Thread by @narora216, When was the last time you were paged about a serum Cl- [...]

When was the last time you were paged about a serum Cl- level? Probably never.

Despite being the most abundant anion in the body, Cl- is under appreciated

Here’s why it matters (esp in heart failure!)

#tweetorial #medtwitter #nephtwitter #cardiotwitter #NSMC

There is evidence supporting the use of hypertonic saline in patients with decompensated heart failure

See excellent blog post by @aldorodrig

https://www.renalfellow.org/2019/04/03/the-paradox-of-hypertonic-saline-use-in-heart-failure/

Mechanistically it never made sense to me, until I realized I may be focusing on the wrong ion

The Paradox of Hypertonic Saline Use in Heart Failure - Renal Fellow Network

The general notion is that edematous states like acute decompensated heart failure (ADHF) respond to the combination of sodium restriction and diuretic therapy. In fact, non-adherence to sodium...

https://www.renalfellow.org/2019/04/03/the-paradox-of-hypertonic-saline-use-in-heart-failure/

Chloride MAY be the

here. Something that will hopefully be more clear after the completion of ongoing trials

https://clinicaltrials.gov/ct2/show/NCT03446651?term=lysine+chloride&draw=2&rank=2

In heart failure patients

Cl- is associated with

1. Poor Prognosis
2. Neurohumoral activation
3. Diuretic Resistance

Mechanism and Effects of Manipulating Chloride Homeostasis in Acute Heart Failure - Full Text View...

Mechanism and Effects of Manipulating Chloride Homeostasis in Acute Heart Failure - Full Text View.

https://clinicaltrials.gov/ct2/show/NCT03446651?term=lysine+chloride&draw=2&rank=2

Let's establish that

Cl- has prognostic consequences in HF

Cl- associated with

mortality

Assoc. is INDEPENDENT of serum Na levels

Unclear whether

Cl- is a therapeutic target or a marker of disease severity, ie

sodium levels by

V2 provides no mortality benefit

Let's establish that Cl- has prognostic consequences in HFCl- associated withmortalityAssoc. is INDEPENDENT of serum Na levelsUnclear whetherCl- is a therapeutic target or a marker of disease severity, ie sodium levels by V2 provides no mortality benefit

Cl- plays a vital role in kidney physiology

The Macula densa

renin release in response to a

in CHLORIDE levels via the NKCC2 transporter

Infusion of Cl-, either with Na or lysine,

PRA, not seen with other sodium salts = renin release is dependent on Cl-

Cl- plays a vital role in kidney physiologyThe Macula densa renin release in response to a in CHLORIDE levels via the NKCC2 transporter Infusion of Cl-, either with Na or lysine, PRA, not seen with other sodium salts = renin release is dependent on Cl-

This is important due to the role of neurohumoral activation in heart failure pts

Initially compensatory to maintain organ perfusion

Becomes maladaptive over time (hence benefit of RAAS inhibitors)

So hypothetically maintaining normochloremia MAY reduce RAAS activation

This is important due to the role of neurohumoral activation in heart failure ptsInitially compensatory to maintain organ perfusionBecomes maladaptive over time (hence benefit of RAAS inhibitors)So hypothetically maintaining normochloremia MAY reduce RAAS activation

Low Cl- also plays a role in diuretic resistance

Common problem in HF pts

Loop diuretic resistance is due to DCT hypertrophy

In rat models, loop diuretic infusion

the number of NCC cotransporters

How does this relate to Cl-?

Cl- is assoc. with

diuretic efficiency

Low Cl- also plays a role in diuretic resistanceCommon problem in HF ptsLoop diuretic resistance is due to DCT hypertrophyIn rat models, loop diuretic infusionthe number of NCC cotransportersHow does this relate to Cl-?Cl- is assoc. with diuretic efficiency

What’s the mechanism?

The

may be the WNK kinases, specifically WNK1 and WNK4, which regulate the sodium chloride cotransporter (NCC)

Simplistic view: WNK1 stimulates and WNK4 inhibits NCC activity

Both WNK1 and WNK4 have been shown to be intracellular chloride sensors

Missense mutations in WNK4=

NCC & DCT hyperplasia (as seen w/diuretic resistance!)

Cl- insensitive WNK4

develop HTN and

NCC activity

WNK1 autoactivation is inhibited by Cl-

With

Cl- WNK1 autophosphorylates and becomes active

Cl-=

WNK1 &

WNK4=

NCC

Missense mutations in WNK4=NCC & DCT hyperplasia (as seen w/diuretic resistance!)Cl- insensitive WNK4develop HTN andNCC activity WNK1 autoactivation is inhibited by Cl- WithCl- WNK1 autophosphorylates and becomes activeSo Cl-=WNK1 & WNK4= NCC

Conclusion:

In heart failure patients Cl- is independently associated with

Poor Prognosis

Neurohumoral Activation

Diuretic Resistance

Yet another reason you should care about chloride

Thanks to @amyaimei for help editing this tweetorial

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