What is the efficacy of urea for hyponatremia?

Comment by InpharmD Researcher

Literature on the use of urea for hyponatremia are limited to observational studies, with most patients experiencing syndrome of inappropriate antidiuretic hormone secretion (SIADH). While data shows urea works as an osmotic diuretic to increase serum sodium concentrations, authors suggest the observed increases may not be clinically significant even though they are statistically significant from baseline.

Background

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]

References:

[1] Rondon-Berrios H. Urea for chronic hyponatremia. Blood Purif. 2020;49(1-2):212-218. doi:10.1159/000503773
[2] Hoorn EJ, Spasovski G. Recent developments in the management of acute and chronic hyponatremia. Curr Opin Nephrol Hypertens. 2019;28(5):424-432. doi:10.1097/MNH.0000000000000528
[3] Adrogué HJ, Tucker BM, Madias NE. Diagnosis and Management of Hyponatremia: A Review. JAMA. 2022;328(3):280–291. doi:10.1001/jama.2022.11176
[4] Wendt R, Fenves AZ, Geisler BP. Use of Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone: A Systematic Review. JAMA Netw Open. 2023;6(10):e2340313. doi:10.1001/jamanetworkopen.2023.40313

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the efficacy of urea for hyponatremia?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

Urea for the Treatment of Hyponatremia

Design

Retrospective, multicenter, observational, cohort study

N= 58

Objective

To examine the effectiveness, safety, and tolerability of urea for the treatment of inpatient hyponatremia

Study Groups

Urea (N= 58)

Inclusion Criteria

Admitted to one of 4 adult hospitals; diagnosed with hyponatremia (plasma sodium <135 mEq/L) at the time of admission or during their hospitalization; received one or more doses of oral urea during hospitalization

Exclusion Criteria

None described

Methods

This was a retrospective study involving one health system in Pennsylvania (4 hospitals). Patients with hyponatremia who received urea were identified for inclusion. Patients who received urea as the only drug for hyponatremia were matched to other patients during the admission dates who did not receive urea.

Duration

July 2016 to August 2017

Outcome Measures

Plasma sodium concentrations

Baseline Characteristics

 

Urea (N= 58)

 

Age, years (IQR)

68 (55-79)  

Male

60.3%  

Hyponatremia etiology

SIADH

Thiazide diuretics

Heart failure

Hypovolemia

Kidney disease

Adrenal insufficiency

Cirrhosis

 

81%

12%

10%

10%

7%

3%

2%

 

Other therapies for hyponatremia

Fluid restriction

Sodium chloride tablets

Loop diuretics

Normal saline

Vasopressin antagonist

Hypertonic saline

 

88%

38%

33%

21%

10%

7%

 
Urea was administered at a dose ranging from 7.5 to 90 g/d for a median duration of 4.5 days (IQR, 3-8). 
IQR: interquartile range; SIADH: syndrome of inappropriate antidiuretic hormone secretion

Results

Endpoint

Urea (N= 58)

p-value

Plasma sodium, mEq/L (IQR)

Baseline

End of therapy

 

124 mEq/L (122-126)

131 mEq/L (127-134)

<0.001

Only 12 patients received only urea for SAIDH, and they were compared to 12 other patients who did not receive urea. Among urea only–treated patients, plasma sodium increased by 2.5 mEq/L (IQR, 0-4.5) over the first 24 hours of therapy (p= 0.02) and from a baseline of 125 mEq/L (IQR, 122-127) to 131 mEq/L (IQR, 129-136) at the end of urea therapy (p= 0.001). Compared to urea-untreated patients, the increase in serum sodium during the first 24 hours was significant (2.5 mEq/L vs -0.5 mEq/L; p= 0.04).

A greater proportion of urea only-treated patients achieved normonatremia, but this was not significantly significant (33% vs 8%; p= 0.08).

Adverse Events

One patient discontinued urea due to dysguesia. No other adverse events were noted or reported. No patients experienced overly rapid correction of plasma sodium.

Study Author Conclusions

Oral urea, now available in the United States, seems to be effective for the treatment of inpatient hyponatremia and that it is safe and well tolerated. Randomized trials that assess the efficacy, safety, tolerability, and costs of this preparation of urea in larger numbers of hospitalized and ambulatory patients are needed to establish the precise therapeutic role of this agent for the management of hyponatremia.

InpharmD Researcher Critique

Limitations of this study include the small sample size and retrospective nature from one health system. There was lack of a definitive comparison group, with the authors not evaluating patients treated when urea was not available. The only comparison made was an even smaller sample size and exclusive to SIADH. 



References:

Rondon-Berrios H, Tandukar S, Mor MK, et al. Urea for the Treatment of Hyponatremia. Clin J Am Soc Nephrol. 2018;13(11):1627-1632. doi:10.2215/CJN.04020318

 

Safety and Efficacy of Urea for Hyponatremia

Design

Retrospective, single-center, observational, cohort study

N= 74

Objective

To evaluate the safety and efficacy of urea in the treatment of hyponatremia

Study Groups

Urea (n= 74)

Inclusion Criteria

Adult inpatients who received at least 1 dose of urea while hospitalized

Exclusion Criteria

Patients taking urea prior to hospitalization

Methods

This was a retrospective study from a single center in Ohio. Admitted patients with hyponatremia were given urea at a standard dose of 15 mg BID along with erum sodium collection every 12 hours. Notably, the clinicians could use different urea dosing and/or more frequent serum sodium monitoring.

Duration

October 2018 to November 2019

Outcome Measures

Serum sodium level changes

Baseline Characteristics

 

Urea (n= 74)

Age, years (IQR)

67 (60-80)

Male

54%

Length of stay, days

15 ± 15

Hyponatremia etiology

SIADH

Heart Failure

Cirrhosis

Chronic Kindey Disease

Unknown

 

59%

3%

1%

1%

20%

Hyponatremia treatment

Urea alone (monotherapy)

Normal saline infusion

Sodium chloride tablets

Hypertonic saline infusion

Loop diuretics

 

53%

26%

16%

7%

7%

IQR: interquartile range; SAIDH: syndrome of inappropriate antidiuretic hormone secretion

Results

The median serum sodium increased by 2 mEq/L (IQR, 0-4 mEq/L) per day after urea administration. A significant difference in serum sodium was observed between baseline and discharge or discontinuation (124.2 ± 4 vs 130.1 ± 5.1; p< 0.001).

A subgroup analysis comparing patients receiving urea monotherapy (n= 39) to those receiving urea with concomitant therapy (n= 35) found no significant differences in mean baseline serum sodium (p= 0.734), 24 hours (p= 0.855), and at discharge or discontinuation (129 ± 4.3 vs 131 ± 5.8; p= 0.230).

Adverse Events

Six (8%) patients experienced serum sodium overcorrection within the initial 48 hours of urea therapy; there were no instances of osmotic demyelination syndrome.

Urea was discontinued in 38 patients; the primary reason was due to palatability reported in 20 patients. Other reasons for discontinuation were serum sodium overcorrection (n = 5), serum sodium normalized (n = 5), ineffective response (n = 3), elevated BUN (n = 2), and anticipated cost barrier upon discharge (n = 1). Additionally, one patient died during therapy and another patient became NPO.

Study Author Conclusions

Urea appears to be an effective treatment for hyponatremia; however, patient tolerance, the rate of serum sodium overcorrection, and outpatient affordability may limit its use.

InpharmD Researcher Critique

This study is limited by the retrospective, single-center design without a comparison group. Results seen showed statistically significant increases in serum sodium; however, the results may not be deemed clinically significant due to small increases and overlapping standard deviations.



References:

Hammonds WM, Keating EA, Smetana ME, Smetana KS, Bond MM. Safety and Efficacy of Urea for Hyponatremia. Hosp Pharm. 2022;57(3):365-369. doi:10.1177/00185787211037548