What is the treatment for cystine stones?

Treatment of Cystine Stones

The treatment of cystine stones requires aggressive hydration (≥4 liters daily) combined with dietary sodium and protein restriction as first-line therapy, with urinary alkalinization using potassium citrate to achieve a pH of approximately 7.0, and addition of tiopronin for patients who fail conservative measures or have large recurrent stone burdens. 1, 2

First-Line Conservative Management

Aggressive Hydration

• Maintain oral fluid intake of at least 4 liters per day to dilute urinary cystine concentration below 250 mg/L 3, 1
• This target is significantly higher than for other stone types because cystine has poor solubility even at normal urine pH 1
• Fluid intake must be distributed throughout the day and night to maintain consistent dilution 4

Dietary Modifications

• Limit sodium intake to 100 mEq (2,300 mg) or less daily, as lower sodium intake directly reduces cystine excretion 3, 1
• Restrict animal protein intake to decrease cystine substrate load, since all animal-origin foods are rich in cystine and methionine (which metabolizes to cystine) 3, 1
• Dietary therapy must be offered in combination with pharmacological therapy for optimal outcomes 3

Urinary Alkalinization

• Administer potassium citrate to increase urinary pH to approximately 7.0-7.5 to enhance cystine solubility 1, 2, 4
• Potassium citrate is strongly preferred over sodium citrate to avoid increasing sodium load, which would paradoxically increase cystine excretion 1
• The alkaline pH range of 7.0-7.5 is critical because cystine solubility increases dramatically at these pH levels 5, 4

Second-Line Pharmacological Therapy

Cystine-Binding Thiol Drugs

• Offer tiopronin to patients who are unresponsive to dietary modifications and urinary alkalinization, or those with large recurrent stone burdens 1, 2
• Tiopronin is the preferred first choice over D-penicillamine due to better efficacy and fewer adverse events 1
• Tiopronin works by undergoing thiol-disulfide exchange with cystine to form a water-soluble mixed disulfide, thereby reducing the amount of sparingly soluble cystine 6
• The drug shows rapid onset and offset of action, with fall in cystine excretion on the first day of administration 6
• Tiopronin is FDA-approved for prevention of cystine stone formation in adults and pediatric patients 9 years of age and older with severe homozygous cystinuria 6

Dosing and Efficacy

• The decrement in urinary cystine is generally proportional to dose: expect a reduction of 250-350 mg/day at 1 g/day dosing, and approximately 500 mg/day at 2 g/day dosing 6
• Up to 48% of the dose appears in urine during the first 4 hours and up to 78% by 72 hours 6

Important Caveats with Thiol Drugs

• Poor patient compliance is common due to adverse effects, which limits the effectiveness of these agents 5
• Proteinuria, including nephrotic syndrome, has been reported, particularly in pediatric patients receiving greater than 50 mg/kg per day 6
• D-penicillamine, while effective, has more severe side effects and is rarely severe enough to prevent its use, but tiopronin remains preferred 1, 7

Monitoring and Follow-Up

Initial Assessment

• Obtain a 24-hour urine specimen within six months of initiating treatment to assess response to dietary and/or medical therapy 1, 8
• Target urine volume should be greater than 3 liters daily, with cystine concentration maintained below 250 mg/L 1, 5

Long-Term Monitoring

• Obtain annual 24-hour urine specimens for long-term follow-up, with more frequent monitoring for active stone formers 1, 8
• Perform periodic blood testing to assess for adverse effects in patients on pharmacological therapy, particularly thiol drugs 1, 8
• Frequent clinical and ultrasound follow-up is needed to encourage patient compliance and assess efficacy and tolerance of treatment 4

Common Pitfalls to Avoid

• Do not underestimate the fluid requirement: 4 liters daily is often necessary, not the 2-2.5 liters recommended for other stone types 1
• Do not use sodium citrate for alkalinization: this increases sodium load and paradoxically worsens cystine excretion 1
• Do not delay thiol drug therapy in patients with large stone burdens or frequent recurrence: conservative measures alone may be insufficient 1, 2
• Do not neglect nighttime hydration: cystine concentration must be maintained below threshold throughout the entire 24-hour period 4
• Cystine stones are often resistant to extracorporeal shock wave lithotripsy, so percutaneous surgery or ureteroscopy are preferred extraction techniques when intervention is needed 4

Clinical Context

Cystinuria accounts for only 1-2% of adult kidney stones but up to 10% of pediatric stone disease 5, 9. These patients experience more stone events and surgical interventions compared to other stone formers, potentially contributing to faster progression to chronic kidney disease and end-stage kidney disease 9. Successful medical therapy requires extensive lifestyle changes and carries significant adherence challenges, making early diagnosis and aggressive management critical 9.