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

Abstract

Rationale & ObjectiveThe 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 aimed to address these questions. Study DesignThis PRISMA-guided study examined published research across four electronic databases. Study PopulationsPatients with SIADH-related hyponatremia. Selection CriteriaClinical trials and observational studies reporting at least one outcome related to serum sodium concentration, symptom resolution, or adverse effects after oral or nasogastric urea administration. Data ExtractionData extraction was performed independently by two reviewers using a standardized form recording study characteristics, participant demographics, intervention details, and treatment outcomes. Analytical ApproachA 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 to other treatment modalities. Subgroup analyses were conducted based on treatment duration and SIADH severity. ResultsUrea 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, two, five, seven, and fourteen days, as well as after one 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: -0.93-2.55), p = 0.36) and vaptans [MD = -1.96 (95%CI: -4.59-0.66, p = 0.14) 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 most common. LimitationsAs no RCTs investigating urea as a treatment for hyponatremia were identified for inclusion, these analyses were based on observational studies. ConclusionsUrea 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.