Clinical Laboratory Strategies: August 26, 2010

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Managing Hemodialysis Patients with NT-proBNP
Study Looks for Utility Beyond Cardiovascular Disease
By Bill Malone

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is well-known for its use in diagnosing heart failure, and more recently, long-term cardiovascular disease outcomes. Now a new study described in this issue of Strategies has demonstrated NT-proBNP’s potential as a marker of extracellular fluid volume in hemodialysis patients.

Recently, controversy has developed among nephrologists as to the utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in monitoring cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). CVD is the leading cause of death in patients with CKD, and NT-proBNP has been demonstrated to be a valuable biomarker of heart failure. However, CKD presents a more complicated picture when it comes to NT-proBNP and other natriuretic peptides, due to that fact that these molecules are among many degraded by renal tubular neutral endopeptidases, a system that CKD can impede or shut down. Studies have found that BNP falls during a course of dialysis as diffusion removes natriuretic peptides along with other waste products. Furthermore, CKD causes edema, which in turn stretches the walls of the heart and pushes more natriuretic peptides into the bloodstream. These factors mean that natriuretic peptides also correlate with a CKD patient’s fluid volume, a critical variable in managing dialysis patients.

The authors of a recent study sought to bring clarity to this dilemma by measuring extracellular volume status pre-and post-dialysis and examining its relationship to NT-proBNP (Clin J Am Soc Nephrol 2010;5:954-955). The study involved 72 stable hemodialysis patients and determined fluid volume before and after dialysis using multifrequency bioimpedance and measured NT-proBNP using the Roche ECLIA immunoassay. Echocardiograms and nuclear imaging were used to assess cardiac function. Based on simple correlation, the researchers found NT-proBNP to be associated both with extracellular fluid volume overload and cardiac dysfunction. Probing deeper, however, logistical regression analysis revealed the strongest correlation was with the predialysis ratio of extracellular water to total body water, followed by postdialysis mean arterial blood pressure, dialysate calcium concentration, and change in fluid volume with dialysis.

While initially this finding might be counterintuitive for clinicians who are familiar with looking to NT-proBNP exclusively for cardiac-related disease, the potential for NT-proBNP to help maintain optimal weight for hemodialysis could be a boon for nephrologists, said Andrew Davenport, MD, FRCP, an author of the study. “One of the big issues in looking after hemodialysis patients is trying to determine what their optimal weight should be,” he said. “If a patient passes no urine, then they will put on weight between dialysis sessions. And the key question is how much fluid weight to remove during the dialysis treatments to render them back to their euvolemic state. If one removes too much fluid, then the patient is at risk for low blood pressure and other serious problems, so any sort of blood test or other variable we can measure that can help us decide how to adjust the person’s target weight is of great benefit.” Davenport is a consultant nephrologist and honorary senior lecturer at Royal Free Hospital, Royal Free University College Hospital Medical School in London.

Extracellular fluid volume frustrates nephrologists because it can be difficult to accurately measure, emphasized Stephen Seliger, MD, assistant professor of medicine in the division of nephrology with a secondary appointment in epidemiology and public health at the University of Maryland School of Medicine in Baltimore, Md. “To develop an accurate dialysis prescription, you have to know how much volume to remove and at what rate, and to do that you have to know the extracellular volume,” he said. “Unfortunately, some patients can have several extra liters without having clinical manifestations, while others can have clinical symptoms with very little, so the clinical symptoms don’t correlate all that well.”

Seliger agreed that if results can be confirmed by further research, the present study could confer a greater significance for NT-proBNP in managing dialysis patients. “Although most nephrologists know that NT-proBNP can have strong prognostic value in dialysis patients, the test hasn’t come into widespread use yet because it’s not clear how one would use that to change therapy,” he said. “I think this paper has the potential for a more direct effect on clinical care if it can be replicated in larger studies, and perhaps in a somewhat more rigorous fashion.”

Currently, the most common method of measuring extracellular fluid volume is bioimpedance, which calculates the response of externally applied electric current. Blood, fat, muscle and other elements of body mass each exhibit a certain level of electrical resistivity. For some patients bioimpedance is quick and easy, but it poses problems for many, explained Davenport. There are a number of different bioimpedance devices and each pose problems. For example, some require the patient to stand on them, which is relatively simple for some individuals, but not workable for those who are sicker. Other devices use electrodes placed on the arms and legs of the patient; however these are not only more costly, but also require that the electrodes be placed in the exact same place every time for accurate serial measurements. Bioimpedance can also be a problem if a patient has a pacemaker, metal joints, hip replacements, and other variables. All these challenges make the idea of a blood test more appealing, Davenport said. On the other hand, use of bioimpedance in the study is an important caveat, since it’s known to have inaccuracies and, despite routine use in clinical practice, is not the gold standard measurement of extracellular fluid volume.

If further studies are able to lend more support to this new use of NT-proBNP, the marker’s utility in CVD would not be challenged, Seliger stressed. “In end stage renal disease [ESRD], most cardiovascular physiology is completely unbalanced, so it would be hard to extrapolate these findings to a non-uremic, non-ESRD population,” he said. “NT-proBNP is correlated to lots of other things and it has independent prognostic value well beyond that provided by standard measures of heart structure and function. The finding here is generally consistent with other literature in that way. One wouldn’t want to come away saying that even in ESRD there is no correlation with heart function and NT-proBNP, rather I think the message is that measures of volume status are much stronger determinants of it.”

In the paper, the researchers argue for using NT-proBNP for this purpose only within the clinical context. “Raised BNP with normal hydration status should prompt cardiac investigation, whereas increased values of both parameters warrants reappraisal of post-dialysis dry weight, and if over-hydrated then targeted weight reduction can be monitored by serial reductions in bioimpedance and BNP measurements,” the authors wrote.

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Managing Hemodialysis Patients with NT-proBNP