|Year : 2010 | Volume
| Issue : 2 | Page : 262-268
|Clinical significance of N-Terminal Pro-B-type natriuretic peptide (NT-proBNP) in hemodialysis patients
Imed Helal1, Raja Belhadj2, Amira Mohseni2, Lilia Bazdeh3, Habiba Drissa3, Fethi ELyounsi1, Taieb Ben Abdallah1, Jaouida Abdelmoula2, Adel Kheder1
1 Department of Nephrology (Pr Kheder), Charles Nicolle Hospital, Tunis, Tunisia
2 Department of Biochemical, Charles Nicolle Hospital, Tunis, Tunisia
3 Department of Cardiology, Charles Nicolle Hospital, Tunis, Tunisia
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|Date of Web Publication||9-Mar-2010|
| Abstract|| |
Circulating biomarkers play a major role in the early detection of cardiovascular disease. The purpose of this study was to determine levels of N-Terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in hemodialysis (HD) patients and to examine the relationship of this marker to left ventricular hypertrophy and to cardiac dysfunction. Plasma NT-proBNP concentrations were measured in patients undergoing chronic HD, who did not any clinical evidence of heart failure, (n=32; mean age 43.14 ± 12 years; sex-ratio 1.8) as well as healthy volunteers (n=32; mean age 45.84 ± 1.9 years; sex-ratio 1). In addition, the correlation between plasma NT-proBNP concentration and parameters of echocardiography was examined. The plasma NT-proBNP levels in the HD patients were significantly higher (14422.6 ± 13757.8 pg/mL) than those in healthy volunteers (39.21 pg/mL) (P< 10 -3 ). In addition, the area under the receiver operating characteristic curve (ROC) revealed that the cut-off level of NT-proBNP was 288 pg/mL. On univariate analysis, the plasma NTproBNP concentrations, in patients on HD, correlated positively with age (P= 0.004; r=0.5), systolic (P= 0.046; r= 0.36) and diastolic blood pressures (P= 0.037; r= 0.37), residual diuresis (P= 0.09; r= 0.3), the left atrial diameter (LAD) (P= 0.006; r= 0.55), left ventricular mass index (LVMI) (P= 0.01; r= 0.44) and negatively with albumin (P= 0.01; r= -0.44). However, there was no correlation between plasma levels of NT-proBNP and gender, body mass index (BMI), mean period on dialysis, pulse pressure, dry weight and left ventricular dysfunction. On multivariate analysis, only age (P= 0.014, RR= 2.8) was associated with significantly increased levels of NT-proBNP. Further studies are needed to carefully assess the diagnostic accuracy and prognostic value of NT-proBNP in patients on HD.
|How to cite this article:|
Helal I, Belhadj R, Mohseni A, Bazdeh L, Drissa H, ELyounsi F, Abdallah TB, Abdelmoula J, Kheder A. Clinical significance of N-Terminal Pro-B-type natriuretic peptide (NT-proBNP) in hemodialysis patients. Saudi J Kidney Dis Transpl 2010;21:262-8
|How to cite this URL:|
Helal I, Belhadj R, Mohseni A, Bazdeh L, Drissa H, ELyounsi F, Abdallah TB, Abdelmoula J, Kheder A. Clinical significance of N-Terminal Pro-B-type natriuretic peptide (NT-proBNP) in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2020 Jul 3];21:262-8. Available from: http://www.sjkdt.org/text.asp?2010/21/2/262/60065
| Introduction|| |
Circulating biomarkers play a major role in the early detection of cardiovascular disease such as heart failure. In recent years, natriuretic peptides have become promising candidates in this respect;  particularly, B-type natriuretic peptides (BNP) have attracted much attention. The circulating half-life of BNP is 23 mins, whereas the inactive terminal fragment (NT-proBNP) has a much longer half-life (60-120 mins), which is of relevance for its use as a diagnostic tool.  The clinical benefit of using these markers to screen for cardiovascular (CV) risk has been well documented in the general population. ,,, Patients with chronic kidney disease (CKD), including hemodialysis (HD) patients, have one of the highest CV risk scores. In this population, the clinical benefit of NT-proBNP measurements has not been well established. ,, The fact that HD patients have significantly elevated BNP and NT proBNP levels ,, has been considered a major limitation for its use as a diagnostic tool. Elevated levels were attributed to chronic fluid overload, rendering measurement of NT-proBNP levels unreliable. However, considering the CV burden of patients with CKD, ,,,,,,, there is a definite need to explore the diagnostic value of NT-proBNP levels and to establish the valid normal ranges in these patients.
In this study, we measured serum NT-proBNP levels in stable patients on chronic HD without clinical signs of progressive heart failure, and investigated its pathophysiological significance. In particular, our aim was to determine a cut-off NT-proBNP value adjusted for HD patients.
| Patients and Methods|| |
We studied 32 stable patients who had been on HD for at least six months at the Charles Nicolle hospital. All patients were clinically stable and gave informed consent. Patients with acute cardiac disease and/or acute cardiac failure were excluded from the study. Clinical characteristics and laboratory data of the patients are shown in [Table 1]. All HD patients received regular dialysis using the cellulose-triacetate or polysulphone dialyzer three times per week in sessions lasting four hours each. The dialysate was bicarbonate buffered, the dialysate flow rate was 500 mL/ min, and blood flow ranged from 250 to 300 mL/min.
Plasma NT-proBNP concentrations were also measured in 32 control subjects. These subjects were carefully screened to exclude cardiac or other systemic disease.
In all patients, trans-thoracic echocardiogramphy was performed on an inter-dialytic day in the evaluation phase.
M-mode and two-dimensional images as well as spectral- and colour-flow Doppler recordings were obtained (ATL). Left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), inter-ventricular septal thickness (IVST), left atrial diameter (LAD) and left ventricular posterior wall thickness (LVPWT) were measured.
Left ventricular ejection fraction (LVEF) was calculated by standard techniques. Left ventricular mass (LVM) was calculated by the regression equation described by Devreux and Reichek; LVM = 1.04 x [(IVST+LVPWT+LVDd) 3 - LVDd 3 ] - 13.6. This value was divided by the body surface area to determine the left ventricular mass index (LVMI), presented in g/m 2 . LVMI was defined as LVMI > 47 g/m 2 for females and > 50 g/m 2 for males.
We collected blood samples from all patients before the commencement of a dialysis session, from the venous line. The samples were collected in chilled tubes containing ethylenediamine tetraacetic acid (EDTA) and were immediately centrifuged at 4°C. Plasma was separated and stored at -20°C until assays were performed. NT-proBNP was measured using a comercially available electro-chemoluminescence immunoassay that was performed on a Roche E2010 modular analytics system. All other biochemical parameters were measured with routine laboratory methods.
| Statistical Analysis|| |
We used the SPSS statistical software 11.5 (Lead Technologies Inc., Chicago, USA) for statistical analysis. Data are expressed as mean ± SD. Each factor was contrasted by univariate analysis, using either unpaired student's t test for continuous variables, or by K2 analysis for non-continuous data. Significant factors by univariate analysis were then compared by multivariate analysis and the relative risk (RR) for each was calculated. We calculated a receiver operating characteristic (ROC) curve in order to establish an NT-proBNP cut-off value that discriminates HD patients from control subjects. Because of its abnormal distribution, the plasma NT-proBNP values were logarithmically transformed before regression analysis was performed. Statistical significance was defined by P value less than 0.05.
| Results|| |
General Patient Characteristics
The baseline characteristics of the 32 patients included in the study are shown in [Table 1]; the mean age 43.14 ± 12 years, sex-ratio was 1.8 and there was no clinical evidence of heart failure. Among the healthy volunteers, the mean age was 45.84 ± 1.9 years and sex-ratio was 1. [Table 2] depicts the echocardiograph findings, LV mass and LV function in the patient population. Twenty-three patients (72%) had LVH on echocardiography. Diastolic dysfunction was present in 19 patients (59%).
The plasma NT-proBNP levels in the HD popoulation were significantly higher (14422.6 ± 13757.8 pg/mL) than those among healthy subjects (39.21 pg/mL) (P< 10 -3 )
In addition, by creating ROC curves, we identified a cut-off value for NT-proBNP that discriminates between HD patients and control subjects [Figure 1].
An NT-proBNP cut-off value of 288 pg/mL resulted in a 100% specificity and sensitivity.
| Correlation Study|| |
On univariate analysis, plasma NT-proBNP concentrations among HD patients correlated positively with age (P= 0.007; r= 0.41), pre-HD systolic (P= 0.046; r= 0.36) and diastolic blood pressures (P= 0.037; r= 0.37), residual diuresis (P= 0.09; r=0 .53), the LAD (P= 0.009; r= 0.53), LVMI (P= 0.01; r= 0.44) and negatively with BMI (P= 0.04; r= -0.32) and albumin (P= 0.01; r= -0.44).
However, there was no correlation between plasma levels of NT-proBNP and gender, mean period on dialysis, pulse pressure, dry weight and left ventricular dysfunction.
On multivariate analysis, only age of the study patients (P= 0.014, RR= 2.8) was associated with significantly elevated NT-proBNP levels underlining that it is an independent factor [Figure 2]. NT-proBNP levels were also statistically significantly associated with BMI (P = 0.07, RR= -2).
| Discussion|| |
The measurement of the plasma concentration of cardiac natriuretic peptides, particularly BNP, in uremic patients on chronic dialysis, has proved to be useful for the diagnosis of LVH and for excluding the presence of LV dysfunction. Left ventricular hypertrophy and LV dysfunction are currently considered the strongest predictors of cardiovascular and total mortality in the dialysis population. , LVH is a notoriously pervasive complication in end-stage renal disease with a prevalence rate ranging from 60 to 80%. LV systolic dysfunction is relatively much less frequent, with its prevalence being approximately 15%.  Our study again further confirms in a dialysis population the high prevalence of these alterations. If these alterations are to be a target for intervention, simple and reliable methods, specifically validated in the dialysis population are needed. Echocardiography is undoubtedly of proven value, and most agree that serial echocardiographic studies in patients entering renal replacement therapy is a better system to identify and treat alterations in LV mass and function in these patients. However, hospital-based echocardiographic services are often stretched, and for this reason, in routine clinical practice, this technique is applied much less often than desirable. The situation is probably similar to that of general practice.  Echocardiography apart, there are no simple and validated methods to clinically diagnose these abnormalities in dialysis patients. Echocardiogram, which is a widely available method in the general population, has a sensitivity that may reach at most 40%,  and its use in dialysis patients poses additional problems. Thus, the opportunity for intervention on LVH and systolic dysfunction is in part limited by the availability of simple, easily accessible diagnostic tools.
In the present study, we investigated whether the natriuretic peptide NT-proBNP may be of help in the assessment of LVH in patients on maintenance HD, since its diagnostic potential has been extensively studied in patients with normal kidney function. ,,, We found clearly elevated NT-proBNP levels in our HD patients; in fact, even patients without a diagnosis of LVD showed values more than ten-fold higher than the normal range given by the manufacturer. Our finding is in line with repeatedly reported increased levels of natriuretic peptides as a result of reduced renal excretion and chronic volume overload in CKD patients without LVD. ,,,, We have to point out, however, that a recommendation for specific reference values in order to use NT-proBNP routinely as a diagnostic tool to separate LVD from over-hydration in these patients is not available yet.
The brain natriuretic peptide was first isolated from a porcine brain and has potent biological effects, as does the atrial natriuretic peptide.  Plasma brain natriuretic peptide levels are very low or not detectable in normal subjects; the brain natriuretic peptide is a novel cardiac hormone secreted mainly from the ventricules in patients with heart failure.  It has been reported that high left ventricular end-diastolic pressure or low ejection fraction might stimulate the secretion of brain natriuretic peptide. , However, there have been only a few reports on the mechanisms involved in the reduction of brain natriuretic peptide levels after HD in patients with chronic renal failure. ,
he present study confirms previous reports that plasma NT-proBNP levels are increased in dialysis patients. However, the current study does not confirm previous reports that NTproBNP is a biomarker for LVH in patients with uremia, and is probably influenced by isolated renal dysfunction. Also, we found that only the age of patients was associated with a significant increase of NT-proBNP levels, indicating that other factors and interventions were probably biased by age. Another explanation for the present data is that aging is a major risk factor for cardiac disease and the increase in the levels of the peptides is dependent on age.
Our study has limitations, with the most important being the small number of our study population. Also, we focused on patients without overt heart failure because, we believed that in overt heart failure, echocardiography is almost always performed to confirm the clinical diagnosis and to incorporate anatomic and hemodynamic information into the clinical decision process. Thus, the diagnostic value of these peptides for overt heart failure, although likely, cannot be extrapolated from our data. The third limitation derives from the fact that we did echocardiographic studies and plasma sampling during the dialysis interval rather than immediately before or after dialysis. While this approach is probably ideal from a physiological standpoint (the volume status approximates the individual steady state between dialysis sessions), it demands an additional outpatient appointment during a non-dialysis day. Pre-dialysis sampling tends to shift upwardly the diagnostic thresholds of these peptides, and it remains to be seen whether this affects the diagnostic power of NT-proBNP. Nonetheless, it is common practice in many dialysis centers to periodically reexamine patients in the dialysis interval, and this may be a good occasion for NT-proBNP testing. Finally, although we analyzed data both on the basis of prospectively preset thresholds and on retrospectively defined "best cut offs," the diagnostic potential of BNP was maximized by the second, retrospective, approach. Thus, these retrospective thresholds, which are specific for patients on dialysis, remain to be prospectively tested in other dialysis centers to prove the external validity of our findings.
| Conclusion|| |
In this study, we found that only the age of patients was associated with a significant increase of NT-proBNP levels, indicating that other factors were probably biased by the age. Finally, we can summarize that NT-proBNP is not a good marker of cardiovascular disease or water overload in HD patients. These low-molecular peptides are similar to beta2-microglobulin and other low molecular weight peptides and proteins that accumulate in blood due to decreased glomerular filtration rate. Their elimination during HD is influenced by the type of HD membrane. Further work is needed to carefully assess the diagnostic accuracy and prognostic value of NT-proBNP in HD patients.
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Department of Nephrology, Charles Nicolle Hospital, Boulevard 9, Avril1006, Tunis
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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