Urea to Treat Hyponatremia Due to Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Systematic Review and Meta-Analysis

Rationale & Objective: The use of urea to treat hyponatremia related to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has not been universally adopted due to questions about effectiveness, safety, and tolerability. This systematic review and meta-analysis of observational studies addresses these questions. Study Design: This PRISMA-guided study examined published research across 4 electronic databases. Study Populations: Patients with SIADH-related hyponatremia. Selection Criteria: Clinical trials and observational studies reporting at least 1 outcome related to serum sodium concentration, symptom resolution, or adverse effects after oral or nasogastric urea administration. Data Extraction: Data extraction was performed independently by 2 reviewers using a standardized form recording study characteristics, participant demographics, intervention details, and treatment outcomes. Analytical Approach: A meta-analysis was conducted using the restricted maximum likelihood method for the random effects model to assess the effect of urea treatment on serum sodium and serum urea compared with other treatment modalities. Subgroup analyses were conducted based on treatment duration and SIADH severity. Results: Urea treatment significantly increased serum sodium (mean difference [MD], 9.08 [95% CI, 7.64-10.52], P < 0.01) and urea (MD, 31.66 [95% CI, 16.05-47.26], P < 0.01) in patients with SIADH, albeit with significantly high heterogeneity. Subgroup analysis based on the treatment duration showed a significant rise in the serum sodium level after 24 hours and 2, 5, 7, and 14 days, as well as after 1 year of treatment. Greater increases in serum sodium levels after treatment with urea occurred in patients with severe (<120 mEq/L) (MD, 18.04 [95% CI, 13.68-22.39]) than with moderate (120-129 mEq/L) (MD, 7.86 [95% CI, 6.78-8.94]) or mild (130-135 mEq/L) (MD, 8.00 [95% CI, 7.31-8.69]) SIADH-induced hyponatremia. Urea treatment was comparable to fluid restriction (MD, 0.81 [95% CI, −0.93 to 2.55], P = 0.4) and vaptans (MD, −1.96 [95% CI, −4.59 to 0.66], P = 0.1) but superior to no treatment (MD, 7.99 [95% CI, 6.25-9.72], P < 0.01). Urea was associated with minor adverse events, with poor palatability being the most common. Limitations: As no randomized controlled trials investigating urea as a treatment for hyponatremia were identified for inclusion, these analyses were based on observational studies. Conclusions: Urea is safe and effective for managing SIADH-induced hyponatremia. These finding suggest that urea may be a useful treatment modality in resource-limited settings or when other treatments are contraindicated or poorly tolerated. Trial Registration: Registered at PROSPERO with study number CRD42024511685.