Comment on “Overnight Dexamethasone in Primary Aldosteronism Screening in Patients on Interfering Therapy (ODEPRASC): A Diagnostic Interpretability Study Protocol”

Dear Editor, We read with great interest the study by Kmieć et al. [1] examining whether overnight dexamethasone suppression can improve the interpretability of aldosterone-to-renin ratio (ARR)-based screening for primary aldosteronism in patients receiving renin–angiotensin–aldosterone system–interfering therapy. The protocol addresses a clinically relevant diagnostic barrier that continues to limit the detection of a common and treatable cause of hypertension. The proposed design directly addresses real-world constraints that undermine guideline-recommended screening, particularly the impracticality of full medication withdrawal in many patients with hypertension. By embedding ARR reassessment within clinically indicated testing and stratifying analyses across medication constellations, the investigators aligned methodological rigor with everyday practice. The use of paired pre- and post-dexamethasone measurements within the same individual strengthens internal interpretability and allows diagnostic refinement without increasing patient burden [2]. The protocol prespecifies a clinically meaningful endpoint focused on reducing equivocal screening results rather than maximizing binary discrimination. This approach prioritizes decision utility, which is central to screening effectiveness. The planned temporal validation across the development and confirmation cohorts enhances confidence in the threshold stability. Importantly, the analytic strategy links interpretability gains to downstream confirmatory testing, maintaining clinical relevance rather than isolating statistical performance [3]. Accounting for corticotropin-dependent variability in aldosterone secretion is a translationally grounded innovation. Suppression-based normalization of hormonal fluctuations is a biologically plausible contributor to ARR instability, which remains unaddressed by standard screening algorithms. The integration of urinary aldosterone excretion as a secondary anchor further strengthens translational coherence by linking screening refinement with established physiological measures [4]. This study advances an individualized diagnostic paradigm by adapting ARR thresholds to the medication context while minimizing treatment disruption. This strategy directly supports broader screening uptake, a priority identified in contemporary hypertension guidelines. The potential to reduce equivocal results without mandating confirmatory testing in all patients aligns with evolving views that favor streamlined diagnostic pathways when the pretest probability is high. The ODEPRASC protocol presents a clinically attuned and methodologically robust approach for improving primary aldosteronism screening under pragmatic conditions. If successful, this strategy could meaningfully enhance the diagnostic yield and support earlier targeted management in a population that remains substantially underdiagnosed. R.S. contributed to conceptual framing, computational and interpretability perspectives, and manuscript refinement. S.B. conceptualized the study protocol, coordinated the diagnostic framework, and finalized the manuscript. N.D. contributed to clinical context integration, drafting, and protocol clarification. All authors reviewed and approved the final manuscript. The authors have nothing to report. The authors have nothing to report. Ethical approval will be obtained prior to study initiation, as per institutional and regulatory requirements. The authors declare no conflicts of interest. Generative AI tools were used only for language refinement and formatting. All protocol design and interpretative rationale were developed by the authors. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.