence is directed at increasing the solubility of cystine. Increased fluid intake increases urine volume and dilutes cystine. Ingestion of alkali increases urine pH and increases cystine solubility. Restriction of dietary animal protein and salt will decrease the amount of cystine in the urine.Two thiol drugs,d‐penicillamine and tiopronin, break the disulfide bridge of cystine and form drug–cysteine complexes which are soluble in the urine.New potential drugs, identified by atomic force microscopy, have been identified as novel mimics of cystine that can inhibit cystine crystal growth. They appear effectivein vitroandin vivoin a mouse model in whichSlc3a1has been knocked out.