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doi:10.1378/chest.06-1758
(Chest. 2007; 131:402-409)
© 2007 American College of Chest Physicians
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N-terminal Pro-Brain Natriuretic Peptide and Renal Insufficiency as Predictors of Mortality in Pulmonary Hypertension*

Hanno H. Leuchte, MD; Michal El Nounou, MD; Juergen Christian Tuerpe; Bertram Hartmann, MD; Rainer A. Baumgartner, MD; Michael Vogeser, MD; Olaf Muehling, MD and Jürgen Behr, MD

* From the Division of Pulmonary Diseases (Drs. Leuchte, El Nounou, Baumgartner, Muehling, and Behr, and Mr. Tuerpe), Department of Internal Medicine I, Department of Nephrology (Dr. Hartmann), and Department of Clinical Chemistry (Dr. Vogeser), Ludwig Maximilians University, Klinikum Grosshadern, Munich.

Correspondence to: Hanno H. Leuchte, MD, Division of Pulmonary Diseases, Department of Internal Medicine I, Ludwig Maximilians University, Klinikum Grosshadern, Munich, Marchioninistr. 15, 81377 Munich, Germany; e-mail: Hanno.Leuchte{at}med.uni-muenchen.de

Abstract

Background: N-terminal pro-brain natriuretic peptide (NT-proBNP) is a byproduct of the brain natriuretic peptide (BNP) that was shown to be of prognostic value in pulmonary hypertension (PH). The role of NT-proBNP in PH has to be determined, especially under the influence of renal impairment that might lead to an accumulation of the peptide, and may be a sign of increased mortality per se.

Methods: We assessed NT-proBNP, BNP, renal function, and hemodynamic parameters (during right-heart catheterization) in 118 consecutive patients with isolated PH, excluding left-heart disease. Depending on the calculated creatinine clearance, patients were classified into different groups of renal function. Correlation analysis was performed on all key parameters. Results were then compared between the levels of renal function. The prognostic value of each parameter was assessed during a mean follow-up period of 10 months.

Results: Twenty-two patients (approximately 19%) had significantly impaired renal function (creatinine clearance < 60 mL/min). Although the overall levels of NT-proBNP were correlated with hemodynamics, we observed no correlation in the group with significant renal dysfunction. Moreover, NT-proBNP was related to creatinine clearance. Finally, NT-proBNP and renal insufficiency were independent predictors of death during univariate and multivariate analysis, whereas BNP only predicted mortality in univariate analysis.

Conclusions: The diagnostic accuracy of NT-proBNP as a parameter of the hemodynamic status is diminished by renal function. However, NT-proBNP could be superior to BNP as a survival parameter in PH because it integrates hemodynamic impairment and renal insufficiency, which serves as a sign of increased mortality per se.

Key Words: pro-brain natriuretic peptide • pulmonary circulation

Pulmonary hypertension (PH) is a cause of morbidity and mortality in a variety of diseases.123456 Increased pulmonary vascular resistance (PVR) leads to raised pulmonary artery pressures (PAPs) and an increased right-heart workload. The natriuretic peptide system is activated in this context as a sign of neurohumoral activation in PH of different etiologies.78 Brain natriuretic peptide (BNP) is the biologically active form of a prohormone that is secreted from cardiomyocytes and is of special interest as it is known to correlate with the hemodynamic severity, functional impairment, and prognosis of patients with idiopathic and associated forms of PH5910 However, BNP has a short half-life in blood samples, making a rapid processing of samples necessary. On the contrary, N-terminal pro-BNP (NT-proBNP) is not metabolized in blood and is eliminated only via the kidneys, resulting in a significant longer half-life.1112 This could be an advantage and may favor the measurement of NT-proBNP in clinical routine, and even more since there is evidence that NT-proBNP seems to reflect disease severity in idiopathic and associated forms of pulmonary arterial hypertension (PAH).131415161718 Consequently, measurements of NT-proBNP have entered many ongoing clinical treatment trials in PH as an efficacy parameter. However, renal insufficiency could lead to an accumulation and influence the validity of NT-proBNP. In addition, the interpretation of NT-proBNP values is difficult because there are no data supporting the prognostic role of NT-proBNP in PH, and extrapolating such information from BNP data is not adequate because of the obvious differences in the physiology of BNP and NT-proBNP.

Since renal dysfunction may develop in hemodynamically compromised patients or may exist as an independent comorbidity, we aimed to clarify its impact on the diagnostic validity of both natriuretic peptides (BNP and NT-proBNP) as hemodynamic markers. Another aim was to investigate renal insufficiency as a prognostic marker in PH in comparison with NT-proBNP and BNP.

Materials and Methods

Study Design
One hundred eighteen consecutive patients with stable PH and kidney function were classified according to the Venice conference6 and were evaluated prospectively. Written informed consent was obtained from every patient. All procedures were in accordance to the institutional guidelines. Patients with significant left-heart disease were excluded. In general, left-heart catheterization was performed in patients > 40 years of age and if the left heart could not be entirely assessed during echocardiography. Patients < 18 years old as well as patients with acute renal failure and/or end-stage renal disease undergoing hemodialysis were excluded.

Right-Heart Catheterization
Right-heart catheterization was performed as described before.10 Hemodynamic parameters were obtained in recumbent position and included heart rate, right atrial pressure (RAP), PAP, as well as pulmonary capillary pressure. Cardiac output (CO) was obtained using triplicate measurements with the thermodilution method. Calculated parameters were PVR and cardiac index (CI).

Sampling and Assay
Blood was drawn from a peripheral vein and analyzed for routine laboratory parameters, NT-proBNP, and BNP. For serum NT-proBNP (Roche Elecsys proBNP; Roche Diagnostics; Mannheim, Germany)12 and plasma BNP (ADVIA Centaur BNP; Bayer HealthCare; Fernwald, Germany)19 measurements, we used two commercially available assays. The age- and gender-adjusted values for NT-proBNP and BNP ranged from 84 to 222 pg/mL and from 18 to 75 pg/mL, respectively. In order to avoid an underestimation and overestimation of the individual values of NT-proBNP and BNP, we calculated a normalized ratio for each patient. This ratio was calculated as follows: measured value (NT-proBNP or BNP) divided by age- and gender-adjusted normal values. Consequently, the increase of an individual level resulted in a ratio > 1.5

Estimation of Creatinine Clearance and Classification of Renal Insufficiency
Patients were receiving a stable dose of diuretics during the evaluation of renal impairment. Creatinine clearance was estimated on a simple calculation according to a formula by Rule and colleagues,20 incorporating serum creatinine, age, and gender. Four stages of renal insufficiency were classified according to Levey et al,21 and patients were defined as having "no to mild renal insufficiency" (creatinine clearance ≥ 60 mL/min) or "moderate to severe renal insufficiency" (creatinine clearance < 60 mL/min).

Survival Estimates
Survival was estimated from the day of completion of the NT-proBNP/BNP tests until last patient contact or cardiopulmonary death with a follow-up rate of 100%. All deaths resulted from cardiopulmonary causes.

Statistical Analysis
Data are reported as mean ± SEM. Depending on the normal distribution of parameters, correlation analysis and comparison between groups were performed using the Spearman correlation coefficient and Student t test for unpaired samples or Mann-Whitney U test, respectively. The correlation was tested for two-sided significance. Univariate Cox proportional hazards regression analysis was used to test the prognostic value of each variable followed by a stepwise multivariate analysis.

The survival rate was derived from Kaplan-Meier curves. A receiver operating characteristic (ROC) curve analysis was performed to compare the predictive potential of all parameters.

Results

Patient Characteristics and Comparison of PAH vs Non-PAH Patients
PAH patients were younger and had more prominent hemodynamic impairment than non-PAH patients. All subgroups of PH-comprised patients with renal insufficiency and the usage of diuretics were not different between groups (Table 1 ).


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  		Table 1. Patient Characteristics: PAH vs Non-PAH

 
Correlation of NT-proBNP With Clinical and Hemodynamic Parameters: Impact of Renal Function
Overall, the normalized NT-proBNP values were significantly correlated with hemodynamics as well as serum creatinine (r = 0.52) and were inversely correlated with the calculated creatinine clearance (r = – 0.33; all p < 0.001) [Table 2 ]. These correlations were observed in all groups irrespective of the etiology of PH (data not shown). Absolute NT-proBNP values showed comparable results (data not shown). Overall, the normalized as well as absolute NT-proBNP values correlated with the respective normalized and absolute BNP values (both r = 0.76; p < 0.001) [Fig 1 ].


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  		Table 2. Correlation Analysis of Hemodynamic Parameters and Natriuretic Peptides Depending on Renal Function*

 

Figure 1
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  		Figure 1. Correlation of NT-proBNP and BNP.

 
In patients with creatinine clearance > 60 mL/min, correlations of hemodynamics and NT-proBNP were stronger. The normalized NT-proBNP and normalized BNP values were strongly correlated (r = 0.8; p < 0.0001).

In patients with a creatinine clearance ≤ 60 mL/min, however, normalized NT-proBNP levels were only correlated with RAP. All other hemodynamic parameters did not correlate to NT-proBNP. Nevertheless, normalized NT-proBNP and BNP concentrations were correlated (r = 0.65; p = 0.001).

Correlation of BNP With Clinical and Hemodynamic Parameters: Impact of Renal Function
Overall, as expected, normalized plasma BNP values showed a significant correlation with hemodynamics (independent of the renal impairment) and serum creatinine (r = 0.38; p < 0.001) but were not related with creatinine clearance (Table 2). NT-proBNP and BNP levels were not correlated with age, weight, height, or body mass index.

Correlation of Hemodynamic Impairment and Renal Insufficiency
We observed a slight correlation of serum creatinine with mean PAP (r = 0.22; p < 0.05), PVR (r = 0.24; p < 0.01), and RAP (r = 0.29; p < 0.01), and an inverse correlation with CO (r = – 0.23; p < 0.05) and CI (r = – 0.3; p < 0.01). Moreover, creatinine clearance showed a slight inverse correlation with RAP (r = – 0.19; p < 0.05) and a slight correlation with CO (r = 0.2; p < 0.05) and CI (r = 0.25; p < 0.05).

Risk Estimates of Mortality
Intending to assess different risk factors of death, we performed a univariate analysis as a first step. NT-proBNP and BNP levels that were 2.5-fold above normal (normalized ratio, 2.5) and a creatinine clearance < 60 mL/min increased the risk of death significantly (Tables 234 ). Using the multivariate analysis, a stepwise introduction of covariates was performed for these parameters. Again, elevated NT-proBNP levels (2.5-fold above normal) and a creatinine clearance < 60 mL/min were significant predictors of mortality in multivariate analysis. Moreover, a normalized NT-proBNP level of 2.5 was still a significant risk factor of death when a normalized BNP ratio was the covariate. But this was not observed vice versa.


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  		Table 3. Predictors of Mortality in Univariate Analysis

 

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  		Table 4. Predictors of Mortality in Multivariate Analysis*

 
Survival Estimates Based on NT-proBNP, BNP, Renal Insufficiency, and Hemodynamic and Clinical Variables
The impact of these risk factors on observed survival was assessed by Kaplan-Meier analysis (Fig 234 ). Sixty-six of 118 patients (55.9%) had elevated NT-proBNP levels of at least 2.5 times above normal. Of these patients, 13 patients (19.7%) died within 25.6 ± 3.4 months. In contrast, only 1 of the remaining 52 patients (1.9%) died within 44.28 ± 1.9 months (p < 0.01).


Figure 2
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  		Figure 2. Impact of high NT-proBNP ratios on survival in PH patients.

 

Figure 3
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  		Figure 3. Impact of high BNP ratios on survival in PH patients.

 

Figure 4
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  		Figure 4. Impact of renal insufficiency on survival in PH patients.

 
Regarding BNP, 50 patients (42.4%) had levels of at least 2.5 times above normal. Ten of these patients (20%) died within 22.37 ± 3.11 months. Four of the remaining 68 patients (5.9%) died within 42.58 ± 1.82 months (p < 0.05).

Twenty-two patients (18.64%) had an impaired creatinine clearance of < 60 mL/min. Six of these patients (27.3%) died within 13.58 ± 1.71 months, whereas only 8 of the 96 patients (8.3%) with a creatinine clearance > 60 mL/min died within 38.48 ± 3.04 months (p < 0.01).

Ninety-four patients (79.66%) were in functional World Health Organization (WHO) class 3 or 4. All 14 deaths occurred in this patient group (14.85%), whereas none of the patients in WHO class 1 or 2 died (p < 0.05). None of the hemodynamic or remaining clinical parameters were significant predictors of mortality in our study population.

Comparison of Different Predictors of Mortality
Fourteen of 118 patients (11.9%) died during follow-up. ROC curve analysis was performed to differentiate between various risk factors of death. During this analysis, a normalized NT-proBNP level of 2.5 was the only prognostic parameter that predicted a significant number of these deaths (area under the curve, 74.6%; p < 0.001).

Discussion

PH is a disabling disease with a high mortality. Natriuretic peptide levels serve as noninvasive markers that reflect the severity of PH and significantly aid in the management of these patients. BNP and NT-proBNP concentrations are increasingly used in various treatment trials and daily practice. NT-proBNP might be an attractive parameter in this context because of its long half-life in human blood (up to 3 days, room air) and its fully automatic analysis.12 However, little is known about the impact of renal dysfunction on the diagnostic accuracy of natriuretic peptides in PH. Moreover, at this time, we lack information to support the prognostic value of NT-proBNP and renal insufficiency in this population.

In this study, an elevated NT-proBNP 2.5-fold above normal predicted mortality and served as an independent risk factor of death in patients with PH. In addition, a significantly impaired renal function (creatinine clearance < 60 mL/min) was another prognostic marker in this population. As expected, mortality was related to increased BNP levels (2.5-fold above normal). However, during multivariate analysis, only NT-proBNP independently predicted mortality, while BNP did not. The superiority of significantly elevated NT-proBNP levels in terms of the prognostic value was confirmed during ROC curve analysis. In left-heart disease and sickle-cell disease, NT-proBNP adds prognostic information beyond conventional risk factors1822. Very recently, NT-proBNP was found to be a prognostic parameter in a smaller group of PH patients.23 However, this present study is the first to directly compare NT-proBNP and BNP in a large cohort of patients with isolated PH as prognostic markers. Different mechanisms could be responsible for the superiority of NT-proBNP as a mortality parameter. Although NT-proBNP and BNP are released from cardiomyocytes on an equimolar basis, circulating concentrations of NT-proBNP are higher than those of BNP.24 The half-life of BNP is significantly shorter than that of NT-proBNP because BNP is cleaved by neutral endopeptidases, is cleared via a specific receptor,25 and is excreted—to a lesser extent—via the kidneys.26 In contrast, NT-proBNP is only excreted renally without prior degradation, making it more resistant against short-term influences. Moreover, in terms of prognostic information, the integration of renal insufficiency could be of advantage, since a marked renal insufficiency (ie, creatinine clearance < 60 mL/min) was a mortality parameter itself in our cohort. Since one of our findings confirmed BNP as a prognostic parameter, these assumptions are not contradictory to previous observations in idiopathic PAH.9

Based on the observation that the magnitude of NT-proBNP elevation depends on renal function in PH, it seems plausible that the correlation of hemodynamic parameters and natriuretic peptides is reduced in renal insufficiency (which we observed in almost 20% of the population!). With regard to NT-proBNP, levels were related to serum creatinine and calculated clearance. Although all important hemodynamic parameters of PH showed a good correlation with the NT-proBNP levels in the study population as a whole, RAP was the only parameter that correlated with NT-proBNP in patients with markedly impaired creatinine clearance. Since BNP concentrations were influenced by renal function to a minor degree, BNP levels showed good correlation with the severity of hemodynamic impairment irrespective of the renal function. Our data are neither in conflict with preceding studies13151627 that describe a correlation between NT-proBNP and hemodynamic parameters in patients with PAH (although these studies did not consider the influence of renal insufficiency), nor are they contradictory to the above observation of the predictive values of NT-proBNP and BNP. Since survival in PH is not solely correlated to the severity of hemodynamic impairment,28 integration of renal insufficiency as a risk factor of death seems to be of advantage. However, we did not characterize the development of NT-proBNP under the influence of specific therapies for PH and/or renal insufficiency. Nevertheless, since there is a close correlation of BNP and hemodynamic parameters, even in the presence of moderate renal insufficiency and during long-term follow-up,29 this might underline the role of BNP as a follow-up parameter in PH.

Since renal insufficiency is a known significant risk factor for death30 and seems to develop in a significant number (20%) of patients with PH, it seems to be of crucial relevance to recognize it as a mortality parameter in PH. Renal function was inversely related to the magnitude of the hemodynamic impairment in our trial, suggesting that a diminished renal perfusion is one factor that leads to renal insufficiency in PH patients. However, we cannot conclude on this because we did not definitely exclude other etiologies of renal insufficiency in our study population.

Our study had limitations. One is the heterogeneity of the study population because we included patients with a variety of associated forms of PH. However, the main findings of our study were reproducible in all major subgroups. In addition, PH has been shown repeatedly to be a major risk factor of death irrespective of the underlying disease, and natriuretic peptides are not influenced by lung functional impairment. Another limitation is that we estimated renal function on a simple estimation of creatinine clearance and do not provide repetitive data. However, we included only patients with stable renal function and stable doses of diuretics. Despite these limitations, we conclude the following: (1) in PH, NT-proBNP, BNP, and renal insufficiency are risk factors of death; (2) NT-proBNP is superior to BNP as mortality parameter because it integrates renal impairment and is less susceptible to short-term influences; and (3) the diagnostic accuracy of NT-proBNP as a noninvasive follow-up parameter of the hemodynamic variables seems to be inferior to that of BNP in patients with impaired renal function.

Acknowledgements

This article contains a significant portion of the doctoral thesis of Mr. Juergen Christian Tuerpe. The excellent assistance of Mr. Tobias Meis and Mrs. Elisabeth Becker and her team is gratefully acknowledged.

Footnotes

Abbreviations: BNP = brain natriuretic peptide; CI = cardiac index; CO = cardiac output; NT-proBNP = N-terminal pro-brain natriuretic peptide; PAH = pulmonary arterial hypertension; PAP = pulmonary arterial pressure; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; RAP = right atrial pressure; ROC = receiver operating characteristic; WHO = World Health Organization

The authors have no conflicts of interest to disclose.

Received for publication July 18, 2006. Accepted for publication August 29, 2006.

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