Urea for Treatment of Hyponatremia in Patients With SIAD Unresponsive to Fluid Restriction

Efficacy of Oral Urea Supplementation in Patients With SIAD Not Adequately Controlled With Fluid Restriction

Hyponatremia due to SIAD is frequently insufficiently corrected by fluid restriction alone, which remains the first-line therapy but is often poorly tolerated. Urea supplementation is recommended as second-line therapy.

This prospective study evaluates the effectiveness of oral urea supplementation in patients with chronic SIAD and persistent hyponatremia despite fluid restriction.

Hyponatremia (serum sodium, s-Na <135 mmol/L) is the most common electrolyte disorder in hospitalized patients, with prevalence increasing with length of hospital stay. Among hypotonic euvolemic hyponatremias, the syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause and is characterized by impaired free water excretion. SIAD may result from central nervous system disorders, pulmonary diseases, malignancies, or medications, and remains a diagnosis of exclusion.

When possible, treating the underlying cause can resolve the syndrome; however, in many cases the cause remains unknown and therapeutic options are limited. First-line treatment is fluid restriction, which is often insufficient and difficult to maintain in the long term. AVP receptor antagonists, such as tolvaptan, are effective but expensive and may carry a risk of overly rapid correction of serum sodium.

Second-line therapy recommended by current guidelines is urea supplementation, which has shown safety and efficacy in normalizing serum sodium. However, most available evidence derives from retrospective studies, and prospective data are limited.

This study aims to evaluate the effectiveness of urea supplementation in patients with chronic, mildly symptomatic SIAD-related hyponatremia not adequately controlled by fluid restriction (≤1500 mL/day), and to explore its effects on neuroendocrine adaptation, body fluid composition, and bone metabolism.

Inclusion Criteria:

• Confirmed diagnosis of SIAD established prior to study inclusion, defined as:
• Plasma sodium concentration <135 mmol/L
• Plasma osmolality <300 mOsm/kg
• Urine osmolality >100 mOsm/kg
• Urine sodium concentration >30 mmol/L
• Intact adrenal and thyroidal function and no use of diuretics in the last 4 weeks
• Clinical euvolemia, defined as an absence of signs of hypovolemia (orthostasis, tachycardia, decreased skin turgor, dry mucous membranes) or hypervolemia (edema, ascites)

Fulfillment of all diagnostic criteria at baseline (day 0) was not mandatory, as the diagnosis of SIAD had already been established prior to study inclusion based on overall clinical assessment.

- Written informed consent obtained

Exclusion Criteria:

• Chronic hypotonic hyponatremia secondary to another etiology
• Presence of moderate to severe symptoms attributable to plasma hypotonicity
• Severe hypotonic hyponatremia (serum sodium <120 mmol/L)
• Another ongoing drug treatment for hyponatremia (including vaptans and salt tablets)
• Severe hepatic insufficiency
• eGFR <45 mL/min/1.73 m²
• Pregnancy or breastfeeding
• Known allergy or intolerance to urea
• Patient refusal or inability to provide written informed consent