welcome back this is part two of the chapter on the kidneys chapter 12 we had just finished summarizing the four steps of renal processing filtration reabsorption secretion and excretion and we are moving on to how we assess kidney function in order to understand some of the measures I have to explain a little bit about where some stuff comes from so so here's some background information uh about protein metabolism and Ura and where that comes from so over on the left um oh and I took these images also from that video that I mentioned before the crash course video uh so you'll remember proteins are large macro molecules they're made of smaller units called amino acids amino acids are called that because they have the so-called amine group it's a nitrogen with a couple of hydrogen stuck on it if we use the protein that we eat if we use that protein for building some more muscle or for I don't know making hemoglobin or for making something um that amine group stays right where it is but if we use the protein either for fuel right away or we use it um uh to make uh some sugars believe it or not you can convert proteins into carbohydrates um or we convert it into adose orose into lipids to store an adapost tissue if if those things happen then we have to take this amine group off and that's got to go somewhere and um the the process of taking it off happens in the liver uh let's see amino acids okay so in the in the liver the amino group is removed when you take that off um it forms ammonia this is bad news for the body um it's especially bad for the nervous system um and you will have patients whose liver is malfunctioning and it's not able to get rid of this ammonia it's it's it's really hard on the the nervous system as you find so what the liver does um instead of leaving all this toxic ammonia hanging around um it puts two ammonia together and it forms a molecule known as Ura this is a lot less toxic than ammonia but it's still a waste product we still need to get rid of it so it gets out into the bloodstream and then the kidneys are going to get rid of it when we measure how much you Ura um is in the the blood it's referred to as blood Ura nitrogen not quite sure why they don't just call it Ura but it's not it's called blood Ura nitrogen okay the other waste product that we keep track of is something called creatinin and it confuses everybody um creatinin is not poison um it's just that it's a really good marker for uh how well the kidneys are functioning so let's talk a little bit about where it comes from there is a molecule called creatine um creatine in fact some people take it as a supplement um what its job is it it can hold on to a phosphate group and you remember when you put a phosphate group on something you phosphorate it it it's a way of like increasing the energy of this molecule and so for example um we use ATP to to pay for stuff like uh sodium potassium pump we have to pay it so we pay it with ATP we put that phosphate group on to um the the sodium potassium atpa um to get it to pump some sodium and potassium well how do you get the phosphate group on the ATP in the first place well you put it on during phosphorilation over in the mitochondria sometimes you need to recycle this ADP adenosine diphosphate you need to recycle it back into ATP really fast and you don't want ADP to ever have to be waiting for a phosphate group and so that's the role that create that creatine and creatine phosphate play is as soon as we use up the ATP use it to pay for something the ADP can get back to the mitochondria and get another phosphate group put on it really fast um doesn't have to wait for it so if you had all the time in the world ADP would get its phosphate group it's going to happen but in those cases where you need a lot of this ADP recycled quickly that's the huge advantage of creatin and creatine phosphate is that it slams that that extra phosphate group back on the ADP making ATP really really fast and so the people who take creatine phosphate um are folks who do explosive kinds of movements um so athletes that need a lot of power really fast uh like for example um football players uh baseball players uh weightlifters um when you're going to use a lot of muscles and you need those muscles uh to contract very quickly we've gone over muscle contraction before and when you know the calcium movement and thein and the actin and all of that um that's using a huge amount of ATP and you want to replace that really really fast that's where the creatine is so beneficial um athletes that don't benefit from this are things like you know um I was going to say chronic um uh oh my gosh what is it called longdistance Runners um longdistance swimmers you know people who are doing they're exercising they're using their muscles but uh they don't need all the ATP all at once right now there's time and so there's not a huge benefit to taking creatin but all of our muscles athl athletes or non-athletes um all of us have creatine in our muscles and its role is this to put that phosphate group back on the ATP when we need it quickly if you need an an analogy for understanding this you know um think about uh fashion shows when you have models walking on the catwalk and then they come back and then it seems like 10 seconds later they walk back out again and they have a whole new outfit on they didn't do that by themselves there's a bunch of people backstage that are helping with the removing of the clothes they could change their own clothes they know how to do it they've got the capacity to do it they just can't do it that fast and so that's where the helpers come in the you know trying to do the turnaround faster and that's where creatin come comes in and so it's a natural compound it's present in all of our muscles um and some of it breaks down every day so let's see over here on the right we have creatine this is the molecule as it's functioning in the muscle it becomes creatine phosphate with that extra phosphate group that it can slam onto an ADP but they'll it'll sometimes break down to creatinine this is not useful this creatinine is not able to do this job and so this is just a waste product it's just a small percentage of the the creatine becomes creatinine every day so creatine it's the functional molecule it speeds up making ATP um and the creatinine is just the used up version and it's a waste product it's just that it's an easy waste product keep track of if you need another way of thinking about it as far as this waste goes I think about it as it's eggshells for example um it's just trash it's not super dangerous but if I have a way of assessing eggshells you know if I could just like feel through the garbage bags in my house and I couldn't see anything and I couldn't measure anything else I could just feel the the cracking of the eggshells like okay I can detect that that's how I'm going to keep track of say how often the trash is being removed um or if I'm getting a buildup of trash in my house it's not that the eggshells are super important it's just that there there's something that that can be detected and measured and kept track of that's all the creatin creatinin is so measuring kid function one of the measures that we're most interested in is how much fluid is passing through uh the glomeruli that's known as the glomular filtration rate and ideally there would be some magical way where we could you know monitor each and every one of the glami all day long and just see how much stuff is flowing through there there is no way to measure that that carefully directly and so we assess it um mostly as an estimate so usually GFR you'll see a little letter E in front of it it means estimated um and we can estimate it using some kind of marker something that's already in the blood um and that's what endogenous means something that's already in our body what's usually used as the marker is creatinine and it's not Ura you would you might think it would be Ura but it turns out Ura varies too much I mean yes it varies with kidney function but it can also vary with other things like how much protein did you take in and you know how how how much are you using for fuel and how much are you using to store how much are you using to build so it's not Uria is not a great consistent measurement for this that's why we use creatinine but again think eggshells it's just it's just a a waste product that we can keep track of if there's some reason that you absolutely need a a a better estimate of the glomerular filtration rate then instead of relying on some endogenous marker that's going to vary depending on how muscular somebody is and how how much exercise they're getting um let's use an actual measurement in that case we use an exogenous uh marker something that's actually infused into the patient we know exactly how much we're giving you we can test how much is in your blood and then we can watch um how much is coming out and we can watch what's happening to the blood level of this thing um that's what we mean by measured rather than estimated this is typically not done we just usually do an estimated glomular filtration rate and usually use creatinine to you to to do this estimate so it represents the total amount of filtration that's occurring in other words the sum of all the filtration that's happening in all of the nephrons as nephrons uh decline in function if they're damaged or if they you know the cells are dying off um due to kidney disease that glomerular filtration rate is going to come down and down and down then there's this other measurement um this is known as the renal clearance rate it's not the same thing as the glomular filtration rate but it's what the estimated glomular filtration rate is based on um so instead of estimating total filtration how much stuff is going through the kidneys it's looking at how efficiently are the kidneys removing a specific thing in other words in one minute how much blood can be completely cleared of a certain substance okay now some things should have zero clearance we should not be clearing them at all uh a couple of examples um small nutrients things like glucose small suited sugar um and amino acids those are the building blocks of the proteins but they're not proteins themselves there's the smaller bits that make up the proteins those things are small enough that they slip through the glomerulus they just slip out into the filtrate so they're filtered out because they're so small but then we pull those back in we reabsorb those I'm going to do an aside here um if we start detecting glucose in the urine that is a sign that the patient is diabetic um because if the blood glucose level is under 80 milligrams per deciliter and that's super high but if the number is under that the kidneys can manage to pull the glucose all the glucose back in this is going to come up later in in the lecture when we talk about um a particular medication that has an impact on the kidneys so yeah so glucose under normal circumstances glucose and amino acids they get filtered out because they're little but they're valuable stuff and so we pull them back in uh through re reabsorption uh so we did zero clearance we shouldn't see either of those things in the urine and likewise large proteins we shouldn't see those in the urine either um but those shouldn't even be filtered out things like albumin which is the most prevalent protein in the blood um the clotting factors the complement proteins none of that stuff should be coming out in the filtrate other in other um on the other hand um some things like creatinine they have great clearance very high clearance um one creatinine gets filtered out in that first step and then it's not reabsorbed because we don't want that that's a waste product um and then on top of that we do some more secretion we actively push it out of the blood and put it into the filtrate so creatinine clearance is so good that that is the molecule that we typically use to estimate the glomular filtration rate and there are formulas that you can use to to estimate fular filtration rate and you take into consideration things like how um how old is the patient and that's related to how much muscle mass do we think they have um and whether they're male or female all right the units um if we're estimating it at the milliliters per minute um if we're measuring it again you have to do a 24-hour urine collection because we want to get every molecule of uh creatinine that that this patient is peeing out it requires a a strict 24-hour urine collection a little bit more about renal clearance and Drug dosing um so our textbook goes in a little bit about the antibiotics so penicillin and many of the antibiotics they actually have high clearance they get filtered out unless they're bound to proteins so some formulations of some drugs are actually designed this way they're um so the medication actually doesn't need to to to work it doesn't need to be attached to a protein but if it if we don't make it attached to a protein it's going to just come out in from the glus every time um and so um some medications are formulated so they will hold on to say albumin um and that way it it's harder for the body to get rid of it so we can have the action of that drug longer um but many of the medications even though they're not being filtered they're still actively secreted by the tubular cells so when prescribing medications that get cleared by the kidneys one has to consider the glomular filtration rate in other words consider the health of the patient kidneys because if the kidneys are not working well they're not going to filter the the medication out and so we're going to get delayed drug clearance which again sounds like oh that's good we're going to get more bang for our butt a little bit of medication and lasts a long time but if you dose them the same way you do somebody with healthy kidneys then uh they're the the medications can build up to toxic levels and so with our older patients a little medication goes a long way we have to um keep track of which medications are cleared by the kidneys all right so injuries uh glomerular injuries and disorders they're the capillaries the glomular capillaries are vulnerable to damage and these are some of the the sources of the damage diabetes one of the worst the uncontrolled diabetes when the blood glucose is so high um patients with chronically high blood sugar they end up suffering from what's known as diabetic nephropathy you know with the A1C test you know that glucose binds to the hemoglobin that's how the A1C test works as you're basically seeing how much of the hemoglobin has glucose bound to it well glucose binds to other proteins too and um unlike the red blood cells that get replaced all the time our other other cells aren't being replaced and so this glucose protein binding this glycated uh protein formation it leads to inflammation it leads to fibrosis um and so initially what we get is a a breakdown in that barrier um and so where before proteins were not filtering out now this this barrier is breaking down and so it's got big old holes in it and protein can slip out and so when we see protein in the urine proteinuria that's a sign that there's damage in the glomerulus ultimately um this is going to lead to fibrosis and then we're not even we're not going to get even little things filtered out um that's chronic kidney disease the other thing that uh we see commonly in the clinical setting that causes damage to the glami is hypertension so it's damaging the afferent and efferent arterials um promoting atherosclerosis um that's going to narrow the Lumen of these uh some of the blood vessels so we're decreasing blood flow is one of the things that happens but with the elevated um blood pressure especially elevated above a certain level actually coincidentally it's also 180 um elevated above that level we get hyperfiltration so you're pushing more fluid through the tubules are overloaded so uh the posit analogy we dump out more than 20% of what was in there just more stuff comes out and the tubules get overloaded initially but again this leads to damage of the glome maruli and chronic kidney disease there are some infections that of course can have an impact on GLA functioning kidney infection um and there are autoimmune problems that can happen and we're going to continue this on the next slide when we have immune mediated glomular damage um we get this inflammation within the glami we call that Glon nephritis and what happens um you remember that there are antibodies our our V cells matured into plasma cells and they've been a bunch of antibodies um or antibody antigen complexes the antibodies have already attached to something else but they're in the bloodstream right so they go through the glomeruli well some of those things kind of stick deposit in the glami that can activate the complement Cascade um that draws in lymphocytes monocytes nutrifil recruited to the area more inflammation the glal get damaged we get swelling uh of of the cells um this blocks uh flow through the capillaries um glomular filtration rate goes down sometimes we will see a a very acute presentation of these symptoms um the one that's most famous is the strep throat post strep throat or streptococus pyogenes you may remember this from the first module when we did the infectious diseases um strep is famous for this it doesn't happen to everybody who get has had a strep infection but it does happen and it happens especially commonly in children so sometimes children present with all these you know kidney problems that they've never had before um and in getting the history from the family we find out that the kid recently had a strep infection or they're currently having a strep infection um we can also see um chronic problems with the autoimmune system with the immune system in the case of autoimmune conditions like uh lupus for example this can result in chronic kidney damage some of the symptoms that we see in on the urinary side of things uh decrease in urine production uh protein in the urine remember the the filtration mesh got holy got big openings in it um you may it may get so big that You' actually get red blood cells coming out um hematuria uh red blood cell casts okay this is a difficult concept for me as a student to understand um I thought well what's the difference between hematuria and red blood cell cast and it's the difference more analogies um in in your house sometimes there's dirt on the floor um and where did this dirt come from um well if it's all dusty little Dusty particles you don't know you know that may have just washed in or blown in you know because the door was open or the windows were open and some stuff blew in but if it comes out in like a little square there's some weird little shape of dirt that's from a boot you know that's that's like mud that got into a boot it's got a particular shape to it and it just fell out of the boots tread onto your floor that's what a cast is it's dirt in a in a particular shape and so it's a cast of the nephrons um and so if you have a bunch of cells that are kind is stuck together with protein that's coming out of the nephrons that means there's some damage up above it this this blood is not from say a bladder infection this is coming up from the kidneys or coming sorry coming down from the kidneys and then the dark Tec colored urine again sign that you you have um some blood in the urine uh systemic manifestations blood tests azotemia so emia means in the blood AO it it refers to nitrogen and I can tell you the history about it if you're interested um but Azo AO just refers to nitrogen and so it's an indication that there's going to be some increase in a nitrogen measure um so blood Ura nitrogen um serum creatinine because the kidneys are not working well to get rid of they're not filtering well um they're not getting rid of a lot of water we get the retention of the water and so that we may see hypertension we may see an increase in blood pressure because more fluid is staying inside the circulatory system uh again more fluid we got fluid overload we're going to get edema increased pressure in the capillaries is going to push some of that fluid out into the tissues so emia of the face upper extremities in children you might even see a CES a swelling in the abdomen and fatigue all right blood to the kidneys renal blood flow you'll see this abbreviated sometime as RBF um like here for example uh so kidney vasculature can dilate or constrict those uh afferent arterials they can shut down or open up um to maintain a steady flow of of blood through through the glome line so even when the blood pressure varies this is known as Auto regulation because the kidneys themselves are taking care of this step so let's walk through this graph on the x-axis we have arterial blood pressure so normal these ranges I shouldn't say normal typical um down here if the blood pressure is is too low and I'm sorry I'm just looking at the Blue Line I should not uh if we're looking at arterial blood pressure um we have um actually doesn't matter we have low low low low blood pressure here if the blood pressure is very low we're not going to be able to profuse the kidneys adequately but within the normal limits of blood pressure you can go up or you can come back down and that the kidneys are just really good at this you know they just regulate how much blood they're going to let through and so if we can if the kidneys are able to uh dilate the blood vessels or constrict the blood vessels they're able to maintain this steady renal blood flow no matter what's happening out in the systemic circulation blood pressure may go up because the person's stressed or may go down because whatever reason it goes down um but the glomerular filtration rate stays steady as well and it's because the renal blood flow is kept so steady above a certain level above 180 the the renal blood flow increases there no way around and that's where some of the damage comes from now in cases of extreme hypotension oops oh my goodness where are we in cases of extreme hypotension we're way down here um yeah the kidneys uh get overridden so in extreme hypotension the sympathetic nervous system can override the kidneys the kidneys are saying oh I'm going to dilate and let more blood in and the and the sympathetic nervous system says no you're not you're going to clamp down um because we need that blood to get up to the brain and we need it for the heart and so if this is a a shortterm thing that it causes a a transient decrease in glomular filt filtration rate and a transient decrease in kidney function then great the kidney can recover but if this hypotensive state goes on for hours um the kidneys can develop a problem as we'll Define shortly there are pre-renal intrarenal and postrenal causes of kidney failure this refers to a pre-renal cause of renal failure and that is the blood supply to the kidney so pre-renal failure it's not pre-failure it's prerenal something coming to the kidney um due to lack of perfusion all right nefron tubular function um each part of the nephrons do something they have CL characteristic roles um we've mentioned this repeatedly more than 99% of the glomular filtrate gets pulled back in so what we end up uh releasing as urine is it's a small fraction of what originally became filtrate at some point uh we're going to look at the different parts proximal tubal we get lots of reabsorption we get some secretion Loop of Henley we get reabsorption of water and sodium and chloride uh distal tubule we get some reabsorption of these electrolytes and collecting duct we do the final regulation the final fine-tuning of things and let me see we've gone on for some time so I'm gonna uh make a decision to call it here um this will be the end of part two and I'll see you in part three for more of the details