The Role of Chloride in Cardiorenal Syndrome: A Practical Review

Abstract

Chloride, long considered a passive extracellular anion, has emerged as a key determinant in the pathophysiology and management of heart failure (HF) and cardiorenal syndrome. In contrast to sodium, which primarily reflects water balance and vasopressin activity, chloride exerts broader effects on neurohormonal activation, acid-base regulation, renal tubular function, and diuretic responsiveness. Its interaction with With-no-Lysine (WNK) kinases and chloride-sensitive transporters underscores its pivotal role in electrolyte and volume homeostasis. Hypochloremia, frequently observed in HF patients treated with loop diuretics, is independently associated with adverse outcomes, diuretic resistance, and arrhythmic risk. Conversely, hyperchloremia-often iatrogenic-may contribute to renal vasoconstriction and hyperchloremic metabolic acidosis. Experimental data also implicate chloride dysregulation in myocardial electrical disturbances and an increased risk of sudden cardiac death. Despite mounting evidence of its clinical importance, serum chloride remains underappreciated in contemporary risk assessment models and treatment algorithms. This review synthesizes emerging evidence on chloride's role in HF, explores its diagnostic and therapeutic implications, and advocates for its integration into individualized care strategies. Future studies should aim to prospectively validate these associations, evaluate chloride-guided therapeutic interventions, and assess whether incorporating chloride into prognostic models can improve risk stratification and outcomes in patients with heart failure and cardiorenal syndrome.

Keywords: cardiorenal syndrome; chloride; diuretic resistance; heart failure; hyperchloremia; hypochloremia; neurohormonal activation.

Figure 1

Renal chloride handling: The majority of filtered chloride is reabsorbed in the proximal tubule via both passive and active transcellular mechanisms involving Cl⁻/base exchangers and Na⁺/H⁺ exchangers. Acetazolamide (ACTZ), by inhibiting carbonic anhydrase, indirectly promotes proximal chloride reabsorption. In the thick ascending limb of the loop of Henle, chloride is reabsorbed through the Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2), the pharmacologic target of loop diuretics such as furosemide. In the distal convoluted tubule, thiazide-sensitive Na⁺/Cl⁻ cotransporters and Cl⁻/HCO_3⁻ exchangers mediate further reabsorption. The collecting duct finalizes chloride handling via pendrin and sodium-dependent Cl⁻/HCO_3⁻ exchangers in intercalated cells. Sites of action for furosemide, thiazides, acetazolamide (ACTZ), and mineralocorticoid receptor antagonists (MRAs) are highlighted. Abbreviations: ACTZ: acetazolamide; ATP: Adenosine Triphosphate; ENaC: epithelial sodium channel; MRA: mineralocorticoid receptor antagonist; NKCC2: Na⁺/K⁺/2Cl⁻ cotransporter. This figure is an original illustration created by the authors for educational purposes.

Figure 2

Clinical approach to serum chloride abnormalities in patients with heart failure. This algorithm outlines the evaluation and management of hypochloremia, hyperchloremia, and normal chloride levels in heart failure. Hypochloremia is further differentiated into profiles reflecting chloride depletion or hemodilution, based on sodium and urine chloride levels. Management strategies include tailored use of diuretics, fluid restriction, and chloride repletion. Hyperchloremia prompts evaluation for causes such as IV saline overload and metabolic acidosis. Serum and urine electrolytes, arterial blood gases, and volume status guide individualized therapy [15]. Abbreviations: ABGs: air blood gases; ACTZ: acetazolamide; HF: heart failure; IV: intravenous; MRAs: mineralocorticoid receptor antagonists; SGLT2i: sodium–glucose cotransporter-2 inhibitor. This is an original, clinically oriented figure developed by the authors to support practical decision-making based on chloride profiling in HF.