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Technical Briefs |
1 Klinikum der Philipps-Universität Marburg, Department of Clinical Chemistry and Molecular Diagnostics, 35033 Marburg, Germany;2 Klinikum Fulda, Department of Internal Medicine III, Fulda, Germany
aauthor for correspondence: fax 49-6421-2865594, e-mail hg.wahl{at}med.uni-marburg.de
The measurement of natriuretic peptides for the diagnosis of heart failure has been a major breakthrough in cardiology (1)(2). B-Type natriuretic peptide (BNP) is synthesized as preproBNP mainly in the ventricular myocardium. On ventricular myocyte stretch, preproBNP is enzymatically cleaved to proBNP and released in the form of the hormonally active BNP and the inactive N-terminal proBNP (NT-proBNP). Both BNP and NT-proBNP have been shown to reflect heart failure severity (1), but studies on their sensitivity and specificity for different degrees of heart failure produced conflicting results (3)(4)(5)(6). Both BNP and NT-proBNP can be used for the diagnosis of heart failure, but there are important differences between the two tests, particularly regarding influence of age and renal function (1). In addition to glomerular filtration, BNP is eliminated from plasma mainly through natriuretic peptide receptors and degraded by neutral endopeptidases (7)(8)(9). In contrast, NT-proBNP possibly is largely eliminated by glomerular filtration only (4). This explains the strong influence of renal function on NT-proBNP concentrations. Because of the normal decrease in glomerular filtration rate with increasing age, the diagnostic cutoff for NT-proBNP depends on age (1). This is also true for BNP(10), but to a much lesser extent. Importantly, both BNP and NT-proBNP concentrations can be increased in the setting of hemodialysis (11)(12)(13)(14). The prevalence of chronic heart failure is significantly increased in dialysis patients and is associated with left ventricular hypertrophy, which may be secondary to volume overload and hypertension (15)(16)(17). Reports on the effect of hemodialysis on plasma concentrations of BNP and NT-proBNP showed significant decreases in BNP (11)(14)(18) and significant increases in NT-proBNP (11). This different behavior was explained (11) by both the different sizes of BNP (3.5 kDa) and NT-proBNP (8.5 kDa) and their different half-lives [
20 min (19) and 60–120 min (20)(21), respectively]. The decrease in BNP plasma concentrations could be attributable to reduced production/secretion of BNP caused by a reduction in plasma volume, elimination by dialysis, or both of these factors (1)(11).
In this study we investigated the effect of the dialysis procedure on BNP concentrations by hemodialysis, measuring BNP (ADVIA BNP assay; Bayer) and NT-proBNP (Elecsys proBNP; Roche Diagnostics). To address the unanswered question of elimination, we measured the concentrations in both plasma and, for the first time reported, in the corresponding dialysis fluid. Although these assays have not been validated for dialysis fluid, the results can be used to compare the relative effects of different membranes. Pre- and postdialysis samples (EDTA plasma) were drawn from 17 chronic hemodialysis patients [11 men and 6 women; mean (SD) age, 72.3 (6.2) years; mean (SD) duration of hemodialysis treatment, 5.6 (2.9) years]. Patients were treated with the Genius Therapy System (Fresenius Medical Care) and assigned to either low-flux (Polyflux 14 L; Gambro) or high-flux membranes (F 60 S; Fresenius Medical Care). The term high-flux membrane refers to a membrane with a high ultrafiltration rate. Because high-flux membranes tend to have larger pores, clearance of mid-molecular-weight molecules is usually higher than with low-flux membranes. Aliquots of the dialysis fluid were collected in EDTA-containing tubes for plasma preparation. The mean (SD) duration of dialysis was 4.4 (0.5) h, and the mean volume of the ultrafiltration was 2.6 (0.9) L. All samples were centrifuged immediately and stored at –20 °C, and all were analyzed at the same time. Postdialysis samples were adjusted for volume changes by use of the hematocrit.
All patients (n = 17) showed increased mean (SE) concentrations for BNP [738 (120) ng/L] and NT-proBNP [25 366 (9062) ng/L] in predialysis specimens. Even the postdialysis concentrations of both BNP [555 (159) ng/L] and NT-proBNP [24 933 (9828) ng/L] were increased. The approved cutoffs for the diagnosis of heart failure in non-renal-decreased populations (1) are 100 ng/L for BNP, and 125 ng/L (age <75 years) and 450 ng/L (age 
75 years) for NT-proBNP. Hemodialysis caused mean (SE) decreases of 21.6 (7.1)% for BNP and 10.1 (4.3)% for NT-proBNP (n = 17). The mean BNP decrease in the group of patients treated with the low-flux membrane (n = 4) was 18.5 (1.9)% compared with 22.5 (9.4)% in the group treated with the high-flux membrane (n = 13). Whereas treatment with the high-flux membrane also caused a decrease in NT-proBNP of 18.4 (2.3)%, treatment with the low-flux membrane led to an increase in NT-proBNP of 16.8 (4.9)%. Moreover, each patient treated with the low-flux membrane showed this increase in NT-proBNP plasma concentration after hemodialysis (Fig. 1
), but none of the patients treated with the high-flux membrane showed this postdialysis increase. With the exception of two patients (both treated with the high-flux membrane), all patients had decreased BNP concentrations after hemodialysis (Fig. 1
). One of the two patients mentioned above had the lowest predialysis BNP value (92 ng/L). The other patient was the only one with no change in blood volume, as estimated by a hematocrit of 0.35 before and after dialysis. The length of hemodialysis treatment (4 h) for these two patients was within the range for all other patients, as was the ultrafiltrate volume (2.2 L). Without these two cases, the mean decrease of 21.6 (7.1)% for BNP becomes 30.2 (5.8)% for all patients, and for the patients treated with the high-flux membrane (n = 11), it changes from 22.5 (8.1)% to 34.5 (5.5)%.
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Natriuretic peptide concentrations in the combined dialysis and ultrafiltrate fluid were 13–183 ng/L (median, 25 g/L) for BNP and 75–846 ng/L (median, 223 ng/L) for NT-proBNP. Mass balances were calculated as the product of these concentrations and the total volume (dialysis fluid and ultrafiltrate). The mean (SE) mass balance for BNP was 3282 (871) ng with higher values for the group treated with the high-flux membrane [3603 (1106) ng] compared with the group treated with the low-flux membrane [2238 (900) ng]. The total amount of NT-proBNP eliminated showed a mean mass balance of 40 382 (14 809) ng with higher values for the group treated with the high-flux membrane [49 910 (18 674) ng] compared with the group treated with the low-flux membrane [9416 (4416) ng].
Recently, Clerico and Emdin (22) published a review on the diagnostic accuracy and prognostic relevance of the measurement of cardiac natriuretic peptides. They pointed out the conflicting results of the few studies published for the clinical relevance of these assays in patients with renal failure. In our study, we therefore investigated the effect of the dialysis procedure on concentrations of BNP and NT-proBNP in hemodialysis patients. Both BNP and NT-proBNP are clearly increased in plasma from hemodialysis patients, with much higher concentrations for NT-proBNP, causing a mean (SE) NT-proBNP:BNP ratio of 28.0 (4.4). After hemodialysis, this ratio increased to a mean value of 36.0 (6.8). The mean NT-proBNP:BNP ratio in ambulatory patients with heart failure was reported to be 8.53 (0.33) (23), but we must emphasize that in the case of dialysis with low-flux membranes, where we observed an increase in plasma NT-proBNP, there is still elimination of NT-proBNP by hemodialysis, as was demonstrated by the results obtained for the dialysis fluid.
Both BNP and NT-proBNP are eliminated during hemodialysis, but they show different behaviors depending on the chosen dialysis membrane. BNP is cleared by both high- and low-flux membranes, with high-flux membranes giving higher clearance (mass balance) and reduction rates. NT-proBNP has clearance and reduction rates similar to BNP when high-flux membranes are used but very low clearance with low-flux membranes, leading to an increase in postdialysis plasma concentrations. This may be explained in part by the different molecular masses of BNP (3.5 kDa) and NT-proBNP (8.5 kDa). Both BNP and NT-proBNP seem to be released into the circulation during the hemodialysis session as shown by increasing postdialysis plasma concentrations in spite of demonstrated clearance. In contrast to NT-proBNP, circulating plasma BNP concentrations seem to be affected by acute intradialytic events. Additional studies are needed to test the influence of dialysis treatment on plasma concentrations of BNP and NT-proBNP and to elucidate the interdependence of the production, release, and elimination of these peptides in dialysis treatment.
Acknowledgments
We thank B. Scheckel, A. Honig, S. Geis, and B. Metzler for excellent technical assistance.
References
The following articles in journals at HighWire Press have cited this article:
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  M. Codognotto, A. Piccoli, M. Zaninotto, M. Mion, M. Plebani, U. Vertolli, F. Tona, L. Ruzza, A. Barchita, and G. M. Boffa Renal Dysfunction Is a Confounder for Plasma Natriuretic Peptides in Detecting Heart Dysfunction in Uremic and Idiopathic Dilated Cardiomyopathies Clin. Chem., December 1, 2007; 53(12): 2097 - 2104. [Abstract] [Full Text] [PDF]
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 S. Anwaruddin, D. M. Lloyd-Jones, A. Baggish, A. Chen, D. Krauser, R. Tung, C. Chae, and J. L. Januzzi Jr Renal Function, Congestive Heart Failure, and Amino-Terminal Pro-Brain Natriuretic Peptide Measurement: Results From the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study J. Am. Coll. Cardiol., January 3, 2006; 47(1): 91 - 97. [Abstract] [Full Text] [PDF]
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S. Anwaruddin, D. M. Lloyd-Jones, A. Baggish, A. Chen, D. Krauser, R. Tung, C. Chae, and J. L. Januzzi Jr Renal Function, Congestive Heart Failure, and Amino-Terminal Pro-Brain Natriuretic Peptide Measurement: Results From the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study J. Am. Coll. Cardiol., December 13, 2005; (2005) j.jacc.2005.08.051v1. [Abstract] [Full Text] [PDF]
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