Lectures

Diabetes Insipidus (DI)

by Carlo Raj, MD
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    00:01 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.

    00:26 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.

    01:13 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.

    02:34 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.

    02:45 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.

    05:11 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.

    05:24 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.

    05:42 #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.

    06:22 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.

    07:46 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.

    08:52 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.

    09:06 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.

    09:36 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.

    10:20 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.

    10:47 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.

    11:21 Now let us talk about ADH and the fact on your cell when we set this picture for you.

    11:26 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.

    12:10 Once ADH bound through receptor, how is it worked through? Now, this if by chemistry.

    12:15 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.

    12:56 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.

    14:04 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.

    14:55 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.

    15:13 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.

    20:04 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.

    20:21 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.

    20:42 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 in green.

    21:50 Management of nephrogenic diabetes insipidus. Before we move on, think about your patient.

    21:55 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.

    22:06 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.

    22:47 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.

    23:01 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.

    23:11 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.

    24:42 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.

    24:54 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.

    26:06 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.

    26:42 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.

    28:06 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.

    28:32 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.

    31:25 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.

    31:50 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.

    32:37 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.

    33:14 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.

    33:33 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.

    33:52 But why is it that your urine is too hyposomotic? Because the receptors aren't functioning.

    33:57 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.

    34:16 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.

    35:08 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.

    35:39 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.

    36:04 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.

    36:21 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.

    37:37 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.

    37:56 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.

    38:25 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.


    About the Lecture

    The lecture Diabetes Insipidus (DI) by Carlo Raj, MD is from the course (Nephrogenic) Diabetes Insipidus (DI). It contains the following chapters:

    • Nephrogenic Diabetes Insipidus
    • Etiology of Nephrogenic Diabetes Insipidus
    • Actions of ADH
    • Management of Nephrogenic Diabetes Insipidus
    • Differentials

    Included Quiz Questions

    1. Diabetes mellitus type I
    2. Diabetes mellitus type II
    3. Myasthenia gravis
    4. Androgen Insensitivity syndrome
    5. Pseudohypoparathyroidism
    1. Aquaporin2 channels on principal cell membrane
    2. Urine volume
    3. Clearance of water
    4. Plasma ADH concentration
    5. Plasma osmolarity
    1. Release of ADH is inhibited from the posterior pituitary.
    2. Urine osmolarity is decreased.
    3. Clearance of free water will be positive.
    4. It may be induced by administration of demeclocycline.
    5. Water reabsorption is decreased in the distal tubules.
    1. Receptor and/or subsequent signaling pathway defect.
    2. Insufficient production of hormone.
    3. Excessive negative feedback.
    4. Insufficient precursors for hormone production.
    5. None are correct.
    1. Aquaporin2 gene mutation
    2. Arginine vasopressin 2 receptor gene mutation
    3. Factor VIII gene mutation
    4. Von Willebrand factor gene mutation
    5. V1 receptor mutation
    1. Renal tubular necrosis
    2. Demeclocycline administration
    3. Arginine vasopressin 2 receptor gene mutation
    4. Aquaporin 2 gene mutation
    5. Chronic lithium use
    1. Epithelial sodium channel on the principal cell
    2. NaCl symport on the principal cell
    3. ROMK channel on the intercalated cell
    4. Na-H+ antiport on the intercalated cell
    5. Na-K+ ATPase on the principal cell
    1. Hemophilia A
    2. Hemophilia B
    3. Thrombocytopenia
    4. Von Willebrand disease type III
    5. Bernard-Soulier syndrome
    1. Cyclic AMP
    2. ATP
    3. Adenylate cyclase
    4. Calcium
    5. Phosphodiesterase
    1. Vasodilation of blood vessels.
    2. Increased permeability to urea in the distal tubules.
    3. Increased reabsorption of water in the distal tubules.
    4. Release of Factor VIII from endothelium.
    5. Release of von willebrand factor from endothelium.
    1. Phosphodiesterase
    2. Protein Kinase A
    3. None of these are correct.
    4. Na-K-ATPase
    5. Adenylate cyclase
    1. Prostaglandin E2 receptor agonist
    2. Demeclocycline
    3. Acetaminophen
    4. COX2 inhibitors
    5. Cryoprecipitate
    1. Functioning Factor VIII levels
    2. Plasma osmolarity
    3. Platelet count
    4. Bleeding time
    5. Partial thromboplastin time
    1. Dilutional hyponatremia
    2. Osmotic diuresis
    3. Central Pontine myelinolysis
    4. Hypovolemia
    5. Cell swelling and lysis
    1. Amiloride - ENac
    2. Furosemide – NaK2Cl cotransporter
    3. Thiazides – ENac
    4. Amiloride – NaCl symporter
    5. Thiazides – NaCl symporter
    1. Prevent osmotic diuresis
    2. Improve nutritional status
    3. Increase the urine output
    4. Induce weight loss
    5. Prevent hypertension
    1. Furosemide
    2. Hydrochlorothiazide
    3. Spirinolactone
    4. Amiloride
    5. ACE inhibitors
    1. Central diabetes insipidus
    2. Hypocalcemia
    3. Nephrogenic diabetes insipidus
    4. Hypertension in the elderly
    5. Hypertension in African Americans
    1. SIADH
    2. Central diabetes insipidus
    3. Water drinking
    4. Water deprivation
    5. Nephrogenic diabetes insipidus
    1. Free water clearance
    2. Urine osmolarity
    3. Thirst
    4. Serum ADH concentration
    5. Plasma osmolarity
    1. Blood pressure
    2. Plasma renin activity
    3. Urine Ca concentration
    4. Serum magnesium concentration
    5. Plasma aldosterone concentration
    1. Bartter syndrome
    2. Gitelman syndrome
    3. Conn syndrome
    4. SIADH
    5. Liddle syndrome
    1. Liddle syndrome
    2. SIADH
    3. Bartter syndrome
    4. Reninoma
    5. Conn syndrome

    Author of lecture Diabetes Insipidus (DI)

     Carlo Raj, MD

    Carlo Raj, MD


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