Proposal for New Classification and Practical Use of Diuretics According to Their Effects on the Serum Chloride Concentration: Rationale Based on the “Chloride Theory”

Abstract

Currently, diuretic therapy for heart failure (HF) pathophysiology is primarily focused on the sodium and water balance. Over the last several years, however, chloride (Cl) has been recognized to have an important role in HF pathophysiology, as both a prognostic marker and a possible central factor regulating the body fluid status. I recently proposed a unifying hypothesis for HF pathophysiology, called the “chloride theory”, during HF worsening and recovery, as follows. Chloride is the key electrolyte for regulating both reabsorption of tubular electrolytes and water in the kidney through the renin–angiotensin–aldosterone system and distributing body fluid in each compartment of the body. As changes between the serum Cl concentration and plasma volume are intimately associated with worsening HF and its recovery after decongestive therapy, modulation of the serum Cl concentration by careful selection and combination of various diuretics and their doses could become an attractive therapeutic option for HF. In this review, I will propose a new classification and practical use of diuretics according to their effects on the serum Cl concentration. Diuretic use according to this classification is expected to be a useful strategy for the treatment of patients with HF.

Chloride in Heart Failure Syndrome: Its Pathophysiologic Role and Therapeutic Implication

“…The recommended dose escalation therapy based on 2.5 times the home dose for patients with acute HF is often accompanied by serum electrolyte disturbances already existing at the initial presentation and/or appearing during HF treatment [108]. A more thorough understanding of the 'chloride theory' of HF pathophysiology [15][16][17][18] would provide valuable insight and rational strategies for pharmacologic resolution of decongestion [85], as described below.…”

“…A new diuretic classification is proposed on the basis of the effects of a diuretic on the serum chloride concentration, including diuretic effects at the nephron and on sodium and potassium electrolytes (Table 1) [85]. Loop/thiazide diuretics are potent chloride-depleting diuretics [46,[109][110][111].…”

Clinical Significance of Spot Urinary Chloride Concentration Measurements in Patients with Acute Heart Failure: Investigation on the Basis of the ‘TubuloGlomerular Feedback’ Mechanism

“…The present study suggests that acute HF patients with a low urinary Cl concentration in the pre-treatment test may be expected to have loop diuretic resistance because such an acute HF phenotype already exhibits compromised renal and cardiac functions under a highly activated neurohormonal system, as was similarly reported by Hanberg et al [20]. Urinary Cl-centered information linked to the 'tubulo-glomerular feedback' model may be useful for deciding therapeutic options, because loop diuretic-resistant acute HF patients with a low urinary Cl concentration may respond well to treatment with Cl-regaining diuretics, such as acetazolamide, vasopressin receptor antagonist, and sodium-glucose cotransporter-2 inhibitor [34]. Acute HF patients with low urinary Cl concentration might be candidates for treatment by renin-angiotensin-aldosterone system blockade if there are no contraindications, such as coexisting renal dysfunction, hypotension, and HF with preserved ejection fraction [35].…”

Plasma Renin Activity after Diuretic Treatment in Patients with Stable Heart Failure: With Special Reference to its Association with Electrolyte Chloride

“…Under decongestive therapy for worsening HF, this theory predicts that PRA would be enhanced under lowering of the serum Cl concentration by Cl-depleting diuretic therapy, such as the use of loop/thiazide diuretics. In contrast, renin activity would likely be depressed or suppressed when the serum Cl concentration is enhanced by treatment with Cl-regaining diuretics or Cl supplementary treatment [6,8,29]. Observations of the present study support the 'chloride theory' for HF pathophysiology [6][7][8] by disclosing interactions between the serum Cl concentration and neurohormonal activities during resolution of acute HF, i.e., stable HF patients with low PRA had high serum Cl concentrations, and conversely, those with high PRA had low serum Cl concentrations (Table 4).…”

“…Observations of the present study support the 'chloride theory' for HF pathophysiology [6][7][8] by disclosing interactions between the serum Cl concentration and neurohormonal activities during resolution of acute HF, i.e., stable HF patients with low PRA had high serum Cl concentrations, and conversely, those with high PRA had low serum Cl concentrations (Table 4). Thus, the 'chloride theory' for HF pathophysiology [6][7][8] could provide a primary care management system for diuretic treatment of HF patients, with attention to the serum Cl concentration and changes central to this system [29].…”