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Brain & Heart Hypochloremia in refractory heart failure

in the proximal renal tubule. In HF, renal insufficiency (Figure 2), which leads to Na and water reabsorption. The
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causes diuretic resistance due to inadequate tubular discovery that Cl directly inhibits these WNKs provided a
diuretic concentrations, which is due to reduced renal molecular phenomenon that links Cl to the WNK pathway
perfusion and impaired proximal tubular secretion. 29-32 and Cl transport. Many recent studies have reported that
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Furthermore, secretion of diuretics is decreased due to WNKs sense low Cl levels in the body. Once Cl is bound to
endogenous organic anion accumulation, which competes the active site on WNKs, autophosphorylation is inhibited,
with loop diuretics such as furosemide at the receptors on and Na-K-2Cl cotransporters and Na-Cl cotransporters
the organic anion transporter. Therefore, higher doses of are reduced. This causes a decrease in renal Na levels and
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loop diuretics are necessary to counter this competitive water reabsorption. The activities of both loop and thiazide
inhibition and achieve therapeutic urinary concentrations diuretics are regulated by Cl. 37-39 There is a different tubule-
in individuals with CHF with renal impairment. In general, glomerular response to different classes of diuretics,
abrupt administration of diuretics, especially loop diuretics with loop diuretics altering it whereas others do not. The
in healthy individuals, can activate the RAAS reflexively, blockade of the Na-potassium Cl cotransporter reduces the
which, in turn, causes additional salt and water retention reabsorption of Na and water. This leads to the depletion
and makes diuretic therapy less effective. 34 of ECF volume and subsequent neurohormonal activation.

There are several possible mechanisms proposed for 8. HF treatment and hypochloremia
diuretic resistance in patients with HF. However, the
mechanisms that cause Na retention and altered loop diuretic 8.1. Restriction of salt
pharmacokinetics theories are the most widely accepted and The dietary intake of salt, most commonly NaCl, affects
discussed. A decrease in renal blood flow limits diuretic the concentration of serum electrolytes. Although there is
delivery to the kidneys, coupled with low eGFR, which limited evidence that salt or fluid restriction improves volume
reduces tubular Na delivery. Both of these mechanisms overload in patients with CHF, the HF treatment guidelines
can play a role in diuretic resistance. Loop diuretics block still use this strategy for symptomatic relief. However,
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reabsorption at the macula densa in the loop of Henle, which the detrimental effects of salt restriction are focused on,
causes vasoconstriction of the afferent arteriole through the possibly due to the further activation of neurohormonal
tubule-glomerular feedback mechanism. This inhibition mechanisms and HF progression. This activation may be
of tubule-glomerular feedback with loop diuretics should due to hypochloremia, hyponatremia, or both. There is no
enhance renal blood flow and GFR. However, aggressive established evidence that low dietary salt intake reduces
use of diuretics in diuretic-resistant HF may raise serum electrolyte levels. Furthermore, the clinical effect of salt
creatinine levels in these patients. 35
restriction in patients with HF has not yet been established. 41
7.1. Role of Cl in salt sensing
8.2. HF pharmacotherapy
It has been proposed that Cl is the primary ion involved in There is no clear evidence that diuretic therapy offers
the renal ability to sense volume overload in AHF. This is mortality benefits in patients with HF. Diuretics are the
because only Cl-containing solutions elicit a renal response main therapy for treating volume overload and symptomatic
compared to non-Cl solutions. Studies have shown that relief from congestion. 41,42 This phenomenon results in
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Cl also reduces renin release from the kidneys, an effect not free water retention and increased hypochloremia. Loop
observed with non-Cl salts. Therefore, Cl has a significant
role in the response to volume overload, regulation of fluid diuretics can increase the excretion of Cl by 20-fold. There
status, and RAAS activation, both of which are disturbed in is more Cl loss with loop diuretics as compared to Na
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the setting of AHF. Newer studies explain the relationship and K. The Na-K-2Cl pump in the thick ascending limb
between serum Cl and diuretic targets. It was observed that allows Na reabsorption in the distal nephron, leading to
hypochloremic individuals had higher renin levels than reduced hyponatremia with loop diuretics. However,
non-hypochloremic individuals. 36,37 Cl reabsorption is distally limited. Thiazide diuretics
inhibit Na-Cl channels in the distal tubule, causing both
7.2. New concepts in Cl metabolism hypochloremia and hyponatremia. Moreover, when
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combined with salt restriction, loop diuretics may further
Recent studies suggest the role of with-no-lysine kinases
(WNKs). These are serine-threonine kinases in the distal reduce tubular delivery and reabsorption of Cl and worsen
hypochloremia in this setting.
45,46
convoluted tubules that normally phosphorylate and
activate many kinases that further activate the Na-K-2Cl Mineralocorticoid receptor antagonist (MRA) therapy
and Na-Cl cotransporters (NKCC and NCC). In this way, may not improve hypochloremia but can prevent a further
WNKs cause the upregulation of Na-K-2Cl cotransporters decrease in Cl concentration in HF. There is no evidence

Volume 2 Issue 1 (2024) 5 https://doi.org/10.36922/bh.2257