Continuing with our discussion of our overview, we have A, B, C, D, E all set up here.
With A, B, C, D, E walking through this, we're going to put some of these together as you shall see.
And when we do, we will talk about those segments of the nephron in great detail
so that you understand exactly the mechanism, the things that that part or that segment
of the nephron is responsible for doing. We'll add in some pathology, put in some pharmacology,
and obviously discuss a few adaptation issues as you shall see. Let’s take a look at segment A,
which is the proximal convoluted tubule in great detail. Here, let me set up the picture for you.
You must understand, the lumen is the urine. You see that on your left. And then you have,
what kind of a membrane is this? This membrane here, in fact, is your apical or luminal membrane.
And then you have your epithelial cell, which is your PCT. That’s exactly where we are.
And then you have the basolateral membrane which is then facing the what, please?
The blood. Basolateral facing B, the blood. In other words, facing the interstitium.
Have you set this up clearly now? What are the mechanisms and what are the different processes
that you’re already familiar with in the PCT? Ooh, lot of reabsorption taking place here at this point.
And by that we mean two-thirds of your sodium, potassium, chloride. You’re also taking up
quite a bit of amino acids. How much of your glucose are you taking up? In previous discussions,
we’ve had close to 100% of your glucose that’s being reabsorbed, haven’t we? Close to 100%,
and that’s the one that I want us to, at this juncture, pay attention to. With this glucose,
well, it can’t do it by itself. It requires a cotransporter, and this comes in the form of your sodium.
But in order for this to begin, you begin at the sodium potassium pump in the basolateral membrane.
You see the sodium potassium pump. And it is imperative that you pay attention to ATP. Why?
I told you earlier that if, if the proximal convoluted tubule was undergoing a process of ischemia,
lack of blood flow, you're not then delivering proper oxygen to the cell. And so therefore,
the cell is not producing proper amounts of ATP because instead of aerobic,
we’ll be travelling through anaerobic. And so therefore, you’re not feeding your biochemical processes
of TCA nor electron transport chain. My point is this. If that ATP isn’t working as well
then that cell may then perish. So those areas of the nephron that are extremely susceptible to hypoxia,
PCT is one of them for the reason of that ATP. Now, continuing our discussion, as the sodium
is being pumped out into the interstitium, how much sodium is left inside the cell? Not as much.
What have you created? You’ve created a gradient for sodium to rush in or be reabsorbed
from your urine into the cell. Along with it, it may then bring in a number of substances
in the form of symport, or we can do two things at the same time here. You can jump to another
exchange, and this exchange that we’re seeing here is an antiport between sodium and hydrogen, right?
But the basic premise, you begin at the pump. Always do that for me. And as long as
it begins at the pump, then everything else makes sense in terms of reabsorption.
That has to be understood. Now, this path that we’re seeing here is transcellular, right?
They’re moving through the cell. So that’s glucose. Let’s talk about bicarb. Bicarb coming from the blood
filtering through, what kind of PH? You know this being an alkalotic, right? It is an alkalotic substance.
So bicarb is then filtered through. And tell me about bicarb. Most of it is reabsorbed. 80% is reabsorbed.
Indirectly or directly? Indirectly. As soon as you hear bicarb, physiologically, you’re thinking about
which formula. You have your bicarb plus hydrogen and you have formation of your carbonic acid.
That does not require carbonic anhydrase. Is that clear? Where are all the different places
where this formula you will see and have seen repetitively? Nephrology - renal system,
gastroenterology - GI system, especially with what’s called this postprandial alkaline tide,
and then up in the lungs, there once again, we’ll be dealing with bicarb, right?
But as soon as you hear bicarb, you’re thinking about this formula right off the bat.
Automatically, it connects with hydrogen, you form your carbonic acid. Ah, now you have
enzyme number one. “What does that mean, Dr. Raj?” Enzyme number one is carbonic anhydrase,
number one. So you have this enzyme which will then take carbonic acid and you form
your carbon dioxide and you form your water. Okay. Now, this is going to get readily reabsorbed
into the epithelial cell. What are you going to do now? Carbonic anhydrase number two,
do you see those bolden? Very important that you know this. Every second carbonic anhydrase,
which is going to take that carbon dioxide and water, and form your carbonic acid, and spontaneously
dissociates into hydrogen bicarb. Now, don’t get caught up in the details where you forget the objective.
What are we trying to do? Reabsorb bicarb. How much? 80%. Is that clear? Now, this bicarb
that you are reabsorbing, is this newly synthesized or is this the reabsorbed type?
Obviously, this is the recycling of bicarb. When you talk about newly synthesized bicarb,
that will be done further in the collecting duct but not here. But at this point, we’re reabsorbing.
If you've understood this much, we're in good shape. Now, the only little clinical tag
that I wish to bring to attention is the fact that what if you had a patient that was in high altitude.
So tell me about high altitude. Work with me here. Obviously, you know me well enough now
where I can’t just go pass a particular segment or piece of information and just go through
with the basics. No, no, no, no. This is medicine, people. So I want to go into high altitude.
If you go with the high altitude, what happens to your environment? You’re beyond air.
Beautiful up here, beautiful. Go to Rockies, huh? Go to Alps. I don’t know. Whatever.
There you are. You're looking at the landscape. It’s so pretty up here. But what happens
with barometric pressure? It drops. Barometric pressure drops. Normally, at sea level,
you’ve memorized 760 mmHg. And when you go into high altitude, the barometric pressure drops.
Maybe it drops down to 250. Oh, that’s really bad. So you’re taking the air here.
Okay. But once again, the barometric pressure is decreased. You continue forward
and you travel through your trachea, down through your alveoli and such.
And eventually, well, guess what? Your barometric pressure is decreased. And so therefore,
how is the body going to respond? How is the body going to respond? [panting sound].
That’s not a panic attack. That’s me in high altitude, okay? If you’re having panic attack right now,
take a brown paper bag. Breathe with me. But anyhow, high altitude, breathing really quick,
breathing really quick, what happens to carbon dioxide? You’re blowing it off, blowing it off,
blowing it off. Where am I? High altitude. You’re blowing off your carbon dioxide,
what happens to your pH? Increases, right? What’s that called? Respiratory, respiratory alkalosis.
So therefore, what must you do in the kidneys days later in which you can compensate?
What must you do down in the kidneys, here we go. This is where the clinical correlation's
taking place. This is where the beauty of everything that you’re learning comes into play.
Work with it. So the kidney, days later, is going to compensate by doing what? Getting rid of bicarb.
Why? Because you're in a state of respiratory alkalosis. Why? Because you’re in a high altitude.
And what does that mean? Oh, decreased barometric pressure. The body wants to then breathe more
obviously. Are we clear? So you’re trying to get rid of the bicarb, aren’t you?
But let’s say that your patient doesn’t get rid of the bicarb quick enough. We have acute
high-altitude sickness. So give me a drug that you know of that inhibits carbonic anhydrase.
Acetazolamide, okay? So acetazolamide inhibits our carbonic anhydrase. If you do look,
then where is my bicarb? It’s stuck in the urine and you’re facilitating the compensatory mechanism
of the kidney in a patient that has respiratory alkalosis. So therefore, now we’re good.
I’m giving you clinical correlations so that you clearly see the application and you’re not just
sitting there and memorizing it. Now you think PCT, okay, good. You’re clear. You give yourself
a little bit of a drug and put yourself in a situation, pathologically, physiologically, things will stick.
Let’s continue. What about the descending? Well, as we continue down the descending,
what’s happening to water? It’s being reabsorbed, is it not? Of course, it is. As water is coming out,
then what remains within the urine? It’s becoming more hypertonic. By the time you come
to loop of Henle, naturally speaking, naturally speaking, without any influence of the hormone,
listen to this statement so that you do not get this question wrong. Without the influence
of a single hormone, what would be that region of the nephron that is most hypertonic,
without the influence of a hormone? Obviously, the medullary loop of Henle
because water is being reabsorbed. Nephron, the urine has electrolytes in it, solute.
So by the time you come to the actual loop, you’ll find it to be quite hypertonic
but without the influence of any hormone. Why did I keep saying no influence of that hormone?
Because if there was influence of hormone such as ADH, then the collecting duct would also be
quite hypertonic. Are we clear? But at this point, we’re at the loop. So passively reabsorbs water,
where am I? Coming down the descending limb, impermeable to solute, we did talk about that,
hence hypertonicity. Now, we go to – look where you are – thick ascending limb.
First and foremost, thick ascending limb, that box that you’re seeing is the most important
component of the thick ascending limb. Once again, clinical correlation. First and foremost,
sodium potassium two chloride. Let’s set up the picture. The urine on the left,
epithelial cell in the middle. What epithelial cell? Thick ascending limb. And on the right
is your blood or interstitium. Okay. And we have a symport of three substances.
What does symport mean? Same direction, movement. The three substances, sodium, potassium,
stop there. What are those in terms of charges? Cations, right? Well, isn’t the body about homeostasis
and maintaining balance? Yes. Well, you have two cations. What must you then have
to balance out the cations? How about a couple of anions? Ah, welcome to two chloride. Are we clear?
So you have sodium potassium two chloride. That creates the balance that you require.
This is a symport. Now, this would be another area that is extremely susceptible to hypoxia
because it’s very much dependent on that sodium potassium ATPase pump. So the pump
is removing the sodium. It’s putting the potassium back into the cell. Stop there. Why?
Because this potassium – pay attention – that potassium is being pumped back into the cell.
Potassium is also being brought in by the symport. And as you know, where do you find more potassium
to begin with, ICF or ECF? Answer, I-C-F. So, if there’s already so much potassium in the ICF
and you’re putting more in there, at some point, the potassium wants to do what? Explode.
It wants to come out and it does. That potassium, and we’ve talked about this in physiology,
if you haven’t understood it, understand it now, which is not shown here but that potassium
may then back-leak. It may then back-leak into the urine. You’ve heard of back-leak, haven’t you?
And so, that back-leak of potassium back into the urine will then facilitate the reabsorption
paracellularly. What’s para mean? Between the cells. You see that big, green epithelial cell?
And then, you have another epithelial cell? And you have a space there? That’s paracellular.
So that potassium with back-leak will then force other cations including magnesium
and some of that calcium to then get reabsorbed through the paracellular route. You want to know that.
You want to know the concept of paracellular or you want to know the concept of back-leak,
and all because of too much potassium inside the cell. Interesting things? Sure. Are we quite done? No.
That’s sodium potassium two chloride. Give me a diuretic, give me a drug in which it inhibits
that particular symport. It’s called loop diuretic, furosemide. That loop diuretic, as you know,
one other point that I wish to make too, is that loop diuretic, we’ll talk about this coming up,
a loop diuretic will not reach the sodium potassium two chloride through the glomerulus.
Think about what I just said. A loop diuretic does not exert its effect or action by being filtered,
and then making it into the thick ascending limb. It doesn’t work like that, ladies and gentlemen.
The loop diuretic is going to work by, from the blood, the plasma, it’s going to get secreted
with the help of, well, transporters. That’s important. Then, it will then work on the
sodium potassium two chloride to do what? What are you trying to do? Loop diuretic.
Well, who’s your patient? Maybe he has pulmonary edema secondary to congestive heart failure.
What might you want to do to get rid of that fluid? A loop diuretic, huh? So there’s ease of breathing.
Okay. But the problem is this. When there’s loop diuretic, what are you going to lose?
Everything, everything. You’ll lose sodium potassium two chloride and you’ll lose all your calcium.
Not good. So be careful. And so, you have to monitor specifically which electrolyte?
That goes back to your basics. What’s the most important electrolyte that is responsible
for maintaining resting membrane potential? It’s called potassium. Potassium is the most important
electrolyte for maintaining resting membrane potential. Now, with the loop diuretic,
what’s going to happen? There goes the potassium. Bye-bye, potassium. You’re flushing it
down the toilet. So therefore, you start thinking about maybe giving your patient
a potassium-sparing drug. So potassium has to be quite monitored when you’re using a drug like a loop.
We’ll talk more about that later. And then finally, there is a disease here, a pathology
that will knock out the sodium potassium two chloride. And the name of that disease, we’ll talk about later.
Coming up. It’s called Bartter. All right. So we have two major. We have Gitelman and we have Bartter.
Now, Bartter, it’ll be the fact that it behaves like a loop. You haven’t heard of that before. That’s okay.
Bartter. Upcoming. Important. Couple of genes that we have to talk about that you may or may not
be familiar with. But you'll hear it here first. Let’s continue. Here’s a back-leak. Why?
Potassium being accumulated in your cell excessively. At some point, it backs into the urine.
Therefore, bringing about paracellular reabsorption of magnesium, calcium. It’ll be best,
in terms of learning, to predict as to what’s going to happen by closing our eyes and conceptualizing.
Then later on, we take a look at the picture or the text, it’ll make sense and it’s coming together
like that. Now, we get into the distal convoluted tubule, okay? Please leave PCT behind.
Our discussion quickly went through thick ascending limb and now we’re into distal convoluted tubule.
As soon as you hear this, the number one hormone that should come to mind, PTH.
Set up the picture again? Are we quite clear? Urine, left side, lumen. What’s in the middle?
Epithelial side. What’s in the right side? The interstitium and the blood. Okay. What is PTH
responsible for here specifically in the distal convoluted tubule? Only, only reabsorption of calcium.
Only. Why do I keep saying only? Because PTH also does what? It flushes phosphate down the toilet
normally and physiologically. That is not taking place here. The PTH, as you’ve learned, and its effect
of inhibiting the reabsorption of phosphate will be in the PCT. That’s important.
And the last bit of component of PTH and its effect of activating whom? Calcium,
well, calcitriol. Another important calcium homeostatic hormone, vitamin D. That’s through activating,
that enzyme is, you tell me, good, 1-alpha-hydroxylase. But that would not be here.
Once again, that’s in the PCT. So let’s just talk about PTH and its receptor, and as to how
you are going to bring about calcium reabsorption. Let's begin at the top with the sodium potassium pump.
There it is. Removing sodium. What happens to sodium concentration within the cell? It decreases.
Then you have a symport mechanism. And here’s sodium and chloride. Approximately 25%
of your sodium only is being reabsorbed. Majority of it? The majority of it was already done in your PCT.
So this takes care of a little bit more sodium. Chloride is going to come out. And then, you take a look at
the basolateral membrane, please. You have an antiport that you're seeing there.
Then with the help of PTH, it will then reabsorb my calcium. It’s important that you pay attention there.
Okay now, let me give you a couple of pathologies. What if you have hyperparathyroidism?
Hyperparathyroidism, primary, not secondary, primary. That means that, think about your
parathyroids around your thyroid gland. That’s four of them. And it’s an adenoma producing too much
parathyroid hormone. Welcome to primary hyperparathyroidism. Tell me about your calcium levels.
It'll work on the distal convoluted tubule to reabsorb calcium. Welcome to hypercalcemia.
And if it's hyperparathyroidism, primary type, what is it going to do to phosphate levels in the PCT?
It will further inhibit the reabsorption. Welcome to hypophosphatemia. And last little thing
that you want to keep in mind with PTH is always check for renal function. We’ll talk more
about that later. But right now though, I’m giving you one example for hyperparathyroidism.
The only other thing that I wish to bring to attention is that receptor, and by chemistry, by chemistry,
we talked about a receptor known as G protein. You know about Gs, and Gi, and Gq. You tell me.
I’ll tell you why this is so important. You tell me which G protein does PTH work through.
It’s called Gs. Really? Mm-hmm. What if you find a pathology in which you’d find decreased levels
of cyclic AMP in the urine? Wow! How do you relate all these together? Gs. What’s the number one
letter you’re thinking about Gs? A-A-A-A, adenylyl cyclase. You convert your ATP into cyclic AMP
and your protein kinase A. You think of Gs, you think of A, right? So you have your adenylyl cyclase
and ATP, and cyclic AMP, and you have your protein kinase A. Are we good? So as long as you have PTH
working properly, you should find just enough cyclic AMP in the urine to make sure
that you're properly functioning. If it's primary hyperparathyroidism, obviously, you'd find
too much cyclic AMP. Would you give me a name of a pathology where the receptor isn't working?
I didn't even know such a condition existed. Yes, you did. Yes, you did because now you call it
knuckle knuckle dimple dimple. What? Now unbelievably, this patient, short stature,
fourth and fifth digit, the knuckle which is a metacarpophalangeal, you don't have a knuckle.
They're dimpled. It's inverted. Why? It's crazy. But that's how this patient is going to present.
A short patient, knuckle knuckle dimple dimple, fourth and fifth digit, their knuckles are not present.
They're not properly formed. And the receptor isn't working properly, so you find decreased levels
of cyclic AMP in the urine. Welcome to pseudohyperparathyroidism. Wow! Dr. Raj, I had no idea
that all this stuff could be derived by looking at a simple picture like this. Yes, you did.
You just never applied yourself. So now, we take a look at our collecting duct. In our collecting duct,
these are things that, once again, physiologically are important for us. We spend
quite a bit of time with this. Let's put all these together. Once again, set up the picture.
We have the lumen and the urine. We have the epithelial cell. And we have the interstitium, correct?
Reabsorption means what? From the urine out into the blood. Secretion means
you’re going into the urine. Clear? Next, when we do our collecting duct, take a look where we are.
We have two major cells. We have a principal cell, intercalated cell. Your emphasis and focus
should be principally, pun intended, on the principal cell. Now, the hormone that we’re going to bring in
here will be aldosterone. Why? Maybe your patient had decreased blood pressure.
Maybe your patient had congestive heart failure. Are we clear about those? Decreased blood pressure,
decreased perfusion to the renal artery. Here comes my renin. Ah, I kick off my RAA System.
Congestive heart failure, my heart is dead, and more of my plasma, my transudate is being
hydrostatically pushed into the interstitium. Welcome to maybe pulmonary edema
and dyspnea and such. If it’s right side, welcome to positive GBD and pitting edema. What’s my point?
When this fluid has escaped the blood vessel and has gotten into an interstitium,
well, how was the juxtaglomerular apparatus going to interpret this? Decreased effective
circulating volume, right? So therefore, welcome to RAAS again. So here's my aldosterone.
and all this. If you've missed that discussion about CHF, cardiology, and then here,
aldosterone comes in and it binds to the receptor. Where? Well, the receptor will be bound to,
let’s say, on the basolateral membrane. Once it works upon that receptor which is then called,
well, aldosterone receptor, and that’s important for you to understand because you can have
what's known as aldosterone receptor antagonist. Give me the drug, spironolactone,
clinical tag there. Stop. This aldosterone can do what with the sodium potassium pump?
What is its main objective? To reabsorb sodium. So it will stimulate that pump, or on the luminal
membrane or the apical membrane, that’s called epithelial sodium channel, eNaC,
so to reabsorb sodium through there as well. Now, understand though, they will not have you
differentiate between, well, which one doesn’t work more. That's a ridiculous question.
It doesn’t accomplish anything. Aldosterone will do everything in its power to reabsorb sodium.
Stop there. What else does aldosterone do? It works here to get rid of your potassium.
In other words, secrete on potassium. Clear? What's the third and final thing that aldosterone does?
I want you to drop down to the intercalated cell. You see that? The intercalated cell.
That intercalated cell, I want you to focus upon. I need you to find hydrogen and that hydrogen
is being secreted into the urine. Guess who does this. Aldosterone does. Let me give you
a very common enough cause of secondary hypertension, in which upon imaging study of the adrenal,
Let’s say a CT, you find a tumor within the adrenal cortex in which you're strictly producing
only aldosterone. So this is not buffalo hump, moon face, it’s not Cushing's, strictly increase
in hypertension or blood pressure, secondary type. This is Conn’s syndrome. I’ve mentioned this
a few times because I want you to get in the habit of understanding your labs. If you have aldosterone
in excess, specifically, what's my sodium level as a concept? Increased. Please give me a value.
Above 145, number one. Number two, if you have too much aldosterone, what happens to potassium?
It’s being secreted out. Give me a number. Less than 3.5. So far, so good. Number three, hydrogen
or too much aldosterone, you're secreting hydrogen into the urine. Tell me about the pH.
Alkalotic, increased. Are we good? If you're not, review that concept real quick.
In Addison’s, I would ask you to do this. With Addison’s, I want you to compare Conn’s with Addison’s.
In Addison's, you're deficient of aldosterone. Primary adrenal insufficiency. All the labs will be reversed.
Decreased sodium, hyperkalemia, decreased pH. You understand this? You’ve understood
a bunch of pathologies. Let’s continue. Here as well, we have ADH, ADH receptors.
How many kidneys do you have? Oh, one. Two. Very good. V2 receptors. Why do we call these V?
Because they're vasopressin. It's another name for ADH. Where else may ADH work?
A name, vasopressin, V1, on your blood vessels, bringing about vasoconstriction.
Through V2, you're going to insert aquaporins. And if need be, what do you mean need be?
I just ran through the desert. Oh, that's a lot of sweat. I’m losing a lot of fluid. I am losing more water
than I am sodium. Dr. Raj, when I sweat, and I taste myself, I taste mighty good. What does that mean?
I taste salty. Okay, fine. You like salt. That’s great. But understand, you’re losing more water. Clear?
Okay. So if you're losing more water than salt, what is your plasma osmolarity, please? Good. Increased.
Are we good? Your plasma osmolarity is increased. Where are you now? Who’s going to detect this
immediately? Who's going to detect this immediately? Hypothalamus. Hypothalamus. Through whom?
Osmoreceptors. So you sweat so much, huh? And you’re losing that water.
The body wants to replenish it. Where is it going to get it from? The kidney. Kidney.
Are you understanding this? So who are you going to release? Who are you going to release?
ADH, antidiuretic hormone. Here comes ADH to the rescue, at least initially.
And it works in the V2 receptors, puts in, inserts aquaporins. Were you going to reabsorb more water?
Now, you tell me. On the side of the urine, be careful when you do such questions.
And if you're dealing with attendings and such in your CPC, you will differentiate between
urine osmolarity and plasma osmolarity. Do that every single time. Here with ADH working,
what kind of urine are you producing? Good. Concentrated hypertonic urine. Excellent.
So far, so good? This is the collecting duct issues here.