Urea is presented as an emerging treatment option for chronic hyponatremia. Over 90% of oral urea is absorbed in the upper gastrointestinal tract, with less than 4% reaching the colon where it's metabolized into ammonium by bacterial ureases. Urea distributes in total body water and behaves as an ineffective osmole because it rapidly crosses cell membranes, penetrating muscle tissue and reaching steady-state concentrations within 1 hour. Its permeability across the blood-brain barrier is less, taking up to 10 hours to penetrate brain tissue. Thus, in the brain, urea acts as a partially effective osmole. The half-life of oral urea is about 2 hours, and a dose is excreted in urine within 12 hours. [1], [2], [3]
As an osmotic diuretic, urea works effectively in nephron segments with high water permeability and low urea permeability, such as the connecting tubule, cortical collecting duct, and OMCD. This helps explain urea's ability to increase free water excretion based on the solute excretion dependency. The use of urea in SIADH shows effects on decreasing natriuresis and contributing to a positive sodium balance, which aids in increasing plasma sodium levels. Oral or enteral urea therapy (15-60 g/d) increases the serum sodium level by promoting water diuresis; 30 g of urea (500 mOsm) is associated with 1 L of water excretion when urine osmolality is 500 mOsm/kg. [1], [2], [3]
Preliminary evidence from small case series in Europe has shown the efficacy of oral urea in increasing plasma sodium with minimal side effects. However, these studies often lacked control groups and were based on small patient numbers. In the United States, a novel formulation of oral urea (Ure-Na) became available in 2016, regarded as a medical food by the FDA, thus not requiring a prescription. A study conducted at the University of Pittsburgh Medical Center (Table 1) showed a significant increase in plasma sodium levels in patients treated with urea, supporting its potential efficacy in treating hyponatremia. Additional studies, including one exclusively performed in cancer patients, have also confirmed the efficacy of urea. [1], [2], [3]
A 2023 systematic review evaluated the efficacy and safety of oral urea as a treatment for syndrome of inappropriate antidiuretic hormone secretion (SIADH). The review included 23 studies comprising 537 patients with SIADH, out of which 462 were treated with urea. The findings from these studies suggest that oral urea effectively increases serum sodium concentration, with the pooled mean baseline serum sodium at 125.0 mmol/L and a mean increase of 9.6 mmol/L after treatment. The duration of urea treatment was a median of 5 days, and the increase in serum sodium after the first 24 hours was noted to be 4.9 mmol/L. Adverse events reported were minimal, mainly involving distaste or dysgeusia, and no cases of osmotic demyelination syndrome (ODS) were reported. Data on resource use, such as length of hospital stay, were too infrequently reported to draw conclusions. Despite the absence of randomized clinical trials and the reliance on lower-quality evidence, this review suggests that urea may be an effective, safe, and inexpensive option for managing SIADH, warranting further research. [4]