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Letters to the Editor |
1 Universitätsklinik für Kinde und Jugendliche, Loschgestrasse 15, 91054 Erlangen, Germany
aAuthor for correspondence. Fax 49-9131-8533714; e-mail manfred.rauh{at}kinder.imed.uni-erlangen.de.
To the Editor:
Recent studies suggest that the B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) may be useful diagnostic tools in children with congenital heart disease or cardiomyopathy (1)(2)(3). Reference data, however, are rare, especially for children. The aim of this study was to measure plasma concentrations in a control population of infants and children, using the Elecsys NT-proBNP assay (Roche Diagnostics).
EDTA plasma (centrifuged at 3000g for 5 min and frozen at -20 °C until analysis; stable for 12 months as provided by the manufacturer) was obtained from 13 neonates (<1 month of age) and from 78 children (37 girls and 41 boys; median age, 6.1 years; range, 4 months to 18 years). Patients with cardiac, renal, and hepatic diseases as well as water and electrolyte disturbances were retrospectively excluded from the study according to their diagnoses.
Concentration limits were calculated by regression analysis based on formulas derived from Virtanen et al. (4), which makes it unnecessary to partition the reference data into subgroups. A relatively small sample size is sufficient. This is of great advantage considering the costs and difficulties in collecting samples from large reference groups, especially pediatric samples. Because the variability of NT-proBNP increased with its mean concentration, we used natural log transformations in the regression analyses. After transforming the data back to the original scale, we established nomograms using the 2.5th, 50th, and 97.5th percentiles with 95% confidence intervals (Fig. 1
).
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The NT-proBNP concentration was highest during the first days of life (range, 1121–7740 ng/L) with a rapid decrease (Fig. 1
, inset) similar to that described for BNP because of assumed perinatal circulating changes (5)(6). We observed no significant difference between plasma concentrations in male and female children (median, 62.3 ng/L; mean, 83.4 ng/L; range, 11–379 ng/L; Mann–Whitney test, P = 0.74). The lack of significance may be attributable to the small sizes of the groups. A negative correlation between age and concentration was evident for individuals >1 month (r = -0.45; P <0.001). On the basis of the 97.5th percentile curve, the maximum value of 299 ng/L (age, 1 year) decreased to 48 ng/L (age, 16 years). For adults, increased reference limits according to age are provided by the supplier (97.5th percentiles for age <50 years, 153 ng/L for females and 88 ng/L for males; for adults 50–65 years of age, 334 ng/L for females and 227 ng/L for males).
Very few studies have been published on the determination of BNP and NT-proBNP in the blood of neonates and children. Using the Biomedica system, Mir et al. (3) reported considerably higher limits and a slight decrease with age (range, 626–5531 ng/L; mean, 2630 ng/L; n = 109; age range, 11 days to 17 years) in children. Differences in antibody specificity and cross-reactivity with circulating NT-proBNP split products may be responsible (7).
ProBNP is cleaved into the two fragments NT-proBNP and BNP. However, in contrast to the decreasing values of NT-proBNP with increasing age, plasma concentrations of BNP have been reported to be constant in children 1–10 years of age (6). Further investigations are needed to elucidate the determinants for this change in ratio. Differences in the metabolic clearance of both peptides during childhood may cause the different distribution of NT-proBNP/BNP in plasma according to age (1). Nonspecific interference and unknown preanalytical effects cannot be excluded at this time.
In conclusion, in studies involving measurements of blood in pediatric patients, it is important to establish age-matched reference values. Results of BNP studies should be reported with annotation of the assay used.
References
The following articles in journals at HighWire Press have cited this article:
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  A. El-Khuffash and E. J Molloy Are B-type natriuretic peptide (BNP) and N-terminal-pro-BNP useful in neonates? Arch. Dis. Child. Fetal Neonatal Ed., July 1, 2007; 92(4): F320 - F324. [Abstract] [Full Text] [PDF]
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 A. Dodge-Khatami, E. V. Buchel, W. Knirsch, A. Kadner, V. Rousson, H. H. Dave, U. Bauersfeld, and R. Pretre Brain natriuretic peptide and magnetic resonance imaging in tetralogy with right ventricular dilatation. Ann. Thorac. Surg., September 1, 2006; 82(3): 983 - 988. [Abstract] [Full Text] [PDF]
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 A. Hammerer-Lercher, R. Geiger, J. Mair, C. Url, G. Tulzer, E. Lechner, B. Puschendorf, and R. Sommer Utility of N-Terminal Pro-B-Type Natriuretic Peptide to Differentiate Cardiac Diseases from Noncardiac Diseases in Young Pediatric Patients Clin. Chem., July 1, 2006; 52(7): 1415 - 1419. [Abstract] [Full Text] [PDF]
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 A. Koch, S. Zink, and H. Singer B-type natriuretic peptide in paediatric patients with congenital heart disease Eur. Heart J., April 1, 2006; 27(7): 861 - 866. [Abstract] [Full Text] [PDF]
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A. Hammerer-Lercher, J. Mair, G. Tews, B. Puschendorf, and R. Sommer N-Terminal Pro-B-Type Natriuretic Peptide Concentrations Are Markedly Higher in the Umbilical Cord Blood of Newborns than in Their Mothers Clin. Chem., May 1, 2005; 51(5): 913 - 915. [Full Text] [PDF]
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B. Bar-Oz, A. Lev-Sagie, I. Arad, L. Salpeter, and A. Nir N-Terminal pro-B-Type Natriuretic Peptide Concentrations in Mothers just before Delivery, in Cord Blood, and in Newborns Clin. Chem., May 1, 2005; 51(5): 926 - 927. [Full Text] [PDF]
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