Cystinuria

What is Cystinuria?

Cystine kidney stones are not very common, making up just 1% to 2% of all kidney stones. However, they are more prevalent in children, accounting for 6% to 8% of all kidney stones in pediatrics. Most people with cystinuria, a condition that results in cystine stones, will experience their first stone during their teens or early twenties.

The term “cystine” originates from its initial identification as “bladder calculi” back in 1833.

Kidney stones are the only noticeable symptom of cystinuria. The main treatment involves increasing urinary volume and adjusting pH levels using hydration and special oral medications. If these measures aren’t enough, additional medications, mainly thiol-based drugs, are used.

It’s worth mentioning that while most people with cystinuria will only form pure cystine stones, about 40% may also develop mixed stones that contain other substances like calcium oxalate, phosphate, or struvite.

Compared to those forming calcium stones, people with cystine kidney stones generally have larger stones, need more urological procedures, form stones more frequently, and start forming stones at a younger age. They also have a higher chance of damaging their kidneys and experiencing chronic kidney failure. Furthermore, those with cystinuria often have lower health-related quality of life due to many episodes of reoccurring stones and related surgeries. However, preventive therapy can improve these scores.

What Causes Cystinuria?

Cystinuria is a disease that is passed down through families, and happens because of a genetic problem in the body. This issue affects how well certain substances like cystine, ornithine, lysine, and arginine are absorbed by the kidney. Importantly, out of all these substances, only cystine forms stones because it doesn’t dissolve easily.

Interestingly, in people with cystinuria, cystine also doesn’t get absorbed well from the intestines into the body. However, other factors balance out this problem.

Cystinuria becomes a problem because cystine isn’t very soluble in urine, especially at the body’s normal temperature and pH levels (which is a measure of how acidic or basic a liquid is). The good news is that the more alkaline (basic) the urine is, especially with a pH above 7, the more cystine can dissolve.

Additional substances in urine like certain large molecules, electrolytes, and ions also make cystine more soluble.

Scientists have found that this disease can be caused by changes in specific genes on two different chromosomes. However, different types of these genetic changes don’t seem to make the disease any worse or better. For instance, they don’t affect how many stones form or when the first stone forms.

That’s why, typically, people with cystinuria aren’t tested to see which gene is changed. But, this type of testing can be helpful in making sure the diagnosis is correct, understanding more about the disease, and giving advice to family members.

Risk Factors and Frequency for Cystinuria

Cystinuria, a hereditary condition passed down in families, is the main reason people get kidney stones. It is seen worldwide, with incidences varying from country to country

• The highest incidence rates are seen in Great Britain and Spain, where it affects 1 in 2,000 people.
• In the US, it affects 1 in 7,000 people.
• In Australia, 1 in 4,000 people have the disease.
• On average, sufferers from this disease form a new kidney stone every one to two years, and may need surgery about once every three years.
• By middle age, a typical patient has gone through seven surgeries.
• More than one out of every four cystinuric stone formers can develop other types of urinary stones, particularly after certain types of kidney stone treatments.
• Men are twice as likely to get this disease as women.
• People usually develop their first cystinuria-related kidney stone at 22.
• 22% of cystinurics will start forming stones as children.
• Without proper treatment, there’s a 45% chance of the disease recurring three months after surgery. If treated, the recurrence rate decreases to 25% after three years.

Even though the disease has a high risk of causing some kidney damage (up to 70%), it only causes total kidney failure in less than 5% of patients. Also, 20% to 40% of cystinuria sufferers might also have other kidney-related abnormalities. Rarely, diseases like hemophilia, muscular dystrophy, Down syndrome, inherited pancreatitis, and retinal damage can occur in people with cystinuria.

Signs and Symptoms of Cystinuria

People suffering from cystine stones typically experience similar symptoms to any other individual dealing with obstructive urolithiasis. However, they often start to show symptoms at an earlier age, even during childhood. Common symptoms include acute flank pain with blood in the urine, often accompanied by nausea and vomiting. This pain often begins around the back and radiates towards the groin. There may also be tenderness in the costovertebral angle, which is the area of your back where the ribs join the spine. Blood in the urine is a frequent symptom, although about 15% of people with obstructive stones may not show this sign. A critical piece of information when diagnosing cystine stones is the patient’s personal or family history of cystinuria or cystine stone formation.

• Symptoms often appear in early age or childhood
• Acute flank pain (pain on the side of the body between the upper abdomen and back)
• Blood in the urine (hematuria)
• Nausea and vomiting
• Pain radiating from the back towards the groin
• Tenderness in the costovertebral angle (where the ribs join the spine)
• Personal or family history of cystinuria or cystine stone formation

Testing for Cystinuria

If someone has hypercystinuria, they may have a rotten egg smell in their urine due to the fact that cystine contains sulfur. Upon urinalysis, a routine test to check for various substances in your urine, you might find hexagonal cystine crystals, which are a significant clue towards cystinuria. These crystals can be seen about 25% of the time in early morning urine samples.

The sodium cyanide-nitroprusside test is typically conducted as the first lab test for cystinuria since it’s fast, easy and gives a good estimate of cystine levels in the urine. In this test, the resultant purple color indicates the presence of cystine. But, it can sometimes give false positives if you’ve got certain conditions or are on specific medications. It isn’t the most reliable, though, and is considered outdated due to its limited sensitivity and the need to use unstable reagents.

Quantitative 24-hour total cystine level testing is the approved way to measure urinary cystine, usually performed through ion-exchange chromatography or liquid chromatography-tandem mass spectrometry. A definitive diagnosis of cystinuria necessitates a 24-hour urine test for cystine, along with testing the chemical makeup of any stones found. For younger children, there are age-related standards for first-morning urine cystine concentration.

The cystine supersaturation test assesses cystine crystallization potential and how well prophylactic treatments are working, while the “cystine capacity” test measures how well the urine can dissolve a cystine sample. However, this test isn’t practical because it’s labor-intensive and not very sensitive, limiting its availability. For anyone on thiol-based medications, the supersaturation test isn’t reliable.

Imaging techniques such as X-rays, ultrasound, and CT scans will be needed to confirm whether cystine stones are obstructing anything. Plain X-rays often don’t show cystine stones clearly unless they are big enough. Ultrasound is preferred when dealing with children or pregnant women as it can identify large cystine stones and detect hydronephrosis, a condition characterised by excess fluid in the kidney. CT scans, on the other hand, are considered the gold standard to diagnose urolithiasis (stones in the urinary system) as they can show cystine stones clearly.

In special cases like a cystinuric fetus, showing a hyperechoic (highly reflective) colon on an ultrasound before 36 weeks suggests fetal cystinuria with 89% certainty. In those cases, genetic testing to confirm the early diagnosis of cystinuria is recommended.

Treatment Options for Cystinuria

The current recommended treatment for cystine stones begins with conservative measures, such as diet, hydration, and balancing uric acid levels. If these methods don’t work, then medication is usually the next step. Existing cystine stones are treated similarly to other kidney stones, but their high relapse rate and resistance to common stone-breaking methods should be taken into account.

A diet low in sodium can help reduce the risk of cystine stones. Foods high in methionine, a component in cystine stones, should also be avoided. These include turkey, beef, fish, pork, tofu, milk, cheese, nuts, beans, and some grains. Drinking citrus juices and mineral water with lots of bicarbonate can also help reduce the buildup of cystine.

Hydration is key for managing cystine stones, since more fluid going through the kidneys helps to dilute the concentration of cystine. It’s recommended that patients drink enough water to produce at least 3000 ml of urine a day. This might require nighttime waking to urinate and drink more water.

Keeping up such high levels of water intake can be difficult for patients. Regular check-ins with their doctors can help them stay on track. There are medications available that can help lower the concentration of cystine in the urine. However, they’re usually only advised if hydration and diet adjustments are not enough, as some can have notable side effects.

Additionally, cystine stones are more resistant to common stone-breaking methods, such as shockwaves. Therefore, surgical treatment options are usually considered earlier and for smaller stones than in other types of kidney stones. It’s important to completely remove all cystine stones and fragments, as this can help reduce the chance of the stones returning.

Patients are generally monitored with methods like renal ultrasounds and urine tests, which help doctors to keep track of the patients’ stone production and the effectiveness of their treatment. Improvement may require extra effort, but the results can greatly improve patients’ health and quality of life.

What else can Cystinuria be?

Physicians considering a diagnosis need to keep in mind a number of possible conditions that might seem similar. The following conditions might come up in such considerations:

• Constipation
• Diverticulitis (inflammation of the digestive tract)
• Pancreatitis (inflammation of the pancreas that requires immediate treatment)
• Fungus ball in the kidney or the tube that drains urine from the kidney to the bladder (ureter)
• Gallstones (hardened deposits in the gallbladder)
• Inflammatory bowel disease (chronic inflammation of the digestive tract)
• Liver abscess (pus-filled mass inside the liver)
• Nephrolithiasis (kidney stones)
• Nutcracker syndrome (a condition affecting the veins of the kidney)
• Peptic ulcer disease (sores in the stomach lining)
• Prostate or cervical cancer
• Pyelonephritis (kidney infection)
• Pyonephrosis (pus-filled kidney)
• Renal cell carcinoma (a type of kidney cancer)
• Splenic abscess (pus-filled mass in the spleen)
• Sloughed papilla (a blockage of the ducts from the kidneys)
• Ureteral urothelial carcinoma (cancer in the cells lining the ureters)
• Ureteropelvic junction obstruction (blockage of urine flow from the kidneys)
• Urinary tract infection and inflammation of the bladder in females

It’s crucial for doctors to thoroughly evaluate each of these possibilities through the appropriate tests to ensure an accurate diagnosis.

What to expect with Cystinuria

People with cystinuria, a condition causing particular types of kidney stones, often have a lower quality of life than the general population. Treatment can be tough to endure and sometimes ineffective. These patients tend to need more surgeries than patients with other types of kidney stones and are at a greater risk of developing long-term kidney disease. However, the risk of reaching a stage of severe kidney failure is less than 5%.

Factors contributing to this risk include the extent of kidney tissue damage, age, presence of other medical conditions, and history of kidney surgeries. Most adult patients with cystinuria will have a kidney filtration rate lower than 90 ml/min, which is considered suboptimal. Additionally, between 29% and 51% of patients experience high blood pressure. The risk of developing high blood pressure is higher for men, older individuals, and those with more advanced kidney failure.

Possible Complications When Diagnosed with Cystinuria

Cystinuria leads to several complications, all caused by the presence of numerous kidney stones. These complications can include damage and scarring in the kidneys and ureters, pain, multiple surgeries, and eventual kidney failure. To prevent these complications, proactive measures are used, involving increased fluid consumption and controlling the pH of urine.

• Damage and scarring to kidneys and ureters
• Pain
• Multiple surgeries
• Eventually leading to kidney failure
• Increased fluid consumption and control of urine pH for prevention

Preventing Cystinuria

Educating patients about cystinuria is absolutely necessary. Essentially, if patients do not take the right preventative steps, they can end up harming their kidneys, which could even lead to kidney failure. So, it is crucial to remind them repeatedly about the importance of staying properly hydrated and maintaining the right levels of acidity in their urine.

Teaching patients how to measure their urine’s specific gravity, pH levels, and its volume over a 24 hour period can really assist in adjusting and improving their treatment. The goal should be to have a daily urine volume of 3 liters and a pH level of 7.5.