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.

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

  1. Sal

    Hello, I am currently living in the Philippines. Retired here in July 2016. I was living in Augusta, Ga where I was diagnosed as having custine stones in my left kidney. The Army hospital there removed two stones that were blocking the urethra. In November 2017, I had another attack, same problem, same kidney. The stone was extracted an having heard horror stories about wat kidney stones look like I was shoked to see that the stone appeared to look like a pebble. I went a while without problems and in Dec 2017, I had another stone about 8.9mm. The Urologist here suggested doing shock wave treatment, in Jan 2018 had the procedure done and all went well. Begining Feb, I had another attack, this time they found three stones, again in my left kidney. The big on blocking th urethra was 1.8 CM..the other two were higher in the kidney smaller one is 6mm and the one next to it 8.9mm. The 1.8 was again addressed with shock wave and a stent placed in the urethra. Painfull. Went back to check the status of the stones two weeks later, and apparently the large stone broke into two large horizontal sections. The top half was pulverized while the second joine the other two in the higher position..last week we again used the shock wave to address the larger stone..if this went well they will yet again use shock wave to attempt to pulverize the two smaller stones. I was put on strict diet, given 15mg potassium citrate 3 X a day, and I have begun to drink approximately3 1/2 lt of alkaline water 9.4 ph a day..are all these shockwave treatments dangerous to my kidney? My left kidney seems to be the only one involved in the production of stones. Anything more I can do? Thankyou for reading this long dissertation.

    • Fredric Coe, MD

      Hi Sal, Cystinuria is a complex disease. Treatment is based on very high urine volume – up to 4 liters or more a day and throughout the evening and night. The potassium citrate is good. The big problem is to keep the hydration steady as stones can form rapidly. If things continue with so many surgeries, there are medications your physicians can use. Regards, Fred Coe

  2. Juanita

    For those of us with cystinuria, what is the ok amount of animal protein that we can consume daily? I have suffered with this disease for 20 years now, I have had several different types of surgeries (10 surgeries in 10 weeks) to rid the egg sized stones in each of my kidneys. I have been to several university studies with no more information given than my regular urologist. I live in Missouri and have even went through director of urology Barnes hospital St. Louis, MO as my doctor. But still not finding any different treatments or meds than my urologist hadn’t already told me. I am now going to attempt to take Thilo to see if I can tolerate it. Otherwise, if this does not work, what other medicines or treatments should be tried. I have already taken the Urocit-K (80 mEq) daily. Can not take the depencinalamin as I am allergic to penicillin. Any suggestions?

    • Fredric Coe, MD

      Hi Juanita, The secret in cystinuria is to measure urine cystine supersaturation and use it to guide fluids, alkali, and drugs if needed. Only Litholink sells such a test, but it is excellent and you need it. Usually it takes 4 or more liters of urine volume a day to bring supersaturation down, and enough potassium citrate to raise urine pH near 7.9. As for protein intake, go to the lower edge of normal – 0.8 gm/kg/d. If you can achieve a SS below 0.5 with these measures stones should abate. If not, consider the drugs. Remember, fluids – urine volume – needs be high all day and you need to get up at least once a night to keep from making crystals. Regards, Fred Coe

  3. Lee Silver

    Hi Dr. Coe,

    Thank you for this great website, which is very helpful and informative. I am writing because my daughter, who is 24 years old, has had a very extensive history with cystine kidney stones. She lives in Scottsdale, Arizona, and both her urologist and her nephrologist, have said they have never seen anything like the problems that she is experiencing with cystine stones. She is otherwise a very healthy, active 24 year old, who was a college athlete (she played tennis). She is very health conscious and she exercises every day and eats very healthy. Her first experience with kidney stones was when she was in high school. In the 7 or 8 years since then, she has been hospitalized 8-10 times due to kidney stones and has had at least 40 stones removed. In October, 2016, the had her worst experience to date with kidney stones as she was hospitalized for over a week due to a large, dense stone being lodged in her urether, which lithotripsy failed to make a dent in. As a result, urine backed up into her kidney, causing a severe kidney infection. Her urologist ultimately had to perform a percutaneous nephrolithotomy by inserting a tube into her back that ran into her kidney to remove the stone. He not only removed the stone lodged in her urether, but he also removed approximately a dozen other stones that were in her right kidney. The stones were tested, which revealed that they were 100% cystine stones. As a result, she currently gets an ultrasound and an x-ray every six months because her stones get so big so fast. In March, 2017, her urologist removed another dozen or so stones that were in her left kidney.

    Despite drinking approximately 100 ounces of water per day and taking potassium citrate for six months, the ultrasound/x-ray that she had in September, 2017 showed that she had developed a 1.3 centimeter stone in her left kidney in the past six months. Consequently, her urologist went in and removed this stone in October, 2017. Every time she has stones removed she has to get a stent that remains in for approximately a week and usually causes her a lot of discomfort and pain. Within the past week, her doctors discovered that she now has a large stone approximately 2 centimeters in her right kidney and a similar size stone in her left kidney, both of which developed just within the last six months. This is despite being on Potassium Citrate and Sodium Bicarbonate. She was also prescribed Thiola, but had to discontinue taking this drug to because she developed severe rashes and itching. Her cystine levels are fairly high, as her 24 hour cystine excretion for a 24 hour period is about 1,000 mg. Her sodium intake (Na) intake is 160, which I understand is not too bad.

    These cystine stones are causing her to suffer every time she has a procedure done, and appear to form at least every six months. Her doctors in Scottsdale do not seem to have any answers, and we are desperate for help. Any suggestions that you can provide would be tremendously appreciated! Thank you for taking the time to read this and respond. Lee.

    • Fredric Coe, MD

      Hi Lee, When cystine stones come so often and so fast despite apparent high fluid intake and meds to raise urine pH the problem us usually some indeterminacy in fluids over the day or night, or perhaps, the fluids are not enough to lower cystine SS far enough given the amounts of cystine she loses in her urine. This is complex because figuring out the former needs some finesse – people often miss a critical period even when very smart and trying hard. Overnight may be the worst of it. I can offer to see her, which might just be worthwhile, but apart from that I am really too far away to be of any significant help. You are right – this situation cannot be left as is. Regards, Fred Coe

      • Lee Silver

        Hi Dr. Coe. Thank you for your response. I would like to make an appointment for her and I to see you. What is the best way to do that? Lee.

        • Fredric Coe, MD

          Hi Lee, My secretary is Kathleen Dineen 773 702 1475; tell her how you got to me and that the problem is cystinuria. If your daughter has not had cystine evaluation via Litholink, we need to get it from that company or do it here. It is special testing. Please check. My private email is Regards, Fred Coe

    • Lindah Denovan

      She needs to watch her salt intake and reduce the amount of animal protein. Also, add 2 tablespoons of lemon juice to each liter of water she drinks each day, which should be about 5 liters. I am 53 and have had over 50 operations to keep my kidney stones at bay. My left kidney is now very small. You can stop the stones by taking penacilamine, but there can be some side effects – you would need to investigate this.

  4. Tracey

    Hi Dr. Coe, I was diagnosed with cystinuria (stones are 100% cystine). Is there a doctor and or a dietician you can refer me to in South Florida that specialize is this rare hereditary disorder. I’m in Broward county, Fort Lauderdale area.

    • Fredric Coe, MD

      Hi Tracy, Your disease poses problems in medical prevention and surgical management, and I do not know of a stone center near you. The university program at Miami is closest and although I do not recognize the faculty perhaps one or more have taken on an interest in your problem. The alternative is travel to a center. You are right in wanting care from physicians who have managed a number of patients like you. Regards, Fred Coe

  5. Christy

    I was diagnosed via biopsy and blood and urine tests in 2014 with idiopathic hyperoxaluria, but your Web site led me to look back at my last 24-hour urine sample about two years ago. That report found “marked hypocitraturia” with urine citrate at 223 mg/day. My pH was 5.616. At the time of the test I was taking 20 mEq of potassium citrate twice a day (40 mEq daily) for the hyperoxaluria. Since that time my eGFR has improved to Stage III kidney disease. Recently, my primary doctor was concerned about my potassium and suggested I eliminate the potassium citrate. I mentioned this 2016 report to him, and he said to reduce the potassium citrate to 10 mEq once a day. My nephrologist said either no potassium citrate tablets or one 10 mEq tablet per day would be fine. Do I have hypocitraturia, or is this hypocitraturia incidental to my hyperoxaluria diagnosis? Is there a frequency with which I should have 24-hour urine tests? Should I be drinking more water? I now drink at least 84 ounces a day and pursue a very strict diet.

  6. MaryAnn Roberts

    Hi Dr. Coe; First I’d like to thank you for this very informative website. I’ve learned so much from you and appreciate your hard work and the sharing of information you’ve found. Like other kidney stone patients, I’m very grateful to you and for you. As a kidney stone patient, I began having stones only 2 1/2 years ago (I’m years old). As of this year they’re coming fast and steady, at every 2 to 3 weeks, and I am exhausted. I discovered your website as well as Jill’s Facebook page only 2 months ago, after great frustration over the lack of information I was receiving from my urologist. I just received some lab results in the mail. It says that my last stone was “cystine, qualitative”. Does this mean I have cystinuria? It certainly would explain my past several months. My question to you, other than the one above, is that do you think my urologist is giving me adequate care? I see him several times each month this year (and frankly, I cannot afford to visit any longer!) we take a CT kub scan, a urine sample, sometimes sign me up for a shock wave lithotripsy with stent. I’ve been hospitalized in both October and November due to the stent and pain issues. Thanks to your website, I’ve begun the diet and drinking lemon water, had my 24 urine test (very informative!), and I’m told, have had 20 CT kub scans over the past 2 1/2 years, with recommendation to no longer receive them due to radiation over exposure. I feel like I’m running in a hamster wheel with no good results. However, I live in a smaller city (Eugene, Oregon) and this is the only urology practice in our county. I have been forced to cancel my upcoming appointments as I’m so deeply in debt due to the kidney stone costs. I simply don’t know what to do! Would you please consider my situation and make any recommendations that may help me? Or am I at the correct place in this situation? I’m just exhausted and getting no where, hence quite frustrated. Any suggestions would be more than welcome! And please forgive me if this is the wrong platform for me to ask general yet personal questions. I will be ever so grateful for any suggestions and/or recommendations you may have. Thank you very much!

  7. Jeffery Reavis

    Dr. Coe,
    Thank you for all the helpful Q&A’s! I really appreciate the help, since this disease is very complex and is sometimes difficult to find answers too. I have cystinuria and have a quick question.
    Since Methionine is high in fish/seafood, is fish oil (for omega 3’s) harmful for us who have cystinuria?


  8. Allanda

    My 13yr old son had an egg-sized cystine stone removed June 5. August 10 he noticed his urine stream weakening. Is it possibly he could have another stone in that short of time?


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