CHAPTER 9: 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.

90 Responses to “CHAPTER 9: CYSTINURIA: An Introduction for Patients”

  1. Nikiysha Lee

    I’m so glad I found this article. I was just diagnosed with cystinuria after major kidney surgery to remove stones at 45 yrs old! I’ve had 6 surgeries so far this year. I had a nephrectomy tube for 6 months and have been hospitalized numerous times for sepsis. Ive been through a lot this year in every aspect of my life…so I’m glad when my newest urologist was able to finally remove the stones and save my kidney. He also was able to diagnose me and has prescribed Potassium for me. He said he’s never had a patient with cystinuria and he is very committed to getting me well and improving my quality of life. I’m very fortunate for that because before I was referred to him I couldn’t see the light at the end of the tunnel and felt like a Guinea pig for my previous Dr. I’m actually from Chicago and now live in Georgia can you recommend anyone in Georgia that maybe my Dr can consult with on suggestions for my treatments? I’m just sooo ready to get back to my life especially my 7yr old son. Thank you in advance for any recommendations you may have.

    • Fredric L Coe, MD

      Hi Nijiysha, cystinuria needs special treatment. The author of the study you read, Dr Anna Zisman, does all of our cystinuria work. Her secretary is Banita Williams 773 792 1475 – and she can arrange a telemedicine consult for you that can help direct your physician as the drug treatment for your condition. Regards, Fred Coe

  2. Imtiaz Patel

    Hi Azisman,

    Thanks for sharing this post. I must say this is the best article I have read on Cystinuria ever. Please I read that cystine solubility increases with ph of the urine. How true is that?

    • Fredric L Coe, MD

      Hi Imtiaz, it is true. Potassium citrate to raise urine pH is part of conventional cystine stone prevention. Regards, Fred Coe

  3. Stan K.

    I’ve been dealing with this miserable existents of cystine stones for 45 years! I’ve been laught at, ridiculed, even thrown out of emergency rooms by incompetent doctors. Someone help us poor Bastards who suffer every day!!!!!!

    • Fredric L Coe, MD

      Hi Stan, Cystine stones are indeed preventable, and hardly a matter for mirth or other bad behavior. I would seek consultation at a referring center and get proper treatment. Because of COVID all of us do telemedicine so you can have your pick. Fred

  4. Sandra Lobach Virk

    I have Cystinuria. I’ve known since I was 24yrs old when I ended up in the ER with an obstructed 15mm stone that the bypassed for 4 months with a tube until insurance agreed to let them do lithotripsy on me. I’ve since had several more lithotripsies, nephrostomy tubes (again waiting 4 months) until they approved basket retrievals and so many things I can’t even remember anymore. I’ve been abused by physicians who decided I was being a baby and did a basket retrievals while I was in a storage room without any pain medication whole I screamed in pain. A nurse even quit stating, “I’m didn’t sign up for this garbage”. Anyways, I’ve passed a couple dozen stones a year for awhile there. I wasn’t talking care of myself. Depressed over losing my business because I was hospitalized over and over while passing stones and being treated for infections. I’ve nearly died several times. Septic infections the first time. Took months to recuperate. I’ve had many IV antibiotics and fluid for dehydration. Central Line PICC lines. At home for 3-4 months at a time on an IV. I’m on SSI now and the depression from it is keeping me in bed 98% of the time. This disease has taken my life and after a couple dozen physicians either not educated or caring enough to take care of me I’ve given up. I read everything I can and been guinea pigd so bad by one Dr that my stones went from cystine to calcium oxalate after told to take huge amounts of C vitamin for months I became completely impacted on both sides. Then this quack did a stone analysis, saw I passed a calcium stone and yelled at ME telling me I’m drinking too much milk and get out of his office!!! I could write a book! Ha! After all this the only treatment I’m doing now is trying to learn how to drink so much water I float away and stones float out. Any advice you have I’d be interested in though. Thank you, Sandra Eileen

    • Fredric L Coe, MD

      Dear Sandra, If your stones have been cystine, and you passed a calcium stone perhaps it was a lab error – mix up with another patient, or perhaps calcium phosphate if you take large amounts of alkali for the cystinuria, or perhaps other errors, but withal your care has not been ideal. I would think your physicians might want to obtain a second opinion for you or refer you to a center for stone disease. If you say where you live I could suggest possibilities. Regards, Fred Coe

  5. Maria

    Hello Dr Coe. Is it possible for someone to have cystinuria but to not produce/pass stones?
    In our family, two of my children have cystinuria (both produce stones regularly). This means that I am a carrier of the gene. My mother is in her mid-70s and is then (by extension) also a carrier (we know there are more people in her close family with cystinuria). She has never had any stones (that she’s aware of). She hasn’t been tested for cystinuria.

    However, she has frequent kidney infections (three/four times per year) that make her really unwell.
    She experiences fever, chills, weakness, slight nausea, frequent urination, high blood & high leukocytes count in urine.
    She doesn’t experience flank/back pain/renal colic, though.
    Her doctor prescribes antibiotics that clear up the infection.

    I wonder if the underlying problem here might be kidney stones/cystinuria?
    Would you recommend a CT to check if there are some stones lying in her kidney that are triggering this recurrent issue?
    Do you think it would be worth requesting a 24-hour urine test to confirm that she has cystinuria?
    Thank you in advance for any advice.

    • Fredric L Coe, MD

      Hi Maria, the easiest way to determine your mother’s risk is a urine test for cystine. Carriers have low levels usually and cannot make stones. It is true some are higher. A CT is also reasonable – ultra low dose protocol works for stones. Regards, Fred Coe

      • Maria

        Many thanks. We’ll try to arrange a CT to check for a possible stone. Her doctors have ordered various scopes/tests in recent years to determine why she so frequently has blood in her urine and her regular UTIs. No cause was identified.
        But she hasn’t been checked for stones/cystinuria. We’re only now suspicious that it might be the cause because of the recent diagnosis in the grandkids.
        Thank you.

  6. Michael

    Hello Dr. Coe. I a m a 60 year old male who was diagnosed with Cystinuria 30 years ago. I actually saw you as a patient at University of Chicago referred by Dr James Lingeman after he performed a number of stone removal procedures. I was hoping to get a referral for a nephrologist with some experience with the condition in the southeastern Michigan area. Please let me know if you have any recommendations?

    Thank you, Michael

    • Fredric L Coe

      Hi Michael, I am afraid I do not have a name in mind, exactly. Perhaps south east Michigan is closer to Indianapolis than Chicago and Dr Lingeman can provide care. Sorry. Regards, Fred

    • Kathryn Jewell

      Check out the International Cystinuria Foundation Facebook, and website. The facebook site is a closed group, but we have over 1000 members. This question comes up often in our group conversations.

      • Fredric L Coe

        Hi Kathryn, Good advice, thanks for posting it. Regards, Fred

  7. Samantha Longhurst

    I’ve finally after 8 years and 5 operations been diagnosed. I am under the amazing team at Guys Hospital in London. My question is what is a safe urine oh level for someone with cystinuria? I am ranging from 6-8 throughout the day?

    • Fredric L Coe

      Hi Samantha, cystine solubility increases with urine pH up to above 7. The problem is calcium phosphate crystallization, but if you are maintaining a very high urine volume – hopefully – and do not have high urine calcium – determined by 24 hour testing – a high steady pH around 7 or more is beneficial. Regards, Fred Coe


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