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.

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

  1. Erin

    Hi Dr Coe, my beautiful 9 month old baby has found to have cystinuria incidentally found during a urine metabolic screen. So far asymptommatic. I’ve scared myself silly reading online and worrying about his future. Can we control this? Is there hope for new medications/treatment in the future? Do people manage an ok quality of life? I need some Hope here. Thanks for your time.

    Reply
    • Fredric L Coe

      Hi Erin, Yes; cystinuria can be controlled, people grow up normally and can live long lives. But you should seek medical care for your baby at a center that has expertise in this disease. The screen may not be the full cystinuria but just the trait – heterogeneous not homologous – and if so it is without any risk at all. I do not know where you live but if I did I could try to suggest places for you. Regards, Fred Coe

      Reply
      • Erin

        Thanks Dr Coe
        I live in Sydney. Still waiting for genetic results but our specialist feels it’s likely homozygous given his cystine level was 400.

        Reply
        • Fredric L Coe

          Hi Erin, He does indeed as that is a lot of cystine. Nothing works so well as high fluids, from the beginning. Likewise a diet rich in fruits and veggies – as possible over time – to maintain high urine pH. You need a specialized clinic for this problem, as it is not common. Fred

          Reply
  2. Christian

    Dr. Coe,
    I’m from germany and had my first kidney stone in march 2019 (Age 36) which required no surgery. They send the stone to the lab and said it is an Cystin Stone. I’m not sure but my urologist said he does not think is it Cystin. I do not have a chance for a second lab check. The only thing I have is a self made picture (https://imgur.com/a/OreNQyS). The stone was about 1cm/0,4inch. It looks like we do not have this much 24h urin check ups since no one does it. Do you know if there are more stones growing – are they grow in the same kidney or any tips how to detect if it was an Cystin stone? Thank You.

    Reply
    • Fredric L Coe

      Hi Christian, The lab found the stone to be cystine, and it looks that way, so let’s assume the lab is right. Cystinuria needs treatment. If you cannot get 24 hour urine cystine excretion measured – remarkable given that Germany is a very highly advanced country! – assume that is the correct answer and maintain a very high urine volume – 4 liters/day of urine if possible, and add either potassium citrate medication (your physician needs to do this) and/or considerable fruits and veggies to raise urine pH and thence cystine solubility. CT scanning is ideal to detect these stones, and ultra low dose machines have so lowered radiation that risk is minimal. Be careful because these stones can grow rapidly and become very large. As for your physician, perhaps he knows something I do not as he seems to believe the lab is incorrect. I would discuss this with him/her, because cystine stones are very easy for labs to identify. Regards, Fred Coe

      Reply
  3. Alex Kowalczykowski

    My son wasdiagnosed with cystenuria at age 4 and is now 23. He has been passing stones much more frequently lately. Could this be related to his using whey protein powder.

    Reply
  4. Peter Emanuel

    Dr Coe,

    I am not sure if it is appropriate to ask my question here, or in private. Please remove this message if it is inappropriate.

    As someone with homozygous cystinuria I am interested in finding out what causes the condition’s severity to be so highly variable, and why it tends to have a more severe course in males. (Beyond structural abnormalities, and the fact males have a longer ureter etc.)

    Have you, or any other researchers, noticed – if only anecdotally – anything similar between cystinurics who are more severely affected, and cystinurics who are less severely affected? (Traits or circumstances which may seem unrelated to the condition such as height, personality, disposition, alcohol consumption etc.)

    When I was first diagnosed with cystinuria I read about an androgen-dependent form of the condition which affects certain breeds of dog. For those unfortunate animals, they are at least lucky in that the cystinuria can be cured by medical and surgical castration.

    Unless I am mistaken, my understanding is that humans do not have an equivalent androgen-dependent form of cystinuria, and so there is no equivalent cure.

    However, as a layman I still wonder: Have serum sex steroid hormone levels been investigated with regard to cystinuria and differences in disease severity (e.g., stone size, frequency, cystine excretion levels, cystine crystalluria)?

    While there may not be an androgen-dependent form of cystinuria in humans, do you think it is possible that testosterone could still play a role in disease activity – and severity – for at least some cystinurics? Do you know if testosterone levels have been studied in humans with cystinuria, and ruled in or out as a factor with the condition?

    If there is anything you can talk about along these lines, please do so!

    Regards,

    Peter

    Reply
    • Fredric L Coe

      Hi Peter, In a brief look in PubMed under cystinuria and androgen, I found no useful article. Under cystinuria and sex I found this recent article showing a higher prevalence of hypertension among male cystinurics age 16-40; I found this rather nerdy article on cystine solubility being lower in male urine and some fancy measurements to try to find out why. This article and the preceding one mention that males have a worse course vs. females as if it were received wisdom, and this confirms your question. In fact, cystinuria has a variable course vis renal disease even though the genetic causes are few and well defined. But no articles mention the male sex hormone per se as crucial. Regards, Fred Coe

      Reply
    • Christine

      I have a dog with cystinuria. From what I’ve found in my research, the androgen dependent type is only found in canines. I just neutered my Pointer a few months ago and hoping it works!

      Reply
    • Christine

      But you may want to contact Dr. Giger and/or Dr. Henthorn at UPenn. They study cystinuria and may be able to answer this question more definitively for you.

      Reply
      • Peter Emanuel

        Dr Coe,

        Many thanks for your reply. I have had a chance to review each of the PubMed articles and no doubt will have questions in the future since the condition is, alas, a lifelong companion. For now, may I simply ask if you know of someone in Australia with expertise (or an interest) in cystinuria? Although I reside in Queensland, if you know of anyone in Australia, it would be a good start!

        Regards,

        Peter

        __

        To Christine,

        I hope that the neutering of your Pointer proves to be a permanent cure! Thank you for the two names, I will pursue them. I am curious to learn how and why neutering can cure the androgen-dependent form of the condition.

        Reply
        • Fredric L Coe

          Hi Peter, It is far away and I know no one to recommend. But in general for such an uncommon disease a university based physician is better as more likely to have accumulated experience. Regards, Fred Coe

          Reply
  5. Anne Richard

    have been diagnosed with Cystinuria. I live in Orange County CA which is near Los Angeles CA.
    Could you suggest a nephrologist or a center in this Area who is versed in the management of this condition?

    Reply
    • Frederic L Coe

      Hi Anne, Your condition can be controlled very well, but you should be in a university based program. I believe UCI is in Orange County. Dr Ralph Clayman is a superb talent and friend of mine who I would contact for help. Feel free to use my name as a reference. Regards, Fred Coe

      Reply
  6. dan gerber

    Dr. Coe
    I have recently been forming cysteine bladder stones in the past 3 years and now have completed my 4th operation to have them removed. Size of a quarter. My younger brother and older sister have developed these types of kidney stones for years (since their twenties-they are now mid fifties and sixties). My other brother had his first bladder stone operation but it was uric stone. Mine have all tested to be cysteine. My brother and sister have been on potassium citrate for years and have not developed bladder stones.(but have had kidney stone operations infrequently). I have discussed recently with my urologist about going on potassium citrate but he states that is for kidney stones not bladder stones. I have increased my water consumption after this recent surgery. Should I try Crystal LIght, or bicarbonate tablets. Otherwise, I am in excellent health and taking no other medication. I really don’t want to start pill medication if i can avoid it. Seems like the lemon juice in water would work also to help me. With extremely busy worklife, it is hard to get this water down during the day but I am committed to trying a program. Each surgery costs me my deductible approximately 2k a year. My urologist seems hesitant to do anything regarding this. My recovery from surgeries is instant so it has not been a problem. I will be turning 60 soon but don’t want to continue the surgery route. Thiola seems interesting but extremely expensive! all these routes of medication see expensive. Is there a diet program for lowering cysteine. My wife is lost and needs help. I am not a big meat eater, just occasionally, and typically only eat one meal a day. Vegan diet seems like a big lifestyle change though. We live close to chicago and UM in AA. thanks for this webpage as i am becoming more proactive in my care. Should I get a second opinion? It is a respected doctor who has helped me with stricture issues, prostate cancer, etc. etc. but i dont get the hestitancy towards trying to treat this.

    Reply
    • Frederic L Coe

      Hi Dan, You have cystinuria, it is in your family, and you would benefit from more stable and focused prevention aimed at cessation of more stones. If you can come to Chicago, we can provide for you. Our secretary, Karen Niswander, is at 773 702 1475. She can arrange for you. Regards, Fred Coe

      Reply
  7. Deirdre

    Just curious… I was diagnosed with Cystinuria 30+ years ago when my family was routinely screened after my sister was diagnosed with it after having kidney stones. I’ve never had a stone, nor do I take mispotcit anymore (stopped that 10 years ago) and I don’t follow a low sodium, low protein diet. I drink about 2l fluid a day. My count was vey high when diagnosed and doctors couldn’t understand why I never formed stones. How common is it to have asymptomatic Cystinuria – I ask as I can’t find much info on it?
    Also, is there a link with memory issues? In the last 6 years or so, I’ve noticed my memory has small blanks in it that only after prompting, do I start to recall what I forgot. It worries me as I used to have a really good memory. Only other medical info that’s a little unusual is I have asymptomatic hypotension (92/60) and had pre-eclampsia (235/140) with my first pregnancy. I mention these in case there’s an underlying thread. Thanks in advance.

    Reply
    • Frederic L Coe

      Hi Deirdre, screening positive may not mean real cystinuria, but I gather your 24 hour urine cystine excretion rate was measured and found high. How high matters a lot, as stones are a mechanical consequence of too much cystine to dissolve in the urine volume produced. Your physicians need to be sure how much urine volume you need to undersaturate your urine. Litholink performs excellent cystine testing and I would recommend you get a 24 hour urine done by them for this. If you already did, they provide a cystine SS value. Just because you never formed a stone does not mean you will not, and if you have not had imaging you may have one. So be sure of all of the forgoing. Regards, Fred Coe

      Reply
  8. Beverly Danielson

    Dr Coe,
    Our daughter has just been diagnosed with Cystinuria and her doctor immediately wants to put her on medication. She is 22 years old, college athlete and otherwise very healthy. She had her first stone in Jan and has since passed 7 other stones. This is has a total shock to us all. I am worried about the long term effects of the medication. Should we try diet changes and fluid intake first? Would you consider evaluating her? We live in NC but will do whatever we need do to make sure she receives the best possible care. Thank you.

    Reply
    • Fredric Coe, MD

      Hi Beverly, I would advise using Litholink cystine testing with supersaturations – one of their routine commercial products. Fluids enough to keep 24 hour cystine supersaturation below 0.5 should reduce stone formation well in most cases and perhaps make the drugs unnecessary or at least permit very low dose. Monitoring the drug, if used, also needs the Litholink testing as only they have systems the drugs do not interfere with. Your physician can place the order as a special kind of stone testing, and your and your daughter can read the cystine SS values as well as s/he. If things seem complicated, you can of course come to see me and I can take care of all this for her. Regards, Fred Coe

      Reply
  9. Marilyn

    Hi Dr. Coe,
    I am a dietitian. Can you please tell me the physiology behind limiting sodium for Cystine stone formers? I understand the rationale for other types of stones with the relationship to calcium, but I would like to understand it here as well. I like to be able to explain the mechanism to my patients simply so they can understand the “why” of the restriction.
    Also, I am having a very hard time finding reliable information for methionine levels in food. What do you use? Would you say that as long as a person is keeping protein to 0.8 gm/kg, this will help keep methionine levels in check? Is 0.8 gm/kg your recommendation for the general Cystine stone forming population?
    In a nutshell – adequate fluids to produce 3-4 liters of urine output, consistent fluid intake throughout day and even upon wakening in the night, low sodium, avoiding excessive protein – is this the diet advice for this patient group?
    Lastly, I have a patient, Cystine stone former, that adds a BCAA supplement to his water. I understand methionine is not part of the ingredients, but I still feel uncomfortable with it. Any thoughts in particular to Cystine stone former and this type of supplement?
    Thank you thank you for your continued guidance!

    Reply
    • Fredric Coe, MD

      Hi Marilyn, Cystinuria arises from a defect in one or another proximal tubule transporter. Low sodium diet increases total PT sodium and water reabsorption via increase in angiotensin 2 activity (and probably increased sympathetic nerve traffic as well). The overall increase will increase all amino acid reabsorption as a byproduct, cystine included. The diet sodium is, as you know, not low but at the present US optimal of about 65 mEq/day. BCAA do not include cystine and do not produce it, so I think it is irrelevant. Warm Regards, Fred

      Reply

Leave a Reply