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

Effect of Protein Supplementation on Plasma Sodium Levels and Urinary Urea Excretion in Patients With SIAD - a Monocentric Open- Label Proof-of-concept Study -The TREASURE Study

This study aims to investigate whether a 7-day dietary high protein supplementation of 90 grams per day increases plasma sodium levels in hyponatremic patients with chronic SIAD.

Enrolled patients will receive first dietary high protein supplementation for one week. After a wash-out phase of at least one week, the patients will receive oral urea for another week.

Study Overview

• Status: Completed
• Conditions: Syndrome of Inappropriate Antidiuresis (SIAD)
• Intervention / Treatment: Dietary supplement: Protein supplementation; Dietary supplement: Oral urea

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Basel, Switzerland, 4031
    • University Hospital Basel, Department of Endocrinology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: single arm: Phase 1: protein supplementation, Phase 2: Urea

Dietary supplement: Protein supplementation; Patients will receive a box with 7 sealable of 90-gram protein containers that will be dissolved in maximal 1L liquid (i.e., water or milk) that should be integrated in the usual daily hydration volume documented at baseline and taken daily for the following 7 days, while keeping their usual meal composition and usual fluid intake. A wash-out period of minimum 7 days between Protein supplementation and Oral urea will be performed.; Dietary supplement: Oral urea; Patients will receive a box with 7 30-grams urea sealable containers. The total daily oral urea dosage of 30 grams that will be dissolved in maximal 1L of a liquid of choice (water, milk, juice, …) that should be integrated in the usual daily hydration volume documented at baseline and taken daily for the following 7 days, while keeping their usual meal composition and usual fluid intake.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma sodium concentration, (mmol/l)	The change of blood sodium during protein supplementation regimen will be visualized by means of line plots and boxplots for patients with chronic SIAD.	from baseline to 7 days after protein supplementation (7 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in estimated glomerular filtration rate (eGFR), (ml/min/1,73m2)	Change in estimated glomerular filtration rate (eGFR)	from baseline to 7 days after urea supplementation (up to 21 days)
Change in blood and urine osmolality, (mOsm/kg)	Change in blood and urine osmolality	from baseline to 7 days after urea supplementation (up to 21 days)
Change in blood and urine potassium, (mmol/L)	Change in blood and urine potassium	from baseline to 7 days after urea supplementation (up to 21 days)
Change in blood and urine creatinine, (umol/L)	Change in blood and urine creatinine	from baseline to 7 days after urea supplementation (up to 21 days)
Change in blood and urine urea, (mmol/L)	Change in blood and urine urea,	from baseline to 7 days after urea supplementation (up to 21 days)
Change in blood and urine uric acid, (umol/L)	Change in blood and urine uric acid	from baseline to 7 days after urea supplementation (up to 21 days)
Change in blood and urine glucose, (mmol/L)	Change in blood and urine glucose	from baseline to 7 days after urea supplementation (up to 21 days)
Change in copeptin, (pmol/l)	Change in copeptin	from baseline to 7 days after urea supplementation (up to 21 days)
Change in aldosterone, (pmol/l)	Change in aldosterone	from baseline to 7 days after urea supplementation (up to 21 days)
Change in renin, (mIU/L)	Change in renin	from baseline to 7 days after urea supplementation (up to 21 days)
Change in MR-proANP, (pmol/l)	Change in MR-proANP	from baseline to 7 days after urea supplementation (up to 21 days)
Change in NT-proBNP, (pmol/L)	Change in NT-proBNP	from baseline to 7 days after urea supplementation (up to 21 days)
Change in oral daily fluid intake, (ml)	Change in oral daily fluid intake assessed by a self-completed drinking protocol	from baseline to 7 days after urea supplementation (up to 21 days)
Change in body weight, (kg)	Change in body weight (kg)	from baseline to 7 days after urea supplementation (up to 21 days)
Change in both systolic and diastolic blood pressure, (mmHg)	Change in both systolic and diastolic blood pressure (mmHg)	from baseline to 7 days after urea supplementation (up to 21 days)
Change in heart rate, (beats/minute)	Change in heart rate (beats/minute)	from baseline to 7 days after urea supplementation (up to 21 days)
Change in general well-being measured by visual analogue scale (VAS, 0-10)	Change in general well-being measured by visual analogue scale (VAS, 0-10), with a range from 0 "worst well-being" to 10 "excellent well-being".	from baseline to 7 days after urea supplementation (up to 21 days)
Number of signs of hyponatremia (vertigo, headache, nausea, attention deficit, mental slowness, forgetfulness, gait instability) assessed by a questionnaire (yes/no)	number of signs of hyponatremia (vertigo, headache, nausea, attention deficit, mental slowness, forgetfulness, gait instability) assessed by a questionnaire (yes/no)	from baseline to 7 days after urea supplementation (up to 21 days)
Short-term change in plasma sodium level (mmol/L)	Short-term change in plasma sodium levels in patients with a plasma sodium concentration <125 mmol/L at baseline.	at day 1 (after treatment start)

Collaborators and Investigators

• Sponsor: University Hospital, Basel, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2021
• Primary Completion (Actual): February 20, 2023
• Study Completion (Actual): February 20, 2023

Study Registration Dates

• First Submitted: July 21, 2021
• First Submitted That Met QC Criteria: August 2, 2021
• First Posted (Actual): August 3, 2021

Study Record Updates

• Last Update Posted (Estimate): February 21, 2023
• Last Update Submitted That Met QC Criteria: February 20, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: hyponatremia; protein supplementation; urea; plasma sodium level
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Endocrine System Diseases; Hypothalamic Diseases; Pituitary Diseases; Water-Electrolyte Imbalance; Inappropriate ADH Syndrome
• Other Study ID Numbers: 2021-01116; kt21ChristCrain2

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No