CYSTINURIA: An Introduction for Patients

What is Cystinuria and Who Gets It?

ZismanUCCystinuria is a rare genetic disorder that results in abnormally high level of cystine in the urine. High levels of cystine in the urine predispose to kidney stone formation, so patients are diagnosed when they present with kidney stones. The featured image shows the first such stone.

Much of what is known about human genetic disorders is summarized in a remarkable resource which some of you might want to consult. Here are some salient facts about the disease. Cystinuria occurs in 1 in 7,000 people worldwide. As the disorder is genetic, there is variability in its occurrence based on who your ancestors were. For example, it occurs in 1 in 100,000 people in Sweden, but is far more common in Israeli patients of African origin: 1 in 2,500.   In the United States, the incidence is about 1 in 15,000 individuals. While clearly rare, it is responsible for 2-3% of all kidney stones, and is even more common in kids (about 5%) as stones are generally less common in the young. Because of the genetics of cystinuria, it is not uncommon to have siblings afflicted with the disorder, particularly in larger families. It is important to note that cystinuria is a different disorder from cystinosis, which I will not discuss further here.

What is Cystine Anyway?

Cystine is a non-essential amino acid, meaning that our bodies are able to make it from other proteins (and that we don’t need to obtain it from the diet).  Cystine is formed from two molecules of cysteine, another amino acid, that are connected via a disulfide bond.

Cystine is found in multiple tissues, including tendons, skin and hair. For example, whether you have straight or curly hair is determined by the number of cystine disulfide bonds that you have. Hair products that make your hair curly promote formation of the cystine disulfide bonds, while hair relaxers work to break these bonds apart. How curly your hair is has no bearing on your risk of stone disease, however.

What Is the Problem in Cystinuria?

Patients with cystinuria have an abnormally functioning protein in the part of the kidney that is responsible for reabsorbing cystine (and a few other amino acids). The abnormality is also in the intestine, but this is does not seem to be of clinical significance. Because cystine is generally very insoluble, it precipitates in the kidney and leads to formation of kidney stones. Patients with cystinuria typically begin to form and pass kidney stones in childhood, though later diagnoses can also happen. Compared to other kidney stone types, cystine stones tend to grow bigger and faster, often in both kidneys. A stone that grows to take up a large part of the kidney called a staghorn stone is a particularly troubling, and not uncommon, complication.

What Causes The Disease?

Cystinuria is generally an autosomal recessive disease, so an individual has to inherit two abnormal copies of a gene (one from each parent) that is responsible for cystine transport within the kidney. In rare instances, only one defective copy of a gene may be inherited, but in these situations the abnormal levels of cystine in the urine are lower than in the classic form.  This generally means that there is a lower likelihood of stone formation, all other things being equal.

I have been told that I have cystine stones – now what?

It is critical to prevent stone formation in people with cystinuria as these stones can get very big very quickly. Not only do people with cystine stones undergo a high number of procedures and surgeries, but also compared to the more common stone types, their kidney function is more often impaired.

The biggest key to preventing cystine stones (as most others) is to maintain a very high fluid intake. In the case of cystine stones, we can estimate exactly how much a person needs to drink by their total daily cystine excretion, which can be obtained from a 24-hr urine collection – or better yet several. Once we know how much cystine, on average, a person makes, we can determine how much fluid intake is necessary.Typically, at least 3-4 liters of urine are required daily, and often much more than that. Variety helps to maintain such high intakes.

We also know that making the urine more alkaline (less acidic) is a cornerstone of therapy in patients with cystinuria.  Some patients with cystine stones have a high urine pH (how we measure the level of acid excretion in the urine) naturally, but others require medication to increase the urine pH. The most commonly used medication is potassium citrate.

In addition, we know that making dietary changes can also help decrease the amount of cystine in the urine, which can help prevent recurrent stone formation.  Decreasing the amount of salt in the diet (the lower the better, but at a minimum less than 2300 mg per day) as well as moderating protein intake can be very helpful.

What If Dietary Changes, Fluids, and Urinary Alkalinization Are Not Enough?

Frequent monitoring with 24-hour urine collections is key to make sure that urine cystine concentrations remain in a safe range. In a subset of patients, low dietary sodium intake, increased fluid intake, and urinary alkalinization will still not be sufficient to decrease urine cystine concentrations to safe levels. Others will not be able to comply with the necessary changes despite their best efforts. In those circumstances, your doctors can consider using a thiol-binding medication such as tiotropin or d-penicillamine. These medications may have a variety of side effects, so your doctor will have to monitor your blood tests closely.

The medications act by competition. Two cysteine molecules combine together to make one cystine moleculeThe drugs resemble cysteine and can combine with cysteine to form ‘mixed disulfides’ two dissimilar molecules linked through their sulfur atoms. These mixed molecules are far more soluble than cysteine. In principle, one might think such molecular elegance would be a perfect cure, but drugs with free sulfur atoms combine with many kinds of proteins and when they do this the immune system may recognize them and react against them, causing a drug reaction. 

Because of such complications, one tends to reserve drugs for those patients who cannot control their stones with fluids, and diet changes. Unfortunately such patients are not uncommon.

20 Responses to “CYSTINURIA: An Introduction for Patients”

  1. Crystal Cordell

    I’m a medical assistant and mother of a 9 year old girl, whom has recently been had a dx of kidney stones. I was able to collect some during her recent hospital stay, they were sent to the lab. No word back yet, but from the appearance of the stones (And continuation of her symptoms) they look like cystine stones. I will shortly be taking her to see a pediatric nephrologist in NOLA, and was wondering what questions etc should I bring up with that doctor. What should I take note of that may make it easier for them to treat her? I’m asking not only as a mom but as a trained CCMA .

    Reply
    • Fredric Coe, MD

      Hi Crystal, If the stones are cystine everything depends on keeping cystine supersaturation down. The drugs can have side effects so I always try my best with high fluids, low sodium – reduces cystine losses – and alkali, as well as a normal – not overly high – protein intake. Drugs are an add on when these measures fail. So the diet and fluid measures are up to you, as you imply and as you pursue them it makes treatment with drugs – the medical side – a lot easier and potentially can permit lower drug doses. Regards, Fred Coe

      Reply
  2. Lesa D Hess

    I will be starting Thiola and to be honest I am quite scared to take it due to the potential side effects. I currently have a blood disorder of Polycythemia and am worried it could affect me in a negative way.

    Reply
    • Fredric Coe, MD

      Hi Lesa, You are prudent given a primary blood disorder. Your hematologist needs to determine safety. He/she has special expertise and can make a proper assessment. The question is beyond the reach of the persons preventing your stones. Regards, Fred Coe

      Reply
  3. ebss

    My 8 year old, who has a serious metabolic liver disease (Glycogen Storage Disease 1b) was found to have a stone last month, after flank pain, an elevated urine WBC (23) and metabolic derangement that persisted despite her usual GSD treatment. Given her GSD, we assumed it would be uric acid or calcium related, but a 24hr urine profile for Cystinuria was done (sent to Mayo) and all levels were elevated– with arginine and lysine being as much as 3.5x the upper limit. We are awaiting appointments with her geneticist and a new urologist, but are wondering if this one test is enough for diagnosis? She hasn’t passed the stone and an u/s of her other kidney was not performed, so we don’t know what else might be there. Kidney stones run in our family and I have a history of drug resistant kidney infections and hydronephrosis, which makes us wonder about the genetic link. Are there particular doctors you’d recommend for pediatric cystinuria, particularly with medically complex children? Given the seriousness and management required for GSD (which ranges from metabolic crisis to chronic neutropenia and inflammatory bowel disease), we want to have the most experienced doctors to weigh in and be able to coordinate care with her other specialists. Any insight would be great appreciated!

    Reply
    • Fredric Coe, MD

      Hi Blair, cystine, arginine and lysine are all basic amino acids and the elevation suggests some transport shared defects, but risk of stone from increased urine cystine depends upon the quantities present in the urine. I believe the GSD is causing what may be minor transport defects and the amounts of cystine are too small to support stone formation. The one test is certainly not sufficient to diagnose a second – potentially unrelated – genetic disease like cystinuria. In Type 1 GSD the common cause of stones is high urine calcium and low urine citrate, and I know of no reported cases of combined cystinuria and GSD Type 1; however I am always willing to learn. If there is doubt about the significance of the urine cystine Litholink Corp – LabCorp subsidiary – produces a urine cystine supersaturation test that is patented to them and very definitive. Ask your geneticist if the amounts of cystine warrant such extra testing. Regards, Fred Coe

      Reply
      • ebss

        Thank you for the insight! I don’t think there is any thinking at this point that the GSD and cystinuria would be related. Her uric acid is well controlled, though her UA calcium was high (this was the original assumption– that these were calcium stones). I’ll definitely ask about the additional testing. It’s possible that the lab that did her whole exome testing might be able to run the Next Gen Cystinuria panel with the sample they have on hand. If that’s the case, we’ll ask about that too. Can a very high protein diet skew the Cystinuria 24hr Profile test? Would it potentially lead to elevated urine amino acids as well?

        Reply
        • Fredric Coe, MD

          Hi, Like you I much doubt cystinuria is an issue. Very high protein can increase urine cystine very modestly. The high urine calcium is well known in GSD Type 1. The dibasic amino acids are elevated as you noted, and perhaps this is diet. Overall I am not overly concerned about the cystine. Regards, Fred Coe

          Reply
  4. Desirae Green

    Our 2-year-old daughter is suspected to have cystinuria. She goes for surgery this week to remove a large, fast growing stone. She does seem to have had all the symptoms in the past, and was septic one week after her first birthday, credited to an undiagnosed kidney infection. We are trying to wrap our minds around this diagnosis. She receives 4 doses of the potassium citrate solution a day, as well as hydrate, hydrate, hydrate. I have 2 questions, that hopefully you can shed some light on. 1. She has not seemed to be in pain for the past year. Once we have this large stone removed, I am guessing that it has been blocking other stones from passing. So, should we expect pain? 2. We also have a 4-month-old son. When we asked if we should have him tested, the doctor suggested just waiting until he’s potty-trained. Is that a general recommendation about this disorder? or do you think we should insist on having him tested? Appreciate your thoughts and time.

    Reply
    • Fredric Coe, MD

      Dear Desirae, Cystinuria is an autosomal recessive genetic disorder – almost always – so your son has a 1 in 4 chance of having it. He would have a 50% chance of being a carrier but that is a benign and common situation. I would not bother to test him until later, and a simple spot urine will do – if negative he does not have the disease. As for your daughter the main issue is very high urine volumes for life – as early as possible and given she has had large stones perhaps a thiol agent. This is a disease for peds specialists in cystinuria management and very urgent she have such. Like all stone diseases cystine stones cause obstruction and foster infection, but these grow fast and large and so are very dangerous unless controlled. Warm regards, Fred Coe

      Reply
  5. Sandy Pemberton

    I have had cystinuria for 45 years and for all of that time I have been taking Penicillamine tablets, along with 3 litres of water, diluted juice and weak tea and coffee, which I list each day to make sure I reach my total.
    During this time I stopped taking the medication for a while and ended up with staghorn cystine stones which were removed surgically. A couple of other times when my drinking was not good due to traveling, I formed small stones which were removed with laser treatment. Penicillamine has worked for me.

    Reply
  6. Jackie

    Can you give me a general recommendation on when a stone-forming patient should be tested for cystinuria? As I understand it, the nitroprusside test can easily be false-negative, but genetic testing can cost close to $1000, and I’d like to get an idea of when enough suspicion of the disease is enough to justify the costs of testing.

    My husband has had stones since age 21 (first stone surgery, unfortunately testing the retrieved stone came back as “inconclusive”) and stone surgery twice. He gets major kidney colic episodes at least twice a year, sometimes more. He hasn’t had another stone tested, although we will be trying harder to catch one. Throughout his life, he has complained of episodes of sulphurous-smelling urine. The doctors always give him antibiotics for this, but urine cultures almost never find any bacteria. This seems odd to me, but I don’t know how often urine cultures fail to culture genuine infections.

    He recently had a CT scan ordered because of severe kidney colic pains (again), and there were several 3 – 7mm stones in each kidney. The stones were radio-opaque. They did not find any radio-opaque stones in the ureters, although his kidney colic pain location has been moving lower from the upper flank, to the lower pelvis, for several weeks. Is it extremely unlikely that a CT scan would miss a cystine stone? The doctors tell us the odds of there being a stone that a CT scan misses are almost zero, even a cystine stone.

    Does this combination of symptoms point enough suspicion at a cystinuria diagnosis to warrant spending quite a bit of money on the testing, or am I grasping at straws here? I am hoping to find a reason he has such recurrent stones, and has had for so long. Dietary management under Calcium stone assumptions has proved of no value in reducing the number of stone episodes.

    Reply
    • Fredric Coe, MD

      Hi Jackie, The sure way to diagnose cystinuria is those stones. Stone analysis will reveal cystine in all cases, along with any additional crystals that might be present. No stone should be inconclusive from a stone lab – in some cases there are no crystals, but otherwise you need a better lab.The nitroprusside test is quite sensitive, actually, and gives false positives. It sounds like the problem here is your physicians are not getting the laboratory support they need and deserve in order to take care of your husband. Here is a pretty good plan for how to proceed with stone prevention. The stones themselves are very important as you have surmised and if the lab cannot get a reliable answer they need to return the samples so a better lab can do the work. Stone analysis is quite routinized and failure to identify crystals is not common. I will correct your type. Regards, Fred Coe

      Reply
  7. April

    Started having stones at age 6… I have had multiple surgeries and pass them every week… The pain is the worst… I hate this disease…cysteine stones

    Reply
    • Fredric Coe, MD

      Dear April, Cystine stones are indeed very serious and hard to control. In my own work the most important part is very high urine volumes day and night + potassium citrate to raise urine pH above 7 + reduced sodium and protein intake, but it sounds like that has not been enough in your case. Your comment does not specifically post a question so I cannot add more. Regards, Fred Coe

      Reply
  8. william Ramey

    My wife is very sick with these stones. She’s been in the hospital more this year than she’s actually been at home. She passes stones almost once a week. She’s taking Thiola but no luck with it. We need more help if possible…

    Reply
    • Fredric Coe, MD

      Hi William, This is a difficult disease in some cases because cystine supersaturation can be hard to reduce and not all commercial vendors produce a urine cystine supersaturation measurement. I have emailed you directly. Regards, Fred Coe

      Reply
  9. Paul agius

    Have had this disease since childhood. Had staghorn , left kidney removed at 18 years old. Thanks. Go to hospital almost yearly to remove blocked stones

    Reply
    • Fredric Coe, MD

      Hi Paul, Cystinuria surely is a bad stone disease, and loss of a kidney an especial hazard. You already probably know about the importance of nocturnal hydration, sometimes overlooked. Some stone testing vendors have cystine supersaturation – Litholink is one of them. Their testing panel is of particular value for people like you who have so much trouble. You need to keep the 24 hour average SS below about 0.5 to allow for peaks during the night or even daytime. Alkali are worth it, though a weak addition; moderation of protein intake likewise. The thiol drug is very helpful if you are tolerant of it, but I would not rely on it so much as use it WITH hydration, the latter as if there were no drug. Regards, Fred Coe

      Reply

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