Why We Don't Know the Answer May Be More Important Than the Specific Question (Editorials) (Clinical Report‪)‬

Kemperman et al. (1) have evaluated the relationship of B-type natriuretic peptide (BNP; measured by the Bayer assay) and N-terminal proBNP (NT-proBNP; measured by the Roche assay) in patients treated with a left ventricular assist device (LVAD). They report that the relationship of the results of the two assays changes after prolonged support on a LVAD. Before LVAD use, the ratio of NT-proBNP to BNP is higher than after improvements in hemodynamics with use of the LVAD. They suggest that the initial high ratio reflects impaired renal clearance of NT-proBNP because of abnormal hemodynamics and that the subsequent decrease in the ratio reflects improved renal clearance in response to LVAD support. This may be the case and is one reasonable interpretation of the data given that glomerular filtration was significantly, although modestly, reduced in most patients before use of the LVAD. This hypothesis is consistent with other data suggesting a relationship between BNP and NT-proBNP and renal function (2). However, other explanations are possible, relating to the characteristics of the assays themselves and to physiologic factors in this special group of patients. Many of the issues we will raise ideally should have been explored during the development of the natriuretic assays themselves or during their clinical validation. Thus, there is a need not only to reflect on the specific issues related to BNP and NT-proBNP in patients with impaired renal function but also to ask why, so often, the critical analytical and clinical data that would help answer questions like this are not available in the literature. Initial analytical validation studies tend to be designed to allow an assay to be shown to be useful and/or to pass regulatory muster. There is then some attempt to define a normal reference interval and ultimately an attempt to find a clinical niche for the assay. When, on occasion, data are published from these studies, they often fail to answer many of the questions that need to be addressed regarding quality specifications of an assay. This is clearly the situation for the BNP and NT-proBNP assays, but not unique to them. Because of similar problems with cardiac troponin, the IFCC Committee for Standardization of Markers of Cardiac Damage (C-SMCD) defined in detail the analytical criteria for troponin assays to meet if they are to be suitable for clinical use (3). None of those criteria are unusual, but they are more than is currently mandated by regulatory agencies and far more than what is usually performed or reported in clinical studies using BNPs or cardiac troponins. The IFCC document also suggests, as recommended by the European Society of Cardiology/ American College of Cardiology task force on the redefinition of acute myocardial infarction (4), that the characteristics of all assays for troponin be published in peer-reviewed journals. This needs to be the case for natriuretic peptide assays also. One can take the list from the quality-specification troponin report and define most of the relevant issues that one might want to know about preanalytical and analytical issues for BNP and NT-proBNP assays. They include but are not limited to the following: