Chloride at the spotlight-but not alone: towards a multi-ionic diuretic strategy.

Diuretic resistance in heart failure and the cardiorenal syndrome is traditionally managed by escalating diuretic doses, yet this approach often fails to address the underlying pathophysiology. Emerging evidence challenges the sodium-centred paradigm and identifies chloride as a key determinant of diuretic responsiveness, tightly interconnected with potassium, magnesium, and acid-base balance. Disturbances in this multi-ionic network promote maladaptive tubular responses, neurohormonal activation, and persistent sodium retention, ultimately leading to diuretic resistance. Clinical and mechanistic data consistently show that hypochloraemia, often accompanied by hypokalaemia and metabolic alkalosis, is associated with impaired natriuretic efficiency and worse outcomes. Through a representative clinical case, we illustrate how a physiology-guided, multi-ionic strategy-focused on identifying and correcting the specific biochemical drivers of resistance rather than intensifying diuretics-can restore diuretic response and achieve effective decongestion. Diuretic resistance should not be viewed as a failure of dose, but as a failure of understanding. A personalized, multi-ionic approach that integrates chloride, potassium, magnesium, and acid-base status offers a more coherent and effective framework for managing congestion in heart failure.