An interventional study of urea in SIAD - Syndrome of Inappropriate Antidiuresis, sponsored by University of Turin, Italy. Recruiting at 1 site in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-04-14.
Sponsored by University of Turin, Italy · Not applicable, Interventional, and Treatment
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.
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:
Participants will receive oral urea supplementation for 42±4 days, followed by a 10±2-day washout period
Dietary Supplement: urea
Patients with persistent hyponatremia (sodium corrected for glucose \<135 mmol/L) after ≥1 week of fluid restriction (≤1500 mL/day) will receive urea 30 g/day (2 sachets; 1 in the morning and 1 in the evening) dissolved in water, while maintaining fluid restriction ≤1500 mL/day. Blood and urine evaluations will be performed at day 1, day 21±4 and day 42±4, with additional assessments (Montreal Cognitive Assessment \[MoCA\] questionnaire and bioelectrical impedance vector analysis \[BIVA\]) at selected visits. Urea dose adjustments will be based on serum sodium at day 21±4: 45 g/day if Na 130-134 mmol/L, or 60 g/day if Na \<130 mmol/L (maximum 60 g/day). In case of intolerance, the dose will be reduced by one sachet from the planned dose. After day 42±4, urea will be discontinued. A final evaluation will be performed 10±2 days after discontinuation.
Change in serum sodium levels
Change in serum sodium from baseline to assess the acute and chronic effectiveness of urea therapy in outpatients with SIAD not adequately compensated by fluid restriction (≤1500 mL/day)
Time frame: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation
Changes in copeptin, NT-proBNP, and MR-proADM levels
Changes in copeptin, NT-proBNP, and MR-proADM levels from baseline to day 42±4 and after urea discontinuation at 10±2 days, to evaluate chronic neuroendocrine response to urea therapy
Time frame: Baseline, day 42±4, and 10±2 days post-therapy
Bioimpedance adaptation
Changes in intra- and extracellular fluid volumes as assessed by bioimpedance vector analysis (BIVA) from baseline to day 42±4 and after urea discontinuation at 10±2 days
Time frame: Baseline, day 42±4, and 10±2 days post-therapy
Bone turnover markers
Changes in serum C-terminal telopeptide (CTX) and N-terminal pro-peptide of type 1 collagen (PINP) from baseline to day 42±4 and after urea discontinuation at 10±2 days, to evaluate bone metabolism response to variation of serum sodium levels
Time frame: Baseline, day 42±4, and 10±2 days post-therapy
Cognitive performance
Changes in Montreal Cognitive Assessment (MoCA) scores from baseline to day 42±4, to evaluate the effect of sodium increase normalization on cognitive function
Time frame: Baseline and day 42±4
Variation in other Serum and Urinary Analytes
Blood (potassium, creatinine, urea, uric acid, glucose, plasma osmolality) and urine analytes (potassium, creatinine, urea, uric acid, urine osmolality, and fractional excretion of sodium, potassium, urea, and uric acid) will be assessed at baseline, day 1, day 21±4, day 42±4, and 10±2 days post-therapy to evaluate changes following initiation and discontinuation of urea supplementation, and to explore potential predictors of treatment response and remission of hyponatremia
Time frame: Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation
Plan to share: No
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University of Turin, Italy