Cystinuria

Cystinuria is an inherited (genetic) disorder of the transport of an amino acid (a building block of protein) called cystine resulting in cystinuria (an excess of cystine in the urine) and the formation of cystine stones.

Obstruction of the urinary tract puts pressure back up on the ureter and kidney. It causes the ureter to widen (dilate) and the kidney to become compressed.

Obstruction of the urinary tract also causes the urine to be stagnant (not moving). Stagnant urine is an open invitation to repeated urinary tract infections.

What is the effect of urinary obstruction on the kidney?

The pressure on the kidneys and the urinary infections result in damage to the kidneys. The damage can progress to renal insufficiency and end-stage kidney disease which require renal dialysis or a kidney transplant.

Although cystine is not the only overly excreted amino acid in cystinuria, it is the least soluble of all naturally occurring amino acids. Cystine precipitates, or crystallizes out of urine and forms stones (calculi) in the kidney, ureter, bladder, or anywhere in the urinary tract.

The cystine stones (below) compared in size to a quarter (a U.S. $0.25 coin) were obtained from the kidney of a young woman by percutaneous nephrolithotripsy (PNL), a procedure for crushing and removing the dense stubborn stones characteristic of cystinuria.

What problem do the cystine stones cause?

Small stones are passed in the urine. However, big stones remain in the kidney (nephrolithiasis) impairing the outflow of urine while medium size stones make their way from the kidney into the ureter and lodge there further blocking the flow of urine (urinary obstruction).

Cystinuria is caused by the defective transport of cystine and several other amino acids through the cells of the kidney and the intestinal tract.

How common is cystinuria?

Cystinuria is one of the more common genetic disorders. Its overall prevalence is about 1 in 7,000 in the population.

Cystinuria is the most common defect known in the transport of an amino acid.

What is a transport defect?

Within the body, many molecules are able to pass across the membranes that surround cells. These molecules can accomplish this feat due to specific transport systems. These systems include special receptors on the membrane of the cell and special carrier proteins. The receptor recognizes the molecule and receives it on the cell membrane. Then the molecule hitches a ride through the cell membrane on the back of a carrier protein.

With such remarkable specificity, it is little wonder that sometimes there are defects in transport systems. Several dozen different diseases are now known to be due to transport defects.

Is cystinuria hereditary?

The genetics of cystinuria are complicated.

There are, as mentioned, 3 types of cystinuria. They are termed cystinuria type I (abbreviated CSNU1), cystinuria type II (CSNU3), and cystinuria type III (CSNU3). Each type of cystinuria can be inherited as an autosomal recessive trait. For example, in a family each parent may have one CSNU1 gene (and a normal gene paired with it) while their boy or girl may have the misfortune of receiving the CSNU1 gene from both of them, thereby acquiring cystinuria.

Cystinuria type I (CSNU1) is caused by a mutation (a change) in a gene (the SLC3A1 amino acid transporter gene) which is situated on chromosome 2p16.

Cystinuria type 2 (CSNU2) is, quite remarkably, also caused by a gene in 2p16.3. Studies of families with both cystinuria I and cystinuria II have shown that the genes for CSNU1 and 2 are at exactly the same spot in chromosome 2p16.3 and in fact both involve the same gene (the SLC3A1 amino acid transporter gene).

CSNU1 and 2 are therefore said to be allelic. The fact that CSNU1 and 2 are allelic means that genetic compounds can form, producing three clinical types -- persons with not just CSNU1/CSNU1 and CSNU2/CSNU2 but also the compound type CSNU1/CSNU2.

Cystinuria III (CSNU3) is due to a mutation at a separate location, namely at chromosome 19q13.1.

The stones that form in cystinuria are directly or indirectly responsible for all of the signs and symptoms of the disease, including:

• Hematuria - blood in the urine;
• Flank pain - pain in the side, due to kidney pain;
• Renal colic - intense, cramping pain due to stones in the urinary tract;
• Obstructive uropathy - urinary tract disease due to obstruction; and
• Urinary tract infections.

What are the laboratory findings in cystinuria?

The key laboratory finding is a large amount of cystine in the urine. There are also increased urinary levels of 3 other amino acids with a similar structure -- lysine, arginine, and ornithine. The membrane transport for cystine is unique to cystine but serves to transport all 4 so-called dibasic amino acids -- lysine, arginine, orthnithine and, of course, cystine.

This excess of amino acids in the urine constitutes aminoaciduria. Some persons (heterozygotes) carrying just one gene for cystinuria have aminoaciduria, although milder. There are actually 3 types of cystinuria. Carriers of 2 of these types of cystinuria (types II and III) show abnormal amounts of cystine in their urine. 

Because of the potential effectiveness of treatment, early diagnosis of cystinuria is important in all persons, regardless of age, who form urinary stones. Failure to diagnose cystinuria early and treat it consistently with the utmost vigor can result in morbidity (illness) and mortality (death). Survival may depend upon dialysis or a kidney transplant.

High fluid intake: The foremost aim of treatment is to prevent the formation of cystine stones. This goal is attained mainly by increasing the volume of urine. The reason for the increased urine volume is simple. By increasing the volume of urine, the concentration of cystine in the urine is reduced which prevents cystine from precipitating from the urine and forming stones.

Cystine stones in many patients can be dissolved and new ones prevented by a high fluid intake. What high fluid intake means in this context is an absolute minimum of 4 liters (roughly 4 quarts) per day. An intake of 5 to 7 liters a day is ideal. The fluids must be spaced out, including through the night. It has been said that people with cystinuria must realize that "for them, water is a necessary drug."

Alkalizing the urine: Another strategy that has been attempted to treat cystinuria is alkalization of the urine. The rationale is that in an alkaline (nonacidic) liquid, cystine tends to stay in solution and there it does no harm. To make the urine alkaline, sodium bicarbonate (and similar substances) have been used. This treatment is not without hazard because it can, while preventing cystine stones, lead to the formation of other types of kidney stones.

Penicillamine: For people with cystinuria in whom a consistent, conscientious high fluid intake does not succeed in halting the formation of stones, another option available is regular treatment with a drug called penicillamine. Penicillamine (Cuprimine, Depen) acts to form a complex with cystine that is 50 times more soluble than cystine itself. The side effects of penicillamine are rarely severe enough to prevent its use.

Percutaneous nephrolithotripsy (PCNL): The stones in cystinuria are too dense to be broken up by shock waves produced outside the body (extracorporeal shock wave lithotripsy) as can be done with some other types of common kidney stones. Instead, a technique designed for removing dense (and very large) stones is utilized: percutaneousnephrolithotripsy (PCNL).

PCNL is performed via a port created by puncturing the kidney through the skin and enlarging the access port to 1 cm (about 3/8 inch) in diameter. There is no surgical incision. PCNL is done under real-time live x-ray control (fluoroscopy). Because x-rays are involved, a super-specialist in radiology (an interventional radiologist) may perform this part of the procedure. The endourologist (another subspecialist) then inserts instruments via this port into the kidney to break up the stone and remove most of the debris from the stone.