hi everyone this is lecture 22 urinary system so the urinary system is the system that includes the kidneys as their working unit and then the rest of the system that releases urine after the kidneys produce it so I'm going to introduce you to the urinary system also called the renal system renal refers to kidneys and we're going to talk about the kidney function and the regulation of the kidneys through that we'll talk about the processes of glomular filtration tubular reabsorption tubular secretion and plasma clearance as the kidney is working so just a review of the kidney the kidney has a large blood supply which branches throughout the middle of the kidney which is the medulla and the outer portion of the kidney which is the cortex the working units of the kidney are located through the cortex and the medulla and they will produce urine urine then drop by drop will enter into the renal pelvis and exit out of the URS from the URS the urine will enter the bladder where it is stored and then out the urethra we'll talk about the differences between the male and female urethra when we get to the reproductive lecture which is our next lecture so the urinary system is made up of the kidneys the working unit of the kidney is the nephron and after the nephrons and the kidneys produce urine urine will exit the kidneys through the uers then to the bladder and then out of the body through the urethra so this is just an overview of the kidneys within the body and I want to emphasize here the heavy blood supply that enters and leaves the kidneys so the kidneys are the primary organs of the urinary system at less than 1% of the total body weight they receive 20 to 25% of the total cardiac output in other words they have a huge blood supply which enters through the renal artery the fun the functions of the kidney include maintaining blood volume maintaining fluid and electrolyte composition of the blood that is balancing the water and the ions within the blood maintaining acid base balance eliminating metabolic waste and other substances activating vitamin D which helps with calcium and phosphate absorption in the small intestine and production of certain hormones the kidneys can produce EPO which increases red blood cell production they also produce renin which part which is part of the renin Angiotensin aldosterone system for water and salt conservation so what exactly is urine urine is a fluid waste product that is produced by the kidneys it normally contains water ions nitrogenous waste and small soluble compounds basically urine is a filtrate of the blood so the blood enters the kidneys is filtered and whatever substances the kidneys decide to keep out of the blood will enter the urine whatever substances are necessary will be returned to the blood as the blood returns to the body so the composition of urine will change as a function of blood and kidney regulation so the urine should not contain components of the blood that are necessary for the basic function of the blood it should not contain blood cells it should not contain the large proteins in the blood which help to maintain the osmotic balance of the blood and presence of blood cells en large proteins could indicate damage to the kidneys so the nefron is the working unit of the kidney the nephron is what actually does the work of deciding what should stay in the blood and what should be removed from the blood to enter the urine so the nefron actually produces the urine through this process and there are over 1 million nephrons in each kidney nefron will remove exchange and add materials to and from from the blood in order to regulate blood composition so what I want you guys to ask as you're going through the urinary system are two questions what should stay in the blood and what needs to be removed from the blood so the blood will enter the kidneys and the regulated blood leaving the kidneys will return to the body so what do we need to maintain in the blood as the the nefron begins to filter and act on the blood and then the blood in in is also going to have waste that needs to be removed so I want you also to ask what should leave the blood and exit the body so think about waste and other products that need to leave the blood and how can the kidneys do that so overall this large blood supply is going to enter the kidney and Nephron by nephron little little by little the the kidneys will remove waste regulate the fluid composition regulate the ions and regulate the acid base composition so that the blood leaving the kidney is regulated and filtered and then that blood will be returned to the body and general circulation whatever is in excess in the blood that needs to be removed then will exit out and be ex exed through the urine so I want to take a moment and this is important please get out a piece of paper and we're going to draw the anatomy of the Nephron together okay so entering the nefron is a large blood vessel called the aarant arterial the AER arterial and branches into a tuft of capillaries that looks like a ball of yarn that tuft of capillaries is called the glomerulus and then the blood exiting the glomerulus will leave out the E faret arterial and that will continue to Branch around the kidneys in a group of capillaries called the per tubular capillaries surrounding the glomerulus is a large capsule which is the start of the nefron so that capsule is called Bowman's capsule and it's lined with epithelial cells and it has a hollow center so together Bowman's capsule plus liquid marus is called the renal cor pusle so again renal cor pusle is Bowman's capsule plus glus so what's going to happen is that the blood is going to enter the aarant arterial and travel through the Glarus and it will first be filtered and that that filtrate is going to enter Bowman's capsule from there there is a series of winding tubules I'm just going to draw this way we call the proximal convoluted convoluted for winding tubule and then there's a long dipping down Tule it makes a big loop and we call that the loop of Henley so the urine filtrate is going to travel through the proximal convoluted tubule and then down the loop of Henley and then back up the loop of Henley so we call this the descending Lane of the loop of penley and the ascending limb of the loop of family from there we enter into another structure that is winding and it's further away in terms of how long the filtrate has traveled from Bowman's capsule so this we call the distal convoluted tubule and I abbreviate these as PCT proximal convoluted tubule and DCT distal convoluted Tule then the last stop before the urine exits out the renal pelvis is called the collecting duct so the filtrate will travel up the A7 limb of the loop of penley through the distal convoluted tubule and then down the collecting duct where the urine will exit out the body what I want you to notice is that I have drawn the peritubular capillaries up here that's for Simplicity it turns out that the peritubular cap players are winding all around all around the nefron structure so they're really everywhere so I should really draw them all over the place and so I want you to remember that there will be constant exchange back and forth between the peritubular capillaries and the urine filtrate that will happen all throughout the nefron so we have the aerin arterial which enters the glus the glus then puts filtrate into Bowman's capsule the blood will leave the ephant arterial and the filtrate will enter the proximal convoluted tubule from the efferent arterial then the blood will enter the peritubular capillaries and the filtrate will continue down the loop of Henley which is wrapped with peritubular capillaries for the loop of Henley we have the descending limb which goes down the loop of Henley and the ascending limb which goes up the loop of Henley from there is the distal convoluted tubule and the collecting duct so look over here and you'll see a more anatomically correct diagram so the picture that I just drew for you is with relation to how the filtrate flows from start to finish what you now need to do with the picture is take that nice linear flow take the distal convoluted tubule and wrap it around so it goes back and touches the aparent arterial and that's the picture that you see here so here's your aparent arterial and let's just follow the path of the filtrate it's going to enter Bowman's capsule and then a series of winding tubes which are the proximal convoluted tubule and then it's going to go down the descending limb of the loop of Henley and up the ascending limb now here's the distal convoluted tubal which twists back and touches the aparent arterial so all of this is distal convoluted tubal traveling through until we get to the Final Exit which is the collecting duct and then the urine will exit the um exit the renal pelvis so this is basically how I drew it for you but remember this is a linear path as if we've stretched out the nefron to go from start to finish anatomically we need to take this end the distal convoluted tubule and twist it back over so that it touches the aarant arterial and we'll talk about the significance of that and its regulation so this is a summary diagram for your reference for later now let's talk about what is actually happening throughout these tubules there are three main processes in the nefron that regulate blood and in the process of regulating blood produce the urine the first is glomular filtration glomular filtration is separation of big from small so this is separation of cells and large proteins those should stay in the blood from the plasma and whatever is dissolved in the plasma basically small molecules so the plasma will enter the nefron and the cells and the large proteins will stay behind that is a filtration process then the second process is tubular reabsorption reabsorption means that you're taking fluid or substances from the filtrate and putting it back into the blood the Last process is tubular secretion where something that is in the blood that has not yet been filtered out will be put into the blood selectively to make sure that that particular waste substance is removed from the blood and out the urine so first let's talk about glomular filtration glomular filtration is what I refer to as the pasta strainer so think about a pasta strainer right or some people call it a colander I guess it depends on where you're from right so a pasta strainer has lots of little tiny slits in the bottom right and you dump your your pasta or your soup or whatever it is you're trying to filter and all the big stuff the pasta stays behind and what ends up in the pot is the fluid and anything small enough to fit through all those tiny little slits so this is what happens with gular filtration so there are these tiny little filtration slits that I'll show you in a second that allow small molecules through but keep the large molecules namely the proteins and the large cells in the blood so the blood is going to enter in the aparent arterial and pass through the glomular membrane so this is at the glus what do we want to stay in the blood we want large proteins and cells to stay in the blood so they will stay and they will exit the aparent arterial what do we want to enter into the filtrate so we can begin to regulate it well basically everything else we know we need to keep large proteins and cells we're not sure about what's left in the filtrates we're going to put everything that's small enough into the tubules so what should go into the tubules is going to be water ions small molecules anything that is small enough to fit through the tiny slits in the filtration membrane so these are going to enter the filtrate at Bowman's capsule so the aarant arterial will bring the blood in and then the membrane at the Glarus is going to act like a Posta strainer it's going to keep the large cells and proteins which would be the pasta in this example back in the blood and allow the fluid and small molecules to enter into the kidneys so they can now regulate it so this is what the glomular membrane looks like so these are the openings and the spaces that the small molecules will have to travel through to get into Bowman's capsule so there are three components of the glomular membrane that will filter the blood through there's the glomular wall the glus is a capillary so the wall of the capillary is just like any other capillary simple squamous epithelium but these capillaries are unusual these are a particular type of capillary that contains large pores those large pores are called fenestrations fenestra means window so these are large pores or holes that will allow some molecules to pass across the capillary wall towards the filtrate then there's a small basement membrane the basement membrane is a glycoprotein gelatinous layer that is also full of collagen so this layer will act like kind of like a cheesecloth so you add little holes in the capillaries that let some small molecules fluids through and then you have a basement membrane that will let even small smaller molecules through leaving some of the larger molecules behind and then finally we have one more level of slits and these are actually in the capsule so there are these cells called phocytes that wrap around the capsule and one pooy will have sort of a cell body here and then these big foot processes so pod or poto refers to feet these big stretching out feet and they will link together and make these slits that lay across the capsule so these little slits will act like another second pasta strainer and they will keep large molecules out of the filtrate and only allow fluid and small molecules through so here is a picture of how all of that is happening but I think that it would help you if we drew it out so let's draw it out so we are here where the blood has entered the aparent arterial and is now going to be pushed out of the glomerulus into Bowman's capsule everything that stays behind in the blood will leave the eent arterial so let's zoom in here on the Glarus so we have the aarant arterial coming in and then capillaries I'm not going to draw the whole TFT of capillaries these capillaries have pores in them or fenestrations so they are fenestrated capillaries so some small substances and fluids are going to be able to get through those fenestrations they will also pass through a basement membrane and then they will enter the capsule which again has these filtration splits covering them from the Poo sites so the Poo sites don't make up the capsule the phocytes cover the capsule and create these slits which will have one more pass of filtering such that what enters the capsule is going to be fluid and small molecules and those will continue as the filtrate that will enter the rest of the nefron what stays behind will be blood cells red blood cells white blood cells and proteins large proteins Albin proteins Etc and those will exit out and stay in the blood through the e arterial so the blood keeps large cells and proteins the fluid and small molecules enter the filtrate and this is the process of glome filtration so here is a nice diagram from the book showing the aarant arterial which then becomes the glomular capillaries and the glomular capillaries are surrounded by poo sites so you have the fenestrations you have the fenestrations in the capillaries the basement membrane surrounding the capillaries and then the phocytes forming the filtration slits from there whatever is able to pass through those three layers of filtering will enter this capsule drawn here in yellow and become the filtrate that goes into the the rest of the Nephron the blood will continue to pass through the epher arterial and continue to be regulated as it crosses the remainder of the nefron so there's a a actual picture of the glomular membrane with the fenestrations of the capillary the basement membrane and the phocytes that form the slits here's a really cool picture of a poite these are neat cells so there's the cell body of the pooy and then you can see how it stretches out these fingerlike processes and then they intertwine with other phocytes to form these filtration SL so I hate to do this to you guys because we just did uh net filtration pressure for capillaries and bulk flow but since you did that you guys should be experts now so we have to now talk about something similar to capillary bulk flow and this is glomular filtration pressure so glomular filtration this process of getting filtrate into Bowman's capsule is regulated by various pressures at the glomular membrane so the capillary blood pressure will be the main driving force just like in bulk flow where the arterial and Venus uh vual blood pressure were the main driving force there same thing here but we also just like bulk flow will have opposing forces which are the osmotic pressures so we're going to have our outward pressures driving fluid out of the capillary and we will have our inward PR pressures driving fluid back into the cabulary so um let's just draw this briefly to give you guys an overview of this type of filtration pressure and if you didn't understand capillary bulk flow um this will be a similar process so this may help you understand that as well so this is glomular filtration pressure and what we want to look at to get the glomular filtration pressures is the sum of outward pressures minus the sum of inward pressures just like we did for bulk flow so our outward pressures for glomular filtration are going to be hydrostatic from the capillaries our main inward pressure is going to be osmotic pressure in the capillaries we will also have a hydrostatic pressure that is from the filtrate oops sorry an osmotic pressure that is from the filtrate that will drive fluid into the filtrate and we will also have a hydrostatic pressure from the filtrate that will drive fluid away from the filtrated into the capillaries so it looks like this we have the glomerulus and then we have have Bowman's capsule so for the Glarus the major pressure that will be driving fluid out is going to be blood pressure so this is a hydrostatic pressure that is forcing fluid out of the GL glus and we call this the hydrostatic pressure of the glomular capillaries in other words P glus or pressure of the glomerulus this is approximately a positive 55 mm of mercury there will also be within the blood an osmotic pressure with all of the proteins that are in the blood and solutes drive fluid towards them so this is going to be an inward pressure due to solutes driving fluid into the glara so this is going to be the osmotic pressure of the gulus and that pressure turns out to be about3 mm of mercury we also have hydrostatic pressure so there is fluid in Bowman's capsule that also drives and pushes fluid back towards the blood that hydrostatic pressure of the filtrate is about 15 millim of mercury and we're just going to call that h P of Bowman's capsule and that is about5 the last is osmotic pressure that would drive fluid into Bowman's capsule if there was damage to the glomular filtration membrane and somehow blood and proteins got into Bowman's capsule that would drive fluid with an osmotic pressure sucking fluid towards the solutes but in this case there's no pathology the blood and proteins stay in the blood so the osmotic pressure of the filtrate is zero so now we just take our outward pressures and we subtract our inward pressure so we have 55us 30 + 15 45 and our glomular filtration pressure is going to be about 10 mm of mercury into Bowman's capsule out of the blood to Bon's capsule so why do we care about this we care about this because ultimately the blood pressure that is coming into the glomerulus is driving filtration and if we want to regulate filtration the easiest way to regulate that is to change the blood pressure coming in so the rate of glomular filtration is very important clinically for assessing the health of the kidneys assessing kidney disease and looking at kidney failure because this is the first pass of flu fluid entering the kidneys and without glomular filtration or with low glomular filtration the kidneys don't have any fluid to work on so looking at the net filtration pressure we need to take into account how much blood pressure is coming in and the basic properties of the glomular membrane so the total filtration rate or the total amount that is being filtered through the glus will be the net filtration pressure that we just calculated multiplied by a factor called K which um represents the properties of the membrane so the properties of the membrane such as the size of the pores and the capillaries the size of the filtration slits of the phocytes are also modifiable in addition to the pressures and that will give us our total GFR the total for the entire system daily average GFR is about5 to 125 milliliters per minute and you will if you move forward clinically use glomular filtration rates as a way to assess the health of the kidneys so as I said the regulation of GFR can be altered by regulating blood pressure there are other ways to regulate GFR you can regulate the protein concentration in the blood that will affect the osmotic pressure pulling fluid back into the blood so that will oppose filtration you can regulate your level of hydration which will affect the pressure in the glomerulus and the pressure in the filtrate as you increase water the hydrostatic pressures will increase GFR can also be affected by obstruction in the urinary tract so obstructing the obstructing the urinary tract can affect the pressure in the capsule but the main way to affect GFR is through blood pressure or mean arterial pressure this is the variable that will cause the biggest changes so there are two ways that the kidneys can compensate and change mean arterial pressure one is through local mechanisms which we call Auto regulation there's two ways the myogenic and tubulo gular feedback another is extrinsic or outside regulation through the sympathetic nervous system so the idea here is that as you change the blood pressure coming in you will ultimately change the glomular capillary pressure which will ultimately affect the hydrostatic pressure and the net filtration pressure if you increase all of those pressures by increasing arterial blood pressure you can increase GFR and vice versa if you cut off the blood flow or the blood pressure to the glarius you will decrease GFR so first Auto regulation is the main way that kidneys sort of on a moment by basis maintain constant GFR so this is to B basically um as the arterial blood pressure changes the kidneys will regulate GFR to compensate for that to maintain the same pressure within the Glarus no matter how the blood pressure is changing so if GFR is too high sense that it is too high then the aparent arterial will be closed off through Vaso constriction not fully closed off but blood flow will be decreased and local blood flow will slow down to the glomular capillaries and there will be less GFR if it is found that GFR is too low the aperin arteria will be dilated and that will increase flow to Bowman's capsule and get more filtrate through so the first way to do this is oh I guess I should show you guys these instead of waving my hands okay I'll show you the diagrams so if we go from a normal size to vasil constriction that will decrease blood flow to the Glarus and ultimately decrease GFR if we however go from a normal size to a dilated aarant arterial that will increase blood flow to the G Glarus and increase GFR so the first way to do this is the myogenic mechanism the aparent arterial actually automatically constricts if it is stretched so if mean arterial pressure in the body increases that will stretch the apher arterial the aparent arterial will Vaso constrict to try to keep GFR constant so rather than fluctuating continuously as the blood pressure changes in the body there is auto regulation within the kidneys to maintain a ferent arterial pressure despite what changes might be happening in the body so if they're over stretched then they will vasoconstrict to bring JFR back down the second way that the kidneys can do this locally is through something called tubulo glomular feedback remember when we talked about the distal convoluted tubule wrapping back around and touching the ather and arterial well that's what this picture is showing so what you're actually looking at here is a piece of the distal convoluted tubule this is one of the last stops of the filtrate before it leaves the kidneys so this is a very handy place for the kidneys to assess how are things going in the filtrate is the filtrate actually successfully um being formed or do we need to give it more time so at this point there are specialized cells in the distal convoluted tubule that will sense the filtrate and we'll talk to the aparent arterial those specialized cells in the distal convoluted tubule that touch nearby the aent arterial are macula Dena cells within the aent arterial we also have specialized cells that will listen to the macula Dena and these are called the granular cells together this whole apparatus of the distal convoluted tubule and the aeren arterial communicating about how the filt is doing its job is the jua glomular apparatus so here is an example of how it works if we have high pressure in the glomerulus the macula Dena will sense that there is high salt and high fluid flow through the filtrate so if the filtrate is moving too fast it will send a lot more salt and fluid in a particular time than normal it will then release a ATP and a Denine and the granular cells will sense that ATP and a Denine and vasal constrict so if pressure is too high in the filtrate that will go down the line and get sensed in the distal convoluted tubule by the macula Dena they will then tell the granular cells to cause basil constriction in the Aether and arterial to slow down the flow and bring GFR back down to normal so here's a zoom in of that jua glomular apparatus and this is a nice picture which shows you basically where we are in the nefron so here we have our glamist the filtrate let's say the filtrate got very high and that passed through the proximal convoluted Tule passed through the loop of Henley and then also stayed high in the distal convoluted tubule at this point that that high pressure high salt high fluid movement travels through the distal convoluted tubule it can talk to the Aether and arterial and slow down GFR to balance the last way to regulate GFR is through the sympathetic nervous system so we've talked a lot about sympathetic nervous system regulation of cardiovascular changes what does the sympathetic nervous system do to blood vessels in general do you remember vasil constriction so this is no different the a ferent arterial when it gets sympathetic nervous system input will Vaso constrict and it does that to shut down or slow down GFR what does the sympathetic nervous system overall due to the urinary system now this should make sense based on what you know about what the sympathetic nervous system does the sympathetic nervous system does not want the body to be producing high amounts of urine why because you're running from the Bear right so you can't be urinating and and producing urine and spending energy producing urine when you're trying to put energy into your brain and skeletal muscles to run from the bear so the sympathetic nervous system will actually slow down blood flow to the glomerulus by vasal constricting the aparent arterial it's going to constrict the aperin arterial slow down GFR and slow down urinary production also turns out to have an effect on nearby cells in the juular apparatus and pooy contraction that will decrease the size of the filtration slits and prevent entry of fluid and small molecules even further from entering the tubules so we're going to decrease the filtrate rate by decreasing blood flow into the nefron we will also decrease the filtration mechanically by closing down the filtration membrane overall the sympathetic nervous system decreases GFR so this is a summary of the sympathetic nervous system regulation so essentially if arterial blood pressure increases then excuse me let's start back up here so essentially if arterial blood pressure is too low in the whole body then that will be detected by the nervous system that will increase sympathetic activity which wants to increase cardiac output and increase total peripheral resistance to bring blood pressure in the whole body back up by doing that it will increase vasil constriction in order to divert blood to the important areas and increase totally arterial blood pressure vasil constricting locally at the kidneys is going to decrease GFR to decrease urine output that will ultimately lead to less loss of fluid and salt and increase arterial blood pressure long term okay do you guys understand glomular filtration if not pause go back and review your notes before we get to T to reabsorption so now that we have gone through the filtrate process we're now going to take that filtrate and selectively decide what gets to stay and what should go so tubular reabsorption is a selective process of taking needed substances from the filtrate and putting them back into the blood so remember that the filtration process through the filtration membrane was not specific to any molecules it was only a size filtration so anything small and fluid is now in the filtrate including a lot of things that the body needs so the glomular filtrate is going to contain a lot of fluid ions and small molecules from the blood that the blood needs back so starting with the proximal convoluted tubal now we will select transport the valuable substances that the blood needs back to the peritubular capillaries those will be then returned to the blood and return to the body anything that the tubules don't recognize they don't know anything that um is in excess that will stay in the filtrate and exit as urine so we're going to take the filtrate through the remaining tubules and return valuable sub substances to the blood anything then that is not necessary to be returned to the blood will stay in the filtrate and enter as waste so for normal GFR at 125 milliliters per minute about 124 milliliters per minute is returned to the blood so this is 99% of water 100% of sugar for nutrients 99.5% of salt will all be put back into the blood so the body knows water sugar salt that needs to go back but what will exit and leave the body will be any excess ion ions Ura and toxins will become concentrated in the filtrate so we're going to do reabsorption by location and talk about the processes the remaining tubules so first the proximal convoluted tubule the proximal convoluted tubal is going to reabsorb a lot of salt a little bit of water some chloride all the glucose possible amino acids phosphate Ura and potassium we'll talk about secretion in a moment and control as we go through the loop of Henley is going to reabsorb about 25% of the total salt about 15% of the total water and some chloride the distal convoluted tubul and collecting duct will reabsorb more salt about 8% of the total more water and more chloride so you may notice as you look at these three lists that the M majority of reabsorption happens right away in the proximal convoluted tubule and then after that through the loop of Henley the distal convolu tubul and collecting ducts it's really just salt and water balance basically the concentration of the urine that is being altered so for this we need to talk a little bit about cellular transport that is happening in the tubules so reabsorption happens through the process of selectively transporting substances from the tubules into the blood so we need to draw this out a little bit just to give you guys a picture so we finished filtration which happened between the glus and Bowman's capsule and now the filtrate is moving into the proximal convoluted tubule where the majority of reabsorption is going to happen so let's zoom in here on the cells within the proximal convoluted tub so what we have in the proximal convoluted tubule are epithelial cells lining then we have the Lumen where the filtrate is entering so where the filtrate coming in the epithelial cells of the proximal convoluted tubule you're going to have some fluid and then from there we'll have the peritubular capillaries winding all over the tubules and waiting to get their substances back so what is already currently in the peritubular capillaries from the filtration process already in the peritubular capillaries will be blood cells and proteins okay so this is all blood it came from the eeper arterial which came from the glomerulus which came from the aparent arterial right it's just going to be densely filled now with proteins and cells there will be some fluid because not all the fluid enters the filtrate but in the filtrate now we have the fluid and small molecules and we want to return important substances through the epithelial cells of the proximal convoluted tubule through to the interstitial fluid of the proximal convoluted tubule and then back into the blood so how is selective transport achieved what do we use think back to our um cellular transport lectures that you guys did at the beginning of this semester we need some protein channels so we're going to have channels from the tubular Lumin to the tubular epithelial cells also need to have channels from the basil lateral membrane or this base membrane to the interstitial fluid and then substances can enter the peritubular capillaries so this is all re absorption and reabsorption is the process of returning needed substances from the filtrate back to the blood and it requires selective channels so let's look at some specifics of this type of transport so reabsorption can be passive or active I want you guys to think back to your membrane transport lectures and this is the same idea so passive transport is when you have no energy required to pass from the tubule to the blood so we're getting across the membrane the phospholipid BL layers of the tubule cells and some cases you don't need energy to do that they can just follow their gradients from high to low in other cases you have active transport where ATP is required for at least one step this is secondary active transport where the sodium gradient will be set up by a sodium potassium pump and then a sodium gradient will be used to transport other material so the sodium potassium atpa pump is present in the basil lateral membrane throughout several of the tubules the sodium gradient then is maintained by pumping sodium out of the tubules and keeping sodium low inside the tubule cells this will be the driving force for sodium to leave the tubules and we can use that sodium gradient for co-transport of important molecules so for example glucose amino acids water will follow chloride will follow and then the Chang in concentration of urine um can also be done through sodium use use of of sodium gradients so removing sodium will also remove water from the filtrate and then finally this can also be done to regulate blood volume so if we change the sodium content in the blood we can change the water content of the blood and we'll do this through hormonal mechanisms to regulate blood volume and blood pressure so this is what it looks like you have the sodium potassium pump in the basil lateral membrane and that will keep the sodium levels inside the tubular cells low that ensures that if you have any sodium in the filtrate it will move from high to low into the tubular cells and then you can picky back on that sodium movement to bring in glucose amino acids Etc so TMax is the maximum amount of mov across the membrane for any given molecule so we also call this renal threshold so when a plasma con concentration of a substance exceeds the ability of the carriers then it will be in excess and it will stay in the filate and be lost in the urine here's an example glucose has a fairly High renal threshold because it has a high T Max value so up to approximately 300 milligrams per 100 Ms in the blood of glucose you will get constant filtration and reabsorption so glucose will enter the filtrate glucose will be returned to the blood all the way until you get to 300 mgram of glucose per 100 milliliters of blood once you hit that point you've maxed out your channels and no further reabsorption Beyond 300 migs per mil can occur once you get there anything above that will be excreted in the urine so as T-Max is reached reabsorption cannot increase and the remainder of glucose will be excreted this actually quite a high value so even if you have a giant chocolate cake for dinner the glucose will be entirely reabsorbed and you won't see any sugar in your urine that will only be in pathological cases where you reach extremely high high um levels of plasma concentration of glucose in the blood because of say diabetes or other conditions other molecules however have a low threshold that means they normally don't have a lot of channels or there normally aren't any channels in the tubular membrane so phosphate is an example of that any excess phosphate in the blood will be be quickly eliminated in the urine because there are very few phosphate channels in the tubules hormones however can adjust the renal threshold for phosphate if more is needed in the body and that will simply be done by increasing phosphate channels in the tubular cells so after these sodium gradients are established other molecules can follow water will follow flowing through aquaporin channels where 65% of water will be recovered by the end of the proximal convoluted tubule 15% will be um recovered by the loop by the loop of Henley the remainder of water will be regulated by hormones in the distal convoluted tubule and the collecting duct chloride will also follow sodium following the electrical gradient created by the sodium gradient as the water leaves the filtrate Ura will become concentrated and about 50% will be of Ura will be reabsorbed due to its small size so here's an example of how it works for water so here we have the sodium moving through because of its gradient water will then follow the sodium as long as there are water channels present for the water to move in so there are water channels in the tubular Lumen so water will enter the tubul cells and there are water channels in the basil lateral membrane so water can then exit the tubules and go into the blood here's just a summary of where we are so far where for normal glomular filtration rate about 125 milliliters of filtrate will enter the proximal convoluted tubule from there we will have active transport of sodium and water will follow along with that active transport of sodium other molecules such as glucose and amino acids will also follow and be reabsorbed into the peritubular capillaries later on down the line as the urine gets more concentrated passive diffusion of Ura can also occur so what's left anything that is not actively reabsorbed left in the filtrate will be excreted in the urine this will include molecules that hit their T-Max and molecules that are small enough to enter the filtrate at the glomular membrane but do not have Transporters for reabsorption so this will include wastes like uric acid waste creatinine waste phenol and other toxins that don't have Transporters to return to the blood so the regulation of tubular reabsorption happens through hormones first the renin Angiotensin aldosterone system affects sodium reabsorption and increases the amount of sodium that returns to the blood A&P and BNP will oppose that and decrease sodium reabsorption and then water reabsorption will happen mainly through the action of ADH or vasopressin ADH will increase water reabsorption and maintain blood volume so first for the RAS pathway so the renin Angiotensin aldosterone system the net effect is to increase sodium reabsorption and this will be done through mainly the collecting duct and the distal convoluted Tule this happens because of the granular cells in the aparent arterial and the macula Dena cells in the distal convoluted tubule so the granular cell cells have Barrow receptors that will sense blood pressure and if blood pressure is too low they will cause renin to be secreted the macula Dena have sodium chloride receptors and if sodium chloride gets too low because ultimately filtration and blood pressure was too low then they will also send signals to secrete renin this can in finally be um triggered by sympathetic nervous system ination to the granular cells as well so here's how it works and let's draw this out so if the granular cells sense that blood pressure is too low or if the macula Dena sense that sodium chloride is too low or if the sympathetic nervous system simply is triggered by stress or low blood pressure then renin will be released so renin is actually an enzyme it's an enzyme that converts a molecule called angiotensinogen into Angiotensin one Angiotensin one will travel through the blood and be converted by another enzyme called Ace which is present in totally randomly present in the lungs so Ace will convert Angiotensin one to Angiotensin 2 and that will stimulate several things but ultimately it's going to stimulate the adrenal cortex to produce aldosterone yes Angiotensin 2 has some of its own actions it can increase phasal constriction in the body it can also stimulate thirst but ultimately its most important effect is to stimulate the adrenal cortex the adrenal cortex then will produce aldosterone aldosterone will increase sodium channels specifically in the tubular [Music] Lumen of the collecting duct and the distal convoluted tuule that will ultimately increase sodium reabsorption which will allow for increase water and increase blood volume an increase in blood volume will increase blood pressure to counteract what was initially sensed as low blood pressure so ultimately the RAs pathway is present to maintain blood volume and the kidneys are a place that can sense small changes and large changes in blood volume and send signals out to the rest of the body to help to increase blood volume those signals will ultimately act through the kidneys to increase sodium reabsorption and water will follow so I want you to notice how many body systems are involved in this blood volume regulation this pathway is absolutely essential to life and deficits in aldosterone can be life-threatening so ultimately the liver produces angiotensinogen renin from the kidneys converts that to Angiotensin one ace from the lungs converts it to Angiotensin 2 angot s in two signals to increase thirst and vasil constriction But ultimately signals to the adrenal cortex to increase aldosterone aldosterone then acts on the kidneys to increase sodium which will conserve salt and ultimately conserve water in the body and that helps to correct the initially low blood pressure that was felt and sensed by the kidneys so aldosterone ultimately regulates sodium and the levels of sodium in the blood increased aldosterone will increase sodium reabsorption and decrease sodium excretion it also has an effect on potassium secretion and if we go back you will see that it not only inserts sodium channels into the Lumin it also increases sodium potassium pumps so the sodium potassium pump is twofold it helps to maintain the gradient so that sodium will enter the tubule cells it can also help to get rid of potassium and secrete potassium out of the cells we'll get to secretion in just a moment A&P and BNP oppose aldosterone by inhibiting renin ultimately this will decrease sodium reabsorption and decrease blood volume these are triggered by stretch of the heart muscle indicating the heart has been overloaded by too much blood volume and they will then act to decrease blood volume and blood pressure so now we need to talk about how urine gets concentrated beyond the reabsorption processes so we're done with reabsorption now we're going to get to urine concentration and secretion so urine is concentrated because of the gradient that is set up by the loop of Henley so the loop of Henley establishes and maintains an osmotic gradient that can be used to facilitate water and sodium reabsorption this ranges from the upper cortex values of the loop of Henley 300 millios molar to the lowest medulla values or the deepest medulla 1200 100 Milli osmolar this is created by something called a countercurrent exchange where fluid moves down and up the loop of Henley in the opposite direction of the way that fluid is moving through the Vasa recta so what we have is a different level of channels in the descending and ascending limb of the loop of Henley the descending limb of Loop of Henley has high aquaporin where water will leave the ascending limb has high sodium and chloride transport where sodium and chloride will leave so if we break down the kidney into cortex and medulla the proximal convoluted tubule and distal convoluted tubules will be in the cortex and it is only the loop of Henley that stretches down into the medulla so at the top of the loop of Henley and within the proximal convoluted tubule they are sitting in fluid that is 300 mosmol that is isotonic to the blood as you dip down into the medulla the loop of Henley gets into further and further highly concentrated environment so you can see from this diagram how that Anatomy works so the proximal convoluted tubule is in the cortex the loop of Henley dips down into the medulla where it gets more and more concentrated outside of the loop of Henley and then goes back up towards the cortex where it goes to the distal convoluted tubule back and isoosmotic conditions and then the collecting duct dips back down through the medulla and this is important for actually using the gradient that's established so partly this works because of the different composition of channels that are present in the fil in in the loop of Henley so high water channels through the decending limb means that a lot of water leaves out of the descending limb that will concentrate the filtrate and pump water out so the filtrate will be highly concentrated by the time it gets to the bottom of the loop of Henley and then that highly concentrated filtrate will start to go back up the loop of Henley and sodium chloride or salt will be pumped out of the filtrate from there that sodium chloride can be pumped in excess such that it actually can become hypotonic or very low salt concentration so from the proximal convoluted tubule down the filtrate can lose water and from the bottom of the loop of Henley up to the distal convoluted tubule the filate can lose salt to become more dilute but it will be a lower volume of dilute urine so the dilute urine will enter the distal convoluted tubule and the osmotic gradient in the medulla will be maintained and used by the distal convoluted tubule and the collecting duct to increase water reabsorption so I think we need to draw this out even though you guys be patient I know we're getting towards the end of the lecture but let's draw it out so the proximal convoluted tubal is going to be in the the cortex so here's the cortex of the kidney and then the loop of Henley dips down into the medulla and then back up towards the cortex so the medulla because of the way that the blood vessels surrounding the loop of Henley are um twisting and turning and moving in different directions with respect to the fluid ultimately this gradient is set up such that you have 300 millios molar extracellular fluid outside of the loop of Henley at the top near the cortex and that gets more and more concentrated in the medulla I will be honest with you guys and that I have been teaching this for a long time and I have read many textbook accounts of this countercurrent exchange and I have never found anything that satisfactorily explains this countercurrent exchange and why it works and how it's set up if you guys find something let me know let's just accept that the countercurrent exchange produces this highly concentrated environment that the loop of Henley dips down into so the filtrate is going to enter the loop of Henley and travel down and as it does it's going to lose water that's going to decrease the volume of the filtrate and increase its concentration as it then moves up the ascending limb it's going to lose sodium chloride that will cause it to be dilute or low solute by the time it gets back to the distal convoluted tubule what's cool about this is that this can be regulated such that at the end the collecting duct can now use this gradient so it's actually not in the loop of Henley that the concentration is important the loop of Henley is important for the setup so the loop of Henley sets up the gradient and the collecting duct is going to use the gradient so now in the collecting duct we're going to have hormone regulation to take the final filtrate before it exits out the urine and concentrate or change how much sodium and how much water stays in the filtrate and how much remember is going to go back to the blood so the hormones that we just talked about first we have aldosterone if we increase aldosterone we will increase sodium back to to the blood now here's our final hormone which is ADH ADH is going to increase water back into the blood so that both aldosterone and ADH will cause volume loss and concentration loss in the urine that is in order to retain the sodium and water in the blood so hormones will regulate the collecting dect aldosterone and ADH to increase sodium retention or reabsorption and increase water retention or reabsorption and that ensures that the urine is low volume and we don't lose too much water or salt so low salt so the regulation of water is going to happen by using the osmotic gradient in the medulla and the use of ADH or vasopressin to insert aquaporin into the collecting duct this is a graded response that can slightly increase or decrease based on need and this is why if you drink a lot of liquid you will have a high volume of dilute urine and if you do the opposite if you dehydrate yourselves which is most of us right be honest guys we don't drink enough water you will have a low volume of very um concentrated urine so up to 20% of total water reabsorption can be increased at the distal convoluted tubule and the collecting duct what's interesting is that caffeine and alcohol block ADH so you will get an increase in urine output even if you're dehydrated from the caffeine and the alcohol and this doesn't do much for the body and that's why you can get hangovers and migraines from caffeine and alcohol so here's how it works the ADH will increase aquaporin in the Lumen so here is the Vaso presser ADH which is being released from the blood where does it come from do you guys remember the posterior pituitary so it's sent from the posterior pituitary into the bloodstream it will bind to receptors in the uh collecting duct and through a second messenger system will increase insertion of aquaport when it does that more water will enter the tubule cells and that water will then be able to move from the tubular cells into the blood so the filtrate has normally a concentration of about 100 millias molar as it enters the distal and con and distal and collecting distal convoluted tubule and collecting ducts and if you don't have vasor depress that high volume dilute urine will be lost this is what you see with alcohol intake and caffeine intake where you get a lot of dilute urine clear looking urine and high volumes of it exiting the body with vasopressin water is removed from the filtrate and returned to the blood such that urine becomes more concentrated and here your textbook is showing you it will be a darker yellow color and you will have less volume of it because that water will be returned to the blood and it won't be lost in the urine okay we're almost there guys a little bit on tubular secretion and then we'll be done so tubular secretion is the process now of taking anything that was in the blood that hasn't yet been eliminated so this is a last step to make sure okay do we have everything we want in the blood have we gotten rid of everything out of the filtrate so tubular secretion is an active use of channels to put substances into the filtrate that have not yet been eliminated or not enough has been eliminated from the blood this is how acid base is balanced because we can remove hydrogen ions this is how potassium is balanced because we can secrete potassium ions and we can also remove certain toxins and other organic ions through specific Transporters so go back to our initial summaries secretion in the proximal convoluted tubal is primarily going to be acid and other ions there's no effective hormones but there is a sodium pottassium pump in the proximal convoluted tubule in the loop of Henley secretion can be sodium and chloride and that helps to maintain the osmotic gradient but there's no effective hormones and there is still a sodium potassium pump in the loop ofle in the distal convoluted tubule secretion of acid can occur and secretion of pottassium can occur it is controlled by all of those hormone processes we just talked about secretion and excretion of sodium will be regulated by aldosterone reabsorption and secretion of water will be regulated by ADH and sodium regulation will be uh uh sodium regulation will be opposed by& and BNP and again we always have the sodium potassium pumps so let's look at acid secretion acid secretion is regulated in order to maintain acid base balance so normally um this will cause urine to be slightly acidic as we're removing acid um due to metabolic wastes and and other Wast in the body so the urine pH is normally a little bit more acidic than the blood a pH of about six and this will primarily occur in the proximal convoluted tubule distal convoluted tubule and collecting duct this is because we have hydrogen ion pumps and hydrogen potassium pumps and sodium hydrogen co-transporters Within These tubules this will be balanced ultimately with bicarbonate reabsorption the complexities of this process could take us an entire lecture but I'm going to leave it here for now in that we can secrete acid if we need to if acid is too high in the blood and then acid secretion can be balanced by conserving bicarbonate in the blood or excreting bicarbonate in the blood alongside of the um acid secretion and excretion secretion can also occur for pottassium potassium is tightly regulated to maintain electrical gradients remember that we want low pottassium in the extracellular fluid this is especially important for the heart and to maintain sodium potassium pump activity secretion will occur in the distal convoluted tubule and the collecting duct it will partly be because of the sodium potassium pump moving potassium into the tubules so you'll have high potassium in the tubular cells because of the sodium potassium pump and then you'll have a high to low gradient causing potassium to move from the inside of the cells into the filtrate where it will be excreted in the urine you will then also have potassium channels to allow the potassium to pass through and enter the Lumen that secretion will be stimulated by aldosterone and it will balance the sodium reabsorption that is also stimulated by aldosterone there's just a zoom in of that picture where you have high potassium inside the cells because of sodium potassium pump and then you have a potass Channel which allows the potassium to follow its gradient and be secreted into the filtrate where it will be excreted out of the urine so here's just a reminder of aldosterone I'll let you guys review this later and the last piece is that we can also secrete organic ions this can include hormones foreign compounds pesticides pollutants food food additives medications this becomes important when you look at the pharmacology of certain medications and how much they will be removed from the blood by the kidneys it affects the dosing of many medications and there are two types of carriers they are not selective so they generally will take anion of any organic class of molecules or they will take cations of a general organic class of molecules what this means is that organic ions with negative charge will compete for carriers and organic ions of positive charge will compete for carriers this is where you can get drugs competing during elimination and that can cause drug interactions so two drugs that use the same carriers will reach their T-Max sooner if they are given together so if you have one medication that would normally be eliminated at a certain rate and then another medication that comes in and fills up its channels for elimination that can cause that other medication to be much higher in the body so you have to have dose adjustments for certain compounds especially medications that use the same carriers as other medications so there are several summaries in your textbook I suggest that you redraw the nefron and go through Point by point where everything is occurring and I'll leave you with this the total plasma clearance of Any Given molecule is going to be a balance between the filtration rate and the reabsorption rate the net excretion of urine will be about 1 Mill per minute so urine is produced at a rate of 1 ml per minute so substances can be excreted out of the plasma at a rate of 1 mil per minute this is plasma clearance the rate for any given substance will depend on how well it can be filtered how big it is how well it can be reabsorbed how many channels are present and how much will be secreted how many channels will be present in the opposite direction to get it rid of it in the in the filtrate so some examples creatinine is filtered through the glus but it is not reabsorbed there are no channels to reabsorb it and is not secreted so its rate of clearance is exactly equal to its filtration and can be used as a measure for GFR clinically glucose will be filtered and 100% reabsorbed at normal levels its rate of clearance will be much less than GFR Z there will be no glucose in the urine in normal condition so it has a zero clearance rate acid on the other hand will be filtered but it will be actively secreted so its rate of clearance will be much higher than GFR because it is actively added in addition to what is filtered a lot will be added added to the urine so once urine is produced it needs to be removed so we have stretch receptors in the bladder wall that will sense about 250 to 400 milliliters of volume and send signals through the parasympathetic nervous system to stimulate bladder contraction and open the internal urethal sphincter the external urethal sphincter is voluntary skeletal muscle and can override that if the time is not convenient for the urine to exit so the bladder will fill as a process of urine being produced in the kidneys stretch receptors will activate parasympathetic neurons that will cause the bladder to contract and empty if the time is right the internal urethal sphincter will open along with with the external urethal sphincter will allow that to stay open and urination will occur if not the external urethal sphincter will close around the internal urethal sphincter and we can hold it until later all right you guys have been holding it for a long time this was a long lecture thank you for your patience please let me know if you have any questions