What are thiol (thiol-containing) drugs used for in the treatment of cystinuria?

Thiol-Containing Drugs in Cystinuria Treatment

Thiol-containing drugs such as tiopronin (alpha-mercaptopropionylglycine) are used as second-line therapy for patients with cystinuria who are unresponsive to first-line treatments including high fluid intake, dietary sodium and protein restriction, and urinary alkalinization, or who have large recurrent stone burdens. 1, 2

Mechanism of Action

• Thiol drugs work by forming soluble complexes with cystine through thiol-disulfide exchange reactions, creating mixed disulfides that are more water-soluble than cystine alone 3
• This reaction reduces the amount of sparingly soluble cystine in urine, decreasing supersaturation and stone formation risk 3
• The reduction in urinary cystine is generally proportional to the drug dose, with a rapid onset and offset of action 3

Treatment Algorithm for Cystinuria

First-Line Therapy

1. High fluid intake

   • Target urine output of at least 3-4 liters per day to dilute urinary cystine concentration below 250 mg/L 2, 1
   • This requires oral intake of approximately 4 liters per day, significantly higher than for other stone types 2

2. Dietary modifications

   • Limit sodium intake to 100 mEq (2,300 mg) or less daily to reduce cystine excretion 2, 1
   • Restrict animal protein intake to decrease cystine substrate load 1, 2

3. Urinary alkalinization

   • Potassium citrate to increase urinary pH to approximately 7.0-7.5 1, 2
   • Potassium citrate is preferred over sodium citrate to avoid increasing sodium load 1, 2

Second-Line Therapy: Thiol-Containing Drugs

When to initiate thiol drugs:

• When patients are unresponsive to first-line measures 1, 2, 3
• In patients with large recurrent stone burdens despite optimal first-line therapy 1, 2
• When urinary cystine remains supersaturated despite optimal hydration and alkalinization 4, 5

Preferred Thiol Drug Options:

1. Tiopronin (alpha-mercaptopropionylglycine)

   • First choice due to better efficacy and fewer adverse events compared to D-penicillamine 1, 2, 6
   • FDA-approved indication: "prevention of cystine stone formation in adults and pediatric patients 9 years of age and older with severe homozygous cystinuria, who are not responsive to high fluid intake, alkali, and diet modification alone" 3
   • Initial dosage: 800 mg/day for adults, typically divided into three doses 3
   • Average effective dosage: approximately 1,000 mg/day 3
   • Pediatric dosing (≥9 years): 15 mg/kg/day, not to exceed 50 mg/kg/day 3

2. D-penicillamine

   • Alternative option but associated with more adverse effects 2, 7, 6
   • Less favorable side effect profile affecting bone marrow, kidney, liver, gastrointestinal tract, and skin 6

Monitoring and Follow-up

• Measure urinary cystine 1 month after initiation of thiol therapy and every 3 months thereafter 3, 8
• Obtain a 24-hour urine specimen within six months of initiating treatment to assess response 1, 2
• Annual 24-hour urine specimens for long-term follow-up, with more frequent monitoring for active stone formers 2
• Periodic blood testing to assess for adverse effects, particularly with thiol drugs 1, 2
• Common adverse reactions to monitor with tiopronin (≥10%): nausea, diarrhea, oral ulcers, rash, fatigue, fever, arthralgia, proteinuria, and emesis 3

Important Considerations and Pitfalls

• Proteinuria, including nephrotic syndrome and membranous nephropathy, has been reported with tiopronin use 3
• Pediatric patients receiving >50 mg/kg/day of tiopronin may be at increased risk for proteinuria 3
• Hypersensitivity reactions can occur with thiol drugs 3
• Traditional cystine assays may not reliably distinguish between cystine and soluble thiol drug-cysteine complexes, requiring specialized testing methods 5, 8
• The solid-phase cystine capacity assay can reliably measure urinary cystine even in the presence of thiol drugs 4, 5
• Breastfeeding is not recommended during tiopronin therapy 3
• Dose carefully in elderly patients with monitoring of renal function 3