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

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

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

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

eIF-5A, DHS and DOHH are overexpressed in the glioblastoma cell lines G55T2 and U87-MG.

<p>(A) Expression levels of eIF-5A, -A2, DHS and DOHH were analysed by qPCR (mean ±SD, n = 3; *:P<0.05; **:P<0.001 ) in primary normal human astrocytes (NHA) compared to G55T2 and U87-MG cell lines. SYBR green Ct values were normalized against GAPDH expression and calculated using the 2^−ΔΔCT method. (B) Overexpression of eIF-5A, DHS and DOHH was confirmed by immunoblotting with whole cell lysates (35 µg protein per sample).</p