Urinary NT-proBNP is Independently Associated with Long-term Prognosis of Mortality in Chronic Heart Failure

Special Article – Novel Markers in Heart Diseases

J Dis Markers. 2015;2(3): 1027.

Urinary NT-proBNP is Independently Associated with Long-term Prognosis of Mortality in Chronic Heart Failure

Carsten G Jungbauer*, Stefan Stadler, Christoph Birner, Markus Resch, Ekrem Ücer, Sabine Fredersdorf, Lars S Maier and Andreas Luchner

Klinik und Poliklinik fuer Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany

*Corresponding author: Dr. Carsten Jungbauer, Klinik und Poliklinik für Innere Medizin II – Kardiologie, Universitätsklinikum Regensburg, 93042 Regensburg, Germany

Received: May 24, 2015; Accepted: July 13, 2015; Published: July 15, 2015


Aims: Plasma NT-proBNP is the established heart failure marker. Recently, several studies showed that NT-proBNP may have potential as a urinary marker due to its renal arterio-venous clearance. The objective of this study was to assess the prognostic capacity of urinary NT-proBNP for patients with chronic heart failure.

Methods: NT-proBNP (Elecsys proBNP®, Roche) was assessed simultaneously in fresh spot urine and plasma from 149 patients with chronic heart failure. During a 5-year-follow-up, data was obtained regarding allcause mortality (n= 47) and a combined endpoint of all-cause-mortality and rehospitalisation due to congestive heart failure (n= 67).

Results: Urinary and plasma NT-proBNP were both significantly elevated in patients suffering from an event compared to patients without event (each p< 0.05). Urinary NT-proBNP above the 75th percentile incorporated significant prognostic information regarding all-cause mortality and the combined endpoint (each p<0.05). In cox-regression analysis, urinary NT-proBNP as well as plasma NT-proBNP were both independent predictors for all-cause mortality (each p< 0.05), beside age, diabetes and ejection fraction (EF). Only plasma NT-proBNP was a significant predictor for the combined endpoint (p <0.05; urinary NTproBNP p= n.s.), beside age, male gender, diuretic use and EF. The combination of urinary NT-proBNP and plasma NT-proBNP showed additive prognostic value compared with plasma NT-proBNP alone.

Conclusions: Urinary NT-proBNP incorporated significant and independent predictive value, especially regarding all-cause mortality. Measurement of urinary NT-proBNP seems to be a promising method for heart failure prognostication.

Keywords: Urinary NT-proBNP; Heart failure; Cardiac markers; Natriuretic peptides


AUC: Area Under the Curve; CI: Confidence Interval; EF: Ejection Fraction; GFR: Glomerular Filtration Rate; JVP: Jugular Venous Pressure; LVD: Left Ventricular Dysfunction; NT-proBNP: N-Terminal pro-Brain Natriuretic Peptide; OR: Odds Ratio; ROC: Receiver Operating Characteristic.


N-terminal pro-brain natriuretic peptide (NT-proBNP) is an established heart failure biomarker. NT-proBNP incorporates strong predictive value in heart failure, but also in other cardiac conditions [1-7].

NT-proBNP undergoes predominantly renal clearance–opposite to BNP, which is cleared by enzymatic degradation through neutral endopeptidase and receptor-mediated clearance beside renal extraction [8-10]. NT-proBNP can be detected in the urine and seems to have important potential as a urinary marker of heart failure. Investigation of urine is simple and non-invasive, which may be very attractive under special conditions, e.g. in medical practices without own laboratory. However, studies of urinary NT-proBNP are very sparse [11-15], particularly studies using fresh, unfrozen samples [16,17]. Even less data is available regarding the prognostic capacity of urinary NT-proBNP [13,18].

It was therefore our aim to assess urinary NT-proBNP for the first time in fresh urine regarding its long-term predictive value in comparison with plasma NT-proBNP levels. We analysed plasma and urinary NT-proBNP simultaneously from fresh samples in a cohort of patients with chronic heart failure and performed a 5-years-followup.


Study procedure

Between January 2008 and June 2008, 150 patients with structural heart disease participated in the study. Patients were recruited from the heart failure outpatient’s clinic of university hospital Regensburg after presenting with stable disease over 6 months. According to the ESC guidelines criteria, heart failure was diagnosed in patients with typical signs and symptoms and objective evidence of a structural or functional abnormality of the heart at rest [19]. Patients with acute myocardial infarction, pulmonary embolism or stroke in the last 6 months were not included. In addition to that also patients with severe chronic pulmonary disease and severe or end stage chronic renal disease were excluded (KDOQI stage 5 with eGFR < 15 ml/ min/1.73m2 or on dialysis). Patients between 18 and 80 years who were able to sign the consent form and suffering from ischemic or dilated cardiomyopathy were included into the study.

Every participant was interviewed (NYHA stage, drugs, especially diuretic dose) and physically examined (edema, pulmonary rales, elevated JVP). Ejection fraction (EF) was echocardiographically evaluated by Simpson´s method. EGFR was calculated according to the CKD EPI formula from plasma creatinine, sex and age [20].

Survival confirmation and date of death were obtained from hospital or death registries or by confirmation of relatives. Further, the composite of rehospitalisation for congestive heart failure and allcause mortality was used as combined endpoint.

The study was approved by the institutional ethics committee (vote 07/152) and was performed in accordance with good clinical practice guidelines and with the standards established for human experimentation by the Declaration of Helsinki.

Sample processing and biochemical analyses: To gain the requested results, blood samples and fresh spot morning urine samples were sent to the central laboratory immediately after collection on the same day. The urine samples were collected into standard urine collection tubes without the addition of degradation inhibitors. Blood was collected into a serum tube according to our local laboratory protocol. The Elecsys 2010 NT-proBNP assay (Roche Diagnostics, Mannheim, Germany) was used for analysis of both urinary and plasma NT-proBNP immediately upon receipt of the samples. The analytical range was 5-35000 pg/ml. The feasibility of the Elecsys 2010 NT-proBNP assay to accurately determine urinary NT-proBNP was shown previously [16]. All urinary biomarkers were normalized to urinary creatinine in order to minimize dilutional bias, especially in a blended heart failure collective prescribed with diverging diuretic dosis.


Descriptive data are presented as mean (+/-SEM), medians (IQR) or percentages. Normally distributed values were evaluated with Student´s unpaired two-sided T-test. The Mann-Whitney-U-test was used for continuous variables. For follow-up analysis, we constructed Kaplan-Meier survival curves reflecting the relationship between the time of follow-up and probability of reaching the endpoints. Patients were followed for a mean duration of 53 months (IQR 49 – 66 months); only one patient was lost to follow-up. Upon analysis, in 149 patients the following endpoints were observed: a total of 47 allcause mortalities and 67 combined events of rehospitalisation(s) due to congestive heart failure and all-cause mortality. The median of the patients collective and dichotomization for < and >= 75th percentile were each used as binary cut point for all markers and the Kaplan- Meier curves were compared by log-rank test. Multivariable Cox proportional hazard analyses were performed as stepwise regressions with backward elimination to evaluate possible associations between each marker and both endpoints. Age, male gender, BMI, ischemic cardiomyopathy, history of hypertension, diabetes or stroke, diuretic use were included into cox regression analysis. Biomarkers (urinary and plasma NT-proBNP, eGFR, urinary albumin) and EF were used as continuous variables in Cox regression analysis. Further, the combination of plasma and urinary NT-proBNP was analysed to discriminate an additional value of the combined use of both markers (Figure 2a).