Effect of Protein Supplementation on Plasma Sodium Levels and Urinary Urea Excretion in Patients With SIAD

Hyponatremia (blood sodium <135 mmol/l) is the most frequent electrolyte and fluid disturbance with a prevalence up to 30% in hospitalized patients. The most common etiology of euvolemic hyponatremia is the syndrome of inappropriate antidiuresis (SIAD) which is also the main etiology of hyponatremia overall. Urea osmotic diuresis has been reported to cause hypernatremia in critically ill patients in intensive care unit (ICU), showing that urea can influence sodium levels. Increasing solute intake with oral urea represents a valid treatment approach to increase urine volume and solute free water clearance through osmotic diuresis and reduction of urinary sodium excretion in SIAD. In Switzerland, urea is a medical food prepared as a compounding agent by pharmacies. Endogenous proteins and dietary protein are metabolized into nitrogen which is metabolized to soluble excretable urea by the liver. Protein intake could represent an osmotic relevant source of urea. The Jone's factor of 6,25 is commonly used to convert nitrogen to protein equivalent, assuming an average nitrogen content of 16% in protein (100g protein / 6,5 = 16g nitrogen).

Urea (CH₄N₂O) contains 46,6% nitrogen (atomic weight of nitrogen = 14 g/mol, atomic weight of urea = 60,1 g/mol). Using these ratios, 30g urea would correspond to 14g nitrogen and 87,5g protein. In this study, a 90g protein supplementation will be used, which corresponds roughly to 30g urea, in form of a daily intake of protein powder (Whey Protein®, foodspring GmbH, Germany or Clear Whey Isolate®, MyProtein THG Company, United Kingdom), which is freely marketed as food in Switzerland. Both interventional products are not considered as drugs.

Patients with a plasma sodium concentration <125 mmol/L are at increased risk for overcorrection, i.e., an increase in plasma sodium levels >10 mmol/L in the first 24 hours of treatment. An additional visit will be planned on the second day of treatment in order to recognize rise over this limit and initiate relowering counteractions, which will include the skip of the second powder intake and oral fluid intake.

This study is to analyze whether protein supplementation can increase plasma sodium levels in patients with SIAD by increasing urinary urea excretion.

Inclusion criteria

• previous documented diagnosis of chronic SIAD
• confirmed diagnosis of SIAD at screening visit defined as:

• plasma sodium concentration <135 mmol/L, measured in lithium heparin plasma
• Plasma osmolality <300 mOsm/kg
• Urine osmolality >100 mOsm/kg
• Urine sodium concentration >30mmol/l
• Clinical euvolemia, defined as an absence of signs of hypovolemia (orthostasis, tachycardia, decreased skin turgor, dry mucous membranes) or hypervolemia (edema, ascites)

Exclusion criteria

• lactose intolerance, celiac disease, milk protein allergy, soja allergy, nuts allergy or known hypersensitivity or allergy to one of the components of the protein supplementation (Whey Protein®, foodspring GmbH, Germany or Clear Whey Isolate®, MyProtein THG Company, United Kingdom)
• inborn metabolic disorders implying carbohydrate, lipid or protein metabolism - severe symptomatic hyponatremia in need of treatment with 3% NaCl-solution or in need of intensive/intermediate care treatment at time of inclusion
• Risk factors for osmotic demyelination syndrome: hypokalaemia (K <3,4 mmol/L), malnutrition, advanced liver disease, alcoholism.
• contraindication for lowering blood pressure
• type 1 diabetes mellitus
• uncontrolled type 2 diabetes mellitus (defined as HbA1c >8.0%)
• uncontrolled hypothyroidism
• uncontrolled adrenal insufficiency
• reduction of eGFR <60 mL/min/1,73 m2 (KDIGO G3, G4 and G5) or end stage renal disease (dialysis)
• severe hepatic impairment (ALAT/ASAT >3x upper limit) or advanced symptomatic liver disease defined as past or current hepatic encephalopathy, liver cirrhosis Child C or decompensated (bleeding, jaundice, hepatorenal syndrome).
• treatment with a diuretic, a SGLT2 inhibitor or a corresponding combined preparation, lithium chloride, urea, vaptans, demeclocycline in the two weeks before screening.
• severe immunosuppression defined as leucocytes <2G
• pregnancy, wish to become pregnant during study period or breastfeeding
• end of life care
• Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc.
• Current participation in another intervention study
• lack of capacity or other reason preventing from giving informed consent or following study procedures.