Ji Soo Kim (@KimneyJ), Wesley Hayes, Detlef Bockenhauer
Welcome back to part 3 of our tour through tubulopathies. If you missed parts 1 or 2, I’d say follow Julie Andrews’ advice and ‘start at the very beginning’, it is after all a very good place to start (Day 1, Day 2). Unless you have a mad crush on the loop of Henle, in which case, today’s the day for you!
The Loop of Henle
The loop of Henle is where water gets reabsorbed. Salt reabsorption in the thin and thick ascending limbs creates a concentration gradient, encouraging water reabsorption in the thin descending limb. In the thick ascending limb, Na+ and Cl- gets reabsorbed and K+ gets recycled back into the lumen. The recycled K+ establishes a lumen-positive charge across the epithelium – this encourages uptake of cations like Ca2+ and Mg2+ between cells.
Because the thick ascending limb removes solutes without water, it is also called the “diluting” segment. The urine is actively diluted and, in the process, the interstitium is concentrated. This generates the osmotic gradient for regulated water reabsorption downstream in the collecting duct
The thick ascending limb is also where the ‘Macula Densa’ cells live. The Macula Densa is situated where the thick ascending limb, distal convoluted tubule and glomerulus touch each other and is where the ‘tubuloglomerular feedback’ happens. The Macula Densa senses NaCl concentration in the tubular fluid.
Ok, so how does it all work? The diagram below explains the cascade triggered when the macula densa responds to low NaCl (and as water follows salt, it’s a proxy for low BP)
Why is this important?
Imagine the thick ascending limb’s ability to reabsorb salt is impaired. This short-circuits your tubuloglomerular feedback. As the macula densa cells are similar to the other cells in the thick ascending limb, the impaired salt reabsorption is interpreted as insufficient delivery. It thinks your problem is not enough fluid going through the glomerulus. As per the diagram above, the renin-angiotensin-aldosterone system (RAAS) goes into overdrive to increase your salt and water reabsorption, but you keep losing salt because the MAIN PROBLEM is you’re not able to reabsorb the salt!!!
That’s why the classic hallmark of Bartter Syndrome is:
- Hypochloraemia (not enough reabsorption at the loop of Henle, leading to…)
- High Renin/Aldosterone levels, but persistent low or normal blood pressure + Hypovolaemia
- Hypokalaemia + Metabolic Alkalosis (hyperaldosteronism = increased distal tubular sodium reabsorption at the expense of more potassium and hydrogen ion excretion)
- Hypercalciuria (Remember the lumen-positive charge across the epithelium thanks to potassium recycling? Well it’s not happening. So, calcium stays in the urine instead of getting reabsorbed)
DID YOU KNOW?
Furosemide acts on the Na-K-Cl (NKCC2) co-transporter? That’s why if you looked at the blood and urine of a patient on furosemide, it looks a bit like Bartter syndrome (Type 1)!
There are 5 types of Bartter Syndrome
WHY SENSORINEURAL DEAFNESS IN TYPE 4?
The inner ear depends on an efflux of chloride to depolarize hair cells. Knocking the Barttin protein or both CLCNKa and b means both chloride channels are impaired.
Hypokalaemic Metabolic Alkalosis
We can put Bartter syndrome in the context of hypokalaemic metabolic alkalosis right here:
So then how do we manage a tubulopathy with low fluid, low potassium, chloride and metabolic alkalosis?
- Replace electrolytes ENTERALLY if possible – You might never achieve a ‘normal potassium level’ (remember that slit in the bucket analogy from yesterday – that unless you fix the leak, refilling is futile!). But fear not; as long as the child is asymptomatic from hypokalaemia and it’s >2.5mmol/L, you’re doing AMAZING!
- Rehydrate with fluids. Again, allow free access to water!
- Remember: the hyperaldosteronism and consequent hypokalaemic alkalosis is the kidney’s physiologic response to salt wasting. Thus, the most physiologic treatment for this is salt supplementation
- In severe hypokalaemia, your local friendly nephrologist may consider prostaglandin synthesis inhibitors (i.e. indomethacin, ibuprofen), or amiloride or spironolactone. That’s right. You just saw NSAIDs being deliberately prescribed! The reduced transportation of chloride in Bartter syndrome = more prostaglandins being produced. Prostaglandins means RAAS activation. NSAIDs cuts out the prostaglandins triggering the RAAS and stop the kidney from going into overdrive.
So lets add the Loop Of Henle to our summary table that we started yesterday:
We’ll continue to add to that over the next two days.
So, we’ve successfully looped-the-loop. But don’t forget all about Bartter syndrome; he’ll pop up again tomorrow when we discuss the Distal Convoluted Tubule. See you then…