Greetings, so today we're going to talk about acid-base balance in the body, and in particular, the role of the kidney in maintaining acid-base balance. And so why are we even interested in acid-base? The thing that you should remember is that if we have a pH, that is too many free hydrogen ions within the body, then the body becomes too acidic. That can cause denaturation of proteins, and if we have a situation where the blood becomes too basic, we can also have denaturation of proteins. And the proteins that we could lose, their activity that we could lose would be enzymes, channels, transporters, and so the body essentially would not be able to maintain metabolism, and it comes to a rip roaring halt. So we need to maintain the body pH then within a very narrow bracket. And we talked about this a little bit already in the respiratory lectures, but today we want to look at how the kidney is involved. So our learning objectives then are, number one, we're going to describe how the body buffers the free proton that enters either from the diet or is generated by metabolism by each day. Secondly, we want to explain the role of the lung and of the bicarbonate CO2 buffer pair in maintain the stability of the pH within the body. And third, we want to talk about the role of the kidney in reabsorbing the filtered bicarbonate to maintain the plasma pH, so this is just simply what's filtered from the plasma. And four, we'll talk about the role of the kidney in reabsorbing the filtered proton to maintain the plasma pH. Okay, so let's get started. So the first thing we need to remember is, what are acids and bases? So acids are substances that donate protons, and bases are substances that accept protons. And in our biological systems, the fluid systems have such very, very low free amounts of protons that we use a logarithmic scale to describe how much we have within the biological system. And so this is called the pH, and the pH is measured, the scale goes from 14 to 7 to 0. A pH of 0 is very acidic, a pH of 7 is neutral, and a pH of 14 is very basic. And as you recall, within the stomach we had a pH of 2, so we have very, very acidic pH within the stomach. But for the most part the bodies pH is between a pH of 7.35 and 7.45, and we usually refer to it as a pH of 7.4. All right, so why do we have a change in pH as we go through our daily lives? And it is because of two things. One is that coming in from the diet, we have fatty acids, we have amino acids, we have sulfates, we have phosphoric acids, and those are components of the food material that we're bringing in. So, this is from the diet. The second acid input that's occurring is that we are generating through metabolism, aerobic metabolism, we generate CO2 and water. And technically CO2 is not an acid, but physiologists view CO2 as a volatile acid, and we'll talk a bit about that in just a few minutes. In anaerobic metabolism, we can generate a lactic acids and ketotic acids. So there are conditions then where we can through metabolism generate a lot of acids, and then through our diet we're bringing in a lot of acids. The body is challenged to deal with this, because on a daily input, the amount of the acids that come in is usually about 1 milliequivalent per kilogram of body weight. So if we have an individual who is 70 kilograms, there could be as much as 70 milliequivalents of acids being delivered to the body on the daily basis. The first thing that the body has to do is to buffer this material, and it does so by binding the protons, the free protons then to intracellular proteins and in particularly to hemoglobin. The second thing is that buffers it with the extracellular buffering system, which is bicarbonate. So it immediately is buffering the free protons. But the body still has to get rid of the acids, and the way that it does so, is then through ventilation, it simply uses the lung to blow off CO2. And as you blow off CO2, then you are releasing a proton from the body. So the ventilation occurs within a few minutes, where our buffering system occurred instantaneously, essentially within seconds. And the kidney, as we all know, is a little slow, and so the kidney then is going to be regulating the acids by its urine output. And the kidney is going to be putting out the fixed acids. The fixed acids are the things like sulfuric acid, phosphoric acid, these are acids which can not be released by breathing through the lung. And the kidney also is going to generate an ammonium ion, and an ammonium ion and the fixed acids effectively trap the free proton. And once it's bound to either a phosphate group or sulfate group or to ammonia, then what happens is that it no longer adds to the pH. So it's removed then from the body. And this material will be excreted into the urine, but the kidney takes a few hours in order for it to reach a balance. Our end result is that the plasma is going to have a pH of about 7.4, and that the urine can have a variable pH but that the urine pH also stays fairly neutral. So there are important terms that we have to remember, and you were all given these when we were doing the respiratory system, but we want to sort of refresh your memory. So the first is acidemia, and the acidemia, emia always means in the blood. So this would be an acid in the blood. So acidemia is a state in which our blood pH, the arterial blood, is going to be less than 7.35. The second term that we need to remember is alkalemia. Alkalemia, again, in the blood means an alkilosis within the blood. That is it's a basic condition, and that basic condition simply means that the pH is going to be greater than 7.45, and then again, it's our arterial blood. When we talk about acidosis, this is the process that lowered the blood pH to, if it's an acidosis, to less than 7.35, and alkalosis is the process that raises the arterial blood pH to above a 7.45. Okay, so then the other thing that we have to remember is the lung. The activity of the lung. And that is simply that the ratio bicarbonate to CO2 is what determines pH. And you all know that as you increase the PaCO2, that is the partial pressure for CO2 within the blood, that the blood is becoming more acidic. And that obviously, the opposite occurs if we decrease the amount of PaCO2. That is, we blowoff our CO2, then we are making the blood become more basic. And that's just simply what we learned within the respiratory system. We can also change the other part or the other component of the equation, which is the carbonic anhydrase equation, and that is simply bicarbonate. If bicarbonate levels within the blood decrease, the situation becomes more acidic. And if the bicarbonate in the blood is increasing, then our blood is becoming more basic. And the equation that we're referring to is the carbonic anhydrase equation, where we can take CO2 and water, and we can form carbonic acid, and then it will dissociate into a proton and bicarbonate. If we increase the amount of CO2 and drive that off into the lung, that is we're removing it from the body, then we pull the reaction in this direction and we are losing the proton. And this is just something that you all know, and that this is regulated by the respiratory control center within the brain, so that if we have a rise in pH, a rise in circulating acids, that you will start to ventilate at a faster rate. But what is the role of the kidney in this? And the role of the kidney in this is going to be a little more complicated. So the first is, is that the kidney needs to reclaim all of the filtered bicarbonate that has occurred. So as bicarbonate is coming across the filtration barrier within the glomerulus, it is freely filters, and the proton is freely filtered. So they will enter into the renal tubual lumen in the same concentrations that they were in, in the plasma. So the bicarbonate and the proton bin is within the filtrate, and on the blood side, we want to move the bicarbonate back to the blood. And we talked about this a couple of lectures ago when we said that bicarbonate is not able to get across the proximal convoluted tubules, that the tubules do not have a transporter for bicarbonate. But that we can convert the bicarbonate and the proton into carbonic acid, and that that will then convert them into water and CO2 in the presence of carbonic anhydrase, which is present on the luminal surfaces of the PCT epithelial cells. The water in the CO2 entered the cells, and the proton then is removed from the cells and taken back into the lumen of the tubule. And that's done so with a proton ATPase, and it's also done so in a cotransporter, an antiporter with sodium. So sodium enters the cell and the proton goes back out into the lumen of the tubule. The bicarbonate, which was filtered. This bicarbonate then is now on the inside of the cell. And this bicarbonate leaves at the basal surface with an anti-porter, where chloride enters the cell, the bicarbonate leaves the cell, and then can enter into the blood. So we have a circuitous route for reabsorption of the bicarbonate where we have to first convert it to water and CO2, and then reconvert it to bicarbonate and a proton once we're inside the cells. But that the absorption of filtered bicarbonate in the proximal convoluted tubule takes up the majority of the bicarbonate that's within the filtrate. So this is going to be reabsorbing, then, about 70 to 80% of the filtered bicarbonate. And importantly, it requires the activity of the carbonic anhydrase. Now, later in the tubules, in a separate region, which is going to be in the distal convoluted tubule and in the collecting duct, we have a set of cells, which are called intercalated cells. These cells are interspersed among the principle cells, and they're fewer in number than the principle cells in this region, but these intercalated cells are what balances pH. So there's two types of intercalated cells, there's the A cell and the B cell. The A cell, the type A cell, secretes the proton, and we will end up with an acidic urine. The type B cell secretes bicarbonate, and we will end up with a basic urine. So how does this work? So what I've drawn here is an intercalated A cell. The lumen is on this side and the blood, this our peritubular capillary, is on this side. What we have is that bicarbonate and the proton are delivered from the filtrate into this distal region of the lumen of the tubules. And here we will generate carbonic acid and the carbonic acid in the presence of carbonic anhydrase, we will then make water and CO2. The water in the CO2 can enter into these cells. These cells are impermeable to bicarbonate directly, but you can move water and CO2 into the cells, and once they're inside the cells, then we can regenerate with carbonic anhydrase. The activity we can regenerate the bicarbonate, and this is a bicarbonate then can leave from the base, go across the basal surface of the cells, and enter into the blood and chloride enters into the cell. So we use an antiporter to move the bicarbonate out of the cells and into the blood in exactly an analogous manner to what we had done in the proximal convoluted tubule. Where in the proximal convoluted tubule it was 70 to 80% of the bicarbonate in the filtrate, here we're only using about the other 30 to 20% of filtered bicarb. The proton, and from these cells has multiple exit sites. One of them is again our proton ATPase, which is a pump. It simply moves protons out of the cell. We also have a proton exchanger, which the proton will leave and sodium will enter, and that's analogous to what we have in the proximal convoluted tubule. But in this region there's also an ATPase, which moves protons out of the cell, and a potassium enters the cell. So that means that when we have a condition where we have an acidic condition, and we want to be moving protons out of the body, so we're going to be losing protons into the urine, but moving the bicarbonate back into the blood under these conditions then, we will change the proton balance. And we will be moving protons, not protons, but potassium, we will be moving potassium into the cells, and then eventually potassium will exit the cells down the B channel and enter into the blood. So under these conditions where we have an acidic urine, or we have an an acid condition within the body, then we will have an increase in the potassium concentration within the plasma. That increase in the potassium concentration then can lead to hyper, hyper, meaning high, kalemia. And again, this is potassium in the blood. Now, that's the type A cell. The type B cell sits right next to the type A cells, and if the situation for the body is that the body has a very high basic pH, and it wants to get rid of bicarbonate. It doesn't want to be bringing bicarbonate back into the body, then the type A cell is not active, but the type B cell in this area is active. And this cell is the mirror image of the type A cell. So if you took the type A cell and you simply flipped it over and you had then your bicarbonate chloride antiporters on the lumenal surface of these cells. Under these conditions then, we are secreting the bicarbonate into the lumen of the tubule, and we're moving the proton then into the cell and eventually into the blood. So the type B cell then under these conditions, we would not have a rise in blood potassium, but we would actually have a decrease in blood potassium. And so it's the converse of the type A cell, and this would give us a hypokalemia condition. And that's when we have a very basic situation, and we have an alkalosis, which is occurring within the body. Now, the kidneys' job is to get rid of the excess bicarbonate. Okay, so what's are key concepts then? So the first of these is that our daily diet and metabolism generates a net increase in acids. And secondly, that the kidneys along with the lungs are going to maintain the body's pH by regulating the bicarbonate CO2 buffer system. The lungs will exert an immediate effect. This is within a few minutes by controlling the PaCO2, and the kidneys have a slower effect by controlling the bicarbonate and the proton concentration. And the kidney is going to move a proton back into the body when there's an alkalosis that's occurring within the blood. And the kidney is then going to be excreting the bicarbonate, and it does the reverse when we have an acid condition. So if we have too many protons, we're going to excrete the protons into the urine, and we're going to be moving bicarbonate back into the blood. And so the third concept then is the kidneys maintain this acid-base homeostasis. They reabsorb the filtered bicarb and that's occurring in the proximal convoluted tubule. That's just simply to move all of our buffering system back into the blood, because it would be very expensive for the body to lose all of that bicarbonate. It needs it for immediate neutralization then of the protons. And secondly, that the kidney then excretes either the bicarbonate or the proton into the urine depending on the body's needs. And again, when you look at these cases, then what you want to to think about is what does the body need? Does the body have a pH that's too high, that is sort of an alkaline condition, or does the body have a pH that's too low? Okay, so see you in the next lecture.
