SIAD - Syndrome of Inappropriate Antidiuresis
Conditions
Keywords
hyponatremia, urea, plasma sodium level, SIAD
Brief summary
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.
Detailed description
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.
Interventions
DIETARY_SUPPLEMENTurea
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.
Sponsors
University of Turin, Italy
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in serum sodium levels | Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in copeptin, NT-proBNP, and MR-proADM levels | Baseline, day 42±4, and 10±2 days post-therapy | 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 |
| Bioimpedance adaptation | Baseline, day 42±4, and 10±2 days post-therapy | 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 |
| Bone turnover markers | Baseline, day 42±4, and 10±2 days post-therapy | 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 |
| Cognitive performance | Baseline and day 42±4 | Changes in Montreal Cognitive Assessment (MoCA) scores from baseline to day 42±4, to evaluate the effect of sodium increase normalization on cognitive function |
| Variation in other Serum and Urinary Analytes | Baseline, day 1, day 21±4, day 42±4, and 10±2 days post urea discontinuation | 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 |
Countries
Italy
Outcome results
None listed