Management of Hyponatremia

Treatment Considerations

Co-administration of diuretics with tolvaptan increases the risk of too rapid correction of serum sodium, which can lead to osmotic demyelination syndrome, as recommended by the American College of Cardiology/American Heart Association guidelines 1
Tolvaptan may be considered for short-term treatment in patients with heart failure and hyponatremia, despite water restriction and maximization of guideline-directed medical therapy, with a Class IIb recommendation (Level of Evidence B) from the American College of Cardiology/American Heart Association guidelines 1, 2
The American College of Cardiology/American Heart Association guidelines recommend vasopressin antagonists in hospitalized patients with volume overload and severe hyponatremia, with a Class IIb recommendation (Level of Evidence B) 1, 2

Diuretics may be cautiously reintroduced with close monitoring after stabilization, if still needed for volume management 1
Patients with cirrhosis should be treated for short-term only, according to the American Association for the Study of Liver Diseases 3
Serum sodium should not increase more than 8 mmol/L per day, and not more than 8 mmol/L in 24 hours, to avoid osmotic demyelination syndrome and central pontine myelinolysis, as recommended by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases, with a strength of evidence rated as high 3, 4, 5

Tolvaptan is contraindicated in ADPKD patients with pre-existing liver disease due to the significant risk of drug-induced liver injury, as recommended by the FDA 6
The recommended initiation dose of tolvaptan is 45 mg AM / 15 mg PM, with a titration dose of 60 mg AM / 30 mg PM, and a target dose of 90 mg AM / 30 mg PM, as supported by the KDIGO guidelines and the European Medicines Agency 6
The following dosing schedule is recommended:
Initiation dose Titration dose Target dose
45 mg AM / 15 mg PM 60 mg AM / 30 mg PM 90 mg AM / 30 mg PM
Monthly liver function tests are recommended for the first 18 months, and every 3 months thereafter until drug discontinuation, with holding tolvaptan and repeating LFTs within 48-72 hours if ALT/AST >2× ULN or >2× baseline, as recommended by the FDA 6

Initiation dose	Titration dose	Target dose
45 mg AM / 15 mg PM	60 mg AM / 30 mg PM	90 mg AM / 30 mg PM

Patients should be advised to drink enough water to replace urinary losses, and to implement a "sick-day plan" to skip doses during risk of volume depletion, with a strength of evidence rated as high 6
Approximately 5% of ADPKD patients treated with tolvaptan show elevated liver enzymes, and all patients with evidence of possible drug-induced liver injury should be followed until abnormalities return to normal or baseline, with a strength of evidence rated as high 6
Hyperuricemia and potential for dehydration and hypovolemia requiring intervention are also possible adverse effects of tolvaptan therapy, with a strength of evidence rated as moderate 6
Other adverse effects of vaptans include thirst, dry mouth, increased urination, phlebitis and injection site reactions, hypokalemia, and hypotension, with a strength of evidence rated as moderate 4

Tolvaptan is not routinely recommended for children and young people with ADPKD, but off-label use can be considered at clinician discretion in children at high risk of early progression, as recommended by the KDIGO guidelines 7
Vaptans are contraindicated in patients with hypovolemic hyponatremia, inability to sense or respond to thirst, anuria, and patients taking strong CYP3A inhibitors, as stated by the European Medicines Agency and the FDA 5, 8, 4
Vaptans should be used with caution in patients with hepatocellular carcinoma (HCC) and only for short-term treatment of severe hyponatremia, with mandatory liver function monitoring, with a strength of evidence rated as moderate 3
In patients with cirrhosis, vaptans should be used for short-term treatment only, with reduced dosing in uncompensated cirrhosis, and long-term use of satavaptan was associated with increased mortality, with a strength of evidence rated as high 4, 3

A low sodium diet can help reduce cyst growth in ADPKD patients with compensated chronic liver disease, as suggested by research published in a reputable journal in 2019 7
High water intake (2-3 liters per day) is recommended for patients with eGFR ≥30 ml/min/1.73 m², although the source of this recommendation is not directly cited

Tolvaptan has demonstrated a reduction in eGFR decline by approximately 1.3 ml/min per 1.73 m² per year, and a reduction in total kidney volume growth by 2.7%, with a strength of evidence rated as high and moderate, respectively 6
Tolvaptan has also shown a decreased incidence of UTIs, kidney stones, hematuria, and kidney pain, with a strength of evidence rated as moderate 6