What are the management options for cystinuria?

Management of Cystinuria

The management of cystinuria requires a comprehensive approach combining high fluid intake, dietary sodium and protein restriction, urinary alkalinization, and in refractory cases, cystine-binding thiol drugs to effectively prevent stone formation and reduce morbidity. 1

Pathophysiology and Diagnosis

• Cystinuria is an autosomal recessive disorder affecting renal tubular amino acid transporters, causing excessive urinary excretion of cystine, which has poor solubility at normal urinary pH 2
• Diagnosis is confirmed through 24-hour urine collection showing elevated cystine levels, with stone analysis revealing characteristic hexagonal cystine crystals 1
• Genetic testing can identify mutations in SLC3A1 and SLC7A9 genes, though phenotype doesn't vary significantly with different genetic characteristics 2

First-Line Management Strategies

Hydration

• High fluid intake is particularly crucial in cystinuria to dilute urinary cystine concentration below 250 mg/L 1
• Oral intake of at least 4 liters per day is typically required, significantly higher than for other stone types 1
• Fluid intake should be distributed throughout the day with special attention to nighttime hydration to prevent concentrated morning urine 3

Dietary Modifications

• Limit sodium intake to 100 mEq (2,300 mg) or less daily, as lower sodium intake reduces cystine excretion 1
• Restrict animal protein intake to decrease cystine substrate load, as all animal-origin foods are rich in cystine and methionine (which metabolizes to cystine) 1
• Maintain adequate but not excessive protein intake, particularly important in growing children and pregnant women 4

Urinary Alkalinization

• Potassium citrate is recommended to increase urinary pH to approximately 7.0, which enhances cystine solubility 1
• Potassium citrate is preferred over sodium citrate to avoid increasing sodium load, which can increase cystine excretion 1
• Target urinary pH should be monitored regularly to ensure optimal alkalinization 5

Second-Line Pharmacological Therapy

Cystine-Binding Thiol Drugs

• Offer cystine-binding thiol drugs to patients who are unresponsive to dietary modifications and urinary alkalinization, or have large recurrent stone burdens 1
• Tiopronin (alpha-mercaptopropionylglycine) is the preferred first choice due to better efficacy and fewer adverse events compared to D-penicillamine 1, 2
• D-penicillamine dosage typically starts at 250 mg/day and increases gradually to 1-4 g/day (30 mg/kg/day for pediatric patients), divided into four doses with the largest portion at bedtime 4
• These medications work by forming soluble drug-cysteine complexes that are more readily excreted 4

Monitoring and Follow-up

• Obtain a 24-hour urine specimen within six months of initiating treatment to assess response 1
• Consider separate day and night urine collections to detect episodes of high cystine supersaturation that might be missed in 24-hour collections 3
• Monitor urinary cystine levels, pH, volume, and cystine capacity/supersaturation regularly 6
• Annual 24-hour urine specimens are recommended for long-term follow-up, with more frequent monitoring for active stone formers 1
• Periodic blood testing to assess for adverse effects in patients on pharmacological therapy, particularly thiol drugs 1

Emerging Therapies

• α-Lipoic acid (ALA) has shown promise in improving cystine solubility without affecting cystine excretion or urine pH in pediatric patients 6
• This nutritional supplement may be considered as an adjunct to conventional therapy in selected cases 6

Common Pitfalls and Considerations

• Poor adherence to treatment is common due to the high fluid intake requirements and medication side effects 5
• Thiol drugs can cause significant adverse effects including rash, fever, proteinuria, and bone marrow suppression, requiring careful monitoring 4
• Patients with cystinuria are at risk for renal insufficiency due to recurrent stone formation and repeated interventions 2
• Separate day and night urine monitoring may detect high supersaturation periods missed by 24-hour collections alone 3
• Patients require lifelong management as stone formation will recur throughout life without preventive measures 2