1892

• Oral Urea was First Used a Diuretic (Kidney Int, 2015) [MEDLINE]

1962

• Oral Urea (at a Dose of 45 g qday) was First Reported for Use as a Diuretic in Heart Failure (Kidney Int, 2015) [MEDLINE]

1960’s

• Intravenous Urea Administration was the Standard of Care for Increased Intracranial Pressure and Increased Intraocular Pressure (Kidney Int, 2015) [MEDLINE]
  • Intravenous Urea was Typically Intravenously Mixed with an Inert Sugar (Such as Fructose or Glucose) to Prevent Intravascular Hemolysis
    • Commercial Preparations
      • Ureaphil: discontinued in 2006
      • Urovert: discontinued decades ago
  • Urea was Subsequently Replaced by Mannitol (see Mannitol)
    • Mannitol is More Stable, Easier to Prepare, Less Likely to Induce Intravascular Hemolysis, and Less Likely to Cause Tissue Injury with Extravasation

1980’s

• Decaux and Co-workers Reported the First Use of Oral Urea to Induce Water Excretion in 1980 and Have Advocated its Use for >30 Years (Kidney Int, 2015) [MEDLINE]
  • Urea is Effective and Well-Tolerated in the Management of Hyponatremia Due to Multiple Etiologies
    • Cirrhosis (see Cirrhosis)
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure)
    • Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (see Syndrome of Inappropriate Antidiuretic Hormone Secretion)
    • Psychogenic Polydipsia
    • Syndrome of Nephrogenic Antidiuresis

Hyponatremia Associated with Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) (see Hyponatremia and Syndrome of Inappropriate Antidiuretic Hormone Secretion)

Rationale

• Oral Urea May Be Considered in the Following Groups of SIADH Patients
  • Patients Who Do Not Respond to Fluid Restriction
  • Patients Who are Unable to Be Fluid Restricted
  • Patients Who Require Maintenance of Serum Sodium Level After Successful Treatment of Symptomatic Hyponatremia
• Goals of Initial Therapy of Hyponatremia (see Hyponatremia)
  • Increase Serum Sodium by 4-6 mEq/L (and <8 mEq/L) Per 24 hrs
    • If the Patient is Symptomatic (Acute or Chronic Hyponatremia), Increase the Serum Sodium by 4-6 mEq/L within the First 6 hrs, Then Maintain the Serum Sodium at a Constant Level for the Remainder of the 24 hr Period
    • In Chronic Hyponatremia, Rapid Correction (or Overcorrection) of the Serum Sodium Increases the Risk of Osmotic Demyelination Syndrome (ODS) (see Osmotic Demyelination Syndrome)

Properties of Urea

• Urea (Molecular Weight 60g) is Relatively Hydrophilic and Does Not Readily Permeate Artificial Lipid Bilayers
  • Urea is Considered an “Ineffective Osmole”, Due to the Presence of Urea Transporters Which Facilitate Urea Diffusion Across Most Cell Membranes
    • Although Urea Crosses Systemic Capillary and Muscle Cell Membranes Almost as Rapidly as Water, its Reflection Coefficient Across Brain Capillaries is Approximately 0.5 (Intermediate Between that of a Completely Permeable Solute, Such as Ethanol, and that of a Completely Impermeant Solute, Such as Sodium)
  • Therefore, a Rapid Increase in Plasma Urea Concentration Resulting from the Administration of Urea Creates an Osmotic Gradient Across the Blood–Brain Barrier Which Promotes Water Flow Out of the Brain
  • Urea Reliably Decreases Brain Edema Even if it Does Not Increase the Serum Sodium Concentration, But the Increase in Serum Sodium Caused by Urea Excretion is Highly Variable and Unpredictable Because of Differences in Fractional Excretion of Urea and in Urine Osmolarity
• Urea Induces Osmotic Excretion of Free Water

Oral Urea Administration and Absorption

• Urea Tastes Bitter
  • Oral Urea is Better Tolerated When Mixed with Sweeteners
  • Rapid Administration of Larger Urea Doses by Nasogastric Tube May Cause Vomiting and Diarrhea
• Oral Urea is Rapidly Absorbed from the Gastrointestinal Tract

Urea Excretion

• Urea is Freely Filtered by the Glomerulus
  • About Half the Filtered Urea is Excreted in the FInal Urine Along with Electrolyte-Free Water
  • In the Setting of Normal Renal Function, All of the Administered Urea is Excreted within Approximately 12 Hours

Oral (PO)

• Dose (Urea-Na Powder, Lemon-Lime Flavor): 15-30 g BID
  • Mix Each 15 g Dose with 3-4 Ounces of Water or Juice
  • Maximum Daily Dose: 60 g/day

Dose Adjustment

• Hepatic: no dose adjustment required
• Renal: no dose adjustment required

Use in Pregnancy (see Pregnancy)

• xxx

Use During Breast Feeding

• xxx

Gastrointestinal Adverse Effects

• Gastrointestinal Upset

Renal Adverse Effects

Elevated Blood Urea Nitrogen (BUN) (see Elevated Blood Urea Nitrogen)

• Epidemiology
  • May Occur
    • Studies Demonstrate an Increase in the BUN Values Around 25 mg/dL (Clin J Am Soc Nephrol, 2018) [MEDLINE]

Hypernatremia (see Hypernatremia)

• Epidemiology
  • May Occur with Excessive Urea Administration