Continuing our discussion on the concentration
of urine. Up until now, we looked at ADH,
looked at its control and then went into SIADH
in great detail. Now let us take a look at
diabetes insipidus, the opposite of but nonetheless
an important difference to keep in mind when
you have plasma and urine osmolarity at hand.
So we have nephrogenic diabetic insipidus.
Now what we will do here ladies and gentleman
is under renal or nephrology, we will strictly
only be managing nephrogenic diabetic insipidus.
I want to make sure that we are clear because
there is no important piece of information
that is left out in your lecture series with
me. The central diabetes insipidus, we will
be dealing with that in endocrinology. Is
that clear? So here let us keep things relevant
and all that I will bring to your attention
is the pathology of diabetes insipidus, nephrogenic
in the category of nephrology. With that said,
let us continue and before we move on, though,
let us talk about the basic definition and
predict as to what is going to happen in our
patient with nephrogenic diabetes insipidus.
Nephrogenic that means there is a problem
with the kidney in which ADH is not working
properly. Now just to make sure we are clear.
If you have a patient that has SIADH maybe
perhaps secondary to small cell lung cancer.
We talked about that in great detail. Then
you would purposely induce nephrogenic diabetes
insipidus by giving a drug such as demeclocycline
so that you can deal with SIADH. However now
we will come to the actual primary disease
of nephrogenic diabetes insipidus. There is
not going to be your V2 receptors working
properly. You are not going to be able to
properly reabsorb your water. If that is the
case, you are going to create massive diluted
urine. This clearance of that water, which
is free will be absolutely positive. Remember
the clearance of water is zero and that is
where all are really focused upon if clearance
of water was zero. It is the fact that you
are producing urine that is obligated meaning
with sodium. It is not free of solute, but
if you are producing lots of diluted urine
and you are clearing this and understand there
is going to be a lot more free water than
there is going to accompanied with solute.
So there is going to be a lot more free water
thus the clearance of water here is going
to be positive. All that is what we predicted.
Let us continue.
Plasma osmolarity increase. Are you seeing
it? You are losing diluted urine thus plasma
osmolarity increases. It stimulates the posterior
pituitary to do what? To produce even more
ADH, but obviously, it is not going to do
anything. So this is a condition in which
and let us now draw some parallels. If the
receptors are not working, give me some pathologies
in which the receptors are not working properly.
PTH receptors aren't working properly. What
is that diagnosis? That is pseudohypoparathyroidism.
Your testosterone receptors are not working
properly. Give me that diagnosis. Androgen
insensitivity syndrome. Your insulin receptors
are not working properly. Give me that diagnosis.
Diabetes mellitus type II. Here we have the
receptors for ADH not working properly. Why
am I bringing all this up? Technically speaking
clinically. Each one of those situations that
I just gave you including this one where we
have ADH receptors and B2 receptors are not
working. The PTH receptors in pseudohypoparathyroidism
is not working. The receptors of testosterone
is not working. The insulin receptor is not
working. Clinically at some point in time
in that disease course of those differentials
that I gave you, you would always expect that
whole amount level to be what? High, because
the receptor is not working you are going
to get feedback mechanism where all my goodness
I want, I want, I want, I want more hormone,
want more hormone, want more hormone, want
more hormone. Hence in pseudohypoparathyroidism,
you will find increased PTH. Hence an androgen
insensitivity syndrome, you find an increase
in testosterone. Listen. You could in diabetes
type II within obese patient with insulin
resistance actually have increased in insulin
and you will. Hence, you will have many of
the pathologic courses or sequelae that we
see in diabetes type II. Here we are going
to have too much ADH. Are you drawing the
parallels now? I cannot talk about this in
good faith without telling you that there
are other diseases that have behaved the same
way. Let us continue. So circulating ADH levels
now you can see confidently and understand as to
why it is elevated, but who is not responding?
The principal cells.
Let us take a look at etiology of nephrogenic
diabetes insipidus. The most common causes
of ADH resistance severe enough to produce
polyuria are in the following situations.
Stop there and take a look at polyuria. As
soon as you hear polyuria, you should be thinking
about three major mutations. The three major
differentials and mutations that we will talk
about are upcoming, but the differentials
include diabetes insipidus. #2 Diabetes mellitus.
#3 Psychogenic polydipsia. Psychogenic polydipsia,
what does that mean? I don't care if you are
you are sick in the head and the voice is
in your head and telling you to kill me. Well,
that is great. The problem is up in the brain,
but not in the kidney. So even if you are
drinking too much, are you going to produce
dilute urine? Yes, you are. So, therefore,
polyuria, three major differentials. They
include diabetes insipidus, diabetes mellitus,
and psychogenic polydipsia. Now, how to differentiate
easily between Mellitus and insipidus. Glucose
right. If you find hyperglycemia, what is
your diagnosis of polyuria? Diabetes mellitus.
If you don't find hyperglycemia, you have
effectively ruled out diabetes mellitus and
now you are left with two other causes. Now
we will talk about the further differentials
in management in terms of tests such as water
deprivation so on and so forth as we continue
through the lectures. But at this point let
us take a look at some important mutations
that are occurring within the receptors of
the kidney in which your ADH isn't working
properly. So here we have the following. There
is excellent mutation and what you must keep
in mind is we have Arginine Vasopressin Receptor
AVPR2 gene. You must know at some point in
time in your medical journey, you will be
asked about the mineral acid arginine, you
should already know that the name for ADH,
which is vasopressin. You should next know
well what is the name of the receptor that
you have in the kidney, the two kidneys hence
V2 receptors. Welcome to arginine vasopressin
receptor2 gene. Memorize that x-linked recessive
Now there is another one with AR autosomal
recessive or autosomal dominant mutation of
aquaporin-2 gene and in these instances what
is happening? It is the fact that your receptors
aren't functioning properly and thus your
ADH is quite high and you produce polyuria.
Now clinical differentiation by lack of release.
There is an important concept here. You should
remember the vasopressin also works in your
blood vessel. That receptor is V1 receptor,
isn't it? Responsible for vasoconstriction.
In addition to that, there is every possibility
that at some point in time, you might want
to give vasopressin so that you are then causing
the release of vonWillebrand factor, a factor
VIII to deal with certain issues including
your vonWillebrand disease or maybe even perhaps
something like hemophilia A. Do you remember
this? Vasopressin. Okay now. Say that the
gene for the receptors for vasopressin are
not working properly. Are you going to be
effectively releasing vonWillebrand factor
and factor VIII? Now you will not read the
statement. Clinically differentiation by lack
of release of vonWillebrand factor and factor
VIII from the endothelial cells because the
receptors have not become mutated. Keep that
in mind. Do not forget that at some point
time once again I am going to refer to this
Adults: Chronic lithium big time. Let us talk
about this. Lithium, well who is your patient?
Oh! sometimes I feel crazy. I feel like I
can conquer the world. We have grand new ideas.
In other times, he wants to go back home and
go hide in a closet and not talk to anyone
and maybe perhaps have suicidal ideation.
Let me talk about bipolarism. So chronic lithium
is what the patient is taking. When lithium
is taken, please understand that this is not
referring to the management in your brain
about polarism; however, as far as your kidney
is concerned that is its ENAC. It is important
to let you know what that is? E is epithelial.
Before I begin, I want you to go to the collecting
duct in the nephron in your head. Can you
conceptualize? Are you there with me? That
collecting duct on the side of the apical
luminal membrane facing the urine is the epithelial
side or the epithelial cell, it has a sodium
channel on the apical side. That is called
epithelial Na sodium channel, ENAC. This is
how lithium is then going to replace the sodium
in a channel. Lithium is then going to enter
the tubular epithelial cell okay. Now, what?
You are worried about what? You are worried
about nephrotoxicity. You might be worried
about your patient developing diabetes insipidus.
What kind? Nephrogenic. The problem is this.
What is on the basolateral membrane? The basolateral
membrane has a sodium potassium pump. So why
can’t can you do to get rid of the lithium?
Dr. Raj if you tell me that lithium replaces
the sodium in that sodium channel, then why
doesn't the lithium replace the sodium to
then work through the sodium-potassium pump
to get out of the cell? I don't know. It doesn't.
Okay. I am sorry. I really. It is all my fault.
The lithium doesn't get on to the pump. I
don't know why. I really don’t. But what
I do know in which you should know is that
lithium will now replace the sodium on the
sodium-potassium pump. Thus, where is your
lithium now accumulating? In your renal tubular
epithelial cell. Are you then bringing about
nephrotoxicity? Yes, you are. Are the receptors
working properly? No, they are not. What would
be a drug-induced cause of nephrogenic diabetes
insipidus? Chronic lithium use. Let us continue.
Now let us talk about ADH and the fact on
your cell when we set this picture for you.
This is the principal cell. Where are you?
You are down in the collecting duct. You have
the lumen and there out be the urine. Clear.
The lumen that you are seeing on the left
is the urine. On the other side of the cell
is the blood into the interstitium. Now we
are going to walk through the course of ADH
and how it works and a couple of important
things which you have to know here because
you will be asked questions about how this
mechanism works so it is the second messenger.
Okay. ADH bounds with receptor. What is the
name of this receptor? V2 receptor. What is
at least one gene mutation that you want to
know? That is called arginine vasopressin
AVP receptor2 mutation. x-linked recessive.
Once ADH bound through receptor, how is it
worked through? Now, this if by chemistry.
GS that GS is AAAA. Adenocyclase takes the
ATP, turns it into cyclic AMP. Cyclic AMP
protein kinase bring about phosphorylation.
What kind of aquaporin? AQP stands for aquaporin2
being inserted where? On the luminal membrane
so then you can reabsorb that water. Now a
couple of important things. You see this GS
and you see the cyclic AMP. That is important
because I am going to give you a tasty piece
of information here that you just got to eat
up. It is about bypassing this receptor and
seeing as to whether or not you can work through.
What is it called? That breaks down cyclic
AMP? Phosphodiesterase. So in the receptor
area what if you inhibit phosphodiesterase.
Increased cyclic AMP. Is it possible? It is
just possible that there is enough research
out there and you might get a question versus
wow! my patient is nephrogenic diabetes insipidus
#1 or you see this as being #1. That is the
pathology on the blood side, but what if you
are able to bypass the receptor? What might
you want to give? Hybrid inhibition of phosphodiesterase.
You have seen that before. The concept was
also used in cardiology from ecology as well.
Let us continue. In the presence of ADH, we
know that aquaporins are put in. What kind
are they? Type II. Once they are put in, then
you will allow for water to be reabsorbed.
Make it more permeable. Now inform take a
look at the top here. You can bypass the receptor
with a prostate gland E2 receptor and the
reason that I say that is because well prostate
gland in E2 and you should remember this.
This is lovely physiology that is then now
being derived and this is how you want to
think. Remember my job is to give you as many
angles as possible for possible question that
is thrown at you and if you don't understand
the fundamentals and things become a little
complicated and maybe downright impossible.
That is not going to happen between you and
I. So a prostate gland E2 receptor may then
stimulate you see #2. That #2 as long as you
are able to stimulate that adenocyclase and
you bypass the receptor because what is my
disease? Nephrogenic diabetes insipidus. Then
you have created the signal transduction pathway
moving forward in which you can then insert
aquaporin and perhaps managed effectively
your patient with diabetes insipidus nephrogenic
type. Beautiful, isn't it? I would think so.
Keep that in mind. Research those of you that
are interested in pursuing your Ph.D. after
your Medicine, Plenty of room out there. Plenty
of room, but this is a relevant topic that
is hot and so, therefore, is quite relevant,
which you need to know at this juncture.
Actions of ADH. Once again I wish to reiterate
the emphasis here with ADH is going to be
its effect on the kidney and when it comes to
pathology. In nephrology, we will be focusing
and have been focusing upon nephrogenic diabetes
insipidus, which just came up of a very important
discussion as to the mechanics of your ADH
receptors on your V2 receptors and the fact
that it works with GS. Spend a little bit
of time with that concept so that you understand
at some point in time if they do oppose a
question, how do you bypass the receptor while
you do everything in your power to then increase
production of the cyclic AMP so that you can
then insert the aquaporins and continue through
the process of reabsorption of water. Now
with that said once again we reiterate the
V2 receptors are on the kidney and specifically
in the collecting duct and as long as your
ADH is present. Would you please take a look
at the picture here where you will find on
your left side the actual medulla and the
lumen and as you move distally through the
collecting duct, we go from proximally less
than 300 all way down to 1200. Wow! what is
normal isotonic plasma osmolarity? Approximately
300. Here we have urine osmolarity at 300
moving all way to 1200. Do you think that
the effective ADH is present here? Of course,
it is and so, therefore, you are going to
reabsorb that water and as you move from the
lumen and over to your right is your vasa
recta. What does that mean to you? Your peritubular
capillaries. Reabsorption is taking place
and putting that water back into the plasma
with the help of ADH. Now that will be your
primary focus. Now what I wish to bring to
your attention one more time is the fact that
ADH also known as arginine vasopressin may
then work upon your blood vessel in which
as you see here would be responsible for releasing
some of its von Willebrand factor. Now what
will you also find to be interesting is the
most of your factors, your coagulation factors,
in fact, are being produced where? You see
the liver there on top. On your right a big
gray mass that is your liver and that is going
to be producing all of your coagulation factors
except a few and those few include von Willebrand
factor and that you have factor VIII. Where
would these be coming from? These would be
then coming from your endothelial cells. Now
the receptors that you find here are V1 receptors.
They are responsible for, do you see this?
It is kind of looks like a bottleneck, doesn't
it? Mean to say that as we take a look at
the diameter of the blood vessel on top, it
looks narrowed and there would be the effects
of ADH being exerted upon your blood vessel
whereas if you take a look at the bottom portion
blood vessel, you will find any ADH down here?
No, you don't. So, therefore, what is this
state of my blood vessel? Not vasoconstricted.
Let us continue. So now you are releasing
von Willebrand factor. What must factor VIII
have in its association? It is optimum functioning
of factor VIII. Obviously von Willebrand factor.
I am going to bring another pathology appear
one more time all about reinforcement. If
you have a female and she is bleeding excessively
during her menses, then you get labs in which
you start reading the following. You will
find an increase in PTT and you will find
an increase in bleeding time and with that
type of history, you are most likely. Well,
what is your next step of management? There
is something called and we will talk about
this called ristocetin assay. Now ristocetin
is a very expensive test. That is important
for you to know. That is why you don’t readily
call or request for a test of ristocetin because
it is too expensive. Now as said it may be
seen in the idealistic world, oh! you can
order whatever you want. Now that is not the
case. You have a doctor but hospital is a
business. When you have a business, what are
you looking for? Cost effectiveness and how
to generate revenue. Unfortunately, you are
in a situation where you are responsible for
that as well. So, therefore, you next step
of management to confirm your von Willebrand
disease, in fact, is your risocetin. Now what
I wish to also brings to attention now this
makes sense. Take a look at factor VIII. If
you don't have von Willebrand factor, factor
VIII isn't working properly. If factor VIII
isn't working properly, well you remember
from hemodynamics the factor VIII is part
of the intrinsic coagulation pathway. The
intrinsic coagulation pathway is then tested
with PTT. What was the that I gave you in
von Willebrand disease that was elevated PTT.
Is that clear? Why? Because then factor VIII
isn't working properly. That is test #1. Okay,
but then what is the other test that I mentioned?
Bleeding time. I will give you the times later,
but actually, I will give it to you now. Why
not? Two to seven minutes is bleeding time.
Well, here you will find your bleeding time
to be greater than seven minutes. How does
this occur, please? It is a fact that you
require von Willebrand factor to then bind
to platelets. So if you don't have the von
Willebrand factor, guess what? Your bleeding
time is going to be elevated. Confirming von
Willebrand disease. Let us continue.
Vasopressin analogs for the management of
von Willebrand disease type I. Now understand
there are five if not more different types
of von Willebrand disease, the one that you
want to know for sure in which you are deficient
of von Willebrand factor is type I von Willebrand
D disease. What is an analog here that you
want to use to release the von Willebrand
factor? How about some vasopressin? There
it is. In addition, what are the conditions
might you be thinking about to treat with
vasopressin? There is hemophilia A. What is
hemophilia A? AB89. What I am saying? In the
alphabetic order, A comes first. Chronological
order 8 comes first. Factor VIII deficiency
is hemophilia A. Vasopressin may release factor
VIII. Let us continue. Now the supra-physiologic
levels. ADH works
on V1, where is that? On your blood vessel,
therefore, bringing about vasoconstriction
that is which you are seeing here bold
Management of nephrogenic diabetes insipidus.
Before we move on, think about your patient.
The receptors aren’t working properly. Therefore
how much urine polyurine. What are you producing
diluted urine? Tell me about clearance of
water? It is increased. Increased free water.
So far so good. In the meantime, when you
are losing all the fluid, tell me about your
plasma. Your plasma osmolarity is increased.
Now if you have a child that has nephrogenic
diabetes insipidus in addition there is going
to be further a loss of fluid. Welcome to
vomiting, diarrhea, fever there might be sweating
taking place. What is your first step of management?
IV fluids. You have to granted the fluid might
be leaving excessively from the urine, but
please understand you still must give it because
if you don't have the fluids, then what happens
to your blood pressure? My goodness. It drops
like crazy. That is your first step of management.
Next D5W. What does it mean? It is basically
pure water. Now you have given it but the
only problem is the fact that you are looking
for and may then bring about dilutional hyponatremia.
What is important by D5W? It is the fact that
you have to have that dextrose where if it
gets rapidly metabolized, it slows down or
retards the entry of water into the cell.
What are you preventing? Rapid swelling and
lysis of your cell. Now, why would you even
think about giving D5W? What kind of fluid
is D5W? Hypotonic, isn't it? It is hypotonic
and tell me about your patient with nephrogenic
diabetes insipidus. Plasma osmolarity ridiculously
high. So, therefore, what might you want to
give to then decrease the plasma osmolarity?
How about some hypertonic fluid? You see as
to how our discussion earlier of IV fluids
is absolutely relevant to what is happening
here. Take a look at 0.22. 0.22 represents
extreme hypertonic. What is normal saline?
0.9. What is half normal saline? 0.45. Here
is 0.22. That is quite hypertonic. Next what
else might you want to do? Decreased dietary
solute preventing osmotic diueresis. Everything
that you turn to do ladies and gentleman after
your ABCs what ABC mean to you. Whenever you
have a patient what are some of the first
questions that you are asking so? It is the
airway block. What about the breathing or
what about the circulation? So if the circulation
is affected here in nephrogenic diabetes insipidus,
it is IV fluids. Next well why not decrease
some of the solutes? Maybe some of that "salt"
your sodium so that you prevent further osmotic
diuresis. Diuretics. This is interesting.
Please pay attention here. Okay. Let us go
way back to look at the nephron and we had
a distal convoluted tubule. Think about that.
Are you there? Distal convoluted tubule. Good.
What kind of symporter do you have? It is
called sodium chloride symporter. It is the
diluting segment and what receptor is it very
sensitive to or what hormone is the receptor
based sensitive to? PTH. What does that mean?
Calcium reabsorption. What kind of diuretic
works in that area? Thiazide. Now as counterintuitive
as it may see to give a diuretic, do not give
your patient with nephrogenic diabetes insipidus
or loop diuretic, you get kicked out of the
hospital. Oh! my goodness. But it is shown
that thiazide now really the mechanism and
the theory behind it is quite complicated.
So let us not go there. You go there on your
own time and our time let us make sure that
you are clear. A diuretic that you would only
use in the setting of the nephrogenic diabetes
insipidus will be thiazides. So, two unique
features actually three unique features of
thiazides that you must know. #1 the African
population, elderly that have hypertension.
Your drug choice or antihypertension is thiazide.
Point #1 that makes perfect sense. #2 if you
have a patient that has too much calcium where,
in the urine, then thiazides may be used to
remove the calcium from the urine. Isn't that
a unique feature? Yes, it is. #3. Thiazides
can be set or can be administered in the setting
of nephrogenic diabetes insipidus. Fascinating.
What does it do? Weight loss of 1.5 kg can
reduce the urinary output by 50 percent and
that has been shown to occur by giving thiazides.
Look at this. You are reducing the urine output
by greater than 50 percent. That seems pretty
effective to me that the mechanism let us
know at this point research has given us that
outcome. Next, the effect mediated by hypovoilemia-induced
increase in proximal sodium and water reabsorption,
thereby diminishing water delivery to the
ADH-sensitive site is the most common theory
to be tested and so therefore by doing this
then maybe just perhaps you are resulting
in reduced urinary output by giving it diuretic
known as thiazides. Now finally the problem
is this. Amiloride in patients with reversible
lithium-induced nephrotoxicity. Isn't this
interesting? What does this mean? Remember
that lithium and who is your patient? Adult
may be and why would the adult be taking lithium
for long periods of time. Maybe they are crazy
and then maybe they are depressed. Crazy,
depressed. Bipolarism right. With bipolarism,
taking lithium over long period of time, the
lithium then works in ENAC. We had that discussion
interesting. What about amiloride? Works in
the ENAC. So amiloride in a patient that has
had lithium induced nephrogenic diabetes insipidus
and you get to the point where it is irreversible.
Hopefully, amiloride is your drug of choice.
Management of nephrogenic diabetes insipidus
really ladies and gentleman this is out of
the press. You are probably hearing all of
this for the first time. You want to confirm
this sure. Walk into a clinic and kick butt
and be hoisted on the shoulders of your peers
and you will see as to how effective you are
as being a medical student or resident and
so forth. Let us continue.
Now, ultimately management of nephrogenic
diabetes insipidus. Now what we are going
to walk through here is the following of very
important table. Examples, we will talk about
the differentials in the first column. We
will talk about serum ADH, plasma osmolarity,
urine osmolarity and this is great here because
we can actually compare both of the osmolarity
compartments adjacent to one another by urine
flow rate and then free water clearance. Let
us begin. Let us say that you conducted water
deprivation test. Close your eyes. Water deprivation,
what happens to plasma osmolarity? Increased.
You see that. Next water deprivation well
you have now plasma osmolarity. You are inducing,
for the most part, none of the water in your
plasma. It is increased. So what is the body
trying to do? The body releases ADH. Take
a look at the second column. That ADH comes
in what is going to work? Collecting duct
and you are going to create what kind of urine?
Good. Hyperosmotic urine. What do you think
happens to your flow rate when ADH is working?
It is low. Stop. Tell me about free water
clearance. What does free water mean to you?
No obligation to any electrolytes. Okay. So
now you have increased ADH in the setting
of water deprivation. Let us say a better
word for this is reabsorption of water from
the collecting duct. What is your clearance
of free water? Negative. What is it meant
when you have clearance of water being zero?
It is not solute-free. What does it mean if
you have clearance of free water being positive?
That means that you are getting rid of too
much water in SIADH or in the setting of ADH
obviously your clearance would be negative.
That must be understood. Now that lays down
the foundation. Now we can move quicker through
the differentials. SIADH what does that mean?
Too much. Tell me. Plasma osmolarity, but
here it would be decreased because you are
moving too much of your ADH. Do you understand
that? I want you to compare this plasma osmolarity
with SIADH and water deprivation because it
is important that you walk through chronological
and logical steps. If you are water deprived,
where do you go first? The plasma. If it is
SIADH, what do you go first? ADH. Why? If
it is water deprivation, plasma osmolarity
increases thus resulting in increased ADH.
If it is SIADH, what is it? Yeah ADH is increased
in excess. Then you can go through the rest
with hyperosmotic urine sure. Low yes negative.
The rest are the same. But if you don't spend
time understanding those two differentials
and why ADH is increased and why the plasma
osmolarity is opposite to one another, then
you missed the entire point and you just memorize.
There is no way to memorize this table and
question gets questions right. You cannot.
You understand this table, then you go into
clinic and then you go into doing exams, guaranteed
to get everything right. First water drinking.
With water drinking, where do you want to
go first? Good. Plasma osmolarity. So when
you drink water, your plasma osmolarity would
be low especially excessively. If your plasma
osmolarity is low, tell me about your osmoreceptors.
They are not going to stimulate release of
ADH. Your ADH is now going to be suppressed.
If that is now suppressed, then tell me about
your urine osmolarity. It is going to be hypoosmotic
urine. So therefore when you have more dilute
urine that you are producing because the lack
of ADH, then tell me about your clearance
of free water. It would be positive and your
flow rate will be increased. Once you get
that done, you will notice the other two.
We will talk about here with diabetes insipidus.
Your focus here ladies and gentleman should
be on nephrogenic, but now jut to be complete
I have also listed central. With central diabetes
insipidus, where is my problem? Good. The
ADH was never released. If the ADH was never
released centrally, then what happens to your
urine osmolarity? It is going to be a really
low hypoosmotic and then you have positive
clearance. Next what about nephrogenic? We
just talked about this in great detail so
they should be perfectly clear your kidneys
and the receptors are known as V2 receptors.
May I ask you what that mutatio was one more time?
It was arginine vasopressin
receptor2 gene in which receptors are not
responding to ADH and so therefore what kind
of urine are going to produce? You are going
to produce really really hypoosmotic urine.
Good. Stop there for one second. I told you
this earlier. This was a concept. If the receptor
in a pathologic condition are not functioning,
what is always the state of the hormone that
should be working on it. High, high, high.
Good. Take a look to ADH, ridiculously high.
But why is it that your urine is too hyposomotic?
Because the receptors aren't functioning.
They are still clearing lots of free water
and urine flow rate is going to be high. You
spend a little bit of time on this table.
Understand the pathophysiology for each one
of these parameters. Seriously. Clinically
speaking, there is no way that you didn't
get a single question wrong.
Now with these differentials, we have taken
a look at these before, but the parameters
here are a little a bit different, but incredibly
important. Let me set this up. We have the
condition and the differentials in the first
column. We will have the blood pressure went
only relevant to your pathology. PRA stands
for plasma renin activity and the aldosterone
magnesium only once relevant and urine calcium
when it is only relevant. That what you find
in red is what you truly paying attention
to because that unique for that particular
pathology. Blue is going to be the consequence
of. So let us begin. In Bartter syndrome,
where is my pathology? It is going to be in
the thick ascending limb. It is a problem
with the sodium, potassium to chloride, isn't
it? So you are going to have issues with what
exactly? You are going to have issues with
your concentrating ability and diluting ability.
What else to talk about the Bartter syndrome?
We said that there would be increase in prostate
glandins. So, therefore, one step of management
a border, in fact, is indomethacin. In addition,
Bartter syndrome has a unique feature in which
I want to go to last column here where the
urine calcium is elevated, elevated, elevated.
On this entire table of differentials, Bartter
syndrome is going to be the only one that
you and I are going to see as having hypercalciuria.
So, therefore, is it possible just possible
that you might have secondary hypoparathyroidism?
Yes or no? Good. Yes. You will have secondary
hypoparathyroidism. Now in Bartter syndrome,
there would be an increase in aldosterone
and because of that, you would have a decrease
in plasma renin activity. Keep that in mind.
Let's move on.
In Gitelman syndrome, where are you? My problem
is in the thiazide-sensitive. You remember
that your sodium channel cotransporter T gene.
T representing the thiazide-sensitive. Here
right off the back with Gitelman, I want you
to go to urine calcium. You see the difference.
Here you find your calcium to be really low
and with Gitelman, the two big things here
is an increase in PRA, plasma renin activity
and an increase in aldosterone. Now in addition
to your urine calcium being quite low, the
serum magnesium will be low. There is enough
information here with Gitelman and once again
in terms of electrolytes and the pathophysiology,
you should not be able to get or you should
be able to answer any question confidentially
and of the two conditions here, Gitelman and
Bartter, what is more, common in our society?
Gitelman, Gitelman, Gitelman. So you want
to spend a little bit more time on Gitelman
in getting these facts down because it is
much more common than Better. But I can clearly
say that both are commonly asked.
Liddle syndrome is interesting. With Liddle
syndrome, all that you want to know is the
labs here and that would be good enough for
you to get any question right. I don't want
to be in a situation where every once in a
while you are doing a question and you might
not know one condition, but do not know two
or three conditions is rather frustrating.
Liddle syndrome, you will find an increase
in blood pressure and you will find a decrease
in plasma renin activity and aldosterone.
That is the forest you need to go now with
Liddle know that it exists. Now SIADH, we
talked about this earlier. We will then find
an increase in ADH. You are then going to
find an increase in blood pressure. In SIADH,
you will not find pitting edema euvolemic.
You have a decrease in aldosterone and a decrease
in plasma renin activity. Once again what
did I say? Euvolemic. Why? It is SIADH. Is
that really reabsorbing or secreting sodium
any of that functioning here? No. So sodium
is not going to be part of the equation when
you have that fluid accumulation. That is
interesting and should be known. In Conn's
syndrome, what is my problem? It is the primary
adrenal cortex in which you are only producing.
You see that arrow in orange. That is my primary
problem. Too much aldosterone, decrease in
plasma renin activity, your patient has what
kind of hypertension? Secondary hypertension
and then we have reninoma. Reninoma where
is your problem? Where do you begin? Take
a look at the orange arrow. It is plasma renin
activity first and with that occurring understand
that your blood pressure here is, in fact,
going to be increased. This is then called
secondary once again hypertension. Two very
important tables they give you a bunch of
differentials that are then affecting the
kidney in some way, shape or form, this table
might or might not be too familiar. Make it
familiar. All these labs will be shown and
it is important that you come up with good
differentials. You will be impressed.