Thread by @narora216

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
👉 renalfellow.org/2019/04/03/the…

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

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

👉🏾 clinicaltrials.gov/ct2/show/NCT03…

In heart failure patients ⬇️ Cl- is associated with

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

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

💡 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-

🔥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

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

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

🔥So ⬇️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