Diabetes Insipidus (DI): Etiology

by Carlo Raj, MD

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    00:00 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.

    00:12 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.

    00:30 #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.

    01:10 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.

    02:34 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 little discussion.

    03:40 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.

    03:54 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.

    04:25 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.

    05:08 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.

    05:35 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.

    06:09 Now let us talk about ADH and the fact on your cell when we set this picture for you.

    06:14 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.

    06:58 Once ADH bound through receptor, how is it worked through? Now, this if by chemistry.

    07:04 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.

    07:44 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.

    08:53 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.

    09:43 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.

    About the Lecture

    The lecture Diabetes Insipidus (DI): Etiology by Carlo Raj, MD is from the course (Nephrogenic) Diabetes Insipidus (DI).

    Included Quiz Questions

    1. AVPR2 gene mutation
    2. CFTR gene mutation
    3. TP53 gene mutation
    4. BRCA1 gene mutation
    5. BRCA2 gene mutation
    1. Lithium
    2. Labetalol
    3. Lamotrigine
    4. Levothyroxine
    5. Lorazepam
    1. cAMP
    2. cGMP
    3. mTOR
    4. AMPK
    5. VEGF
    1. Hyperglycemia
    2. Polyuria
    3. Hyperkalemia
    4. Hypoglycemia
    5. Hypernatremia
    1. Phosphodiesterase inhibition
    2. Phosphodiesterase activation
    3. Phospholipase C activation
    4. Phospholipase C inhibition
    5. Adenylyl cyclase inhibition

    Author of lecture Diabetes Insipidus (DI): Etiology

     Carlo Raj, MD

    Carlo Raj, MD

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    Brilliant, as always!
    By Inaamul Hassan J. on 21. March 2021 for Diabetes Insipidus (DI): Etiology

    Helpful, demonstrated good insights and teaches in an enjoyable and logical manner

    Very helpful !
    By Leona H. on 26. October 2019 for Diabetes Insipidus (DI): Etiology

    As always I enjoy and learn so much from you Dr. Raj