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Cystinuria Support Network

Cystinuria

By David S Goldfarb, M.D.
Director, Kidney Stone Prevention Program, St. Vincents Hospital
Professor of Medicine and Physiology, NYU School of Medicine

First published in:
ENCYCLOPEDIA OF LIFE SCIENCES

© Macmillan Reference Ltd

Cystinuria accounts for 1% of kidney stones. Two of the genes responsible for the disorder, SLC3A1 and SLC7A9, have been identified. The identification of SLC3A1 made cystinuria the first disorder of amino acid transport with an identified gene.

Introduction

The physiological organization of the kidney requires that the renal tubules reabsorb significant proportions of the solutes contained in the filtrate formed across the glomerular basement membrane. Cystinuria is a disorder of the proximal tubule’s reabsorption of filtered cystine and dibasic amino acids (lysine, ornithine, arginine). Cystine, first identified as a component of a unique form of urinary tract stone in 1810, is poorly soluble, unlike the other amino acids whose absorption is affected. The inability of cystinuric kidneys to reabsorb cystine leads to the amino acid’s relatively high concentration and subsequent precipitation in the urine and the formation of urinary tract stones. Although kidney stones affect as many as 12% of males and 7% of females in Western societies, most stones are composed of calcium salts; cystinuria accounts for no more than 1% of urinary tract stones. Yet the associated stone formation is often notable for the frequency of recurrence and the large size of the stones. The genetic locus for the classical recessive form of cystinuria has been identified. Mutations of this gene account for defective absorption of cystine and dibasic amino acids in the renal proximal tubule. The identification of this mutation for cystinuria makes it the first abnormal gene that is the basis of a disease of amino acid transport. A second gene, which when mutated accounts for other cases of cystinuria, and may, in rare cases, cause an autosomal dominant form of the disease, has also been discovered.

Pathophysiology of the Disease

Genetics

Cystinuria is a genetic disorder that classically demonstrates autosomal recessive inheritance. This means that an abnormal gene must be inherited from both parents for the disease to be manifested, and that the disorder is not sex-linked. Most cases have been shown to involve mutations in genes called either SLC3A1 or SLC7A9. The parents of a patient with cystinuria are heterozygotes, with one defective gene and one normal one, and do not, in cases with mutations of SLC3A1, have manifestations of the disease. Instead, they are carriers and, should they reproduce with another carrier, will pass the disease on to 25% of their offspring. There are some more unusual families, with mutations in SLC7A9, that manifest autosomal dominant inheritance with one defective gene sufficient for cystine stone formation.

Early studies of families with affected members suggested that there were at least three types of cystinuria (Rosenberg et al., 1966). The three types were based on measurements of urinary cystine excretion in the parents of affected children (obligate heterozygotes for the dysfunctional gene), as well as of the patients themselves. The type I patients were those with the highest urinary cystine excretion. The patients had no increase in plasma levels of cystine following oral intake of cystine, demonstrating that intestinal absorption was also defective. This was also confirmed by studying cystine transport in intestinal epithelial cells taken from biopsies of affected patients. Most patients were in this class. The parents of these type I patients were silent carriers who had normal amounts of cystine in the urine (0 to 100 ?mol of cystine per gram of creatinine). Patients with type II cystinuria had some cystine transport across intestinal epithelial cells, but again, no increase in plasma cystine levels was seen after oral loading. The type III patients had reduced amino acid uptake by intestinal cells compared with unaffected people, but enough remained so that plasma levels rose after oral loading. The parents of type II patients had marked increases in urinary cystine excretion that appeared high enough to cause occasional stone formation (>900 ?mol of cystine per gram of creatinine). These occasional heterozygote cystine stone formers could be considered to have an incompletely recessive, or semi-dominant disease. The type III parents, obligate heterozygotes, had a milder elevation in urinary cystine excretion compared with that of the type II parents (100-900 ?mol of cystine per gram of creatinine). Since the classification preceded identification of the affected genes, the genetic basis for the varying phenotypes was not clear. The continued utility of this classification scheme is currently being reassessed as studies correlating manifestations of the disease, or phenotype, to the genetic abnormalities proceed (Leclerc 2002). It may be more useful to refer to type I and non-type I cases.

Genetic studies, called linkage analyses, of DNA from families with cystinuria were used to identify a defective gene located on human chromosome 2p (Lee et al., 1993). When the DNA from the affected chromosomal location is injected into frog eggs, transport of cystine and dibasic amino acids from outside the egg to the inside occurs more rapidly than before the DNA injection (Palacin et al., 1996). This confirmed that the injected DNA sequence is a gene that codes for a protein important for cystine transport across membranes. The name of the gene that codes for the cystine transporter, originally termed rBAT (‘related to b0,? amino acid transporter’; see below), is now SLC3A1 (SLC3 for solute carrier family 3) in the international Genome Data Base. Some investigators continue to use the rBAT designation for the class of similar genes encoding basic amino acid transporters in other systems, and for the protein products of the genes as well. The normal SLC3A1 gene appears to encode a 663-amino acid heavy subunit of the cystine transporter which is required for the complete transporter to work properly. The protein has sugar groups attached to it, which makes it a “glycoprotein”.

More than 40 mutations have been demonstrated in the SLC3A1 gene to account for cystinuria. The nature of the observed mutations is variable and includes several different mechanisms of disrupting normal protein synthesis. These include both small and large deletions of DNA base pairs from the gene (Saadi et al., 1998). One of the most common genetic alterations in SLC3A1 is called M467T. It codes for an amino acid substitution in the transport protein of threonine for methionine at position 467. This abnormal gene is relatively common in Mediterranean populations. It accounts for 40% of the abnormal genes in a Spanish cohort of families. It is relatively rare, however, in a well-studied group of patients in Quebec, Canada.

From studies designed to correlate specific abnormal genotypes with phenotypic presentation in the Canadian patients, it is evident that type I cystinurics have mutations in both of their SLC3A1 genes (Goodyer et al., 1998). The two mutations each patient inherits may be but are not necessarily the same; a different mutation in the same gene may be inherited from each of the parents to cause the disease.

The Libyan Jews studied in Israel, and some Italian families with a relatively high incidence of cystinuria, have either type II or type III cystinuria and do not have mutations in SLC3A1. Instead, from linkage analyses, these populations were found to have mutations located on the long arm of chromosome 19 (19q). A second mutation coding for cystinuria was found here and called SLC7A9 (Feliubadalo et al., 1999). The normal SLC7A9 gene encodes a 487 amino acid subunit of the cystine transporter called b0,? AT (AT, for amino acid transporter). It therefore appears that mutations in SLC7A9 are responsible for cases previously designated as Type II or Type III. The cause of the differences in the phenotypic manifestations of these two categories with apparently identical genotypes is unclear. More than 30 mutations in this gene have been identified. The most common mutation in the Libyan Jews resulted in a methionine replacing the expected valine amino acid residue (V170M) in the protein.

More recent studies demonstrate that Type I phenotypes are actually caused in some patients by one mutation in SLC3A1 and a simultaneous mutation in SLC7A9 (Leclerc 2002a). Another gene, SLC7A10, on chromosome 19q, may also account for some non-Type I cases (Leclerc 2002b).

Cystine transport

Kidney

Amino acid reabsorption, including that of cystine, is nearly complete by the end of the proximal tubule. Only 0.4% of the filtered cystine appears in the urine. This fractional excretion rises from 0.4% in normal people to 100% of the filtered load or more (implying some cystine secretion) in patients with cystinuria. Cystine transport has been studied in cell membranes taken from the proximal renal tubule of humans, rats and rabbits. There appear to be at least two transport systems for cystine absorption. The one affected in cystinuria is a high-affinity system which mediates uptake of cystine and the dibasic amino acids at the apical, or brushborder membrane of the straight, third segment (S3) of the proximal tubule (figure 1). This high-affinity process is augmented by a low-affinity process which transports only cystine and not the dibasic amino acids. It is present in the earlier convoluted tubule (S1 and S2) of the proximal tubule (Palacin et al., 1996). The gene coding for it has not yet been identified though one suggested possibility is that the SLC7A9 product codes for a subunit of this low-affinity transporter (Goodyer 2000). Its definitive involvement in any cases of cystinuria has not yet been demonstrated. After uptake across the apical membrane each molecule of cystine is reduced intracellularly to two molecules of cysteine (figure 2) which exit the cell across the basolateral membrane.

The mechanism of cystine uptake activated by the SLC3A1 and SLC7A9 products has beenintensively studied in frog egg cells and cultured renal epithelia. The characteristics of the system resemble those of a system, termed b0,?? of neutral (0) and dibasic (?) amino acid transport (denoted by the superscripts) studied in mouse blastocysts. Unlike uptake of other solutes such as glucose, and other amino acids such as glycine, cystine transport is sodium-independent, so that its uptake can proceed without the presence of sodium in the tubular lumen. Instead, it appears to require the exchange of cystine outside the cell, moving into the cell, for neutral amino acids, such as alanine inside the cell, moving out. The transport process is electrogenic, meaning that it generates a charge across the membrane. Since at the pH of the tubular fluid the amino groups of cystine and the basic amino acids are protonated and have a positive charge, the effect of cystine absorption is to depolarize the relatively negative cell interior, i.e. to make the cell interior less negative. The movement of cystine or cysteine out of the tubular cells and into the blood does not appear to be affected in cystinuria.

The DNA sequence of the SLC3A1 gene is predicted to produce a protein that would differ from most other well-studied amino acid transporters in that it would traverse the cell membrane relatively infrequently with only three or four transmembrane domains, or segments. This makes it unlikely to be a typical membrane channel. The protein also has several sites that could have sugar residues attached, a post-translational process called glycosylation that may be important for normal function or regulation. The effect of specific mutations is now being studied. One recent study suggests that the M467T mutation leads to an impairment in glycosylation of the protein after its synthesis in the endoplasmic reticulum of the cell (Chillaron et al., 1997). Interrupted movement of the synthesized protein from the endoplasmic reticulum to the cell membrane has been demonstrated.

The SLC7A9 product b0,? AT is predicted to cross the cell membrane with 12 transmembrane domains. This protein is a member of a class of proteins called glycoprotein-associated amino acid transporters: the gpaAT family (Verry 2003). In this case, the protein interacts via covalent bonds with the normal SLC3A1 product, the glycoprotein rBAT. The two proteins join via a sulfide bridge between them to form a heterodimer composed of light (b0,? AT) and heavy (rBAT) components. Placing both genes into cells in tissue culture leads rBAT to appear at the cell surface instead of being blocked after its synthesis in the endoplasmic reticulum. Uptake of the dibasic amino acid arginine can also be demonstrated when both genes, but not one, are present in cultured cells. The SLC7A9 product b0,? AT is the catalytic subunit, while rBAT is required to place the transporter in the membrane. Other mutations in SLC3A1 and SLC7A9 may more effectively abolish the synthesis of the protein products.

The failure to reabsorb the relatively poorly soluble cystine can lead to stone formation when the concentration of cystine exceeds cystine solubility. Crystals of cystine precipitate from solution and probably adhere at some point to the urinary epithelium, the cells that line the collecting system of the kidney. The mechanisms that cause crystals to adhere and initiate stone formation, rather than pass into the urine without harm, are poorly understood. Only recently have interactions been demonstrated between cell membranes and calcium oxalate crystals (far more common than cystine crystals). Whether these phenomena studied in cell culture are relevant to the human calcium stone disease, and whether they relate to cystine stone formation are not yet known. Another study of calcium oxalate stone formation has shown that crystals may form in the renal interstitium, the tissue in between the nephrons and vasa recta, and then erode through to the urinary space where they presumably grow larger (Evan). Again, the relevance of this interesting phenomenon to cystinuria is not known and not yet studied.

Wherever they first form, or nucleate, crystals may grow, as additional cystine joins at the crystal surface, and they may aggregate, as larger crystals begin to join and stick to each other. Crystal formation, growth and aggregation are more likely when urine is supersaturated with cystine. Supersaturation is a ratio of the activity of cystine in a given urine to the activity of cystine at equilbrium, when no more cystine can be dissolved in a urine sample (Nakagawa 2000). Values greater than 1 represent supersaturated solutions, and presumably a higher risk for stone formation and growth. Values less than 1 represent undersaturated urine and should be associated with less stone activity. Factors affecting supersaturation include the concentration of cystine (so that greater urine volume leads to lower supersaturation) and pH so that high urinary pH (more than 7.0) reduces supersaturation. With a protein-containing diet, urine pH averages about 6.0 for a 24-hour period, and may be as low as 4.5–5.5 between meals. These low values cause higher supersaturation values and can cause cystine precipitation and stone growth.

Eventually crystal aggregates are large enough to be called stones; they can be large enough to be seen without a microscope. Larger stones that break free of their attachments to the cells lining the collecting system can then impair the flow of urine and cause pain when in the urinary tract. It is important to note, however, that disease activity does not correlate perfectly with urinary cystine concentration or pH. Patients may experience stone formation only sporadically and some, despite having two genes for cystinuria, may never form a stone. Other patients with identical genotypes, may have onset of stone disease at different ages and with differing severity. The other variables that influence stone activity are unknown and may include promoters or inhibitors of cystine precipitation, aggregation or adherence to epithelia.

Intestine

The high-affinity cystine transporter composed of the heavy (rBAT) and light subunits (b0,? AT) is also present in the apical brushborder membranes of the jejunum where it mediates absorption of cystine, dibasic amino acids and some neutral amino acids as well. Although cystine absorption by the intestine following an oral cystine feeding is impaired in most patients with cystinuria, cystine deficiency is not clinically significant. This is because the intestine’s absorption of oligopeptides, short amino acid chains, is intact. Adequate cystine, as well as the other affected dibasic amino acids (ornithine, lysine and arginine), can be absorbed in this form, combined with other amino acids. Plasma levels of these amino acids may be normal, or slightly reduced. Dietary methionine, the absorption of which is not affected by cystinuria, serves as a precursor for the body’s cystine requirement. One study of sulfur-containing compounds and sulfate balance in cystinurics demonstrated decreased urinary excretion of sulfates, and decreases in glutathione in white blood cells, suggesting a deficiency in intracellular cystine and cysteine (Martensson et al., 1990). Though glutathione is an important antioxidant, no clinically significant consequence of the abnormal sulfur metabolism and loss of urinary amino acids has been demonstrated in people with cystinuria.

Frequency and Clinical Importance

Cystinuria accounts for no more than 1% of all kidney stones, yet it is one of the most common genetic diseases. It is estimated that the gene is carried by as many as 0.01% of the general population, with the disease occurring in 1 in 7000 people. The Jews of Libyan origin studied in Israel are found to have the disease in as many as 1 in 2500. The United States has a lower incidence of about 1 in 15 000 people. The incidence of stones in patients with cystinuria is not perfectly known since not all people with two genes coding for cystinuria actually form a stone. Patients with type I cystinuria appear much more likely to form stones in their early years but most patients with type II or III usually do not form stones until they are older (Goodyer et al., 1998). The Quebec Genetic Network Neonatal Screening Program screens all newborns for cystinuria. The incidence of persistent cystinuria was 562 cases per million infants, a rate seven times higher than for clinically manifested cystinuria in the adult population of Quebec. This confirms that many cystinurics will not form kidney stones.

Major Clinical Features and Complications

Diagnosis

The only clinically significant feature of cystinuria is recurrent nephrolithiasis. (The disease should be distinguished from cystinosis, which is marked by the intracellular accumulation of cystine in tissues.) The urine in patients with cystinuria usually demonstrates cystine crystals (figure 3), which have a flat, hexagonal appearance in acid urine. The resultant stones are pale yellow in colour (figure 4). In alkaline urine, the crystals are soluble and therefore not seen. They should therefore be sought in the first morning urine, which tends to be the most acid and concentrated. Their appearance in the urine is the simplest way to make the diagnosis since they are not seen in people without the disease. Normal adults excrete less than 25 mg (100 ?mol) of cystine for every gram of creatinine excreted. (Creatinine is a waste product of muscle metabolism, the excretion of which does not vary from day to day). Homozygous Type I cystine stone formers excrete more than 250 mg (1 mmol) per gram of creatinine.

All patients who experience an episode of nephrolithiasis, but particularly children and those with a first episode before the age of 30, should be screened for cystinuria. This is conveniently accomplished by the addition to urine of sodium cyanide and sodium nitroprusside, which in the presence of cystine form a purple-red colour. The test is sensitive to cystine excretion as low as 75 mg per gram of creatinine. The test may therefore detect some asymptomatic heterozygote type II or type III parents, who themselves may very infrequently form a stone. The test may also detect children who are heterozygotic for the defective SLC7A9 gene. These children may have higher levels of cystine excretion in their first year of life so that they resemble type I homozygotes. As they mature, their cystine excretion falls to levels consistent with homozygous type II or III cystinuria, and they are much less likely to form stones (Goodyer 1993).

Clinical course

The age of onset of stone formation appears to depend on the patient’s genotype. In the patients studied in Quebec, more than 50% of untreated type I patients had a first stone episode in the first decade of life (Goodyer et al., 1998). This finding was in contrast to the patients with type II or III cystinuria who did not have stones in their first decades. The type I patients had higher cystine excretion rates, and were more likely to have urinary cystine concentrations that exceeded predicted cystine solubility at the pH of the collected urine.

The frequency of recurrent stones in an individual can range from only a few stones in a lifetime to many stones each year. Similarly the size of stones ranges from ‘gravel’ passed frequently and with little discomfort, to ‘staghorn’ calculi. These relatively massive stones fill the collecting system of the kidney, with branches extending into the calyces to resemble a deer’s antler. Possible complications of all stones include obstruction of the urinary tract, which usually presents with severe, sudden onset of flank pain. Blood in the urine may be noted, and on occasion, obstruction can predispose to infection of the urine as well. In such cases, fever may be apparent, and white blood cells are noted in the urine. Unrelieved obstruction leads to renal dysfunction, but since this rarely affects both kidneys simultaneously, renal failure and the need for dialysis are quite rare. In the most extreme instances, the combination of obstruction and infection may lead to nephrectomy, removal of a kidney. Patients with a single kidney are at greater risk for renal failure should the remaining kidney become obstructed. Many stones may be detected by imaging studies and remain asymptomatic for many years, with the factors causing stones to break off and fall into the urinary tract remaining unknown.

Cystine stones are most often at least partially radioopaque, meaning that they do not allow full penetration of X-rays and do appear on plain radiographs. This is because of the density of the molecule’s disulfide bond. They may be less dense than calcium stones. Occasionally, some cystine stones are better demonstrated by ultrasound of the kidneys or by helical computed tomography (CT). CT is rapidly becoming the imaging procedure of choice for all stones, because of its unmatched diagnostic sensitivity and speed (Dalrymple 1998). Its relatively high cost remains an impediment to its more widespread use. However, cost is falling as the procedure requires no injection and less technician time, and often preempts the need for additional diagnostic testing. Both CT and ultrasound, unlike plain radiographs, may be useful to demonstrate hydronephrosis (dilatation of the urinary tract), when symptoms of obstruction occur. The traditional intravenous pyelogram (IVP), which requires injection of a potentially nephrotoxic radiocontrast agent, is still used for demonstrating the anatomy of the urinary tract, particularly if a surgical procedure is likely to be needed.

Approaches to Management

Medical therapy

There are two goals of the treatment of cystinuria designed to prevent stone formation. The first is to alter the characteristics of the urine so that the large amount of cystine excreted is maintained in a soluble state, in order to avoid its precipitation. The second goal is to reduce the absolute amount of cystine excreted (Barbey 2000). The latter is more difficult to achieve. Increasing urine volume by increasing oral fluid intake may suffice in some cases to lower cystine concentration and avoid stone formation. A standard estimate of cystine solubility is that 250 mg (1 mmol) can be dissolved in 1 litre of urine. Urinary cystine excretion in 24 hours can be measured and oral fluids prescribed to maintain a concentration less than 250 mg L?1. Maintaining higher urine flow rates around the clock should be emphasized. Fluid intake at bedtime is important since increased urinary concentrations of cystine usually accompany sleep with its attendant decrease in fluid intake. Increased sweat losses due to heat and exercise also will reduce urine flow and require an appropriate increase in intake.

A reduction of absolute cystine excretion, not just concentration, requires reduction in the intake of methionine, the amino acid precursor of cystine. The major dietary sources of methionine are animal protein-containing products. However, even vegetarianism does not completely reduce cystine excretion, as some proportion of the cystine that appears in the urine is generated endogenously from normal metabolic processes. Though restriction of animal protein may reduce cystine excretion, it is often not well tolerated by people used to eating various forms of meat and its efficacy as a preventive strategy has not been demonstrated convincingly.

Another major determinant of cystine solubility is urine pH, a measure of the concentration of protons, or hydrogen ions, H?. Addition of acid to a solution leads to increased proton concentration and a decreased pH. Addition of base, or alkali, diminishes H? concentration by buffering, or neutralizing protons and causes increased pH. Normally, in people eating a diet containing animal protein, urine pH tends to be relatively acidic between meals and increases after eating. Cystine solubility increases with increases in urine pH, or urinary alkalinization. This can be achieved through manipulation of diet or by oral supplementation with base.

The major dietary source of protons is animal protein. Reduction of animal protein intake by reduction of ingestion of beef, fowl, pork, eggs and fish is therefore a method of alkalinizing the urine. Less acid is ingested and therefore fewer protons need to be excreted by the kidneys, the organs that maintain the body’s acid–base balance. Restricting intake of animal protein therefore doubly serves to alkalinize the urine and reduce cystine generation. Reduced protein intake is usually accompanied by reciprocal increases in ingestion of fruits and vegetables that are relatively high in organic anion content. These organic anions, such as malate and citrate, contain carboxyl groups which are metabolized by the liver. Their metabolism yields bicarbonate, the blood’s major circulating buffer. Asbicarbonate is synthesized, protons are consumed and fewer protons must be excreted by the kidneys. The net effect is to increase urine pH and improve cystine solubility. The maximal effect occurs at urine pH above 7; maintaining pH in the more alkaline realm of at least 7.5, up to 8, is therefore desirable (figure 5).

Supplementation with oral base may be necessary for urinary alkalinization (Barbey 2000). This supplementation is usually accomplished by oral intake of citrate, an organic anion which represents base, since its metabolism by the liver consumes protons. Sources of citrate include dietary intake of citrus fruit and juices, and pharmacologic supplementation. Citrate can be given as either the sodium or potassium salt or combinations of the two. Potassium citrate is preferred since increases in urinary sodium excretion cause increases in urinary cystine excretion. For this reason, dietary restriction of table salt (sodium chloride) is also recommended to reduce cystine excretion.

Drugs containing thiol (sulfhydryl) groups (figure 2) can accomplish further reduction of cystine excretion. Available agents include penicillamine and tiopronin (also known as ?-mercaptopropionylglycine). These thiol drugs reduce the sulfur bridge in cystine and combine with the resultant cysteines to form soluble drug–cysteine complexes. Both drugs are associated with side effects that may limit long-term use. The angiotensin-converting enzyme inhibitor captopril, often used in the management of heart failure, hypertension and chronic kidney disease, also contains a thiol and may have a modest effect on cystine excretion as well (Sakhaee and Sutton, 1996).

A new approach to the management of cystinuria may come from measurement of cystine supersaturation (see above). The supersaturation reflects urinary concentration of cystine (determined by cystine excretion and urine volume), urinary pH and the presence of thiol drugs. The tendency of crystals to form in the kidney and the contributions of all of these variables, can be expressed by a single value. Values significantly greater than 1 presumably represent supersaturated values likely to be associated with stone formation while values less than 1 represent undersaturated urine and should be associated with a much lesser tendency for stones to form. Whether these values will lead to improved management of the clinical course of patients has not yet been determined (Nakagawa 2000).

Surgical therapy

The likelihood of spontaneous passage of stones out of the urinary tract, regardless of composition, is most dependent on their size. Stones that are more than 5 mm in diameter have a likelihood of spontaneous passage of less than 50%, while stones more than 7–8 mm in diameter rarely pass. Such stones usually require some form of surgical therapy. Staghorn calculi also will not pass without surgical intervention. Options for therapy are now more successful, less invasive and less dangerous than in past years. ‘Open’ surgery, in which the kidney is cut open longitudinally should rarely be performed today for even the largest stones, if the most modern techniques are available (Segura, 1996). For large stones, one choice is percutaneous nephrostolithotomy (PCNL), which requires fibreoptic endoscopes to be placed through the flank and into the kidney through one or more tracts. Lasers are then used to directly fragment the stones (Teichman, 2002). For smaller stones, a less traumatic technique called ureteroscopy (URS) allows these lasers to be passed into the urethra, the bladder, and then up the ureters to find and fragment obstructing stones. Both PCNL and URS may be followed by chemolysis, direct infusion into the urinary tract of alkalinizing chemicals that can further dissolve residual fragments. Another option is extracorporeal shock-wave lithotripsy (ESWL) which uses an electrically generated shock, focused at the stone from outside the body, to shatter it into passable fragments. Popular for management of calcium stones, this therapy is less effective for cystine stones, which are harder and less easy to fragment. This form of lithotripsy often fails to adequately fragment larger stones as well.

In rare instances of cystinuria, stone disease may be so severe that both kidneys could be damaged irreparably, leading to renal failure. With current techniques, devastating renal failure is nearly always avoidable. Should renal failure occur, treatment with renal transplantation would be appropriate after institution of dialysis. Cystinuria would not be expected to recur after renal transplantation since the tubular transport of cystine in the transplanted kidney would be normal.

Summary

Cystine absorption by the kidneys is mediated by transport systems in the proximal tubule that are defective in cystinuria. Several genotypes have been described, with evidence of mutations affecting at least two different genes: one called SLC3A1 located on chromosome 2, and another called SLC7A9 located on chromosome 19. Many mutations in the SLC3A1 gene have been identified which appear to cause similar phenotypes, with recurrent nephrolithiasis, often starting at an early age, the only clinical manifestation. Mutations in SLC7A9, and perhaps in SLC7A10 cause a more mild disease of later onset, but can also rarely cause stones in heterozygotes, an autosomal dominant form of disease. Increasing urine volume and urine pH are the main therapies that reduce stone formation and growth. Pharmacological reduction of cystine to cysteine with thiol drugs is also useful. Since these medical therapies often fail, patients are fortunate that newer surgical therapies have reduced the morbidity of stone removal.

References

  • Barbey F, Joly D, Rieu P, et al. (2000) Medical treatment of cystinuria: critical reappraisal of long-term results. Journal of Urology 163:1419-23.
  • Chillaron J, Estevez R, Samarzija I et al. (1997) An intracellular trafficking defect in type I cystinuria rBAT mutants M467T and M467K. Journal of Biological Chemistry 272: 9543–9549.
  • Dalrymple NC, Verga M, Anderson KR, et al. (1998) The value of unenhanced helical computerized tomography in the management of acute flank pain. Journal of Urology 159:735-40.
  • Feliubadalo L, Font M, Purroy J et al. (1999) Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b0,?AT) of rBAT. Nature Genetics 23: 52–57.Goodyer P, Saadi I, Ong P, Elkas G and Rozen R (1998) Cystinuria subtype and the risk of nephrolithiasis. Kidney International 54: 56–61.
  • Goodyer P, Boutros M, and Rozen R. (2000) The molecular basis of cystinuria: an update. Experimental Nephrology 8:123-7.
  • Leclerc D, Boutros M, Suh D et al. (2002a) SLC7A9 mutations in all three cystinuria subtypes. Kidney International 62:1550-9.
  • Leclerc D, Wu Q, Ellis JR, Goodyer P, and Rozen R (2002b) Is the SLC7A10 gene on chromosome 19 a candidate locus for cystinuria? Molecular Genetics and Metabolism 73:333-9.
  • Lee W, Wells RG, Sabbag RV, Mohandas TK and Hediger MA (1993) Cloning and chromosomal localization of a human kidney cDNA involved in cystine, dibasic, and neutral amino acid transport. Journal of Clinical Investigation 91: 1959–1963.
  • Martensson J, Denneberg T, Lindell A and Textorius O (1990) Sulfur amino acid metabolism in cystinuria: a biochemical and clinical study of patients. Kidney International 37: 143–149.
  • Nakagawa Y, Asplin JR, Goldfarb DS, et al. (2000) Clinical use of cystine supersaturation measurements. Journal of Urology 164:1481-5.
  • Palacin M, Chillaron J and Mora C (1996) Role of the b0,?-like amino acid-transport system in the renal reabsorption of cystine and dibasic amino acids. Biochemical Society Transactions 24: 856–863.
  • Rosenberg LE, Downing S, Durant JL and Segal L (1966) Cystinuria: biochemical evidence for three genetically distinct diseases. Journal of Clinical Investigation 45: 365–371.
  • Saadi I, Chen X, Hediger M et al. (1998) Molecular genetics of cystinuria: mutation analysis of SLC3A1 and evidence for another gene in the type I (silent) phenotype. Kidney International 54: 48–55.
  • Sakhaee K and Sutton RAL (1996) Pathogenesis and medical management of cystinuria. In: Coe FL, Favus MJ, Pak CYC, Parks JH and Preminger GM (eds) Kidney Stones: Medical and Surgical Management, pp. 1007–1017. New York: Lippincott-Raven.
  • Segura JW (1996) Surgery of cystine stones. In: Coe FL, Favus MJ, Pak CYC, Parks JH and Preminger GM (eds) Kidney Stones: Medical and Surgical Management, pp. 1019–1024. New York: Lippincott-Raven.
  • Teichman JM (2002) Laser lithotripsy. Current Opinion in Urology 12:305-9.
  • Verrey F, Closs EI, Wagner CA, et al (2003) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Archives epub ahead of print.

Further Reading

  • Auge BK, Preminger GM (2002) Surgical management of urolithiasis. Endocrinology and Metabolism Clinics of North America 31:1065-82.
  • Akakura K, Egoshi K, Ueda T et al. (1998) The long-term outcome of cystinuria in Japan. Urology International 61: 86–89.
  • Bushinsky DA (1998) Nephrolithiasis. Journal of the American Society of Nephrology 9: 917–924.
  • Chow GK and Streem SB (1998) Contemporary urological intervention for cystinuric patients: immediate and long-term impact and implications. Journal of Urology 160: 341–344.
  • Dell KM and Guay-Woodford LM (1999) Inherited tubular transport disorders. Seminars in Nephrology 19: 364–373.
  • Goodyer PR, Clow C, Reade T and Girardin C (1993) Prospective analysis and classification of patients with cystinuria identified in a new born screening program. Journal of Pediatrics 122: 568–572.
  • Leveillee RJ, Lobik L (2003) Intracorporeal lithotripsy: which modality is best? Current Opinion in Urology 13:249-53.
  • Palacin M, Estevez R, Bertran J and Zorzano A (1998a) Molecular biology of mammalian plasma membrane amino acid transporters. Physiological Reviews 78: 969–1054.
  • Palacin M, Estevez R and Zorzano A (1998b) Cystinuria calls for heteromultimeric amino acid transporters. Current Opinions in Cell Biology 10: 455–461.

Figure Legends

Figure 1

cystine transport cartoon

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 2 subunits (making it a heterodimer), the protein products of SLC3A1 (rBAT, the heavy component) and SLC7A9 ((b0,? AT, the light component). Inside the proximal tubule cell, cystine is reduced to 2 molecules of cysteine which exit across the basolateral membrane. Back to article

Figure 2

chemical structure

Chemical structure for cystine, a combination of two molecules of cysteine. Two thiol (-SH) containing drugs used for treatment are penicillamine and ?-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. Back to article Back to article again

Figure 3

cystine crystal

Typical hexagonal cystine crystal in urine. Courtesy Louis Herring Lab, Orlando, Florida. Back to article

Figure 4

staghorn calculus

A staghorn kidney stone composed of cystine. Courtesy Louis Herring Lab, Orlando, Florida. Back to article

Figure 5

chart

Curve of increasing cystine solubility with increasing urinary pH. Back to article

Glossary

Dibasic amino acid

An amino acid containing two amide groups, both of which can accept a proton at physiological pH, becoming positively charged.

Extracorporeal shock-wave lithotripsy

Procedure in which an electric impulse outside the body creates a shock-wave that can be focused in order to fragment kidney stones.

Glomerular filtration

Process by which plasma is filtered across the relatively permeable glomerular basement membrane by the hydrostatic pressure of the blood.

Heterodimer

A molecule composed of two different subunits.

Lithotripsy

Process of breaking stones via shock wave, laser energy, or pneumatic force.

Proximal tubule

The initial part of the tubule that reabsorbs about two thirds of the glomerular filtrate back into the blood. It consists of a convoluted tubule (segments S1 and S2) and a straight third segment (S3).

Ureteroscopy

Procedure in which a flexible fibreoptic endoscope is passed up the ureter in order to diagnose and treat obstructions and other urologic disorders. Lasers and other instruments may be used through the scope to fragment kidney stones.