Tolvaptan Usage for ADPKD
Tolvaptan is recommended for adults with ADPKD who are at risk of rapid kidney disease progression, with a starting dose of 45 mg in the morning and 15 mg 8 hours later, gradually titrated to a target dose of 90 mg/30 mg to slow eGFR decline by approximately 1.3 ml/min per 1.73 m² per year. 1
Patient Selection Criteria
Tolvaptan should be considered for:
- Adults with ADPKD at risk of rapid progression
- Patients with preserved kidney function but evidence of disease progression
- Patients who can tolerate the aquaretic side effects and comply with monitoring requirements
Tolvaptan should NOT be used in:
- Patients with pre-existing liver disease or elevated liver enzymes
- Patients unable to respond appropriately to thirst
- Patients with hypovolemic hyponatremia
- Patients taking strong CYP3A inhibitors
- Patients with anuria
- Patients with hypersensitivity to the drug 2
Dosing Protocol
| Initiation dose | Titration dose | Target dose |
|---|---|---|
| 45 mg AM / 15 mg PM | 60 mg AM / 30 mg PM | 90 mg AM / 30 mg PM |
- Uptitration should occur after ≥1 week
- Continue until approaching kidney replacement therapy
- Consider downtitration with concurrent CYP3A inhibitors, intolerance, or liver enzyme elevations 1, 3
Monitoring Requirements
Liver Function
- Monthly liver function tests for the first 18 months
- Every 3 months thereafter until drug discontinuation
- Hold tolvaptan and repeat LFTs within 48-72 hours if ALT/AST >2× ULN or >2× baseline
- Permanently discontinue if ALT/AST ≥3× ULN unless another explanation for liver injury is found 1, 3
Hydration Status
- Ensure adequate hydration (2-3 liters of water per day)
- Advise patients to drink enough water to replace urinary losses
- Interrupt treatment during situations causing volume depletion or inability to compensate for aquaresis
- Implement a "sick-day plan" to skip doses during risk of volume depletion 1
Efficacy and Benefits
Tolvaptan has demonstrated:
- Reduction in eGFR decline by approximately 1.3 ml/min per 1.73 m² per year
- Reduction in total kidney volume growth by 2.7%
- Decreased incidence of UTIs, kidney stones, hematuria, and kidney pain 1, 4
The efficacy extends to older patients (56-65 years) with CKD G3 or G4, showing similar benefits as in younger populations 4.
Side Effects Management
Aquaretic Effects
- Polyuria, nocturia, polydipsia, and thirst are common and expected
- Advise patients to drink liquids without sugar or fat
- Adopt low-sodium intake to reduce polyuria
- Individual adjustments should include adapting schedule, timing, and doses to the patient's activities 1, 5
Hepatotoxicity
- Approximately 5% of ADPKD patients treated with tolvaptan show elevated liver enzymes (vs 1% with placebo)
- Follow the monitoring algorithm for potential tolvaptan-induced liver injury
- All patients with evidence of possible drug-induced liver injury should be followed until abnormalities return to normal or baseline 1, 3
Other Side Effects
Special Populations
Children and Adolescents
- Tolvaptan is not routinely recommended for children and young people with ADPKD
- Off-label use can be considered at clinician discretion in children at high risk of early progression based on large total kidney volume, rapid kidney growth, family history, etc.
- Recent trials show pharmacodynamic activity in pediatric ADPKD with manageable aquaretic effects 1, 6
Alternative Therapies
- High water intake (2-3 liters per day) is suggested for people with ADPKD and eGFR ≥30 ml/min per 1.73 m²
- mTOR inhibitors, metformin, and statins are NOT recommended to slow disease progression
- Somatostatin analogues should not be prescribed for the sole purpose of slowing eGFR decline but can be considered for severe symptoms due to massively enlarged kidneys 1
Clinical Pearls
- Tolvaptan causes a small, reversible reduction in eGFR initially, likely reflecting its impact on compensatory hyperfiltration
- The benefits of tolvaptan in slowing kidney function decline appear to be independent of its effects on total kidney volume growth 7
- Careful patient selection and counseling are essential for successful implementation of tolvaptan therapy 8