Cystinuria Treatment & Management

Updated: Mar 19, 2018
  • Author: Chandra Shekhar Biyani, MS, MBBS, DUrol, FRCS(Urol), FEBU; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
  • Print
Treatment

Approach Considerations

The foundation of cystine stone prevention is adequate hydration and urinary alkalinization. When this conservative therapy fails, the addition of thiol drugs, such as D-penicillamine, alpha-mercaptopropionylglycine (tiopronin), and captopril, are added to the regimen. Disappointingly few advances in the medical treatment of cystinuria have occurred over the last 10-15 years. No therapy currently addresses the underlying derangement of dibasic amino acid transport. [15, 40, 41]

A multidisciplinary approach to care, including involvement of nephrologists, renal dietitians, and nurses, should be initiated early in the disease. Treatment of the patient with cystinuria requires close cooperation between the urologist and the nephrologist. Maintaining high diuresis of 2.5 to 3 L/d or more, regularly distributed throughout the night and day, even when sulfhydryl compounds are given, appears to be the major factor predictive of therapeutic success. Regular clinical, radiological, and biochemical surveillance appears to be of primary importance to maintain good long-term compliance with medical treatment.

Next:

Medical Care

Management algorithm

Overall, for a patient with cystinuria who does not have a stone, first-line therapy in most cases is a conservative approach, including large-volume fluid intake (urine output >2.5 L/d), regular urine pH monitoring (urine pH of 6.5 to 7), dietary restrictions, and urinary alkalization with potassium citrate.

If this standard therapy fails to achieve the urinary cystine concentration of less than 300 mg/L, then medical therapy with D-penicillamine, alpha-MPG, or captopril must be added.

Treat patients with stone disease according to the location of the stone. The expertise of a urologist and a radiologist is important for decision-making processes, and stone site and size also influence further management. See the treatment algorithm image below.

Treatment algorithm for cystinuria. Treatment algorithm for cystinuria.

Hydration

The average homozygous patient with cystinuria excretes 600-1400 mg of cystine per day. The solubility of cystine at a pH level of 7 is 250-300 mg/L. Therefore, one of the oldest and most effective cystine stone–prevention techniques is hyperdiuresis to decrease urinary cystine concentration. Early studies by Dent et al in the 1960s showed that hydration alone could prevent stone recurrence in up to a third of patients. This finding was corroborated by subsequent studies. [7]

The goals of hydration therapy are urine volumes in excess of 2.5 L/d. This goal may require ingesting up to 5 L of water per day. [42] Patients should drink 240 mL of water every hour during the day and 480 mL before retiring and at least once during the night. Patients should monitor the specific gravity of their urine using reagent strips, with a goal of achieving a value less than 1.010.

Alkalinization

Alkaline urine can prevent the precipitation of cystine calculi and can even aid in dissolution. Urinary pH must be more than 7.5 for stone dissolution to occur. Alkalizing beverages such as mineral water, rich in bicarbonate and low in sodium (1500 mg HCO3/L, maximum 500 mg sodium/L), and citrus juices are preferred.

Paradoxically, a urine pH level of more than 7.5 can cause a predisposition to the formation of calcium phosphate calculi. For stone prevention, urinary pH must be maintined at 7-7.5.

With any alkalinization therapy, monitoring of urinary pH is essential. Currently, however, Nitrazine paper and standard pH dipsticks have no clear color differentiations in the pH level range of 6-7.5. UriDynamics, a small company in Indianapolis, Ind, has developed a new test strip called StoneGuard II that includes an additional color block at a pH level of 7.5. The colors produced  and corresponding pH levels are as follows:

  • Yellow-orange – pH  5
  • Yellow-green – pH 6
  • Green-yellow – pH  6.5
  • Light green – pH 7
  • Green with blue cast – pH  7.5
  • Greenish blue –  pH 8

No interference from common medications, nutritional supplements, or blood has been observed with StoneGuard II. It also has a pad to measure specific gravity over a range of 1.000-1.030.

Potassium citrate is the first-line alkalinizing drug. [42] The typical adult dose is 60-80 mEq/d divided into 3-4 doses (15-20 mL/d), titrating the dose as needed to maintain a urine pH within the target range of 7-7.5.

Acetazolamide inhibits the brush-border carbonic anhydrase of the proximal convoluted tubule, thereby increasing urinary bicarbonate excretion. Acetazolamide is not widely used as a first-line drug and is of questionable efficacy.

Sodium bicarbonate was used in the past for alkalinizatoinbut is no longer recommended as a first-line agent. The sodium ion may actually increase the amount of cystine excreted.

Chelating agents

Cystine-binding and cystine-reducing agents share the ability to dissociate the cystine molecule into disulfide moieties with much higher solubilities than the parent molecule. These drugs are thiol derivatives. The treatment goal is excretion of less than 200 mg/d of urinary cystine, and this must be monitored yearly. Start these agents when hydration, dietary, and alkalinization therapies fail.

Cystine-binding agents can dissolve cystine calculi, but this feat usually takes many months to years. They are best suited for stone prevention after surgical debulking of the stone burden, and they possibly help soften cystine stones in preparation for ESWL.

Penicillamine

Penicillamine is a first-generation chelating agent that combines with cystine to form a soluble disulfide complex (50 times more soluble than cystine), thus preventing stone formation and possibly even dissolving existing cystine stones. Three types of isomers of penicillamine are known and include D, L, and DL. Only the D form should be used clinically.

The effect of the drug is dose dependent. A 250-mg/d increase in dose decreases the urinary cystine level by 75-100 mg/d. Doses of 1-2 g/d are effective in reducing the urinary cystine level to 200 mg/g of creatinine.

The prevalence rate of adverse reactions is approximately 50%; therefore, routine use is limited. Adverse effects include rash, arthralgia, leukopenia, gastrointestinal intolerance, and nephritic syndrome.

Long-term therapy may lead to vitamin B-6 (pyridoxine) deficiency. Thus, vitamin B-6 supplementation (50 mg/d) is needed.

Alpha-mercaptopropionylglycine (tiopronin)

Alpha-mercaptopropionylglycine (tiopronin) is a second-generation chelating agent with a chemical structure and mechanism of action based on a thiol disulfide exchange reaction. Tiopronin should be considered first if conservative therapy fails because it has been shown to be approximately 1.5 times as effective as D-penicillamine, both in reducing urinary excretion of free cystine and increasing the amounts of soluble mixed disulfide in the urine. [27]

The drug is not excreted in the urine, so the cyanide-nitroprusside test is an effective qualitative screening method for monitoring the control of cystinuria. A positive test result indicates the need for an increased dosage.

Another advantage of this agent is its lower toxicity profile. In a multicenter trial by Pak et al, 69% of subjects discontinued D-penicillamine because of adverse reactions, compared with 31% for tiopronin. [17]

Captopril

Although captopril has sometimes been promoted for the management of cystinuria, it is not approved by the US Food and Drug Administration (FDA) for the treatment of cystinuria, and it does not appear in the urine in sufficient amounts to be useful. [27]  

Bucillamine

Bucillamine (Rimatil), a dithiol compound, is a third-generation chelating agent that has been available only in Japan and South Korea. [43] In vitro studies showed that incubation of L-cystine with bucillamine and tiopronin resulted in substantially lower L-cystine levels than  with tiopronin alone. When used for treatment of rheumatoid arthritis, bucillamine has shown a low toxicity profile. Therefore, it is probably well tolerated by patients with cystinuria.

Following an FDA grant of orphan drug designation to bucillamine for the treatment of cystinuria, a phase II study has been initiated. The primary outcome measures will be the incidence of treatment-emergent adverse events (safety and tolerability). The secondary outcome measures are 24-hour urine cystine excretion and 24-hour urine cystine capacity. [44]  

L-cystine dimethyl esters (L-CDME) and L-cystine methyl esters (L-CME)

These agents are effective inhibitors of cystine crystal growth. Preliminary in vivo studies have demonstrated promising results. An L-CDME concentration near 2 mg/L was associated with therapeutic effects. Because of effectiveness at lower concentrations, these agents may have fewer adverse effects and better tolerance than others. [45]

Previous
Next:

Surgical Care

Surgery is indicated for patients with large calculi that are unlikely to dissolve and those with calculi that are causing obstruction or symptoms. Smaller stones can be monitored as part of an aggressive medical treatment plan, with the hope of dissolution and/or spontaneous passage. The ultimate goal of surgery is to make the patient free of stones. While the risk of recurrence is unchanged, the time to recurrence is significantly lengthened.

Surgical options can be broadly classified into the following six modalities:

  • Extracorporeal shockwave lithotripsy (ESWL)

  • Retrograde endoscopic lithotripsy and extraction

  • Percutaneous nephrolithotomy

  • Multimodal therapy

  • Percutaneous nephrostomy for chemical dissolution

  • Open surgery (urethra, bladder, ureter, kidneys)

Extracorporeal shockwave lithotripsy

ESWL is especially effective for cystine stones smaller than 1.5 cm in diameter, although overall stone-free rates are lower than those for stones of other composition.

Because of their hardness and homogeneous amino acid composition, most cystine stones require two to three times the usual number of shocks to adequately fragment the stone. Multiple treatments are often necessary to achieve acceptable stone-free rates.

When considering candidates for ESWL, some authors suggest an upper limit of 1.5 cm for upper ureteral or renal cystine calculi. Kachel et al in 1991 recommended limit ESWL to renal calculi smaller than 1 cm in diameter. [46]

ESWL is appropriate in the treatment of ureteral cystine calculi. Stones not visualized after fluoroscopy can still be opacified by either retrograde or intravenous contrast administration to allow for lithotripsy.

Patients taking thiol derivatives may have cystine calculi that are more fragile because the cystine is replaced by apatite in approximately 30% of cases. These calculi may be easier to treat with ESWL.

Retrograde endoscopic lithotripsy and extraction

Historically, retrograde endoscopic treatment of cystine calculi was associated with complications and a low success rate compared with stones of other composition of equal size and location in the urinary tract. This was largely due to technical limitations in scope design and the failure of electrohydraulic lithotripsy to adequately fragment stones.

Currently, a retrograde approach is suitable for mid-to-distal ureteral cystine calculi when using high-energy modalities such as holmium:YAG laser or pneumatic shock devices (eg, Lithoclast). Smaller proximal ureteral calculi may also be treated in a retrograde fashion.

The role of retrograde treatment of renal calculi and large proximal stones is less clear, although ESWL and percutaneous surgery are generally preferred for larger stones. However, one study reports 5 of 6 patients with renal calculi 1.5-3 cm in diameter who were successfully treated via a retrograde approach with intracorporeal electrohydraulic lithotripsy.

Percutaneous nephrolithotomy

Percutaneous nephrolithotomy is the criterion standard for cystine renal calculi larger than 1-1.5 cm in diameter and for calculi for which ESWL or retrograde surgery has failed.

Ultrasonic lithotripsy readily fragments most cystine stones, although re-treatment rates are still approximately 50% compared with approximately 15% for other calculi. Stone-free rates after multiple treatments range from 40%-86%, although recurrence rates are high, approaching 50%-70% at 5-year follow-up despite postoperative medical management.

Multimodal therapy

For large cystine stone burdens, such as occurs with full staghorn calculi, multimodal therapy may help achieve better stone-free rates.

So-called sandwich therapy involves initial percutaneous ultrasonic lithotripsy followed by ESWL and then repeat ultrasonic lithotripsy or flexible nephroscopy and laser lithotripsy.

Percutaneous nephrostomy for chemical dissolution

Direct irrigation of renal calculi with chemodissolution agents through a percutaneous nephrostomy tube was successful in treating a limited number of patients in the late 1970s and early 1980s.

The two most commonly used agents were acetylcysteine (Mucomyst) and tromethamine-E (THAM-E). Acetylcysteine creates soluble disulfide complexes with cystine, similar to the action of D-penicillamine. In addition, percutaneous administration of alkalinizing agents can create a pronounced alkaline milieu. A solution containing 60 mL of a 20% solution of N-acetylcysteine and 300 mEq of sodium bicarbonate per liter of saline is recommended. Tromethamine-E is an organic amine buffer with a pH of 10.2.

Treatment times range from weeks to months. Given the extended treatment times, relatively low success rates, and success of ESWL and percutaneous nephrolithotomy, this modality is rarely used today. Some urologists may still use chemodissolution to help achieve stone-free status in patients with fragments remaining after percutaneous nephrolithotomy or ESWL or for patients unable to tolerate surgery.

Open surgery

Given the success of percutaneous nephrolithotomy, ESWL, and endoscopic retrograde approaches, open surgery is not indicated as first-line therapy for cystine calculi anywhere in the kidneys or ureters, with rare exceptions. Large bladder calculi may be amenable to open surgery, but these stones can also be treated with laser or electrohydraulic lithotripsy.

Ureteral substitution with small intestine has been reported in highly select cases. [47]

Previous
Next:

Diet

Cystine is formed during the metabolism of methionine; therefore, a diet low in methionine is effective. To be effective, dietary methionine must be reduced to 1 g/d. Unfortunately, a primarily vegetarian diet is generally not accepted by patients. Thus, a well-balanced mixed diet with relatively low-protein content (0.8 g protein/kg body weight/d) is recommended. [42]

Cystine excretion increases with high-sodium intake. Processed foods contain large amounts of sodium chloride and are best avoided. Other dietary considerations include the following:

  • Methionine: Instruct patients to avoid foods with very high methionine content, including stockfish and eggs, and to reduce their consumption of meat, fish, poultry, and cheese. One study reported decreased cystine production (by approximately 500 µmol/d) with reduced methionine intake.

  • Low-sodium diet: Reducing sodium intake from 300 mmol/d to 50 mmol/d can decrease cystine excretion by 650 µmol/d (156 mg/d).

  • Glutamine: A series from 1979 reported by Miyagi et al indicated reduced cystine excretion with oral or intravenous glutamine. However, this effect has not been duplicated in other studies. [48]

Dietary guidelines for patients are as follows:

  • Eat only small amounts of protein-rich foods such as meat, fish, sausages, eggs, cheese, and soybeans

  • Consume foods with a low protein content, such as fruits, vegetables, salads, and cereals

  • Limit additional salt during meals; limit canned foods, smoked foods, and pickled foods

  • Increase dietary fiber intake

Previous
Next:

Prevention

Family screening helps identify patients with a genetic predisposition for cystinuria.

Hydration sufficient to maintain urine output of at least 2.5 L per day is a well-accepted stone-prevention measure. Dietary restrictions must be instituted and followed. Urinary alkalization is necessary.

Previous
Next:

Long-Term Monitoring

Initial follow-up follow-up for patients with cystinuria consists of the following:

  • Ensure that patients are following a diet low in protein and sodium chloride.
  • Determine urinary pH level, and check first-morning urine for cystine crystals.
  • Repeat 24-hour urinary cystine measurements until the cystinuric state is well controlled and stable.
  • Check renal function regularly. Red blood cell, white blood cell, and platelet counts should be monitored for patients on D-penicillamine and tiopronin.
  • Abdominal radiography and renal ultrasonography should be routine.

Patients should be taught to use Nitrazine paper to check their urinary pH level and to try to titrate the medication and diet on their own. In addition, continuing regular follow-up is mandatory because of the relentless tendency of cystine stones to recur. Patients should have frequent clinical, radiological, and laboratory surveillance. Annually perform 24-hour urine testing and imaging for patients with stable disease.

 

Previous