Circulation Journal

Official Journal of the Japanese Circulation Society

ORIGINAL ARTICLE
http://www. j-circ.or.jp Heart Failure

Urine Osmolality Estimated Using Urine Urea Nitrogen,

Sodium and Creatinine Can Effectively Predict Response
to Tolvaptan in Decompensated Heart Failure Patients
Teruhiko Imamura, MD; Koichiro Kinugawa, MD, PhD; Shun Minatsuki, MD;
Hironori Muraoka, MD; Naoko Kato, PhD; Toshiro Inaba, MD; Hisataka Maki, MD;
Taro Shiga, MD, PhD; Masaru Hatano, MD; Atsushi Yao, MD, PhD;
Shunei Kyo, MD, PhD; Issei Komuro, MD, PhD

Background:  Urine osmolality (U-OSM) is valuable to predict response to tolvaptan (TLV) in decompensated heart
failure patients, but measurement of U-OSM is not always available on site.

Methods and Results:  Data were collected from 66 hospitalized patients with decompensated heart failure who
had received TLV at 3.75–15 mg/day. U-OSM, which was estimated using the following formula: 1.07 × {2 × [(urine
sodium (mEq/L)] + [urine urea nitrogen (mg/dl)] / 2.8 + [urine creatinine (mg/dl)] × 2/3} + 16, was well correlated with the
actual measurement (r=0.938, P<0.001). Criteria consisting of C1 (estimated baseline U-OSM >358 mOsm/L) and
C2 (%decrease in estimated U-OSM >24% at 4–6 h after the first TLV dose) significantly discriminated responders
from non-responders (P<0.05).

Conclusions:  Response to TLV can be predicted using U-OSM, which can be estimated using urine urea nitrogen,
sodium, and creatinine concentration data.   (Circ J 2013; 77: 1208 – 1213)

Key Words: Hyponatremia; Responder; Vasopressin

P
atients with heart failure (HF) have many critical prob-
lems along with disease progression. For example,
severe congestion sometimes results in fatal pulmo-
nary edema and low systemic perfusion eventually results in
multiple organ dysfunction.1 Maximum medical treatment in-
cluding β-blockers, angiotensin-converting enzyme inhibitors
or angiotensin II receptor blockers, or diuretics has not always
resolved the aforementioned problems, especially in severe
cases.2,3 Among them, hyponatremia is often complicated with
severe HF, which is considered to be associated with poor prog-
nosis,4 but no sufficient treatment for hyponatremia has been
established so far.
Recently, vasopressin type 2 (V2) receptor antagonists have
been developed, and one of these drugs, tolvaptan (TLV), is
available for HF patients with hyponatremia or symptomatic
congestion.5 TLV has been demonstrated in several studies to
reduce congestion through increased excretion of free water in
urine,6 stabilize hemodynamic state,7 and correct hyponatre-
mia.8,9 We previously reported cases in which TLV could im-
prove hyponatremia without compromising hemodynamics in
stage D HF.10 In the application of TLV in real practice, how-
ever, TLV is ineffective in a certain number of patients with
HF.11 We recently proposed novel criteria consisting of 2 pa-
rameters involving urine osmolality (U-OSM) that can predict
efficacy of TLV in decompensated HF patients: (1) baseline
U-OSM >352 mOsm/L; and (2) % decrease in U-OSM >26%
at 4–6 h after the first dose of TLV.12 Measurement of U-OSM,
however, is not always available in all institutes on site. The
aim of the present study was therefore to estimate U-OSM
using urine biochemical data, which is measurable in almost
all medical facilities, use estimated U-OSM to predict the ef-
ficacy of TLV for decompensated HF patients.
Methods
Estimation of U-OSM Using Urine Biochemical Data
We surveyed urine samples obtained in the early morning just
before use of any medicine including diuretics from 120 pa-
tients (66 with HF; 54 without HF). Fifty-four patients without
HF were admitted to hospital for ischemic heart disease or
arrhythmia between September and October 2012 (mean age,
66.2±13.9 years; male, 74.1%). Sixty-six patients with HF com-
prised the study group. We compared measured U-OSM using
the concentration of various biochemical substances. The con-

Received October 23, 2012; revised manuscript received November 13, 2012; accepted December 12, 2012; released online January 12,
2013   Time for primary review: 19 days
Department of Cardiovascular Medicine (T. Imamura, S.M., H. Muraoka, N.K., T. Inaba, H. Maki, T.S., M.H., A.Y., I.K.), Department of
Therapeutic Strategy for Heart Failure (K.K., S.K.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Mailing address:  Koichiro Kinugawa, MD, PhD, Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine,
University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.   E-mail: kinugawa-tky@umin.ac.jp
ISSN-1346-9843  doi: 10.1253/circj.CJ-12-1328
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.77, May 2013

Estimated U-OSM Predicts Response to TLV
tribution of 3 major substances (ie, sodium, urea nitrogen, and
creatinine) to U-OSM was accommodated as follows:
2   × [urine sodium (mEq/L)] + [urine urea nitrogen (U-UN)
(mg/dl)] / 2.8 + [urine creatinine (U-Cre) (mg/dl)] × 2/3.
A formula to estimate U-OSM was deduced from a regression
analysis between measured U-OSM and the aforementioned
summation of 3 components among 120 patients with/without
HF.
Subjects
We enrolled 66 patients with decompensated HF who had
received TLV 3.75–15 mg/day for more than 1 week between
February 2011 and September 2012 at the University of Tokyo
Hospital. TLV dose was determined by attending physicians,
and was maintained during the study period. All patients were
suffering fluid retention regardless of maximum medical treat-
ment including β-blockers, angiotensin-converting enzyme
inhibitors or angiotensin II receptor blockers unless contrain-
dicated or intolerant. Concomitant use of i.v. drugs such as
human atrial natriuretic peptides, phosphodiesterase III inhibi-
tors, dobutamine, and dopamine as well as furosemide was
continued if any, and the dose was not changed at least 2 days
before TLV and during the study period. Patients with hypo-
volemia, severe systemic infection or inflammation, end-stage
renal failure on hemodialysis, severe valvular disease, and acute
myocardial infarction within 1 month, were excluded from the
present study. During TLV treatment, restriction of water in-
take was relaxed according to weight loss to avoid hypernatre-
mia. All patients were assigned to New York Heart Associa-
tion (NYHA) class III or IV. The study protocol was approved
by the Ethics Committee of Graduate School of Medicine,
University of Tokyo [application number 779 (1)].
Variables Evaluated
Baseline clinical data included demographics, and laboratory
and echocardiographic parameters obtained within <24 h be-
fore TLV dosing. No patient was placed on a urine catheter,
and urine samples were obtained at each time of urination, in
which U-OSM, urine sodium, potassium, urea nitrogen, creati-
nine, and specific gravity (SG) were measured. Baseline urine
Circulation Journal  Vol.77, May 2013
1209
Figure 1.   Relationship between measured urine
osmolality (U-OSM) and summation of 3 osmotic
substances in patients with/without heart failure
(HF). Red bar, regression line: 1.07× (summation
of 3 osmotic substances) +16.
sample was obtained in the early morning just before the first
TLV dose. The second urine sample was obtained at 4–6 h after
the first TLV dose. Urine volume (UV) during the first day (day
1) was compared with that at 1 day before TLV dose (day 0).
Patients whose day 1 UV had increased compared with day 0,
were defined as responders, and the reverse were non-responders.
Statistical Analysis
All statistical analysis was done with PASW Statistics 18
(SPSS, Chicago, IL, USA) and JMP9 (SAS Institute, Cary, NC,
USA). Continuous variables of responders/non-responders were
compared using unpaired t-test or Mann-Whitney test as ap-
propriate. Categorical variables of responders/non-responders
were compared by chi-square test or Fisher’s exact test as
appropriate. To construct categorical variables from continu-
ous data, a cut-off point was obtained from receiver operating
characteristic (ROC) analysis. Comparison among 3 groups
stratified with the new criteria was carried out using analysis
of variance with Tukey’s test. Each demographic parameter of
responders/non-responders was compared by unpaired t-test.
Estimated U-OSM was compared with the measured value
using paired t-test. Unless otherwise specified, all data are
expressed as mean ± SD. Probability was 2-tailed, with P<0.05
regarded as statistically significant.
Results
Measured Urine Osmolality and Urine Biochemical Data
Urine sodium had a weak correlation with measured U-OSM
(r=0.233, P=0.007), whereas U-UN and U-Cre had strong cor-
relations with measured U-OSM (r=0.880 and r=0.665, respec-
tively, both P<0.001). Summation of the 3 urine osmotic sub-
stances had a strong correlation with the measured value, and
the regression line
[ measured U-OSM (mOsm/L)] ~ 1.07 × [summation of 3
urine osmotic substances (mOsm/L)] + 16
was constructed for patients with/without HF (r=0.965, P<0.001;
Figure 1). Therefore, U-OSM was estimated according to this
regression formula. The estimated U-OSM was statistically
indistinguishable from the actual measured U-OSM (366.3±
1210 IMAMURA T et al.

Table.  Subject Characteristics vs. TLV Response

% Increase in UV % Increase in UV
P-value
>0% (n=42) <0% (n=24)
Demographic parameters
   Dose of tolvaptan (mg/day) 6.6±4.0 6.9±4.1 0.795
  Age (years) 51.1±17.6 66.4±21.1 　0.002*
  Male 33 (78.6) 14 (58.3) 0.081
   Body mass index (kg/m2) 22.8±4.0 21.7±2.4　　 0.209
   Etiology of ischemia 6 (14.3) 5 (20.8) 0.359
   Systolic blood pressure (mmHg) 94.2±12.4 99.7±18.4 0.342
Concomitant medication
   Furosemide (mg daily) 57.4±19.9 62.0±47.7 0.652
   Spironolactone (mg daily) 25.1±20.6 22.9±17.9 0.674
   Trichlormethiazide (mg daily) 0.5±1.0 0.4±0.5 0.781
  β-blocker 36 (85.7) 20 (83.3) 0.529
  ACEI/ARB 37 (88.1) 19 (79.2) 0.057
  Catecholamine infusion 17 (40.5) 11 (45.8) 0.672
Laboratory parameters
   Serum sodium (mEq/L) 132.8±6.5　　　　 133.7±6.3　　　　 0.614
   Serum potassium (mEq/L) 4.2±0.4 4.3±0.4 0.341
   Serum BUN (mg/dl) 31.3±15.1 48.6±27.5 　0.002*
   Serum creatinine (mg/dl) 1.3±0.6 2.4±1.4 　0.001*
   Serum albumin (g/dl) 3.5±0.4 3.3±0.6 0.059
   Serum total bilirubin (mg/dl) 1.4±1.3 1.1±0.6 0.058
   Serum osmolality (mOsm/L) 276.1±13.5　　 278.0±10.4　　 0.558
   Plasma arginine vasopressin (pg/ml) 8.2±3.6 11.5±19.0 0.450
   Plasma BNP, log10 pg/ml 2.79±0.47 2.72±0.43 0.578
Urine parameters
   Urine volume on day 0 (ml/day) 1,358±361　　　 1,382±624　　　 0.856
   Urine volume on day 1 (ml/day) 2,232±1,048 1,149±445　　　 　<0.001*　
  U-OSM (mOsm/L) 519.5±156.8 310.0±88.0　　 　<0.001*　
   U-OSM after 4 h (mOsm/L) 284.4±105.7 297.8±80.0　　 0.593
   Estimated U-OSM (mOsm/L) 506.8±152.9 313.4±71.8　　 　<0.001*　
   Estimated U-OSM after 4 h (mOsm/L) 294.6±102.7 292.3±79.3　　 0.925
  U-sodium (mEq/L) 54.6±31.4 55.6±34.4 0.569
   U-sodium after 4 h (mEq/L) 55.6±34.4 51.0±22.4 0.510
  U-potassium (mEq/L) 31.9±15.5 29.7±7.5　　 0.061
   U-potassium after 4 h (mEq/L) 29.5±15.5 26.4±11.6 0.382
   U-urea nitrogen (mg/dl) 785.0±316.7 399.3±161.0 　<0.001*　
   U-urea nitrogen after 4 h (mg/d) 343.6±192.2 342.6±158.3 0.983
  U-creatinine (mg/d) 103.6±51.0　　 50.5±38.3 　<0.001*　
   U-creatinine after 4 h (mg/d) 39.7±25.4 50.9±40.6 0.171
   Urine specific gravity 1.0136±0.0048 1.0097±0.0043 　0.017*
   Urine specific gravity after 4 h 1.0081±0.0037 1.0093±0.0037 0.341
Echocardiographic parameters
   LV diastolic diameter (mm) 59.5±11.7 58.9±16.4 0.883
   Ejection fraction (%) 34.6±21.5 37.5±12.2 0.517
   Cardiac index (L · min–1 · m–2) 2.5±0.4 2.7±0.8 0.325
  E/e’ 13.2±4.8　　 14.1±3.8　　 0.524
  eRVsP (mmHg) 52.4±13.1 46.5±12.9 0.634
Symptom
   NYHA class IV 18 (42.9) 11 (45.8) 0.815
Data given as n (%) or mean ± SD.
ACEI/ARB, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers; BNP, B-type natriuretic peptide;
BUN, blood urea nitrogen; E/e’, ratio of early diastolic filling velocity to early mitral lateral annulus velocity; eGFR,
estimated glomerular filtration rate; eRVsP, estimated right ventricular systolic pressure; LV, left ventricle; NYHA,
New York Heart Association; TLV, tolvaptan; U-, urine; U-OSM, urine osmolality; UV, urine volume.

Circulation Journal  Vol.77, May 2013

Estimated U-OSM Predicts Response to TLV
Figure 2.   Proportions of each urine biochemical substance consisting of whole urine osmolality among responders/non-respond-
ers (A/B) during the first tolvaptan treatment. *P<0.05 (paired t-test compared with baseline).
157.4 mOsm/L vs. 365.1±148.7 mOsm/L, P=0.806, paired t-
test). Measured urine SG had only a weak correlation with
measured U-OSM (r=0.391, P=0.01).
Baseline Patient Characteristics
Sixty-six patients with decompensated HF were enrolled in
this study. The baseline characteristics are listed in Table. The
mean age was 55.2 years (range, 16–90 years) and most pa-
tients (71.2%) were male. Eleven patients (16.7%) had isch-
emic etiology, and the other patients had non-ischemic etiol-
ogy including dilated cardiomyopathy, n=17; dilated phase of
hypertrophic cardiomyopathy, n=3; cardiac sarcoidosis, n=2;
constrictive pericarditis, n=4; adult congenital heart disease,
n=5; hypertensive heart disease, n=10; and any other etiology,
n=14. Serum arginine vasopressin was detectable in all patients
(average, 8.1 pg/ml; range, 1.0–85.2 pg/ml) despite the rela-
tively lower serum osmolality (average, 276.2 mOsm/L; range,
243–295 mOsm/l). Twenty-nine patients (43.9%) had NYHA
class IV, and the others had NYHA class III.
All patients had received standard medical therapy includ-
ing β-blockers (84.8%), angiotensin-converting enzyme inhibi-
tors or angiotensin II receptor blockers (84.8%), and diuretics,
that is, furosemide (average, 71.3 mg/day; range, 20–240 mg/day),
spironolactone (average, 31.5 mg/day; range, 0–75 mg/day), and
thiazides (average, 0.5 mg/day; range, 0–4 mg/day). Twenty-
eight patients (42.4%) had received continuous catecholamine
infusion. Mean TLV dose was 5.7 mg/day. Non-responders
were older, had more impaired renal function, and had lower
baseline U-OSM compared with responders. After 1 week of
TLV treatment, body weight reduced and serum sodium con-
centration increased significantly in responders compared with
non-responders (1.6±2.1 kg vs. 0.2±2.0 kg and 1.4±2.4 mEq/L
vs. –0.3±1.4 mEq/L, P=0.025 and P=0.002, respectively). Plas-
ma B-type natriuretic peptide had a trend to decrease after 1
Circulation Journal  Vol.77, May 2013
1211
week of TLV treatment in responders compared with non-re-
sponders (–237.4±348.1 pg/ml vs. –55.7±453.3 pg/ml, P=0.141).
During the study period, there was no adverse event such as
hypernatremia, hypovolemia, or worsening of renal function.
The proportions of the 3 urine biochemical substances that
constitute U-OSM among responders/non-responders are given
in Figure 2. U-UN was the most dominant substance during
TLV treatment in both responders/non-responders. Osmolal-
ity of U-UN and U-Cre significantly reduced after TLV treat-
ment among the responders, whereas that of urine sodium re-
mained at the same level during TLV treatment.
Prediction of TLV Efficacy by New Criteria
ROC analysis showed that the cut-off for baseline estimated
U-OSM and %decrease in estimated U-OSM were 358 mOsm/L
and 24%, respectively, for the prediction of TLV efficacy.
New criteria consisting of (1) baseline estimated U-OSM
>358 mOsm/L; and (2) %decrease in estimated U-OSM 4–6 h
after the first TLV dose >24% could distinguish the double
positive group from the double negative group significantly
for the efficacy of TLV (P<0.05; Figure 3A). The criteria had
a high area under curve (AUC, 0.948) for the prediction of
efficacy of TLV (Figure 3B).
We also performed ROC analysis for urine SG, which
showed that the cut-off for baseline urine SG and % decrease
in urine SG 4–6 h after the first TLV dose were 1.010 and
0.296% for the prediction of efficacy of TLV. The combina-
tion of these 2 conditions of urine SG had significantly lower
AUC to predict TLV efficacy than the criteria derived from
estimated U-OSM (0.734 vs. 0.948, P=0.0152; Figure 3B).
Discussion
In the present study we have shown that U-OSM could be
1212
Figure 3.  (A) Increase in urine volume after the first tolvaptan (TLV) dose among the 3 groups stratified by the new criteria and
(B) receiver operating characteristic (ROC) curves of 2 criteria constructed using estimated urine osmolality (U-OSM) or urine
specific gravity (SG). *P<0.05 (analysis of variance with Tukey’s test compared with the double negative group). AUC, area under
the ROC curve.
estimated using urine biochemical data for urine sodium,
U-UN, and U-Cre concentrations regardless of the presence of
HF. Moreover, responders/non-responders to TLV could be
successfully distinguished using new criteria that consisted of
2 conditions: C1, estimated baseline U-OSM >358 mOsm/L;
and C2, % decrease of estimated U-OSM >24% at 4–6 h after
the first TLV dose.
In general, various osmotic substances are excreted in human
urine including sodium, potassium, chloride, calcium, creati-
nine, urea nitrogen, uric acid, phosphorus, glucose, protein,
and others.13 As the dominant osmotic substances, we adopted
urine sodium, U-UN, and U-Cre to construct the formula to
estimate U-OSM, analogous to the estimation of serum osmo-
lality, that is:
[serum osmolality (mOsm/L)] = 2 × [serum sodium (mEq/L)] + 
[serum blood urea nitrogen (mg/dl)] / 2.8 + [serum glucose
(mg/dl)] / 18.14
We did not use urine glucose, because it was not detectable in
any of the present patients. Summation of the 3 osmotic sub-
stances was well correlated with actual measured U-OSM
according to the regression line:
[ measured U-OSM (mOsm/L)] ~ 1.07 × [summation of 3
osmotic substances (mOsm/L)] + 16.
Obviously, there may exist other minor osmotic substances
that were ignored in this study,15 which would be accounted
for by the constant 16 mOsm/L. We emphasize that the for-
mula is valuable regardless of the presence of HF. Urine SG
has been known to correlate with U-OSM traditionally,16 but
it appears to be too crude to estimate U-OSM precisely, as
shown in previous studies.17,18 In the present study, urine SG
was not a good predictor of TLV response.
Circulation Journal  Vol.77, May 2013
IMAMURA T et al.
We previously demonstrated that U-OSM is a useful tool
to predict efficacy of TLV among decompensated HF pa-
tients, that is, a >26% decrease in U-OSM from baseline of
>352 mOsm/L for the first 4–6 h well predicted responders to
TLV.12 Non-responders may have chronic kidney disease
(CKD) with attenuated expression of the V2 receptor/aquapo-
rin 2 system, in which the kidneys no longer have concentrat-
ing ability, with lower baseline U-OSM.19–21 Previous studies
have shown that many CKD patients lose the diluting ability
as well as the concentrating one, which is consistent with the
lack of significant decrease in U-OSM on TLV treatment among
non-responders.22 Cut-offs for the new criteria calculated using
urine biochemical data were almost identical to those previ-
ously given using actual measured U-OSM.
Sodium is well known to be a dominant osmotic substance
in serum,23 whereas urea nitrogen has been shown to be a major
osmotic substance in urine.24 U-UN and U-Cre were signifi-
cantly correlated with measured U-OSM, and decreased sig-
nificantly along with decreased U-OSM after TLV treatment
in responders, which resulted from dilution of these osmotic
substances by enhanced excretion of free water.7,25 In contrast,
urine sodium concentration remained the same during TLV
treatment, despite decrease of U-OSM in responders, which
might mean enhanced excretion of sodium, albeit TLV had been
thought to enhance solely excretion of free water.26 Patients
with advanced HF are often refractory to diuretics because of
renal congestion, reduced renal perfusion, and enhanced reab-
sorption of sodium ion in renal tubule.27 Amelioration of the
aforementioned vicious cycle by TLV treatment might acute-
ly improve efficacy of natriuresis by concomitant diuretics,
although we doubt if 1 day is long enough to improve renal
condition by TLV. Recently, AVP has been reported to stimu-
late reabsorption of sodium ion through the epithelial Na-
Estimated U-OSM Predicts Response to TLV
channel (ENaC) in the distal nephrons.28 TLV inhibits V2 re-
ceptor, which may repress ENaC activity and improve excretion
of sodium ion.29
Study Limitations
We acknowledge that the present study has several limitations.
First, this study was conducted retrospectively in a single cen-
ter, hence there was a limited number of patients and patient
selection bias. The present formula should be analyzed pro-
spectively for its ability to estimate measured U-OSM.
Second, we regarded increases in UV during the first 24 h
after TLV treatment as a sign of responsiveness to TLV. We
consistently confirmed that hyponatremia and fluid retention
improved in responders. Long-term effects of TLV among
responders should be addressed in future studies.
Third, all of the present patients had no detectable glucose
or protein in urine, which could potentially increase U-OSM.
In this regard, the present formula is limited with regard to pa-
tients with severe diabetes mellitus or nephritis. When patients
had significant urinary sugar, we may simply add “urine glu-
cose (mg/dl)/18” to the formula.14 It is better, however, to mea-
sure U-OSM directly in the presence of proteinuria because
there has been no known method to estimate U-OSM in such
cases.
Fourth, systolic blood pressure was not different between
responders/non-responders. Cardiac index, estimated right ven-
tricular systolic pressure, and E/e’ ratio (ratio of early diastolic
filling velocity to early mitral lateral annulus velocity) calcu-
lated from echocardiographic data were also not significantly
different between responders/non-responders. Therefore, base-
line hemodynamics did not appear to affect response to TLV.
We did not, however, perform invasive hemodynamic mea-
surements in most of the patients, and we could not exclude
the possibility that severe low cardiac output might result in
apparent unresponsiveness to TLV because of insufficient
renal perfusion in some cases.
Conclusions
U-OSM can be estimated accurately by using U-UN, urine so-
dium, and U-Cre data. The efficacy of TLV is well predicted
by the new criteria consisting of estimated U-OSM, which is
non-invasive and easy to calculate without direct measure-
ment of U-OSM.
Acknowledgments
This work was supported in part by a Grant-in-Aid for the JSPS Postdoc-
toral Research Fellow from the Japan Society for the Promotion of Sci-
ence (no. 224943) to N.K., a grant for clinical epidemiology research from
the Japanese Heart Foundation, the Japanese Association for Cerebro-
Cardiovascular Disease Control and AstraZeneca to N.K. and K.K., and
a domestic collaborative research grant from the Pfizer Health Research
Foundation to N.K. and K.K..
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