Author + information
- Suetonia C. Palmer, MB ChB, FRACP and
- A. Mark Richards, MD, PhD, DSc, FRCP, FRACP* ()
- ↵*Reprint requests and correspondence:
Dr. A. Mark Richards, Department of Medicine, University of Otago Christchurch, P.O. Box 4345, Christchurch 8140, New Zealand
Plasma B-type natriuretic peptides (BNP and the amino-terminal portion of proBNP [NT-proBNP]), both reflecting myocardial wall tension, are established biomarkers for diagnosis, risk stratification, and prognosis across populations with or at risk of cardiovascular disease. Observational studies consistently show that elevated circulating B-type natriuretic peptide levels correlate with declining kidney function. Further, plasma NT-proBNP levels are elevated more than BNP for a similar decrement in glomerular filtration rate. The widely reported assumption is that NT-proBNP—and less so BNP—accumulate in kidney disease because of impaired renal clearance.
The issue of relative production and clearance of a biomarker is an important one; plasma B-type natriuretic peptides potentially lose clinical utility as determinants of myocardial stress if kidney function plays a progressively more important role (relative to cardiac function) in determining plasma peptide levels as kidney function declines. With the rapidly increasing prevalence of kidney disease in human populations (1) and the guideline acceptance of B-type natriuretic peptide levels as diagnostic tools in heart failure, the processes of B-type natriuretic peptide clearance are pivotal to the interpretation of plasma levels as measures of myocardial function.
Observational data linking natriuretic peptides and kidney function are at best hypothesis forming; the mechanisms for elevated B-type natriuretic peptide levels in people with renal dysfunction remain unclear. The pivotal question remains unresolved: does kidney function determine peptide levels through clearance or confound peptide levels through its powerful association with prevalent cardiac disease, which causes elevated cardiac production of BNP and NT-proBNP? Further, although known processes (receptor-mediated clearance and enzymatic degradation) eliminate BNP, mechanisms for NT-proBNP clearance remain unknown. In contrast to BNP (2), the proportional roles of renal and extra-renal tissue in removal of circulating NT-proBNP remain both unmeasured and uncertain.
In this issue of the Journal, van Kimmenade et al. (3) directly measure and compare BNP and NT-proBNP levels across the renal circulation of 165 hypertensive patients undergoing angiography for suspected renal artery stenosis. Most patients had an estimated glomerular filtration rate (eGFR) above 30 ml/min/1.73 m2. As expected, plasma immunoreactive BNP and NT-proBNP and the plasma ratio of NT-proBNP to BNP inversely correlated with eGFR. Renal fractional extractions of BNP and NT-proBNP were 21% to 22% and 16% to 18%, respectively. Whereas eGFR predicted the fractional extraction of both BNP and NT-proBNP, the ratio for renal extraction of NT-proBNP to BNP (FENT-proBNP/BNP) was unrelated to eGFR, suggesting that BNP and NT-proBNP are equally dependent on renal function for elimination. Multivariable analysis, incorporating clinical (age, body mass, blood pressure, hematocrit), renal (relative renal plasma flow, peptide fractional extraction, and eGFR), and cardiac (left ventricular ejection fraction, left ventricular mass index, and E/A ratio) variables, identified eGFR, renal plasma flow, and left ventricular mass index but not fractional peptide extraction as independent predictors of circulating B-type peptide levels.
Since the introduction of B-type peptides into clinical practice, confusion has existed about their utility in the context of renal dysfunction. Circulating BNP is reportedly less reliant on kidney function for removal and therefore a more robust clinical biomarker in kidney disease. Propagation of this belief, often firmly held, ensued after some observational studies showed a closer inverse relationship between plasma NT-proBNP and creatinine clearance. In fact, similar or identical correlations for both NT-proBNP and BNP with eGFR are observed when the peptides are assayed together in patients with coronary artery disease or undifferentiated dyspnea, although such analyses are limited by the small proportion of patients with eGFR <30 ml/min/1.73 m2(4–6). Further, clearance of BNP is different from NT-proBNP; the well-defined mechanisms for BNP elimination by natriuretic peptide receptor C and neutral endopeptidase contrast with the unknown processes for NT-proBNP degradation. The absence of known elimination pathways for NT-proBNP and evidence for urinary NT-proBNP immunoreactivity have prompted speculation of a more important role for renal clearance of NT-proBNP by glomerular filtration compared with other processes of degradation.
The current report echoes 3 similarly conducted smaller studies (<20 patients) all showing concordant renal fractional extraction for BNP and NT-proBNP (7–9). The strength of the new analysis is a sample size large enough to sustain regression analyses showing that renal fractional extraction does not independently predict circulating levels for either peptide.
Although data showing equal dependence on eGFR for elimination of both peptides are novel, the mechanisms for relatively higher circulating NT-proBNP levels in renal impairment remain unclear. Further, it would have been interesting to observe whether renal extractions of NT-proBNP and BNP within an individual were statistically similar (or different) when directly compared.
The ratio of circulating NT-proBNP to BNP immunoreactivity increases as kidney function declines without a corresponding elevation in fractional renal NT-proBNP extraction, suggesting a saturable clearance mechanism for NT-proBNP that is independent of glomerular filtration or augmented clearance of BNP with lower eGFR. Lack of correlation between urinary NT-proBNP immunoreactivity and contemporaneous plasma NT-proBNP levels and eGFR (10) supports the possibility that NT-proBNP clearance is at least in part independent of eGFR. In this regard, it would be of interest to know whether other tissues degrade immunoreactive NT-proBNP; evidence for extraction across other sites in the human circulation would provide indirect support for additional processes of NT-proBNP degradation. Although renal fractional extraction of both BNP and NT-proBNP is lower with impaired GFR, such a correlation does not prove causation—that glomerular filtration is the major mechanism through which B-type natriuretic peptides inversely associate with renal function. Indeed, the predictive power of renal peptide extraction is lost when incorporated into a multivariable model alongside eGFR and cardiac characteristics including both left ventricular ejection fraction and mass index, hence retaining the possibility that higher peptide levels in kidney disease are a true positive finding. In other words, higher B-type natriuretic peptide levels in chronic kidney disease may signal clinically important cardiac pathology. Preservation of prognostic information given by BNP and NT-proBNP beyond that provided by conventional risk factors including cardiac structure and function, even in patients with markedly impaired kidney function, supports the concept that peptide levels remain a powerful reflection of cardiac status in kidney disease. Measuring cardiac secretion of both peptides in patients with a range of eGFRs would provide valuable information to support or refute this hypothesis.
That NT-proBNP and BNP are equally dependent on renal function for clearance is an advance for clinical application of these biomarkers. As van Kimmenade et al. (3) suggest, these analyses need to be conducted in patients in whom the B-type natriuretic peptides are most widely used in real life—those with heart failure with and without severely impaired eGFR (<30 ml/min/1.73 m2). Further, the assay used for each peptide in the current study only measures degradation of peptide epitopes detected by the antibodies for that particular assay. Clearance of both BNP and NT-proBNP may have been different using assays with differing antigen specificities, which also might provide insight into the processes of degradation for NT-proBNP.
Dr. Richards has had consultancy connections with both Biosite, which markets a B-type natriuretic peptide assay, and Roche Diagnostics, which markets an amino-terminal pro–B-type natriuretic peptide assay. Dr. Richards has received honoraria and research grant support from Roche Diagnostics.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
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