What Is Cystinuria?

Overview

Proteins are basically the building molecules of our body. Proteins are made of individual amino acids held together by peptide bonds. There are 21 amino acids known to have a biological functional role. An amino acid is made of an amino group and a carboxylic group. Dibasic amino acids are the ones with multiple amino groups. Cysteine is one of these amino acids. Two cysteine amino acids join together to form an amino acid cystine.

Cystinuria is a rare disease caused due to the defective transporter of dibasic amino acids also called COLA transporter across the kidney tubules and GI tract. In a normal individual cystine excretion is less than 30mg/day while cystinuria patients excrete 400mg to 3600mg/day. As a result, frequent urinary lithiasis or stone formation is the main clinical manifestation seen. It is an autosomal recessive disorder and cystinuria patients develop frequent cystine stone formation consequently, lifelong complications such as hypertension and chronic kidney disease eventually end up in kidney failure.¹ In adults, nearly 1-2% of all kidney stones are cystine stones while contributing to 6% of all pediatric cases of kidney stones. Around the first two decades of life, cystinuria patients start showing the symptoms earlier in boys than girls. A major portion of these cystine stones are composed of amino acid cystine, a few proportion of which comprises other stone formers such as calcium phosphate, calcium oxalate, or struvite. 

Based on the children with a family history, cystinuria is classified as normal (type I), moderate (type III), or (type II) with significant cystine excretion 

Causes of cystinuria

Cystinuria is a rare disease in which reabsorption of cystine across the kidney tubules is impaired. Therefore there is excess cystine excretion and cystine stone formation in the urinary tract. 

Cystinuria is caused by the inherited mutation of SLC7A9 gene on chromosome 19 and SLC3A1 mutation on chromosome 2. One of the subunits of transporter across kidney tubules and GI tract is encoded by SLC3A1 gene. The transporter is required for the tubular reabsorption and intestinal transport of dibasic amino acids cysteine, ornithine, lysine, and arginine (COLA). Cystine is the only amino acid amongst these that is least soluble under physiological urine pH and capable of forming stones. Because of defective reabsorption there is high cystine excretion in urine. Although these COLA amino acids are water soluble, with the exception of cysteine, it has the capacity to dimerize and form cystine which at acidic urine pH precipitate and forms cystine stones also called cystine calculi . Because of frequent stone formation these patients are more prone to developing chronic kidney disease.²

Signs and symptoms of cystinuria

The symptoms of Cystine stone is similar to a normal kidney stones or obstructive urinary lithiasis such as: 

• pain around the abdomen and sides ( flank pain) extending to the groin 
• Renal colic 
• microscopic or gross Hematuria (blood in urine)
• painful urination (dysuria)
• Vomiting
• fever 

The symptoms may vary in children. They are:

• Hematuria
• Dysuria
• minor facial dysmorphism
• mild to moderate intellectual disability
• low muscle tone (hypotonia)
• growth hormone deficiency
• recurrent urinary tract infection.

In infants vague symptoms such as;

•  Irritability
•  Vomiting
•  unmotivated crying

Patients without urinary obstruction are asymptomatic which can be detected incidentally through imaging tests.

Management and treatment for cystinuria

The prime concern about cystinuria is to prevent the supersaturation of cystine so that it does not form cystine crystals. It is done by managing cystinuria in a stepwise manner. Treatment is similar to other bladder stones involving hydration, analgesics and surgical intervention.

The primary treatment mode is to maintain the urinary pH and urinary volume through hydration and the use of oral alkalinizing medications. The daily fluid intake is increased to at least 3.5 - 4L/day. By maintaining the alkaline pH of urine, it increases the solubility of cystine. Alkalinization is done by using potassium citrate. Patients are self-taught to use pH test strips at home to keep up the alkaline urine pH.

By restricting sodium and protein intake from the diet reduces the cystine level in the body and cystine crystal formation as well as its excretion. In addition, methionine, the precursor of cystine, is depleted by minimising the intake of animal proteins such as fish, poultry, meat, and eggs. In children, completely restricting protein will have an impact on their growth. 

On failing these conservative measures, the second line of treatment, cystine-binding thiol drugs and newer therapies are used. Thiol based drugs work by splitting the bonds between two cysteine molecules and making them water soluble.³

Diagnosis

Cystinuria is diagnosed via stone analysis, microscopic examination of the urine sediment, and quantification of urinary cystine suggesting hyperexcretion. 

Stone analysis is a gold standard diagnostic test for identifying different kidney stones. On microscopic examination of cystine crystals, yellow-brown hexagonal cystine crystals are observed. Cystine consists of sulphur, thus the urine smells like rotten eggs.

The amount of cystine excreted in the urine and the volume of urine gives the Cystine concentration. Hyperexcretion of urinary cystine in 24 hours is measured as a standard test for cystinuria. Nitroprusside cyanide test is used to determine cystine concentration. In healthy individuals <30 mg of cystine is excreted while in cystinuria patients >300 mg/day of cystine is excreted. It is a test done to plan your treatment.

Cystine stones cannot be detected via plain X-Ray as they are radio-opaque and require CT scan without contrast offering the highest sensitivity and specificity. Because of radio exposure in children's renal ultrasound is preferred as the first-line imaging. Patients having recurrent kidney stone or urinary tract stones appearing as staghorn and hexagonal-shaped cystine calculi have to be removed surgically.

Patients with a family history of cystinuria or parental consanguinity should be screened by genetic testing and require genetic counselling. Genetic testing helps in confirming diagnosis, classifying the disease and counselling the family members.

Risk factors

The known risk factors are a mutated SLC7A9 gene on chromosome 19 and an SLC3A1 mutation on chromosome 2.

Complications

The cystine stones are larger in size compared to small kidney stones and tend to have more risks of urinary obstruction and do require surgical procedures to remove them. The patients are also at a higher chance of facing chronic kidney failure than the ones with normal kidney stones. Hypertension is also a common complication of cystinuria.

FAQs

How can I prevent cystinuria?

Cystinuria is an hereditary condition with recurrent cystine stone formation. Stone formation can be prevented by hydration, limiting protein intake, use of cystine-binding thiol drugs, and alkalizing medications.

How common is cystinuria ?

Cystinuria is a rare disease with a prevalence of 1 in 7000 cases worldwide.

When should I see a doctor?

As soon as you experience pains associated with stone formation such as abdominal pain, painful urination, hematuria accompanied with fever and diarrhoea. In infants, uncommon crying, irritation and discomfort with a family history of cystinuria.

Summary

Cystinuria is a stone disease caused by a genetic mutation of the gene SLC7A9 and SLC3A1. The main feature of the disease is recurrent stone formation obstructing the urinary tract. It is diagnosed through microscopic observation of the cystine stone, cystine concentration tests and CT scan. It can be treated by managing the factors around it so that cystine is not precipitated and stone formation is prevented. At the same time, drugs are available to treat cystinuria. Cystinuria can be treated but cannot be cured completely.