Classic “stop sign” crystals seen in the urine of patients with cystine urinary stone disease are illustrated. Most cystinurics do not have these crystals in their urine but when they are present they confirm the diagnosis.
WHAT ARE CYSTINE STONES?
Cystine stones account for 1-2% of all renal stones and 6-8% of calculi in children. Unlike most stones, they are caused by a genetic mutation and are inherited. This condition is called “cystinuria” and individuals can inherit one gene (heterozygous) or two genes (homozygous). There is no sexual predilection and patients may present at any age. The primary symptom of having cystinuria is the formation of urinary calculi. Stones may be present in single, multiple, or large staghorn configurations. Pure cystine stones are not easily visible on plain x-rays due to their sulfur content.
A strong family history of kidney stones, development at a young age, or recurrent stone disease are suggestive of the diagnosis. Hexagonal “stop sign” crystals discovered during microscopic examination of urinary sediment are highly indicative of having the disease, but are found in only 17-26% of patients with homozygous cystinuria. Cystine stones are amber in color. Stone analysis will confirm the diagnosis.
Cystine is an amino acid and normal individuals excrete low amounts in the urine (18 milligrams cystine/gram creatinine). Simple heterozygous adults (those with one inherited gene) usually excrete <150 mg/g of creatinine. Most homozygous cystinurics (with the more severe two gene inheritance), in comparison, excrete >250 mg/g creatinine.
The limited solubility of cystine is responsible for spontaneous crystallization and subsequent stone formation when it is present in high concentrations. Urinary pH, or the acidity, does have a profound effect on cystine solubility, however, and manipulating the pH is one of the mainstays of therapy to dissolve and preventive cystine stones.
Cystinuria is caused by a genetic mutation that results in abnormal (decreased) small bowel absorption and kidney reabsorption of cystine and three other amino acids: ornithine, lysine, and arginine. Three types of genetic mutations can lead to cystinuria.
Urinary levels of cystine are elevated in patients with cystinuria despite decreased bowel absorption because of the kidney abnormalities allow cystine to “leak” into the urine. The primary source for urinary cystine is due to the body’s breakdown of its precursor, methionine, an amino acid present in many foods.
Cystinuric patients can develop stones with amazing rapidity. Surgical treatment alone is destined to failure. Patients and their families also require genetic counseling, medical management, and regular followup evaluations.
Medical therapy is directed at dissolving existing calculi and preventing formation of new calculi. Four methods of achieving these goals have been utilized: (1) increasing fluid intake to decrease the relative concentration of urinary cystine; (2) altering urinary pH to increase cystine solubility; (3) decreasing the amount of urinary cystine by dietary modifications; and (4) binding urinary cystine with medications to form more soluble compounds.
Urinary cystine concentration can most simply and effectively be lowered by increasing urinary volume. Fluid intake adequate to keep the urinary concentration of cystine below its solubility level throughout the day is the goal. This goal is difficult to achieve in homozygous patients and requires almost continual fluid intake throughout the day and repeated intake at night to prevent nighttime increases in cystine urine concentration. Patients should be encouraged to drink fluid prior to going to bed and at least once during the night (total intake 2.5-4 liters daily).
Alkalinization takes advantage of the pH dependence of cystine solubility. An elevated urinary pH can be achieved by divided-dose administration of alkali medications (citrate, bicarbonate, or mixed preparations). Potassium containing formulas are preferable to sodium containing preparations because they do not enhance calcium and cystine stone formation. Citrate may be preferred to bicarbonate because of its relatively prolonged duration of action. Urinary alkalinization above a pH of 7.5 may increase the tendency for calcium stone formation (especially calcium phosphate) due to the tendency of these stones to form in a non-acidic high pH environment. Patients can be instructed to adjust the dose of medications using home urine pH paper tests (similar to home pregnancy tests) to maintain their urinary pH between 7.2 and 7.5. Methionine is a precursor of cystine and dietary restriction in theory could lead to decreased cystine production and urinary concentrations. Rigid methionine dietary restriction is very difficult however and of limited benefit.
Methods to increase cystine solubility by binding it to various medications have been developed. The chemical structure of cystine, with its disulfide bond joining two cysteine molecules, makes it amenable to this approach.
Captopril can form a disulfide bond with cystine and render it more soluble. This thiol-cysteine mixed disulfide is 200 times more soluble than cystine. The effectiveness and mechanism of captopril therapy remains controversial.
D-penicillamine and alpha mercaptopropionylglycine (a-MPG) have documented efficacy in reducing cystine excretion. They both undergo disulfide exchange with cystine to form more soluble mixed disulfide compounds. The disulfide exchange reaction is facilitated by an alkaline urinary pH. Both D-penicillamine and a-MPG appear to decrease renal excretion of cystine in addition to increasing cystine solubility. Urinary cystine excretion frequently falls below 200 mg/g creatinine. Over 50% of patients discontinue D-penicillamine due to severe adverse affects. a-MPG is better tolerated by most patients. Adverse affects occur in 75% of patients but are generally less severe. a-MPG has similar effectiveness to D-penicillamine. Patients who fail medical therapy or who are symptomatic require surgical treatment.
ESWL has a reduced success rate for the treatment of cystine stones. The organic nature and uniform structure of pure cystine make them the least fragile of all urinary calculi. Cystine stones less than 1.5 cm respond more favorably to ESWL than stones larger than 1.5 cm. These stones may require substantially more shocks than equivalent sized non-cystine calculi.
Small cystine calculi in the distal ureter usually can be managed easily with ureteroscopic basketing and extraction. Electrohydraulic and ultrasonic lithotripsy, older technologies, often failed due to the hardness of cystine calculi. Laser lithotripsy was also initially frequently ineffective but its success has improved with the current generation of holmium lasers, which are able to successfully fragment these stones.
Percutaneous surgery should be considered in patients with complex cystine stones, a large stone burden, or stones that have failed medical management, ureteroscopy, or ESWL. Cystinuria is a lifelong disorder requiring frequent intervention and thus open surgery should be avoided.
Cystine calculi can be dissolved by percutaneous and retrograde direct irrigation. The solutions used are based upon the same principles as for oral dissolution therapy: creating an alkaline environment to increase cystine solubility and causing a disulfide exchange reaction to create a more soluble compound. Percutaneous irrigants include N-acetylcysteine, N-acetylcysteine with bicarbonate, bicarbonate, and tromethamine-E. The success rate is limited in the presence of mixed cystine stones, since calcium and struvite components will not dissolve and the alkaline environment may actually promote hydroxyapatite and struvite growth.
In many patients with a large stone burden, PNL, ESWL, and chemolysis will all likely be required to achieve a stone free status. Every attempt should be made to render a patient stone free in order to reduce long-term problems. Recurrences are frequent even after a stone free status is achieved, highlighting the importance of medical therapy and frequent follow up evaluation to monitor progress.