Cystinuria is a condition that causes kidney stones. Men and women are affected equally. Most patients start getting symptoms in their twenties, although it can be earlier in childhood or later.

The most obvious symptom caused by kidney stones is pain, especially the pain known as renal colic. Renal colic typically starts as pain in the back and in the side, and may move down to the groin. It comes in waves, building up to severe pain over a few minutes, then easing a little before building up again. Adults and older children are clear about which side hurts, but little children cannot describe it and simply complain of tummy pain.

Not all kidney stones cause renal colic. Some stones are tiny and pass in the urine without pain. Larger stones tend to block the drainage of urine from the kidney leading to pain. In Cystinuria symptoms vary a lot. Some patients have very few kidney stones in a lifetime and few symptoms, while others get several new stones a year.

People with kidney stones are at increased risk of getting a urinary infection. The symptoms of urinary infection include pain on passing urine (dysuria). This is similar to that caused by a stone in the lower urinary tract, such as the bladder or urethra.

In the long-term the kidneys may become damaged. This happens if there are repeated blockages to the flow of urine, and especially if there is urinary infection as well. If damage is extensive kidney failure can occur, but this is rare. Patients are not able to tell how much damage has happened from how they feel. Tests are therefore needed to find out if Cystinuria has caused kidney damage or reduced kidney function. Usually this an ultrasound scan and a blood test.

Getting the right diagnosis

It is important that the diagnosis is made correctly. Kidney stones of any kind are relatively common in the general population, particularly in middle and older age groups. By contrast Cystinuria is rare. Only 1% of kidney stones in adults are due to Cystinuria. A kidney stone is more likely to be Cystinuria if there is a family history of Cystinuria or if the first stone forms at a young age. Young people with kidney stones and those with a family history of stones need tests to find the cause.

Cystinuria is diagnosed by analysing the stone itself. In Cystinuria it is almost entirely made of cystine. Cystine is an amino acid that is required for many of the normal proteins that make up the body. If the stone itself is not available for analysis, the amount of cystine in a urine sample can provide the answer, as it will be much higher than in people without Cystinuria.

Treatment

Cystinuria cannot be cured but it can be managed with little disruption to normal living. The aim of treatment is to keep cystine dissolved in the urine so that it doesn’t form crystals that build up to form stones. There are three ways of doing this:

1. Keeping the urine dilute

Patients with Cystinuria may be encouraged to drink extra amounts of water (4-5 litres) each day and sometimes during the night too. This should only be done after discussion with the patient’s doctor and dietician. The aim is to dilute the urine continuously so that the cystine is less likely to form stones. As well as increasing water intake, patients should also reduce their salt intake by not adding salt to food and avoiding processed and canned foods with high salt levels. This is because salt draws extra cystine into the urine.

2. Making the urine slightly alkaline

As an amino acid, cystine dissolves best in a slightly alkaline solution. Urine can be acidic or alkaline depending on the body’s requirements and the kind of foods that have been eaten. The urine can be made slightly alkaline either by dietary changes (see below) or by taking mild alkalis as medicines. Taking alkali medicines should only be done under the supervision of a doctor.

Potassium citrate is commonly used to alkalinise the urine. It comes as a liquid known as Mist Pot Cit. It tastes metallic and rather unpleasant. There is an alternative fizzy form called Effercitrate, which some find more agreeable. In the USA a tablet form of Potassium Citrate is available but this is not widely available in the UK.

Sodium bicarbonate (bicarbonate of soda) has also been used in patients who cannot get along with potassium citrate. However the high sodium content can promote other types of stones to form, like calcium stones.

Reducing the amount of meat in the diet and increasing the intake of fruits and vegetables is likely to help, although this has not been scientifically proven. It may help by making the urine slightly alkaline and by reducing the amount of methionine (another amino acid) that gets converted to cystine in the body. Dietary changes are best done with advice from a Dietician, especially if the patient is a growing child.

3. Chelating medicines

Chelating medicines are sometimes required by patients who continue to form stones in spite of the two steps above. These are specialist medicines that are usually prescribed by a hospital doctor and need careful monitoring with blood tests. They work by binding to the surface of a cystine crystal, preventing more cystine from building up on it. The three medicines most often used are Tiopronin (Trade names: Thiola Captimer and Acadione), D-penicillamine (Trade name: Distamine) and Captopril (Trade name: Capoten).

Tiopronin is most commonly used as it has fewer side effects than penicillamine. It is usually taken three times a day and the dose is adjusted according to the amount of cystine in the urine. Tiopronin is unlicensed in the UK. It needs to be imported and is only prescribed on the sole responsibility of the doctor. Sometimes there are supply problems.

Imaging

A number of different techniques may be used to help identify where a kidney stone is located. This will help detemine the appropriate form of treatment.

An type of x-ray called a KUB (Kidney, Ureter, Bladder) can show stones anywhere along the urinary tract. However not all types of stones show up on x-rays, especially pure cystine stones which require an ultrasound to be seen.

Ultrasound scanning uses high-frequency sound waves to detect stones in the kidney. However it is not very good at seeing stones in the ureters. Ultrasound scanning is used to monitor for stones, and is the first choice of imaging in children.

Sometimes an intravenous urogram (IVU) (also known as an intravenous pyelogram or IVP) is used. A special dye that shows up on X-rays is injected into a vein in the arm. As the kidneys filter the dye out of the blood and into the urine, the X-ray image highlights any blockages. IVUs used to be the preferred imaging method, but now CT scans are thought to be more accurate.

A computed tomography (CT) scan is a series of X-rays of the body at slightly different angles. A computer then puts the images together. CT scans involve a significant radiation dose so is usually only used for adult patients presenting with stones and not for routine monitoring.

A small kidney stone may be able to pass through the urinary system naturally. However if a kidney stone is larger there is a risk that it will get stuck. If so there are various techniques to remove it. The type of treatment will depend on the size and location of the stone. A good review of how surgery can help remove stones is given on the Cystinuria UK website.

I was diagnosed with Cystinuria in 2009 after being admitted to A&E with severe pain in my stomach and lower back. A scan showed a small stone in my left kidney and a large stone in my right which must have been forming over some time. I had laser surgery and a nephrostomy (a tube placed into the kidney) to remove these, and have had a single further laser surgery over the following four years to remove stones which could not pass naturally. I attend a regular outpatient appointment with my nephrologist and renal consultant, in conjunction with ultrasound investigations and scans when necessary. I try to drink around 4L of water a day, but do not currently take medication.

Life proceeds fairly normally on a day-to-day basis. My greatest challenges are remembering to drink enough fluids on busy days at work and explaining to people unfamiliar with the disease that it has nothing to do with calcium and eating too much dairy! I am now an expert on the public toilet locations in my home town and have developed specialist skills in obtaining the best magazine in any waiting room.

There have been very difficult times, frightening and painful, especially at the beginning when just being in hospital was a new experience. However, I have always been very well cared for by all members of the medical teams involved in my stone prevention and treatment. Cystinuria is a rare disease – doctors don’t have all the answers, but I feel confident that they are doing everything within their power to get them, and I hope that the Cystinuria Rare Disease Group will play a large part in that effort.

The Cystinuria UK website aims to provide clear and concise information for patients with Cystinuria and their friends and family.

The latest Cystinuria Patient Day was held on Saturday March 30th 2019 at Guy’s Hospital, London For more information please visit www.cystinuriauk.co.uk/patient-day

Details of previous events can be found below.

2014 – Guy’s Hospital, London

2015 – University of Bristol

2016 – Freeman Hospital, Newcastle

2017 Guy’s Hospital, London

People with Cystinuria have a problem with the transport of cystine (an amino acid) in the kidney. In the kidney, blood plasma is filtered to form a watery fluid that is processed to finally become urine. In processing the fluid, substances that the body needs are recovered. Waste products are left behind in the urine.

Cystine is something that should be recovered, but isn’t. It gets left behind in the urine. Having too much cystine in the urine is a problem because it does not stay dissolved. Instead, it forms microscopic crystals, and these crystals clump together to form stones. Three other amino acids, called ornithine, lysine and arginine, are also left behind in excess quantities in the urine. This is because they share the same faulty recovery system in the tubules of the kidney. However these other amino acids don’t form crystals.

Inheritance of Cystinuria

Because Cystinuria is inherited, it can be helpful to test for abnormalities in the genes known to cause it. There are two genes that are important in Cystinuria, SLC3A1 and SLC7A9. A mutation in either of these genes can lead to excess cystine in the urine.

Cystinuria is inherited in different ways. Most patients need two copies of the faulty gene to develop the disease (autosomal recessive inheritance). For a few, only one copy is sufficient (autosomal dominant inheritance).

Autosomal recessive inheritance

These patients have two copies of a faulty gene. One copy is inherited from each parent. In this type of inheritance, parents are ‘carriers’, as they are healthy but can pass on the abnormal gene. One copy of the faulty gene is not enough to cause disease in these families. If both parents are carriers there is a 1 in 4 chance of their offspring having Cystinuria and a 1 in 2 chance that an offspring would be a carrier.

This can be seen in Figure One below:

Figure One: Autosomal recessive inheritance in Cystinuria a = faulty gene A = normal gene

Autosomal dominant inheritance

Occasionally, only one copy of a faulty gene is enough to cause disease. A patient with this form of Cystinuria can pass the condition on to their children. The risk of this happening for each child is a 1 in 2 chance.

This can be seen in Figure Two below. In this example it is the mother who has the condition, but males and females are at equal risk of inheriting the disease.

Figure Two: Autosomal dominant inheritance in Cystinuria a = faulty gene A = normal gene

At the moment it is not known why some people form stones when others don’t. We also don’t know why some people with only one faulty gene can vary from being unaffected, to having high levels of cystine in the urine, to forming cystine stones.

At the moment there are two laboratories in the UK that analyse these genes. The test requires a blood sample. For more information please click here.

The Cystinuria Rare Disease Group (RDG) is working together to understand more about Cystinuria.

We want to find out how many people in the UK have Cystinuria and how it affects them. This means we could provide better information for newly diagnosed patients, and optimise treatment. To do this the RDG is registering patients with Cystinuria to the National Renal Rare Disease Registry (RaDaR).

Moving forward, the database will be used to find suitable people to take part in future research trials into the value of new treatments. If you are interested in finding out more about the registry (RaDaR) or the activity of the RDG please visit the Cystinuria RDG page.