Glucose. In that previous graph by chance, if
you were a little confused, it absolutely
warrants further discussion so much so that we
need to take a look at this in great detail.
So that whole graph with glucose is just giving
you an overview, but if you don't understand
or if you haven't understood the depths of
glucose handling or renal handling of glucose
might be little complicated, but let us now
simplify things and be more technical. To
begin with, we have filtered load. What does
that mean to you? It means that what is coming
through the efferent arteriole and approximately
20% which is then your filtration fraction
and how much do you have left on the efferent
side if it is renal plasma flow? It will be
480. What is the normal renal plasma flow
coming in? Approximately 600. So 120 has come
through and filtered and we are left with 480.
Want you to continue. Set up this picture
here that you are seeing on the left and now
we are at the level of the peritubular capillaries.
You see that big fat red arrow? That is your
peritubular capillary and now there is modification
is taking place in the nephron. You see that
yellow arrow. That represents your nephron.
Are we clear? Where we are in a nephron
represents the proximal convoluted tubule?
The PCT. That is where the majority of our
modification of our urine will be taking place
at this juncture. Reabsorption, what does
that mean to you? You are bringing that substance
from the lumen, from the urine back into the
blood. What does secretion mean? It means
that you are putting the substance into the
urine. Let us talk about glucose. Should you
normally find glucose in your urine completely
being cleared? Not at all. If you start finding
glucose in the urine, obviously you are suspecting
hyperglycemia and some type of underlying
issue. Are we clear about this? Next, that
glucose that is being reabsorbed just keep
it simple. It is 100%. The glucose
that is being reabsorbed at a rate or at a
percentage of 100, requires transporters. It
cannot do by itself. It is not a simple diffusion
where it just passes through the membrane. Now
where am I? Close your eyes. You are in the
urine, lovely place to be and you have your
epithelial cell and what epithelial cell?
The tubular epithelial cell and what is the
name of the membrane facing the urine? It
is called the apical membrane or the luminal
membrane and glucose does not and cannot diffuse
by itself by simple diffusion. It requires
help. What kind of help? It is a cotransporter.
The cotransporter many at times your substance
such as amino acid, phosphate and such will
use sodium as being the cotransporter to bring
that substance or in other words reabsorb
that substance from the urine into the epithelial
cell. Okay fine. So here is the glucose in
the epithelial cell. You have got out of the
urine granted. Are we done? No, no, no.
The entire process of reabsorption is from the
urine into the blood. So now we were inside
our cell, the tubular epithelial cell. Are
you there? Next, we have now to cross the
basolateral membrane. So now you have to go
to the other side where the blood is and that
is called the basolateral membrane and the
basolateral membrane has a pump. Every single
basolateral membrane on a cell has this pump.
It is called the sodium-potassium ATPase pump.
Now the PCT has the highest concentration
of the sodium-potassium ATPase pump. In pathology,
when there is ischemia taking place. What
does ischemia mean? Lack a blood flow along
with that, more importantly, the RBCs are
not providing and delivering oxygen. Now,
what happens? You don't go through proper
aerobic glycolysis. You don't produce enough
ATP. What happens to the pump? It doesn't
work. Correct okay. So that we will talk about
later and one of the major components or major
regions of the nephron that is susceptible
to such damage especially to hypoxia would
be the PCT for this very reason. So that sodium-
potassium pump is going to pump the sodium
into the blood making the concentration of
sodium less within the cell so that the sodium
can come from the urine along with it it is
going to bring glucose and that cotransporter
will then take the glucose out into the blood.
How much reabsorption? 100%. So for you
to have effective glucose reabsorption,
what must you have? Please know this because
you will get questions on that glucose transporter.
You must have a GLUT. You must have a
glucose transporter or otherwise
you can't have reabsorption. Keep that in mind
as you move through here.
Next, what if there is no net transportation.
Your filter load is then equal to what the
ER means here is excretion rate. Once again
the filtered load is that which is being filtered.
That is not equal to what is necessarily excreted.
Now if there is no modification, meaning what?
No reabsorption, no secretion, then it is
equal to excretion rate. In other words, clearance.
Wonderful. Now lets go on to reabsorption.
Now close your eyes. Don't look at this. Predict it.
If it is reabsorption, now what happens? That
which is being filtered gets reabsorbed. Okay.
Once it gets reabsorbed, tell me about its
excretion. There is going to be more filtration.
There is going to be less excretion. Welcome
to filtered load being greater than excretion,
Why? It got reabsorbed. It didn't get excreted.
That would be something like your glucose.
Now, what if it was something like para amino
hippuric acid or hippurate? What if there
was a creatinine? Tell me about those substances.
Secreted. If something is secreted into the
urine. Tell me about the excretion rate. It
is greater than filtered load and see as to
how important it is for you to pay attention
to the language and terminology of medicine
in general, but here specifically with nephrology.
Otherwise, you will be sitting there cracking
your head wasting precious time and even then
you are not even sure as to whether you got
it right. You want to be confident about everything
that you are saying. Let us talk about the
graph now. Set this up and a lot of things
going on here. It is like, remember in cardiology,
we did the mixed cardiac function curve. Don't
you love that. Well, you are going to love
this too. A lot of things going on. This is
glucose. In general, just tell me the big
picture. Does it get filter glucose? Yes,
it does. Does it get excreted? Does it get
cleared? No. Does it get reabsorbed? Yes.
How much? Close to 100%. Does it get
secreted? Absolutely not. Have you set that
up? If you miss what I just said. Review what
I just discussed. Now move on. Okay. Let us
set up the graph. On the X axis, it represents
the concentration of now specifically glucose.
In our previous lecture, we have looked at
the X axis being plasma concentration of many
many many substances including pH, inulin
so on and so forth. This is strictly only
glucose. On the Y axis, now this where it
get tricky. Work with me. On the Y axis, there
is going to be many parameters and some of
these parameters include excretion. It represents
the filtered load and represents the reabsorption
and we are going to dissect every single one
of these till it makes sense to you. Pay attention.
Okay. When you are initially speaking, with
glucose, you have filtering. So whatever it
is as far as glucose in your plasma, it gets
filtered. What are we calling this physiologically
and clinically? Filtered load. I want you to do
something else. DC versus filtered load. Do you see
the green line. I want to come way back down
to zero and I kind of what to think of this
being as a zipper. Okay. Work with me here.
So there are two lines initially at 0.0.
In the filtered load, it is hidden underneath
that green line. Please work with me here
and what that green line represents is well
for the most part whether or not a substance
is being reabsorbed as you shall see. So as
we increase the plasma glucose concentration,
what happens to filter load? It starts increasing.
There is more glucose, which you have in your
plasma the more that has been filtered. Absolutely.
Now that which is being filtered, is there going
to be complete reabsorption? Absolutely. So
initially speaking lets start to see the
end on the X axis that means normal. So normal
levels of glucose. Give me a normal level.
Lets stick to 100. A plasma glucose level
of 100. Lets stick to that and say that your
glucose level is at 100 in your plasma. Is
it being filtered? Yes. That is your filtered
load is being completely reabsorbed. That
is correct. How can you confirm this on this
graph Dr. Raj? Now you take a look at the
blue line, that means excretion. That is excretion
rate the blue line. Wow! so early on at normal
what about my blue line? It is nonexistent.
Why? Because the only glucose would be reabsorbed.
Are you literally seeing this in your head?
It is amazing, isn't it? That a graph is able
to give you such a joy but it's also because
I am a dork. Anyhow. so now the excretion is
completely at 0. Why? At normal levels, plasma
glucose will be filtered. It is being completely
reabsorbed and there is no excretion. Ah!
beautiful. Normal physiology. Now let us start
increasing say that your patient is prone
to hyperglycemia. Why or maybe there is diabetes
mellitus type II. Maybe there is obesity involved
so on and so forth. You are increasing glucose
up to 200 now. So now you hit T. Now be careful.
That T does not represent Tmax. That T represents
threshold. The threshold for what? Glucose.
What does that even mean? That means that
if you hit that threshold, it is the early,
early sign of glucose now appearing in your
urine. Have you understood the definition
of threshold? It is not the same thing as
Tmax at all. Now, why is that important for
you? Clinically speaking.
Let us take a pregnant lady, remember the pregnant
woman we talked about and you tell me what
is the creatinine clearance in a patient
who is normally pregnant? Increased or decreased.
Take your time. Plasma volume in a pregnant
lady especially at the end of the first trimester
increases by how much? Oh! maybe up to
50% it might increase. That is a lot
of plasma volume. You are going to increase
your hydrostatic pressure and you are going
to clear more creatinine. We talked about
that earlier. If you are not clear about this,
this would be a good time for you to review
this. Next, now as you increase the amount
of glucose in a pregnant lady is that normal?
Yes, it is. Why? Remember the fetus and its
placenta is producing a growth hormone analog
biochemically and that growth hormone analog
coming from the placenta is called human placento
lactogen, not HCG. This is HPL. What kind of
effect has HPL have on the mother in terms
of handling the glucose? Tell me about that
fetus? It is starving. Mumma, feed me. So
the fetus wants to eat. Feed the poor fetus.
So the mother has to make sure that she has
enough glucose in her plasma to not only
feed herself but more importantly, whom? The
fetus. What do you know about glucose? Does it
cross the placenta barrier. Of course,
it does. So that HPL allows for glucose to
be increased in the maternal, maternal female.
Okay. So that you know about plasma glucose
increasing and you know about her plasma volume
increasing in a female. Then what do you think
happens overall to renal threshold meaning
the earliest sign of glucose appearing in
the pregnant woman in her urine, would it be later
meaning with the threshold be increased or
with the threshold be decreased where you
would find glucose in the urine very early.
Obviously decreased. So what is threshold
mean to you? The earliest sign of glucose
being found in the urine. Fact physiologically
knows that don't miss the question and use
your common sense and the things that you
know about pregnancy to answer that question.
Let us move on.
We are going to continue increasing glucose.
Okay. Now we get into glucose transporters.
Where are they located? Well, they are located
where you have your basolateral membrane allowing
your glucose not to be reabsorbed back into
the blood. Do you not? So this is then going
to help you bring out your glucose to reabsorb
it and as you increase your glucose further,
further, further and further, while now you are
going to start saturating your transporters.
So what if you start increasing the amount
of glucose that you find in the urine. You
are going to form a curve. You see that green
line there. That is the curve. That is called
splay. What does that mean? That means that
you have more and use it to your advantage, where
you can think of it as being now the glucose
is spilling into the urine further. That is
called splay. It is not just a perpendicular
curve that is a curve and the reason for that
is because the transporters are being saturated
further with an increase in plasma glucose
increasing the amount of spillage of glucose
in urine. Now we have the threshold. Now we
have splay. Now the last point that we have
is finally Tmax. So what is Tmax? It is the
maximum amount of transporters being completely
saturated at approximate plasma glucose of
370. So all way up close to 400, wow! that
is a lot of glucose. What is approximately
normal? One hundred. So now that your glucose
up to 400 maybe your patient has complete
uncontrolled diabetes mellitus and a plasma
glucose here of 400 maybe getting close to
diabetic ketoacidosis. If I have a plasma
glucose of 400 every single glucose transfer
enhancements saturated, you have had what
is called as transport maximum and what happens
to your excretion? Take a look at the blue line. Every single
glucose now. Not every single. Excuse me. Those glucose
that have saturated their transporters are now
spilling into the urine and you find your
excretion of glucose rising. The only thing
that I wish to bring to your attention is
the following. Tell me about the reabsorption
at this point of glucose even at 400. I didn't
block those transporters, did I? So all those
transporters still hardly trying to move the
glucose and reabsorb it. Yes, it is. But the
problem is the plasma glucose is so high that
it continues to spill into the urine. The
next question and the most important one is
the following based on everything we just
talked about in terms of excretion rate. If
you know that glucose is being reabsorbed even
at maximum, then is your filter load equal
to excretion rate for glucose or is your filter
load greater than excretion rate. The filtered
load will still be greater than excretion
rate even at maximum transporter, allow that
concept to set in because what happens those
transporters are still reabsorbing. The plasma
glucose has no influence on the dysfunction
of the transporters. So transporters are working
maximum hence Tmax. That is the full picture
of this graph of glucose. You understand this
with every single aspect of filter load, splay,
threshold, Tmax, and excretion. You can’t
miss a single question with physio, pathology
what they may throw at you in terms of what if
you get a question where the transporters
were blocked. Tell me about the relationship
between excretion rate and filter load or
clearance and GFR. If those transporters were
blocked, which is a very good question that
at some point you will be asked, then understand
that glucose which is being filtered is equal
to that which is being excreted. So you have
your GFR equal to clearance if the transporters
were blocked. Here we have no blockage of
our transporters. It is the only way that
you truly will understand this. Let us now
So here inulin, mannitol, and sucrose, what
about these substances? You pay attention
to inulin. What do you know about inulin?
Inulin is it filtered? Yes, it is. It is modified
at all in the PCT. No, it is not. Take a look.
You find no secretion and you find no reabsorption.
So thus inulin, mannitol, and sucrose, these
will be filtered. But they will not be reabsorbed
or secreted. Thus filtered load equals excretion
rate. Thus, clearance equals GFR for inulin.
Next, what is going on here? In the PCT and
we have reabsorption or secretion? Which one
is this, please? Reabsorption. What do you
know about sodium, potassium, chloride and
such? They are reabsorbed, aren't they? And
when reabsorption is taking place, tell me
as to what your relationship is between filter
load excretion rate. Filtered load is greater
than excretion rate because it is being reabsorbed.
Tell me about clearance in GFR. Clearance
will be less than GFR because it is being
reabsorbed. Are you good with the language
here? It is only once you go with the language,
then once again maybe we may move on. Glucose,
amino acids, and ketone bodies once again
reabsorbed. Well, lots of glucose reabsorption.If
you have creatinine, high plasma PAH and potassium
load. This is a little interesting here.
If you have high PAH, well this is interesting
because, at high PAH, this goes back to a
graph on a previous discussion where if you
have high PAH, you will notice that it is
secreted. That is what is going on here. So,
therefore, clearance will be greater than
GFR or in other words, excretion rate will
be greater than filtered load. Same thing
for all intended purposes and the thing is though
that this is not going to equal renal plasma
flow because at a high rate it will be closer
to GFR. What do you know about creatinine?
Slightly secreted in approximation of GFR.
I want you to compare this. Pay attention
to this. The high PAH with low PAH. The low
levels of PAH very low plasma concentration
of PAH, tell me about its effect or how does
it function in the PCT? It is going to get
completely secreted. I want you to pay attention
to big, thick blue arrow there compared to
the little blue arrow that you are seeing
with high PAH in the previous picture that
big, thick blue arrow represents complete
secretion of para amino hippuric acid into
the PCT. Not a single para hippuric or hippurate
is being further sent through the peritubular
capillary. So, therefore, you can confirm
and clearly say that clearance is equal to
renal plasma flow at low levels of para amino
hippuric acid or you can say that we have
excretion rate is then equal to your renal
plasma flow. Isn't it? A better way of saying
this clearance is equal to renal plasma flow
because everything is being secreted. Once
this is clear, then we can move on.