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

Marco Montomoli1, Maria Ines Gil Martins Roxo2, Miguel González-Rico1

  • 1Department of Nephrology, Clinical University Hospital of Valencia; INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain.

Clinical Kidney Journal
|June 19, 2026
PubMed

Insights

Diuretic resistance in heart failure is often due to electrolyte imbalances, not just dose. Correcting chloride, potassium, and acid-base balance can restore diuretic effectiveness and improve outcomes.

Area of Science:

  • Cardiology
  • Nephrology
  • Clinical Physiology

Background:

  • Diuretic resistance in heart failure (HF) and cardiorenal syndrome (CRS) is a significant clinical challenge.
  • Traditional management focuses on escalating diuretic doses, often overlooking underlying pathophysiology and leading to treatment failure.

Purpose of the Study:

  • To challenge the sodium-centric view of diuretic resistance.
  • To highlight the critical role of chloride and other ions (potassium, magnesium) in diuretic responsiveness.
  • To propose a physiology-guided, multi-ionic strategy for managing diuretic resistance in HF.

Main Methods:

  • Review of emerging evidence on the multi-ionic determinants of diuretic response.
  • Analysis of clinical and mechanistic data linking hypochloraemia to impaired natriuresis.
  • Illustration through a representative clinical case study.

Main Results:

  • Hypochloraemia, often with hypokalaemia and metabolic alkalosis, is associated with diuretic resistance.
  • Disturbances in the multi-ionic network promote sodium retention and neurohormonal activation.
  • A multi-ionic, physiology-guided approach can restore diuretic response and achieve decongestion.

Conclusions:

  • Diuretic resistance in HF is better understood as a failure of physiological understanding rather than diuretic dosing.
  • A personalized, multi-ionic strategy addressing chloride, potassium, magnesium, and acid-base balance offers effective decongestion.
  • This approach provides a more coherent framework for managing HF congestion.
Keywords:
chloridechronic kidney diseasediuretic resistanceelectrolyte disordersheart failuremagnesiummetabolic alkalosispotassiumvolume assessment

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