Overview and Calculations – Renal Glucose Transport and Reabsorption

00:01 Glucose. In that previous graph by chance, if you were a little confused, it absolutely warrants further discussion so much so that we need to take a look at this in great detail.

00:16 So that whole graph with glucose is just giving you an overview, but if you don't understand or if you haven't understood the depths of glucose handling or renal handling of glucose might be little complicated, but let us now simplify things and be more technical. To begin with, we have filtered load. What does that mean to you? It means that what is coming through the efferent arteriole and approximately 20% which is then your filtration fraction and how much do you have left on the efferent side if it is renal plasma flow? It will be 480. What is the normal renal plasma flow coming in? Approximately 600. So 120 has come through and filtered and we are left with 480. Want you to continue. Set up this picture here that you are seeing on the left and now we are at the level of the peritubular capillaries.

01:09 You see that big fat red arrow? That is your peritubular capillary and now there is modification is taking place in the nephron. You see that yellow arrow. That represents your nephron.

01:20 Are we clear? Where we are in a nephron represents the proximal convoluted tubule? The PCT. That is where the majority of our modification of our urine will be taking place at this juncture. Reabsorption, what does that mean to you? You are bringing that substance from the lumen, from the urine back into the blood. What does secretion mean? It means that you are putting the substance into the urine. Let us talk about glucose. Should you normally find glucose in your urine completely being cleared? Not at all. If you start finding glucose in the urine, obviously you are suspecting hyperglycemia and some type of underlying issue. Are we clear about this? Next, that glucose that is being reabsorbed just keep it simple. It is 100%. The glucose that is being reabsorbed at a rate or at a percentage of 100, requires transporters. It cannot do by itself. It is not a simple diffusion where it just passes through the membrane. Now where am I? Close your eyes. You are in the urine, lovely place to be and you have your epithelial cell and what epithelial cell? The tubular epithelial cell and what is the name of the membrane facing the urine? It is called the apical membrane or the luminal membrane and glucose does not and cannot diffuse by itself by simple diffusion. It requires help. What kind of help? It is a cotransporter.

02:53 The cotransporter many at times your substance such as amino acid, phosphate and such will use sodium as being the cotransporter to bring that substance or in other words reabsorb that substance from the urine into the epithelial cell. Okay fine. So here is the glucose in the epithelial cell. You have got out of the urine granted. Are we done? No, no, no.

03:16 The entire process of reabsorption is from the urine into the blood. So now we were inside our cell, the tubular epithelial cell. Are you there? Next, we have now to cross the basolateral membrane. So now you have to go to the other side where the blood is and that is called the basolateral membrane and the basolateral membrane has a pump. Every single basolateral membrane on a cell has this pump. It is called the sodium-potassium ATPase pump.

03:46 Now the PCT has the highest concentration of the sodium-potassium ATPase pump. In pathology, when there is ischemia taking place. What does ischemia mean? Lack a blood flow along with that, more importantly, the RBCs are not providing and delivering oxygen. Now, what happens? You don't go through proper aerobic glycolysis. You don't produce enough ATP. What happens to the pump? It doesn't work. Correct okay. So that we will talk about later and one of the major components or major regions of the nephron that is susceptible to such damage especially to hypoxia would be the PCT for this very reason. So that sodium- potassium pump is going to pump the sodium into the blood making the concentration of sodium less within the cell so that the sodium can come from the urine along with it it is going to bring glucose and that cotransporter will then take the glucose out into the blood.

04:48 How much reabsorption? 100%. So for you to have effective glucose reabsorption, what must you have? Please know this because you will get questions on that glucose transporter.

05:00 You must have a GLUT. You must have a glucose transporter or otherwise you can't have reabsorption. Keep that in mind as you move through here.

05:09 Next, what if there is no net transportation. Your filter load is then equal to what the ER means here is excretion rate. Once again the filtered load is that which is being filtered.

05:21 That is not equal to what is necessarily excreted. Now if there is no modification, meaning what? No reabsorption, no secretion, then it is equal to excretion rate. In other words, clearance.

05:34 Wonderful. Now lets go on to reabsorption. Now close your eyes. Don't look at this. Predict it.

05:40 If it is reabsorption, now what happens? That which is being filtered gets reabsorbed. Okay.

05:46 Once it gets reabsorbed, tell me about its excretion. There is going to be more filtration.

05:52 There is going to be less excretion. Welcome to filtered load being greater than excretion, Why? It got reabsorbed. It didn't get excreted. That would be something like your glucose.

06:07 Now, what if it was something like para amino hippuric acid or hippurate? What if there was a creatinine? Tell me about those substances. Secreted. If something is secreted into the urine. Tell me about the excretion rate. It is greater than filtered load and see as to how important it is for you to pay attention to the language and terminology of medicine in general, but here specifically with nephrology. Otherwise, you will be sitting there cracking your head wasting precious time and even then you are not even sure as to whether you got it right. You want to be confident about everything that you are saying. Let us talk about the graph now. Set this up and a lot of things going on here. It is like, remember in cardiology, we did the mixed cardiac function curve. Don't you love that. Well, you are going to love this too. A lot of things going on. This is glucose. In general, just tell me the big picture. Does it get filter glucose? Yes, it does. Does it get excreted? Does it get cleared? No. Does it get reabsorbed? Yes. How much? Close to 100%. Does it get secreted? Absolutely not. Have you set that up? If you miss what I just said. Review what I just discussed. Now move on. Okay. Let us set up the graph. On the X axis, it represents the concentration of now specifically glucose. In our previous lecture, we have looked at the X axis being plasma concentration of many many many substances including pH, inulin so on and so forth. This is strictly only glucose. On the Y axis, now this where it get tricky. Work with me. On the Y axis, there is going to be many parameters and some of these parameters include excretion. It represents the filtered load and represents the reabsorption and we are going to dissect every single one of these till it makes sense to you. Pay attention.

08:03 Okay. When you are initially speaking, with glucose, you have filtering. So whatever it is as far as glucose in your plasma, it gets filtered. What are we calling this physiologically and clinically? Filtered load. I want you to do something else. DC versus filtered load. Do you see the green line. I want to come way back down to zero and I kind of what to think of this being as a zipper. Okay. Work with me here. So there are two lines initially at 0.0.

08:39 In the filtered load, it is hidden underneath that green line. Please work with me here and what that green line represents is well for the most part whether or not a substance is being reabsorbed as you shall see. So as we increase the plasma glucose concentration, what happens to filter load? It starts increasing. There is more glucose, which you have in your plasma the more that has been filtered. Absolutely. Now that which is being filtered, is there going to be complete reabsorption? Absolutely. So initially speaking lets start to see the end on the X axis that means normal. So normal levels of glucose. Give me a normal level.

09:21 Lets stick to 100. A plasma glucose level of 100. Lets stick to that and say that your glucose level is at 100 in your plasma. Is it being filtered? Yes. That is your filtered load is being completely reabsorbed. That is correct. How can you confirm this on this graph Dr. Raj? Now you take a look at the blue line, that means excretion. That is excretion rate the blue line. Wow! so early on at normal what about my blue line? It is nonexistent.

09:52 Why? Because the only glucose would be reabsorbed. Are you literally seeing this in your head? It is amazing, isn't it? That a graph is able to give you such a joy but it's also because I am a dork. Anyhow. so now the excretion is completely at 0. Why? At normal levels, plasma glucose will be filtered. It is being completely reabsorbed and there is no excretion. Ah! beautiful. Normal physiology. Now let us start increasing say that your patient is prone to hyperglycemia. Why or maybe there is diabetes mellitus type II. Maybe there is obesity involved so on and so forth. You are increasing glucose up to 200 now. So now you hit T. Now be careful.

10:36 That T does not represent Tmax. That T represents threshold. The threshold for what? Glucose.

10:44 What does that even mean? That means that if you hit that threshold, it is the early, early sign of glucose now appearing in your urine. Have you understood the definition of threshold? It is not the same thing as Tmax at all. Now, why is that important for you? Clinically speaking.

11:02 Let us take a pregnant lady, remember the pregnant woman we talked about and you tell me what is the creatinine clearance in a patient who is normally pregnant? Increased or decreased.

11:12 Take your time. Plasma volume in a pregnant lady especially at the end of the first trimester increases by how much? Oh! maybe up to 50% it might increase. That is a lot of plasma volume. You are going to increase your hydrostatic pressure and you are going to clear more creatinine. We talked about that earlier. If you are not clear about this, this would be a good time for you to review this. Next, now as you increase the amount of glucose in a pregnant lady is that normal? Yes, it is. Why? Remember the fetus and its placenta is producing a growth hormone analog biochemically and that growth hormone analog coming from the placenta is called human placento lactogen, not HCG. This is HPL. What kind of effect has HPL have on the mother in terms of handling the glucose? Tell me about that fetus? It is starving. Mumma, feed me. So the fetus wants to eat. Feed the poor fetus.

12:20 So the mother has to make sure that she has enough glucose in her plasma to not only feed herself but more importantly, whom? The fetus. What do you know about glucose? Does it cross the placenta barrier. Of course, it does. So that HPL allows for glucose to be increased in the maternal, maternal female. Okay. So that you know about plasma glucose increasing and you know about her plasma volume increasing in a female. Then what do you think happens overall to renal threshold meaning the earliest sign of glucose appearing in the pregnant woman in her urine, would it be later meaning with the threshold be increased or with the threshold be decreased where you would find glucose in the urine very early.

13:07 Obviously decreased. So what is threshold mean to you? The earliest sign of glucose being found in the urine. Fact physiologically knows that don't miss the question and use your common sense and the things that you know about pregnancy to answer that question.

13:22 Let us move on.

13:23 We are going to continue increasing glucose. Okay. Now we get into glucose transporters.

13:28 Where are they located? Well, they are located where you have your basolateral membrane allowing your glucose not to be reabsorbed back into the blood. Do you not? So this is then going to help you bring out your glucose to reabsorb it and as you increase your glucose further, further, further and further, while now you are going to start saturating your transporters.

13:52 So what if you start increasing the amount of glucose that you find in the urine. You are going to form a curve. You see that green line there. That is the curve. That is called splay. What does that mean? That means that you have more and use it to your advantage, where you can think of it as being now the glucose is spilling into the urine further. That is called splay. It is not just a perpendicular curve that is a curve and the reason for that is because the transporters are being saturated further with an increase in plasma glucose increasing the amount of spillage of glucose in urine. Now we have the threshold. Now we have splay. Now the last point that we have is finally Tmax. So what is Tmax? It is the maximum amount of transporters being completely saturated at approximate plasma glucose of 370. So all way up close to 400, wow! that is a lot of glucose. What is approximately normal? One hundred. So now that your glucose up to 400 maybe your patient has complete uncontrolled diabetes mellitus and a plasma glucose here of 400 maybe getting close to diabetic ketoacidosis. If I have a plasma glucose of 400 every single glucose transfer enhancements saturated, you have had what is called as transport maximum and what happens to your excretion? Take a look at the blue line. Every single glucose now. Not every single. Excuse me. Those glucose that have saturated their transporters are now spilling into the urine and you find your excretion of glucose rising. The only thing that I wish to bring to your attention is the following. Tell me about the reabsorption at this point of glucose even at 400. I didn't block those transporters, did I? So all those transporters still hardly trying to move the glucose and reabsorb it. Yes, it is. But the problem is the plasma glucose is so high that it continues to spill into the urine. The next question and the most important one is the following based on everything we just talked about in terms of excretion rate. If you know that glucose is being reabsorbed even at maximum, then is your filter load equal to excretion rate for glucose or is your filter load greater than excretion rate. The filtered load will still be greater than excretion rate even at maximum transporter, allow that concept to set in because what happens those transporters are still reabsorbing. The plasma glucose has no influence on the dysfunction of the transporters. So transporters are working maximum hence Tmax. That is the full picture of this graph of glucose. You understand this with every single aspect of filter load, splay, threshold, Tmax, and excretion. You can’t miss a single question with physio, pathology what they may throw at you in terms of what if you get a question where the transporters were blocked. Tell me about the relationship between excretion rate and filter load or clearance and GFR. If those transporters were blocked, which is a very good question that at some point you will be asked, then understand that glucose which is being filtered is equal to that which is being excreted. So you have your GFR equal to clearance if the transporters were blocked. Here we have no blockage of our transporters. It is the only way that you truly will understand this. Let us now move on.

17:43 So here inulin, mannitol, and sucrose, what about these substances? You pay attention to inulin. What do you know about inulin? Inulin is it filtered? Yes, it is. It is modified at all in the PCT. No, it is not. Take a look. You find no secretion and you find no reabsorption.

17:58 So thus inulin, mannitol, and sucrose, these will be filtered. But they will not be reabsorbed or secreted. Thus filtered load equals excretion rate. Thus, clearance equals GFR for inulin.

18:15 Next, what is going on here? In the PCT and we have reabsorption or secretion? Which one is this, please? Reabsorption. What do you know about sodium, potassium, chloride and such? They are reabsorbed, aren't they? And when reabsorption is taking place, tell me as to what your relationship is between filter load excretion rate. Filtered load is greater than excretion rate because it is being reabsorbed. Tell me about clearance in GFR. Clearance will be less than GFR because it is being reabsorbed. Are you good with the language here? It is only once you go with the language, then once again maybe we may move on. Glucose, amino acids, and ketone bodies once again reabsorbed. Well, lots of glucose reabsorption.If you have creatinine, high plasma PAH and potassium load. This is a little interesting here.

19:09 If you have high PAH, well this is interesting because, at high PAH, this goes back to a graph on a previous discussion where if you have high PAH, you will notice that it is secreted. That is what is going on here. So, therefore, clearance will be greater than GFR or in other words, excretion rate will be greater than filtered load. Same thing for all intended purposes and the thing is though that this is not going to equal renal plasma flow because at a high rate it will be closer to GFR. What do you know about creatinine? Slightly secreted in approximation of GFR. I want you to compare this. Pay attention to this. The high PAH with low PAH. The low levels of PAH very low plasma concentration of PAH, tell me about its effect or how does it function in the PCT? It is going to get completely secreted. I want you to pay attention to big, thick blue arrow there compared to the little blue arrow that you are seeing with high PAH in the previous picture that big, thick blue arrow represents complete secretion of para amino hippuric acid into the PCT. Not a single para hippuric or hippurate is being further sent through the peritubular capillary. So, therefore, you can confirm and clearly say that clearance is equal to renal plasma flow at low levels of para amino hippuric acid or you can say that we have excretion rate is then equal to your renal plasma flow. Isn't it? A better way of saying this clearance is equal to renal plasma flow because everything is being secreted. Once this is clear, then we can move on.