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.