Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Cystinuria

What is Cystinuria?

• Cystinuria is an inherited autosomal recessive disease that is characterized by high concentrations of the amino acid cysteine in the urine, leading to the formation of cystine stones in the kidneys, ureter, and bladder.​
• Cystinuria affects approximately 1 in 10,000 people.​
• Cystinuria is an inherited metabolic disorder that affects males and females in equal numbers. ​
• Symptoms of this disorder typically begin between 10 and 30 years of age, although elevated cystine excretion may be found in infancy. ​
• The disorder occurs in approximately 1 in 7,000 to 1 in 10,000 people in the United States. The prevalence of cystinuria varies in different countries.​
• ​​Cystinuria can pose unique and significant challenges that are distinct from those associated with the more common kidney stones.
  • More than 80% of people with cystinuria develop cystine kidney stones by age 20.
  • It has been reported that patients experience an average of 1 stone formation per year.

How Do You Get It?

• Cystinuria is the cause of approximately 10% of all kidney stones in children.​
• Cystinuria is inherited as an autosomal recessive genetic trait. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. ​
  • Cystinuria is caused by changes (mutations) in the SLC3A1 and SLC7A9 genes. These genes encode a protein complex that helps control the reabsorption of amino acids (such as cystine) in the kidneys. Mutations in these genes disrupt the function of the protein complex, causing cystine to become more concentrated in the urine. As the concentration of cystine increases, cystine crystals and/or stones begin to form in the urinary tract leading to the many signs and symptoms associated with cystinuria.​
• Cystinuria is a rare genetic disorder. The affected population is generally between 10-30 years of age, although some infants may also demonstrate signs of the disorder​
• No specific racial or ethnic group affiliation is observed

What Are The Symptoms?

• Cystinuria is primarily characterized by a buildup of the amino acid, cystine, in the kidneys and bladder. This leads to the formation of cystine crystals and/or stones which may block the urinary tract. Signs and symptoms of cystinuria are a consequence of stone formation and may include:​
  • Sharp pain in the lower back (known as renal colic)​
  • Blood in urine (hematuria)​
  • Blockage of renal tubes (ureters)​
  • Urinary tract infections (the stones offer a surface for bacteria to adhere and grow)​
  • Pyelonephritis (kidney inflammation as a consequence of bacterial infection)​
  • Kidney stones, either consisting of cystine alone, or in combination with calcium to form large stones
    • Cystine stones are typically harder, larger, and occur more frequently than other kidney stones, resulting in significant pain and morbidity (e.g., loss of kidney function). Disruption of normal daily living is often an unfortunate consequence of living with cystinuria.​​
  • Severe pain on one side, which may worsen over the next several days​
  • Lower back pain; pain in the genital area​
  • Abdominal discomfort and pain​

How Is It Treated?

• Cystinuria is a chronic condition and many affected people experience recurrent cystine stones in the urinary tract (kidneys, bladder and ureters). In rare cases, frequent kidney stones can lead to tissue damage or even kidney failure.
•  Therefore, maintenance and prevention are important aspects of healthy living for people with cystinuria.​ Maintenance and prevention can include:
  • Regular consultation with a knowledgeable specialist​
  • Annual CT or ultrasound tests to assess stone presence​
  • Regular urine testing to monitor cystine excretion​
  • Frequent at-home urine pH testing to ensure elevated pH for improved cystine solubility (if urinary alkalization is part of your treatment regimen)​
• The primary objective of treatment for cystinuria is to reduce the cystine concentration in the urine.
  • Goals of treatment: stone prevention by lowering urinary cystine concentration to <250 mg/L, avoiding surgery, and keeping kidneys working normally to prevent long-term damage.​​
• Thiol may be begun at a dosage of 800mg/day in adult patients with cystine stones.
  • Thiol compounds have the ability to bind to cystine, forming a disulfide complex that does not cause the formation of stones and may help to dissolve kidney stones. 
  • Alpha-mercaptopropionylglycine (alpha-MPG)/ Thiol– is a second-generation chelating agent with a similar mechanism of action, but is generally tolerated better that C-penicillamine.
    • α-Mercaptopropionylglycine has lower incidence of side effects compared with d–penicillamine and, therefore, is sometimes preferred, although both drugs are effective in reducing kidney stone incidence. ​​​
• The best way to prevent cystine stone formation in your patients is by encouraging adherence to their treatment plans and regularly monitoring their cystine levels to determine the best regimen to keep cystine concentration <250 mg/L.​
• Due to the chronic, genetic nature of cystinuria, cystine stones are constantly forming as a result of cystine buildup. Even if your patients are not experiencing a stone-related event, they are at risk. It is therefore critical to develop a treatment plan focused on managing cystine levels.
• D-penicillamine/ Cuprimine– is a chelating agent that increases the solubility of cystine, reducing the effects of cystinuria. Approximately half of all patients experience adverse reactions with this therapy, which limits their therapeutic use. These effects may include rash, gastrointestinal effects, arthralgia, leukopenia and nephritic syndrome. ​
• Captopril is an ACE inhibitor drug usually used to treat hypertension that forms a thiol-cystine mixed disulfide that has a higher solubility and can reduce the formation of stones. This is usually used a second-line therapy option when other treatments have failed to produce an adequate response.
• In mild cases of cystinuria, judicious urinary alkalinization and fluid may suffice but in more severe cases, a thiol agent, such as tiopronin or d–penicillamine, should be added
• Non-drug approaches can include:
  
  • Surgery- When the stones in the urinary tract are large in size and cause significant pain, there may be a need for surgical removal to relieve symptoms. There are several different surgical procedures that may be performed, depending on the specific circumstances.
  • Diet Modifications- Patients should eat a diet low in protein and sodium, and high in fruits and vegetables.
  • Urinary Ph– Patients should maintain a urine pH level between 6.5 and 7.0, often made possible by taking potassium alkali.
  • Hydration– Patients should consume >3 L of fluid per day (10 glassfuls, 10 oz each) to achieve a minimum urine output of 2 L per day on a consistent basis.​

Where Can I Learn More???

• Check out our cornerstone on this disease here.
• Learn more about this disease from the National Kidney Foundation.