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European Journal of Heart Failure 2006 8(6):621-627; doi:10.1016/j.ejheart.2005.11.011
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© 2005 European Society of Cardiology

Diagnostic and prognostic value of urine NT-proBNP levels in heart failure patients

Raquel Cortésa, Manuel Portolésa, Antonio Salvadorb, Vicente Bertomeuc, Fernando García de Burgosd, Luis Martínez-Dolzb, Esther Roselló Lletía, Vicente Climente, Alejandro Jordánd, Rafael Payáf, Francisco Sogorbe and Miguel Riveraa,*

a Research Center La Fe Hospital Valencia, Spain
b La Fe Hospital Valencia, Spain
c San Juan Hospital Alicante, Spain
d Elche Hospital Alicante, Spain
e General Hospital Alicante, Spain
f General Hospital Valencia, Spain

* Corresponding author. Address: Jose Maria Haro, 59, puerta 59, 46022 Valencia, Spain. Tel.: +34 96 37 61 98; fax: +34 96 197 30 18. E-mail address: rivera_jmi{at}gva.es (M. Rivera).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Plasma NT-proBNP levels are sensitive markers of ventricular dysfunction. However, studies of natriuretic peptides in urine are limited.

Aims: To compare urine and plasma NT-proBNP levels and to investigate the diagnostic and prognostic value of urine levels in heart failure (HF).

Methods: Urinary and plasma NT-proBNP levels were measured in 96 HF patients and 20 control subjects. The patients were functionally classified according to the NYHA criteria.

Results: Urine NT-proBNP was higher in HF patients than in control subjects (94 ± 31 pg/ml vs. 67 ± 6 pg/ml, p < 0.0001), correlating with plasma NT-proBNP levels (r = 0.78, p < 0.0001). Urinary levels were elevated in the more severe functional classes and diminished in obese patients. Urine NT-proBNP was a good tool for diagnosis of HF, the area under the curve (AUC) being 0.96 ± 0.02 (p < 0.0001), and for predicting 12-month cardiac events (p = 0.011). To determine the prognostic power of urinary NT-proBNP in detecting 12-month cardiac mortality, we obtained an AUC of 0.75 ± 0.10 (p = 0.015).

Conclusion: Urinary NT-proBNP, a relatively simple non-invasive test, is a new candidate marker for the diagnosis and evaluation of prognosis in HF and for the characterization of functional status in these patients.

Key Words: Natriuretic peptides • Urine • Heart failure

Received June 9, 2005; Revised September 26, 2005; Accepted November 21, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure (HF) is a disease that is characterized by poor prognosis and quality of life. It is the most costly cardiovascular disorder in western countries, therefore, early identification and therapy for patients at high risk of developing HF or left ventricular dysfunction is required. Although echocardiography is the gold standard for diagnosis, it is not always readily available, especially in primary care [1]. Biochemical markers, such as the natriuretic peptide family, have been shown to be useful in the diagnosis of this syndrome. Plasma levels of brain natriuretic peptide (BNP) and its N-terminal precursor, N-terminal pro-BNP (NT-proBNP), are highly sensitive markers of ventricular hypertrophy [2,3] and/or left ventricular dysfunction [4-6], including congestive HF [7] and acute myocardial infarction [8]. In established disease, these biomarkers also offer prognostic value and may be useful to guide therapy [9].

The majority of studies on the diagnostic and prognostic potential of natriuretic peptides in HF have been performed on plasma samples [10]. However, assessment of the concentration of natriuretic peptides in urine, a non-invasive and simple test, may be useful in certain circumstances. Previous studies on the presence of natriuretic peptides in urine and their clinical significance are limited. The presence of C-type natriuretic peptide (CNP) has been demonstrated in the kidney and urine of patients with congestive HF [11]. In addition, urinary excretion of N-terminal pro-atrial natriuretic peptide (N-ANP) has been investigated in patients with kidney disease [12], BNP was described and its molecular form characterized in urine specimens of normal humans [13] and urine NT-proBNP has been determined in normal volunteers subjected to tilting and volume loading [14]. Furthermore, several studies have recently been published using urinary NT-proBNP levels as a diagnostic aid for left ventricular systolic dysfunction, using a non-competitive immunoluminometric assay [15,16], which is different from the assay employed in this study. These studies highlight the potential of this relatively simple urine test for the diagnosis of HF. However, the prognostic value of urinary NT-proBNP levels has not been studied to date.

Therefore, the aims of this study were to analyze the presence of NT-proBNP in human urine, to compare the urine levels with those found in plasma, and then use these results to investigate the potential diagnostic and prognostic value of urinary NT-proBNP in HF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
A total of 116 subjects were studied, of these 96 were consecutive HF patients and 20 were age- and gender-matched controls. Heart failure was diagnosed according to the European Society of Cardiology (ESC) HF criteria: electrocardiogram, chest X-ray and echo-Doppler study [17]. Aetiology of HF was multifactorial, as follows: ischaemic cardiomyopathy (45%), dilated cardiomyopathy (39%), hypertensive cardiomyopathy (13%) and valvular disease (3%). All patients were functionally classified according to the New York Heart Association (NYHA) criteria and were receiving standard medical treatment following the guidelines of the ESC [17]. Subjects in atrial fibrillation, with acute coronary syndromes, acute and chronic liver, pulmonary and renal diseases were excluded. Twenty-seven patients were obese with a body mass index (BMI)≥30 kg/m2.

All of the control subjects presented a normal echo-Doppler study, electrocardiogram and haematological and biochemical analyses.

All subjects gave informed consent to participate in the study, which was approved by the appropriate institutional review boards or ethics review committees of each study centre. The study was conducted in accordance with the guidelines of the Declaration of Helsinki.

2.2. Urine and blood sampling
Venous blood was collected by venipuncture with the subject supine having rested quietly for at least 30 min. Subjects also provided a urine sample, the first urine of the day [18,19]. After centrifugation at 1300 rpm and 4 °C for 10 min, urine and plasma samples were separated and stored in cryotubes at –80 °C until assayed. Before the analysis, the urine samples were centrifuged twice at 13,200 rpm at 4 °C for 30 min to avoid possible NT-proBNP measurement interferences produced by the precipitation of salts in urine.

2.3. NT-proBNP determination
NT-proBNP levels in serum and urine were determined in duplicate using an electrochemiluminescence immunoassay (Elecsys 2010 from Roche Diagnostics, Germany) based on the sandwich principle [20]. Results are expressed in pg/ml for both urine and blood samples. The lower detection limit was 5 pg/ml and the coefficient of intra-assay variation was 2.6%.

2.4. Echo-Doppler study
The echo-Doppler study was performed using the standard echocardiographic procedures of the hospitals involved in the study, as applied in routine clinical practice, with 2.5 MHz transducers. Cardiologists assessing left ventricular function were blinded to the results of the NT-proBNP assay. Two-dimensional images, Doppler spectrum and colour Doppler were stored on videotape and analyzed off-line at a central laboratory, using a computerized system (Eco-dat; Software Medicina SA). For each patient in regular rhythm, four consecutive beats were measured and averaged for each Doppler variable.

To obtain ejection fraction (EF), the area-length method was used and calculated as 100*[(telediastolic volume–telesystolic volume)/telediastolic volume]. By pulsed Doppler, peak flow velocity in early diastole (E wave) and during atrial contraction (A wave) was measured at valve level, calculating E/A ratio.

2.5. Statistical analysis
Results are presented as mean±SD. Results for each variable were tested for normality using the Kolmogorov Smirnov method. Data showing no normal distribution were compared using the Mann-Whitney test and categorical clinical variables were compared with Fisher's exact test. Plasma NT-proBNP levels were correlated with those in urine using Spearman's rank correlation coefficient. Natriuretic peptide data were log-transformed before stepwise linear regression analysis to determine the independent predictors of urinary NT-proBNP levels. The discrimination of the best model was based on the principle of the least mean square and higher R-square. Regression analysis included sex, age, plasma NT-proBNP, serum creatinine, obesity (BMI>30 kg/cm), EF and E/A ratio as independent variables and urine NT-proBNP levels as dependent variable.

The relativity sensitivity, specificity and predictive value of urinary and plasma NT-proBNP levels for the absence or presence of HF were assessed by construction of receiver operating characteristic (ROC) curves. Logistic regression was performed on HF patients to evaluate the power of urine NT-proBNP in combination with EF, NYHA classes, age and obesity for prediction of 12-month events (mortality+cardiac admissions). ROC curve was also calculated to predict 12-month cardiac mortality from urinary NT-proBNP levels. The HF patients were divided into two groups based on urine peptide levels above and below 92.61 pg/ml to study differences in outcome rates using Fisher's exact test. This cut-off value was chosen based on the statistical results of the ROC curve, calculated to analyze the predictive value of urinary peptide levels in detecting cardiac mortality. All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS 10.1) software (SPSS Inc., Chicago, Illinois). A p value<0.05 was considered significant for all parameters.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Clinical characteristics of patients are summarized in Table 1. Differences in urinary and plasma NT-proBNP levels between controls and patients were highly significant (p<0.0001) (Table 2). Furthermore, in HF patients plasma NT-proBNP levels were higher than urinary levels, but in control subjects peptide levels were more elevated in urine (Table 2). Urinary NT-proBNP levels showed good correlation with plasma NT-proBNP levels (r=0.78, p<0.0001) in our study population. In HF patients the correlation was r=0.66, p<0.0001, but in control subjects urine and plasma NT-proBNP levels showed no significant relationship.


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  		Table 1 Characteristics of heart failure patients

 


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  		Table 2 Comparison of urine and plasma NT-proBNP levels between heart failure patients and control subjects

 
The ROC curve of urine NT-proBNP for detection of HF yielded an area under the curve (AUC) of 0.96±0.02, p<0.0001 compared with the diagonal (Fig. 1). When a ROC curve was plotted for plasma NT-proBNP, a slightly higher AUC (0.98±0.01) was found (Fig. 1). From the ROC for urinary NT-proBNP, the optimal cut-off value (74.23 pg/ml) had a sensitivity and specificity of 93% and 95% for detection of HF, with positive and negative predictive values of 90% and 94%, respectively.


Figure 1
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  		Fig. 1 Receiver operating characteristic curve of N-terminal pro-brain natriuretic peptide (NT-proBNP), urinary and plasma levels, for the detection of heart failure.

 
Recently, we have reported that obese subjects with heart failure have lower NT-proBNP plasma levels than non-obese HF patients [21]. In accordance with these findings, our current study found that obese patients had lower urine NT-proBNP levels than non-obese patients (84.7±9.8 vs 98.7±35.7 pg/ml, p=0.005) (Fig. 2). Furthermore, a multivariate linear regression analysis was used to test the independent predictive value of obesity on urine NT-proBNP levels in these patients. However, the best model associated with urine NT-proBNP levels did not include obesity as an independent predictor, but plasma NT-proBNP (p<0.0001) and plasma creatinine (p=0.016) accounted for an r2 of 0.76.


Figure 2
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  		Fig. 2 Box plots showing urinary NT-proBNP (N-terminal pro-brain natriuretic peptide) levels in obese and non-obese heart failure patients. Boxes display median (horizontal bars), interquartile ranges (lower and upper limits of boxes) and 5th and 95th percentiles (error bars).

 
Fig. 3 illustrates the distribution of NT-proBNP urine levels as a function of NYHA functional class (NYHA I: 77±10 pg/ml, NYHA II: 88±16 pg/ml, NYHA III: 123±51 pg/ml) (p<0.0001). The mean urinary level was significantly elevated in deteriorated NYHA classes and there were significant differences between NYHA I patients and control subjects (77±10 vs. 67±6, p=0.025). Results obtained in NT-proBNP plasma samples according to NYHA classes are similar to previous published studies (Fig. 3).


Figure 3
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  		Fig. 3 Distribution of urinary (A) and plasma (B) NT-proBNP (N-terminal pro-brain natriuretic peptide) levels according to the degree of functional deterioration (New York Heart Association class). Boxes display median (horizontal bars), interquartile ranges (lower and upper limits of boxes) and 5th and 95th percentiles (error bars).

 
Furthermore, to investigate whether urinary NT-proBNP levels are independent predictors of 12-month events (mortality+cardiac admissions) a logistic regression was performed including EF, NYHA class, age and obesity, as well as urinary NT-proBNP levels. When the multivariate model was applied, urinary NT-proBNP level was a strong predictor of cardiac events (p=0.011), with an odds ratio 4.5 for the presence of cardiac event. Fig. 4 shows the ROC curve for urinary NT-proBNP to determine its prognostic power for detecting 12-month cardiac mortality, the AUC being 0.75±0.10 (p=0.015), plasma NT-proBNP levels showed a slightly higher AUC (0.80±0.09, p<0.015) for detecting mortality. Finally, to analyze HF patients according to urinary NT-proBNP levels, two groups were formed based on urinary NT-proBNP levels above and below 92.61 pg/ml. The 12-month-combined cardiac events (mortality+admissions) in the group of HF patients with NT-proBNP<92.61 pg/ml was 14 (21%) compared to that with NT-proBNP>92.61 pg/ml, which was 16 (52%) (p=0.006). When cardiac mortality was compared, significant differences were also obtained (p=0.006) (Table 3).


Figure 4
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  		Fig. 4 Receiver operating characteristic curve of urinary and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in predicting 12-month cardiac mortality in heart failure patients.

 


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  		Table 3 The cardiac events for heart failure patients in based on a NT-proBNP cut-off value of 92.61 pg/ml

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Natriuretic peptides are strong diagnostic markers of ventricular hypertrophy [2,3] and/or left ventricular dysfunction [4-6]. However, previous studies on the presence of natriuretic peptides in urine and their clinical significance are limited [13-16]. The present study demonstrates that NT-proBNP levels are detectable in the urine of HF patients and control subjects, as reported in a previous study with healthy male volunteers [14]. Furthermore, higher NT-proBNP levels were found in plasma than in urine in 94% of HF patients, compared with only 10% of control subjects. These findings are contrary to previous reports [15,16]. These differences may be due to the fact that control subjects had a different peritubular renal circulation, resulting in little tubular reabsorption of this peptide into the bloodstream [22,23]. Moreover in the HF patients, urinary NT-proBNP levels showed good correlation with plasma levels, but the relationship did not improve when the urinary peptide levels were normalized according to the urinary creatinine levels [15,16], probably due to the different renal kinetics of these two molecules [24,25].

The influence of age, sex, systolic and diastolic ventricular function, serum creatinine and obesity on NT-proBNP plasma levels is well established [26-28]. To investigate how these variables affect urinary NT-proBNP levels, a stepwise linear regression was performed. NT-proBNP plasma levels and serum creatinine were independent predictors for urinary NT-proBNP levels in our HF patients. The dependence on plasma NT-proBNP and serum creatinine is not surprising, even at our creatinine values (1.21±0.7 mg/dl), because renal excretion is currently regarded as an important clearance mechanism [29]. Obesity was not an independent predictor of urinary NT-proBNP in this model, however, urinary NT-proBNP levels were diminished in obese patients (Fig. 2).

Previous studies have demonstrated the usefulness of plasma NT-proBNP levels in the diagnosis of HF [30,31] and left ventricular dysfunction [28,32-34]. Thus, it is not surprising that urinary NT-proBNP levels are also powerful predictors of HF.

Analysis of the area under the ROC curve of the current data suggests that under the design conditions of our study, a urinary NT-proBNP cut-off value of 74.23 pg/ml, discriminates HF patients from control subjects. Plasma NT-proBNP levels presented a slightly higher area under the ROC curve. Both testing methods showed similar sensitivities, specificities and negative predictive values and would be effective in the exclusion of a diagnosis of HF [34]. However, recently Ng et al. [16] showed low values of specificity and predictive positive value of plasma and urine NT-proBNP levels to diagnose left ventricular dysfunction in a community-screening study, using a non-competitive immunoluminometric assay to calculate the natriuretic peptide levels [15], which is different from the assay used in this study.

In the characterization of functional status in HF patients, mean urinary NT-proBNP levels were significantly elevated in the worse NYHA classes. Furthermore, differences were found between control subjects and patients in NYHA classes I, II and III.

An important issue in the determination of urine NT-proBNP is its prognostic value, and therefore, a logistic regression analysis was performed, including urinary NT-proBNP levels, EF, NYHA class, age and obesity, to predict 12-month outcome (mortality+cardiac admissions). Urinary NT-proBNP level was a strong predictor of cardiac events (p=0.011), with an odds ratio of 4.5 for the presence of a cardiac event. Furthermore, when a ROC curve for predicting 12-month cardiac mortality was constructed, urinary NT-proBNP levels showed an AUC of 0.75±0.10.

To analyze the cardiac events in HF patients using urinary NT-proBNP levels, two groups were formed according to the cut-off value (<92.61 pg/ml) obtained from the ROC curve used to predict cardiac mortality. The 12-month combined event rate was 21% in patients with low urinary NT-proBNP compared to 52% in those with NT-proBNP levels>92.61 pg/ml. The difference was 4% versus 24%, for mortality alone.

Further studies to evaluate the utility of urinary NT-proBNP levels in guiding treatment decisions in patients with HF are now required. In particular, the utility of this non-invasive test must be proven in clinical practice (i.e., in a multicentre primary care study). This test may make natriuretic peptide levels more accessible for the general practitioner, with an additional potential benefit in terms of cost-effectiveness [35].

4.1. Limitations of the study
This study focuses on the analysis of NT-proBNP in the urine of HF patients, but the determination of the other natriuretic peptides such as BNP, and CNP, may also provide useful additional information. Another consideration is the fact that most of the patients in our study had moderate heart failure (NYHA II). A larger number of patients in worse functional classes may have given interesting additional results.

This study did not focus on a screening population; instead the test was applied to 96 patients with clearly confirmed HF and 20 controls, who were clearly free of HF. Thus, although the present data suggest the usefulness and applicability of this test, longer-term follow-up of a larger number of unselected patients is now required to confirm these findings.

In this study we used the first urine of the day for testing, as in previously reported studies [18,19]. It would have been interesting to confirm our findings with a full 24 h urine collection. However, due to the difficulty in collecting full 24 h urine in these ambulatory patients this was not done.

The Roche Elecsys 2010 analyzer is configured to test plasma NT-proBNP samples, and this could influence the urine NT-proBNP determinations. However, the good results obtained, when using the Roche Elecsys 2010 analyzer to calculate urine NT-proBNP for diagnostic and prognostic purposes, supports the utility of the measurements.

A common limitation in this kind of study is that the HF patients are receiving conventional therapy, and it is known that several drugs can reduce NT-proBNP levels. However, this study confirms that a high degree of neurohormonal activation persists in HF patients, even during standard therapy, and NT-proBNP values are useful for diagnostic and prognostic purposes.

4.2. Conclusions
This work shows that NT-proBNP can be determined in human urine and that urinary NT-proBNP is a new candidate marker for the diagnosis and prognosis of heart failure patients and for the characterization of functional status of these patients. This raises the possibility of using this relatively simple non-invasive test in primary care or in specific conditions where the collection of blood samples could be problematic. However, a large multicentre study to clarify the diagnostic power of urinary NT-proBNP levels in a general population is now required.


   Acknowledgement
 
The research support was from the National Institute of Health Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III, FIS 01/0943 Project, Spain.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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S. C. Palmer, Z. H. Endre, A. M. Richards, and T. G. Yandle
Characterization of NT-proBNP in Human Urine
Clin. Chem., June 1, 2009; 55(6): 1126 - 1134.
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E. C H J Michielsen, J. A Bakker, R. R J V. Kimmenade, Y. M Pinto, and M. P V. Dieijen-Visser
The diagnostic value of serum and urinary NT-proBNP for heart failure
Ann Clin Biochem, July 1, 2008; 45(4): 389 - 394.
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M. Schou, F. Gustafsson, C. N. Kistorp, P. Corell, A. Kjaer, and P. R. Hildebrandt
Effects of Body Mass Index and Age on N-Terminal Pro Brain Natriuretic Peptide Are Associated with Glomerular Filtration Rate in Chronic Heart Failure Patients
Clin. Chem., November 1, 2007; 53(11): 1928 - 1935.
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A M. Richards
Variability of NT-proBNP levels in heart failure: implications for clinical application
Heart, August 1, 2007; 93(8): 899 - 900.
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