Transcribed by Albert Cheng Organ Systems Renal Physiology I and II

4/17/14

Water (intake and how we lose water) [Dr. Schiff] Ok, today were going to start talking about water and the fact that the major regulation of the water in the body is done by the kidneys. There are other ways in which we get water, primarily from drinking water but by drinking other liquids as well and eating food. Food contains water. And on the other hand, we get rid of water in a number of different ways besides urine. So the sources of water are generally water, liquids, or food, which we metabolize. Anything that contains a hydrogen ion if its oxidized ends up producing water. And thats how camels survive in the desert. They dont carry water with them. What they carry is fat. Thats what the hump on the camel is. The fat when it gets metabolize produces water. So its a way of carrying water in a sense that it doesnt dilute all the fluids in your body but its a source of water thats kinda portable. We lose water through urine for sure. But we also lose water every time we breathe. Remember in respiration, you saw that one of things that happens as you inspire air is that as it passes through mucus covered membrane originally in the nasal turbinate and then going on down through your pharynx, it becomes humidified. So the air taken in from the outside world is dry for the most part unless youre in a place with absurdly high humidity. The air you exhale is saturated with water vapors so youre losing water every time you breathe. We lose water by sweat. We lose water through our intact skin even though were not aware of it. This is sometimes referred to as insensible or un-sensed, we dont feel it. Water loss because the skin is not 100% waterproof barrier. And this becomes even more so when you have injured, abraded, scraped, and burnt skin, which have even less of a water barrier. But even healthy skin, you lose a certain amount of water through it. You lose water in your feces, in urine, and occasional other losses of water when you vomit. You cut yourself and bleedlose blood. Menstrual blood flow, which we will get to in a couple of weeks. Tears and nasal mucus, all of these things are using up the bodys supply of water. All this water has to be balanced. The interesting thing is if you run down the list of ways you consume water, its mostly a matter of drinking. But if you look go through the list of ways of getting rid of water, you lose water in sweating but sweating is regulated by your bodys attempt to regulate body temperature. If youre hot, you sweat. If youre cold, you dont sweat. So all of these other mechanisms of water loss are regulated by other parameters. Sweat is the easiest example because its regulated by your body temperature. And yet theres a certain amount of water you have to lose to get rid of the water you produce by metabolism or that you consume by drinking it. And thats where the kidneys come in. Structure of Kidney (and analogy to saliva/sweat glands) Now youve seen in Dr. Wishes lecture, the structure of the kidney. The fact that you have a cortex on the outside, medulla going in towards the center where the pelvis is. You have within the cortex, you have these glomeruli and each glomerulus (there a million of themthats not an exact number just a ballpark number) is the origin of

a series of tubules that changes character as it runs along called the nephron. You can sort of think of the glomerulus followed by the nephron as a gland. Think of salivary/sweat glands. What you basically have in any sorts of gland is a mechanism by which theres filtration of waterwater comes into it from plasma and then it producesand the cells secrete whatever else gets secreted into this product of the glandsaliva or sweat. And then you have a duct, and as the secreted fluid passes along the duct, it gets modifiedsome things get reabsorbed or secreted into it by the cells of the duct. And the concentrations of various components of the secretions get changed. And finally, you end up with a final liquid thats produced at the end of the duct. By analogy to the nephron and kidney, this is essentially what we are referring to as urine. This analogy does not work perfectly for a number of reasons. First of all, the purpose/major function of a gland is to produce its secretions. Salivary glands function is to produce saliva. A sweat glands main function is to produce sweat. Digestive glands, which Dr. Wishe discussed earlier, have as their main function to produce whatever it is that they are secretingvarious enzymes mixtures and so on. Here the main product/main function of a nephron is NOT to produce urine. Thats like saying the main function of the factory is to produce the garbage that it puts out. Urine is garbage. So its not a desirable product or something were going to great effort to produce. What it is is the nephrons of the kidney regulate the contents of plasma. Regulate the amount of plasma and remove what shouldnt be theretakes out the garbage. It keeps what should stay in the plasma. But it gets rid of the garbage and thats what gets put in the dumpster outside. Thats the urine. Urine is the stuff were getting rid of. The other reason that this sort of analogy to the gland doesnt quite work is that filtration is not from capillaries the way it is in most glands. Most glands have a capillary bed that provides plasma and plasma gets filtered into the interior of the gland structure. Here theres much more complicated mechanism going on that regulates and produces the filtrate. Were talking about enormous volume of water that has to get processed in order to purify the blood/plasma and get rid of the garbage.

Nephron/Glomerulus/Blood flow within arterioles and capillaries So lets start by looking at a nephron. The nephron begins with the glomerulus. Dr. Wishe gave you the structure of the glomerulus. Its found in the cortex of the kidney and by being in the cortex of the kidney, its surrounded by tissues that have normal isotonic osmolality something like 310 mOsm per kg of water. But its supplied by an arteriole. Heres your glomerulus and to follow with Dr. Wishes general nomenclature, theres your vascular pole and urinary pole (which is a bad term because its not urine yet). And what happens is you have an arteriole going inthis is the vascular pole which supplies blood, and you also have another arteriole going out. This is very interesting here. Let me complete this circle here (referring to drawing). You have blood supply going in through an arteriole and this is called the afferent arteriole. Theres another arteriole leaving the glomerulus, which is called the efferent arteriole. Between these, theres a capillary bed. Already, youre seeing something different from the standard model of the circulatory system that Kinally presented. Course normally blood flows from big arteries to smaller arteries to arteriole into capillaries and then into venules and veins. But here the blood flowing into this capillary bed is now going from the capillary bed back into the efferent arteriole, which takes blood away from the glomerulus. So whats going on here? And why do we have this 2nd arteriole? And where does this arteriole lead? This efferent arteriole then does what arterioles generally do; they divide and form a capillary bed. It eventually leads to a whole bunch of capillaries all over the cortex of the kidney. And these are referred to as peritubular capillaries. These are your ordinarily everyday blood capillariesthe kind that have their blood pressure close to zero (~13-20mmHg) and feeds into veins. So whats going on here? You have your blood coming in from your arteriole, theres your capillary bed, and it goes out through an arteriole, which leads to another capillary bed. This sort of arrangement where you have blood flowing from an arteriole into capillaries and these capillaries go into another vesselin this particular case it is an arteriole because its muscular and has all the properties of an arteriolesand this leads to another capillary bed which eventually drains into venules and veins and so on back to the heart.

Portal Systems Whenever you have 2 capillary beds in sequence like that, its referred to as a portal system. A portal system is usually used for transporting something from one capillary bed to another. There are 3 portal systems in the body. One you recently had, its referred to as the hepatic portal system. You have blood flow into the blood vessels around the small intestine. It collects into the hepatic portal veinthese are capillaries that are supplied by your peripheral circulatory system, goes into capillaries that surrounds your small intestine, picks up food and nutrients, and carry it to the liver wherewell its not really a 2nd set of capillariesits the sinusoids and so on but they sort of function the same way. Large surface area and the liver can absorb whats being carried to it. Eventually, it does whatever it does and it all drains off into other veins and general circulatory system. The 2nd portal system that were gonna get to when we discuss (Dr. Lopez will discuss this) the endocrine system which involves the hypothalamus and pituitary gland. Theres a hypothalamic-pituitary portal system where a small vein carries stuff from capillaries in the hypothalamus down to capillaries in the pituitary and transport hormones that way. Youll be getting into that in a week or so. So dont worry about it now. This is the 3rd type of portal system. Its called a portal system because it has two capillary beds in sequence/series and blood flows through one capillary bed and through another. Dynamics of Capillary Pressure and Filtration

This is the capillary inside the glomerulus. Dr. Wishe gave you the whole structure of them. Im not going to repeat that and filtration takes place there which then feeds into the efferent arteriole. This time this portal vessel from one capillary bed to another is the efferent arteriole. These are the peritubular capillaries, which lead into veins. What is the advantage of having this efferent arteriole as an arteriole? An answer is that think back to Dr. Kinallys lecture on circulation. This is the part of organ systems where you keep looking back to show you the unity of this whole first year course. What happens in an arteriole is that it is a resistance vessel that provides resistance. You should know this for the midterm for gods sake.

Resistance vesselsas blood flows through it, the pressure drops. Blood pressure drops when you get into arterioles and then you get into capillaries. Mean arterial pressure (MAP) up here is about 100mmHg. And by the time you get to the veins, youre somewhere in the 13-20mmHg range. Lets stay 20mmHg. Theres this pressure drop of 80mmHg caused by the resistance of blood flow passing through an arteriole. This is in the regular part of circulation everywhere except here. The reason for that is thisyoure starting out with your MAP of 100mmHg and youre going down to veins where the pressure is gonna be low (20mmHg). This is a drop of 80. But here youre passing through the afferent arterioleso blood goes from the arteries at a 100 down to the afferent arteriole and then it goes through a bunch of capillaries inside the glomerulus and from there it goes down the efferent arteriole and eventually reaches other capillaries or veins and youre down to about 20mmHg. Theres 80mmHg drop as you pass through this pathways. Theres nothing new about that. Whats new is that you dont have pressure drop in the capillary beds because the flow is slow and theres no muscular tone and then you have another arterial, thus another pressure drop. The total pressure drop going through the afferent arteriole and then through efferent arteriole is 80mmHg. So lets just assume, and its approximately correct to assume, that the pressure drop here is about 40mmHg and the pressure drop here is about 40mmHg. Total is 80mmHg. Its not exactly a 50/50 split but its close. If thats the case, whats the blood pressure here? 60 because you started at a 100 here and you drop 40 giving you 60 and from the 60 you drop another 40 ending up with 20mmHg. Blood pressure at the end of afferent arteriole and the beginning of the efferent arteriole is about 60mmHg. Whats the blood pressure/hydrostatic pressure in these capillaries? 60mmHg because the pressure going into it and coming out of it because theres no drop in capillaries is 60mmHg. Now remember in the old days, we used to call it Starlings equation, the way to figure out whether filtration versus absorption takes place in a capillary. You have the hydrostatic pressure minus the external pressure and you throw in the osmotic pressure on both sides (theyre the opposite direction) and you see where the difference lies. Normally, the higher the hydrostatic pressure of blood going through a capillary, the more filtration takes placefluid leaving the capillary. And if theres less pressure difference, then theres less and theres also perhaps some sort of reabsorption (fluid moving into capillary). This occurs in normal capillaries but this is not a normal capillary. This is a capillary with 60mmHg of pressure inside it. So theres gonna be a lot of filtration taking place. Theres a lot of fluid that leaves the capillaries. Remember Bowmans capsule and Bowmans space. And you have various limitations on what actually can get filtered in these capillaries. And you have the slits, pinnacle, and basement membrane so on and so forth. Basically, you dont get any particles or any blood cells that get filtered. Only plasma gets filtered and even in the plasma if you have fairly large proteins (over 70,000 molecular weight), theyre held back but smaller molecules will go along with the water and the plasma plus the regular solutes (Na, Cl, and whatever else you got in your basic seawater). And you get removal by filtration of a lot of plasma in the blood coming in through the afferent arteriole. So what typically happens is this: Heres the glomerulus and heres a capillary, you got a certain amount of plasma going through plus cells; cells eventually come outI

should bend this around to distinguish between vascular and urinary pole. Almost about 19% of plasma gets filtered. Its a lot easier to say 20. The amount of blood that goes in through the afferent arteriole, only 80% of that plasma volume comes out into the efferent arteriole. Thats why as Dr. Wishe pointed out, the efferent arteriole is smaller in diameter to the afferent arteriole. Because of the high pressure, you got 20% of the plasma filtered. Theres an interesting side effect. Lets say youre starting out with a hematocrit in your blood around 45. That means every 100ml of blood has 45ml of red blood cells and 55ml of plasma roughly. Out of that 55ml of plasma, youre filtering 11ml. So now you got 45ml of red cells and only about 44-45 ml of plasma. So the blood in the efferent arteriole is about plasma and blood cells, which means your hematocrit is about 50. So you have this polycythemia going on with a higher concentration of red cells in the efferent arteriole. Thats just a little side thing you dont have to worry about itworry about it for exam purposes but dont worry about it for real life. The blood going into the efferent arteriole then provides what are called peritubular capillaries because these are the capillaries that surround the rest of the nephronthe rest of this tubulesthe duct of the gland so to speak. How much are we talking about? Im not a very big person on memorizing numbers but typically with standard/average cardiac output and so on. Over the course of a day (24hour), that 19% of plasma flow through the glomeruli and you multiply this by 2 million glomeruli (1 million in each kidney). You actually filter something like 180L per day. Obviously, you arent 180 liters. You dont have 400 lbs of water in you. So obviously, with very little thought about it, somewhere along this process before this 180 L a day of filtrate eventually ends up producing a certain amount of urine. Youre going to reabsorb most of it because your average urine output is per day is 2 liters. So if you filter in all of your nephron/glomeruli 180 L a day, youre going to have to reabsorb 178 L a day as all of this passes through the nephron. And well be spending a lot of time discussing what happens to that 180 L a day as you pass through the nephron. So heres your glomerulus, blood comes in, blood goes out, capillary filtrate ends up in Bowmans space within Bowmans capsule, and at the what Dr. Wishe refers to as the urinary pole is the beginning of the nephron. Proximal Convoluted Tubules

The first bit of nephron you come to is referred to as the proximal convoluted tubules (PCT). PCT is called proximal because its near the glomerulus. Its convoluted because it twists and turns and does a lot of wiggling around. As the filtrate produced passes through PCT, there is significant amount of reabsorption. Where does this reabsorption go? It goes into peritubular capillaries which are sort of surrounding this wholetheyre throughout the cortex of the kidney. So anything that gets reabsorbed into extracellular/extratubular space here gets picked up by these capillaries and end up adding to the blood flow volume going through these peritubular capillaries. Well be getting back to these peritubular capillaries later on in a week of soless than a week. What actually goes on in the PCT? Theres filtrate moving along. What is the composition of filtrate? Well consider the concentrations of plasma which is basically your seawater that we all started out as plus some proteins. Any proteins over 70,000 molecular weight are not filtered. Small solutes are dissolved in addition to the usual seawater, which is the usual NaCl solution. One of these things is some small proteins. For the most part, its essentially whats called a simple filtrate of plasma except for the items removed such as larger protein. You get essentially the plasma. A solute, anything dissolved in the plasma, that is filtered freelythis is the term we use freely filtered means the filtrate in the beginning of the PCT or within Bowmans space has the same concentration of that solute as there was in the plasma. Its true for sodium, potassium, chloride, glucose, most amino acids, and anything thats seasonally soluble in water and small. The concentration here will be the same as the concentration in those capillaries or in the circulating blood plasma. What youve got is these freely filtered solute are in the filtrate and the filtrate is going through the PCTso heres your tubulestake a slice through itits made of up cells and whats going on in it. If you look at these cells, what you have is near the outer part of the cell, you have lots of mitochondria producing lots of ATP, which means you can do a lot of work. What kind of work? Well here you have your Na/K ATPase, everybodys favorite molecule and it pumps 3Na for 2K in. Chloride follows the sodium to maintain electroneutrality. But remember for most cell membranes, potassium is freely permeable. So potassium does not stay where you put it. It can move back out the cell, it can stay in the cell whatever. The main point is your sodium is reabsorbed. What does that do? It decreases the Na ion concentration inside these cells cytoplasm which creates a larger than usual gradientnormally ECF such as the filtrate has a higher concentration than the cytoplasm of a cell. But if you got these mitochondria generating ATP and lots of sodium being pumped out of these cells, the Na concentration is lower than normal inside these cells. So theres gonna be a tendency of Na in the filtrate to move into the cells from which it gets pumped out on the other side. Theres a problem of course. This is not an electrically excitable cell. The problem is this cell membrane has very little Na permeability as most cell membranes do. So you need some way of getting more Na across this membrane and there are 2 approaches nature has taken. One is instead of a nice smooth membrane, the cell puts out these structure that greatly increase the surface area of the cell called the brush border which gives you essentially a lot more surface area. So sodium can with difficulty get across the membrane, if you increase enormously the surface area of that membrane, theres that much more chance for Na to get

across. You got this brush border, which greatly increases the surface area so that some sodium can get in that way and theres one other factor. And that is on this membrane facing the lumen of the tubules, youve also got some Na transporter but theyre mini-typesperhaps youve seen them in the digestive systemthese are Na-glucose symporters or cotransporter which pick up a molecule of glucose and Na ion and together ferry them across the cell membrane from the filtrate into the cytoplasm of the cell. This is a 1 to 1 molar ratio (1 sodium ion and 1 glucose molecule). But think about the ratio of concentrations here. The concentration of Na in the filtrate is like 145mM because thats your basic seawater Na concentrations. When I saw seawater, Im referring to all extracellular fluid with the exception of endolymph. So you have about 145mM of Na. What about glucose? Well, the concentration of glucose in a normal person is about 5mM. Think about everyday things. Im sure everybody in this room if he/she knows someone with diabetes who is constantly measuring blood glucose level. The average the blood glucose level is about 90mg/deciliter, which is multiply that by 10 equal to 900mg per liter. The molecular weight of glucose is 180. So you have 5mM times 180 equal to 900 mg. The point Im leading to is the concentration of glucose compared to concentration of Na in the filtrate is about 28 times more sodium than glucose. So if you take 1 Na and 1 glucose at a time, eventually youre gonna run out of glucose in the filtrate because if you take 5mM of glucose, it will drop Na concentrations from 145 to 140 mMnot a really major to do. So whats gonna happen is its gonna facilitate a certain amount of Na reabsorption but its gonna take essentially all the glucose in the filtrate out of the filtrate and have it reabsorbed into the cell. So the glucose moves into the cell and eventually the glucose permeability across the other side of the cell will lead to it being reabsorb by peritubular capillaries and get it back into the peripheral circulation. Glucose is conserved. Would you expect this to be an evolutionary good thing? Yea cause for most of our evolution, food is scarce. Its only now that people are getting fat. But the body evolved to hang on to whatever nutrient it could hold. If you can manage to eat something that makes glucose, you want to keep it. You went out and spent a lot of energy doing a lot of work to get that food. So this is a mechanism that evolution preserved by not letting you just lose all of your glucose in your urine. So the point is that glucose does not appear in the filtrate beyond the PCT. The passage through the PCT keeps all of the glucose from passing any further in the nephron. This will come up later again because the rest of the nephron never sees any glucose in the filtrate. The rest of the nephron is always zero and in a normal healthy person, theres zero glucose in the urine. What goes on as the filtrate passes through the PCT? You started out by filtering something like 180L per day. By the time, you get through the PCT, heres whats going onyoure spending a lot of energymitochondria producing a lot of ATP driving the pumpNa gets pumped out of the cells from the filtrate and in the process it also takes glucose. When you do that, remember, Na is the primary osmotic contributor to the osmolality of the filtrate. So this is now dilute as it moves along the PCT compared to the cytoplasmic ion concentrations. Osmotically, water is going to follow the Na. And as water goes, so does everything else thats dissolved in the water. Its called the solvent drag cause the water, the solvent; if it moves so

does everything dissolved in it. So what you end up doing is reabsorbing Na by the pump, Cl by maintaining electrical balance, K and all the other solutes following the water, and the water by way of following the Na and Cl osmotically. What you end up doing is reabsorbing about 2/3 of what gets filtered at the glomerulus. So by the time you reach the end of the proximal convoluted tubules, youre down to about 60L a day of filtrate. You reabsorb about 2/3 of everything. Well, theres one exception to the 2/3 of everything. That is you reabsorbed 100% of glucose in the normal healthy person.

BREAK TIME Before we go further along the nephron pass the PCT, we have to kinda take a whole look at the structure of the kidney as a whole. And basically what you have isheres a kidneythis is all cortex up hereyou have lobes of medulla that are distinct from the cortex...I should put more of a dotted line herethat project into the interior of the kidney and the cortex projects inwards a little bitheres another one and this is all cortex out here and so on. What happens in the functioning of the kidney is that we gradually build up an increase osmolality of the interstitial spacethats the in between the cells, the extracellular fluid becomes very hypertonic the deeper you go into the medulla to the point where normally, up in the cortex the tissue osmolality is about 310 mOsm/kg of water. Osmolality is measuring the number of dissolved particles perthe physical chemistry types and thermodynamicists absolutely assure us that you cant say per liter, its per kilogram of water. Theres very little

difference. But its 310 mosm per kg of waterthats your basic isotonic seawater. But as you go down into the medulla, into each of these pyramids of the medulla, the osmolality greatly increases from the 310 up to about 1200 or even 1400 mosm. Now what were going to try and do is discuss what happens to the nephron, how the nephron is affected by the hypertonic tissue that its passing through as structure known as the loop of Henle, dip down into the medulla, and come back up towards the cortex. And what weve got herealso its the loop of Henlethe part of the medulla that is actually maintaining this hypertonic medulla. So the nephron is maintaining the hypertonicity of the extracellular space in the medulla. And at the same time, this extracellular space being so hypertonic affects what goes on in the nephron. Loop of Henle - descending limb of the loop of Henle (DLH) So what typically happens is this: you start off with a glomerulus, blood vessels in and out, PCT, and then at the end of the PCT, you have a structure known as the loop of Henle, which dips down into the medulla, turns around usually referred to as a hairpin loop and it goes back up to the cortex again. So heres cortex and heres medulla. The loop of Henle has two major components: theres the descending limb of Henle (DLH) and the ascending limb of Henle (ALH). The filtrate after its gone through the PCTso you start out with remember 180 L/dayand it ends up down around 60L here and then it goes down and back up the loop of Henle. The properties of the ascending limb and descending limb of the loop of Henle are quite different from each other. In the DLH, what happens is that essentially youre passing through this hypertonic fluid so water is osmotically being drawn out. At the same time, theres lots of solute here (lets say Na) and that moves into the filtrate. As the filtrate moves down to the hairpin turn at the loop of Henle where the extracellular osmolality is perhaps 1200mosm compared to 310 here at the top. This is passing through a very concentrated extracellular space where osmotically its going to suck water out of the DLH and at the same time, Na/Cl/other solutes are gonna diffuse inwards. Now youre not doing any work in particular except for the flow of filtrate that keeps it moving. So whats happening here is osmotically, youre removing a certain amount of water. You start off with 60 L of filtrate reaching the end of the PCT, you end up with about 36 L per day reaching the hairpin loop of the loop of Henle, which suggests that 24L a day are removed from the DLH osmotically. The water is drawn out because youre running this tube through a very hypertonic space and the water tends to move out by osmosis. Remember water moves from a region of low osmotic pressure to high osmotic pressureits sort of a negative pressure in that sense. And so what happens is.but if that was the only case rememberthis is going from 310mosm to 1200mosmthats 4 timesif it was just a matter of removing water to get up to the 1200, you would be removing of the water leaving the water and 4 times the osmolality. Right? This starts out at 300ish and ends up down here about 1200so thats 4 times the osmolality. If it was just a matter of keeping the same solute and letting the water reabsorb, youd have to remove of the water. But you dont have to remove of the water. You remove about 40% of the water. So that proves that there are Na and other solutes moving in as well. So this moves down here and this 36 L of filtrate moves up towards the

cortex again because you put in water at one end of the hose, its gonna come out the other end. So some of this got reabsorbed. A little more than of it remains in the tube. What remains in the tube has to go back up. Ascending Limb of the loop of Henle (ALH) Now the ALH has some unique properties. Its impermeable to water. No water can go in or out. Very few biological membranes you can say that about but this is one. So the 36 L a day that reaches here is 36L a day at this end because theres no change in the amount of water. But what does happen as it goes up? Theres a unique transport system/carrier thats present in the ALH. As youre going up, youre going from a very hypertonic place to a less hypertonic place. This has reach equilibrium going down loop of Henle (descending limb) so that the filtrate is about 1200mosm also otherwise water would keep moving. Is it gonna stay in equilibrium on the way up? Not exactly, what happens is on the outside theres your Na pumpit does a lot of workthere are mitochondria to drive the pump and it pumps the Na from the cells of the tubules into the extracellular space. So Na is being moved from the filtrate into the cells. You have the pump on the serosa side (outside), ATPase that moves the Na from the inside of the cell to the outside space. But theres the problem of getting it across the other membrane. Remember in the PCT, you have a Na/glucose cotransporter but that wont be any good here because theres no more glucose. And you had a brush border, which these cells dont have. So you need something to be able to get the Na from the filtrate into these cells so it can be pumped out. And what you need in the ALH is a carrier in the membrane thats a Na/K/2Cl carrier. In other words, in the filtrate, it picks up 1 Na ion, 1 K ion, and 2 Cl ions so this is all electrically neutral and it takes it across the membrane into the cytoplasm. This is a very efficient; hard-working (its not working, its just a carrier, NO ATP is involved here) transport system for Na, K, and Cl. It moves them from the filtrate into the cells where it gets pumped out into the extracellular space. Now somewhere in there, I put it further down in the bottom of the 2nd page of my handout, theres a link/URL that you should take a look at. What it basically indicates is this: if you have sort of a an assembly line, the filtrate is moving along through this tubule, as it moves along, youre removing Na and solutes and gradually the osmolality will go down. What it basically shows is that if this fluid flows through too fast, the act of removal of solute becomes less efficient because theres not enough carriers to keep up the rate. So the transport system and removal of solutes become a little less efficient. Whereas if you move slowly enough, it becomes more efficient. Thats sorta illustrated on the clip that I gave you the link to. Its worth 3 minutes. So basically what you have here is as you go up the ALH, this active transport mechanism is removing the solute that it picked up on the way down. Remember it got these Na in as it was going down. Here in the ALH, youre not changing the water but youre moving the solutes out by this carrier plus the Na pump. Eventually, you get back to the neighborhood of isotonic osmolality. In fact, you go a little bit beyond that. Ill discuss that tomorrow. What you have here is a mechanism here where youre dipping the loop of Henle down into the medulla and then the loop of Henle goes back up towards the cortex and what has it done to the medulla? This pumping out of the solutes here is what made the medulla hypertonic.

All of these ALH (hundreds of thousands) are pumping Na ions into the interstitial space surrounding the nephron. So thats where the work is done to keep the osmolality of the medulla tissue in the pyramids of the kidney hypertonic. You have to remember this. If you look at the kidney itself, and you look at the separation between the medulla and cortex, theres no barrier there. So if you want this to be 1200mosm while this is 300, you should expect that solutes is going to be moving up and water is going to be moving down because if you have a vessel of water with some salt on one side, eventually if you wait long enough, its all gonna be uniform solution. But heres another case of youre doing a lot of work running up the escalator just to stay in the same placeto pump the solutes in in the descending side and then get removed from the filtrate in the ascending side. The net result is youre keeping this area hypertonic. Part of the problem with having to do this twice is I have to be absolutely sure I dont say something to one section that I dont say to the other. Normally, I dont go back to my notes but these are the notes on NYUClasses. So you still got your 36 L here. This ALH then feeds into once it gets back into the cortex, the distal convoluted tubules (DCT). I just wanna finish this first trip through the nephron. The DCT is in some ways proximal convoluted tubule like. It does many of things that the PCT does but less so. A) It doesnt have a brush border B) It doesnt matter whether it has a Na/glucose transporter because after all there is no glucose around in normal condition Distal Convoluted Tubules (DCT) What it does do is some of the Na in the filtrate in the DCT does get reabsorbed. In fact, about of it and the water goes osmotically and all the other solutes follow with solvent drag. So what you end up with here 36L a day to about 18 L a dayabout of it. This gradually feeds into whats referred to as the collecting tubule (CT) and collecting duct, which is a long duct and the collecting duct runs all the way down to the tips of the pyramids in the medulla. There are far fewer collecting ducts than nephron. As Dr. Wishe pointed out, the collecting duct empties into the calyx at the tips of the medullary pyramids. And there are like a dozen or so collecting duct emptying into each of the 10 or so pyramids. So you got a 100 and change collecting duct in each kidney compared to a million nephrons. So obviously many nephron, many DCT and collecting tubules feed into each collecting duct. And the collecting ducts collect from a lot of nephrons and carry the filtrate down towards the pyramid of the nephron and into the calyx or renal pelvis eventually. Collecting Duct This is your collecting duct and the collecting duct has some interesting properties. The collecting duct as it passes through the hypertonic medulla, you would expect some of the filtrate and water to be osmotically reabsorbed into the hypertonic tissue of the medulla because if you remember, the collecting duct itself is passing through these pyramids of medulla where the osmolality is 1200mosm. Water should be drawn out. The problem is, well its not really a problem, you wanna get the water reabsorbyou have to have a certain amount of permeability to water of the collecting duct. The collecting duct is not freely/readily permeable to water. Theres a regulation mechanism that controls the ability of the collecting duct to be

permeable to water. And specifically, theres a hormone that travels in your circulation. Its formed in the posterior pituitary and well get to that when we discuss endocrinology. And the posterior pituitary produces this hormone, antidiuretic hormone (ADH). Antidiuretic hormone (ADH) ADH is an interesting little molecule; its something like 16 amino acids, 2 of which are cysteine that form a disulfide cross-bridge. So what you end up with is this little peptide but it loops around where this cysteine bridge like a letter Q. ADH act on receptors on the collecting duct to open water transport mechanisms called porins. So ADH activates porins which allows water reabsorption and thats a good idea because how much filtrate is reaching the collecting duct? 18L a day. If you dont have ADH and your collecting ducts are not permeable to water, then none of that gets reabsorbed. And you end up putting out 18L a day of urine. 18L a day of urine is a lot of urine. This is called diabetes insipidus not to be confused with diabetes mellitus, which is sweet diabetes in translation. This is tasteless diabetes. Way back during ancient Greece, there were two different types of people who produced lost of urine. There were some that produced sweet urine. There were some that produced watery, tasteless urine. Ill give you one guess how they distinguish between the two. It took a lot to be a physician those days. Very quickly, they learn that if you put a bowl of urine on the windowsill, it either did or didnt attract flies. So lack of ADH leads to the situation of diabetes insipidus. Diabetes insipidus is not fatal as long as you have access to water to replace the 18L a day youre peeing out. Its inconvenient because if you consider the rest of the urinary tract which Im not going into in these groups of lectures. You have a bladder that starts to give you an urge to empty it when you have about 250mL of urine in it. It can hold twice that easily. You start to get the feeling about 250mL. If youre putting out 18L a day over 24 hours, about every 20 minutes, youre gonna feel the urge to empty your bladder which means you wont be taking long trips on the subway. This mechanism of the lack of ADH was discovered in a group of spontaneous mutant rats that were developed and studied in Vermont. What you have to do is take in a certain amount of ADH to reduce the urine output. ADH is sort of similar to the insulin problem in diabetics. You cant take it orally because the peptides are destroyed by stomach acids. However, ADH can be by a nasal spray. So another clinical triumph. Why dont we stop now and well pick up tomorrow.