Kidney Functions and Regulation Overview

All right, let's begin with chapter 19, the kidneys. So yesterday we talked a lot about the structure of the kidneys. So we're going to be skipping over a good amount of the anatomy today, and we're going to be mostly focusing on functionality. Now the kidneys have several functions in the body. Now these include the regulation of blood volume and pressure. Remember, so that when blood volume increases, so does blood pressure, and the kidneys can release excess fluid to reduce the pressure. They also regulate the osmolarity of the body, excreting or retaining water, as well as maintaining ion balance by excreting or retaining sodium, potassium, calcium, and other ions. Now, they also function in the long-term homeostatic regulation of pH. Remember, the kidneys can excrete both hydrogen ions or bicarbonate ions as needed to maintain that pH of around 7.4. Now, they also excrete waste from the body, removing metabolic waste, xenobiotics, which are foreign substances like drugs or environmental toxins, as well as many hormones that end up in our bloodstream. They are removed in the kidneys. And they also produce hormones of their own. Remember that kidneys synthesize erythropoietin and the enzyme renin that we'll talk about more today, as well as converting vitamin D3 into calcitriol. Now, just very briefly, the urinary system is composed of the ureters, urinary bladder, urethra, and kidneys. So the kidneys filter the blood, modify the filtrate, adding or removing substances, and produce urine. The ureters pass that urine from the kidney to the urinary bladder, which stores it until urination or micturition, which then passes through the urethra and out of the body. So here we see the picture. So blood comes in, you have the abdominal aorta here, blood going into the kidneys to be filtered, coming back after being filtered to the vena cava, and the urine heading down the ureters to the bladder and then out through the urethra. Now, a great deal of blood goes to the kidneys. Somewhere between 20 to 25 percent of cardiac output heads to the kidneys to be filtered. So our blood is being constantly filtered. Now, the nephron... as you hopefully remember from anatomy, is the functional unit of the kidney. It filters the blood. Now, nephrons are made up of two components, a renal corpuscle and a renal tubule. And there are two varieties of nephrons, cortical nephrons that are located mostly within the renal cortex and juxtametallary nephrons that are located near the border between the cortex and medulla. Now, the blood vessels around the nephron form a sort of portal system. right a portal systems anytime when a blood vessel kind of splits into capillaries and comes back together but instead of heading back towards the heart for recirculation it goes somewhere else so in this case the afferent arteriole that enters the renal corpuscle splits into the capillaries that make up the glomerulus and then those come back together to create the efferent arteriole and then become the paratubular capillaries that run around the renal tubule and in juxtametallary nephrons they also become the vasorecta which surrounds the nephron loop and helps to absorb water and ions and then returns to the venules back to the veins back to the vena cava to the heart so we see a picture here cortical nephron being mostly located within the renal cortex juxtametallary nephron which is right near the border and has this really long nephron loop that extends deeply into the medulla. Both types have these paratubular capillaries that run around the renal tubule, as well as the portions of the nephron loop that are mostly in the cortex, whereas in the juxtametallary nephrons, you can see the paratubular capillaries kind of go out and then head down here, following that long nephron loop as becoming the vasorecta, picking up water and ions. and then returning back to venous circulation. Now, remember that the renal corpuscle consists of a ball of capillaries called the glomerulus and the glomerular capsule that surrounds it. The renal tubule consists of the proximal convoluted tubule, the nephron loop, or loop of Henle, and the distal convoluted tubule. Filtrate is created in the renal corpuscle, enters the renal tubule, passes through all of there, and then leaves the renal tubule to enter the collecting system, which empties urine into the renal pelvis and then heads into the ureters. Now, the juxtaglomerular complex, remember, is that location where the very initial portion of the distal convoluted tubule passes near the renal corpuscles. So it's coming back up the nephron loop as it's turning into the distal convoluted tubule. passes right between the afferent and efferent arterioles. And then the soles, sorry, the cells in that location help monitor the composition of the filtrate. And as we'll see, they also release chemical signals that affect things like blood pressure, as well as the amount of filtrate produced in the renal corpuscle. So here we have all of the parts, so the glomerulus. The physiology book calls it the Bowman's capsule, but we call it the glomerular capsule as well. We have the proximal convoluted tubule, the nephron loop, also called the loop of Henle, the distal convoluted tubule, heading to the collecting system, heading out through all of these, remember the entire order from the tip of the renal pyramid into a minor calyx, then a major calyx, then the renal pelvis. And we have a zoom in here just kind of looking at the glomerulus, so literally just a ball of capillaries. Now the three main processes occurring in the kidney are filtration, reabsorption, and secretion. So filtration is the movement of fluid and solutes from the blood and into the capsular space of the renal corpuscle. So this mixture of water and solutes is called filtrate. And it is created as material is pushed through the walls of the glomerulus. You may remember when we were talking about blood pressure kind of pushing things out through there. We'll talk a little bit more about that. But basically, as the filters in the walls of the glomerulus prevent large molecules and cells from moving through, but things like water and small solutes enter into this filtrate that's being produced. and that enters into the capsular space between the two layers of the glomerular capsule. Now, reabsorption is when substances in the filtrate are moved from the renal tubule or the collecting system back into the ECF, so back into the body, either via the paratubular capillaries or the vasorecta. So this is important because, remember, that what gets pushed into the filtrate is completely nonspecific. As long as it's small enough to fit through those filtration barriers, then whatever is in there just gets pushed in there. That includes things like glucose and sodium and all of these other things that our body would like to hold on to. So we need to reabsorb them from the filtrate back into our body. Finally, secretion is when materials from blood are moved into the filtrate, typically from the peritubular capillaries. So this is the movement of extra things into the filtrate. Things that did not get filtered out as they passed through the glomerulus the first time, our body tries to make extra sure that they are removed and put into the filtrate to be excreted. So secretion is a far more selective process than filtration, and it often requires special transport proteins to move substances from the blood and into the lumen of the renal tubule. And we'll talk a little bit about organic ion transporters when we get there. Now the amount of a substance that ends up getting excreted is equal to the amount that gets filtered out in the first place, minus the amount of the substance that gets reabsorbed, and plus any extra amount of the substance that is secreted into the tubule. So we have this as a picture here. So blood coming on in, passing through this ball of capillaries through the glomerulus, and then passes out through the efferent arteriole. So pressure pushes some of the water and solutes into the capsular space. Now, once that is in there, it starts heading down the tube. So the amount that gets filtered out is just that first initial portion. Now, some of it is going to be reabsorbed, especially molecules like glucose that our body really wants to hold onto are pulled out of the tubule, and ideally, none of it makes it out to excretion. On the other hand, there are some molecules our body actively wants to get rid of. Many drugs, like penicillin for example, is actively secreted into the filtrate so that even if it escaped filtration in the first place, it is actively moved into it to make sure that more of it gets excreted. So the final amount that ends up leaving the body is equal to however much was filtered out first minus what headed back into the body plus whatever is added to the filtrate. Now initially the filtrate is almost identical to plasma, like the fluid in our blood, minus the cells and most plasma proteins. And around 180 liters, so that is over 47 gallons of fluid, is filtered every day. And I don't mean passing through the glomerulus, I mean being pushed through the walls of it into the nephron. And it has about the same osmolarity as plasma. So right around 300 milliosmoles. So that means it is isoosmotic with blood at this point. So about seven... percent of the filtrate is reabsorbed in the proximal convoluted tubule. So 54 liters of that initial 180 reach this point. So most of it has already been reabsorbed. So everything else has been reabsorbed by the proximal convoluted tubule and all that's left is this 54 liters per day. Now as it passes through the nephron loop more water and solutes are reabsorbed. Water is absorbed in the descending limb and ions are reabsorbed in the ascending limb. Now, by the end of the nephron loop, only about 10% of that original 180 liters remain. So, 18 liters of filtrate reaches the end of the loop. And at this point, it's very dilute, because a lot of ions were absorbed in the ascending limb of the nephron loop. So now, it's actually more dilute than plasma. Now, as it passes through the distal convoluted tubule, materials are secreted into the filtrate and more materials are reabsorbed, although this reabsorption is very variable because it is under hormonal regulation. Remember, so if there are signals like aldosterone that cause the body to reabsorb more water and sodium, that increase in reabsorption occurs in the distal convoluted tubule. Now on average, only about one and a half liters per day of filtrate becomes urine. So that means out of the 180 liters that pass into the nephron every day, into all of the nephrons combined, 1.5 liters is what ends up being excreted, less than 1% of the original volume. Now that urine can vary in concentration between 100 and 1,200 milliosmoles depending on how hydrated a person is. So 100 would be very, very low osmolarity. So that would... be very dilute urine with lots of water in it. Whereas if the body's pulling out a lot of water, that urine can be as high as 1200 milliosmoles. So that high osmolarity means concentrated urine, which helps the body conserve water. So here we have all the various locations within the nephron. So blood comes in through the afferent arteriole, heads to the glomerulus, and out through the efferent arteriole, then follows along the paratubular capillaries. Now, when it's in the glomerulus, pressure pushes that fluid and solutes out into the capsular space, and about 180 liters per day of filtrate is created in the kidneys. Now, as you can see, a bunch of that reabsorption occurs in the proximal convoluted tubule. So all of the glucose in a healthy individual, along with most of the water and ions and various other things, are actively reabsorbed. And then there is some small secretion in the proximal convoluted tubule, but reabsorption is by far its biggest job. Now at this point, you may be asking yourself, why does the body do all of this? Why does it push out so much stuff if it just has to reabsorb it? And that is because if you filter a lot of stuff out and just selectively pull in things that you want to keep, that means the body doesn't have to recognize every single toxin or xenobiotic substance in order to get rid of it in the body, right? It's all filtered out, and we just pull in the things we want to keep. So that way, anything our body doesn't recognize, it just automatically ends up staying in the filtrate and being excreted. Now, once all of that reabsorption of stuff we want occurs, in the proximal convoluted tubule, the filtrate passes through the nephron loop. In the descending limb, a lot of water is reabsorbed, it's pulled out of the filtrate. And then as it ascends, especially around the thick ascending limb, ions like sodium, chloride, and potassium are reabsorbed here. Now once it gets up here, it's relatively dilute, and there's still only about 10% of the filtrate that was first initially filtered out remaining. And then from here, there is some reabsorption, again variable depending on hormonal controls, and secretion of toxins and other wastes into the tube to get rid of them. Now then it passes out of the nephron into the collecting duct. Again, much, much more reabsorption than secretion occurs here. So reabsorption specifically of water is controlled here by ADH, and we'll again talk more about that later. And at the end, only about 1.5 liters per day, or less than 1% of the original volume actually comes out. And how the osmolarity of that, how concentrated it is, depends on whether the body is holding on to or getting rid of extra water. So this is just a brief discussion of these segments and their processes. Just as a heads up, the physiology textbook has a couple different ways of referring to these things. Again, it calls the Bowman's capsule is what we call the glomerular capsule. They call the nephron loop the loop of Henle. And it refers to the distal nephron as being both the distal convoluted tubule and the collecting duct. Don't worry about all these other nomenclatures, so you don't need to know the way the physiology textbook talks about it. Just have all the structures down from the anatomy books way of discussing it, because that's how they'll be worded on the tests. Now, as blood flows through the glomerulus, only a fraction of it ends up being filtered into the capsular space. And this is called the filtration fraction. Now that's the percent of plasma that enters the glomerulus that gets filtered out into the capsular space. Now it is usually about 20% of the plasma that enters the glomerulus, whereas the remaining 80% of the plasma leaves via the efferent arteriole into the peritubular capillaries. So 20% is about one-fifth. So as it's passing through there, yes, there's still things in it that could be pushed through the walls. There's still plasma. There's still ions. There's still other solutes, but not all of it has time to be pushed out, right? So only 20% of that plasma actually gets pushed out while it's passing through the glomerulus. The other 80% just keeps on going. Now, pressure is what drives glomerular filtration. Briefly alluded to it earlier, but pressure, specifically the blood pressure inside the glomerulus, is what... pushes this water and solutes from the blood into the capsular space. And as this pressure increases, it pushes more material through, which increases the size of the filtration fraction. You can picture the glomerulus as kind of like a sieve, or better yet, like a coffee filter. So if you put some coffee in a coffee filter and then put some water over it, it kind of slowly drips down through. But if you have some of those like cold presses and stuff where you press down on it, you can squeeze more water through by applying more pressure to the filter as it kind of pushes the water through. This also has the side effect of potentially damaging the filter. And as we'll talk about a little bit later, high blood pressure can actually damage the filters inside your kidneys. Now, the three factors that determine how much pressure is moving things out of the glomerulus is has, there's three different components. The first is the driving force that pushes things out, is the capillary blood pressure. So this is the pressure of the blood pushing against the walls of the glomerulus. It pushes the fluid and solutes through the filter into the capsular space. Now, this pressure is not as high as the average arterial pressure, right? Remember, as blood leaves down through the aorta, passing out through the rest of the body, it loses pressure as it travels along. By the time it gets to the glomerulus, this pressure is only about 55 millimeters of mercury, which is still more than enough to push things through the filter. There are two forces that counteract it, though. The first is the capillary colloid osmotic pressure. So this is the osmotic pressure produced by plasma proteins within the capillary, right? Remember, that osmotic pressure is that pressure to kind of equalize the concentration of particles on... both sides of a membrane so that water will move towards areas where things are more concentrated. And the blood has lots and lots of plasma proteins in it to keep its osmotic pressure up. The word colloid is just a fancy term for a mixture of solutes and water. So this is just the pressure from those plasma proteins trying to pull water via osmosis back into the glomerulus. And it's represented by this symbol here, pi. So this is around 30 millimeters mercury. So still not as big as the pressure driving things out. And then the other pressure that resists this flow is the capsule fluid pressure. So this is the pressure of the fluid already in the capsular space. So remember, this whole time, the capsular space, the renal tubule, all of it has filtrate in it that has to be pushed forward. So as... fluid is pushed out of the glomerulus, it needs to move the fluid that's already there further down the renal tubule. And anytime you're pushing on something, it pushes back. So the amount of push you put on it has to be higher than the amount it pushes back. So in this case, the capsule fluid pressure is about 15 millimeters of mercury. So taken all together, we have the capillary blood pressure at 55, and then we subtract both the osmotic pressure and the fluid pressure already inside the capsule. So that pH minus pi minus p fluid. So on average, this gives us the net filtration pressure, which is about 10 millimeters mercury. So 55 minus 30 minus 15 equals 10. And this pressure may not sound like a lot, but it's already more than enough to rapidly push water and solutes through the leaky barriers that make up the filters in the glomerulus and keeps the filtrate moving through the renal tubule. Now, the volume of filtrate produced in a given period of time is what we call the glomerular filtration rate. So this is kind of equivalent to the cardiac output for the heart, right? So for the heart, the cardiac output is the amount of blood that it moves per minute or per second or per day. The time unit doesn't matter, it's volume per time. Now for the kidneys, the glomerular filtration rate is how much is being... moved into the filtrate, being filtered out through the glomerulus over some given unit of time. Now, an average measurement of GFR is what I mentioned earlier, about that 180 liters of filtrate per day. Now, we only have three liters of plasma in our body. So if we are filtering out 180 liters of filtrate per day, that means that it's about all of the plasma in the body is filtered 60 times per day. So This makes sure that if toxins and waste products enter our blood, they are rapidly filtered out, right? They're not going to linger there for hours and days. They are going to be pushed through the kidneys, filtered out, and probably not reabsorbed, instead just excreted and gotten rid of from our body. So by keeping this filtration very, very rapid and having a high GFR, our body gets rid of substances that we don't want in it that much faster. Now the GFR is influenced by two factors, the net filtration pressure and the filtration coefficient. So as we discussed, the net filtration pressure is that capillary blood pressure and that minus the osmotic pressure minus the capsular fluid pressure. Now the net filtration pressure pushes fluid into the capsular space and through the renal tubule. And as it increases, so does the GFR, right? more pressure pushing through pushes more things through. And the net filtration pressure is affected by renal blood flow, as well as, as I mentioned, the capillary blood pressure in the glomerulus. And we'll discuss a little bit about how changing the amount of blood flowing into the glomerulus, or flowing out of it, changes that capillary blood pressure. Now, the other factor is called the filtration coefficient, and it is determined by the total surface area in... all of the glomeruli, all throughout both kidneys, as well as how permeable they are. Now remember, more surface area increases the amount, the speed of absorption, secretion, like there's more space for stuff to move through. And if more permeability, if things get through more easily, it will also lead to a higher glomerular filtration rate. Now, if a glomerulus becomes damaged, it ceases to be an effective filter. And this damage is cumulative over a lifetime and can reduce the filtration coefficient. So essentially, any damage to your kidneys caused by anything, anything that's a renal toxin, anything like high blood pressure that gets uncontrolled in there, whenever a glomerulus is damaged, it is done. But luckily, we have way more nephrons than we need on a typical day to kind of filter our blood. So if we lose a few, it's not the end of the world. Now, the GFR is regulated by constricting or dilating either the afferent arterioles or the efferent arterioles of the renal corpuscle, either the blood coming in or the blood going out. Now, if you constrict the afferent arteriole, it increases the resistance to flow, so that means that blood has a harder time getting into the glomerulus. This decreases the blood flow through it and decreases the GFR. because reduced blood flow equates to a reduced capillary blood pressure. On the other hand, if you constrict the efferent arteriole, so the blood is trying to go out and the efferent arteriole is smaller, that means that the blood inside the glomerulus has to push harder to get through that constricted efferent arteriole. So this reduces blood flow out and That increase in pressure inside increases the glomerular filtration rate. So if you constrict the incoming, so you kind of see here, we have the whole structure. If you constrict the incoming, the afferent arteriole, blood just finds it harder to get into the glomerulus at all. So blood will just take an alternate route and kind of bypass the glomeruli. On the other hand, if the route in is dilated, but the route out is dilated, out, the efferent arteriole is constricted, that means that as blood enters, it has to push harder to get out. So it kind of comes in and gets stuck there for longer and at higher pressure. So you can kind of think about that if you have like if you kind of bent off the end of a hose and saw the hose kind of start to swell up in size as the pressure increased. That's very similar to increasing the resistance constricting the efferent arteriole. So afferent arterial constriction reduces GFR, efferent arterial constriction increases GFR. Now the tissue of the nephron is very sensitive to changes in blood pressure. The filter is very fragile. So the GFR is regulated locally to keep fluctuations in pressure from damaging those filtration barriers. When arterial pressure gets too high, it stretches the smooth muscle in the walls of the afferent arterioles, right? We talked about how blood pressure pushes against the walls. And as they expand, it stretches the smooth muscle. And then they respond by constricting. So the smooth muscles try to resist the force of expansion. And that constriction will reduce blood flow and pressure in the glomerulus. Now, the concentration of sodium and chloride in the filtrate increases when GFR is high. So cells in the juxtaglomerular complex monitor the levels of sodium and chloride in the filtrate, and they can signal the afferent arteriole to constrict if the ion concentration is too high. So remember constriction of the afferent arteriole reduces GFR. Now the reason sodium and chloride increase in the filtrate when GFR is high is that more stuff's being pushed out, right? Just more water, more solutes, more sodium and chloride. And the juxtaglomerular complex monitors as it comes back from the nephron loop into the distal convoluted tubule. And if at that point sodium and chloride are still pretty high in concentration, that means that things are flowing through there too quickly. Things aren't having enough time to be reabsorbed, so it tells the nearby afferent arterial to constrict and slow things down. Now, we kind of see that right here. So those juxtaglomerular cells are located in that little area right between the initial portion of the distal convoluted tubule and the two arterioles. So they can monitor solute concentration and then directly signal the smooth muscle in the afferent arteriole as needed to kind of help control the flow rate at that amount of solute and water being put into the filtrate. to make sure that it's not too high and not too low. Now this is all local regulation, right? Because it either the smooth muscle itself is responding or the Juxtaglomerular cells are putting out a signal to the smooth muscle in the afferent arteriole to help control this. So this local regulation is very effective at maintaining a constant GFR as long as your mean arterial pressure is somewhere between 80 and 180 millimeters of mercury, but this starts to fail at either high or low pressures. So once blood pressure gets too low, then constricting the afferent arteriole doesn't do enough because it was already very, very low to begin with. So the pressure pushing things in there is too low for it to really be affected. On the other hand, when pressure gets really high, it doesn't matter how much you constrict it. as long as, you know, it's never going to constrict so much that it's completely closed, the pressure's still high enough to push extra in there. So outside of this range, things can become dangerous. And chronic hypertension, so if that high arterial pressure stays high for long periods of time, that increases that net filtration pressure, which can damage the kidneys. Now, the GFR can also be regulated through long-distance reflexes. So, for example, the autonomic nervous system can send sympathetic signals in response to a rapid drop in blood pressure. One such cause of a rapid drop in blood pressure might be blood loss. So if you lose a lot of blood, you do not want to be filtering out a lot of water and blood volume. So the sympathetic division sends signals that constrict the renal arterioles and reduce blood flow to the kidneys overall. And again, hormones like angiotensin... affect the vasoconstriction and vasodilation of renal blood vessels. And in chapter 20, we'll talk a little bit more about that renin-angiotensin system. So let's switch over quickly to a video on glomerular filtration. The rate at which the kidneys form filtrate determines how rapidly the blood is cleansed of metabolic wastes, excess ions, and toxins. It's also a key player in the kidney's other homeostatic functions. The total amount of filtrate formed by all the renal corpuscles in both kidneys per minute is called the glomerular filtration rate, or GFR. Normal kidneys produce about 125 milliliters, or about half a cup, of filtrate per minute. To maintain a normal GFR, the body adjusts the glomerular blood flow to maintain a nearly constant glomerular hydrostatic pressure, or GHP. It does this by changing the diameter of the afferent arteriole. Let's use a real situation to see how this works. An emergency room nurse is charting steadily but calmly at her desk. Her blood pressure is 110 over 70 millimeters of mercury and her mean arterial pressure or MAP is 83 millimeters of mercury. Suddenly a code blue is announced and the nurse leaps into action. As she runs to the patient in cardiac arrest her MAP spikes to 97 millimeters of mercury. If her glomerular arterials remained at their normal diameter the increase in GHP would cause a similar increase in GFR, potentially leading to dehydration. However, the increase in her mean arterial pressure causes her afferent arterials to vasoconstrict. This limits glomerular blood flow so that GHP and GFR remain normal. Once her patient stabilizes, the nurse's activity and stress levels decline, and her MAP returns to normal. Her afferent arterials vasodilate. to maintain normal g h p and g f r with the crisis over our nurse takes a brief nap her m a p drops well below the average of eighty three millimeters of mercury if the diameter of her afferent arterioles did not change this reduction in pressure would decrease the glomerular hydrostatic pressure and hence the glomerular filtration rate However, her afferent arterioles respond by vasodilating, thus increasing blood flow to the glomerulus and maintaining GHP and GFR. All right. So let's head back to the presentation. So moving on to reabsorption. So reabsorption is the movement of substances from the filtrate back into the body, and this process involves both active and passive transport within the renal tubule. As you may recall, substance... Transparency is a process that takes place in the epithelium of the renal tubule. side of the cell, the side facing the lumen, travels through the cytoplasm and exits on the basal side. Paracellular transport is movement between the epithelial cells, typically through gaps and leaky junctions from the lumen of the renal tubule and into the ECF. And both transcellular and paracellular transport are used to reabsorb material. Now, sodium ions in particular are reabsorbed transcellularly. So they enter the cell and then move out through the other side via active transport. So the first step is passive. Sodium diffuses through ion channels into the epithelial cells, moving from a high concentration inside the lumen to the low concentration inside the cell. But it is then actively pumped by sodium-potassium ATPase. It's that sodium-potassium. into the ECF, moving from low to high. Now, just remember that the inside of cells typically have very little sodium compared to the outside, so it's easy for it to move in, and then you have to actively transport it on the other side to get it into the ECF. Now, sodium being moved out of the filtrate and into the ECF causes the ECF to become more positively charged than the filtrate. We're moving these positively charged cations into the ECF, so now... Now, inside, there's more anions in the filtrate. So anions, like chloride and bicarbonate, will follow the electrical gradient, traveling from the lumen into the ECF to kind of equalize that electrical gradient. Now, this means that the osmolarity of the remaining filtrate increases, right? So we, sorry, the osmolarity decreases for the filtrate, increases for the ECF. So the sodium and anions moving into the ECF increases the osmolarity of the ECF compared to the filtrate. So water will move from the filtrate by osmosis into the ECF, following the ions. So water tends to follow the movement of ions in order to maintain that osmotic equilibrium. So now we've pumped sodium through. Sodium has caused an electrical gradient that pulled anions through. And sodium and anions moving caused... water to follow along with them to kind of equalize that osmotic pressure. Now as the filtrate loses water, now the remaining solutes become more concentrated. So the remaining solutes include things like urea, potassium, and calcium. So once the concentration of these substances in the filtrate is less than the concentration in the ECF, these substances will move down their concentration gradient into the ECF. So in this way, the active transport of sodium produces a gradient, produces the driving force that pulls water and all of these other solutes into the ECF from the filtrate. So that active transport of sodium powers the movement of the anions, the osmotic movement of water, and then the diffusion of other substances like potassium, calcium, and urea back into the body. So the body is very good at kind of utilizing the energy that's stored in that gradient. to move a lot of things into the body. Now, concentration gradients can also be used to reabsorb other substances by what we call secondary active transport. Remember that primary active transport uses ATP directly, like the sodium-potassium pump, pumping sodium out of the cell and potassium into it. If you then use that sodium gradient, now you're using secondary active transport. So in this case, Because sodium is high in the filtrate and low inside of the epithelial cells, sodium symporters can move things like glucose, amino acids, and other organic molecules into the cell against their gradient by using the energy of sodium. So again, this is the thing where sodium just really, really wants to get inside the cell. And it can use that gradient, that energy of movement, to pull things like glucose, shown here in the picture, along with it. So even though glucose is low in the filtrate and high inside of the cell, that can be overcome by sodium pulling it along. And once glucose is inside the cell, it can passively move into the ECF, into that interstitial fluid, where it can then be picked up by the paratubular capillaries. So in this way, we can make sure that we pull all of the glucose out of the filtrate in order to make sure... that we don't end up losing that valuable energy. Now, any larger particles that get through, such as any peptides or the small plasma proteins that accidentally enter the filtrate, can be reabsorbed through endocytosis. So this also includes many of the small peptide hormones that are filtered out in the urine. So endocytosis brings them into the epithelial cells, but once they are there, They do not have a transporter to move them on the other side, so it's not transcytosis. They're not being moved entirely whole back into the ECF. Instead, endocytosis brings them in, the proteins are then broken down into amino acids, and then moved into the ECF. So, in that way, like a peptide hormone that's in the blood that gets filtered out, then if it gets reabsorbed, it gets broken down into pieces before it enters the ECF. So it's signaling stops. So once it's filtered out, whatever signal that hormone was giving now ceases because the hormone is being broken down. And that is one of the reasons for the so-called half-life of a hormone, because they get filtered out and destroyed over time. Now, you may remember the concept of saturation. So saturation occurs when all the carrier proteins on a cell are occupied by substrates. which is what they bind to. So this is the problem of when you have a certain number of like taxis, but too many people want to ride in it. So all of the other people have to wait around for those taxis to finish delivering their people to their locations before they can pick up another rider. Now the transport maximum is the transport rate at saturation. So it is the fastest rate that the substance can be transported. And in this case we're looking at reabsorption, so it's the fastest that reabsorption can occur. So in the kidneys, the renal threshold is the concentration a substance has to reach for saturation to occur. So at that point there's so much of the substance that the carrier proteins, the transport proteins, can't move it into the body fast enough. So some of it is going to escape reabsorption and may end up being excreted in the urine. So once that substance reaches the renal threshold, it will start to appear in the urine. Now, glucose is a really good example of this because glucose is usually reabsorbed so quickly that none of it ends up in the urine. But if glucose levels in the blood are very high, the transporters can become saturated. Glucose that ends up not having enough time to be reabsorbed ends up in the urine, which is a condition called glucose urea, which is a very common symptoms of diabetes mellitus. So... Here we see in the picture as the concentration of glucose in the blood goes up, the transporters can keep up with it till we get about to four milligrams per milliliter. So once we start to get to that level, saturation occurs. And then if the plasma concentration increases, then we simply can't absorb any more any faster. So all of that extra glucose ends up being excreted along with the urine. because we've reached that renal threshold. So here's several charts showing basically the same idea. So the filtration rate of glucose is proportional to the plasma concentration. So the amount that gets filtered out is always going to be proportional to the amount in the blood, right? Because the filtration doesn't rely on transporters, it's just pushing things through those little filtration slits. On the other hand, transporters get maxed out. So once we reach a certain level in the filtrate, the transporters can no longer move any glucose any faster. So once we reach that renal threshold, then if the glucose increases, then more and more and more of it ends up in the urine being excreted. So typically at healthy blood sugar ranges, you will see that there's no glucose in the urine. Whereas in conditions like type 1 and type 2 diabetes, you'll see that glucose levels get so high that it's not going to be as good as it used to be. that the kidney simply can't reabsorb enough of it fast enough, and you'll start seeing it in the urine. Now, once a substance is reabsorbed, it then moves into the blood, right? So it passes through the epithelial cell, it's in the interstitial fluid on the other side, and then it has to actually be picked up by the paratubular capillaries. Now, the osmotic pressure inside the paratubular capillaries is higher than the hydrostatic pressure of the interstitial fluid around the renal tubule, right? Remember that interstitial fluid's pressure tends to be very, very low, which is one of those reasons why lymphatic vessels need sort of structures that hold them open, for one thing, because especially if anything does increase it a little bit, it'll kind of crush them. But lymphatic vessels'interstitial fluid pressure is much, much, much, much lower than just about any portion of the cardiovascular system. So... Because of that, the osmotic pressure being very, very high is enough to pull solutes and water back into the capillaries. So this is kind of a reverse filtration. So the osmotic pressure is so high that it's pulling things back inside, and it's pulling in all of those things that the renal tubule just reabsorbed. Now, secretion. Secretion is the opposite of reabsorption. It is the movement of materials from the ECF. and into the filtrate. So any substances that get secreted end up being excreted as part of the urine. So most secretion occurs within the distal convoluted tubule. Although some can occur in the proximal convoluted tubule, the DCT, distal convoluted tubule, its primary job is secretion. So secretion is important for the homeostatic regulation of many variables, including potassium and hydrogen ions, as well as unwanted organic compounds and xenobiotics. I've used that word a bit earlier, a xenobiotic. Xeno means alien or foreign. So a xenobiotic is a biological compound that your body didn't make, it's foreign, which can be things like drugs like aspirin or penicillin or toxins like botulin or something produced by bacteria. Now, secretion is an active process that moves substances against gradients. So secretion is always active transport. And it can use primary, secondary, or even tertiary active transport. So secretion transport processes can get pretty complicated. So we won't focus too much on the specifics of the directs, the primary, secondary, and tertiary, so don't worry, you do not need to memorize this diagram. But you should know what an organic ion transporter is. An organic ion transporter is a type of membrane transport proteins that moves organic anions like bile salts or aspirin into the filtrate to be excreted. Now each one can move a broad category of organic anions. So organic anion transporters are not super specific. They can bind to a great deal of organic anions and pump them into the filtrate to get them out of our body. And they use multiple levels of active transport to create these gradients. As you can see, it gets pretty complicated. So it uses first the sodium potassium pump to create that gradient, and then it uses a secondary inactive transport. to create another gradient using that sodium dicarboxylate co-transporter, and then it uses that gradient to power another organic anion transporter. But at the end of the day, all of that complicated mechanism, what it does is it moves the organic anion that we want to get rid of into the cell, and then pumps it into the filtrate. Now excretion is the removal of a substance from the body. As I mentioned before, the amount of substance that gets excreted is equal to how much gets filtered out through the glomerulus, how much gets actively secreted into the tube, and minus how much is reabsorbed. So renal handling is the shorthand that describes how a substance is dealt with by the kidneys. Is it secreted into the tube? Is it reabsorbed from the filtrate? How easily is it filtered out by the glomerulus? All of that is called a substance's renal handling. Now the clearance is a bit of a complicated idea, but I'll try my best to explain it. So clearance is the rate at which a solute disappears from the blood, whether it is excreted or used up or broken down by metabolic activity. So it is expressed as a volume of plasma cleared of a substance in a unit time. So imagine that the blood is passing through the kidneys. If you have a hundred milliliters. blood passing through and 20 milliliters of it gets filtered out. Now if all of a particular substance in that 20 milliliters gets removed so it's not reabsorbed and it passes out and is excreted that means that that 20 milliliters of plasma has been cleared of that substance. I know it's a bit of a complicated idea but it is some volume of your bodily fluid that has all of that substance removed from it in a given unit of time. So a substance with a clearance of 200 milliliters per minute, it means that that substance is removed from 200 milliliters of your plasma every single minute. Now, the clearance of a substance is equal to its excretion rate, which is how much of it ends up in the urine over time, divided by its concentration in the plasma. So how much is going out? divided by how much is still in there. Now the clearance of a substance can be calculated by using two tests, by measuring the excretion rate with a urine sample and measuring the concentration in there, and measuring the plasma concentration using a blood sample. So we can very easily measure the clearance of a substance by just getting the concentration of it in the urine and the concentration of it in the plasma. Now why is this important? Well, clearance can be used as a non-invasive way to estimate the glomerular filtration rate, which is in and of itself an important indicator of kidney health and function. So, for example, glomerular filtration rate, if it starts to drop, that can be an early indication of some kind of kidney failure. And whether it's mild, moderate, or severe is determined by how your filtration rate is being affected. And remember, so one of the things that will drop the glomerular... glomerular filtration rate is if the nephrons themselves are damaged and are no longer working. So you can use this clearance measurement to measure the GFR. Now, not all substances are great for using to estimate the GFR. So for example, if a substance is filtered out of the plasma at the same rate it is excreted, that means it is going to be good for measuring GFR because it's not reabsorbed. And it's not being secreted into the tube. So anything that gets filtered out will be excreted So if you can measure the amount that's excreted and the amount that's in the blood then the clearance of it will be exactly equal to the glomerular filtration rate. Now two substances that more or less fit this description are inulin, notice that's not insulin, there's no s in there, so inulin and creatinine. So inulin is a plant polysaccharide, so like a starch, whose clearance is exactly equal to the GFR. So when you give someone inulin, like you administer it either in the blood or through consuming it, it enters, you know, once it's in the blood, when it's filtered out by the kidneys, it is neither reabsorbed in the proximal convoluted tubule nor secreted into the distal convoluted tubule. So the amount that gets filtered is exactly equal to the GFR. Now, the problem there is that inulin is a plant polysaccharide. It doesn't exist in our body naturally. So we have to administer it to someone and then measure these things over time. So that is costly and time consuming. On the other hand, creatinine occurs naturally in the body as phosphocreatine is broken down. You may remember phosphocreatine as being that quick energy source inside of muscles that can give a phosphate group to ADP to make it into ATP. Now the production and breakdown of creatinine in the body is relatively constant, and so is its plasma concentration. So at any given point in time, the concentration of creatinine in your plasma is relatively consistent. And creatinine clearance almost exactly equals the GFR. But a small, small amount of creatinine is secreted actively into the distal convoluted tubule. So this makes it just a little bit off, but for most people, it's very close to the actual GFR. And because creatinine is a natural product inside of all of us, it makes it a very useful substance if you need to... regularly measure someone's glomerular filtration rate. So it is a very typical test that you will see if you are looking at someone's kidney health by measuring that creatinine in the blood and in the urine. Now, clearances aren't always equal to the GFR. They can be more or less, right? The glomerular filtration rate is telling you how much is being filtered out, but clearance tells you how much is being eliminated from the body. And if you are reabsorbing some of it that gets filtered out, then it's going to be cleared more slowly because you're reabsorbing it. And if you are actively secreting it into the distal convoluted tubule, the clearance will be higher because you're getting rid of even more than got filtered out. So if the clearance is less than the GFR, we know that the substance is being reabsorbed before it is excreted. So for example, glucose usually has a clearance rate of zero. because it is completely reabsorbed in the proximal convoluted tubule. Now, if the clearance is greater than the glomerular filtration rate, some of the substance is being secreted into the filtrate before it is excreted. So, for example, drugs like penicillin, the antibiotic, are actively secreted into the distal convoluted tubule, so that means that its clearance rate will be higher than the GFR. So, we can see here we have... inulin clearance. So inulin, remember, its clearance is equal to the GFR. Once it's filtered out, it is not reabsorbed and nothing is secreted into the tube. So 100% of the inulin that gets filtered gets excreted. On the other hand, glucose, all the glucose that gets filtered gets 100% reabsorbed. So no glucose ends up in there. So the clearance is zero. Now urea is one that is partially reabsorbed. So we don't get rid of all of the urea that we produce because it does play an important role in things like the osmolarity of the medulla of the kidneys in that renal medulla. So as urea is filtered out, about half of it gets reabsorbed. So the amount of urea that ends up being excreted is equal to about half of the GFR. On the other hand, penicillin is actively secreted. So All of that penicillin that gets filtered out is going to be excreted, but also the distal convoluted tubule pumps more penicillin into the filtrate. So its clearance rate is going to be higher, so 150% of the GFR. So I know this is a bit of a hard concept, and hopefully this video will help explain it a little bit more, kind of seeing it in action. In this video, we examine the concept of renal clearance and see how clearance differs from the renal handling of a solute. For this discussion, we will use four common solutes, inulin, glucose, urea, and penicillin. Each solute is handled differently by the nephron. Inulin filters, but is not reabsorbed or secreted. This makes inulin the solute we use to determine the GFR. Glucose filters and in a normal person is completely reabsorbed. Inulin filters and is partially reabsorbed, partially excreted. Penicillin, an antibiotic that is foreign to the body, filters, is not reabsorbed, and some additional is secreted by the nephron so that more is excreted than was filtered. This slide shows our schematic of renal function. Blood comes into the nephron at the afferent arteriole. About 20% of plasma filters into the lumen of the tubule, but the remaining 80% bypasses filtration and enters the peritubular capillaries. Solutes filtered into the lumen of the tubule can be returned to the blood by reabsorption. while a limited number of substances in the peritubular capillaries can be secreted into the lumen. Any solutes in the tubule that are not reabsorbed will be excreted in the urine. Plasma leaving the peritubular capillaries returns to the systemic circulation. This slide shows renal handling of a solute. Renal handling refers to how the kidney tubule deals with a solute, and the units will always be amount of solute. per unit time. For example, inulin, shown here, filters into the lumen, is not reabsorbed, not secreted, and 100% of what filtered is excreted in the urine. This is the renal handling of inulin. If we wish to talk about inulin clearance, we must now include the plasma that brings inulin into the kidney. Here, the red box represents 100 milliliters of plasma. with two inulin molecules. Most plasma again bypasses the glomerulus, but 100 milliliters of plasma containing two inulin filters each minute. All of the plasma that was filtered is reabsorbed. Inulin cannot be reabsorbed, so 100 milliliters of plasma have been cleared of inulin. The inulin that remains in the tubule is excreted. Renal handling of inulin is that all filtered inulin is excreted. Clearance of inulin is 100 milliliters of plasma cleared per minute. Notice that inulin clearance is the same as the GFR. In our second example, we use glucose, which filters and is 100% reabsorbed. The plasma that was filtered... will be completely reabsorbed along with the two glucose. That means that no plasma has been cleared of glucose, so glucose clearance is zero. No glucose has been excreted because all of the filtered glucose was reabsorbed. In this case, glucose clearance is less than the GFR. In our third example, we use urea. and we will assume that half of the urea that filters can be reabsorbed. Here we see the two urea molecules in the 100 mL of plasma, and now half of the urea is excreted in the urine. The other half of the urea is reabsorbed along with the 100 mL of plasma. Renal handling is that urea is partially excreted. Urea clearance is 50 milliliters of plasma cleared of urea per minute. Again, the urea clearance is less than the GFR. Our final example is penicillin. Penicillin will filter, is not reabsorbed, and some additional can be secreted into the lumen of the tubule. Here we see that the 100 mL of plasma are reabsorbed and the two filtered penicillin go into the urine. As the blood is passing through the peritubular capillaries, an additional penicillin is secreted into the lumen and then passes into the urine for excretion. Renal handling of penicillin is that more penicillin was excreted than was filtered. Penicillin clearance is 150 milliliters of plasma cleared of penicillin per minute. In this example, clearance is greater than GFR. By knowing the clearance of solutes and comparing clearance to the GFR, we can explain how solutes are handled by the kidney. Clearance equal to GFR is a solute that is handled like inulin. It is filtered, not reabsorbed and not secreted. If the solute clearance is less than the GFR, we know there is net reabsorption of the solute. And if solute clearance is greater than the GFR, we know there is net secretion of the solute. All right, hopefully that helped cleared some things up. So looking at this, we see more about renal handling. So it shows all the various areas in the nephron where things are reabsorbed as well as secreted. And again, don't worry too much about like secretion in the proximal tubule. It's more important that you know that its primary function is reabsorption. So knowing all of these is not as big a deal as long as you know specifically areas like the proximal convoluted tubule is where most of the reabsorption occurs for everything. That in the nephron loop, water and ions are reabsorbed. reabsorbed here, and we'll talk about that a little more in chapter 20, that in the distal convoluted tubule there's a lot of secretion as well as variable reabsorption of ions like sodium chloride and calcium, and in the collecting duct the big one is the reabsorption of water, which we'll also talk about more in the next chapter. So that is it for chapter 19, but we still have chapter 20, so that'll be a little bit shorter. Let's move on over there. right now. Okay, so chapter 20, Integrative Physiology 2, Fluid and Electrolyte Balance. So, as you can see, we're not doing all of the sections in this chapter. One of the reasons is that we already covered the acid-base handling when we talked about it in Physiology Lab. So, we're just going to focus a little bit on water balance, sodium balance and the ECF volume, and some of the integrated control of volume, osmolarity, and blood pressure. So water intake and output have to be balanced. So water intake can come from ingestion. So primarily, we get our daily water from the food and drink that we take into us. Our metabolism also produces a small amount of water every day. You may remember that breaking down glucose releases H2O and carbon dioxide. So we get rid of that CO2, but we also have that little bit of extra water. And then the other way to get water into us is through an IV. So intravenous injection can add water to the body directly. Now water is lost in many ways, right? Water is lost through our urine and feces is excreted. We lose some through insensible water loss, which is what we call when we lose water through that imperceptible sweating. So even though we do not see big droplets of sweat on us, water kind of evaporates through our, you know, integument, as well as when we're breathing out, right? Our mouths and, you know, Nasal passages are very, very moist, so some of that water leaves as we breathe out. Pathologies can also greatly increase water loss, such as vomiting or diarrhea or even just excessive sweating. All of these can lead to a great deal of water loss. But in general, we need to make sure that the amount coming in equals the amount going out so that we don't become dehydrated. Now, the kidneys play an important role in conserving the body's water. So they can't make new water, but they can reduce the rate at which it is lost. The more fluid that is filtered out in the nephrons, the more filtrate is produced, the more will inevitably end up being excreted, even though we reabsorb a lot. So less water is lost when the kidneys produce highly concentrated urine, when we reabsorb a lot of that water. And this picture here, it kind of shows you what happens at different water levels in the body. So if you have... a lot of water, if it's at an okay level, then your glomerular filtration rate is like pretty high, it is filtering your plasma fast as it can, and it is making sure that excess water is lost in the urine. However, if your GFR starts to drop, I'm sorry, if the water level starts to drop, the GFR will be adjusted to make sure that less is going to your kidneys, so that less filtrates produced, and even less volume is produced. And in fact, if your volume of water in your body drops too low, glomerular filtration can stop, which is really bad, right? Because your body needs to get rid of waste products. It needs to get rid of toxins and all of the excess levels of ions and so forth. So if your glomerular filtration rate is effectively none, then you won't be losing water, but you will basically be coming toxified over time as your body can't get rid of the things it needs to get rid of. Now, the kidneys remove water from urine by osmosis, using the high osmolarity of the renal medulla to pull water out of the renal tubule. Now, this primarily occurs in the nephron loop. I mean, a lot of water is reabsorbed in the proximal convoluted tubule, but a lot of that variable kind of like pulling out that excess last bit of water happens in the nephron loop because it extends deeply into the renal medulla. and especially on juxtametallary nephrons that have those loops that go very deep into the medulla. And that's because the osmolarity of the interstitial fluid in the renal medulla is very high at about 1200 milliosmoles, or four times more concentrated than the plasma in your blood, and the plasma in your blood already had a lot of things in it. So, I mean, to give you an idea, if you had a glass of pure water and filtered out all of the solutes, that would be zero milliosmoles. So 300 is about where plasma is, 1200 is where your medulla, the renal medulla is. And that high osmolarity really helps pull water from the nephron loop. It will pull out so much that the filtrate will reach the same osmolarity, right? So then it becomes isoosmotic and now it can't pull out anymore. But at that point it's already pulled out a lot. Now especially in the thin descending limb of the nephron loop, it is highly permeable to water and allows that water to freely diffuse kind of via osmosis into the medulla. Now, by the time the filtrate reaches the bottom of the nephron loop, especially in juxtametallary nephrons, that filtrate reaches about 1200 milliosmoles, so the same concentration as the renal medulla. Now, as it heads back up, the thick portion of the ascending limb prevents water from leaving. So the renal medulla becomes less concentrated as it gets closer to the cortex. So normally water would be entering back into the tube, but because it's thicker and impermeable to water, that doesn't happen. But we can use the fact that it's very concentrated to help pull out ions like sodium to pump it back into the medulla, and then that helps keep the osmolarity of the medulla high. And in fact, so many ions are removed from filtrate in the thick portion of the ascending limb that the filtrate becomes even more dilute, dilute, than when it entered, so 100 milliosmoles, or only about one-third as concentrated as plasma. Now, it passes through the distal convoluted tubule, where substances can be reabsorbed or secreted, but then the next big change to water comes in the collecting system. So once it's left the distal convoluted tubule, from the connecting tubules into the collecting ducts, so the collecting system also passes through the renal medulla, but its permeability to water is controlled by anti-diuretic hormone, ADH, which is also commonly called vasopressin. So when ADH levels are high, the collecting system is highly permeable to water. So water is pulled out of the filtrate and into the renal medulla. So if water can leave, it will, and it'll enter the medulla and re-enter the body. Because remember, that was very, very dilute. filtrate once it passed through the distal convoluted tubule. So once it gets back to that very, very concentrated medulla, it is easy to pull more water out. However, if ADH levels are low, the collecting system becomes impermeable to water, much like that thick ascending limb of the nephron loop. So all the water in the filtrate, even if it would love to move into the renal medulla, finds that it can't because there's just no way through the epithelium. of the collection system. So here we have the various osmolarities kind of shown here. So from the proximal tubule, a lot is reabsorbed, but it still remains about the same osmolarity as plasma, 300. Now, as it goes down deeper into the medulla, the medulla gets more and more osmotic, like that hyperosmotic. So as it goes down there, it pulls more and more water out until it eventually reaches equilibrium with the, osmotic equilibrium with the renal medulla. Now as it heads back up, that thick ascending limb pulls out lots and lots of ions. Water is not allowed to move out. And by the time it gets up here, so many ions have been reabsorbed that it is much much more dilute. As it passes through the distal tubule, there can be some reabsorption, but again it's controlled by things like aldosterone. And then it passes down through the collecting system through the medulla again. So as it's passing through this area, if ADH is present, then the per... permeable walls allow water to move back into the medulla until the point when if lots of ADH is present and as much water as possible is pulled out of the filtrate, the urine that's created will be around 1200 milliosmoles. So that is as concentrated as it can get. Now ADH controls the collecting systems permeability by changing the number of aquaporins, or water channels, found in the membrane of epithelial cells. And ADH is not all or nothing. ADH has a graded effect. So the more ADH there is, the more aquaporins will be present, which will increase the concentration of the urine produced as it increases the amount of water pulled back into the body. So here we have with lots of ADH and without. ADH. So on the left, the maximum amount of antidiuretic hormone. Remember, antidiuretic means to prevent loss of water, to prevent urination. So antidiuretics reduce the volume of urine produced. And they do that by putting these aquaporins into the walls of the collecting system, causing water to be pulled out. And then that water can then be reabsorbed by either the vasorecta or peritubular capillaries, just... vessels in general in the area and returned back to the body. Whereas whatever's left over ends up very highly, highly concentrated. But without ADH, then that very dilute filtrate cannot lose any more water, right? Because the water, those aquaporin channels are not there. They're not open. Water is not able to osmos out. So instead, it heads on through without losing any more water and comes out very... very dilute, which means a high volume of urine is being produced. All right, so that's how ADH helps affect the water balance of the body. Now let's talk a little bit about sodium and how it increases plasma osmolarity. So extra sodium increasing plasma osmolarity in the absence of water. So let's say you eat a really salty snack which gets you more sodium in your body. This leads to increased ADH release to try to hold on to water so that your body doesn't become too concentrated, too highly osmolar, as well as stimulating feelings of thirst, making you want to drink something. So this is why sometimes when you see salty snacks at a bar, they are there to kind of attempt to get your body to be like, I'm more thirsty. Now, all of this is an attempt to reduce the osmolarity and increase blood volume to keep that ratio of solutes to water at that proper level. So, Now, the hormone aldosterone helps control the sodium balance. So it stimulates reabsorption of sodium as well as secretion of potassium in the distal convoluted tubule. And its signal to be released are things like low blood pressure or low blood volume. So by absorbing more, you know, water as well as more solutes, it keeps that osmolarity constant. And as we'll see a little bit later, If you are very thirsty, if your body is low on water and you do not replenish the salts as well as the water, then that throws off the osmotic balance of your body, right? As it dilutes everything that's already in there. And that dilution can actually cause damage or cause things to go wrong. So your body will just pee out that extra water. It will be excreted if you do not also bring in extra ions to create that osmotic balance. And that's why sports drinks exist. So things like Gatorade are designed to have that mix of electrolytes, those solutes, along with the water to help increase hydration. So the renin-angiotensin system, RAS, also helps regulate blood pressure, volume, and electrolyte balance and heavily involves the kidneys. So it starts when those juxtaglomerular cells detect a drop in blood pressure. So cells in the juxtaglomerular complex are the ones that secrete an enzyme called renin. So renin is not in and of itself a hormone, it is an enzyme that activates a signal. elsewhere in the body. So renin activates with something called angiotensinogen. So just like with pepsinogen and trypsinogen, angiotensinogen is an inactive form of this protein. And renin, or renin, sorry, is what turns angiotensinogen into angiotensin-1. So angiotensin-1 on its own is not doing a lot at this point. So angiotensin 1 has to encounter another enzyme called angiotensin converting enzyme or ACE in the capillaries of the lungs to become angiotensin 2. So it's this big pathway, so there's many steps. Renin is made by the juxtaglomerular cells. Angiotensinogen is a plasma protein that's just floating around and it's made by the liver. Angiotensin 1 has to encounter ACE in order to become angiotensin 2. But that's when the actual bodily effects start to occur. Because angiotensin 2 has many effects on the body. So it is a signal that increases ADH secretion. So the ADH that's stored in the posterior pituitary, angiotensin 2 causes more of it to be released. Angiotensin 2 also stimulates thirst in your brain. So that drive, that motivation, in this case thirst is a drive, right? Because it creates motivated behavior and a goal. It also causes widespread vasoconstriction. So that kind of decreases blood flow to the periphery. And it increases sympathetic signaling to the heart, causing it to beat harder and faster. As well as increasing sodium reabsorption in the proximal convoluted tubule. And all of these things together cause a really sharp increase in blood pressure. So more blood volume. So if we drink... water we get fluid in that increases blood pressure. Vasoconstriction causes the arterioles to constrict which increases blood pressure. Heart beating faster, beating harder, higher blood pressure. And increasing the sodium kind of compensates for that extra water to keep the osmolarity there, keeping the volume up. So all of this leads to blood pressure increases. And it turns out that people with hypertension tend to have issues with this system. So several drugs that treat that hypertension, which is chronic high blood pressure, target the renin-angiotensin system. In fact, one very common class of drugs that target blood pressure are ACE inhibitors. So you may have heard of these before. ACE inhibitors, things like lisinopril, are very common blood pressure medications that reduce the activity of ACE, that angiotensin converting enzyme. So even if the kidneys are releasing renin and angiotensin 1 is being created, ACE inhibitors slow down the production of angiotensin 2, so it can't reach that final step so that the blood pressure does not increase as sharply. So there are any drug that targets any part of this pathway that might, you know, inhibit the release of renin or inhibit the production of angiotensinogen can decrease the amount of angiotensin 2 being produced, but just ACE inhibitors are an example of one that is really common. So first things first, do not worry about memorizing every step in this pathway. This is just an illustration of what we were talking about. So for example, blood pressure drops. So blood pressure drops are what cause the cells in the juxtaglomerular complex to release renin. So it's this whole pathway that ends up with a production of the enzyme renin. Then the angiotensinogen, which is constantly being produced by the liver, is converted into angiotensin 1. Angiotensin 1 interacts with ACE, that angiotensin converting enzyme that's found within capillaries, especially within capillaries in the lungs. And then it's angiotensin 2, which is the main worker here, because this causes arterioles to constrict. It causes the heart to increase the force of its contractions and its brate. It releases ADH as well as stimulating thirst. And can cause the release of aldosterone which increases sodium absorption in the proximal tubule. So all of that work together to get that blood pressure up. Now, despite being regulated together, osmolarity and blood volume can change independently, right? So in the last slide, go back real quick, we see that part of the body's response is just to keep the amount of water coming in and the amount of sodium and other electrolytes coming in about the same to maintain blood volume and osmolarity. So things like aldosterone do both of those things. But that being said, they can, you know, especially due to external circumstances. change independently of each other. So, dehydration, for example, is literally the state of losing water but not ions. And this causes a decrease in blood pressure as well as an increase in osmolarity. So the body responds to dehydration with angiotensin II and ADH release as well as stimulating the thirst drive. So your body has enough ions, but you just need more water. Now other endocrine problems can also disrupt fluid balance. Things like low ADH, like in diabetes insipidus, causes a loss of water through the excretion that needs to be constantly replaced. There are also syndromes that cause high levels of ADH release so that the body has a hard time getting rid of extra water, so that you need to be careful about what comes in, otherwise it can throw off the osmolarity of the body and then there's lots of swelling. So You can see here in the different, if you change volume or osmolarity without changing the other one, these can occur under different circumstances. So, for example, if you drink a lot of water, that's pure water with nothing in it, you can increase your blood volume, which will decrease your osmolarity, which causes problems as your body will then try to urinate all that extra water. On the other hand, you can increase the osmolarity and decrease volume by becoming dehydrated. There's other things. If you want to increase the osmolarity without changing the volume, you could eat a lot of salt without drinking water. If you ingest what they call hypertonic saline, you can increase the osmolarity and the volume at the same time. But that is often causing a problem as well, because if it is hypertonic, you're taking in more sodium than you are taking in water, which makes that osmolarity even worse. So that's why you can't drink seawater and become hydrated. So that's it for chapter 20. We're skipping over the behavioral mechanisms, potassium balance, and acid-base balance is that portion that we talked about in Physiolab. All right, so that is it for this week's chapters. So for next week, remember to kind of look through all of this stuff. I know that we had to move up the physiology lecture final to next week, so if you have any questions, please email me. I will try to get back to everyone on Monday. If you have any questions about any of the chapters, or specifically this section, please come to my office hours. They are 12.30 to 1.30 on Tuesdays. If you come in, I will answer any questions you have there. It's just quicker face-to-face because we can take care of it, like any confusion, without having to go back and forth really slowly. But if you do have any questions at all, please email me. That's matthewj.success.edu or through the Moodle. So just please message me and I will try to get back to you because I know that this is the final everybody's worried about. So I want to help you guys out any way I can. Additionally, if you guys have not seen it yet, the study guide for the physiology lecture final is up. For the other three finals, I am working on those and I will add those. when the finals for those classes are finished. But I just wanted to make sure that you got this one in time because it got moved up to next Friday. So that is it. Remember to do the Pearson homework. That is your last homework for this class. It does have some questions on all of this material that will hopefully help you out. There is a practice quiz for last week's material that should be up on the Moodle that you guys can take. That will help you with the last week's material going over the digestive system physiology. But I do not have one for this. So again, if you have any questions, please ask me. You can review the homework. There's questions at the end of every chapter that cover these things in the book itself, as well as study guides up on the Pearson page. All right. So that is it. I wish you very good luck with your studies. And I will see everybody next week. Take care.

Now the kidneys have several functions in the body. Now these include the regulation of blood volume and pressure. Remember, so that when blood volume increases, so does blood pressure, and the kidneys can release excess fluid to reduce the pressure.

They also regulate the osmolarity of the body, excreting or retaining water, as well as maintaining ion balance by excreting or retaining sodium, potassium, calcium, and other ions. Now, they also function in the long-term homeostatic regulation of pH. Remember, the kidneys can excrete both hydrogen ions or bicarbonate ions as needed to maintain that pH of around 7.4. Now, they also excrete waste from the body, removing metabolic waste, xenobiotics, which are foreign substances like drugs or environmental toxins, as well as many hormones that end up in our bloodstream.

They are removed in the kidneys. And they also produce hormones of their own. Remember that kidneys synthesize erythropoietin and the enzyme renin that we'll talk about more today, as well as converting vitamin D3 into calcitriol.

Now, just very briefly, the urinary system is composed of the ureters, urinary bladder, urethra, and kidneys. So the kidneys filter the blood, modify the filtrate, adding or removing substances, and produce urine. The ureters pass that urine from the kidney to the urinary bladder, which stores it until urination or micturition, which then passes through the urethra and out of the body. So here we see the picture.

So blood comes in, you have the abdominal aorta here, blood going into the kidneys to be filtered, coming back after being filtered to the vena cava, and the urine heading down the ureters to the bladder and then out through the urethra. Now, a great deal of blood goes to the kidneys. Somewhere between 20 to 25 percent of cardiac output heads to the kidneys to be filtered. So our blood is being constantly filtered.

Now, the nephron... as you hopefully remember from anatomy, is the functional unit of the kidney. It filters the blood. Now, nephrons are made up of two components, a renal corpuscle and a renal tubule. And there are two varieties of nephrons, cortical nephrons that are located mostly within the renal cortex and juxtametallary nephrons that are located near the border between the cortex and medulla.

Now, the blood vessels around the nephron form a sort of portal system. right a portal systems anytime when a blood vessel kind of splits into capillaries and comes back together but instead of heading back towards the heart for recirculation it goes somewhere else so in this case the afferent arteriole that enters the renal corpuscle splits into the capillaries that make up the glomerulus and then those come back together to create the efferent arteriole and then become the paratubular capillaries that run around the renal tubule and in juxtametallary nephrons they also become the vasorecta which surrounds the nephron loop and helps to absorb water and ions and then returns to the venules back to the veins back to the vena cava to the heart so we see a picture here cortical nephron being mostly located within the renal cortex juxtametallary nephron which is right near the border and has this really long nephron loop that extends deeply into the medulla. Both types have these paratubular capillaries that run around the renal tubule, as well as the portions of the nephron loop that are mostly in the cortex, whereas in the juxtametallary nephrons, you can see the paratubular capillaries kind of go out and then head down here, following that long nephron loop as becoming the vasorecta, picking up water and ions.

and then returning back to venous circulation. Now, remember that the renal corpuscle consists of a ball of capillaries called the glomerulus and the glomerular capsule that surrounds it. The renal tubule consists of the proximal convoluted tubule, the nephron loop, or loop of Henle, and the distal convoluted tubule. Filtrate is created in the renal corpuscle, enters the renal tubule, passes through all of there, and then leaves the renal tubule to enter the collecting system, which empties urine into the renal pelvis and then heads into the ureters.

Now, the juxtaglomerular complex, remember, is that location where the very initial portion of the distal convoluted tubule passes near the renal corpuscles. So it's coming back up the nephron loop as it's turning into the distal convoluted tubule. passes right between the afferent and efferent arterioles. And then the soles, sorry, the cells in that location help monitor the composition of the filtrate. And as we'll see, they also release chemical signals that affect things like blood pressure, as well as the amount of filtrate produced in the renal corpuscle.

So here we have all of the parts, so the glomerulus. The physiology book calls it the Bowman's capsule, but we call it the glomerular capsule as well. We have the proximal convoluted tubule, the nephron loop, also called the loop of Henle, the distal convoluted tubule, heading to the collecting system, heading out through all of these, remember the entire order from the tip of the renal pyramid into a minor calyx, then a major calyx, then the renal pelvis.

And we have a zoom in here just kind of looking at the glomerulus, so literally just a ball of capillaries. Now the three main processes occurring in the kidney are filtration, reabsorption, and secretion. So filtration is the movement of fluid and solutes from the blood and into the capsular space of the renal corpuscle. So this mixture of water and solutes is called filtrate.

And it is created as material is pushed through the walls of the glomerulus. You may remember when we were talking about blood pressure kind of pushing things out through there. We'll talk a little bit more about that. But basically, as the filters in the walls of the glomerulus prevent large molecules and cells from moving through, but things like water and small solutes enter into this filtrate that's being produced. and that enters into the capsular space between the two layers of the glomerular capsule.

Now, reabsorption is when substances in the filtrate are moved from the renal tubule or the collecting system back into the ECF, so back into the body, either via the paratubular capillaries or the vasorecta. So this is important because, remember, that what gets pushed into the filtrate is completely nonspecific. As long as it's small enough to fit through those filtration barriers, then whatever is in there just gets pushed in there. That includes things like glucose and sodium and all of these other things that our body would like to hold on to.

So we need to reabsorb them from the filtrate back into our body. Finally, secretion is when materials from blood are moved into the filtrate, typically from the peritubular capillaries. So this is the movement of extra things into the filtrate. Things that did not get filtered out as they passed through the glomerulus the first time, our body tries to make extra sure that they are removed and put into the filtrate to be excreted.

So secretion is a far more selective process than filtration, and it often requires special transport proteins to move substances from the blood and into the lumen of the renal tubule. And we'll talk a little bit about organic ion transporters when we get there. Now the amount of a substance that ends up getting excreted is equal to the amount that gets filtered out in the first place, minus the amount of the substance that gets reabsorbed, and plus any extra amount of the substance that is secreted into the tubule. So we have this as a picture here.

So blood coming on in, passing through this ball of capillaries through the glomerulus, and then passes out through the efferent arteriole. So pressure pushes some of the water and solutes into the capsular space. Now, once that is in there, it starts heading down the tube.

So the amount that gets filtered out is just that first initial portion. Now, some of it is going to be reabsorbed, especially molecules like glucose that our body really wants to hold onto are pulled out of the tubule, and ideally, none of it makes it out to excretion. On the other hand, there are some molecules our body actively wants to get rid of.

Many drugs, like penicillin for example, is actively secreted into the filtrate so that even if it escaped filtration in the first place, it is actively moved into it to make sure that more of it gets excreted. So the final amount that ends up leaving the body is equal to however much was filtered out first minus what headed back into the body plus whatever is added to the filtrate. Now initially the filtrate is almost identical to plasma, like the fluid in our blood, minus the cells and most plasma proteins. And around 180 liters, so that is over 47 gallons of fluid, is filtered every day. And I don't mean passing through the glomerulus, I mean being pushed through the walls of it into the nephron.

And it has about the same osmolarity as plasma. So right around 300 milliosmoles. So that means it is isoosmotic with blood at this point. So about seven...

percent of the filtrate is reabsorbed in the proximal convoluted tubule. So 54 liters of that initial 180 reach this point. So most of it has already been reabsorbed.

So everything else has been reabsorbed by the proximal convoluted tubule and all that's left is this 54 liters per day. Now as it passes through the nephron loop more water and solutes are reabsorbed. Water is absorbed in the descending limb and ions are reabsorbed in the ascending limb.

Now, by the end of the nephron loop, only about 10% of that original 180 liters remain. So, 18 liters of filtrate reaches the end of the loop. And at this point, it's very dilute, because a lot of ions were absorbed in the ascending limb of the nephron loop.

So now, it's actually more dilute than plasma. Now, as it passes through the distal convoluted tubule, materials are secreted into the filtrate and more materials are reabsorbed, although this reabsorption is very variable because it is under hormonal regulation. Remember, so if there are signals like aldosterone that cause the body to reabsorb more water and sodium, that increase in reabsorption occurs in the distal convoluted tubule. Now on average, only about one and a half liters per day of filtrate becomes urine.

So that means out of the 180 liters that pass into the nephron every day, into all of the nephrons combined, 1.5 liters is what ends up being excreted, less than 1% of the original volume. Now that urine can vary in concentration between 100 and 1,200 milliosmoles depending on how hydrated a person is. So 100 would be very, very low osmolarity. So that would...

be very dilute urine with lots of water in it. Whereas if the body's pulling out a lot of water, that urine can be as high as 1200 milliosmoles. So that high osmolarity means concentrated urine, which helps the body conserve water. So here we have all the various locations within the nephron. So blood comes in through the afferent arteriole, heads to the glomerulus, and out through the efferent arteriole, then follows along the paratubular capillaries.

Now, when it's in the glomerulus, pressure pushes that fluid and solutes out into the capsular space, and about 180 liters per day of filtrate is created in the kidneys. Now, as you can see, a bunch of that reabsorption occurs in the proximal convoluted tubule. So all of the glucose in a healthy individual, along with most of the water and ions and various other things, are actively reabsorbed. And then there is some small secretion in the proximal convoluted tubule, but reabsorption is by far its biggest job. Now at this point, you may be asking yourself, why does the body do all of this?

Why does it push out so much stuff if it just has to reabsorb it? And that is because if you filter a lot of stuff out and just selectively pull in things that you want to keep, that means the body doesn't have to recognize every single toxin or xenobiotic substance in order to get rid of it in the body, right? It's all filtered out, and we just pull in the things we want to keep. So that way, anything our body doesn't recognize, it just automatically ends up staying in the filtrate and being excreted.

Now, once all of that reabsorption of stuff we want occurs, in the proximal convoluted tubule, the filtrate passes through the nephron loop. In the descending limb, a lot of water is reabsorbed, it's pulled out of the filtrate. And then as it ascends, especially around the thick ascending limb, ions like sodium, chloride, and potassium are reabsorbed here.

Now once it gets up here, it's relatively dilute, and there's still only about 10% of the filtrate that was first initially filtered out remaining. And then from here, there is some reabsorption, again variable depending on hormonal controls, and secretion of toxins and other wastes into the tube to get rid of them. Now then it passes out of the nephron into the collecting duct. Again, much, much more reabsorption than secretion occurs here. So reabsorption specifically of water is controlled here by ADH, and we'll again talk more about that later.

And at the end, only about 1.5 liters per day, or less than 1% of the original volume actually comes out. And how the osmolarity of that, how concentrated it is, depends on whether the body is holding on to or getting rid of extra water. So this is just a brief discussion of these segments and their processes.

Just as a heads up, the physiology textbook has a couple different ways of referring to these things. Again, it calls the Bowman's capsule is what we call the glomerular capsule. They call the nephron loop the loop of Henle.

And it refers to the distal nephron as being both the distal convoluted tubule and the collecting duct. Don't worry about all these other nomenclatures, so you don't need to know the way the physiology textbook talks about it. Just have all the structures down from the anatomy books way of discussing it, because that's how they'll be worded on the tests.

Now, as blood flows through the glomerulus, only a fraction of it ends up being filtered into the capsular space. And this is called the filtration fraction. Now that's the percent of plasma that enters the glomerulus that gets filtered out into the capsular space.

Now it is usually about 20% of the plasma that enters the glomerulus, whereas the remaining 80% of the plasma leaves via the efferent arteriole into the peritubular capillaries. So 20% is about one-fifth. So as it's passing through there, yes, there's still things in it that could be pushed through the walls.

There's still plasma. There's still ions. There's still other solutes, but not all of it has time to be pushed out, right? So only 20% of that plasma actually gets pushed out while it's passing through the glomerulus.

The other 80% just keeps on going. Now, pressure is what drives glomerular filtration. Briefly alluded to it earlier, but pressure, specifically the blood pressure inside the glomerulus, is what...

pushes this water and solutes from the blood into the capsular space. And as this pressure increases, it pushes more material through, which increases the size of the filtration fraction. You can picture the glomerulus as kind of like a sieve, or better yet, like a coffee filter. So if you put some coffee in a coffee filter and then put some water over it, it kind of slowly drips down through. But if you have some of those like cold presses and stuff where you press down on it, you can squeeze more water through by applying more pressure to the filter as it kind of pushes the water through.

This also has the side effect of potentially damaging the filter. And as we'll talk about a little bit later, high blood pressure can actually damage the filters inside your kidneys. Now, the three factors that determine how much pressure is moving things out of the glomerulus is has, there's three different components.

The first is the driving force that pushes things out, is the capillary blood pressure. So this is the pressure of the blood pushing against the walls of the glomerulus. It pushes the fluid and solutes through the filter into the capsular space. Now, this pressure is not as high as the average arterial pressure, right? Remember, as blood leaves down through the aorta, passing out through the rest of the body, it loses pressure as it travels along.

By the time it gets to the glomerulus, this pressure is only about 55 millimeters of mercury, which is still more than enough to push things through the filter. There are two forces that counteract it, though. The first is the capillary colloid osmotic pressure. So this is the osmotic pressure produced by plasma proteins within the capillary, right?

Remember, that osmotic pressure is that pressure to kind of equalize the concentration of particles on... both sides of a membrane so that water will move towards areas where things are more concentrated. And the blood has lots and lots of plasma proteins in it to keep its osmotic pressure up.

The word colloid is just a fancy term for a mixture of solutes and water. So this is just the pressure from those plasma proteins trying to pull water via osmosis back into the glomerulus. And it's represented by this symbol here, pi. So this is around 30 millimeters mercury. So still not as big as the pressure driving things out.

And then the other pressure that resists this flow is the capsule fluid pressure. So this is the pressure of the fluid already in the capsular space. So remember, this whole time, the capsular space, the renal tubule, all of it has filtrate in it that has to be pushed forward.

So as... fluid is pushed out of the glomerulus, it needs to move the fluid that's already there further down the renal tubule. And anytime you're pushing on something, it pushes back. So the amount of push you put on it has to be higher than the amount it pushes back.

So in this case, the capsule fluid pressure is about 15 millimeters of mercury. So taken all together, we have the capillary blood pressure at 55, and then we subtract both the osmotic pressure and the fluid pressure already inside the capsule. So that pH minus pi minus p fluid. So on average, this gives us the net filtration pressure, which is about 10 millimeters mercury.

So 55 minus 30 minus 15 equals 10. And this pressure may not sound like a lot, but it's already more than enough to rapidly push water and solutes through the leaky barriers that make up the filters in the glomerulus and keeps the filtrate moving through the renal tubule. Now, the volume of filtrate produced in a given period of time is what we call the glomerular filtration rate. So this is kind of equivalent to the cardiac output for the heart, right? So for the heart, the cardiac output is the amount of blood that it moves per minute or per second or per day. The time unit doesn't matter, it's volume per time.

Now for the kidneys, the glomerular filtration rate is how much is being... moved into the filtrate, being filtered out through the glomerulus over some given unit of time. Now, an average measurement of GFR is what I mentioned earlier, about that 180 liters of filtrate per day. Now, we only have three liters of plasma in our body. So if we are filtering out 180 liters of filtrate per day, that means that it's about all of the plasma in the body is filtered 60 times per day.

So This makes sure that if toxins and waste products enter our blood, they are rapidly filtered out, right? They're not going to linger there for hours and days. They are going to be pushed through the kidneys, filtered out, and probably not reabsorbed, instead just excreted and gotten rid of from our body.

So by keeping this filtration very, very rapid and having a high GFR, our body gets rid of substances that we don't want in it that much faster. Now the GFR is influenced by two factors, the net filtration pressure and the filtration coefficient. So as we discussed, the net filtration pressure is that capillary blood pressure and that minus the osmotic pressure minus the capsular fluid pressure.

Now the net filtration pressure pushes fluid into the capsular space and through the renal tubule. And as it increases, so does the GFR, right? more pressure pushing through pushes more things through.

And the net filtration pressure is affected by renal blood flow, as well as, as I mentioned, the capillary blood pressure in the glomerulus. And we'll discuss a little bit about how changing the amount of blood flowing into the glomerulus, or flowing out of it, changes that capillary blood pressure. Now, the other factor is called the filtration coefficient, and it is determined by the total surface area in...

all of the glomeruli, all throughout both kidneys, as well as how permeable they are. Now remember, more surface area increases the amount, the speed of absorption, secretion, like there's more space for stuff to move through. And if more permeability, if things get through more easily, it will also lead to a higher glomerular filtration rate. Now, if a glomerulus becomes damaged, it ceases to be an effective filter. And this damage is cumulative over a lifetime and can reduce the filtration coefficient.

So essentially, any damage to your kidneys caused by anything, anything that's a renal toxin, anything like high blood pressure that gets uncontrolled in there, whenever a glomerulus is damaged, it is done. But luckily, we have way more nephrons than we need on a typical day to kind of filter our blood. So if we lose a few, it's not the end of the world. Now, the GFR is regulated by constricting or dilating either the afferent arterioles or the efferent arterioles of the renal corpuscle, either the blood coming in or the blood going out. Now, if you constrict the afferent arteriole, it increases the resistance to flow, so that means that blood has a harder time getting into the glomerulus.

This decreases the blood flow through it and decreases the GFR. because reduced blood flow equates to a reduced capillary blood pressure. On the other hand, if you constrict the efferent arteriole, so the blood is trying to go out and the efferent arteriole is smaller, that means that the blood inside the glomerulus has to push harder to get through that constricted efferent arteriole. So this reduces blood flow out and That increase in pressure inside increases the glomerular filtration rate.

So if you constrict the incoming, so you kind of see here, we have the whole structure. If you constrict the incoming, the afferent arteriole, blood just finds it harder to get into the glomerulus at all. So blood will just take an alternate route and kind of bypass the glomeruli.

On the other hand, if the route in is dilated, but the route out is dilated, out, the efferent arteriole is constricted, that means that as blood enters, it has to push harder to get out. So it kind of comes in and gets stuck there for longer and at higher pressure. So you can kind of think about that if you have like if you kind of bent off the end of a hose and saw the hose kind of start to swell up in size as the pressure increased. That's very similar to increasing the resistance constricting the efferent arteriole.

So afferent arterial constriction reduces GFR, efferent arterial constriction increases GFR. Now the tissue of the nephron is very sensitive to changes in blood pressure. The filter is very fragile.

So the GFR is regulated locally to keep fluctuations in pressure from damaging those filtration barriers. When arterial pressure gets too high, it stretches the smooth muscle in the walls of the afferent arterioles, right? We talked about how blood pressure pushes against the walls. And as they expand, it stretches the smooth muscle. And then they respond by constricting.

So the smooth muscles try to resist the force of expansion. And that constriction will reduce blood flow and pressure in the glomerulus. Now, the concentration of sodium and chloride in the filtrate increases when GFR is high.

So cells in the juxtaglomerular complex monitor the levels of sodium and chloride in the filtrate, and they can signal the afferent arteriole to constrict if the ion concentration is too high. So remember constriction of the afferent arteriole reduces GFR. Now the reason sodium and chloride increase in the filtrate when GFR is high is that more stuff's being pushed out, right? Just more water, more solutes, more sodium and chloride.

And the juxtaglomerular complex monitors as it comes back from the nephron loop into the distal convoluted tubule. And if at that point sodium and chloride are still pretty high in concentration, that means that things are flowing through there too quickly. Things aren't having enough time to be reabsorbed, so it tells the nearby afferent arterial to constrict and slow things down. Now, we kind of see that right here. So those juxtaglomerular cells are located in that little area right between the initial portion of the distal convoluted tubule and the two arterioles.

So they can monitor solute concentration and then directly signal the smooth muscle in the afferent arteriole as needed to kind of help control the flow rate at that amount of solute and water being put into the filtrate. to make sure that it's not too high and not too low. Now this is all local regulation, right? Because it either the smooth muscle itself is responding or the Juxtaglomerular cells are putting out a signal to the smooth muscle in the afferent arteriole to help control this.

So this local regulation is very effective at maintaining a constant GFR as long as your mean arterial pressure is somewhere between 80 and 180 millimeters of mercury, but this starts to fail at either high or low pressures. So once blood pressure gets too low, then constricting the afferent arteriole doesn't do enough because it was already very, very low to begin with. So the pressure pushing things in there is too low for it to really be affected. On the other hand, when pressure gets really high, it doesn't matter how much you constrict it.

as long as, you know, it's never going to constrict so much that it's completely closed, the pressure's still high enough to push extra in there. So outside of this range, things can become dangerous. And chronic hypertension, so if that high arterial pressure stays high for long periods of time, that increases that net filtration pressure, which can damage the kidneys.

Now, the GFR can also be regulated through long-distance reflexes. So, for example, the autonomic nervous system can send sympathetic signals in response to a rapid drop in blood pressure. One such cause of a rapid drop in blood pressure might be blood loss. So if you lose a lot of blood, you do not want to be filtering out a lot of water and blood volume. So the sympathetic division sends signals that constrict the renal arterioles and reduce blood flow to the kidneys overall.

And again, hormones like angiotensin... affect the vasoconstriction and vasodilation of renal blood vessels. And in chapter 20, we'll talk a little bit more about that renin-angiotensin system. So let's switch over quickly to a video on glomerular filtration. The rate at which the kidneys form filtrate determines how rapidly the blood is cleansed of metabolic wastes, excess ions, and toxins.

It's also a key player in the kidney's other homeostatic functions. The total amount of filtrate formed by all the renal corpuscles in both kidneys per minute is called the glomerular filtration rate, or GFR. Normal kidneys produce about 125 milliliters, or about half a cup, of filtrate per minute. To maintain a normal GFR, the body adjusts the glomerular blood flow to maintain a nearly constant glomerular hydrostatic pressure, or GHP.

It does this by changing the diameter of the afferent arteriole. Let's use a real situation to see how this works. An emergency room nurse is charting steadily but calmly at her desk.

Her blood pressure is 110 over 70 millimeters of mercury and her mean arterial pressure or MAP is 83 millimeters of mercury. Suddenly a code blue is announced and the nurse leaps into action. As she runs to the patient in cardiac arrest her MAP spikes to 97 millimeters of mercury. If her glomerular arterials remained at their normal diameter the increase in GHP would cause a similar increase in GFR, potentially leading to dehydration. However, the increase in her mean arterial pressure causes her afferent arterials to vasoconstrict.

This limits glomerular blood flow so that GHP and GFR remain normal. Once her patient stabilizes, the nurse's activity and stress levels decline, and her MAP returns to normal. Her afferent arterials vasodilate.

to maintain normal g h p and g f r with the crisis over our nurse takes a brief nap her m a p drops well below the average of eighty three millimeters of mercury if the diameter of her afferent arterioles did not change this reduction in pressure would decrease the glomerular hydrostatic pressure and hence the glomerular filtration rate However, her afferent arterioles respond by vasodilating, thus increasing blood flow to the glomerulus and maintaining GHP and GFR. All right. So let's head back to the presentation. So moving on to reabsorption.

So reabsorption is the movement of substances from the filtrate back into the body, and this process involves both active and passive transport within the renal tubule. As you may recall, substance... Transparency is a process that takes place in the epithelium of the renal tubule.

side of the cell, the side facing the lumen, travels through the cytoplasm and exits on the basal side. Paracellular transport is movement between the epithelial cells, typically through gaps and leaky junctions from the lumen of the renal tubule and into the ECF. And both transcellular and paracellular transport are used to reabsorb material. Now, sodium ions in particular are reabsorbed transcellularly.

So they enter the cell and then move out through the other side via active transport. So the first step is passive. Sodium diffuses through ion channels into the epithelial cells, moving from a high concentration inside the lumen to the low concentration inside the cell. But it is then actively pumped by sodium-potassium ATPase.

It's that sodium-potassium. into the ECF, moving from low to high. Now, just remember that the inside of cells typically have very little sodium compared to the outside, so it's easy for it to move in, and then you have to actively transport it on the other side to get it into the ECF. Now, sodium being moved out of the filtrate and into the ECF causes the ECF to become more positively charged than the filtrate.

We're moving these positively charged cations into the ECF, so now... Now, inside, there's more anions in the filtrate. So anions, like chloride and bicarbonate, will follow the electrical gradient, traveling from the lumen into the ECF to kind of equalize that electrical gradient.

Now, this means that the osmolarity of the remaining filtrate increases, right? So we, sorry, the osmolarity decreases for the filtrate, increases for the ECF. So the sodium and anions moving into the ECF increases the osmolarity of the ECF compared to the filtrate. So water will move from the filtrate by osmosis into the ECF, following the ions. So water tends to follow the movement of ions in order to maintain that osmotic equilibrium.

So now we've pumped sodium through. Sodium has caused an electrical gradient that pulled anions through. And sodium and anions moving caused... water to follow along with them to kind of equalize that osmotic pressure. Now as the filtrate loses water, now the remaining solutes become more concentrated.

So the remaining solutes include things like urea, potassium, and calcium. So once the concentration of these substances in the filtrate is less than the concentration in the ECF, these substances will move down their concentration gradient into the ECF. So in this way, the active transport of sodium produces a gradient, produces the driving force that pulls water and all of these other solutes into the ECF from the filtrate. So that active transport of sodium powers the movement of the anions, the osmotic movement of water, and then the diffusion of other substances like potassium, calcium, and urea back into the body. So the body is very good at kind of utilizing the energy that's stored in that gradient.

to move a lot of things into the body. Now, concentration gradients can also be used to reabsorb other substances by what we call secondary active transport. Remember that primary active transport uses ATP directly, like the sodium-potassium pump, pumping sodium out of the cell and potassium into it.

If you then use that sodium gradient, now you're using secondary active transport. So in this case, Because sodium is high in the filtrate and low inside of the epithelial cells, sodium symporters can move things like glucose, amino acids, and other organic molecules into the cell against their gradient by using the energy of sodium. So again, this is the thing where sodium just really, really wants to get inside the cell. And it can use that gradient, that energy of movement, to pull things like glucose, shown here in the picture, along with it.

So even though glucose is low in the filtrate and high inside of the cell, that can be overcome by sodium pulling it along. And once glucose is inside the cell, it can passively move into the ECF, into that interstitial fluid, where it can then be picked up by the paratubular capillaries. So in this way, we can make sure that we pull all of the glucose out of the filtrate in order to make sure...

that we don't end up losing that valuable energy. Now, any larger particles that get through, such as any peptides or the small plasma proteins that accidentally enter the filtrate, can be reabsorbed through endocytosis. So this also includes many of the small peptide hormones that are filtered out in the urine. So endocytosis brings them into the epithelial cells, but once they are there, They do not have a transporter to move them on the other side, so it's not transcytosis. They're not being moved entirely whole back into the ECF.

Instead, endocytosis brings them in, the proteins are then broken down into amino acids, and then moved into the ECF. So, in that way, like a peptide hormone that's in the blood that gets filtered out, then if it gets reabsorbed, it gets broken down into pieces before it enters the ECF. So it's signaling stops. So once it's filtered out, whatever signal that hormone was giving now ceases because the hormone is being broken down. And that is one of the reasons for the so-called half-life of a hormone, because they get filtered out and destroyed over time.

Now, you may remember the concept of saturation. So saturation occurs when all the carrier proteins on a cell are occupied by substrates. which is what they bind to. So this is the problem of when you have a certain number of like taxis, but too many people want to ride in it. So all of the other people have to wait around for those taxis to finish delivering their people to their locations before they can pick up another rider.

Now the transport maximum is the transport rate at saturation. So it is the fastest rate that the substance can be transported. And in this case we're looking at reabsorption, so it's the fastest that reabsorption can occur.

So in the kidneys, the renal threshold is the concentration a substance has to reach for saturation to occur. So at that point there's so much of the substance that the carrier proteins, the transport proteins, can't move it into the body fast enough. So some of it is going to escape reabsorption and may end up being excreted in the urine. So once that substance reaches the renal threshold, it will start to appear in the urine. Now, glucose is a really good example of this because glucose is usually reabsorbed so quickly that none of it ends up in the urine.

But if glucose levels in the blood are very high, the transporters can become saturated. Glucose that ends up not having enough time to be reabsorbed ends up in the urine, which is a condition called glucose urea, which is a very common symptoms of diabetes mellitus. So... Here we see in the picture as the concentration of glucose in the blood goes up, the transporters can keep up with it till we get about to four milligrams per milliliter.

So once we start to get to that level, saturation occurs. And then if the plasma concentration increases, then we simply can't absorb any more any faster. So all of that extra glucose ends up being excreted along with the urine. because we've reached that renal threshold.

So here's several charts showing basically the same idea. So the filtration rate of glucose is proportional to the plasma concentration. So the amount that gets filtered out is always going to be proportional to the amount in the blood, right?

Because the filtration doesn't rely on transporters, it's just pushing things through those little filtration slits. On the other hand, transporters get maxed out. So once we reach a certain level in the filtrate, the transporters can no longer move any glucose any faster.

So once we reach that renal threshold, then if the glucose increases, then more and more and more of it ends up in the urine being excreted. So typically at healthy blood sugar ranges, you will see that there's no glucose in the urine. Whereas in conditions like type 1 and type 2 diabetes, you'll see that glucose levels get so high that it's not going to be as good as it used to be. that the kidney simply can't reabsorb enough of it fast enough, and you'll start seeing it in the urine. Now, once a substance is reabsorbed, it then moves into the blood, right?

So it passes through the epithelial cell, it's in the interstitial fluid on the other side, and then it has to actually be picked up by the paratubular capillaries. Now, the osmotic pressure inside the paratubular capillaries is higher than the hydrostatic pressure of the interstitial fluid around the renal tubule, right? Remember that interstitial fluid's pressure tends to be very, very low, which is one of those reasons why lymphatic vessels need sort of structures that hold them open, for one thing, because especially if anything does increase it a little bit, it'll kind of crush them. But lymphatic vessels'interstitial fluid pressure is much, much, much, much lower than just about any portion of the cardiovascular system.

So... Because of that, the osmotic pressure being very, very high is enough to pull solutes and water back into the capillaries. So this is kind of a reverse filtration.

So the osmotic pressure is so high that it's pulling things back inside, and it's pulling in all of those things that the renal tubule just reabsorbed. Now, secretion. Secretion is the opposite of reabsorption. It is the movement of materials from the ECF.

and into the filtrate. So any substances that get secreted end up being excreted as part of the urine. So most secretion occurs within the distal convoluted tubule. Although some can occur in the proximal convoluted tubule, the DCT, distal convoluted tubule, its primary job is secretion.

So secretion is important for the homeostatic regulation of many variables, including potassium and hydrogen ions, as well as unwanted organic compounds and xenobiotics. I've used that word a bit earlier, a xenobiotic. Xeno means alien or foreign. So a xenobiotic is a biological compound that your body didn't make, it's foreign, which can be things like drugs like aspirin or penicillin or toxins like botulin or something produced by bacteria.

Now, secretion is an active process that moves substances against gradients. So secretion is always active transport. And it can use primary, secondary, or even tertiary active transport.

So secretion transport processes can get pretty complicated. So we won't focus too much on the specifics of the directs, the primary, secondary, and tertiary, so don't worry, you do not need to memorize this diagram. But you should know what an organic ion transporter is.

An organic ion transporter is a type of membrane transport proteins that moves organic anions like bile salts or aspirin into the filtrate to be excreted. Now each one can move a broad category of organic anions. So organic anion transporters are not super specific.

They can bind to a great deal of organic anions and pump them into the filtrate to get them out of our body. And they use multiple levels of active transport to create these gradients. As you can see, it gets pretty complicated. So it uses first the sodium potassium pump to create that gradient, and then it uses a secondary inactive transport. to create another gradient using that sodium dicarboxylate co-transporter, and then it uses that gradient to power another organic anion transporter.

But at the end of the day, all of that complicated mechanism, what it does is it moves the organic anion that we want to get rid of into the cell, and then pumps it into the filtrate. Now excretion is the removal of a substance from the body. As I mentioned before, the amount of substance that gets excreted is equal to how much gets filtered out through the glomerulus, how much gets actively secreted into the tube, and minus how much is reabsorbed.

So renal handling is the shorthand that describes how a substance is dealt with by the kidneys. Is it secreted into the tube? Is it reabsorbed from the filtrate?

How easily is it filtered out by the glomerulus? All of that is called a substance's renal handling. Now the clearance is a bit of a complicated idea, but I'll try my best to explain it. So clearance is the rate at which a solute disappears from the blood, whether it is excreted or used up or broken down by metabolic activity.

So it is expressed as a volume of plasma cleared of a substance in a unit time. So imagine that the blood is passing through the kidneys. If you have a hundred milliliters.

blood passing through and 20 milliliters of it gets filtered out. Now if all of a particular substance in that 20 milliliters gets removed so it's not reabsorbed and it passes out and is excreted that means that that 20 milliliters of plasma has been cleared of that substance. I know it's a bit of a complicated idea but it is some volume of your bodily fluid that has all of that substance removed from it in a given unit of time. So a substance with a clearance of 200 milliliters per minute, it means that that substance is removed from 200 milliliters of your plasma every single minute.

Now, the clearance of a substance is equal to its excretion rate, which is how much of it ends up in the urine over time, divided by its concentration in the plasma. So how much is going out? divided by how much is still in there.

Now the clearance of a substance can be calculated by using two tests, by measuring the excretion rate with a urine sample and measuring the concentration in there, and measuring the plasma concentration using a blood sample. So we can very easily measure the clearance of a substance by just getting the concentration of it in the urine and the concentration of it in the plasma. Now why is this important?

Well, clearance can be used as a non-invasive way to estimate the glomerular filtration rate, which is in and of itself an important indicator of kidney health and function. So, for example, glomerular filtration rate, if it starts to drop, that can be an early indication of some kind of kidney failure. And whether it's mild, moderate, or severe is determined by how your filtration rate is being affected.

And remember, so one of the things that will drop the glomerular... glomerular filtration rate is if the nephrons themselves are damaged and are no longer working. So you can use this clearance measurement to measure the GFR. Now, not all substances are great for using to estimate the GFR.

So for example, if a substance is filtered out of the plasma at the same rate it is excreted, that means it is going to be good for measuring GFR because it's not reabsorbed. And it's not being secreted into the tube. So anything that gets filtered out will be excreted So if you can measure the amount that's excreted and the amount that's in the blood then the clearance of it will be exactly equal to the glomerular filtration rate.

Now two substances that more or less fit this description are inulin, notice that's not insulin, there's no s in there, so inulin and creatinine. So inulin is a plant polysaccharide, so like a starch, whose clearance is exactly equal to the GFR. So when you give someone inulin, like you administer it either in the blood or through consuming it, it enters, you know, once it's in the blood, when it's filtered out by the kidneys, it is neither reabsorbed in the proximal convoluted tubule nor secreted into the distal convoluted tubule.

So the amount that gets filtered is exactly equal to the GFR. Now, the problem there is that inulin is a plant polysaccharide. It doesn't exist in our body naturally.

So we have to administer it to someone and then measure these things over time. So that is costly and time consuming. On the other hand, creatinine occurs naturally in the body as phosphocreatine is broken down. You may remember phosphocreatine as being that quick energy source inside of muscles that can give a phosphate group to ADP to make it into ATP. Now the production and breakdown of creatinine in the body is relatively constant, and so is its plasma concentration.

So at any given point in time, the concentration of creatinine in your plasma is relatively consistent. And creatinine clearance almost exactly equals the GFR. But a small, small amount of creatinine is secreted actively into the distal convoluted tubule. So this makes it just a little bit off, but for most people, it's very close to the actual GFR. And because creatinine is a natural product inside of all of us, it makes it a very useful substance if you need to...

regularly measure someone's glomerular filtration rate. So it is a very typical test that you will see if you are looking at someone's kidney health by measuring that creatinine in the blood and in the urine. Now, clearances aren't always equal to the GFR. They can be more or less, right? The glomerular filtration rate is telling you how much is being filtered out, but clearance tells you how much is being eliminated from the body.

And if you are reabsorbing some of it that gets filtered out, then it's going to be cleared more slowly because you're reabsorbing it. And if you are actively secreting it into the distal convoluted tubule, the clearance will be higher because you're getting rid of even more than got filtered out. So if the clearance is less than the GFR, we know that the substance is being reabsorbed before it is excreted.

So for example, glucose usually has a clearance rate of zero. because it is completely reabsorbed in the proximal convoluted tubule. Now, if the clearance is greater than the glomerular filtration rate, some of the substance is being secreted into the filtrate before it is excreted.

So, for example, drugs like penicillin, the antibiotic, are actively secreted into the distal convoluted tubule, so that means that its clearance rate will be higher than the GFR. So, we can see here we have... inulin clearance.

So inulin, remember, its clearance is equal to the GFR. Once it's filtered out, it is not reabsorbed and nothing is secreted into the tube. So 100% of the inulin that gets filtered gets excreted.

On the other hand, glucose, all the glucose that gets filtered gets 100% reabsorbed. So no glucose ends up in there. So the clearance is zero.

Now urea is one that is partially reabsorbed. So we don't get rid of all of the urea that we produce because it does play an important role in things like the osmolarity of the medulla of the kidneys in that renal medulla. So as urea is filtered out, about half of it gets reabsorbed.

So the amount of urea that ends up being excreted is equal to about half of the GFR. On the other hand, penicillin is actively secreted. So All of that penicillin that gets filtered out is going to be excreted, but also the distal convoluted tubule pumps more penicillin into the filtrate.

So its clearance rate is going to be higher, so 150% of the GFR. So I know this is a bit of a hard concept, and hopefully this video will help explain it a little bit more, kind of seeing it in action. In this video, we examine the concept of renal clearance and see how clearance differs from the renal handling of a solute. For this discussion, we will use four common solutes, inulin, glucose, urea, and penicillin.

Each solute is handled differently by the nephron. Inulin filters, but is not reabsorbed or secreted. This makes inulin the solute we use to determine the GFR. Glucose filters and in a normal person is completely reabsorbed. Inulin filters and is partially reabsorbed, partially excreted.

Penicillin, an antibiotic that is foreign to the body, filters, is not reabsorbed, and some additional is secreted by the nephron so that more is excreted than was filtered. This slide shows our schematic of renal function. Blood comes into the nephron at the afferent arteriole. About 20% of plasma filters into the lumen of the tubule, but the remaining 80% bypasses filtration and enters the peritubular capillaries.

Solutes filtered into the lumen of the tubule can be returned to the blood by reabsorption. while a limited number of substances in the peritubular capillaries can be secreted into the lumen. Any solutes in the tubule that are not reabsorbed will be excreted in the urine. Plasma leaving the peritubular capillaries returns to the systemic circulation. This slide shows renal handling of a solute.

Renal handling refers to how the kidney tubule deals with a solute, and the units will always be amount of solute. per unit time. For example, inulin, shown here, filters into the lumen, is not reabsorbed, not secreted, and 100% of what filtered is excreted in the urine.

This is the renal handling of inulin. If we wish to talk about inulin clearance, we must now include the plasma that brings inulin into the kidney. Here, the red box represents 100 milliliters of plasma.

with two inulin molecules. Most plasma again bypasses the glomerulus, but 100 milliliters of plasma containing two inulin filters each minute. All of the plasma that was filtered is reabsorbed. Inulin cannot be reabsorbed, so 100 milliliters of plasma have been cleared of inulin. The inulin that remains in the tubule is excreted.

Renal handling of inulin is that all filtered inulin is excreted. Clearance of inulin is 100 milliliters of plasma cleared per minute. Notice that inulin clearance is the same as the GFR.

In our second example, we use glucose, which filters and is 100% reabsorbed. The plasma that was filtered... will be completely reabsorbed along with the two glucose.

That means that no plasma has been cleared of glucose, so glucose clearance is zero. No glucose has been excreted because all of the filtered glucose was reabsorbed. In this case, glucose clearance is less than the GFR.

In our third example, we use urea. and we will assume that half of the urea that filters can be reabsorbed. Here we see the two urea molecules in the 100 mL of plasma, and now half of the urea is excreted in the urine. The other half of the urea is reabsorbed along with the 100 mL of plasma. Renal handling is that urea is partially excreted.

Urea clearance is 50 milliliters of plasma cleared of urea per minute. Again, the urea clearance is less than the GFR. Our final example is penicillin. Penicillin will filter, is not reabsorbed, and some additional can be secreted into the lumen of the tubule.

Here we see that the 100 mL of plasma are reabsorbed and the two filtered penicillin go into the urine. As the blood is passing through the peritubular capillaries, an additional penicillin is secreted into the lumen and then passes into the urine for excretion. Renal handling of penicillin is that more penicillin was excreted than was filtered.

Penicillin clearance is 150 milliliters of plasma cleared of penicillin per minute. In this example, clearance is greater than GFR. By knowing the clearance of solutes and comparing clearance to the GFR, we can explain how solutes are handled by the kidney. Clearance equal to GFR is a solute that is handled like inulin.

It is filtered, not reabsorbed and not secreted. If the solute clearance is less than the GFR, we know there is net reabsorption of the solute. And if solute clearance is greater than the GFR, we know there is net secretion of the solute. All right, hopefully that helped cleared some things up. So looking at this, we see more about renal handling.

So it shows all the various areas in the nephron where things are reabsorbed as well as secreted. And again, don't worry too much about like secretion in the proximal tubule. It's more important that you know that its primary function is reabsorption. So knowing all of these is not as big a deal as long as you know specifically areas like the proximal convoluted tubule is where most of the reabsorption occurs for everything. That in the nephron loop, water and ions are reabsorbed.

reabsorbed here, and we'll talk about that a little more in chapter 20, that in the distal convoluted tubule there's a lot of secretion as well as variable reabsorption of ions like sodium chloride and calcium, and in the collecting duct the big one is the reabsorption of water, which we'll also talk about more in the next chapter. So that is it for chapter 19, but we still have chapter 20, so that'll be a little bit shorter. Let's move on over there.

right now. Okay, so chapter 20, Integrative Physiology 2, Fluid and Electrolyte Balance. So, as you can see, we're not doing all of the sections in this chapter. One of the reasons is that we already covered the acid-base handling when we talked about it in Physiology Lab.

So, we're just going to focus a little bit on water balance, sodium balance and the ECF volume, and some of the integrated control of volume, osmolarity, and blood pressure. So water intake and output have to be balanced. So water intake can come from ingestion.

So primarily, we get our daily water from the food and drink that we take into us. Our metabolism also produces a small amount of water every day. You may remember that breaking down glucose releases H2O and carbon dioxide.

So we get rid of that CO2, but we also have that little bit of extra water. And then the other way to get water into us is through an IV. So intravenous injection can add water to the body directly. Now water is lost in many ways, right? Water is lost through our urine and feces is excreted.

We lose some through insensible water loss, which is what we call when we lose water through that imperceptible sweating. So even though we do not see big droplets of sweat on us, water kind of evaporates through our, you know, integument, as well as when we're breathing out, right? Our mouths and, you know, Nasal passages are very, very moist, so some of that water leaves as we breathe out.

Pathologies can also greatly increase water loss, such as vomiting or diarrhea or even just excessive sweating. All of these can lead to a great deal of water loss. But in general, we need to make sure that the amount coming in equals the amount going out so that we don't become dehydrated.

Now, the kidneys play an important role in conserving the body's water. So they can't make new water, but they can reduce the rate at which it is lost. The more fluid that is filtered out in the nephrons, the more filtrate is produced, the more will inevitably end up being excreted, even though we reabsorb a lot.

So less water is lost when the kidneys produce highly concentrated urine, when we reabsorb a lot of that water. And this picture here, it kind of shows you what happens at different water levels in the body. So if you have...

a lot of water, if it's at an okay level, then your glomerular filtration rate is like pretty high, it is filtering your plasma fast as it can, and it is making sure that excess water is lost in the urine. However, if your GFR starts to drop, I'm sorry, if the water level starts to drop, the GFR will be adjusted to make sure that less is going to your kidneys, so that less filtrates produced, and even less volume is produced. And in fact, if your volume of water in your body drops too low, glomerular filtration can stop, which is really bad, right?

Because your body needs to get rid of waste products. It needs to get rid of toxins and all of the excess levels of ions and so forth. So if your glomerular filtration rate is effectively none, then you won't be losing water, but you will basically be coming toxified over time as your body can't get rid of the things it needs to get rid of.

Now, the kidneys remove water from urine by osmosis, using the high osmolarity of the renal medulla to pull water out of the renal tubule. Now, this primarily occurs in the nephron loop. I mean, a lot of water is reabsorbed in the proximal convoluted tubule, but a lot of that variable kind of like pulling out that excess last bit of water happens in the nephron loop because it extends deeply into the renal medulla. and especially on juxtametallary nephrons that have those loops that go very deep into the medulla.

And that's because the osmolarity of the interstitial fluid in the renal medulla is very high at about 1200 milliosmoles, or four times more concentrated than the plasma in your blood, and the plasma in your blood already had a lot of things in it. So, I mean, to give you an idea, if you had a glass of pure water and filtered out all of the solutes, that would be zero milliosmoles. So 300 is about where plasma is, 1200 is where your medulla, the renal medulla is.

And that high osmolarity really helps pull water from the nephron loop. It will pull out so much that the filtrate will reach the same osmolarity, right? So then it becomes isoosmotic and now it can't pull out anymore.

But at that point it's already pulled out a lot. Now especially in the thin descending limb of the nephron loop, it is highly permeable to water and allows that water to freely diffuse kind of via osmosis into the medulla. Now, by the time the filtrate reaches the bottom of the nephron loop, especially in juxtametallary nephrons, that filtrate reaches about 1200 milliosmoles, so the same concentration as the renal medulla. Now, as it heads back up, the thick portion of the ascending limb prevents water from leaving.

So the renal medulla becomes less concentrated as it gets closer to the cortex. So normally water would be entering back into the tube, but because it's thicker and impermeable to water, that doesn't happen. But we can use the fact that it's very concentrated to help pull out ions like sodium to pump it back into the medulla, and then that helps keep the osmolarity of the medulla high.

And in fact, so many ions are removed from filtrate in the thick portion of the ascending limb that the filtrate becomes even more dilute, dilute, than when it entered, so 100 milliosmoles, or only about one-third as concentrated as plasma. Now, it passes through the distal convoluted tubule, where substances can be reabsorbed or secreted, but then the next big change to water comes in the collecting system. So once it's left the distal convoluted tubule, from the connecting tubules into the collecting ducts, so the collecting system also passes through the renal medulla, but its permeability to water is controlled by anti-diuretic hormone, ADH, which is also commonly called vasopressin.

So when ADH levels are high, the collecting system is highly permeable to water. So water is pulled out of the filtrate and into the renal medulla. So if water can leave, it will, and it'll enter the medulla and re-enter the body. Because remember, that was very, very dilute.

filtrate once it passed through the distal convoluted tubule. So once it gets back to that very, very concentrated medulla, it is easy to pull more water out. However, if ADH levels are low, the collecting system becomes impermeable to water, much like that thick ascending limb of the nephron loop.

So all the water in the filtrate, even if it would love to move into the renal medulla, finds that it can't because there's just no way through the epithelium. of the collection system. So here we have the various osmolarities kind of shown here.

So from the proximal tubule, a lot is reabsorbed, but it still remains about the same osmolarity as plasma, 300. Now, as it goes down deeper into the medulla, the medulla gets more and more osmotic, like that hyperosmotic. So as it goes down there, it pulls more and more water out until it eventually reaches equilibrium with the, osmotic equilibrium with the renal medulla. Now as it heads back up, that thick ascending limb pulls out lots and lots of ions.

Water is not allowed to move out. And by the time it gets up here, so many ions have been reabsorbed that it is much much more dilute. As it passes through the distal tubule, there can be some reabsorption, but again it's controlled by things like aldosterone.

And then it passes down through the collecting system through the medulla again. So as it's passing through this area, if ADH is present, then the per... permeable walls allow water to move back into the medulla until the point when if lots of ADH is present and as much water as possible is pulled out of the filtrate, the urine that's created will be around 1200 milliosmoles.

So that is as concentrated as it can get. Now ADH controls the collecting systems permeability by changing the number of aquaporins, or water channels, found in the membrane of epithelial cells. And ADH is not all or nothing. ADH has a graded effect. So the more ADH there is, the more aquaporins will be present, which will increase the concentration of the urine produced as it increases the amount of water pulled back into the body.

So here we have with lots of ADH and without. ADH. So on the left, the maximum amount of antidiuretic hormone.

Remember, antidiuretic means to prevent loss of water, to prevent urination. So antidiuretics reduce the volume of urine produced. And they do that by putting these aquaporins into the walls of the collecting system, causing water to be pulled out.

And then that water can then be reabsorbed by either the vasorecta or peritubular capillaries, just... vessels in general in the area and returned back to the body. Whereas whatever's left over ends up very highly, highly concentrated. But without ADH, then that very dilute filtrate cannot lose any more water, right? Because the water, those aquaporin channels are not there.

They're not open. Water is not able to osmos out. So instead, it heads on through without losing any more water and comes out very...

very dilute, which means a high volume of urine is being produced. All right, so that's how ADH helps affect the water balance of the body. Now let's talk a little bit about sodium and how it increases plasma osmolarity. So extra sodium increasing plasma osmolarity in the absence of water. So let's say you eat a really salty snack which gets you more sodium in your body.

This leads to increased ADH release to try to hold on to water so that your body doesn't become too concentrated, too highly osmolar, as well as stimulating feelings of thirst, making you want to drink something. So this is why sometimes when you see salty snacks at a bar, they are there to kind of attempt to get your body to be like, I'm more thirsty. Now, all of this is an attempt to reduce the osmolarity and increase blood volume to keep that ratio of solutes to water at that proper level. So, Now, the hormone aldosterone helps control the sodium balance. So it stimulates reabsorption of sodium as well as secretion of potassium in the distal convoluted tubule.

And its signal to be released are things like low blood pressure or low blood volume. So by absorbing more, you know, water as well as more solutes, it keeps that osmolarity constant. And as we'll see a little bit later, If you are very thirsty, if your body is low on water and you do not replenish the salts as well as the water, then that throws off the osmotic balance of your body, right?

As it dilutes everything that's already in there. And that dilution can actually cause damage or cause things to go wrong. So your body will just pee out that extra water. It will be excreted if you do not also bring in extra ions to create that osmotic balance. And that's why sports drinks exist.

So things like Gatorade are designed to have that mix of electrolytes, those solutes, along with the water to help increase hydration. So the renin-angiotensin system, RAS, also helps regulate blood pressure, volume, and electrolyte balance and heavily involves the kidneys. So it starts when those juxtaglomerular cells detect a drop in blood pressure.

So cells in the juxtaglomerular complex are the ones that secrete an enzyme called renin. So renin is not in and of itself a hormone, it is an enzyme that activates a signal. elsewhere in the body. So renin activates with something called angiotensinogen. So just like with pepsinogen and trypsinogen, angiotensinogen is an inactive form of this protein.

And renin, or renin, sorry, is what turns angiotensinogen into angiotensin-1. So angiotensin-1 on its own is not doing a lot at this point. So angiotensin 1 has to encounter another enzyme called angiotensin converting enzyme or ACE in the capillaries of the lungs to become angiotensin 2. So it's this big pathway, so there's many steps. Renin is made by the juxtaglomerular cells.

Angiotensinogen is a plasma protein that's just floating around and it's made by the liver. Angiotensin 1 has to encounter ACE in order to become angiotensin 2. But that's when the actual bodily effects start to occur. Because angiotensin 2 has many effects on the body. So it is a signal that increases ADH secretion.

So the ADH that's stored in the posterior pituitary, angiotensin 2 causes more of it to be released. Angiotensin 2 also stimulates thirst in your brain. So that drive, that motivation, in this case thirst is a drive, right? Because it creates motivated behavior and a goal.

It also causes widespread vasoconstriction. So that kind of decreases blood flow to the periphery. And it increases sympathetic signaling to the heart, causing it to beat harder and faster.

As well as increasing sodium reabsorption in the proximal convoluted tubule. And all of these things together cause a really sharp increase in blood pressure. So more blood volume. So if we drink...

water we get fluid in that increases blood pressure. Vasoconstriction causes the arterioles to constrict which increases blood pressure. Heart beating faster, beating harder, higher blood pressure.

And increasing the sodium kind of compensates for that extra water to keep the osmolarity there, keeping the volume up. So all of this leads to blood pressure increases. And it turns out that people with hypertension tend to have issues with this system. So several drugs that treat that hypertension, which is chronic high blood pressure, target the renin-angiotensin system. In fact, one very common class of drugs that target blood pressure are ACE inhibitors.

So you may have heard of these before. ACE inhibitors, things like lisinopril, are very common blood pressure medications that reduce the activity of ACE, that angiotensin converting enzyme. So even if the kidneys are releasing renin and angiotensin 1 is being created, ACE inhibitors slow down the production of angiotensin 2, so it can't reach that final step so that the blood pressure does not increase as sharply.

So there are any drug that targets any part of this pathway that might, you know, inhibit the release of renin or inhibit the production of angiotensinogen can decrease the amount of angiotensin 2 being produced, but just ACE inhibitors are an example of one that is really common. So first things first, do not worry about memorizing every step in this pathway. This is just an illustration of what we were talking about.

So for example, blood pressure drops. So blood pressure drops are what cause the cells in the juxtaglomerular complex to release renin. So it's this whole pathway that ends up with a production of the enzyme renin. Then the angiotensinogen, which is constantly being produced by the liver, is converted into angiotensin 1. Angiotensin 1 interacts with ACE, that angiotensin converting enzyme that's found within capillaries, especially within capillaries in the lungs. And then it's angiotensin 2, which is the main worker here, because this causes arterioles to constrict.

It causes the heart to increase the force of its contractions and its brate. It releases ADH as well as stimulating thirst. And can cause the release of aldosterone which increases sodium absorption in the proximal tubule.

So all of that work together to get that blood pressure up. Now, despite being regulated together, osmolarity and blood volume can change independently, right? So in the last slide, go back real quick, we see that part of the body's response is just to keep the amount of water coming in and the amount of sodium and other electrolytes coming in about the same to maintain blood volume and osmolarity.

So things like aldosterone do both of those things. But that being said, they can, you know, especially due to external circumstances. change independently of each other. So, dehydration, for example, is literally the state of losing water but not ions.

And this causes a decrease in blood pressure as well as an increase in osmolarity. So the body responds to dehydration with angiotensin II and ADH release as well as stimulating the thirst drive. So your body has enough ions, but you just need more water.

Now other endocrine problems can also disrupt fluid balance. Things like low ADH, like in diabetes insipidus, causes a loss of water through the excretion that needs to be constantly replaced. There are also syndromes that cause high levels of ADH release so that the body has a hard time getting rid of extra water, so that you need to be careful about what comes in, otherwise it can throw off the osmolarity of the body and then there's lots of swelling. So You can see here in the different, if you change volume or osmolarity without changing the other one, these can occur under different circumstances.

So, for example, if you drink a lot of water, that's pure water with nothing in it, you can increase your blood volume, which will decrease your osmolarity, which causes problems as your body will then try to urinate all that extra water. On the other hand, you can increase the osmolarity and decrease volume by becoming dehydrated. There's other things.

If you want to increase the osmolarity without changing the volume, you could eat a lot of salt without drinking water. If you ingest what they call hypertonic saline, you can increase the osmolarity and the volume at the same time. But that is often causing a problem as well, because if it is hypertonic, you're taking in more sodium than you are taking in water, which makes that osmolarity even worse. So that's why you can't drink seawater and become hydrated.

So that's it for chapter 20. We're skipping over the behavioral mechanisms, potassium balance, and acid-base balance is that portion that we talked about in Physiolab. All right, so that is it for this week's chapters. So for next week, remember to kind of look through all of this stuff.

I know that we had to move up the physiology lecture final to next week, so if you have any questions, please email me. I will try to get back to everyone on Monday. If you have any questions about any of the chapters, or specifically this section, please come to my office hours. They are 12.30 to 1.30 on Tuesdays.

If you come in, I will answer any questions you have there. It's just quicker face-to-face because we can take care of it, like any confusion, without having to go back and forth really slowly. But if you do have any questions at all, please email me.

That's matthewj.success.edu or through the Moodle. So just please message me and I will try to get back to you because I know that this is the final everybody's worried about. So I want to help you guys out any way I can. Additionally, if you guys have not seen it yet, the study guide for the physiology lecture final is up.

For the other three finals, I am working on those and I will add those. when the finals for those classes are finished. But I just wanted to make sure that you got this one in time because it got moved up to next Friday. So that is it.

Remember to do the Pearson homework. That is your last homework for this class. It does have some questions on all of this material that will hopefully help you out. There is a practice quiz for last week's material that should be up on the Moodle that you guys can take.

That will help you with the last week's material going over the digestive system physiology. But I do not have one for this. So again, if you have any questions, please ask me.

You can review the homework. There's questions at the end of every chapter that cover these things in the book itself, as well as study guides up on the Pearson page. All right.

So that is it. I wish you very good luck with your studies. And I will see everybody next week.

Take care.

Transcript for:Kidney Functions and Regulation Overview

Transcript for:
Kidney Functions and Regulation Overview