Ji Soo Kim (@KimneyJ), Wesley Hayes, Detlef Bockenhauer
Back for more? Fantastic. Today we talk all things DCT – distal convoluted tubule. But if you missed how we got to this point then follow these links and, just like Chris Martin, I’ll ‘take you back to the start’ (Day 1, Day 2, Day 3)
The Distal Convoluted Tubule
The Distal Convoluted Tubule plays an important role in sodium chloride reabsorption, potassium secretion and handling of calcium and magnesium. It is the only part of the tubule that uses the NCC transporter (Na+Cl– Co-Transporter) to reabsorb sodium chloride – which comes in handy. NCC transporter activity is mediated by a group of kinases called WNK kinases (“With No-lysine Kinase”). Think of WNK1 and WNK4 as conductors to their NCC transporter orchestra, telling them when to modulate their tune up or down.
The distal convoluted tubule also stands out as a handler of not only salt, but calcium and magnesium. Up until now, these guys were mostly reabsorbed between cells. But here, there are dedicated channels and transporters for calcium and magnesium!
Problems in the DCT
Problems in the DCT can be thought of as ‘salt-wasting’ or ‘salt-retaining’. Let’s start with salt-wasting, which biochemically looks similar (but not identical) to Bartter syndrome.
When salt is wasted in the DCT, the rest of the tubule needs to pick up the slack. The renin-aldosterone-angiotensin-system (RAAS – see yesterday’s post) encourages sodium reabsorption throughout the rest of the tubule, but mainly downstream from the DCT in the collecting duct. To reabsorb the sodium in the collecting duct, it will be exchanged for protons and potassium, leading to hypokalaemia and alkalosis.
Therefore, in salt-wasting tubulopathies of the DCT, you end up hypochloraemic, hypokalaemic, alkalotic and hypovolaemic.
Two such syndromes are Gitelman and East Syndrome
The eagle-eyed amongst you will have noticed that dysfunction in the look of Henle resulted in HYPERcalciuria (as in Bartter’s syndrome), but here in the DCT is causes HYPOcalciuria (as in Gitelman’s syndrome). But why?
Let’s start from the beginning of the tubule. Imagine you are the proximal tubule. Word on the street is that there is volume depletion. You think: ‘Oh crap, I better reabsorb as much sodium and water as I possibly can’. The electrochemical gradient this creates encourages more para-cellular calcium reabsorption.
In Bartter syndrome the loop of Henle’s potassium recycling isnt happening. Therefore the transluminal charge required to encourage calcium reabsorption isn’t there and calcium isn’t reabsorbed in the loop. So, although the proximal tubule worked hard at the top end, the loop of Henle isn’t pulling its weight and that’s why you end up with hypercalciuria.
However, in Gitelman syndrome the loop of Henle’s working just fine. Calcium reabsorption just carries on, so you’re left with increased calcium reabsorption from the proximal tubule AND in the loop of Henle. Hence in Gitelman syndrome: hypocalciuria.
Type 3 Bartter syndrome and Gitelman Syndrome are almost clinically indistinguishable. At the end of the day, only a genetic test can truly distinguish these syndromes apart.
So, we’ve talked about salt-losing tubulopathies in the DCT, but what about salt-retaining? Before we can understand them, we need to talk about the fascinating and vaunted “ALDOSTERONE PARADOX” (Isn’t this exciting?!)
There are two key stimuli for aldosterone secretion: hypovolaemia and hyperkalaemia
If both are present, aldosterone is welcomed with open arms as it stimiulates sodium reabsorption (thus remedying hypovolaemia) in exchange for potassium secretion (thus remedying hyperkalaemia).
But what (here comes the paradox!), if you have hypovolaemia and hypokalaemia? What if you need to retain both sodium and potassium? W(i)NK, w(i)nk, there is a solution! The “WNK kinases” and their many associated friends. Together, they sense the low potassium in the blood and respond by upregulating sodium reabsorption in the DCT. The effect of this is that more sodium is retained in the DCT and therefore less is delivered downstream to the collecting duct, where it would have been exchanged for potassium. Eh voila, now we are also conserving potassium!
So that’s the ‘normal’, let’s get back to the abnormal. What happens if this system misfires and stimulates sodium reabsorption in the DCT even in the absence of hypokalaemia or hypovolaemia? This is where we come to our ‘salt-retaining’ problems:
This is what happens:
- The NCC transporter, responsible for sodium and chloride reabsorption is misfiring. It is ‘over’ reabsorbing sodium and chloride – hence hyperchloraemia.
- You also get excess sodium reabsorption. Remember, anywhere sodium goes, water follows. So you get hypertension
- As we’ve just discussed, sodium is needed in the filtrate downstream in the collecting duct to be reabsorbed in exchange for potassium and protons. Therefore, excess sodium reabsorption here in the DCT means less downstream for those swaps, leaving excess potassium and protons in the blood. So you get hyperkalaemia and acidosis
- The resulting hypertension described leads to a compensatory decrease in sodium reabsorption in the proximal tubule and thus passive calcium reabsorption decreases as well. So you get hypercalciuria.
So in ‘salt-retaining’ tubulopathies of the DCT, you get hyperchloraemic hyperkalaemic acidosis and hypertension
Behold – the mirror-image of Gitelman syndrome: Gordon syndrome! But what’s the best bit? Well to treat Gordon syndrome, you use thiazide diuretics, which act only on the NCC transporter. Remember that thiazides induce a biochemical picture similar to Gitelman. So you are essential treating Gordon with Gitelman, and it works like a charm: everything normalises beautifully.
So, let’s add the DCT to our summary table……
And that’s it – we’ve travelled the length of the tubule! You made it, fame and glory await you in the nephrology clinic…. Hang on, what? There’s more you say?! Collect your thoughts and we’ll see you tomorrow for the Collecting Duct.