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.

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