N-Terminal Pro-Brain Natriuretic Peptide Is a Useful Prognostic Marker in Patients with Pre-Capillary Pulmonary Hypertension and Renal Insufficiency

<div><p>N-terminal pro-brain natriuretic peptide (NT-proBNP) is a routinely used prognostic parameter in patients with pre-capillary pulmonary hypertension (PH). As it accumulates in the presence of impaired renal function, the clinical utility of NT-proBNP in PH patients with concomitant renal insufficiency remains unclear. In a retrospective approach, patients with pre-capillary PH (group I or IV) and concomitant renal insufficiency at time of right heart catheterization (glomerular filtration rate (GFR) ≤60 ml/min/1.73 m²) were identified out of all prevalent pre-capillary PH patients treated at a single center. Forty patients with renal insufficiency (25.8%) were identified and matched regarding hemodynamic parameters with a control group of 56 PH patients with normal renal function (GFR >60 ml/min/1.73 m²). Correlations of NT-proBNP levels with hemodynamic and prognostic parameters (time to clinical worsening and overall survival) were assessed. Overall, GFR correlated inversely with NT-proBNP and had the strongest influence on NT-proBNP levels in a stepwise multiple linear regression model including hemodynamic parameters and age (r² = 0.167). PH patients with renal insufficiency had significant higher levels of NT-proBNP (median: 1935 ng/l vs. 573 ng/l, p = 0.001). Nevertheless, NT-proBNP correlated with invasive hemodynamic parameters in these patients. Using higher cut-off values than in patients with preserved renal function, NT-proBNP levels were significantly associated with time to clinical worsening (>1660 ng/l, p = 0.001) and survival (>2212 ng/l, p = 0.047) in patients with renal insufficiency. Multivariate Cox’s proportional hazards analysis including established prognostic parameters, age and GFR confirmed NT-proBNP as an independent risk factor for clinical worsening in PH patients with renal insufficiency (hazard ratio 4.8, p = 0.007). Thus, in a retrospective analysis we showed that NT-proBNP levels correlated with hemodynamic parameters and outcome regardless of renal function. By using higher cut-off values, NT-proBNP seems to represent a valid clinical marker even in PH patients with renal insufficiency.</p></div

Patients’ characteristics.

<p>Data are presented as mean ± SD or numbers.</p><p>Comparison of means between GFR-groups are performed by Student’s T, Mann-Whitney-U^& or Chi-Square test^§. CTD = connective tissue disease. ^# Other includes HIV, porto-pulmonary hypertension and congenital heart diseases.</p

Glomerular filtration rate (GFR).

<p>Distribution of GFR (ml/min/1.73 m²) among patients’ groups. Mean GFR was 45±11 ml/min/1.73 m² (range: 10 to 58 ml/min/1.73 m²) and 78±14 ml/min/1.73 m² (ranging from 61 to 136 ml/min/1.73 m²).</p

Multivariate Cox’s proportional hazards analysis assessing the predictive value of n-terminal pro-brain natriuretic peptide (NT-proBNP) levels on clinical worsening in 40 PH patients with concomitant renal insufficiency (defined as glomerular filtration rate (GFR) ≤60 ml/min/1.73 m²) in a model with further established non-invasive parameters, age and renal function.

<p>Median of age, 6MWD and GFR in patients with renal insufficiency were used as cut-off values.</p

Overall Survival.

<p>Receiver operating characteristic (ROC) analysis to determine the cut-off value in patients with renal insufficiency (defined as glomerular filtration rate (GFR) ≤60 ml/min/1.73 m²; <b>A</b>). In Kaplan-Meier analysis, higher levels of n-terminal pro-brain natriuretic peptide (NT-proBNP) were significantly associated with poor survival (<b>B;</b> p = 0.047, log-rank).</p

Time to clinical worsening (TTCW).

<p>Receiver operating characteristic (ROC) analysis to determine the cut-off value in patients with renal insufficiency (defined as glomerular filtration rate (GFR) ≤60 ml/min/1.73 m²; <b>A</b>). In Kaplan-Meier analysis, higher levels of n-terminal pro-brain natriuretic peptide (NT-proBNP) were significantly associated with early clinical worsening (<b>B;</b> p = 0.001, log-rank).</p

Additional file 4: Table S3. of Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension

Association of the neutrophil/lymphocyte ratio with demographic, functional and hemodynamic parameters, as well as co-morbidities. (DOCX 16 kb

Additional file 3: Figure S1. of Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension

Receiver operating characteristics (ROC) across transplantation-free survival: ROC analyses across the range of relative numbers of neutrophils and the neutrophil/lymphocyte ratio in all patients with PAH, in patients with incident PAH and in patients with PAH without cardiovascular risk factors. (PDF 285 kb

Additional file 1: Table S1. of Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension

Correlation of differential blood count parameters with functional and hemodynamic parameters of patients with PAH. (DOCX 13 kb