Routine laboratory triage for NT-proBNP elevation may reflect cardiorenal frailty as much as heart failure specificity

Dear Editor,

We read with great interest the report by Ishida and colleagues describing an interpretable decision tree built from routine laboratory data to identify clinically relevant NT-proBNP elevation and embedded into diagnostic support middleware. ¹ The appeal of such a scalable, low-cost triage strategy is obvious, particularly where natriuretic peptide testing is constrained.

Interpretative caution may nevertheless be warranted in how this signal is framed clinically. The model outcome was elevated NT-proBNP rather than adjudicated heart failure, and the tree inherently prioritized serum albumin, estimated glomerular filtration rate, and age. ¹ Those variables are highly plausible determinants of a laboratory-defined high-risk state, but they are not specific to heart failure biology. Recent evidence suggests that hypoalbuminaemia in heart failure is best understood as an inclusive prognostic factor, integrating chronic congestion, low-grade inflammation, malnutrition, renal dysfunction, and frailty rather than serving as a disease-specific marker per se. ²

A similar issue arises for kidney function. In contemporary heart failure cohorts, the same NT-proBNP concentration conveys a substantially higher absolute risk when eGFR is reduced, such that renal dysfunction should not simply be treated as a source of “background elevation” to be discounted. ³ Accordingly, a model enriched by eGFR and albumin may be identifying a cardiorenal-immunometabolic phenotype associated with NT-proBNP elevation, rather than a heart-failure-specific pretest classifier. ³

This distinction may be clinically consequential. Readers may otherwise infer that the tool functions primarily as a surrogate screen for heart failure itself, whereas its more precise value may lie in enriching for patients who warrant downstream heart failure, volume-status, and kidney-focused assessment. Could the authors clarify whether model-positive encounters, particularly those without confirmed heart failure, were enriched for chronic kidney disease, hypoalbuminaemia, or multimorbidity/frailty phenotypes? Such reframing would sharpen the model’s implementation boundary without diminishing its practical importance.