What are the considerations for discontinuing Jynarque (Tolvaptan) in a patient with Autosomal Dominant Polycystic Kidney Disease (ADPKD)?

Considerations for Discontinuing Jynarque (Tolvaptan) in ADPKD

Discontinuation of tolvaptan should be carefully considered as it may lead to accelerated disease progression, but is warranted in cases of serious adverse effects, particularly hepatotoxicity, or when approaching kidney replacement therapy.

Indications for Discontinuation

• Mandatory discontinuation is required if liver enzymes (ALT or AST) increase to ≥3× upper limit of normal (ULN) or if the patient shows signs and symptoms of liver injury 1, 2
• Discontinuation should be considered when approaching kidney replacement therapy if the medication is no longer providing significant benefit 2
• Intolerable aquaresis-related side effects (polyuria, thirst, dry mouth) that persist despite dose adjustment may necessitate discontinuation 2

Disease Progression Considerations

• Tolvaptan slows ADPKD progression by reducing the rate of eGFR decline by approximately 1.3 ml/min/1.73 m² per year and decreasing total kidney volume growth by 2.7% compared to placebo 2, 3
• Long-term studies (up to 11.2 years) show sustained reduction in annual eGFR decline with increasing separation of eGFR values over time between treated and untreated patients 4
• After discontinuation, the protective effect of tolvaptan is lost, and disease progression is likely to return to its natural course 5

Management After Discontinuation

• After discontinuing tolvaptan, patients should increase water intake to 2-3 liters per day to help maintain kidney function 1, 6
• Regular monitoring of kidney function and total kidney volume should continue to assess disease progression 1
• Patients should be counseled about the importance of other protective measures:
  • Low-salt diet 1
  • Regular physical exercise 1
  • Avoiding obesity and smoking 1
  • Avoiding nephrotoxic medications 1

Special Considerations

• For patients with liver injury who discontinue tolvaptan, all abnormalities should be followed until they return to normal or baseline state 1
• If tolvaptan was discontinued due to side effects rather than liver injury, and the benefits outweigh the risks, rechallenge can be considered with more frequent monitoring 1
• Patients with lower baseline GFR may have a different response profile to tolvaptan, with greater fractional free-water clearance per functioning nephron 7

Patient Counseling

• Discuss the expected increase in disease progression rate after discontinuation 5, 4
• Emphasize the importance of continued monitoring and adherence to other protective measures 1
• Provide reassurance that alternative management strategies can still help manage symptoms and slow progression 1
• Address any psychological concerns related to disease progression, as these can significantly impact well-being 1

Decision Algorithm for Discontinuation

1. Mandatory discontinuation:

   • ALT/AST ≥3× ULN or signs of liver injury 1
   • Anaphylactic reaction or severe hypersensitivity 8

2. Consider discontinuation:

   • Approaching kidney replacement therapy 2
   • Intolerable side effects despite dose adjustment 2
   • Patient preference after full discussion of risks/benefits 9

3. Post-discontinuation plan:

   • Increase water intake to 2-3 L/day 1
   • Continue regular monitoring of kidney function 1
   • Reinforce lifestyle modifications 1