Download Effects of Nesiritide and Predictors of Urine Output in Acute

Journal of the American College of Cardiology
2013 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 62, No. 13, 2013
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2013.04.073
Effects of Nesiritide and Predictors of Urine
Output in Acute Decompensated Heart Failure
Results From ASCEND-HF (Acute Study of Clinical
Effectiveness of Nesiritide and Decompensated Heart Failure)
Stephen S. Gottlieb, MD,* Amanda Stebbins, MS,y Adriaan A. Voors, MD, PHD,z
Vic Hasselblad, PHD,y Justin A. Ezekowitz, MBBCH, MSC,x Robert M. Califf, MD,k
Christopher M. O’Connor, MD,y Randall C. Starling, MD, MPH,{ Adrian F. Hernandez, MD, MHSy
Baltimore, Maryland; Durham, North Carolina; Groningen, the Netherlands; Edmonton, Alberta, Canada;
and Cleveland, Ohio
Objectives
This study sought to determine if nesiritide increases diuresis in congestive heart failure patients.
Background
In the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure), 7,141
patients hospitalized with acute decompensated heart failure (ADHF) were randomized to receive nesiritide or
placebo for 24 to 168 h, in addition to standard care. There were minimal effects of nesiritide on survival, future
hospitalizations, and symptoms. However, whether or not nesiritide increases diuresis in ADHF patients is unknown.
Methods
Urine output was measured in 5,864 subjects; of these, 5,320 received loop diuretics and had dose data recorded.
Loop diuretics other than furosemide were converted to furosemide equivalent doses. A total of 4,881 patients had
complete data. We used logistic regression models to identify the impact of nesiritide on urine output and the
factors associated with high urine output.
Results
Median (25th, 75th percentiles) 24-h urine output was 2,280 (1,550, 3,280) ml with nesiritide and 2,200 (1,550,
3,200) ml with placebo (p ¼ NS). Loop diuretic dose (furosemide equivalent) was 80 (40, 140) mg with both
nesiritide and placebo. Diuretic dose was a strong predictor of urine output. Other independent predictors included:
male sex, greater body mass index, higher diastolic blood pressure, elevated jugular venous pressure, recent weight
gain, and lower blood urea nitrogen. The addition of nesiritide did not change urine output. None of the interaction
terms between nesiritide and predictors affected the urine output prediction.
Conclusions
Nesiritide did not increase urine output in patients with ADHF. Higher diuretic dose was a strong predictor of higher
urine output, but neurohormonal activation (as evidenced by blood urea nitrogen concentration) and lower blood
pressure limited diuresis. (J Am Coll Cardiol 2013;62:1177–83) ª 2013 by the American College of Cardiology
Foundation
Nesiritide (synthetic B-type natriuretic peptide [BNP]) was
approved in 2001 for symptomatic relief of acute decompensated heart failure (ADHF), presumably as a result of its
vasodilatory effects. Nevertheless, the renal effects of nesiritide were of particular interest to physicians who hoped that
the drug would aid in diuresing a fluid-overloaded patient
who had poor or worsening renal function. At that time,
From the *University of Maryland, School of Medicine, Baltimore, Maryland; yDuke
Clinical Research Institute, Duke University Medical Center, Durham, North
Carolina; zUniversity Medical Center Groningen, University of Groningen,
Groningen, the Netherlands; xMazankowski Alberta Heart Institute and the
University of Alberta, Edmonton, Alberta, Canada; kDuke Translational Medicine
Institute, Duke University Medical Center, Durham, North Carolina; and the
{Cleveland Clinic, Cleveland, Ohio. This work was supported internally by the
Duke Clinical Research Institute. The ASCEND-HF trial was supported by Scios,
Inc. Dr. Gottlieb is a consultant with Gambro and Otsuka; and has received research
grant support from Johnson and Johnson. Dr. Voors received consultants fees and/or
research grants from Alere, Anexon, Bayer, Cardio3Biosciences, Celladon, Merck/
MSD, Novartis, Servier, Torrent, Travena, and Vifor. Justin Ezekowitz is a consultant
with Johnson and Johnson. Dr. Califf is a consultant to Bayer, Bristol-Meyers Squibb
Foundation, CV Sight LLC, Daiichi-Sankyo, Eli Lilly & Company, Gambro,
Heart.org, Janssen R&D LLC, Johnson and Johnson, Kowa, Novartis, Pfizer,
Regeneron, Roche and Scios; and has received research grant support from BristolMyers Squibb Foundation, Novartis, Amylin, Merck, Schering-Plough Research
Institute, Scios, Johnson and Johnson, and Eli Lilly and Company. Dr. O’Connor, is
a consultant with Johnson and Johnson. Dr. Hernandez is a consultant to Johnson and
Johnson, and Corthera. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose. John Teerlink, MD, served as Guest
Editor for this paper.
Manuscript received December 14, 2012; revised manuscript received April 24,
2013, accepted April 26, 2013.
See page 1184
1178
Gottlieb et al.
Urine Output in Acute Decompensated Heart Failure
preliminary data produced conflicting results about urine output,
and few studies had been done
ADHF = acute
in patients with chronic heart
decompensated heart failure
failure.
BMI = body mass index
With concerns raised about
BNP = B-type natriuretic
the
effects of nesiritide on both
peptide
mortality and renal function
BUN = blood urea nitrogen
(1,2), the ASCEND-HF (Acute
eGFR = estimated
Study of Clinical Effectiveness of
glomerular filtration rate
Nesiritide and Decompensated
Heart Failure) was created. The
results of this large study have been previously published; the
ASCEND-HF found nesiritide to have minimal effects on
survival, hospitalizations, and symptoms (3). Yet, whether or
not nesiritide increases diuresis in patients with heart failure
remains unknown. Furthermore, the factors that predict
and affect urine output in this patient population are not wellstudied or understood. Knowing that the effects of nesiritide
on urine output in patients with heart failure is an important
clinical question, the investigators of the ASCEND-HF
collected data about the acute actions of nesiritide on renal
function. We used these data to assess the impact of nesiritide
on urine output and to determine the factors that lead to
diuresis.
Abbreviations
and Acronyms
Methods
The ASCEND-HF was a randomized, double-blind,
placebo-controlled trial in which nesiritide was administered in addition to standard care. The details of the
methodology and enrollment criteria for the ASCEND-HF
have been previously published (3). The study was approved
by each participating center’s ethics committee or institutional review board, and all participants provided written
informed consent.
A total of 7,141 patients were randomized, and 7,007
patients received the study drug. In 5,864 of these patients,
24-h urine output was measured. Subjects with urine output
greater than the 99th percentile (>7,700 ml) were excluded
from these analyses because of suspicion that the data might
be incorrect. To assure accurate assessment of urine volume,
we excluded the countries that reported less than 60% of these
measurements (Australia, Canada, Germany, New Zealand,
and Sweden). A sensitivity analysis, including all patients,
yielded the same independent predictors of urine output.
A total of 5,320 patients received loop diuretics and had
dose data recorded; of these, 80% received intravenous
furosemide. For the purpose of this analysis, other loop
diuretics were converted to “furosemide equivalent doses.” A
dose of 40 mg of intravenous furosemide was considered
equivalent to 20 mg of both intravenous and oral torsemide,
1 mg of both intravenous and oral bumetanide, and 80 mg of
oral furosemide.
Factors that might impact urine output were analyzed by
generalized linear modeling. A total of 4,881 patients had
JACC Vol. 62, No. 13, 2013
September 24, 2013:1177–83
complete data and comprise the sample reported in these
analyses.
Data analysis. All pre-specified discrete variables are reported as frequencies and counts. Median and the 25th and
75th percentiles are reported for continuous factors.
Normality is tested using the Kolmogorov-Smirnov
statistic. All continuous variables reported in Table 1 were
found to be non-normally distributed. The p values reported in Table 2 are generated from the Wilcoxon rank
sum test and report a non-parametric p value. Generalized
linear modeling was generated to assess the pre-specified
factors’ relationship to outcomes. Pre-specified baseline
factors are reported in Table 1. Modeling assumptions were
verified and residual plots were generated between potential
predictors and outcomes. Transformations were used when
necessary. The log transformation was used for urine
output, blood urea nitrogen (BUN), and diuretic dose. The
stepwise procedure with inclusion level set to <0.05 was
used to attain the significant predictors of outcome. We
generated the main effect for each variable on outcome and
interaction between the main effects and treatment. No
adjustments for multiple comparisons were made. All
Table 1
Candidate Predictor Variables Considered
in the Models
Continuous variables
Age
Systolic blood pressure (SBP)
Diastolic blood pressure (SBP)
Heart rate
Respiration rate
B-type natriuretic peptide (BNP) or N-terminal (NT) pro-BNP
Serum creatinine
Serum blood urea nitrogen (BUN)
Serum sodium
Serum potassium
Total dose of loop diuretics given in first 24 h
Body mass index (BMI)
Categorical variables
Sex
Race
Orthopnea
Dyspnea
Previous weight gain
Paroxysmal nocturnal dyspnea
Pulmonary congestion or edema with rales or crackles
Elevated jugular venous pressure (JVP)
S3
Mitral regurgitation
History of coronary artery disease (CAD)
Peripheral edema
Hospitalized for heart failure within the past year
History of chronic respiratory disease
History of diabetes mellitus
Treatment with nesiritide or placebo
New York Heart Association (NYHA) class
Previous weight gain refers to the investigator’s determination as to whether fluid had been
recently retained by the patient.
Gottlieb et al.
Urine Output in Acute Decompensated Heart Failure
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September 24, 2013:1177–83
Table 2
1179
Baseline Characteristics in Patients With Urine Output Above and Below the
Median Value
Output 2,250 ml
Output >2,250 ml
p Value
Age, yrs
65 (55, 75)
68 (57, 77)
<0.001
Male, %
63.1
69.5
<0.001
50.8
54.2
<0.001
Race, %
White
Black
11.8
18.5
Asian
33.5
22.3
Other
4.0
5.0
CAD, %
56.5
52.6
0.003
Hypertension, %
69.7
74.4
<0.001
3.7
4.6
NYHA class before decompensation
NS
I
II
18.1
18.6
III
49.0
48.3
IV
29.3
28.5
61.8
63.8
Dyspnea
NS
At rest
38.2
36.2
Orthopnea, %
Minimal exertion
74.2
78.2
<0.001
Pulmonary edema, %
69.2
80.1
<0.001
Weight gain, %
59.2
71.3
<0.001
Baseline sodium, mmol/l
139 (136, 141)
139 (136, 141)
NS
Baseline creatinine, mg/dl
1.2 (1.0, 1.5)
1.2 (1.0, 1.6)
Estimated GFR, ml/min/1.73 m2
61 (45, 77)
59 (44, 74)
Baseline BUN, mg/dl
24 (17, 37)
26 (18, 39)
<0.001
Baseline BUN/creatinine ratio
20 (15, 27)
21 (16, 28)
<0.001
991 (546, 1,844)
988 (540, 1,819)
NS
4,791 (2,279, 9,179)
4,091 (1,868, 8,877)
0.002
30 (30, 37)
30 (20, 36)
NS
Baseline BNP (pg/ml [n ¼ 2,173])
Baseline NT pro-BNP (pg/ml [n ¼ 3,208])
Ejection fraction, %
NS
0.0015
Values are mean SD or n (%).
GFR ¼ glomerular filtration rate; other abbreviations as in Table 1.
statistical computations were generated using SAS version
9.0 software (SAS Institute Inc., Cary, North Carolina).
Results
Of the 5,864 subjects with urine output measurements,
66% were male, 52% were classified as white, 15% as black,
and 28% as Asian. The median (25th, 75th percentile)
age was 66 (56, 76) years. Body mass index (BMI) was
27.4 (23.7, 32.5) kg/m2, systolic blood pressure was
123 (110, 140) mm Hg, diastolic blood pressure was
75 (67, 84) mm Hg, and heart rate was 82 (72, 95) beats/
min. The ejection fraction was 30% (20%, 36%) in the 4,562
subjects in whom it was assessed.
Recent weight gain was reported in 65% of subjects, 63%
reported dyspnea at rest, 37% reported dyspnea on minimal
exertion, 72% had a history of hypertension, 35% had a
history of myocardial infarction, and 42% had diabetes mellitus. Baseline creatinine was 1.2 (1.0, 1.6) mg/dl and BUN
was 25 (18, 38) mg/dl. B-type natriuretic peptide was measured in 2,181 subjects and was 990 (543, 1,825) pg/ml,
whereas NT pro-BNP was 4,460 (2,051, 9,030) pg/ml in
3,211 subjects.
Baseline characteristics of patients divided by urine
output above and below the median value of 2,250 ml are
shown in Table 2. After 24 h, BUN increased 0.0 (3.0,
4.0) mg/dl in the low urine output group and 1.4 (2.0,
5.5) mg/dl in the high urine output (p < 0.0001). Urine
output in the first 24 h correlated with the improvement in
dyspnea, with a Spearman’s rank correlation coefficient of
0.123 (p < 0.0001).
Table 3
Final Model of Predictors of Urine Output
Parameter
Estimate
Standard
Error
t Value
Pr > jtj
Baseline BMI
0.0073
0.0011
6.64
<0.0001
Baseline diastolic BP
0.0035
0.0006
5.74
<0.0001
Male sex
0.1139
0.0174
6.54
<0.0001
Previous weight
gain?
0.0999
0.0182
5.48
<0.0001
Jugular venous
distension
0.0927
0.0169
5.47
<0.0001
0.0885
0.0145
6.10
<0.0001
0.0900
0.0111
8.13
<0.0001
Log BUN
Log diuretic dose
BP ¼ blood pressure; other abbreviations as in Table 1.
1180
Gottlieb et al.
Urine Output in Acute Decompensated Heart Failure
Predictors of urine output. The results of the stepwise
modeling of factors that predicted urine output (including all
parameters listed in Table 1) are shown in Table 3. The
statistically significant predictors are shown. Diuretic dose
was a strong predictor of urine output. A doubling of the log
diuretic dose was independently associated with a 7% increase
in the log urine output. The relatively modest increase in
urine output may have been the result of the higher doses
needed in patients with worse renal function (Fig. 1) for
similar urine output (Table 4). The relationship between
furosemide dose and urine output is demonstrated in
Figure 2. There was a correlation between log urine output
and log dose, with a Spearman’s rank correlation coefficient
of 0.154 (p < 0.0001). Also predictive of increased urine
output were male sex, higher BMI, higher diastolic blood
pressure, the presence of elevated jugular venous pressure,
recent weight gain, and a lower BUN.
The increased log urine output in men (12% more than in
women) was associated with 7% higher log diuretic doses;
however, male sex predicted increased urine output, even
after controlling for BMI and diuretic dose. Similarly, larger
people (determined by BMI) received higher doses of diuretics. Patients with higher BUN concentrations received
more diuretics (Fig. 1), but they had less urine output
(Table 4). A doubling in the log of the BUN was associated
with a 6% decrease in log urine output.
Diastolic blood pressure also predicted urine output.
Patients with lower pressures had less urine output, despite
higher diuretic doses. For a 5-U increase in diastolic blood
pressure, there was a 2% increase in log urine output. Patients
with evidence of fluid retention (those with reported weight
gain from baseline and those with elevated jugular venous
pressures) also received higher diuretic doses and had more
diuresis.
Effects of nesiritide. The 24-h urine output was 2,280
(1,550, 3,280) ml for patients who received nesiritide and
2,200 (1,550, 3,200) ml for those who received placebo (p ¼
NS). The dose of loop diuretic was 80 (40, 140) mg in both
patients receiving nesiritide and patients receiving placebo
(p ¼ NS). Because it was important to determine if nesiritide
increased urine output in some subgroups, we modeled the
proven predictors with the addition of nesiritide. As shown in
Table 5, nesiritide did not increase the urine output after
adjustment for all independent predictors of urine output.
Unadjusted comparison of urine output with nesiritide
and placebo in various subgroups is shown in Table 4. There
is no difference between the treatments regarding subgroups
of blood pressure, weight gain, jugular venous pressure, sex,
and age. Subjects with a creatinine or BUN above the median
had a small statistically significant increase with nesiritide.
In hopes of defining subgroups that may benefit from
nesiritide, we further assessed factors that might interact with
nesiritide by looking at interaction terms between nesiritide
and the independent predictors of urine output in the final
model. None of these interaction terms affected the prediction of urine output.
JACC Vol. 62, No. 13, 2013
September 24, 2013:1177–83
Figure 1
Effect of Nesiritide on Log Furosemide Dose in
Selected Subgroups
The figure demonstrates a comparison of nesiritide and placebo on log
furosemide dose in patients within various subgroups. Groups are divided by
median. There were no differences between nesiritide and placebo. Note that
although the median was equivalent in all subgroups, the 75th and 99th
percentiles were higher in those with an elevated creatinine, an elevated BUN, and
a lower DBP; the differences between patients with a creatinine, BUN, or DBP
below and above the median was significant (p < 0.0001). BUN ¼ blood
urea nitrogen (mg/dl); Creat ¼ creatinine (mg/dl); DBP ¼ diastolic blood
pressure (mm Hg); Plac ¼ placebo.
Gottlieb et al.
Urine Output in Acute Decompensated Heart Failure
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September 24, 2013:1177–83
Table 4
1181
Log Urine Output by Characteristics That Predicted Urine Output
Planned Nesiritide
Planned Placebo
p Value
Below median
7.72 (7.31, 8.09)
7.65 (7.31, 8.04)
0.015
Above median
7.74 (7.38, 8.10)
7.74 (7.38, 8.13)
0.560
Below median
7.72 (7.33, 8.06)
7.70 (7.37, 8.10)
0.657
Above median
7.76 (7.38, 8.12)
7.70 (7.31, 8.07)
0.024
Below median
7.74 (7.35, 8.09)
7.74 (7.38, 8.13)
0.418
Above median
7.73 (7.36, 8.10)
7.65 (7.31, 8.04)
0.006
Yes
7.80 (7.39, 8.16)
7.77 (7.38, 8.15)
0.305
No
7.63 (7.30, 7.94)
7.60 (7.26, 7.94)
0.479
Yes
7.78 (7.42, 8.12)
7.76 (7.41, 8.13)
0.495
No
7.65 (7.28, 8.04)
7.63 (7.26, 8.01)
0.229
Below median
7.70 (7.31, 8.06)
7.67 (7.31, 8.04)
0.332
Above median
7.76 (7.38, 8.13)
7.74 (7.38, 8.15)
0.354
Below median
7.78 (7.38, 8.13)
7.74 (7.38, 8.10)
0.068
Above median
7.69 (7.31, 8.04)
7.67 (7.31, 8.06)
0.907
Below median
7.66 (7.31, 8.02)
7.60 (7.28, 7.97)
0.026
Above median
7.81 (7.04, 8.16)
7.80 (7.43, 8.19)
0.788
Male
7.76 (7.38, 8.13)
7.74 (7.38, 8.10)
0.114
Female
7.66 (7.24, 8.01)
7.64 (7.28, 8.01)
0.853
eGFR (median 59.5 ml/kg/min)
Creatinine (median 1.21 mg/dl)
BUN (median 25.06 mg/dl)
Previous weight gain
Jugular venous distension
Diastolic BP (median 75 mm Hg)
Age (median 66 yrs)
BMI (median 27.4 kg/m2)
Sex
Values are median (25th, 75th percentile).
eGFR ¼ estimated glomerular filtration rate; other abbreviations as in Table 1.
Discussion
The ASCEND-HF showed no evidence that nesiritide increases urine output in patients with ADHF. Furthermore,
we could find no subgroup in which nesiritide increased
urine output. Although there was a slight increase in
patients with worse renal function, this increase was not
independent of the factors that predicted urine output. The
interaction terms between treatment and BUN, creatinine,
and estimated glomerular filtration rate (eGFR) were not
significant. We also found no evidence to support the
hypothesis that the use of nesiritide may decrease the
amount of diuretics needed for diuresis (4,5). Although this
may be surprising to those who believe that nesiritide
increases urine output, this finding is consistent with
previous data.
Previous studies that have found nesiritide to have an effect
on sodium and urine output have not studied the ADHF
patient population. In a randomized, blinded, crossover study
comparing placebo and nesiritide, there was no effect on urine
output in patients receiving loop diuretics (6). Rather, increased urine output with physiological or usual pharmacological doses of BNP has only been proven in normal
individuals (7,8). Interestingly, there is also evidence that
when nesiritide is given after cardiac surgery it increases urine
output (9). If this is true, then the acute nature of the
depressed urine output in these patients could explain why
they respond differently than patients with chronic heart
failure. Although the ASCEND-HF evaluated patients with
ADHF, most had chronic disease that could have affected the
renal results.
Heart failure patients may respond differently to nesiritide
than healthy individuals. For example, vascular effects of
BNP differ between patients with and without heart failure
(10). Similarly, a differential response to nesiritide on urinary sodium excretion was seen in one study, with heart
failure patients having a urinary sodium excretion of 27
mmol/min as compared with 190 mmol/min in subjects
without heart failure (11). It is also possible that neurohormonal activation limits the efficacy of natriuretic peptides. Multiple neurohormonal systems affect urine output,
and the impact of natriuretic peptides has been shown to
be modified by the renin-angiotensin-aldosterone (12) and
sympathetic nervous systems (13). There is also a decreased
response in high output failure that is associated with neurohormonal activation (14).
The concentration of nesiritide may also affect the urine
output. In a small study, doses higher than those presently
Gottlieb et al.
Urine Output in Acute Decompensated Heart Failure
1182
Figure 2
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September 24, 2013:1177–83
Relationship Between Furosemide Dose and
Urine Volume
The figure displays the relationship between furosemide dose (in those who
received intravenous furosemide) and urine volume. There was a correlation
between log urine output and log dose, with a Spearman’s rank correlation
coefficient of 0.154 (p < 0.0001).
recommended seemed to induce a natriuresis (15). However,
such doses also have greater hemodynamic effect, which has
led to the use of the lower doses than those studied in the
ASCEND-HF.
Predictors of urine output. In patients hospitalized for
ADHF, diuresis is often a chief goal of therapy. Although
the relationship between fluid loss and dyspnea improvement was statistically significant, the correlation was not
strong. Furthermore, increased urine output was associated
with increased BUN, indicating evidence of increased
neurohormonal activation. These findings suggest that the
cause of decompensation is multifactorial and is usually not
simply fluid retention. Nevertheless, understanding the
factors that lead to diuresis is important because many
patients do present with fluid overload.
Two main factors appeared to affect the ability of patients
to diurese: 1) the dose of diuretic administered; and 2) sicker
Table 5
Final Model of Predictors of Urine Output
With Treatment Added
Parameter
Baseline BMI
Estimate
0.0073
Standard Error
0.0011
t-value
Pr > jtj
6.33
<0.0001
Baseline diastolic BP
0.0035
0.0006
5.74
<0.0001
Male sex
0.1134
0.0174
6.51
<0.0001
Previous weight
gain?
0.0999
0.0182
5.48
<0.0001
Jugular venous
distension?
0.0927
0.0169
5.47
<0.0001
0.0885
0.0145
6.09
<0.0001
Log diuretic dose
0.0902
0.0111
8.14
<0.0001
Treatment
0.0199
0.0163
1.22
0.222
Log BUN
Abbreviations as in Tables 1 and 3.
patients are more refractory to diuresis. Not surprisingly,
diuresis increased when larger doses were administered. The
dose of diuretics was not randomized and thus characteristics that were associated with higher diuretic doses were not
randomly distributed and often also predicted urine output.
Many factors can affect the dose given, but the present
study suggests that it is not merely refractoriness of diuretics
that causes larger doses to be given, but rather that it is the
physician’s reluctance to give higher doses that may limit
adequate diuresis.
Larger patients, men, and those who had more fluid
overload (having elevated jugular venous pressure or recent
weight gain) received higher doses of diuretics and urinated
more. From the data collected, it is impossible to know if
these patients needed more diuresis and were therefore more
aggressively diuresed, or if the physician’s subjective factors
had influenced the dosing. Although these factors are
associated with diuretic dose, they were also independently
associated with urine output. Regardless of these factors, the
finding that higher doses of diuretics were used and that
there was more urine output in patients with a higher BMI
suggests that larger size (which was also associated with men)
causes physicians to be more comfortable with prescribing
higher doses of diuretics.
There does not appear to be neurohormonal reasons
why women should have less diuresis. Indeed, sex differences
in neurohormonal response to endothelin would be expected
to lead to more urine output in women (16). Similarly,
testosterone activates the renin angiotensin system, so that
one might expect men to have decreased urine output (17).
As a result, the differences between men and women are
more likely to be related to diuretic doses or renal function.
The second main cause of decreased diuresis, suggested by
our study, is expected; sicker patients are more refractory to
diuresis. Renal dysfunction, as assessed by eGFR and BUN
concentrations, was associated with less urine output despite
higher diuretic doses. Yet, interestingly, BUN was more
predictive than eGFR, perhaps because BUN reflects both
renal function and avidity for urine retention. An increased
BUN/creatinine ratio reflects neurohormonal activation,
with associated elevations in plasma renin activity, arginine
vasopressin, and endothelin concentrations (18,19). Increases in BUN probably reflect neurohormonal activation
more than any fall in glomerular filtration rate (20), and
BUN plus the BUN/creatinine ratio are more prognostic
than creatinine (18,20–22). Even the association of loop
diuretics and mortality may be related to the elevated BUN
in patients receiving higher doses of loop diuretics, again
suggesting that the elevated BUN reflects neurohormonal
activation (23). Although renal dysfunction is undoubtedly
important, the fact that BUN independently predicts urine
output suggests that the physiology leading to an elevated
BUN is also important.
Despite receiving higher doses of diuretics, those patients
with a lower diastolic blood pressure had less urine output.
This may reflect the severity of their heart failure, but it
Gottlieb et al.
Urine Output in Acute Decompensated Heart Failure
JACC Vol. 62, No. 13, 2013
September 24, 2013:1177–83
also may be related to renal perfusion pressure, as renal
perfusion pressure affects natriuresis induced by natriuretic
peptides (24). Similarly, after renal transplantation, higher
nocturnal blood pressure was associated with increased
urine output (25).
Conclusions
By examining data from the ASCEND-HF, we found that
urine output was most strongly related to diuretic dose,
suggesting that physicians can often increase diuresis simply
by increasing the diuretics. Nevertheless, neurohormonal
activation (as evidenced by BUN concentration) and lower
blood pressure limit diuresis. Nesiritide did not lead to
increased urine output in patients with ADHF. As a result,
new interventions are needed for patients who are refractory
to conventional diuretics.
Reprint requests and correspondence: Dr. Stephen S. Gottlieb,
University of Maryland School of Medicine, 110 South Paca
Street, Baltimore, Maryland 21201. E-mail: sgottlie@medicine.
umaryland.edu.
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Key Words: acute decompensated heart failure
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diuresis
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nesiritide.