Understanding Renal Pathophysiology Basics

Hi there, and welcome to the first of a series of videos on renal pathophysiology. If you haven't guessed it by now, my name is Dr. Bill Deal-Jones. I'm a professor in the Faculty of Health Disciplines at Athabasca University. We'll, of course, be discussing diseases affecting the renal system, and we'll start with a brief overview of kidney basics. And by that I mean kidney anatomy and basic physiology. Because I think this will form an underpinning for the subsequent topics that we'll talk about, which include UTIs, glomerular diseases, renal failure, and renal colic. So we'll begin with a brief description of the kidney. It is one of the retroperitoneal organs in the abdominal cavity, and that is to say it's basically held against the dorsal wall of the abdominal cavity by peritoneum. And this is remarked upon because other organs, most other organs in the abdominal cavity, are actually suspended by mesentery, which is a double fold of peritoneum, which helps afford some protection against trauma. So the kidney, in many ways, is more susceptible to trauma than a lot of other organs. However, it does have an outer connective tissue capsule. which is fairly tough. It's called a glissis capsule. And it owes its classic kidney bean shape to the fact that there is an indentation or area called the renal hilum. And hilum is a fairly generic term which means just that, indentation, through which major vessels come in or out. So vessels leaving the hilum include the renal pelvis and ureter, as well as the renal vein. And of course entering the hilum is the renal artery. And I don't think it's so important to memorize all the different branches of the renal arteries and veins. Rather, what I like to do is focus on some of the growth structure. Similar to many organs, the kidney is divided into an outer cortex and an inner medulla. And I'll draw a little line here, which basically delineates the boundary between cortex and medulla. And in the cortex we find... the bulk of the main functional unit of the kidney, which is the nephron. And I'll go through the different parts of the nephron, but I'll also say that the main filtration unit, the glomerulus and Bowman's capsule, together called the renal corpuscle, is exclusively located in the cortex of the kidney. Other parts of the nephron do... Dive down into the medulla, and these include the lube of Henle and the collecting duct, which, again, I'll highlight for you. I'd mentioned that the nephron is the main functional unit of the kidney, and in this very simplistic diagram of nephron, what I'd like to do is highlight the main functions. The first function we'll speak about is filtration, and filtration is really effected by or... facilitated by mean arterial pressure. And by filtration, I'm referring to the movement between vascular component of the nephron, which is the glomerulus, shown here, and Bowman's capsule. So the greater the mean arterial pressure, or the pressure in the pipes, as it were, the greater the filtration between the Bowman's capsule. and the glomerulus. Now, it's a fairly selective form of filtration, and that selective filtration is by virtue of the fact that we have a very specialized basement membrane, which I'm drawing in green here, which affords some selectivity. So this is the basement membrane, and you'll hear me talk about the glomerular basement membrane or basement membrane diseases a little further on. And this basement membrane has got a negative charge and has got some specialized structure to it, such that only smaller molecules, such as amino acids, glucose, and ions, and water can pass through into Bowman's capsule, but cells, such as red blood cells, and larger proteins, including albumin and immunoglobulins, cannot. be filtered into the nephron, at least not under normal circumstances. Other functions include reabsorption, and by reabsorption we're referring to the movement of solvent and water out of the lumen of the tubule, and I'll draw a little L here for lumen, which designates the inside of the tubule, back into the blood vascular space. And secretion is really the reverse, where we move, by various means, molecules from the... perinephric vascular network into the lumen of the nephron. So let's take a little more detailed look at a nephron. And I'm going to draw one that's a bit more realistic. First of all, this is Bowman's capsule, proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct. So let's label those Bowman's capsule. proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct. I'd also like to elaborate a little bit on the vascular network around the nephron. So we have an afferent arteriole, which enters Bowman's capsule, winds around as the glomerulus, and then leaves as the efferent arteriole. And part of the efferent arteriole goes on to form what's called a peritubular capillary network. So it's basically a capillary network that winds all around the nephron, or at least the tubular portion of the nephron. And that's pretty important because that enables the nephron to both reabsorb and secrete materials between the blood vascular spaces. Alright, so I've already mentioned that the Bowman's capsule is the location where we have filtration occurring, and that filtration is driven by mean arterial pressure. We can regulate the amount of pressure in the glomerulus by means of specialized sphincters in both the afferent arterial, and I'll just write that as AA, afferent arterial, and the... Ephraim arterial, EA. So we have sphincters which can either increase or decrease the flow of blood into the capillary, that is the glomerulus. And incidentally, the glomerulus, as well as the Bowman's capsule, is referred to as the renal corpuscle in some texts. Now, there are a variety of different functions ascribed to different parts of the nephron. For example, in the proximal convoluted tubule, it's really specialized for a lot of absorptive active transport. And so we have being reabsorbed ions, which were initially filtered, glucose, of course, amino acids, and a variety of other metabolites. The loop of Henle is a very specialized structure, and the loop of Henle has got... both a descending limb, one that goes into the medulla, and an ascending limb, which goes up out of the medulla. And the two different limbs have quite different properties. So, for example, the ascending limb here is the site of a lot of active transport. And what's transported out of that? Well, primarily ions, and these ions include sodium. potassium, and chloride. And the transport is such that we actually build up a very salty region around the base of the loop of Henle and the collecting duct. So I'm going to draw a bunch of little dots here, which is my way of indicating that it's a very salty zone out here. And that's actually pretty important. Now, the... The descending limb is quite different. It doesn't actively transport, but what it does facilitate is the movement through osmosis of water. And that's also true of the collecting duck, which is really specialized for the movement of water. And by means which I'll explain in a little bit, we have what's called a countercurrent mechanism, which allows us at the end of the day to make a very concentrated urine. The distal convoluted tubule is also specialized for some ion transport, primarily sodium. And so let's follow what happens to filtrate after it first enters the... front end, as it were, of the nephron. So initially, after filtration, we have filtrate in the start of the proximal convolutubule, which is around 300 milliosmolar. That's essentially the same as the osmolarity of blood. However, by the time we get to the bottom of the loop of Henle, we progressively... increase the osmolarity so that we've got a filtrate osmolarity of around 1200 milliosmolar. And why that happens is essentially, of course, because we're losing water into the salty interstitium, or region around the tubules. Now as we go back up the ascending limb, of course we're pumping ions out. We pump ions out so much that we end up with... an osmolarity which is actually quite low. We end up with about a 100 milliosmolar filtrate by the time we get to the distal convoluted tubule. However, at the end of the day, final urine filtrate is around 1,200 milliosmolar. So how it gets that way really has to do with this countercurrent exchange mechanism. And the countercurrent exchanger is really... Well, the countercurrent is the movement of filtrate down the descending limb and up the ascending limb, and again, ultimately, down through the collecting duct. And because we've got strategically positioned ion transporters, we make the interior very salty. That is, the lower part of the nephron is very salty in the interstitial region, so that's going to... favor the movement of water out of the tubular portion of the nephron into the interstitial space, and from there it can be picked up by the capillaries. So after that brief description, let's redraw our nephron and simplify it a little bit and use it to illustrate where specific hormones affect renal function, as well as where certain diuretics may have an effect. So first of all, two hormones you should know about are aldosterone and antidiuretic hormone, or ADH. ADH, incidentally, has also been called vasopressin in older textbooks. And what aldosterone does is increase sodium reabsorption. And it does so primarily at the distal convoluted tubule and along portions of the collecting duct. Antidiuretic hormone really favors the reabsorption of water. And primarily this happens along the bottom of the collecting duct. And I'll explain a little bit more about how those hormones work in a couple of minutes. What's also, I think, useful here to talk about are some of the diuretics that we may use. And there are four categories of diuretics. There are the so-called carbonic anhydrase, or CA inhibitors, which affect the reabsorption of sodium bicarb. along the proximal convoluted tubule. Of course, another class called the loop diuretics. Of course, the one that all of you know about as a loop diuretic is Lasix or furosemide. And what that does is it targets active transport, particularly out of the ascending limb of the loop of Henle. So-called thiazides. which affect the proximal convoluted tubule primarily. And then we have the potassium sparing diuretics, which primarily affect... the collecting duct. Of course one example you're probably familiar with is a potassium sparing diuretic is spironolactone. So let's talk a little bit more about tubular reabsorption. Tubular reabsorption can be affected by diuretics and can be affected by hormones, as we've just seen. Let's talk a little bit about the actual mechanism. And what I've tried to do is depict a portion, a tubular portion of the nephron to the left here. And the very center of that would be the lumen. And in blue, I've shown an epithelial cell oriented in the same direction. So on the left would be the lumen. Right side would be the interstitial space. And that's the space that's going to be next to the peritubular capillaries. So there are capillaries out here. Now, there are various mechanisms for tubular reabsorption, but what's important to note is that a lot of them are tied to the movement of sodium. And on the interstitial side here, we've got lots and lots of sodium, potassium, ATPases. What they do is they kick out sodium. and bring in potassium, such that we end up with a low sodium concentration gradient inside the cell. What that does is sets up a favorable gradient for the movement of sodium in. And we've got a variety of mechanisms for sodium to move into the cell, including so-called symporters. And an example of a symporter shown here, it's a sodium glucose symport. But we've also got sodium amino acid supporters, in which the movement of glucose or amino acids is tied to the movement of sodium into the cell. And this is really a passive facilitated process. Similarly, we've got antiports. And an antiport is one that moves materials in opposite directions. And an example is the sodium proton antiport. And the sodium proton antiport is useful for... getting rid of hydrogen ions and allowing them to be eliminated. And particularly along parts of the ascending loop of Henle, we've got these potassium chloride and sodium co-transporters. So a lot of transport across a lot of reabsorption across the nephron is tied to sodium. As well, tubular reabsorption is very important with respect to pH balance in the body. And again, I've drawn a little nephron at the upper tubular portion, nephron at the upper left here. And what's important to know is that bicarb and protons are filtered, of course, easily through Bowman's capsule. And one of the things that we'd like to do is we need to conserve... bicarb, because bicarb is a very, very important biological buffer. So how we do that is as follows. So protons and bicarb can reassociate to form carbonic acid, and we can conserve the carbons and oxygens in that carbon dioxide and reuse them by means of carbonic anhydrase. And the way that works is carbonic anhydrase splits carbonic acid into water and carbon dioxide. So there we have the carbons and oxygens again. They come into the cell because they can diffuse easily. And then we reform the carbonic acid by means of intracellular carbonic anhydrase. So carbonic anhydrase results in, again, carbonic acid. This time it's inside the cell. And there, again, the acid dissociates into bicarbon protons. And we've got mechanisms for moving bicarb out of... the cell and back into the interstitial space, also called the peritubular space. And in that peritubular space, again, we've got blood vessels, which can pick up the bicarb where it can be used to buffer. Now, if you're looking at this, you'll say, well, wait a minute, but we're also pumping hydrogen ions back in. Well, to an extent we are, but don't forget we've got other antiporters on the other side here. which can help us kick out protons in exchange for sodium, just as we saw in the last slide. So ultimately, we'll excrete some of those hydrogen ions, but we'll be able to conserve the bicarb. And this is important because bicarb is a very important biological buffer. So if you're looking for a way to summarize this, do so by realizing that we also reabsorb bicarb. And a lot of this happens along the proximal convoluted tubule. Hence, carbonic anhydrase inhibitors can affect this whole process. So we just had an example, a little bit more detailed look at tubular reabsorption and secretion. Now let's turn our attention to the way some of these hormones affect renal function. And we'll start with antidiuretic hormone, or ADH. Essentially what happens is this. There are specialized cells in the hypothalamus, which I'll designate with an H, which detect osmolarity, or they're osmoreceptors. Those osmoreceptors, when they experience an increased osmolarity, such as might happen if somebody's lost a lot of water, And that will trigger the release from nerve terminals in the posterior pituitary, here, of antidiuretic hormone. Now what antidiuretic hormone does is it binds to its receptor, works through some intermediates, and results in an increase in cyclic AMP. Why is that important? Well, cyclic AMP, in turn, causes the insertion into the cell membrane of water channels, shown here in green. Fancy name for those water channels is aquaporins. So ADH results in the insertion of aquaporins, and what does this do? It facilitates the reabsorption of water. The other hormone I mentioned is aldosterone. And any time you see an O-N-E, that's really your sign that it's likely a steroid, which in this case is true. I'm going to give you the punchline first of the story. Aldosterone is a steroid which crosses into the nucleus and results in the upregulation of both sodium channels, which is going to let sodium flow in, as well as parts of the sodium potassium, ATPase. So the net result is the reabsorption of sodium. Now I'm going to give you a very simple rule about the reabsorption of sodium, and that is... water follows sodium. So indirectly, aldosterone also favors the reabsorption of water, which of course will increase blood pressure. Now, let's go back to the start of the story. As part of the nephron, there's a cluster of cells which constitute the juxtaglomerular apparatus. And what the juxtaglomerular apparatus does is it detects changes in osmolarity and in sodium levels. And when it sees, for example, an increase in osmolarity, such as would be the case if we were losing fluid volume, then renin is released. What renin does is it encounters in the bloodstream a protein called angiotensinogen, which is made by the liver. And any time you see O-G-E-N at the end of a word, it's going to indicate it's a precursor of some sort. And renin cleaves angiotensinogen into angiotensin I. Now angiotensin I isn't terribly biologically active, but angiotensin II is. And angiotensin I is converted into II by means of this enzyme called angiotensin-converting enzyme. Now angiotensin II is a very potent molecule. It can affect... blood pressure in a couple of ways. It will, for example, cause vasoconstriction. As well, angiotensin 2 binds the cells in the adrenal cortex, which in turn, you guessed it, releases aldosterone. Now this is a nice point here to tie in a couple of blood pressure meds. So you've heard of drugs with the suffix pril. And anytime you see a prill, it's probably an ACE inhibitor. So examples include enalapril, captopril, and so on. What they do is they target ACE. And if they inhibit ACE, then you don't make as much angiotensin II. If you don't make as much angiotensin II, you have less vasoconstriction and less aldosterone. As well, we've got another class of drugs, which I'll just briefly mention, called the ARBs, angiotensin receptor blockers. So, angiotensin... causes its effects through vasoconstriction and through its influence on aldosterone. So these angiotensin receptor blockers block those receptors. So hence, the PRILs and the ARBs are both pretty good antihypertensives. So we've talked a little bit about the anatomy and physiology of the kidney. Of course... As clinicians, we like to know how well the kidney is performing, and there are a couple of things particularly we want to know. For example, renal clearance, which is really all about how much of a given substance is removed from blood over a given time. We have a couple of ways of measuring that. We can measure it with exogenous markers, or ones we have to inject, such as inulin and peraminoheperic acid, or PAH. But you don't really even have to think about those. The one that you do have to think about is creatinine, which is a nice endogenous marker. And what makes it so nice is the fact that, well, it's certainly filtered at Bowman's capsule, but it's only weakly reabsorbed. So what we're looking at in urine is going to be really primarily the effects of filtration. And that can be used to give us estimates of glomerular filtration rate, which is really our... best marker for how well renal tissue is functioning. And again, creatinine is really the best marker we have. It's a breakdown product from a muscle. It's a breakdown product of creatine. So creatine is, you probably have heard of creatine as a muscle building supplement. Creatinine is a breakdown product of creatine. We can use creatinine levels to give us, as I mentioned, an estimate of glomerular filtration rate. And one way of doing that is taking the urinary creatinine concentration, multiplying it by the volume of blood flow, and dividing that by the plasma creatinine concentration. And that will give us a pretty darn accurate estimate of GFR. Now, typically, we don't bother to do both a urinary and a plasma creatinine measurement. Typically, we can use one or the other, particularly urinary creatinines, to give us some sense of how well the kidneys are working. We can also use serum creatinine levels, and I'll show you how we do that in just a minute. So if we want to get an estimate of creatinine clearance and from there an estimate of GFR, we can use this formula in which... At the bottom, we are looking at serum creatinine levels. And this is a version of a formula named the Cockroft and Galt formula. And what it does is it takes into various parameters that can affect creatinine clearance, including age, weight, gender. And there are a few other estimates that are available, and there are lots of online calculators you can use to get this. But they're based primarily on... serum creatinine levels. Another marker that you'll probably hear about but won't likely use very much in primary care is FINA, or the fractional excretion of sodium. And really what it's telling us about is the amount of sodium excreted, or leaving the kidneys, compared to the amount that's both filtered and reabsorbed. Remember that sodium is indeed filtered and is also reabsorbed. So the filtration occurs at Bowman's capsule, The reabsorption occurs at various points along the tubule. So you see here the formula. Don't bother committing it to memory. Just understand that we use both serum and urinary creatinine and sodium levels. And when would you use it? Well, particularly if you're looking at somebody with acute renal failure and you're wondering whether or not low plasma volume or pre-renal failure is the cause. There are a variety of other indices we can use to look at renal function, including, of course, blood urea nitrogen, creatinine levels, and, of course, BUN to creatinine ratios, various electrolytes, including sodium, potassium, chloride. Also, calcium is a pretty useful divalent cation to look at with respect to kidney function and phosphates. We can estimate, as I've shown, GFR. We can look at creatinine clearance. We can also look at urine volumes, which typically are 800 to 2,000 mLs per 24-hour period. So with that, I'd like to include our introduction to renal pathophysiology, or essentially really what we're talking about is renal physiology, and I hope this will be useful in some of the subsequent videos on the topic. Thanks for listening.

We'll, of course, be discussing diseases affecting the renal system, and we'll start with a brief overview of kidney basics. And by that I mean kidney anatomy and basic physiology. Because I think this will form an underpinning for the subsequent topics that we'll talk about, which include UTIs, glomerular diseases, renal failure, and renal colic. So we'll begin with a brief description of the kidney.

It is one of the retroperitoneal organs in the abdominal cavity, and that is to say it's basically held against the dorsal wall of the abdominal cavity by peritoneum. And this is remarked upon because other organs, most other organs in the abdominal cavity, are actually suspended by mesentery, which is a double fold of peritoneum, which helps afford some protection against trauma. So the kidney, in many ways, is more susceptible to trauma than a lot of other organs.

However, it does have an outer connective tissue capsule. which is fairly tough. It's called a glissis capsule.

And it owes its classic kidney bean shape to the fact that there is an indentation or area called the renal hilum. And hilum is a fairly generic term which means just that, indentation, through which major vessels come in or out. So vessels leaving the hilum include the renal pelvis and ureter, as well as the renal vein.

And of course entering the hilum is the renal artery. And I don't think it's so important to memorize all the different branches of the renal arteries and veins. Rather, what I like to do is focus on some of the growth structure. Similar to many organs, the kidney is divided into an outer cortex and an inner medulla. And I'll draw a little line here, which basically delineates the boundary between cortex and medulla.

And in the cortex we find... the bulk of the main functional unit of the kidney, which is the nephron. And I'll go through the different parts of the nephron, but I'll also say that the main filtration unit, the glomerulus and Bowman's capsule, together called the renal corpuscle, is exclusively located in the cortex of the kidney.

Other parts of the nephron do... Dive down into the medulla, and these include the lube of Henle and the collecting duct, which, again, I'll highlight for you. I'd mentioned that the nephron is the main functional unit of the kidney, and in this very simplistic diagram of nephron, what I'd like to do is highlight the main functions. The first function we'll speak about is filtration, and filtration is really effected by or...

facilitated by mean arterial pressure. And by filtration, I'm referring to the movement between vascular component of the nephron, which is the glomerulus, shown here, and Bowman's capsule. So the greater the mean arterial pressure, or the pressure in the pipes, as it were, the greater the filtration between the Bowman's capsule. and the glomerulus.

Now, it's a fairly selective form of filtration, and that selective filtration is by virtue of the fact that we have a very specialized basement membrane, which I'm drawing in green here, which affords some selectivity. So this is the basement membrane, and you'll hear me talk about the glomerular basement membrane or basement membrane diseases a little further on. And this basement membrane has got a negative charge and has got some specialized structure to it, such that only smaller molecules, such as amino acids, glucose, and ions, and water can pass through into Bowman's capsule, but cells, such as red blood cells, and larger proteins, including albumin and immunoglobulins, cannot. be filtered into the nephron, at least not under normal circumstances.

Other functions include reabsorption, and by reabsorption we're referring to the movement of solvent and water out of the lumen of the tubule, and I'll draw a little L here for lumen, which designates the inside of the tubule, back into the blood vascular space. And secretion is really the reverse, where we move, by various means, molecules from the... perinephric vascular network into the lumen of the nephron.

So let's take a little more detailed look at a nephron. And I'm going to draw one that's a bit more realistic. First of all, this is Bowman's capsule, proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct. So let's label those Bowman's capsule.

proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct. I'd also like to elaborate a little bit on the vascular network around the nephron. So we have an afferent arteriole, which enters Bowman's capsule, winds around as the glomerulus, and then leaves as the efferent arteriole. And part of the efferent arteriole goes on to form what's called a peritubular capillary network. So it's basically a capillary network that winds all around the nephron, or at least the tubular portion of the nephron.

And that's pretty important because that enables the nephron to both reabsorb and secrete materials between the blood vascular spaces. Alright, so I've already mentioned that the Bowman's capsule is the location where we have filtration occurring, and that filtration is driven by mean arterial pressure. We can regulate the amount of pressure in the glomerulus by means of specialized sphincters in both the afferent arterial, and I'll just write that as AA, afferent arterial, and the...

Ephraim arterial, EA. So we have sphincters which can either increase or decrease the flow of blood into the capillary, that is the glomerulus. And incidentally, the glomerulus, as well as the Bowman's capsule, is referred to as the renal corpuscle in some texts.

Now, there are a variety of different functions ascribed to different parts of the nephron. For example, in the proximal convoluted tubule, it's really specialized for a lot of absorptive active transport. And so we have being reabsorbed ions, which were initially filtered, glucose, of course, amino acids, and a variety of other metabolites.

The loop of Henle is a very specialized structure, and the loop of Henle has got... both a descending limb, one that goes into the medulla, and an ascending limb, which goes up out of the medulla. And the two different limbs have quite different properties. So, for example, the ascending limb here is the site of a lot of active transport.

And what's transported out of that? Well, primarily ions, and these ions include sodium. potassium, and chloride. And the transport is such that we actually build up a very salty region around the base of the loop of Henle and the collecting duct. So I'm going to draw a bunch of little dots here, which is my way of indicating that it's a very salty zone out here.

And that's actually pretty important. Now, the... The descending limb is quite different.

It doesn't actively transport, but what it does facilitate is the movement through osmosis of water. And that's also true of the collecting duck, which is really specialized for the movement of water. And by means which I'll explain in a little bit, we have what's called a countercurrent mechanism, which allows us at the end of the day to make a very concentrated urine.

The distal convoluted tubule is also specialized for some ion transport, primarily sodium. And so let's follow what happens to filtrate after it first enters the... front end, as it were, of the nephron.

So initially, after filtration, we have filtrate in the start of the proximal convolutubule, which is around 300 milliosmolar. That's essentially the same as the osmolarity of blood. However, by the time we get to the bottom of the loop of Henle, we progressively...

increase the osmolarity so that we've got a filtrate osmolarity of around 1200 milliosmolar. And why that happens is essentially, of course, because we're losing water into the salty interstitium, or region around the tubules. Now as we go back up the ascending limb, of course we're pumping ions out.

We pump ions out so much that we end up with... an osmolarity which is actually quite low. We end up with about a 100 milliosmolar filtrate by the time we get to the distal convoluted tubule.

However, at the end of the day, final urine filtrate is around 1,200 milliosmolar. So how it gets that way really has to do with this countercurrent exchange mechanism. And the countercurrent exchanger is really... Well, the countercurrent is the movement of filtrate down the descending limb and up the ascending limb, and again, ultimately, down through the collecting duct.

And because we've got strategically positioned ion transporters, we make the interior very salty. That is, the lower part of the nephron is very salty in the interstitial region, so that's going to... favor the movement of water out of the tubular portion of the nephron into the interstitial space, and from there it can be picked up by the capillaries. So after that brief description, let's redraw our nephron and simplify it a little bit and use it to illustrate where specific hormones affect renal function, as well as where certain diuretics may have an effect.

So first of all, two hormones you should know about are aldosterone and antidiuretic hormone, or ADH. ADH, incidentally, has also been called vasopressin in older textbooks. And what aldosterone does is increase sodium reabsorption.

And it does so primarily at the distal convoluted tubule and along portions of the collecting duct. Antidiuretic hormone really favors the reabsorption of water. And primarily this happens along the bottom of the collecting duct. And I'll explain a little bit more about how those hormones work in a couple of minutes. What's also, I think, useful here to talk about are some of the diuretics that we may use.

And there are four categories of diuretics. There are the so-called carbonic anhydrase, or CA inhibitors, which affect the reabsorption of sodium bicarb. along the proximal convoluted tubule.

Of course, another class called the loop diuretics. Of course, the one that all of you know about as a loop diuretic is Lasix or furosemide. And what that does is it targets active transport, particularly out of the ascending limb of the loop of Henle.

So-called thiazides. which affect the proximal convoluted tubule primarily. And then we have the potassium sparing diuretics, which primarily affect...

the collecting duct. Of course one example you're probably familiar with is a potassium sparing diuretic is spironolactone. So let's talk a little bit more about tubular reabsorption. Tubular reabsorption can be affected by diuretics and can be affected by hormones, as we've just seen.

Let's talk a little bit about the actual mechanism. And what I've tried to do is depict a portion, a tubular portion of the nephron to the left here. And the very center of that would be the lumen. And in blue, I've shown an epithelial cell oriented in the same direction.

So on the left would be the lumen. Right side would be the interstitial space. And that's the space that's going to be next to the peritubular capillaries.

So there are capillaries out here. Now, there are various mechanisms for tubular reabsorption, but what's important to note is that a lot of them are tied to the movement of sodium. And on the interstitial side here, we've got lots and lots of sodium, potassium, ATPases.

What they do is they kick out sodium. and bring in potassium, such that we end up with a low sodium concentration gradient inside the cell. What that does is sets up a favorable gradient for the movement of sodium in. And we've got a variety of mechanisms for sodium to move into the cell, including so-called symporters.

And an example of a symporter shown here, it's a sodium glucose symport. But we've also got sodium amino acid supporters, in which the movement of glucose or amino acids is tied to the movement of sodium into the cell. And this is really a passive facilitated process. Similarly, we've got antiports.

And an antiport is one that moves materials in opposite directions. And an example is the sodium proton antiport. And the sodium proton antiport is useful for... getting rid of hydrogen ions and allowing them to be eliminated.

And particularly along parts of the ascending loop of Henle, we've got these potassium chloride and sodium co-transporters. So a lot of transport across a lot of reabsorption across the nephron is tied to sodium. As well, tubular reabsorption is very important with respect to pH balance in the body. And again, I've drawn a little nephron at the upper tubular portion, nephron at the upper left here. And what's important to know is that bicarb and protons are filtered, of course, easily through Bowman's capsule.

And one of the things that we'd like to do is we need to conserve... bicarb, because bicarb is a very, very important biological buffer. So how we do that is as follows. So protons and bicarb can reassociate to form carbonic acid, and we can conserve the carbons and oxygens in that carbon dioxide and reuse them by means of carbonic anhydrase. And the way that works is carbonic anhydrase splits carbonic acid into water and carbon dioxide.

So there we have the carbons and oxygens again. They come into the cell because they can diffuse easily. And then we reform the carbonic acid by means of intracellular carbonic anhydrase.

So carbonic anhydrase results in, again, carbonic acid. This time it's inside the cell. And there, again, the acid dissociates into bicarbon protons.

And we've got mechanisms for moving bicarb out of... the cell and back into the interstitial space, also called the peritubular space. And in that peritubular space, again, we've got blood vessels, which can pick up the bicarb where it can be used to buffer.

Now, if you're looking at this, you'll say, well, wait a minute, but we're also pumping hydrogen ions back in. Well, to an extent we are, but don't forget we've got other antiporters on the other side here. which can help us kick out protons in exchange for sodium, just as we saw in the last slide. So ultimately, we'll excrete some of those hydrogen ions, but we'll be able to conserve the bicarb. And this is important because bicarb is a very important biological buffer.

So if you're looking for a way to summarize this, do so by realizing that we also reabsorb bicarb. And a lot of this happens along the proximal convoluted tubule. Hence, carbonic anhydrase inhibitors can affect this whole process.

So we just had an example, a little bit more detailed look at tubular reabsorption and secretion. Now let's turn our attention to the way some of these hormones affect renal function. And we'll start with antidiuretic hormone, or ADH.

Essentially what happens is this. There are specialized cells in the hypothalamus, which I'll designate with an H, which detect osmolarity, or they're osmoreceptors. Those osmoreceptors, when they experience an increased osmolarity, such as might happen if somebody's lost a lot of water, And that will trigger the release from nerve terminals in the posterior pituitary, here, of antidiuretic hormone. Now what antidiuretic hormone does is it binds to its receptor, works through some intermediates, and results in an increase in cyclic AMP.

Why is that important? Well, cyclic AMP, in turn, causes the insertion into the cell membrane of water channels, shown here in green. Fancy name for those water channels is aquaporins. So ADH results in the insertion of aquaporins, and what does this do? It facilitates the reabsorption of water.

The other hormone I mentioned is aldosterone. And any time you see an O-N-E, that's really your sign that it's likely a steroid, which in this case is true. I'm going to give you the punchline first of the story.

Aldosterone is a steroid which crosses into the nucleus and results in the upregulation of both sodium channels, which is going to let sodium flow in, as well as parts of the sodium potassium, ATPase. So the net result is the reabsorption of sodium. Now I'm going to give you a very simple rule about the reabsorption of sodium, and that is... water follows sodium. So indirectly, aldosterone also favors the reabsorption of water, which of course will increase blood pressure.

Now, let's go back to the start of the story. As part of the nephron, there's a cluster of cells which constitute the juxtaglomerular apparatus. And what the juxtaglomerular apparatus does is it detects changes in osmolarity and in sodium levels. And when it sees, for example, an increase in osmolarity, such as would be the case if we were losing fluid volume, then renin is released. What renin does is it encounters in the bloodstream a protein called angiotensinogen, which is made by the liver.

And any time you see O-G-E-N at the end of a word, it's going to indicate it's a precursor of some sort. And renin cleaves angiotensinogen into angiotensin I. Now angiotensin I isn't terribly biologically active, but angiotensin II is. And angiotensin I is converted into II by means of this enzyme called angiotensin-converting enzyme.

Now angiotensin II is a very potent molecule. It can affect... blood pressure in a couple of ways. It will, for example, cause vasoconstriction. As well, angiotensin 2 binds the cells in the adrenal cortex, which in turn, you guessed it, releases aldosterone.

Now this is a nice point here to tie in a couple of blood pressure meds. So you've heard of drugs with the suffix pril. And anytime you see a prill, it's probably an ACE inhibitor.

So examples include enalapril, captopril, and so on. What they do is they target ACE. And if they inhibit ACE, then you don't make as much angiotensin II. If you don't make as much angiotensin II, you have less vasoconstriction and less aldosterone.

As well, we've got another class of drugs, which I'll just briefly mention, called the ARBs, angiotensin receptor blockers. So, angiotensin... causes its effects through vasoconstriction and through its influence on aldosterone. So these angiotensin receptor blockers block those receptors. So hence, the PRILs and the ARBs are both pretty good antihypertensives.

So we've talked a little bit about the anatomy and physiology of the kidney. Of course... As clinicians, we like to know how well the kidney is performing, and there are a couple of things particularly we want to know. For example, renal clearance, which is really all about how much of a given substance is removed from blood over a given time.

We have a couple of ways of measuring that. We can measure it with exogenous markers, or ones we have to inject, such as inulin and peraminoheperic acid, or PAH. But you don't really even have to think about those.

The one that you do have to think about is creatinine, which is a nice endogenous marker. And what makes it so nice is the fact that, well, it's certainly filtered at Bowman's capsule, but it's only weakly reabsorbed. So what we're looking at in urine is going to be really primarily the effects of filtration.

And that can be used to give us estimates of glomerular filtration rate, which is really our... best marker for how well renal tissue is functioning. And again, creatinine is really the best marker we have.

It's a breakdown product from a muscle. It's a breakdown product of creatine. So creatine is, you probably have heard of creatine as a muscle building supplement.

Creatinine is a breakdown product of creatine. We can use creatinine levels to give us, as I mentioned, an estimate of glomerular filtration rate. And one way of doing that is taking the urinary creatinine concentration, multiplying it by the volume of blood flow, and dividing that by the plasma creatinine concentration.

And that will give us a pretty darn accurate estimate of GFR. Now, typically, we don't bother to do both a urinary and a plasma creatinine measurement. Typically, we can use one or the other, particularly urinary creatinines, to give us some sense of how well the kidneys are working. We can also use serum creatinine levels, and I'll show you how we do that in just a minute. So if we want to get an estimate of creatinine clearance and from there an estimate of GFR, we can use this formula in which...

At the bottom, we are looking at serum creatinine levels. And this is a version of a formula named the Cockroft and Galt formula. And what it does is it takes into various parameters that can affect creatinine clearance, including age, weight, gender. And there are a few other estimates that are available, and there are lots of online calculators you can use to get this.

But they're based primarily on... serum creatinine levels. Another marker that you'll probably hear about but won't likely use very much in primary care is FINA, or the fractional excretion of sodium.

And really what it's telling us about is the amount of sodium excreted, or leaving the kidneys, compared to the amount that's both filtered and reabsorbed. Remember that sodium is indeed filtered and is also reabsorbed. So the filtration occurs at Bowman's capsule, The reabsorption occurs at various points along the tubule.

So you see here the formula. Don't bother committing it to memory. Just understand that we use both serum and urinary creatinine and sodium levels.

And when would you use it? Well, particularly if you're looking at somebody with acute renal failure and you're wondering whether or not low plasma volume or pre-renal failure is the cause. There are a variety of other indices we can use to look at renal function, including, of course, blood urea nitrogen, creatinine levels, and, of course, BUN to creatinine ratios, various electrolytes, including sodium, potassium, chloride.

Also, calcium is a pretty useful divalent cation to look at with respect to kidney function and phosphates. We can estimate, as I've shown, GFR. We can look at creatinine clearance. We can also look at urine volumes, which typically are 800 to 2,000 mLs per 24-hour period.

So with that, I'd like to include our introduction to renal pathophysiology, or essentially really what we're talking about is renal physiology, and I hope this will be useful in some of the subsequent videos on the topic. Thanks for listening.

Transcript for:Understanding Renal Pathophysiology Basics

Transcript for:
Understanding Renal Pathophysiology Basics