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Cystinuria

Cystinuria

Definition

Cystinuria is an inborn error of amino acid transport that results in the defective absorption by the kidneys of the amino acid called cystine. The name means "cystine in the urine."

Description

Cystine is an amino acid. Amino acids are organic compounds needed by the body to make proteins and for many normal functions. When the kidneys do not absorb cystine, this compound builds up in the urine. When the amount of cystine in the urine exceeds its solubility (the greatest amount that can be dissolved), crystals form. As the amount of cystine continues to increase in the urine, the number of crystals also increases. When very large numbers of cystine crystals form, they clump together into what is called a stone.

Causes and symptoms

Cystinuria is a rare disease that occurs when people inherit an abnormal gene from their parents. This disease occurs in differing degrees of severity in people who have inherited either one or two abnormal genes. Humans have two copies of each gene. When both are abnormal, the condition is called homozygous for the disease. When one copy is normal and the other is abnormal, the condition is called heterozygous for the disease. Persons with one abnormal gene can have a milder form of cystinuria that rarely results in the formation of stones.

Severe cystinuria occurs when people are homozygous for the disease. For these individuals, the kidneys may excrete as much as 30 times the normal amount of cystine. Research has shown that this condition is caused by mutations on chromosome number two (humans have 23 pairs of chromosomes).

A person who has inherited cystinuria may have other abnormal bodily functions. In addition to excess levels of the amino acid cystine, high amounts of the amino acids lysine, arginine, and ornithine are found in the urine. This condition indicates that these amino acids are not being reabsorbed by the body.

When excess cystine crystals clump together to form a stone, the stone can block portions of the interior of the kidney or the tube (the ureter) that connects the kidney to the urinary bladder. These cystine stones can be painful, and depending upon where the stone becomes trapped, the pain can be felt in the lower back or the abdomen. Nausea and vomiting can also occur, and patients may sometimes feel the need to urinate often. Cystine stones can also cause blood in the urine. When the urinary tract is blocked by a stone, urinary tract infections or kidney failure may result.

Diagnosis

Small stones (called "silent") often do not cause any symptoms, although they can be detected by an x ray. Large stones are often painful and easily noticed by the patient. Blood in the urine can also mean that a stone has formed.

When the urine contains extremely high amounts of cystine, yellow-brown hexagonal crystals are visible when a sample is examined under the microscope. Urine samples can also be mixed with chemicals that change color when high levels of cystine are present. When the compound nitroprusside is added to urine that has been made alkaline by the addition of ammonia, the urine specimen turns red if it contains excess cystine.

Treatment

No treatment can decrease cystine excretion. The best treatment for cystinuria is to prevent stones from forming. Stones can be prevented by drinking enough liquid each day (about 5-7 qts) to produce at least 8 pts of urine, thus keeping the concentration of cystine in the urine low. Because a person does not drink throughout the night, less urine is produced, and the likelihood of stone formation increases. This risk can be minimized by drinking water or other liquids just before going to bed.

Drug treatments

In addition to drinking large amounts of fluids, it is helpful to make the urine more alkaline. Cystine dissolves more easily in alkaline urine. To increase urine alkalinity, a person may take sodium bicarbonate and acetazolamide. Penicillamine, a drug that increases the solubility of cystine, may be prescribed for patients who do not respond well to other therapies. This drug must be used with caution, however, because it can cause serious side effects or allergic reactions. For those unable to take penicillamine, another drug, alpha-mercaptopropionylglycine (Thiola), may be prescribed.

Surgical treatments

Most stones can be removed from the body by normal urination, helped by drinking large amounts of water. Large stones that cannot be passed this way must be removed by surgical procedures.

Large stones can be surgically removed by having a device called a uretoscope placed into the urethra, up through the bladder and into the ureter, where the trapped stone can be seen and removed. Another method involves using sound-wave energy aimed from outside the body to break the large stone into small pieces that can be passed by urination. This external technique is called extracorporeal shock-wave lithotripsy (ESWL).

For large stones in the kidney, a procedure called percutaneous nephrolithomy may be used. In this procedure, the surgeon makes a small incision in the back over the kidney. An instrument called a nephroscope is inserted through the incision into the kidney. The surgeon uses the nephroscope to locate and remove the stone. If the stone is very large, it may be broken up into smaller pieces by an ultrasonic or other kind of probe before removal.

Prognosis

As many as 50% of patients who have had surgical treatment for a kidney stone will have another stone within five years if no medicines are used to treat this condition.

KEY TERMS

Alkaline A solution is considered alkaline if it contains fewer hydrogen atoms than pure water.

Amino acid An organic compound made of an amino group (containing nitrogen and hydrogen) and a carbolic acid group. Amino acids are an essential part of protein molecules.

Nephroscope An instrument made of a light source in a tube. The tube is inserted into the kidney through an incision in the back and used to locate kidney stones. The stones are broken up with high frequency sound waves and removed by suction through the scope.

Nitroprusside A compound that is used in laboratory tests to identify large amounts of cystine in urine samples.

Uretoscope A tube-shaped device inserted into the body through the urinary system that allows objects to be both seen and grasped for removal.

Prevention

Cystinuria is a genetic disorder that currently cannot be prevented.

Resources

ORGANIZATIONS

Cystinuria Support Network. 21001 NE 36th St., Redmond, WA 98053. (425) 868-2996. http://www.cystinuria.com.

National Kidney Foundation. 30 East 33rd St., New York, NY 10016. (800) 622-9010. http://www.kidney.org.

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cystinuria

cystinuria (sis-tin-yoor-iă) n. an inborn error of metabolism resulting in excessive excretion of the amino acid cystine in the urine due to a defect of reabsorption by the kidney tubules. It may lead to the formation of cystine stones in the kidney.

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cystinuria

cystinuria A genetic disease in which there is abnormally high excretion of the amino acids cysteine and cystine, resulting in the formation of kidney stones. Treatment is by feeding a diet low in the sulphur amino acids methionine, cysteine, and cystine.

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Cystinuria

Cystinuria

Definition

Cystinuria is a relatively common inherited disorder characterized by the formation of cystine urinary tract stones that can lead to obstruction, infection, and eventual loss of renal function.

Description

In cystinuria there is a defect in the movement of cystine and the dibasic amino acids (lysine, arginine, and ornithine) across the epithelial cells of the kidneys and the small intestine. In the kidney, most amino acids are filtered by the glomerulus and reabsorbed by the proximal tubules with little residual amino acid in the urine. In cystinuria, cystine and the dibasic amino acids are not reabsorbed by the tubules of the kidney and eventually build up in the urine. Cystine in high concentrations is insoluble in urine and will form stones (calculi) in the kidneys, bladder, and ureters. The transport defect in the small intestine leads to the accumulation of digestion breakdown products of cystine and the dibasic amino acids in the stool, urine, and plasma. The intestinal defect does not appear to result in any adverse symptoms for the affected individual.

Cystinuria has been classified into three types (I, II, and III) based on the urinary excretion of cystine and the dibasic amino acids among carriers of the disease (heterozygotes) and on the nature of the intestinal transport defect among affected individuals (homozygotes).

The name cystine is derived from the Greek word for bladder, kystis. When the disease was first described in the 1800's, it was thought that the origin of the cystine stones was the bladder. Historically, cystinuria is important because it was one of the four inborn errors of metabolism reported by Sir Archibald Garrod in his famous Croonian lectures in 1908. Although alternate names for the disorder include: cistinuria, cystine-lysinuria, cystine-lysine-arginine-ornithinuria and cystinuria dibasic amnioaciduria, the term cystinuria is used most often to describe the disease.

Genetic profile

Cystinuria is a complex autosomal recessive disorder. Type I cystinuria is completely recessive; carriers have no manifestations. Types II and III cystinuria are incompletely recessive; carriers can display symptoms. Two amino acid transporter genes, SLC3A1 (solute carrier family 3, member 1) located on chromosome 2p, and SLC7A9 (solute carrier family 7 member 9) located on chromosome 19q are known to cause cystinuria. The proteins produced by these two genes apparently interact with one another. An individual with two mutations in the SLC3A1 gene (homozygote) has type I disease. Mutations in the SLC7A9 gene lead to types II and III cystinuria. Types II and III cystinuria are allelic; different changes (mutations) in the same gene lead to alternative forms of the disease. There are some patients who are genetic compounds, they have a type II mutation on one copy of the gene and a type III mutation on the other copy. There are also individuals who may have mutations in both the SLC3A1 gene and the SLC7A9 gene.

Demographics

Cystinuria is considered one of the more common genetic disorders with an estimated prevalence of one in 7,000. Most affected individuals have type I disease. Type II disease is relatively rare. Due to a founder effect, an increased incidence of cystinuria exists among individuals of Libyan Jewish ancestry. Approximately one in 2,500 persons of Libyan Jewish descent has type II disease. The carrier frequency in this population is around one in 25.

Signs and symptoms

Symptoms of cystinuria develop due to the high level of cystine in the urine. Since cystine at high concentrations is insoluble in urine, undissolved cystine accumulates in the urine and affected individuals are prone to recurrent urinary tract stone formation (nephrolithiasis). Also, hexagonal-shaped crystals form in the urine; these crystals signify the presence of cystine in potentially stone-forming concentrations. The onset of cystinuria is variable and symptoms can appear anytime between the first year of life and the ninth decade. Most cystinurics develop symptoms in the second and third decades of life. In many affected individuals the first sign of the disorder is renal colic, a painful condition caused by obstruction of the urinary tract. Obstruction of the urinary tract due to calculi can lead to infection and eventually to renal insufficiency. Less often, complaints such as infection, hypertension, and renal failure are the first reasons cystinuric patients seek medical attention.

Unlike most autosomal recessive disorders, carriers for types II and III cystinuria can be symptomatic. Type II carriers have high urinary excretion of cystine and lysine and type II carriers have moderate excretion of cystine, lysine, arginine, and ornithine. Both type II and type III carriers are at-risk to develop stones. Type I carriers have no excess cystine or dibasic amino acids in their urine and are without symptoms of the disorder.

Although there are reports of an association between cystinuria and neurologic abnormalities, little is known about the mechanism responsible for this nor is the prevalence of this complication among affected individuals known.

Diagnosis

The diagnosis of cystinuria is made at the biochemical level. Molecular (genetic) testing is also available but is generally not the first means of making a cystinuria diagnosis. The simplest approach to diagnosis of this condition is microscopic examination of the urine for the characteristic hexagonal-shaped crystals. Urinary microscopic examination was the primary means of cystinuria diagnosis for many years since the discovery of these crystals by Stromeyer in 1824, and it remains a useful aid in the diagnosis of this condition today. Another widely used screening procedure is the cyanide-nitroprusside test, a test that measures the amount of cystine excreted in the urine in comparison to the amount of creatinine (a protein normally found in urine). In those patients who display crystals and have a positive nitroprusside test, further diagnostic tests such as thin-layer chromatography or high-voltage electrophoresis can identify the specific amino acids (cystine, lysine, arginine, ornithine), and other techniques such as ion-exchange chromatography, liquid chromatography-mass spectrophotometer, and high-performance liquid chromatography may be performed to measure the amounts of these amino acids in the urine.

The type (I, II, or II) of cystinuria in an affected patient can be determined by family studies and/or by study of the intestinal transport defect in an affaected individual. Type I obligate carrriers have normal amounts of urinary cystine and dibasic amino acids. Type II carriers have between nine and fifteen times the normal amount of cystine and lysine in their urine. Type III carriers have up to twice the normal range of cystine and the dibasic amino acids in their urine. The intestinal absorption defect in an affected individual can be demonstrated by oral loading tests and/or by study of the transport of cystine and the dibasic amino acids in an intestinal biopsy specimen from an affected individual.

Testing for mutations in the SLC3A1 gene and the SLC7A9 gene is possible. Over forty mutations in the SLC3A1 gene have been found and almost as many have been detected in the SLC7A9 gene.

Treatment and management

Prevention

The primary goal of treatment of cystinuria is prevention of existing cystine stones through non-invasive means. There are three main categories of treatment: increase cystine solubility, reduce cystine production and excretion, and convert cystine into a more soluble compound. The first step in treatment is to increase cystine solubility via hydration therapy. It is recommended that patients increase their fluid intake such that the concentration of cystine is 200-250 mg/liter of urine. This therapy prevents stone formation approximately two-thirds of the time. Another therapy that increases cystine solubility is known as oral alkalinization. Medications such as sodium citrate, potassium citrate, or sodium bicarbonate increase the pH of urine to levels at which cystine becomes a more soluble compound. To reduce cystine excretion and production, individuals with cystinuria may follow a diet low in sodium and protein.

If the above measures are not successful in preventing stones and/or dissolving existing ones, drug therapy may be necessary. Tiopronin and d-penicillamine are two drugs that are known to bind excess cystine into a form that is more soluble than cystine alone and thus reduce the excessive urinary excretion of this amino acid. Since both tiopronin and d-penicillamine can have adverse side effects, patients on these regimens require follow-up to monitor the efficacy and tolerance of the medication. Other medications that reduce cystine excretion include mercaptopropionylglycine (MPG) and captopril. Although they are not as effective as tiopronin or d-penicillamine, MPG and captopril have fewer side effects.

If stones form despite the above therapeutic regimens, surgical intervention may be required. Surgical management of cystine stones may include dissolution of calculi by irrigation through a catheter, removal of cystine stones by lithotripsy or lithotomy, and renal transplantation. Catheter irrigation is a minimally invasive procedure in which catheters are placed into the ureters and the urinary tract is irrigated with a solution that dissolves the stones over a period of one week to several months. Lithotripsy is a medical procedure used to break a kidney stone into small pieces that can be passed in the urine. In extracorporeal shock wave lithotripsy, a shock wave produced outside the body is used to break up the stone and a catheter placed in the ureter facilitates passage of the stone fragments. In percutaneous nephrolithotripsy, an opening (port) is created by puncturing the kidney through the skin; a specialist then inserts instruments via this opening into the kidney to break up the stone and remove the debris. Lithotomy is the surgical removal of a (kidney) stone.

Prognosis

The prognosis of cystinuria is variable and depends on the level of renal function at the time of diagnosis and initiation of therapy, and the success of preventative measures and surgical management. It is known that males tend to have a more severe course and a higher mortality rate.

Resources

BOOKS

Holton, John B. The Inherited Metabolic Diseases. New York, New York: Churchill Livingstone, 1994.

Rimoin, David, et. al. Emery and Rimoin's Principles and Practice of Medical Genetics. New York, New York: Churchill Livingstone, 1997.

Scriver, Charles R., et. al. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, Inc., 1995.

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

Cystinuria Support Network homepage. <http://www.cystinuria.com/>.

Dawn Cardeiro, MS, CGC

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Cystinuria

Cystinuria

Definition

Cystinuria is a relatively common inherited disorder characterized by the formation of cystine urinary tract stones that can lead to obstruction, infection, and eventual loss of renal function.

Description

In cystinuria there is a defect in the movement of cystine and the dibasic amino acids (lysine, arginine, and ornithine) across the epithelial cells of the kidneys and the small intestine. In the kidney, most amino acids are filtered by the glomerulus and reabsorbed by the proximal tubules with little residual amino acid in the urine. In cystinuria, cystine and the dibasic amino acids are not reabsorbed by the tubules of the kidney and eventually build up in the urine. Cystine in high concentrations is insoluble in urine and will form stones (calculi) in the kidneys, bladder, and ureters. The transport defect in the small intestine leads to the accumulation of digestion breakdown products of cystine and the dibasic amino acids in the stool, urine, and plasma. The intestinal defect does not appear to result in any adverse symptoms for the affected individual.

Cystinuria has been classified into three types (I, II, and III) based on the urinary excretion of cystine and the dibasic amino acids among carriers of the disease (heterozygotes) and on the nature of the intestinal transport defect among affected individuals (homozygotes).

The name cystine is derived from the Greek word for bladder, kystis. When the disease was first described in the 1800's, it was thought that the origin of the cystine stones was the bladder. Historically, cystinuria is important because it was one of the four inborn errors of metabolism reported by Sir Archibald Garrod in his famous Croonian lectures in 1908. Although alternate names for the disorder include: cystine-lysinuria, cystine-lysine-arginineornithinuria and cystinuria dibasic amnioaciduria, the term cystinuria is used most often to describe the disease.

Genetic profile

Cystinuria is a complex autosomal recessive disorder. Type I cystinuria is completely recessive; carriers have no manifestations. Types II and III cystinuria are incompletely recessive; carriers can display symptoms. Two amino acid transporter genes, SLC3A1 (solute carrier family 3, member 1) located on chromosome 2p, and SLC7A9 (solute carrier family 7 member 9) located on chromosome 19q are known to cause cystinuria. The proteins produced by these two genes apparently interact with one another. An individual with two mutations in the SLC3A1 gene (homozygote) has type I disease. Mutations in the SLC7A9 gene lead to types II and III cystinuria. Types II and III cystinuria are allelic; different changes (mutations) in the same gene lead to alternative forms of the disease. There are some patients who are genetic compounds, they have a type II mutation on one copy of the gene and a type III mutation on the other copy. There are also individuals who may have mutations in both the SLC3A1 gene and the SLC7A9 gene.

Demographics

Cystinuria is considered one of the more common genetic disorders with an estimated prevalence of one in 7,000. Most affected individuals have type I disease. Type II disease is relatively rare. Due to a founder effect, an increased incidence of cystinuria exists among individuals of Libyan Jewish ancestry. Approximately one in 2500 persons of Libyan Jewish descent has type II disease. The carrier frequency in this population is around one in 25.

Signs and symptoms

Symptoms of cystinuria develop due to the high level of cystine in the urine. Since cystine at high concentrations is insoluble in urine, undissolved cystine accumulates in the urine and affected individuals are prone to recurrent urinary tract stone formation (nephrolithiasis). Also, hexagonal-shaped crystals form in the urine; these crystals signify the presence of cystine in potentially stone-forming concentrations. The onset of cystinuria is variable and symptoms can appear anytime between the first year of life and the ninth decade. Most cystinurics develop symptoms in the second and third decades of life. In many affected individuals the first sign of the disorder is renal colic, a painful condition caused by obstruction of the urinary tract. Obstruction of the urinary tract due to calculi can lead to infection and eventually to renal insufficiency. Less often, complaints such as infection, hypertension, and renal failure are the first reasons cystinuric patients seek medical attention.

Unlike most autosomal recessive disorders, carriers for types II and III cystinuria can be symptomatic. Type II carriers have high urinary excretion of cystine and lysine and type II carriers have moderate excretion of cystine, lysine, arginine, and ornithine. Both type II and type III carriers are at-risk to develop stones. Type I carriers have no excess cystine or dibasic amino acids in their urine and are without symptoms of the disorder.

Although there are reports of an association between cystinuria and neurologic abnormalities, little is known about the mechanism responsible for this nor is the prevalence of this complication among affected individuals known.

Diagnosis

The diagnosis of cystinuria is made at the biochemical level. Molecular (genetic) testing is also available but is generally not the first means of making a cystinuria diagnosis. The simplest approach to diagnosis of this condition is microscopic examination of the urine for the characteristic hexagonal-shaped crystals. Urinary microscopic examination was the primary means of cystinuria diagnosis for many years since the discovery of these crystals by Stromeyer in 1824, and it remains a useful aid in the diagnosis of this condition today. Another widely used screening procedure is the cyanide-nitroprusside test, a test that measures the amount of cystine excreted in the urine in comparison to the amount of creatinine (a protein normally found in urine). In those patients who display crystals and have a positive nitroprusside test, further diagnostic tests such as thin-layer chromatography or high-voltage electrophoresis can identify the specific amino acids (cystine, lysine, arginine, ornithine), and other techniques such as ionexchange chromatography, liquid chromatography-mass spectrophotometer, and high-performance liquid chromatography may be performed to measure the amounts of these amino acids in the urine.

The type (I, II, or II) of cystinuria in an affected patient can be determined by family studies and/or by study of the intestinal transport defect in an affected individual. Type I obligate carriers have normal amounts of urinary cystine and dibasic amino acids. Type II carriers have between nine and fifteen times the normal amount of cystine and lysine in their urine. Type III carriers have up to twice the normal range of cystine and the dibasic amino acids in their urine. The intestinal absorption defect in an affected individual can be demonstrated by oral loading tests and/or by study of the transport of cystine and the dibasic amino acids in an intestinal biopsy specimen from an affected individual.

Testing for mutations in the SLC3A1 gene and the SLC7A9 gene is possible. Over forty mutations in the SLC3A1 gene have been found and almost as many have been detected in the SLC7A9 gene.

Treatment and management

Prevention

The primary goal of treatment of cystinuria is prevention of existing cystine stones through non-invasive means. There are three main categories of treatment: increase cystine solubility, reduce cystine production and excretion, and convert cystine into a more soluble compound. The first step in treatment is to increase cystine solubility via hydration therapy. It is recommended that patients increase their fluid intake such that the concentration of cystine is 200-250 mg/liter of urine. This therapy prevents stone formation approximately two-thirds of the time. Another therapy that increases cystine solubility is known as oral alkalinization. Medications such as sodium citrate, potassium citrate, or sodium bicarbonate increase the pH of urine to levels at which cystine becomes a more soluble compound. To reduce cystine excretion and production, individuals with cystinuria may follow a diet low in sodium and protein.

If the above measures are not successful in preventing stones and/or dissolving existing ones, drug therapy may be necessary. Tiopronin and d-penicillamine are two drugs that are known to bind excess cystine into a form that is more soluble than cystine alone and thus reduce the excessive urinary excretion of this amino acid. Since both tiopronin and d-penicillamine can have adverse side effects, patients on these regimens require follow-up to monitor the efficacy and tolerance of the medication. Other medications that reduce cystine excretion include mercaptopropionylglycine (MPG) and captopril. Although they are not as effective as tiopronin or d-penicillamine, MPG and captopril have fewer side effects.

If stones form despite the above therapeutic regimens, surgical intervention may be required. Surgical management of cystine stones may include dissolution of calculi by irrigation through a catheter, removal of cystine stones by lithotripsy or lithotomy, and renal transplantation. Catheter irrigation is a minimally invasive procedure in which catheters are placed into the ureters and the urinary tract is irrigated with a solution that dissolves the stones over a period of one week to several months. Lithotripsy is a medical procedure used to break a kidney stone into small pieces that can be passed in the urine. In extracorporeal shock wave lithotripsy, a shock wave produced outside the body is used to break up the stone and a catheter placed in the ureter facilitates passage of the stone fragments. In percutaneous nephrolithotripsy, an opening (port) is created by puncturing the kidney through the skin; a specialist then inserts instruments via this opening into the kidney to break up the stone and remove the debris. Lithotomy is the surgical removal of a (kidney) stone.

Prognosis

The prognosis of cystinuria is variable and depends on the level of renal function at the time of diagnosis and initiation of therapy, and the success of preventative measures and surgical management. It is known that males tend to have a more severe course and a higher mortality rate.

Resources

BOOKS

Holton, John B. The Inherited Metabolic Diseases. New York, New York: Churchill Livingstone, 1994.

Rimoin, David, et. al. Emery and Rimoin's Principles and Practice of Medical Genetics. New York, New York: Churchill Livingstone, 1997.

Scriver, Charles R., et. al. The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, Inc., 1995.

PERIODICALS

ORGANIZATIONS

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

Cystinuria Support Network homepage. <http://www.cystinuria.com/>.

Dawn Cardeiro, MS, CGC

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