Transcribed by Vandeep Bagga Organ Systems Lecture 38 – Renal Physiology VI by Dr.

Schiff

April 22nd, 2014

Scribe Note: Dr. Schiff never took a break, so I began transcribing exactly 50 minutes into the lecture until the end of the lecture. Drawings by Dr. Schiff are at the bottom of the transcript. Dr. Schiff – But, what then happens is this. In this membrane, in many membranes, many many membranes, you’ve seen it already in the red blood cell membrane, specifically, there's a chloride-bicarbonate exchanger. So some of the chloride that followed out of the filtrate by solvent drag, gets put back into the filtrate in exchange for bicarbonate. So the chloride that was taken out gets put back and more bicarbonate is reduced. So, in a sense you get more than the 2/3 in the proximal convoluted tubule reabsorbed. In fact, most of the bicarbonate as you go through the whole nephron, gets reabsorbed by the time you reach the distal end of the distal convoluted tubule. Because your body has a tendency to preserve bicarbonate. So, but if a need should arise, your body can leave some of the bicarbonate down in the distal tubule, leave some of the last bits of bicarbonate in the filtrate to be lost in the urine. So what happens is that you get this attempt to get back to the 7.4 line. And so a situation like this left down, this movement is a respiratory alkalosis. It is caused by your respiratory system, you were hyperventilating. It lowered your CO2 so you moved to the left on the graph. And your in alkalosis territory. You compensate by lowering your bicarbonate by urinating it out, so you end up going towards, this is referred to as renal compensation. The compensation, renal compensation, is an attempt to get back to the pH 7.4 line, you never get there. Once you have an alkalosis like this, you end up still on the alkalosis side of the 7.4 side, you never reach the 7.4 line. So you’re going to end up at some point here, still on the alkalosis side of the 7.4 line. But you’ve done some amount of compensation to get you close to pH 7.4. Suppose on the other hand, you have a decrease in respiration, so your carbon dioxide accumulates. You voluntarily hold your breath. Or you're Bart Simpson and Homer is strangling you! Which happens often enough. Your CO2 levels go up when you cant breathe or as discussed in the CCP, on respiration, if you develop something like emphysema, you have less gas exchange at the lungs so some of the CO2 will stay in your circulation, and you end up, this is a long term thing, with a elevated CO2, this is a respiratory acidosis. Because this is caused by a problem in the respiratory system. And again, your kidney decides to try to compensate this by retaining more bicarbonate so the bicarbonate concentration will go up and bring you towards, but never quite back to, 7.4. So if you raise the CO2 you attempt to get back to homeostasis by raising the bicarbonate. If you lower the CO2 you attempt to get back by lowering your bicarbonate, and this is again a renal compensation. So if the change in the pH is caused by the respiratory system, the compensation is by the kidney, it’s a renal compensation. *student question*

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Transcribed by Vandeep Bagga

April 22nd, 2014

Dr. Schiff – well it filters the same amount, it just reabsorbs less, so that you end up, no wait. If you have high carbon dioxide? I’m sorry. Uh it will reabsorb less, uh reabsorb more, I’m sorry, so that you end up with higher bicarbonate levels in your plasma. Now there is another thing. Suppose you have a, well we generally lump together as metabolic acidosis or alkalosis, and that's caused by something that effects the bicarbonate levels. The most common way this happens, well there is two, one is dealing with the GI tract. In your stomach, you secrete hydrogen ions, into the stomach. Now normally what happens to the hydrogen ions? Well when you secrete the hydrogen ions, you’re leaving bicarbonate in your circulation right? That raises your bicarbonate levels. Normally, the pancreas secretes bicarbonate to neutralize it, as the food chime moves on into the duodenum. The acidity of the stomach is neutralized by the bicarbonate in the pancreatic secretions. So, everything ends up fine. You got this bicarbonate in your blood stream and it gets secreted back into the gut where it neutralizes the hydrogen ions and everything is back to balance. But suppose you interfere with that neutralization process, for example, you secrete acid into your stomach, leaving bicarbonate in your plasma, and then something in what you ate, maybe that 1 more slice of pepperoni pizza, or whatever, didn’t quite sit there well. And you end up leaning forward and returning your lunch to the sidewalk. The acid that you secreted into your stomach is now lost, leaving the bicarbonate in the blood stream behind. So vomiting raises your bicarbonate levels. And all of these things are referred to metabolic, and this would be a metabolic alkalosis where your bicarbonate levels go up. Now, how does your body try to get you back to the pH 7.4 line? Well, you breathe a little bit less. So that you raise your CO2 levels, and it brings you closer to the pH 7.4 line here. Never reach it. This is referred to as a metabolic alkalosis. Anything that has to do with adjusting the bicarbonate levels as a cause of change in pH is referred to as metabolic. And this is your respiratory compensation. And obviously there is a 4th possibility. *student question* Dr. Schiff – Oh, this was um, when for example you vomit, you lose acid. Oh metabolic acidosis? I haven’t gotten to that yet. I said there was a 4th possibility! And that is, well we’re in the wrong season for football, but you ever see a guy catch a punt and run it back 60 yards and given the fine shape that all these fine athletes are in, he is exhausted. And he finds himself hyperventilating. *Dr. Schiff deep breathes* and what he typically does is that he goes to the bench, sits down, and takes an oxygen mask, and breathes oxygen. What's going on here? Ok, he did some work, he ran. Believe me, he gets paid more for running those 60 yards than you’ll ever learn in dental treatment, you’ll ever earn. But anyways, in doing that running, he uses, he drives the metabolism of his leg muscles and other muscles into what's referred to as oxygen debt. He’s using up oxygen, ATP, faster than the mitochondria can get enough oxygen to replace it. So to get those extra 2 ATPs, remember all your building blocks and all that, the glycolysis cycle, you end up with pyruvic acid and then it shifts over to lactic acid to get a couple of ATP out of it. And you end up 2

Transcribed by Vandeep Bagga

April 22nd, 2014

accumulating lactic acid, which of course is an acid, and the lactic acid then the acidity of it neutralizes the bicarbonate and reduces the concentration because you end up generating that hydrogen ion, which ends up binding to bicarbonate and reducing the bicarbonate to generate CO2, which you breathe out. Ok, so, your metabolism, this exercise the guy did, lowers his bicarbonate, this is a metabolic, because it resulted from his metabolism, acidosis. And as usual, his respiratory system, his chemoreceptors, tell him you have too much CO2, so breathe more, to get rid of it. So he tries to get back to the pH 7.4 line by breathing more, and that's a respiratory compensation. Oh the rest of the anecdote I told, and if you watch a few football games you’ll see it, is of course that he felt this need to breathe more, that's the respiratory drive triggered by the chemoreceptors that sense the high CO2 and the low pH, the acidosis. And he figures he must be short of oxygen, which is not the case, his hemoglobin is 98% saturated at least, that's not the situation. So he takes an oxygen mask, which does him no good what so ever. So that's your respiratory compensation, its just the hyperventilation to reduce CO 2 and when you reduce the CO2, you get back to the, towards, but never meets, the pH 7.4 line. So the point is, and again, if you start off with an acidosis, you still have an acidosis, you’re still on the acid side of the 7.4 line. Ok. What do you notice about these curves, you end up with either, in 2 of these possibilities that are quite the opposite to each other. You end up with high CO2 and high bicarbonate in 2 of the possible endpoints. You end with low CO2 and low bicarbonate, because you’re trying to restore the ratio of this to being 20 to 1. So suppose, you’re offered a, you’re given a situation, just might happen on an exam or something, where you’re told what the bicarbonate concentration is, and you’re told what the Pco2 is, after something happens and then there was partial, never complete, compensation. And you want to figure out, where you are. What was the initial event and what was the compensation. This sort of thing makes exam questions. So the first thing you need to know if you're given the pH, that's fine, if you’re not given the pH, but given the bicarbonate and the CO2 pressure, what you have to do is put the bicarbonate pressure up here, 0.03, don’t forget that 0.03, times the CO2 pressure down here, carry out the arithmetic including that 0.03, and you don’t have to memorize log tables the way I was forced to. The whole question is, is this equal to, or above or below 20? This ratio. If its 20, then your at pH 7.4, if its above 20, then your at an alkalosis, if its below 20, you're at acidosis. And then you ask yourself, well, lets say its an acidosis, is the CO2 higher or lower than what it usually is, higher or lower than 40. If you’re in an acidosis with a lower than 40 Pco2, you must’ve gotten there this way: so it was initially a metabolic acidosis with some compensation. On the other hand, if your Pco2 is higher, then you must’ve gotten here this way: it must have been a respiratory acidosis with a metabolic compensation. OK. One last little bit of discussion in terms of the role of the kidney and the regulation of body pH, is that not only does the kidney manage to adjust how much bicarbonate is being released, but, in the urine, but there is also as I said in the distal part of the distal convoluted tubule in the collecting tubule, there is also a last minute 3

Transcribed by Vandeep Bagga

April 22nd, 2014

adjustment, so to speak, of hydrogen ion transport. You see, what happens to the hydrogen ions while we’re doing all these things to the other ions and to the bicarbonate? I mean, we know how to handle calcium, sodium, chloride, potassium, we know how we handle bicarbonate to a certain extent, but the question is, what about the hydrogen ion concentrations? And remember, all of these ions that we’ve been talking about, all these solutes we’ve been talking about, are at much larger concentration than hydrogen ions, what the concentration of hydrogen ions in all this? 10-7. Teeny tiny, very little. Really, there's very little hydrogen ion in all of this, yet, the final adjustment of the pH of the urine we’re going to pass out, is made in the distal convoluted tubule. But there's hydrogen ion transport throughout the nephron. And here's a glomerulus, proximal convoluted tubule, loop of Henle, distal convoluted tubule, collecting tubule, and eventually into the collecting duct. There are 2 mechanisms by which, all while we’re resorbing bicarbonate, we’re actually secreting H+ ions into the filtrate. Remember the kidneys main function is to among other things, includes taking out the garbage. Most metabolic pathways produce acid. You take a perfectly neutral glucose molecule and you end up with lactic acid or acetoacetic acid or from a fat, or something like that, you end up with these acids and you have to get rid of these H+ ions. For most of the nephron, from the proximal convoluted tubule all through most of the distal convoluted tubule, there's a mechanism that goes on for secreting H+ ions into the filtrate, that's referred to as secondary H+ ion secretion. In the distal part of the distal convoluted tubule, I should have drawn that a little further to the left, because it actually includes part of the distal convoluted tubule as well as the collecting tubule. You have what's referred to as primary H+ ion secretion. Now, what does that mean? Secondary H+ ion secretion is, or secondary secretion of any sort, or secondary transport of any sort, is when the ATPase that's doing all the work, is not directly linked to the ion of interest, the ion you’re paying attention to. Alright, here's your lumen, with the filtrate. And this is somewhere in the nephron up to this dashed line, and this is the capillaries out here. And there's a cell. You’ve got a Na+ ATPase here, which creates a Na+ gradient here, so Na+, will tend to move in to the extent that it can cross the membrane, we’ve been through all this already, in the proximal tubule you have the brush border you have the Na+-glucose co transporter and so on. But throughout you also have 1 more transporter that I haven’t mentioned, and that's this. It’s a Na+-H+ antiporter. So when the Na+-K+ ATPase creates a low Na+ in the cytoplasm, that increases the gradient from lumen to cell. That tends to make the Na+ to want to go into the cell and 1 of the ways Na+ goes into the cell is by exchanging for a H+, so H+ in effect gets secreted into the filtrate. And that’s what's referred to as secondary H+ ion secretion. Primary H+ secretion, which occurs in the distal most part of the distal convoluted tubule, the collecting tubule, and to a little bit of the cortical part of the collecting duct, remember the collecting duct spends most of its length in the medulla. But up in the cortex, you have a little bit of activity here in the early parts of the collecting ducts. What you have is, essentially, here’s capillaries, filtrate, you simply have an ATPase that pumps H+ ions. Now where do the H+ come from? Somewhere you need a source of H+ ions inside that cell. So what basically happens is that a certain amount 4

Transcribed by Vandeep Bagga

April 22nd, 2014

of CO2 that is freely diffusible, moves into the cell, CO2 dissolves in water, combines to form carbonic acid, which then dissoaciates into bicarbonate and H+, which gets swapped out for the Na+. Ok? The bicarbonate, what happens to it? Generally, it ends up exchanging for a chloride on 1 side or the other. Usually on the serosal side. Ok. Now, where are we? If I take a break now, this is only going to run about 12-15 minutes, then you’ll get to lunch early, before the lines build up. There’s 3 quick topics, on subject of the endocrine role of the kidney. You’ve already encountered 1 of the endocrine functions of the kidney, the endocrine function of the kidney is that the macula densa actually secretes renin, when it senses indirectly that the GFR is low by seeing a low tonicity, low osmolality of the fluid that is passing by, and then the renin changes angiotensinogen to angiotensin I, and then Angiotensin Converting Enzyme changes that to angiotensin II, which has some local effects in the efferent arteriole, but also acts on the adrenal cortex, which we’ll go into detail next week, and you end up producing aldosterone, and aldosterone leads to formation, synthesis, activation, insertion, into the membrane of Na-K ATPases and the body retains Na and keeps the blood pressure up, raises your mean arterial pressure to a certain extent. Which will increase your glomerular filtration and take care of that deviation from normal GFR, from the fact that your GFR was low. That's 1 bit of endocrinology that the kidney is involved in. Another bit of endocrinology that the kidney is involved in is that there are some cells, probably in the peritubular capillaries, or associated with the peritubular capillaries, that secrete erythropoietin. In case you care about being a linguistic purist, the way I sometimes get into an obnoxious way, that “I” is there but never pronounced. So it’s not pronounced “poy” its pronounced “poe”. And what erythropoietin does is it, well, what stimulates the production and secretion of erythropoietin is hypoxia. If there’s not enough oxygen in the blood, within the capillaries bathing the cells that synthesize this, which is the peritubular capillaries. If they show hypoxic blood, not enough saturation of their RBCs and so on, cells around their secrete erythropoietin, which stimulates bone marrow cells to start the production, Dr. Sitara went through all of this with you, so I am not going into details whatsoever, so you end up producing more RBCs. Because it’s making the assumptions that if your oxygen pressure is low, its possibility because you’re anemic, and therefore you need more RBCs. The 3rd endocrine type thing that the kidney is involved in is Vitamin D. That's called a vitamin because its provided in foods, but its really a hormone, because you don’t need it in your food, unless you’re incapable of producing it, genetic defect, or you live in a cave, because the production of Vitamin D, works this way: in your skin, there is cholesterol. And when UV light strikes it, it hydroxylates it and forms 7cholecalciferol, which is a pre-pro hormone of vitamin D. And this goes to the liver, well it travels through your circulation. As it passed through the liver, the liver hydroxylates it, so you end up with 25-hydroxycholecalciferol, well most generally referred to as vitamin D. If you want to be strict about it, its referred to as Vitamin 5

Transcribed by Vandeep Bagga

April 22nd, 2014

D3, because you're an animal. There are 2 almost identical molecules that are functionally equivalent to each other, slight variations in structure, and they’re referred to as vitamin D3 and vitamin D2. D3 comes from animal tissue and D2 comes from plant tissue, don’t ask me what happened to number 1, because there is no such thing. It is generally just referred to as 25-hydroxy-vitamin D, which is an inactive hormone. All of these are inactive, in terms of getting anything done. But this eventually reaches your kidney! And when the 25-hydroxy-vitamin D reaches the kidney, the kidney has 2 different hydroxylases, it can do 1 hydroxylation, which leads to 1-25-dihydroxy-vitamin D, or it can do a 24 hydroxylation, which leads to a 24-25-dihydroxy-vitamin D. This is also totally useless. The 24-25-dihydroxyvitamin D. The 1-25-dihydroxy-vitamin D, that is the active hormone!!! And this promotes reabsorption of calcium in the distal part of the distal convoluted tubule and the collecting tubule so you don’t lose calcium in your urine, plus, I’ll be going into this in much more detail when we discuss endocrinology, it enables, its absolutely necessary for absorption of calcium from the foods you eat. You eat a piece of cheese, some yogurt, you drink some milk, or you have some liver, that's the least favorite for most people. *student question* Dr. Schiff – uh the distal part of the distal convoluted tubule and also the collecting tubule. Without this 1-25-dihydroxy-vitamin D, you cant absorb ingested calcium from your small intestine, you need this to enable your small intestine to absorb calcium. Why do you need calcium? Well remember 20 something years ago, you had a skeleton this big, and now look at you! That's why. And you even got teeth. And you want to maintain that skeleton, and if you’re pregnant, you may be building another skeleton. So, this is needed to get the calcium into your system. We’ll be discussing calcium again next week. Why have this other pathway? Well, depending on how much calcium you have in your plasma level, you may not want to absorb more calcium, you may have enough. You may want to allow your kidney to lose some calcium in the urine, because you might have too much. Unusual. The point is, that gives you 2 alternative pathways for the 25-dihydroxy-vitamin D to go. If you didn’t have this alternative pathway and you don’t need this, this, the precursor, will buildup, buildup, and have no where to go and nothing to convert to, and eventually this hydroxylase, it will just go through, even though it hasn’t been turned on, even though it’s, these are not optimal conditions. Pathways that are, if you buildup enough substrate for an enzymatic pathway, some of its going to go through. We’ll see this, either late next week or the week after next, in discussing reproduction, and I’ll leave that little surprise for you. So the whole point is, if you don’t need this, you need a way of getting rid some 25-dihydroxy-vitamin D to keep it from building up too high and that's why it provides an alternative pathway. Now, what is the on off switch determining which way the reaction goes? And the on off switch seems to parathyroid hormone (PTH). If you have PTH being secreted, you make this. If you

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Transcribed by Vandeep Bagga

April 22nd, 2014

don’t have PTH, you go that way. What regulates PTH? We will get to it under endocrinology. Ok. Let me just mention something. There were periods in the beginning of the industrial revolution when factories were going and producing so much pollution that no sunlight ever reached the ground in the cities, the cities were dark. They had gas lights on all day because of the pollution. This reaction doesn’t go, if you don’t have sunlight reaching the ground, or of course if you live in a cave. And during those periods of time, in the industrial revolution, there was an epidemic Ricketts. Ricketts is a syndrome in which your body doesn’t make Vitamin D or the 1-25dihydroxy-vitamin D, well it doesn’t make any of the vitamin D, and as a result, you cant absorb calcium from your food, well not optimally. And therefore you have improper bone calcification and tooth calcification, a lot of tooth decay and tooth loss, but also in the growth period of children, they would end up with bowed legs, deformities of various types in the vertebral column, all of which is known as Ricketts. And again we’ll discuss that in the endocrinology unit. In reaction to this, England, Germany, US passed laws requiring the addition of vitamin D to milk. Doesn’t say what kind of vitamin D they were adding, probably the 7-cholecalciferol, so basically they’re bypassing the step that needs the sunlight, so that even kids in the polluted inner city can have strong, straight bones if they can afford milk. And that, even though its probably not need anymore, is still in our milk. Just pick up a container of milk in the supermarket and read ingredients, and it will say milk comma vitamin D. Ok, so have fun, relax tomorrow, and get up bright and early for Thursday.

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Transcribed by Vandeep Bagga

April 22nd, 2014

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