Protein Supplementation in Hyponatremia Due to the Syndrome of Inappropriate Antidiuresis

Hyponatremia (plasma sodium <135 mmol/L) is the most common electrolyte disorder, affecting up to 30% of hospitalized patients. Chronic hyponatremia (>48 hours) is linked to longer hospital stays, higher costs, increased mortality, and morbidity (e.g., falls, fractures, cognitive deficits). The most common cause of euvolemic hyponatremia is syndrome of inappropriate antidiuresis (SIAD), characterized by excessive water retention due to dysregulated vasopressin activity. Treatment options include fluid restriction or increasing water excretion with AVP antagonists, SGLT2 inhibitors, or oral urea.

A recent trial showed that protein supplementation can induce osmotic diuresis and raise sodium levels similarly to oral urea, with better tolerability. Since protein supplementation is often used in hospitalized patients with malnutrition, this study aims to compare its acceptability to fluid restriction in hospitalized SIAD patients. This head-to-head superiority trial will randomize patients to receive either 80 g of dietary protein daily or fluid restriction (1000 mL/day) for up to 5 days. The hypothesis is that protein supplementation is significantly more acceptable to patients than fluid restriction, ultimately improving treatment outcomes.

Inclusion criteria

• Adult patients with confirmed SIAD during the hospital stay or at screening, defined by:
• Plasma sodium concentration <135 mmol/L
• Plasma osmolality <300 mOsm/kg
• Urine osmolality >100 mOsm/kg
• Urine sodium concentration >30 mmol/L
• Clinical euvolemia (no signs of hypovolemia or hypervolemia)

Exclusion criteria

• Lactose intolerance, milk protein allergy, soy allergy, nuts allergy, or hypersensitivity to components of the protein supplement.
• Inborn metabolic disorders affecting carbohydrate, lipid, or protein metabolism.
• Severe symptomatic hyponatremia requiring 3% NaCl or intensive care.
• New (within the last five days) treatment with SGLT2 inhibitors, vaptans or oral urea
• Uncontrolled severe hypothyroidism (untreated)
• Uncontrolled adrenal insufficiency (morning cortisol <150nmol/l)
• eGFR <45 mL/min/1.73 m² (KDIGO G3b-5) or end-stage renal disease (dialysis)
• Severe hepatic impairment or advanced symptomatic liver disease defined as past or current hepatic encephalopathy, liver cirrhosis Child C, or decompensated (bleeding, jaundice, hepatorenal syndrome)
• Pregnancy, breastfeeding, or plans to become pregnant during the study.
• End-of-life care
• Lack of capacity or other reasons preventing from giving informed consent or following study procedures (e.g., due to language problems, psychological disorders, dementia, etc.)
• Treatment with thiazid diuretic (must be stopped at least 48 hours before inclusion)

Post-randomization Exclusion Criteria:

• Type 1 diabetes or uncontrolled type 2 diabetes (HbA1c >8.0%)