Original Investigation | Nephrology

Use of Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

A Systematic Review
Ralph Wendt, MD; Andrew Z. Fenves, MD; Benjamin P. Geisler, MD, MPH

Abstract Key Points

Question Is urea an effective, safe, and
IMPORTANCE Hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone
inexpensive treatment for patients with
(SIADH) are associated with significant mortality and morbidity. The effectiveness and safety of oral
the syndrome of inappropriate secretion
urea for SIADH are still debated.
of antidiuretic hormone (SIADH)?

OBJECTIVE To evaluate the efficacy and safety of urea for the treatment of SIADH. Findings This systematic review of 23
studies involving 537 patients with
EVIDENCE REVIEW A systematic search of Medline and Embase was conducted for controlled and SIADH, of which 462 were treated with
uncontrolled studies of urea for SIADH in adult patients. The primary outcome was serum sodium urea, found that while there is no
concentration after treatment. Secondary outcomes included the proportion of patients with definitive evidence from randomized
osmotic demyelination syndrome (ODS), intracranial pressure, and resource use such as length clinical trials, the available lower-quality
of stay. evidence suggests that urea may be an
effective treatment option. Urea was
FINDINGS Twenty-three studies involving 537 patients with SIADH were included, of which 462 found to increase serum sodium levels
were treated with urea. The pooled mean baseline serum sodium was 125.0 mmol/L (95% CI, 122.6- with a very low risk of overcorrection
127.5 mmol/L). The median treatment duration with oral urea was 5 days. Urea increased serum and infrequently reported adverse
sodium concentration by a mean of 9.6 mmol/L (95% CI, 7.5-11.7 mmol/L). The mean increase in effects, primarily dysgeusia (distorted
serum sodium after 24 hours was 4.9 mmol/L (95% CI, 0.5-9.3 mmol/L). Adverse events were few, sense of taste).
mainly consisting of distaste or dysgeusia, and no case of ODS was reported. Resource use was too
Meaning These results suggest that,
infrequently reported to be synthesized.
while definitive evidence from
randomized controlled trials is currently
CONCLUSIONS AND RELEVANCE In this systematic review of the use of urea in SIADH and despite
lacking, data from previous studies
the lack of randomized clinical trials, lower-quality evidence was identified that suggests that urea
support the hypothesis that urea might
may be an effective, safe, and inexpensive treatment modality that warrants further exploration.
be an effective, safe, and inexpensive
treatment option for patients
JAMA Network Open. 2023;6(10):e2340313. doi:10.1001/jamanetworkopen.2023.40313
with SIADH.

Introduction + Supplemental content

Hyponatremia, a common electrolyte disorder among hospitalized patients, is associated with Author affiliations and article information are
1 listed at the end of this article.
increased mortality. Depending on the serum sodium level and the acuity, clinical presentations may
include gait disturbance or various degrees of neurocognitive impairments.2 A common etiology for
hyponatremia is the syndrome of inappropriate secretion of antidiuretic hormone (SIADH).3 The
therapy for patients with hyponatremia due to SIADH depends on the severity of the hyponatremia
and the clinical condition of the patient.
Although urea is not commonly used for SIADH treatment worldwide, it was recommended for
this purpose in a 2014 joint guideline on diagnosis and treatment of hyponatremia by the European
Renal Association–European Dialysis and Transplant Association, the European Society of Intensive
Care Medicine, and the European Society of Endocrinology.4 However, this recommendation was
classified as weak and was based on the lowest level of evidence (ie, grade D).

Open Access. This is an open access article distributed under the terms of the CC-BY License.

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 JAMA Network Open | Nephrology Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

We therefore aimed to systematically review the currently available evidence for or against urea
for hyponatremia from SIADH. Specifically, our objectives were to systematically review the
effectiveness of urea vs vaptan receptor antagonists (VRAs) in terms of increasing the plasma sodium
concentration of patients with SIADH, the safety of urea vs all other treatment regarding the
incidence of osmotic demyelination syndrome (ODS), the cost of illness of SIADH and specifically the
in-hospital resource utilization including length of stay, intensive care unit usage, specialist
consultations, number or frequency of blood draws, and cost of prescription drugs. Additionally, we
sought to compare the effectiveness of urea against treatments other than VRAs, including
supportive measures such as treating the underlying disease, fluid restriction, sodium administration
with or without a loop diuretic, and the use of demeclocycline or lithium.

Methods
Overview
We conducted a systematic review of the medical literature using Medline and Embase. The results
from searches of previous studies were processed in the cloud software Covidence (Veritas Health
Innovation Ltd). Our objective was to identify and critically evaluate all available studies on urea for
hyponatremia resulting from presumed SIADH, including lower-quality evidence such as case series,
retrospective, and uncontrolled studies. Although it was not feasible to compare the effect of urea
vs a control group (eg, VRAs) via meta-analysis, we pooled the average observed effect of urea on
serum sodium, weighted by study size. Lastly, we calculated the sample size for a trial comparing urea
with another treatment. We followed the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses (PRISMA) reporting guideline. The protocol for the systematic review was
preregistered in PROPSERO (CRD42021213569).

Search Strategy
We conducted our search on 2 databases: the Index Medicus subset within Medline (via the search
interface Entrez PubMed) and Embase (via Embase.com). Medline searches also included PubMed
Central and related databases. Search terms included combinations of medical subject headings or
Emtree terms and other relevant key words (eMethods and eTables 1-4 in Supplement 1). The original
search was conducted on October 10, 2019, and we ran a search update on September 7, 2022.
Additionally, we conducted a gray search by going through review articles for trials not found through
these studies and conducting web searches.

Inclusion and Exclusion Criteria

We included full-length manuscripts, research letters and brief reports, and abstracts and conference
proceedings in English, French, or German in which treatment options studied included oral urea.
The patient cohort or subgroup had to consist of only (or had to be close to 100%) patients with
hyponatremia and a presumed etiology of SIADH. Any or no comparator were acceptable. End points
had to include 1 or more of the following: plasma or serum sodium level; ODS; and resource use, eg,
length of stay or costs (or components of either). Identified reviews of urea treatment for
hyponatremia were searched for references of original studies. We operationalized the following
exclusion criteria for the counts in the PRISMA chart with the short descriptor mentioned in bracket:
a manuscript in a language other than English, French, or German (“wrong language”); one of the
treatments did not consist of only (or close to 100%) patients with hyponatremia with a presumed
etiology of SIADH (“wrong treatment”); a patient cohort or subgroup that did not consist of only (or
close to 100%) patients with hyponatremia who had a presumed etiology of SIADH (“wrong
patients”); and/or none of the end points match our designated end point (“wrong outcomes”).

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 JAMA Network Open | Nephrology Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Data Analysis
We extracted characteristics about the studies—such as study type—as well as about the setting, the
patient population, the urea dose (as well as comparator treatments, if applicable), baseline sodium
and sodium levels after treatment, as well as resources used, such as length of hospital stay, and
treatment length. We arbitrarily defined long-term treatment as mean treatment time measured by
months. In terms of quantitative synthesis, we attempted a random-effects meta-analysis. However,
since there was no one or more uniform treatment available as control group (most studies were
uncontrolled), we decided to pool the effects of urea and other treatments, as available, on the
sodium level, weighted by sample sizes of the studies. We also calculated the sample size of a
potential prospective study that would compare urea with VRAs as well as another one comparing
with fluid restriction, assuming a 2-sided α-level of .05 and a power of 80%. Analyses were
performed in Excel (Microsoft Corporation) and STATA/SE version 17.0 (Stata Corp).

Results
In Medline and PubMed, the systematic search identified 330 database entries during the initial run
and 29 entries during the update. In Embase, 819 and 278 entries, respectively, were identified. After
removing 223 duplicates, there were 1235 records to screen. Of these, 1157 records were excluded
based on screening titles and abstracts. For all of the remaining 78 records, full texts were retrieved
and evaluated. Removing a further 55 records according to our exclusion criteria left us with 23
studies that fulfilled our inclusion but not our exclusion criteria (Figure).
The 23 studies included in our systematic search enrolled 662 participants, of whom 537 had
SIADH and 462 had SIADH and were treated with urea (Table 1; eFigures 1-3 in Supplement 1). The
median (IQR) number of patients treated with urea was 12 (1-36). There were no randomized clinical
trials. Only 2 studies were prospective trials,5,6 20 studies7-26 were retrospective trials, and in 1

Figure. PRISMA Chart

1456 Records identified

359 MEDLINE/PubMed (29 during
the search update)
1097 Embase (278 during the
search update)

223 Duplicate records removed

before screening

1235 Records screened

1157 Records excluded

78 Records sought for retrieval

0 Records not retrieved

78 Records assessed for eligibility

55 Records excluded
13 Wrong intervention
3 Wrong patient population
4 Wrong indication
1 Wrong end points
1 Wrong language
7 Editorial/opinion
22 Review
4 Abstract of a study published
later in full text

23 Studies included in review

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 JAMA Network Open | Nephrology Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Table 1. Study and Patient Characteristics

Baseline urine Urea dose, Primary and
No. of Setting and cohort Follow-up Baseline sodium, osmolality, g/kg body secondary end
Source participantsa Study type description time mmol/L mOsmol/kg weight points
Annoni et al,10 40 Retrospective Belgium; neurosurgical 0.5 d 133 NR Mean, 57 g/d Intracranial
2017 patients with SIADH pressure
Berkman et al,24 152 (27/5) Retrospective Australia (2016); 152 15.1 d Median (IQR) in Median (IQR), 331 Range, 15-90 Accuracy of
2018 patients with the euvolemic (234-501) in the g/d diagnosis,
hyponatremia; 27 with subgroup, 124 euvolemic subgroup management
SIADH, with 5 receiving (121-125) strategy, change in
urea treatment after fluid serum sodium and
restriction failed patient outcomes
Coussement 24 Retrospective France (2000-2010); 5d 125 (6) Mean (SD), 537 Median, 45 Time course of
et al,18 2012 patients with SIADH (159) g/d serum sodium
patients in ICU setting, 18
of 24 patients with a
neurological cause
Decaux et al,20 85 Retrospective Belgium; 50 patients in 2d Mild Mean (SD), 587 46 (25) g/d NR
2010 ICU with SIADH with mild hyponatremia, 128 (153)
hyponatremia, 35 patients (4); severe
with SIADH with severe hyponatremia, 111
hyponatremia (3)
Decaux et al,19 1 Case report Belgium (1978); SIADH 14 d 121 500 Days 1 and 2, Change in serum
1980 secondary to cancer 15 g; day ≥3, sodium
30 g
Decaux et al,23 20 Retrospective Belgium (2011-2016); >360 d Patients receiving Patients receiving 8 Patients, Change in serum
2018 patients with chronic 15 g, 127.5 (3.0); 15 g, 340; receiving 15 g; sodium
SIADH patients receiving 30 g urea, 595 12 patients,
30 g, 126 (2) 30 g
Decaux et al,26 7 Retrospective Belgium (1978-1981); 7d 115 (6) Mean (SD), 514 30 g/d NR
1981 SIADH (79)
Decaux et al,8 1 Case report Belgium; SIADH >5 y 120 NR 30 g/d NR
1993
Gomez-Antunez 3 Retrospective Portugal; internal >6 d Range, 120-129 NR Range, 15-60 NR
et al,25 2013 medicine unit g/d
Gómez Valbuena 1 Case report Spain; internal medicine 48 d 108 NR 30 g/d NR
et al,21 2013 unit
Lindner et al,22 1 Case report Switzerland (2021); 11 d 110 412 30-45 g/d Serum sodium
2021 in-hospital setting
Lockett et al,13 69 Retrospective Australia (2015-2017); 3d Median (IQR): Median (IQR), 551 Unclear Patients achieving a
2019 tertiary care center nadir sodium, 122 (422-724) serum sodium ≥130
(118-126); initial mmol/L at 72 h
sodium 127
(122-128)
Maria Belen 13 (13/6) Retrospective Spain (2016); patients 15 (7-147) 123 NR Range, 15-30 Effectiveness and
et al,11 2019 with symptomatic SIADH g/d safety of
in a tertiary care center: 6 treatments
treated with urea, 7
treated with VRA during
hospitalization
Mena- Martín 1 Case report Spain; outpatients with 7d Nadir sodium, 117; 560 15 g/d NR
et al,12 2020 SIADH secondary to baseline sodium,
amyotrophic lateral 127
sclerosis
Matthews 1 Case report US; SIADH secondary to 29 d 122 NR NR NR
et al,17 2020 subdural hemorrhage,
postacute care setting
Nervo et al,15 36 Retrospective Italy (2013-2018); cancer 60 d 123 (4) Mean (SD), 452 Range, 15-60 Mean serum sodium
2019 patients with SIADH (174) g/d; mean increase after 24 h
(SD), 38.8 and prevalence of
(14.1) g/d eunatremia within
14, 30, and 60 d of
treatment
Perelló- 48 Retrospective Spain (2015-2021); 2.95 (6.29) Nadir sodium, Mean (SD), Mean Range, 15-45 Pre-posttreatment
Camacho et al,9 tertiary care center mo 119.8 (5.0); (SD), 395.7 (128.5) g/d serum sodium
2022 baseline sodium,
125.6 (4.1)
Perez et al,27 33 Unclear Spain (2019); tertiary care 9 mo 125 (4) NR NR Serum sodium level
2020 center before treatment
with urea at 24 h,
48 h, 14 d, and
60 d
Pierrakos 42 Retrospective Belgium (2003-2008); NR 127 (2) Mean (SD), 498 50 g/d NR
et al,14 2012 SIADH secondary to (125) (range,
spontaneous subarachnoid 40-60 g/d)
hemorrhage in an ICU

(continued)

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 JAMA Network Open | Nephrology Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Table 1. Study and Patient Characteristics (continued)

Baseline urine Urea dose, Primary and
No. of Setting and cohort Follow-up Baseline sodium, osmolality, g/kg body secondary end
Source participantsa Study type description time mmol/L mOsmol/kg weight points
Rondon-Berrios 58 (58/12) Retrospective US (2016-2017); Median Patients treated Median (IQR), 365 7.5-90 g/d Changes in plasma
et al,16 2018 subgroup of 12 patients (IQR), 4.5 d with urea only, (361-561) sodium at 24 h and
who received urea as the (3-8 d) 125 (122-127) the end of therapy
sole drug therapy as well as the
proportion of
patients who
achieved plasma
sodium ≥135 meq/L
Sejpal et al,7 1 Case report US; SIADH secondary to NR 122 627 15 g/d for 5 d NR
2022 neuroborreliosis
Soupart et al,6 13 Prospective Belgium (2007-2009); 2y Before VRA, 125 Mean (SD), 487 15-30 g/d Serum sodium level
2012 long-term study prospective, long-term (3); before urea, (162)
study in patients with 126 (5)
chronic SIADH
Woudstra et al,5 13 Prospective case Netherlands (2017-2019); Median 124 (range, Median (IQR), 553 Range, 0.25- Proportion of
2020 series hospitalized patients with (IQR), 5 122-128) (478.5-743) 0.50 g/kg/d, patients reaching
SIADH (2-10) d 1 daily dose normonatremia
except for
doses >40
g/d
a
Abbreviations: ICU, intensive care unit; NR, not reported; SIADH, syndrome of The numbers in brackets refer to the subgroups of patients, if applicable, with SIADH
inappropriate secretion of antidiuretic hormone; VRA, vaptan receptor antagonist. (first number) and with SIADH treated with urea (second number).

study27 the design was clearly stated. For 8 studies, only abstracts were published.11,12,17,21,25,27 All
studies investigated orally taken urea. In 3 studies, urea was also given by nasogastric tube.10,14,20
Most studies had a recommendation for fluid restriction while treating with urea, in 5 studies fluid
restriction was not mentioned10-12,21,27 and in 5 studies not recommended.9,14,15,20,25 Four studies
compared urea treatment with vaptans as comparator.6,11,16,21 Seven studies (30%) were case
reports7,8,12,17,19,21,22 of treatment of an SIADH patient with urea. Ten studies reported more than 20
patients with urea treatment for SIADH9,10,13-16,18,20,23,27 with a mean (SD) of 47.1 (20.2) patients.
The majority of studies included patients with a mean baseline serum sodium of 120 mmol/L or
higher or below 130 mmol/L at the start of urea treatment (Table 1; eFigure 4 in Supplement 1). Three
studies analyzed patients with serum sodium concentration below 120 mmol/L at baseline21,22,28
with 2 studies including patients with serum sodium baseline concentrations 110 mmol/L or
lower.21,22 One study included patients with SIADH who had mild hyponatremia with a mean serum
sodium concentration at treatment start of 133 mmol/L.10 The pooled mean baseline sodium was
125.0 (95% CI, 122.6-127.5) mmol/L.
All studies reported treatment effects of urea with the main outcome being increase in serum
sodium or percentage of sodium normalization (Table 2; eFigures 5 and 6 in Supplement 1). The
median (IQR) treatment duration, weighted by sample size, was 5 (2-90) days. Five studies
investigated long-term treatment effects of urea in SIADH.6,9,15,23,27 Urea, again weighed by sample
size, increased the serum sodium by a mean of 9.6 mmol/L (95% CI, 7.5-11.7 mmol/L) whereas VRAs
increased it by 10.5 mmol/L (95% CI, 7.6-13.3 mmol/L) and fluid restriction by 7.8 mmol/L (95% CI,
−9.8 to 25.5 mmol/L). There was only 1 study that reported the course of serum sodium with no
treatment,24 and the change in serum sodium was zero. The first significant change in serum sodium
with urea occurred within a median of 1 day. The mean increase in serum sodium after the first 24
hours was 4.9 mmol/L (95% CI, 0.5-9.3 mmol/L).
Urea was well tolerated with only a few studies reporting adverse events, mainly consisting of
distaste and or dysgeusia. Additionally, nausea, gastroesophageal reflux, and hypernatremia were
reported in few cases. In a small subset of patients, gustative intolerance led to refusal to take urea or
to interruption of drug intake.5,9,15,16,23 There were no cases of ODS in SIADH patients with urea
treatment. Only 1 study reported overcorrection of serum sodium (an increase of more than 12
mmol/L in 24 hours) with urea treatment without clinical deterioration.14 In this study patients with

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Table 2. Efficacy and Safety Results
JAMA Network Open. 2023;6(10):e2340313. doi:10.1001/jamanetworkopen.2023.40313 (Reprinted)

Baseline and/or
nadir sodium, Final sodium, First significant and Length of stay;
Source mmol/L mmol/L maximum increase Sodium change/d Other efficacy results Safety or adverse events resource use Study conclusion
10
Annoni et al, 133 141 First day >12 h, 8 Median intracranial NR NR Patients with acute brain
2017 pressure decrease, 14 to injury and hyponatremia
11 mm Hg treated with urea had
significant decrease in
intracranial pressure,
independent of changes in
plasma sodium
concentrations
Berkman et al,24 Median (IQR): urea, Median: urea, 13.5; 24-48 h (day 2) 0-24 h: urea, 2.5; fluid NR No ODS; serious adverse NR Treatment associated with
2018 124 (120-125); fluid restriction, 7; restriction, 2.5; 24-48 events (3/5 patients) improvement in serum
fluid restriction, no treatment, 0 h: urea, 4; fluid included unpleasant taste, sodium for nonresponsive or
123 (119-125) restriction, 2-5; 38-72 nausea, and reflux restricted patients;
h: urea, 3; fluid hypertonic (3%) saline
restriction, 0 considered treatment of
choice for severe
symptomatic hyponatraemia
but with careful monitoring
Coussement 125 (6) 136.2 (4.1) (fourth 2 d (second day of 2 d, 6.6 mmol/L; 4 d, NR NR NR Urea administration appears
et al,18 2012 day of treatment) treatment: mean 11.4 mmol/L useful for the treatment of
[SD] sodium, 131.4 SIADH-associated
[3.5] mmol/L) hyponatremia in critically ill
patients
Decaux et al,20 Mild group, 128 Mild, 136 (5); Mild, 2 d; severe, 4; 11 Hyponatremia recurred in Mild: 7 patients developed Mean total urea Urea is a simple and
2010 (4); severe group, severe, 122 (4) 1d 6 patients with moderate hypernatremia (maximum, duration, 6 d inexpensive therapy to treat
111 (3) hyponatremia when urea 155); severe: serum sodium (range, 2-42 d) euvolemic hyponatremia in
was stopped increased >12 mmol/L after the ICU
1 d in 12 patients and
>18mmol/L/48 h in 13
patients; no ODS developed;
7 patients developed
hypokalemia (range, 2.3-3.4
mmol/L)

Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

Decaux et al,19 121 133 NR Day 1, 5 mmol/L; day 2, NR NR NR Urea is a valid treatment of
1980 1 mmol/L; day 3, 3 SIADH, particularly among
mmol/L patients with acute
hyponatremia
Decaux et al,23 128 (3) in 8 136 (1) in 8 patients NR NR All patients normalized Gustative intolerance in 2 NR Urine osmolality is accurate
2018 patients with 15 g with 15 g urea; 136 their serum sodium with patients, continued urea with estimating the response to
urea; 126 (2) in 12 (2) in 12 patients urea and mild water addition of NaHCO3, sucrose mild water restriction,
patients with 30 g with 30 g urea restriction and citric acid to urea acceptable in the long-term;
urea solution, no case of however, small doses of urea
hypernatremia reported could likely patients with low
solute intake and high urine
osmolality.
Decaux et al,26 115 (6) 136 (3.5) NR NR NR NR NR Urea is a safe and efficacious
1981 treatment for SIADH
Decaux et al,8 120 >130 NR NR NR NR NR Oral urea, even during long
1993 periods, is a safe and
effective therapeutic
approach for patients with
October 30, 2023

chronic SIADH, not

controlled
Gomez-Antunez Range: 120-129 >130 Total patients NR NR All patients responded to Increase in blood urea levels NR Urea is an efficient and safe
et al,25 2013 after 6 (5-7) days of treatment in 1 patient method to manage
treatment hyponatremia that can be
well tolerated and can help
avoid fluid restriction
6/12

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JAMA Network Open | Nephrology

Table 2. Efficacy and Safety Results (continued)
JAMA Network Open. 2023;6(10):e2340313. doi:10.1001/jamanetworkopen.2023.40313 (Reprinted)

Baseline and/or
nadir sodium, Final sodium, First significant and Length of stay;
Source mmol/L mmol/L maximum increase Sodium change/d Other efficacy results Safety or adverse events resource use Study conclusion
Gómez Valbuena 108 Urea, 134; tolvaptan, NR No parallel groups, 1 NR NR Daily costs Use of urea as alternative
et al,21 2013 130, fluid restriction, patient, consecutively €33.5-€69 per d treatment therapy tolvaptan
120 treatment with with tolvaptan and in SIADH can get the same
tolvaptan and then urea; €0.30 per d for result that tolvaptan in
change in sodium, 4.6 urea costs normalization of serum
mmol/L sodium, a markedly lower
cost
Lindner et al,22 110 133 (At discharge); NR NR NR 0 6d Vaccination against SARS-
2021 139 (5 d after CoV-2 triggered SIADH
discharge with
continuing urea
treatment)
Lockett et al,13 Median (IQR): NR NR NR Fluid restriction as first- 22.7% With distaste; 0 NR Urea is safe and effective in
2019 initial, 127 (122- line treatment, 65.4%; overcorrections fluid restriction-refractory
128); nadir, 122 urea as first-line hyponatraemia;
(118- 126) treatment, 21.8% and recommended starting dose
second line in 78.2% of urea ≥30 g/d in patients
with SIADH and moderate to
profound hyponatraemia
unable to undergo or have
failed fluid restriction
Maria Belen et al,11 123 Urea group, 133; NR Mean (SD) increase in 3 Patients with urea 3 Patients in tolvaptan group NR In SIADH, tolvaptan has
2019 tolvaptan group, 133 sodium in 24 h: urea, achieved eunatremia, 2 with change in sodium >12 shown to be moderately
4.57 (0-8); 9.9 (−3 to patients died; tolvaptan within 1 d effective, but the correction
21) in tolvaptan (in 3 group, 3 patients was too rapid; urea is an
cases >12 mEq/L in 24 eunatremic, 3 deaths (due alternative of moderate
h) to complications of the efficacy but safer, allowing
underlying diseases) its ambulatory use
Mena- Martín Nadir, 117; 136 At day 7 of NR NR NR NR Outpatient In patients with SIADH, urea
et al,12 2020 baseline at start of treatment administration increases the
treatment, 127 urinary excretion of solutes

Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

and water, significantly
raising sodium levels
Matthews et al,17 122 133 (Day 4 after Sodium after 48 h, NR NR NR NR Dangerously low sodium
2020 treatment with urea) 128 mmol/L level successfully treated
with urea; during treatment,
the patient was able to
continue his rehabilitation
amidst an intricate medical
course
Nervo et al,15 123 (4) 128 (4) after 24 h Sodium increase in NR 55.6% With eunatremia 10 Patients interrupted urea NR Urea was effective in
2019 24 h, 5 (3) mmol/L after 14 d of treatment; treatment, 5 because of rapid correcting chronic
86.1% after 30 d; 91.7% tumor progression, 5 because hyponatremia among cancer
after 60 d; no of drug taste patients with SIADH; almost
overcorrection in any all patients reached
patient eunatremia within 1 mo, and
was well tolerated
Perelló-Camacho Nadir, 119.8 (5.0); 134.4 (4.9) Sodium levels: day NR NR Mild digestive Cost reduction, Urea shown to be safe and
et al,9 2022 treatment start, 1, 129 mmol/L; day symptomatology, 2 patients; 87.9% vs cost-effective treatment
125.6 (4.1) 7, 133.3 (4.9) refused based on palatability, treatment with option for hyponatremia
October 30, 2023

2 patients tolvaptan caused by SIADH

Perez et al,27 125 (4) After 14 d and 60 d, 24 h, 127 (5); 48 h, NR NR NR NR No significant differences in
2020 134 (4) 129 (5) plasma sodium values before
and after urea treatment

(continued)
7/12
 Table 2. Efficacy and Safety Results (continued)
Baseline and/or
nadir sodium, Final sodium, First significant and Length of stay;
Source mmol/L mmol/L maximum increase Sodium change/d Other efficacy results Safety or adverse events resource use Study conclusion
Pierrakos et al,14 127 (2) Total NR; all patients 3 mmol/L (1-6) 3 mmol/L (1-6) increase Hyponatremia reversed in No gastrointestinal or NR Urea effective for SIADH-
2012 became eunatremic increase in <24 h in <24h all patients, plasma sodium hemodynamic adverse related hyponatremia in
at median 3 d of urea returning to >130 and 135 effects; sodium increased patients with SAH; urea
treatment mEq/L after a median ≥12 mEq/L during the first generally well tolerated
(IQR) 1 and 3 d, day of therapy in 4 patients,
respectively; median (IQR) withou clinical deterioration;
sodium increase: day 1, 3 2 patients developed
mEq/L (1-6); day 2, 5 transient hypernatremia
(3-10) mEq/L (maximum, 149 mEq/L),
which resolved ≤24 h
Rondon-Berrios Median (IQR) urea- Median (IQR), 131 Median (IQR) <24 Median (IQR) sodium for No difference in change in 2% Discontinued urea, Urea-only treated Urea effective and safe for
JAMA Network Open | Nephrology

et al,16 2018 only patients, 125 (129-136) h, 2.5 (0- 4.5) urea-only patients in 24 plasma sodium between reportedly due to dysgeusia patients vs urea- the treatment of inpatient
(122-127) h: 2.5 mEq/L (0-4.5) vs urea-only treated patients untreated patients: hyponatremia, and well
untreated patients, −0.5 and urea-untreated median (IQR) tolerated
mEq/L (−2.5 to 1.5); patients (median [IQR], 6 length of hospital
P = .04) mEq/L [3.5-10] vs 5.5 stay, urea-treated,
mEq/L [3-7.5]; P = .51); a 6 d [3.5-7] vs
greater proportion of urea untreated, 6 d
only treated patients [4-6] (P = .74)
achieved normal sodium at
the end of therapy
compared with urea-
untreated patients (33% vs
8%; P = .08)
Sejpal et al,7 122 139 NR NR NR NR NR SIADH resolves with
2022 successful treatment of the
underlying Lyme infection as
was seen in our case
Soupart et al,6 Before vaptan, 125 After 1 y: vaptan NR NR NR Hypernatremia in 1 urea NR Urea has efficacy similar to
2012 (3); before urea, group, 135 (3); urea patient without that of vaptans for treatment
126 (5) group, 135 (2) complications of chronic SIADH

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Woudstra et al,5 124 Median (IQR), 135 NR Day 1, 128 (123-130); Normonatremia in 8/13 Urea was discontinued due to NR Urea is an effective second-

JAMA Network Open. 2023;6(10):e2340313. doi:10.1001/jamanetworkopen.2023.40313 (Reprinted)

2020 (130-137) day 2, 130 (127-132); patients (62%) at the end
end of inpatient of in-hospital treatment;
treatment, 135 median serum sodium level
(130-137) at 2 wk follow-up was 134
mmol/L (range, 132-141);
median serum sodium level
at 6-8 wk, 134 mmol/L
(range, 128-140)
nausea after 4 d of therapy in line treatment strategy for
1 patient, 6 patients reported hospitalized patients with
light to moderate intake hyponatraemia due to
difficulties due to the taste of SIADH; distaste and nausea
urea; urea was not were reported adverse
discontinued in these effects in population, but
patients; no overcorrection mostly did not lead to early
was observed discontinuation

Abbreviations: ICU, intensive care unit; NR, not reported; ODS, osmotic demyelination syndrome; SAH, subarachnoid hemorrhage; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

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nontraumatic subarachnoid hemorrhage with mild hyponatremia (mean [SD], 127 [2] mmol/L) were
treated with a mean dose of 50 g urea, mainly via nasogastric tube.
The sample size for a noninferiority trial comparing urea and VRAs could be quite small, maybe
under 10 patients depending on the safety margin. A trial between urea and fluid restriction with a
superiority design would require at least 106 patients if patients were equally distributed between
the 2 groups.

Discussion
We systematically searched previous studies including patients with SIADH who received urea
treatment. In the 23 studies analyzed, 537 patients with SIADH were reported and 462 were treated
with urea as the only therapy. Due to the absence of randomized clinical trials, in particular ones with
adequate sample sizes, there is no definite evidence for the efficiency of urea in the treatment of
hyponatremia in patients with SIADH. However, the available, lower-quality evidence suggests that
urea is an effective treatment option with a very low risk of overcorrection and rarely reported
adverse effects aside from dysgeusia.
In the pooled analysis we present here, urea increased serum sodium by 10.2 mmol/L within the
reported follow-up time and seemed to be as effective in increasing serum sodium concentration as
the VRA tolvaptan (serum sodium increase of 10.4 mmol/L until end of follow up). The rise in serum
sodium starts as early as 24 to 48 hours after treatment initiation. Nearly all reported patients
improved their serum sodium concentration with urea treatment to a level above 130 mmol/L. The
average urea dose in the 23 studies was 15 g to 30 g urea per day with no reported adjustment to
urine osmolality. For context, the dose recommendation in the European guidelines for treatment of
SIADH4 with urea is 0.25 to 0.50 g/kg per day. Urea raises serum sodium by increasing free water
excretion through an osmotic-diuretic mechanism. The amount of free water excretion and therefore
effectiveness of urea depends among others on the applied dose of urea and the urine osmolality.
With increasing urine osmolality, the necessary dose of urea to improve serum sodium is higher. A
practical guideline on dosing of urea in hyponatremia patients with regard to the initial urine
osmolality exists.29 The risk of overcorrection of serum sodium concentration with urea is very low.
Overcorrection is assumed to be a major contributor to the development of ODS even though a
recent work showed only very low incidences of ODS in a large retrospective cohort of patients with
hyponatremia and found no correlation between rapid corrections of serum sodium and ODS.30 Of
note, the incidence was higher in patients with serum sodium below 110 mmol/L and overcorrection
should, in our opinion, still be avoided especially in high-risk patients. The risk for ODS is still a matter
of concern, and especially in patients at higher risk urea might be a safe and effective therapeutic
option. However, in animal models, urea seemed to protect from ODS.31,32 Regarding the most
common adverse effect of urea, dysgeusia, previous studies suggest that taste of urea can be
improved by adding sucrose and citric acid23 or by dissolving urea in sweetened beverages.
In case of severe acute hyponatremia, 3% sodium chloride infusions will most likely remain
standard of care because they have an even more rapid onset of effect and are easy to titrate.
However, in the outpatient setting, in hospitalized patients with less severe and less acute
hyponatremia, and in patients with triggers that are not easy to control such as psychotropic
medications, urea could be a safe and effective treatment option at low costs. Importantly, a dose-
effect relationship of urea on free water excretion may be present which is dependent on urinary
osmolality. Randomized clinical trials against the criterion standard of 3% sodium chloride infusions
in acute hyponatremia from SIADH or VRA in chronic SIADH would be needed to further evaluate to
potential role of urea in the treatment of hyponatremia in SIADH.

Limitations
There were several limitations to this systematic review. First, evidence from randomized clinical
trials does not exist and few studies even have control groups. In addition to confounding by

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 JAMA Network Open | Nephrology Urea for the Syndrome of Inappropriate Secretion of Antidiuretic Hormone

indication for urea therapy, it is very likely that publication bias was also present since we only
identified trials with positive treatment effects. Also, there was inconsistent handling of fluid
restriction. Finally, treatment of the trigger situation (eg, infection, pain, brain trauma) itself can
improve serum sodium concentration in SIADH patients and in uncontrolled trials this effect cannot
be separated.

Conclusions
In this systematic review, there was no definite evidence regarding urea as a treatment for SIADH.
Randomized clinical trials would be necessary to prove the efficacy of urea for this indication.
However, the data identified in this systematic review support the hypothesis that urea might be an
effective, safe, and inexpensive treatment option for patients with SIADH.

ARTICLE INFORMATION
Accepted for Publication: September 18, 2023.
Published: October 30, 2023. doi:10.1001/jamanetworkopen.2023.40313
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2023 Wendt R
et al. JAMA Network Open.
Corresponding Author: Ralph Wendt, MD, St Georg Hospital, Delitzscher Str. 141, 04129 Leipzig, Germany (ralph.
wendt@sanktgeorg.de).
Author Affiliations: Department of Nephrology, St Georg Hospital, Leipzig, Germany (Wendt); Department of
Medicine, Massachusetts General Hospital/Harvard Medical School, Boston (Fenves, Geisler).
Author Contributions: Drs Wendt and Geisler had full access to all of the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis.
Concept and design: Wendt, Geisler.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Wendt, Geisler.
Critical review of the manuscript for important intellectual content: All authors.
Statistical analysis: Wendt, Geisler.
Administrative, technical, or material support: Wendt, Geisler.
Supervision: All authors.
Conflict of Interest Disclosures: Dr Geisler reported personal fees from GlaxoSmithKline plc and UpToDate, Inc
outside the submitted work. No other disclosures were reported.
Data Sharing Statement: See Supplement 2.

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SUPPLEMENT 1.
eMethods.
eTable 1. Original Search Strategy in Medline
eTable 2. Original Search Strategy in Embase
eTable 3. Search Strategy for the Update in Medline
eTable 4. Search Strategy for the Update in Embase
eFigure 1. Bar Chart of the Number of Subjects
eFigure 2. Histogram of the Number of Subjects
eFigure 3. Box and Whisker Plot of the Follow-up Time
eFigure 4. Box and Whisker Plot of the Baseline Sodium
eFigure 5. Box and Whisker Plot of the Final Sodium in the Urea Group
eFigure 6. Box and Whisker Plot of the Change (Delta) in Sodium

SUPPLEMENT 2.
Data Sharing Statement

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