Greetings, so today we're going to continue our talk about the kidney, We want to talk about the kidney in more detail. In particular, we will discuss the process of filtration, that is, the generation of the filtrate, or the beginning product of urine. We have several things that we need to deal with. The first of the learning objectives is to explain renal clearance and to relate it to what's called the glomerular filtration rate. Recall that the glomerulus is the first capillary bed. We filter materials out of that first capillary bed. The second objective is we to talk about the glomerular filtration rate. How that rate is regulated. Thirdly, we want define autoregulation and the two mechanisms that are involved in autoregulation within the kidney. Fourth, we will explain how the renal blood flow and the glomerular filtration rate are regulated. And five, we will define filtration load of a freely filtered substance. So we have a lot of things to discuss. And so let's get started. As you recall, this is our diagram of the nephron, showing both the vascular portion of the nephron and the renal tubule. The afferent arteriole feeds into the glomerulus, our first capillary bed. Blood is then drained into the efferent arteriole. Blood then leaves the efferent arteriole and enters into a second capillary. Within the cortex, this capillary is called peritubular capillary. This particular capillary runs all the way along the tubule. In the case of the juxtamedullary nephrons, this capillary changes its name to vesa recta. We'll talk about that when we deal with the function of the vasa recta in a later lecture. The functions of these secondary capillary beds are the same, whether it's called peritubular capillary, or vasa recta. The other thing that's shown here is the blind ended renal tubule, where we have Bowman's capsule surrounding or making a cap around the glomerulus. Bowman's Capsule is continuous with the renal tubule itself. As we said in the beginning lecture, we will have a filtration event which will allow fluid and ions to move across this barrier, between the first capillary epithelial cell and the basal lamina. The basal lamina then of the second structure, Bowman's Capsule. It then flows between those epithelial cells themselves and eventually the filtered material enters into the renal tubule. That process is filtration. And as the filtrate moves along the tubule, either reabsorption or secretion, may occur. Eeventually we end up with urine. What is of interest is to know how well the kidney is working. One of the ways to measure this is to measure glomerular filtration rate. If you have a freely filtered substance which is neither reabsorbed nor secreted, then the filtration rate of that substance is going to be equal to the excretion rate. That is, how quickly that substance ends up in the urine. We can measure the filtration rate by taking a timed blood sample. We measure the excretion rate obviously by taking a timed urine sample. We can measure the filtration rate by using a substance Which is not reabsorbed nor secreted, but is freely filtered. This is called clearance, this is the removal of a substance from plasma. One of the substances that's ideal for this type of measurement is called inulin. This is inulin. It's not insulin, but inulin. Inulin is a large of polysaccharide, the polymer of fructose. Inulin is freely filtered. It enters into the tubule, but it's not reabsorbed, and it's not secreted, so that it's excretion rate equals the filtration rate. By using inulin, then we can measure GFR or the Glomerular Filtration Rate. Then if you want to know how quickly some other substance is removed from the body, you can measure its concentration within the plasma. And you can measure it's concentration within urine. You take timed urine and blood samples. By using these three parameters, we can calculate the clearance or the removal of substance from plasma. When we do so, we can calculate its clearance rate. We can then compare it to inulin. And if it's equal to inulin, then we know it was neither reabsorbed nor secreted. But if it's less than inulin, then that implies it has a net reabsorption of the substance, and if it's greater than inulin, then we have a net secretion of the substance. So what actually governs the filtration to begin with? We have two parameters that we have to be thinking about. One is the actual structure of the filtration barrier itself. As I said that's the cells which are lining the epithelium of the glomerulus. These are actually very leaky capillaries, fenestrated capillaries, but that their basal lamina forms a filtration barrier. On the other side there is a fairly leaky epithelium. The cells are called the podocytes. They line the interior of Bowman's Capsule. Between the two layers of epithelium, we have basal lamina. This basal lamina forms a filtration barrier. It repels charged molecules. It also blocks molecules based on size, so that large molecules do not across this barrier effectively. Cells do not get across this barrier. All of the blood cells stay within the blood, that is within the plasma, the fluid phase of the blood. All large molecules such as albumin,and other large proteins stay within the blood. But water and ions do flow across this filtration barrier. Depending upon the size of the solute and its charge, then they can move across the filtration barrier with more or less ease. The second thing that we have to consider are the actual forces that move materials across this barrier. This involves Starling's forces, which we've already talked about in the cardiovascular system. And as you all know, across all capillary beds we have pressure gradients. If the hydrostatic pressure is greater than the oncotic pressure, then fluid leaves the capillary and enters into the intrastitium. The same thing is occurring here. The same forces. The hydrostatic forces of the glomerulus minus the oncotic force of the blood that's within the glomerulus holding the water or moving the water back into the capillary space are the two forces that we have to deal with. In addition to those two forces, in this particular structure we also have to consider the hydrostatic pressure that's within the renal tubule. That's because the renal tubule, is unlike the interstitial fluid found in the interstitium in other parts of the body. The renal tubule is filled with fluid. So there is a pressure within the renal tubule. This is the hydrostatic pressure of the tubule. It will oppose filtration. The filtration pressure, then, is going to be equal to the hydrostatic pressure coming into the glomerulus minus the oncotic pressure, the attraction of water back into the blood, minus the hydrostatic pressure of the fluid, which is sitting within Bowman's capsule. We have to be aware then of the two properties. One is the permeability of the barrier itself to a particular solute. And secondly, the net filtration pressure, which is allowing the material to move across this barrier. Within this particular glomerulus in a normal kidney, there's always filtration and there is not reabsorption. Reabsorption instead occurs along the peritubular capillary, where these Starling forces are different favoring movement of water back into blood. We'll talk about that in the next lecture. But for us right now, we want to remember then that the net filtration pressure is always in a normal kidney promoting filtration Always we generate filtrate within this particular region of the tubule. Now recall that in this region of the tubule there is afferent arteriole coming to a capillary bed and an efferent arteriole, draining that particular capillary bed. THis is unlike any other region in the body. We all know that the arterioles are regulators. If we can change the resistance within the arterioles, we can control the pressure, which is both downstream of the arteriole and upstream of the arteriole. So that the pressure gradients within this system can be altered locally by changing the resistantance within these arterioles, both afferent arteriole and the efferent arteriole. What are we talking about? So let's remember, when we were talking about a normal situation we had an afferent arteriole coming into a capillary. From that afferent arteriole as the blood enters, we will have a net filtration into the Bowman's capsule. BUt not all of the blood is filtered. That there will be some of the blood plasma which will bypass this particular region and move into the peritubular capillary. THat is we are not removing all of the plasma at this point. For each pass though, only a subset of plasma is removed. We're not taking all of the plasma. Otherwise, it would be like sludge and you'd never be able to get the red blood cells through the capillary bed and into the peritubular capillary. Typically, the viscosity does rise, but we don't want that viscosity to rise that much so that there is flow within the peritubular capillary. Now, if we want to increase the amount of filtration that is going to occur across this glomerulus, we can dilate the afferent arteriole. By dilating the afferent arteriole, pressure rises within the capillary. As pressure rises in the capillary, then we have a greater flow and therefore an increase in GFR. We can do the opposite. That is increase resistance within that efferent arteriole by simply constricting or decreasing the radius within the afferent arteriole. And by doing that, by contracting the smooth muscles of the afferent arteriole, the radius dereases and flow decreases from that afferent arteriole. As resistance rises and we now will have a decrease in our GFR. So the glomerulus filtration then will decrease, as we increase resistance within the afferent arterioles. The afferent arterioles are really critical then for regulating the amount of filtration that's actually going to occur within across any given glomerulus and into the Bowman's capsule Each one of the nephrons is able to regulate this particular site. In addition to regulating the afferent arteriole, the efferent arterioles can also be regulated. It can be regulated independent of the afferent arteriole. So what do I mean by that? That is, if you increase the sympathetic nervous system, then we can get an increase in vasoconstriction. The alpha adrenergic receptors that are present on the smooth muscle of the afferent arterioles will constrict and that will increase resistance within the vessel. When we increase resistance, then we will decrease flow within the nephron glomerulus. We have hormones that can also affect the smooth muscle of both the afferent and the efferent arteriole. One of these hormones is a vasoconstrictor called antidiuretic hormone or vasopressin. It works predominantly on the efferent arteriole but it acts on both the efferent and the afferent arterioles. So what will happen when both of arterioles have an increase in resistance? The increase in resistance of the efferent arteriole actually counterbalances the loss of pressure (flow) coming from the increased resistance in the afferent. There is some compensation to some extent but the total filtration pressure within the glomerulus falls. It's a complicated system and so why is it that the body needs to regulate this? Why is the body worrying about doing this? If you think about it, the kidney is simply filtering the blood at all times. So we have 180 liters being filtered per day and as you start doing different exercises or doing different jobs, blood perfusion moves from area to another. That is, the blood delivery goes from one dominant site to another. So for instance, if we start running a marathon, then the muscles in our legs are demanding more blood flow. And as they're demanding more blood flow, then blood is being moved into those skeletal muscles and away from other areas of the body such as the GI tract. But you want the kidney to be working fairly independently of these needs. The kidneys do work independent of most changes in mean arterial pressure. The way the kidney works independently of mean arterial pressure is that it change the resistance within the renal artery and it can change the resistance within its arterioles. Of particular interest, is to change the resistance within the arterioles, which feed the filtration units. This is called autoregulation. The kidney is effectively running independent of mean arterial pressure. It does so between 80 and 180 millimeters of mercury. So as long as the entire body is running with a mean arterial pressure between 80 and 180 millimeters of mercury, the kidney adjusts locally whatever blood pressure that it is getting. This is simply our equation. Remember, flow equals delta P over R. If pressure increases, then an increase resistance returns the flow to its former value. The flow is kept constant within the system. That's effectively what the kidney is doing. This is called autoregulation. Autoregulation is mediated by two major mechanisms. The first is a myogenic mechanism, which you all know. If we deliver more blood to the arterioles, we will stretch the walls. As we stretch the smooth muscles of the walls, then that will open stretch activated channels and allow calcium to enter into those cells and then the smooth muscle cells will contract. We get a contraction of the smooth muscle to bring the vessel back to its original diameter or importantly, the vessel radius. So if we can change resistance as pressure changes, then the flow is kept constant through the system. That's a very local kind of a control. But the kidney also has a second type of control, that's called a tubulo-glomerular feedback. This involves the tubule itself. The tubule self regulates. It sends a signal back to the originating glomerulus to controls the flow through the originating glomerulus. That's what's shown here. Okay, so let's look at our diagram. At the beginning, we have our afferent arteriole, which is feeding blood into the glomerulus, and then coming from that, we have the efferent arteriole that will feed blood into the second capillary. Then within the renal tubule itself, there is a flow of filtrate. As the filtrate is flowing through the renal tubule, the flow of the filtrate is sensed by a set of cells, called the Macula Densa. The Macula Densa sense not only the flow rate of the filtrate through the system, but that it also can sense the amount of sodium in the filtrate as it moves through the system. If the Macula Densa, senses that there is a low flow of filtrate through the tubule. It will then set off a paracrine type of signaling back to the juxtaglomerular cells, which are the smooth muscle cells of the afferent arteriole. These cells are so important they have their own name. They're called juxtaglomerular cells. These cells are sitting right next to the glomerulus. They are the smooth muscle cells of the afferent arteriole. These smooth muscle cells are told to dilate, to relax. The smooth muscle relaxes. The lumen of the afferent arteriole dilates and more fluid flows into the glomerulus. By raising the pressures within the glomerulus, the filtrate pressure increases. More filtrate is generated and thereby more filtrate is delivered to the Macula Densa. That's local control of the flow through the system. Conversely, if there is too high of a flow within the system, then the Macula Densa can also sense this and correct for the flow within the tubules. Now what's interesting about this system is that those juxtaglomerular cells happen also to be endocrine cells. When the Macula Densa senses that there's a low flow rate or a low filtrate within the tubule, it interprets that signal as a low blood pressure i.e., low mean arterial pressure within the systemic circulation that is within the entire body. So, not only do the Macula Densa cells cause the juxtaglomerular cells, the smooth muscle cells, to change, to relax, and thereby dilate the lumen of the afferent arteriole. At the same time those juxtaglomerular cells will secrete the hormone renin. Renin is an enzyme which can activate an entire cascade of factors. Two of which are potent vasoconstrictors. So systemically then, the concentration of two potent vasoconstrictors rises within the cardiovascular system. They will cause an increase in resistance within the systemic circulation, and therefore correct for the perceived low mean arterial pressure which the kidney had interpreted by having a low filtrate flow through the system. We'll talk some more about this regulation, this feedback loop, where the kidney is an important regulator of blood pressure. There are instances where the mean arterial pressure may be outside of that boundary of 80 to 180 millimeters of mercury. One instance, of course, is if you start to exercise. Intense aerobic exercise can drive up the mean arterial pressure to be greater than 180 millimeters of mercury. In this intense exercise, the sympathetic nervous system discharge increases. The sympathetic nervous system then will increase resistance throughout the entire vasculature. By doing that, it will increase the vascular resistance not only within the other portions of the body, but also in the renal artery and thereby affect GFR. Under these conditions, the amount blood being delivered to the kidney decreases. In turn there will be a change in the amount of blood that's be filtered by the kidney. GFR will decrease. In the second instance, we can have a hemorrhage. Let's say you're in a car accident and you cut your leg. You are losing a lot of blood volume. Perhaps you lose a liter to two liters of blood volume. Under these conditions then, the pressures within the body will fall, and baroreceptor firing will decrease. When the firing of the baroreceptors decreases then the sympathetic nervous system discharge increases Again, this will lead to a decrease in glomerular filtration rate. , Instead of having blood going to the kidney, blood is moved towards the heart and the brain. The body has decided that it needs to take whatever is left within the circulatory systems and move it to the two critical organs within the body under these conditions. There's one other concept that we need to talk about. That is called the filtration load. The filtration load is simply that the plasma concentration of a substance times the glomerular filtration rate. In a normal kidney, the glomerular filtration rate is 180 liters per day or 150 milliliters per minute. So it's 150 milliliters per minute [LAUGH]. Sorry, cancel all that. It's 120 milliliters per minute or 180 liters per day. So what are we talking about? An example is as follows. We have glucose in our plasma. The amount of glucose is 100 milligrams of glucose in 100 milliliters of blood. If we multiplied by the glumerial filtration rate or GFR which is 125 millilters per minute, then that we would have 120 milligrams per minute of glucose which is being filtered and entering into the filtrate of the kidney. The interesting thing about glucose is that, although we will filter 125 mg per minute, glucose is normally completely reabsorbed in the proximal convoluted tubule. You'll have zero glucose being excreted from the kidney. Okay, so what are our key concepts then? So the first is this idea of renal clearance, this is the removal of the substance from the blood. If the substance is freely filtered and not reabsorbed and not secreted, then it's clearance is equal to GFR. Inulin is such a substance. Often times the renal physicians, nephrologists, will not use inulin perse to measure GFR, but they use creatinine, which is generated from the metabolism of muscle. In these instances, it gives them an estimate of GFR, because the creatinine is slightly secreted. It's freely filtered by the renal tubule, and it is slightly secreted, so it gives a slightly larger estimate of GFR. The second concept is that the GFR is determined by pressure differences between the glomerulus and Bowman's capsule. These are Starling's forces, the hydrostatic pressure of the capillary minus the oncotic pressure of the blood itself minus, then, the hydrostatic pressure of Bowman's capsule. That is opposing filtration. Third, the GFR, that is the glymerial filtration rate, can be regulated independent of mean arterial pressure between 80 and 100 millimeters of mercury by changing the resistance of the renal arterioles. Local regulation the arteriole, which feeds into the glomerulus of each nephron is called autoregulation. Autoregulation includes the myogenic response, which involves stretch-activated channels that respond to the the transmural pressures within the walls of these arterioles We can get either dilation or constriction in response to changes in pressure in the region to maintain flow constant. Flow equals delta P / R. In addition, autoregulation uses the tubuloglomerular feedback. This response involves the macula densa and the glumerular cells, the JG cells, which are the smooth muscle of the afferent arteriole. These two components are referred to as the juxtaglomerular apparatus. And this can be either a positive or a negative feedback. This particular feedback can cause dilation in tthe afferent arteriole to increases pressure (flow) within the tubule, but it can also cause constriction to decrease pressure within a tubule. GFR can also be regulated by neural inputs and by endocrine hormones. These reflex loops can feedback and again regulate the smooth muscle of the afferent and efferent arterioles. Lastly the filtration load of a freely filtered substance is its plasma concentration times GFR. Okay, so the next time that we meet, then we're going to discuss the other functions of the renal tubules in more detail. So, I'll see you then.
