Cystinuria

Abstract

Cystinuria accounts for 1% of kidney stones in adults and up to 5–7% of stones in children. The two genes responsible for the disorder, SLC3A1 and SLC7A9. 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 of SLC3A1 made 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 of SLC7A9 may 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 effective in vitro and in vivo in a knock‐out mouse model.

Key Concepts

  • Cystinuria accounts for 1% of kidney stones in adults and up to 5–7% of stones in children.
  • The genes responsible for cystinuria, SLC3A1 and SLC7A9, 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 acid l‐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 of SLC7A9 may 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 effective in vitro and in vivo in a mouse model in which Slc3a1 has been knocked out.

Keywords: amino acids; nephrolithiasis; mutations; rBAT ; kidney stones; ureteroscopy; lithotripsy; alkalinisation; methionine

Figure 1. Cartoon of cystine transport. Cystine is filtered across the glomerular capillary membrane into the proximal tubule. Cystine reabsorption from the tubular lumen across the apical membranes of the S3 segments and into the cell is mediated by the amino acid transporter affected in cystinuria. Cystine is exchanged for neutral amino acids like alanine (not shown). The transporter is composed of two subunits (making it a heterodimer) and the protein products of (rBAT, the heavy component) and (b0,+AT, the light component). Inside the proximal tubule cell, cystine is reduced to two molecules of cysteine, which exit across the basolateral membrane.
Figure 2. Chemical structure of cystine, a combination of two molecules of cysteine. Two thiol (–SH) containing drugs used for treatment are penicillamine and α‐mercaptopropionylglycine. Both thiols reduce the disulfide bond in cystine to cysteine and chelate the latter to form a more soluble product. Only the penicillamine–cysteine complex is shown here. Cystine dimethyl ester (CDME) inhibits cystine crystal growth and .
Figure 3. Typical hexagonal cystine crystal in urine. (Courtesy of Louis Herring Lab, Orlando, Florida.)
Figure 4. A staghorn kidney stone composed of cystine. (Courtesy of Louis Herring Lab, Orlando, Florida.)
Figure 5. Curve of increasing cystine solubility with increasing urinary pH.
Figure 6. (a) Micro‐computer tomography images of bladders from 2 mice with cystinuria as the result of being knocked‐out. The mice were treated with water (left panel) or cystine dimethyl ester (CDME, right panel). For each mouse, top panel is a cross‐sectional image and the bottom panel is the intact organ. (b) Stones from the bladder of water and CDME treated mice. (Reproduced with permission from Sahota et al., (2014) © Elsevier.)
Figure 7. (a,b) Atomic force microscopy (AFM) images of a cystine crystal, acquired 12 min apart. (c,d) AFM images of a single center of (c) l‐cystine and (d) d‐cystine crystals during growth. The two stereoisomers grow cylindrically in opposite directions; (e,f) AFM image of a hexagonal growth hillock of cystine (e) before and (f) after addition of CDME (5 mg L−1; 0.02 mM), revealing roughening of the steps. (Reproduced with permission from Rimer et al. (2010) © American Association for the Advancement of Science.)
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Further Reading

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Auge BK and Preminger GM (2002) Surgical management of urolithiasis. Endocrinology and Metabolism Clinics of North America 31: 1065–1082.

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Chillarón J , Font‐Llitjós M , Fort J , et al. (2010) Pathophysiology and treatment of cystinuria. Nature Reviews Nephrology 6: 424–434.

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Fotiadis D , Kanai Y and Palacín M (2013) The SLC3 and SLC7 families of amino acid transporters. Molecular Aspects of Medicine 34: 139–158.

Goldfarb DS (2009) In the clinic: Nephrolithiasis. Annals of Internal Medicine 151: ITC2.

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Thomas K , Wong K , Withington J , et al. (2014) Cystinuria‐a urologist's perspective. Nature Reviews Urology 11: 270–277.

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Goldfarb, David S(Jul 2015) Cystinuria. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002286.pub3]