Jul 26, 2020
This episode is another in the long line of podcast episodes I have done about kidney stones. In this episode we are going to talk about a less common form of kidney stone called a cystine stone, and a metabolic disorder called cystinuria.
Cystine stones comprise about 1% of all stones in adults and about 6% to 10% of stones in children.
Cystinuria is as you would expect by its name is disease that is characterized by high concentrations of cystine in the urine. Because cystine is highly insoluble in urine, frequent kidney stones are the result. Patients with cystinuria are at risk of forming many, many stones over a lifetime.
And the stones begin to form very young in life. Elevated cystine excretion can even be seen in infancy and symptoms of this disorder typically begin between 10 and 30 years of age. The average age at first presentation for cystinuria and kidney stones is around age 12 or 13.
Cystinuria is an inherited disease, one is born with it. It’s an autosomal recessive genetic mutation, which means that you have to get the gene from both your mother and father. The disorder is relatively uncommon, but far from rare. The disorder occurs in approximately 1 in 7,000 to 1 in 10,000 people in the United States. The prevalence of cystinuria varies in different countries and ethnicities. The Swedes, for instance have a low incidence of 1 in 100,000. Cystinuria affects males and females in equally.
There are two gene locations that are involved in creating cystinuria, mutations form in the genes SLC3A1 and SLC7A9, which code for the 2 subunits of a transporter that mediate nearly complete reabsorption of cystine and other dibasic amino acids in the renal proximal tubule and the intestine.
The dibasic amino acids are cystine, ornithine, lysine and arginine (C O L A, cola). In cystinuria all those amino acids can all be found in elevated amounts in the urine. But cystine is the only one that matters to a great deal because it is the one that forms kidney stones. Ornithine, lysine, and arginine are soluble and do not form stones and are merely lost in the urine.
Cystinuria was first correctly described in 1908 by Sir Archibald Garrod, describing it along with three other metabolic abnormalities that he classified as inborn errors of metabolism. The tetrad comprises four inherited metabolic diseases: albinism, alkaptonuria, cystinuria, and pentosuria.
In any young person with a new diagnosis of kidney stones, cystine stones must be considered. Kidney stones are sent for analysis to determine their composition. Cystinurics tend to form stones that are 100% cystine. Cystine stones may be pink or yellow in color after removal, but later they turn to greenish due to exposure to air. People with cystinuria typically produce jagged stones that are small, though some form very large stones. Stones may be accompanied by urinary “gravel,” which consists of yellowish-brown hexagonal crystals.
If a stone cannot be analyzed a suspicion for diagnosis can be made based on other clinical parameters. As I said any young patient presenting with stones should be suspect. The crystals of cystine are easy to distinguish from other crystals in the urine under the microscope. They are hexagonal, translucent, and white.
The urine of a cystinuric may be identified by a positive nitroprusside cyanide test. When urine cystine excretion is greater than 75 mg/L, this spot test will turn the urine purple in color. Quantitative testing is then recommended, such as 1) 24hour urine cystine measurement or 2) Random spot urinary cystine, ornithine, arginine, and lysine excretion normalized by creatinine excretion.
Cystine stone show up only faintly on standard xray of the abdomen due to the sulfide group. Calcium based stones show bright white, uric acid stones usually are radiolucent. Cystine stones can be seen with imaging techniques now more common, such as renal ultrasound and CT scans
Treatment options for a cystine stone depends on the size of the stone as in any other stone. Small stones may pass spontaneously on their own with high fluid intake and, if needed, pain medications. If spontaneous stone passage is unsuccessful, stones may be removed using one of three options: ureteroscopy or extracorporeal shock wave lithotripsy, leaving percutaneous nephrolithotomy for the largest of stones.
Treatment of a single stone episode is not a cure and the patient with cystinuria must focus on prevention to try to decrease the risk of future stone formation. There are three core principles in the prevention of cystine stones.
The first principle is adequate hydration. Crystals precipitate when the concentration of cystine in the urine is above 250 mg/L. The primary objective of treatment for cystinuria is to reduce the cystine concentration in the urine. Consumption of large amounts of fluid–both day and night–maintains a high volume of urine and reduces cystine concentration in the urine. Reducing the concentration of cystine in the urine which prevents cystine from precipitating from the urine and forming stones.
What high fluid intake means in this context is a recommendation of at least 4 liters (roughly 4 quarts) per day. That’s essentially a gallon. More is better. The fluids must be spaced out as well, including through the night. It has been said that people with cystinuria must realize that "for them, water is a necessary drug."
Secondly, cystine is more soluble in urine that has a higher pH. Cystine precipitates if the urine is neutral or acidic.
Making the urine more alkaline (alkalization) with medication such as potassium citrate, sodium bicarbonate and acetazolamide helps cystine to dissolve more readily in the urine. Alkalization is not without risk because a urine with a high pH is at risk of form calcium phosphate stones.
A brief mention here that efforts at urinary alkalization can be hampered by diets too high in salt or proteins so cystinurics should try to reduce salt and protein.
If hydration and alkalization fail then patients are usually started on chelation therapy. Chelating drugs containing a thiol group which exchange a disulfide with cystine. The result is the formation of a drug‐cystine complex which is soluble. The orphan drug alpha-mercaptopropionyl glycine, also known as tiopronin (Thiola) has been approved as a treatment for cystinuria. D-penicillamine and captopril have also been used.