nf0440: if you're all ready to start thank you okay so we're looking about how 
you concentrate your urine so we're going to look at osmolarity and urine 
concentration and then we're going to look at water reabsorption and what 
actually regulates your water reabsorption from the nephron and this brings us 
on to the loop of Henle in the counter current er system now you might remember 
that from A-level and hate it but hopefully i'm going to explain it to you but 
it's really quite important to that you actually understand the principle 
behind it i know it says in your workbook you're not covering it that's because 
namex don't see any point in teaching it but i'm sorry everybody clinicians and 
myself think it's vital at this end so you do get taught it and then we're just 
going to finish up with what happens when it goes wrong and the two clinical 
conditions and these are actually covered in case studies so we skip over the 
er clinical conditions we're just 
not too much detail in the lecture because you get them in case studies to 
actually look at them in more depth so if we have a look at urine production 
first off then so this is your you've got a huge flexibility in how much urine 
you do or don't produce so you've got a minimum of about point-twenty-five er 
point-two-five mls per minute and a maximum of twenty-five but twenty-five's a 
hell of a lot of urine if you've got somebody producing twenty-five mls of 
urine a minute er you probably want to do something about it and it's not 
normal to produce that much urine despite the fact that we can do normal urine 
production most of you probably peeing somewhere between about fifteen-hundred 
and two mls a day and that works out to just if it's fifteen-hundred that's a 
ml per minute is what you're actually producing in the kidney now this is kind 
of an important number because if you were producing two litres of urine a day 
and you'll see why on the next couple of slides that 
actually means you're er peeing out isotonic urine compared to blood plasma and 
that doesn't matter to us er if your kidneys are operating normally that's no 
problem but if you're a renal patient with some impaired function er drinking 
two litres and therefore peeing two litres kind of takes the strain off the 
kidney really so if you've got somebody with impaired renal function two litres 
becomes more important and most of you will know this already you make more 
urine during the day than you do at night because most of you will be able to 
sleep through the night and not get up to go to the loo whereas you might go 
three or four times during the day or even more and if you're pee-, if you're 
making urine less during the night you're also excreting less salts because 
obviously the salts and the water go together so you e-, excrete more salts 
during the day and you pee more urine during the day now obviously this might 
change if you're a shift worker if you work 
nights your system's going to readjust to it because you actually produce more 
water during the day because of what you do because of eating and metabolism so 
if you're er on the reverse system because you're a night worker then you're 
going to be metaboli-, meta-, metabolically more active during the night so 
you're going to pee during the night because effectively their days are just 
reversed but normal day shift workers we make more urine in the day than we do 
at night and this is just important here we're going to talk about A-D-H later 
antidiuretic hormone but the amount of solutes you excrete per day is fixed 
depending on your intake and what you need to get rid of it's the amount of 
water in your urine that varies which is why the osmolarity has to vary you 
don't change your concentration the amount the quantity of solutes that you 
want to excrete so if we just look at how flexible it is this blue bar here 
that's your plasma osmolarity remember i said week 
before last or whichever week it was w-, session one or two your plasma 
osmolarity has to stay very fixed it's it's very narrow band around about two-
hundred-and-eighty milliosmoles in contrast your urine can have this great 
range although it looks like it can make it er more concentrated relative to 
dilution actually it's a tenfold dilution it can manage because it can er 
produce thirty milliosmoles er of urine er it has can be that dilute this is er 
a concentration that's only four times the value of plasma but it's a huge 
range now you can actually work out the concentration of your er osmolarity of 
your urine if you want to and this is what we averagely excrete a day about six-
hundred milliosmoles of salt solutes er on an average normal diet over here and 
therefore you can just put the numbers into this equation and come up with er 
these simple answers so that if you excrete fifteen-hundred mls of urine then 
the concentration of urine's going to be that 
obviously if you excrete double the amount of urine it's less er so i've just 
put that in for you to know about but this is important we're not going to most 
of what we're going to talk about today is how you regulate water via hormones 
and osmosis et cetera but the solute concentration will alter your alter er 
your urine excretion on its own independent of antidiuretic hormone and 
anything else that's going on so just to get the the units up here come like 
that but just remember that a kilogram of water is a thousand mls therefore 
you're actually talking of the molarity effectively it's just that osmolarity 
comes with slightly different units so remember i said a normal person needs to 
excrete on an average diet six-hundred milliosmoles and then that's your 
maximum urine concentration of twelve-hundred so that means to excrete that 
during the day you have to pass five-hundred mls of urine if for some reason 
you want to get rid of this num-, this amount of salt 
depending on your diet or various other conditions the maximum urine 
concentration's still only twelve-hundred so in this case you have to er pee 
fifteen-hundred mls and that is totally independent of whatever else is going 
on if your solute concentration goes up you will need to pass more urine if 
nothing else changes and i've just said that so let's have a look what actually 
happens to water in the nephron so here we have your hundred-and-eighty litres 
of filtrate per day but you only get rid of one per cent which is one-point-
eight here or fifteen-hundred mls that sort of er quantity now these two 
regions of the nephron get rid of somewhere between eighty-five and ninety per 
cent of the water they reabsorb it and this is done passively there's no 
regulation whatsoever now although er from the diuretics lecture with namex if 
you can remember you can modify the absorption of water in these parts of the 
nephron that's a drug action normally you don't regulate 
it whatsoever you just simply reabsorb passively all this amount of water but 
this is what we're going to look at this part of the nephron the collecting 
duct you regulate the amount of water that you reabsorb and that's the bit that 
we're actually going to look at the control of so you only have control of a 
small amount of your filtrate i haven't actually done the numbers but most of 
that hundred-and-eighty litres is going to be reabsorbed here relatively under 
no control whatsoever you only have control over the small proportion the sort 
of ten per cent that actually gets to this part of the nephron so how does the 
er collecting duct regulate water reabsorption so it's regulated by this 
hormone you're going to see it called two things it's antidiuretic hormone 
hence it's A-D-H it's also called vasopressin and the abbreviation's A-V-P 
that's simply 'cause we've got an arginine in the human form of vasopressin and 
depending on the age of the textbook or 
the age of the clinician they might alternate between A-V-P or A-D-H so you 
need to know both of them and the water transport in the collecting duct is 
also passive so if it's passive you need water channels you need something 
physically for the water to move through so in response to antidiuretic hormone 
so antidiuretic it's going to stop you peeing it's going to make you conserve 
water you get water channels er transported into the er ch-, er the cells of 
the the membrane of the tubule cells and we'll see exactly how in a bit later 
but you also need something else water's not going to move on its own you need 
an osmotic gradient so you need there to be a difference in the concentration 
of the er solutes in the filtrate compared to the concentration of solutes in 
the interstitial er tissues surrounding the nephron so you need to produce it 
so you have there's two things you have to have you have to have a very dilute 
urine 
going into the collecting duct and you need to have this osmotic gradient which 
is produced by the counter current system and i've just put down here A-D-H 
also activates the urea er transporter and you'll see why that has a slight 
relevance later but don't get tied up on that so if we have a look at these 
water channels first we're going to take our s-, ways through we're going to 
look first at the water transport and antidiuretic hormone and then we're going 
to look at the generation of the osmotic gradient so it's at least five of them 
at the moment four of them are in the kidney er the the type one is in the 
proximal tubule and in the loop of Henle and this is what er is involved in the 
unregulated water transport it simply flows through the A-Q A-P-Q-one er three 
and four are also in the collecting duct er but these are in the basolateral 
membrane so that's the interstitial tissue er border with the tubule lumen 
remember you've got a kidney tubule cell water has to go into it and 
out of it so these ones here are actually the er aquaporins that control the 
water release from the tubule cells back into the circulation and these are the 
ones we're interested in the aquaporins two and these are the aquaporins that 
go into the lumenal membranes that's the side where the filtrate is and they 
control the loss of water or er from the filtrate into the er eventually into 
the bloodstream so it's the A-P-Q-twos we're talking about today so what's 
antidiuretic hormone it's a very small peptide er and in terms of i've i've put 
down here details but for your interest it's made in the hypothalamus and it's 
released from the pituitary so you've got the hypothalamus and the pituitary 
involved one makes it and one releases it and that's important and it's got a 
very short half-life with most of these peptide hormones you expect them to 
have a very short half-life so the control's quite fine so how do we control 
its release the main mechanism by regulating A-D-H 
release is in the hypothalamus and it has osmoreceptors up here which detect 
changes in plasma osmolarity so if the plasma osmolarity goes up that means it 
becomes more concentrated you want to dilute your plasma so you want to retain 
water you actually release A-D-H from the pituitary and this will then have the 
effect on the kidney er you can see here you've also got this is er obviously a 
diagram taken from the textbook you've got a thirst centre up here so the 
osmoreceptors not only control A-D-H release which is what we're looking at 
today but they also regulate your thirst so you've got the two aspects if you 
become water depleted or your plasma osmolarity goes up you release A-D-H to 
regulate water reabsorption or stop its loss from the kidney but you also 
stimulate your thirst reflex so you drink more so you're putting more fluid in 
as well er there's also i'm not going to dwell on it and i don't know whether 
you covered it in cardiovascular er 
module but the heart also has stretch receptors in the right atrium and they 
respond to blood volume and they can also release A-D-H so that if you've got a 
large blood volume so you want to lose some water they switch off A-D-H 
synthesis or release and vice versa er but that's not part of this module so 
what happens with A-D-H release then so remember i said you want to keep your 
plasma osmolarity at about two-hundred-and-eighty so you can see here just 
above two-hundred-and-eighty you suddenly see this er increase in er A-D-H 
release and this is actually what we've normally got because our plasma 
osmolarity varies between about two-hundred-and-eighty and three-hundred if it 
has to it doesn't it's happier nearer to two-hundred-and-eighty we actually 
always have some A-D-H circulating you would expect to find A-D-H in normal 
people but you can see as it goes up and this isn't a very big difference 
remember your urine osmolarity can go up to twelve-hundred so this 
is up to three-hundred-and-ten is actually a relatively small change you get er 
er a rapid increase in A-D-H release so how does it work so here's your er 
tubule er er cell of the collecting duct so this side is the lumen so this is 
where the urine is now in the collecting duct and this is the blood side but 
remember when talking about blood it actually goes out of the tubule cell into 
the interstitial fluid and then into the blood er vessel and that'll become 
even more apparent as we go through today so you've got vasopressin receptors 
on the er cell surface obviously they pick up er circulating levels of A-D-H 
and i've just put down here these are V-two receptors A-D-H also is a 
vasoconstrictor in which case it acts via V-one receptors to modulate er 
vasoconstrictions primarily in the skin but in other parts of the er body as 
well and if it's acting as a vasoconstrictor it uses V-one type receptors and 
they signal fi-, through phospholipase C whereas these V-two 
receptors which are in the kidney er as we'll see now signal via cyclic A-M-P 
and they also have er a lower level of er you need less A-D-H for the V-two 
receptors to respond than you do for the V-one receptors so they're more 
sensitive so here you go so the A-D-H binds to the receptors cyclic A-M-P 
release pro-, er P-K-C activation and protein phosphorylation that's ec-, your 
standard er activation pathway what the protein phosphorylation does is it then 
allows these inactive water channels er aquaporins to be translocated to the 
membrane once they're inserted in the membrane this then allows water to move 
from the urine into the cell and you notice i'm actually talking about urine 
now because it's into the collecting system so it's urine not filtrate so we're 
actually concentrating our urine we're not concentrating our filtrate so the 
water moves in protein phosphorylation also longer term regulates the er 
transcription of the aquaporin gene so er if you 
have continued stimulation here you'll get aquaporin synthesis which again then 
allows more er water transport to occur and if we look at what happens to the 
er permeability of the tubules so you can see here remember i said the proximal 
er tubule and we've got it split here into two the proximal convoluted and the 
proximal straight and the thin descending loop of Henle they've got a huge 
capacity to er reabsorb water passively by osmosis whereas these regions so 
you've got the thin ascending loop and the thick ascending loop and parts of 
the distal nephron and the collecting system this is the cortical collecting 
duct er are able to absorb small amounts of water whereas the inner medullary 
collecting duct has no water absorption normally but under the control of A-V-P 
you can see both of these two er collecting duct regions er the ability to 
reabsorb water increases dramatically so what stimulates its release i know i 
said er you've got osmoreceptors that er 
detect changes in plasma osmolarity and that's what actually stimulates the 
release of it but what do er what's actually detected so you've got changes 
here of plasma osmolarity if you get alterations in your extracellular volume 
therefore you're becoming dehydrated that will also er change its er release so 
in this case if you become dehydrated you want to retain water so you produce A-
D-H which stops water secretion thirst nausea's quite interesting if you feel 
sick you start producing A-D-H because your body assumes if you feel sick 
you're going to be sick and if you are sick you lose water and lose er fluid 
volume from you so it kind of er as a precaution and also some drugs down here 
so you kind of might need to be aware of people if they're taking certain types 
of drugs and they come in with an abnormal fluid volume that might be why so if 
we look at inhibition of its release which will cause a fluid loss because 
you're not er causing reabsorption again 
plasma osmolarity and then one we all know about alcohol drink too much alcohol 
you have to go to the loo constantly and er happens a lot particularly to boys 
with pints i have to say and the cold as well you go out in the cold weather 
you end up peeing more than normal or you want to and stress will have an 
effect so they're they're the er er physiological stimuli that actually alter A-
D-H release okay so we've looked at the er insertion of water channels into the 
tubular membrane under the control of A-D-H what about the concentration of an 
osmotic gradient so if we look here so this is like a cross section you've got 
cortex outer medulla inner medulla and you can see if you look at sodium and 
chloride they're almost the same but they go up so there's much higher 
concentrations in the medulla than in the cortex and urea goes up and it's 
these three the combination of these three sodium chloride and urea that 
actually makes the inner medulla of the cor-, of the kidney very 
concentrated osmoticallywise so that's what generates an osmotic difference so 
how do we do this so there's a number of mechanisms if we look at urea first 
now remember urea's freely filtered so everything that's circulating would 
potentially be filtered so that's a hundred per cent goes into the er nephron 
of that fifty per cent is reabsorbed early on in the proximal tubule so you've 
got fifty per cent of your total urea concentration going into the nephron down 
here when that goes it goes all the way round gets right round to the 
collecting duct and it's reabsorbed so er and you've got seventy per cent of 
that remaining fifty per cent so the seventy per cent here is reabsorbed goes 
into the medulla because you remember this is all interstitial space between 
these parts of the nephron but some of that is then secreted back into the 
kidney so if you remember urea's one of those strange substances it's filtered 
here it's reabsorbed here and here and it's also 
secreted so you've got b-, all three of the main mechanisms of er urine 
production going on with urea so of this seventy per cent that it secretes into 
the medulla some of that is then taken back up into the nephron and sixty per 
cent so you can see you've got ten per cent difference between what you 
reabsorb and what you put back into the nephron and that ten per cent stays in 
the medulla and because er and it creates er a concentration gradient so you'll 
have less urea at this region and more urea down here and you can see er you 
get ten per cent in your er medulla you retain that that's part of your osmotic 
concentration gradient and then that actually means if you do the sums that 
forty per cent of your filtered load actually ends up being excreted by the 
kidneys but it's this small percentage here that remains in the medulla that's 
important okay loop of Henle did you all do this at A-level no yes did you 
understand it [laughter] [laugh] 
i think that's probably a pretty mixed response hopefully you will [laughter] 
at the end of this can't guarantee it there's always books or you can come and 
ask me but hopefully i'll take you through it now this is absolutely vital 
without a loop of Henle we would not be able to concentrate our urine we'd be 
peeing out as much as we m-, er we filter now it's only present in birds and 
mammals so we're the only er species er birds and mammals that are able to 
actually concentrate their urine anything else what they filter is what they 
pass as urine and that's because we have loops of Henle so if we didn't do 
anything here's your isotonic urine 'cause you remember your filtrate's 
isotonic to your plasma so it's going to come in at two-hundred-and-eighty 
three-hundred millimol-, milliosmoles and that's a hundred-and-eighty litres a 
day so if we didn't concentrate it at all we'd lose a hundred-and-eighty litres 
a day which is about seven-point-five litres an hour you'd be
sitting on the loo constantly apart from the fact you couldn't drink enough to 
replace all the water you were losing so you have to split the loop of Henle 
into three sections for this to work and this is this is what the c-, sections 
consid-, er together actually do but don't worry about that so you have the 
thin descending loop and this is permeable to water and slightly permeable to 
sodium and chloride but it's the permeability to water that's important if we 
look at the er thin ascending loop it's impermeable to water and there's a 
little bit of salt and water transport here as well er s-, er sorry sodium 
chloride transport but the thick ascending loop is what's important as well you 
can see here it has sodium and chloride reabsorption but it's completely 
impermeable to water so you have to remember this side is permeable to water 
this part isn't but this part transports your sodium and your chloride so if we 
have a look so this is basically reiterates what i've said so 
there's your water transport and if you take a section here you can see so this 
is the lumen so this is the side where the filtrate is and that has that takes 
up it's got the sodium er the potassium-two-chloride sodium pump which takes up 
er all of these ions the energy for that comes from the sodium potassium A-T-P-
ase but the net effect of this is that it transports sodium out and chloride 
goes out through this channel so you take up er sodium and chloride from the er 
filtrate and you put it into the interstitial tissue surrounding the nephron 
okay so this is the counter current mechanism so this is this is your loop of 
Henle thin bits thick bits and the numbers kind of refer to the osmolarity but 
don't get tied up with specific numbers it's just to illustrate something 
nobody's ever going to ask you what what the number down here should be or what 
the number up there should be so you have to remember this part is permeable to 
water er this part isn't permeable to 
water but has sodium pumps okay so this is what would happen if nothing 
happened you've got if i just go back one minute if nothing happened here this 
is water coming in and you have to also imagine this is static urine obviously 
the urine's flowing through your nephron continuously but you have to take 
snapshots at it to imagine how the system works so if nothing happened three-
hundred milliosmoles in i know it should be two-hundred-and-eighty but it's 
much neater to use three-hundred for illustration purposes so this is isotonic 
filtrate coming in and if nothing happened whatsoever you'd have isotonic 
filtrate going out flick through those okay so this is what happens those the 
sodium pumps in this part of the er loop of Henle switch on and they pump 
sodium chloride out into the medulla and what they do their aim is to keep a 
two-hundred milliosmole difference between the filtrate coming round here and 
the concentration in the medulla so they s-, 
they switch on these pumps so the medulla becomes concentrated compared to the 
filtrate that's in the loop of Henle now if you remember this part of the loop 
of Henle is permeable to water so at the moment in this situation you have 
dilute filtrate here compared to the interstitial flui-, fluid concentration so 
water flows from a high concentration of water into a lower concentration to 
try and equal it out so water will flow from here into there which will make 
this more concentrated is that clear which is what happens here so then you end 
up with sort of one cycle of urine moving round you've got dilute urine here 
compared to this part of the loop of Henle and compared to when we started here 
where it would have been three-hundred you've now got a t-, er increased 
concentration in the medulla so if we move on one more time the urine moves 
round a bit more so you've still got three-hundred coming in but if you 
remember it was two-hundred here pumps pump 
sodium out so that you get a two-hundred er milliosmole difference this part of 
the nephron says hang on a minute i'm too conc-, i'm too dilute now compared to 
the medulla and water moves from that thin ascending er descending loop into 
the medulla to equalize it so again the concentration in the thin descending 
loop equals that in the medulla whereas the thick ascending loop is a two-
hundred milliosmole difference making this urine or this filtrate more dilute 
and that's it that's all that happens the consequences of this are that 
filtrate coming in here is isoosmotic to your plasma so two-hundred-and-eighty 
by the time it gets down here your filtrate er has become more concentrated 
because it's losing water all the way down here to try and equalize the 
difference between the medulla and the filtrate osmolarity and then when it 
goes up here salt is pumped out which means you have dilute urine c-, er 
filtrate coming out so you have a difference at the top 
wi-, compared to filtrate in and filtrate out it's more dilute is that all 
clear anybody want me to go over it again okay i'll take your silence as that's 
all right and if you don't understand it ask me later okay so we've now 
developed what we've got now is we've got lots of solutes in the medulla and 
they get more and more concentrated the nearer the er tip of the medulla that 
you get to now if you had normal blood flow if you had simply er a straight 
blood vessel going from the cortex through the medulla and into the sort of 
collecting region the the pelvis or the kidney it's going to wash all those 
solutes out because er the water in the solute concentration is simply going to 
er er equalize as the blood vessel go-, travels down through the medulla and 
all that hard work by the loop of Henle is completely obliviated or alleviated 
so remember the blood system's set up differently in the kidney from what you'd 
normally expect so we have the vasa recta remember i mentioned this right 
back in the first er microstructure lecture and these are very specialized 
blood vessels and they parallel the er loops of Henle and they've got very low 
blood f-, er flow if you remember i mentioned that although the kidney has an 
extremely high blood flow for the size of the organ you only get five per-, to 
ten per cent of this actually going into the medulla so that's one of the way 
they conserve this osmotic gradient is not to put too much blood in the medulla 
and it's set just i-, un-, er a high enough flow rate so that you can deliver 
the nutrients and remove what you have to from the medulla and they're also in 
this hairpin arrangement so just to remind you they look like this so you 
remember you have these er bigger vessels coming in and this is the er a 
medullary pyla-, pyramid here so the blood vessels come in and they kind of go 
along the cortex-medulla border and then you get these loops branching off the 
vasa recta which follow round the long loops of Henle 
remember some of the er nephrons have long loops and some have short loops er 
when we're talking about concentration of urine it's the juxta-, er medullary 
nephrons that are important they're the ones with the very long loops of Henle 
and they have these blood vessels that parallel them around so this is how the 
vasa recta works now remember this is slightly different from the er nephron 
because this is a capillary so it's semi-permeable and doesn't have the pumps 
and the impermeability to water that the nephron has so this is a semi-
permeable membrane now permeable to both solutes and water so here we have this 
is the cortex this is the blood coming in at er isoosmotic to your filtrate at 
this stage and but remember in the medulla we've now built up this 
concentration gradient so it's dilute at the tip and more concentrated at the 
bottom and as the er blood flows in down here what happens is that from the er 
dilute filtrate you lose water because 
it's simple diffusion the water wants to try and equate the balance and it's 
effectively concentrated water in the filtrate so it flows to a region of low 
water concentration so it flows out of dilute filtrate into concentrated 
medulla and likewise the solutes do the opposite there's lots of solutes here 
not so many here so to try and er equilibrate that solutes move in now this is 
what i was saying if it was a straight er capillary that then just went on out 
down here all you've done is negate this er concentration gradient you've built 
up but it's again it's arranged like er the loop o-, the loop of Henle is and 
its counter current system so this is what would happen so it becomes more 
concentra-, your blood becomes more concentrated in here as it flows down to 
the tip of the hairpin and somewhere round here it reach-, equi-, er a point of 
equili-, er equilibration between the concentration in the blood and the 
concentration in the medulla but as it then flows back up 
it's going up through a more dilute system and exactly the same happens here in 
terms of the solutes and the waters try to compensate and equal things out but 
they go in the opposite direction so here you've got more solute than you have 
in the medulla so the solutes go out back into the medulla and likewise the 
water from the medulla flows in to try and compensate so the net effect here is 
that although you l-, lose water here and gain solutes which is what you don't 
want because it's a hairpin and goes back up again the opposite happens on this 
er er er this direction and you actually end up with just a small difference 
between your concentration of your blood going in and the concentration of your 
blood le-, leaving and that maintains the concentration gradient in the medulla 
it also does one really other important things 'cause if you remember from 
stones urea and sodium and chloride they're all things 
that can crystallize out so if you had a lot of urea and sodium and chloride 
just sitting in your medulla doing nothing statically they'd crystallize and 
form er crystals in the medulla and stop it working properly if you imagine 
you've got a loop of Henle here and you've got urea going into this space and 
then into here and then out again it kind of keeps the circulation system going 
between the nephron and the blood system and the medulla and that circulation 
prevents any precipitation occurring of the salts that you've got in the 
medulla because this is quite a high you're talking of twelve fourteen-hundred 
er conce-, osmotic concentration here so that's quite concentrated and they 
would precipitate so here you go so this is what you end up with you've got a 
osmotic gradient as you go through the medulla and the thing that a-, then 
allows to happen you've got this osmotic gradient here and this is your 
collecting duct going through it A-D-H is being 
stimulated to insert water channels here and because they work by osmosis the 
water can then flow from the collecting duct back into the medulla and that 
then obviously gets taken away er back into the blood supply and into the sys-, 
er body so that's how it works okay so that's the physiology what happens when 
it all goes wrong and you get some er diseased state well basically you're 
either going to make too dilute or too concentrated a urine that's all that 
happens so this is the first condition we're going to look at this is a 
syndrome of inappropriate secretion of A-D-H means you're secreting A-D-H when 
you shouldn't do it's an antidiuretic hormone it's going to stop you 
concentrating your urine so your blood volume is going to go up and you're 
going to become fluid overloaded so i've put up here this is normally what 
happens it's often er a pituitary tumour which is secreting A-D-H or you get 
them from er ectopic sites some cancer remember a lot of these tumours 
a lot of cancers produce hormones they're not supposed to you get parathyroid 
hormone related peptide produced by er breast cancer er tumours of breast 
cancer origin again some of them produce A-D-H likewise sometimes you obviously 
if you have a pituitary tumour and that metastasizes it's the same cell type so 
that also would account for A-D-H being produced so what are the signs and 
symptoms remember i said you were going to get fluid lo-, overloaded but this 
is only regulating your water reabsorption doesn't affect your sodium so you 
become hyponatraemia er or dis-, you develop hyponatraemia so that's low sodium 
concentration in your blood and that's simply because the sodium has been 
diluted if you look at the total body sodium of these people it's exactly what 
you would expect it's normal but because they've retained more water you've 
diluted the sodium so when you send off i don't know ten mls or whatever to a 
lab and it 
comes back as a molarity of your sodium concentration you're going to think 
their sodium is low now that has effect because low sodium will er have effects 
on your system's physiological systems and we do look at these er actually one 
of the case studies today is er she's got low sodium er but remember it's 
diluted your actual blood body sodium isn't low but you've diluted what you've 
got again er if you've got too much er A-D-H your urine's going to become too 
concentrated when you're not expecting it to become concentrated and again the 
sodium's going to be high in your urine so these are s-, kind of the classic 
symptoms the hyponatraemic the urine's concentrated and the urine sodium's 
quite high and what are the causes i've er i've listed them here er there's a 
range of things and i'll just take you through them but if you simply remember 
it's likely to be a tumour or an inflammatory response or drugs or stress 
that's kind of an easier way of remembering the causes 
of er syndrome of er A-D-H release but if we look here obviously you make and 
release it from the pituitary and hypothalamus so any lesions in that region 
can have problems inflammatory diseases generally will cause A-D-H release or 
can do but obviously if they're in the brain that that's er more likely and 
there's a whole range of other things problems with the lungs also er tend to 
cause er A-D-H release C-O-P-D is a classic symptom where you get A-D-H release 
er and that makes it even worse because if they've got chronic obstructive er 
lung disease already the last thing you want to do is fluid overload these 
people and give their lungs even more of a fluid challenge so that exacerbates 
their problem and tumours and particularly the small cell type in in lungs are 
are bad and then also er certain drugs so okay they've got mixed action so i've 
put a whole load here there's far far far more drugs than i've listed here but 
these are com-, some of the common ones 
oxytocin's important because that happens when you give oxytocin quite often to 
pregnant women if you're inducing labour and you have to bear in mind the 
effect that will have on their fluid system so sometimes you may be inducing 
labour because of pre-eclampsia the last thing you want to do by giving them 
oxytocin is to cause fluid retention as well so you have to be careful when you 
give oxytocin that the person's or monitor their fluid load er carefully er 
Ecstasy as well people who take Ecstasy have a problem with fluid er loss they 
tend to retain it and become very oedematous and that's acting probably via A-D-
H and then just down here post-operatively obviously that's quite specialized 
but the case varies and this trauma would also go in there a sudden fluid loss 
may sometimes activate A-D-H now it may not because if you lose blood you're 
losing isoosmotic er fluid so you're not altering the ratio of er the plasma 
osmolarity you might be getting low plasma volume 
but the osmolarity of it is normal the slight trouble you have sometimes post-
operatively is if you give somebody glucose in the drip because glucose is 
metabolized very quickly to water and whatever's left over so sometimes by 
giving glucose you're er going to exacerbate the fluid overload that's already 
been caused by A-D-H release er and H-I-V people the people that are H-I-V 
positive they have problems about a third of them er produce er A-D-H so just 
bear that in mind so what's the consequences the basic consequences are you end 
up with too much water er so we've talked about having low plasma sodium 
sometimes you get oedema sometimes you don't because this fluid overload is 
primarily a circulatory problem so the fluid overload is still in the blood 
vessels and in your blood volume but obviously sometimes that has the knock-on 
effect of oedema so if somebody you suspect somebody of having S-R S-I-A-D-H 
and they haven't got oedema it doesn't rule it out but 
they may have and i've just mentioned here that if your plasma sodium drops too 
low obviously you're then into problems and it can actually become an emergency 
that you have to deal with okay so that's if you have too much A-D-H so you 
retain fluid what happens if you have the opposite condition you can't 
concentrate your urine and you lose loads of water and this is called diabetes 
insipidus and this is why i keep stressing the importance when you answer a 
question particularly in this module but generally it's a habit you should get 
into you have to be careful that you tell me which tal-, type of diabetes 
you're going to be talking about because er diabetes mellitus has effects on 
the kidney er so i will be asking you questions about that and obviously 
diabetes insipidus so you have to tell me which diabetic condition you're 
you're talking about so there's two conditions so you basically have central or 
nephrogenic er diabetes insipidus and what they 
refer to obviously nephrogenic is er a condition that refers to problems with 
the kidney and central er is a a condition it's a bit misleading it's nothing 
to do with central it's central as in your hypothalamus or your pituitary it's 
your central control system so if it's central it's a problem with the 
synthesis and release if it's nephrogenic it's a problem with the kidneys being 
able to respond so here symptoms are obvious polyurea they produce loads and 
loads of urine the consequences are they have to drink lots to try and 
compensate for this now remember these are symptoms of diabetes mellitus as 
well somebody comes in saying they're you know into your surgery if you're a G-
P and says i'm drinking loads and i'm peeing loads you probably think they had 
diabetes mellitus or you'd want to test their urine for glucose but obviously 
if they're drinking lots and peeing lots no glucose in their urine you might 
start thinking about other forms and they're going 
to have er a low pa-, a plasma os-, a low urine osmolarity because they're 
passing lots out okay so what's the defects so i've talked about this so 
central's a problem with the brain you either don't make it or you can't 
secrete it so the obvious cause is allow for something like trauma or injury or 
infection and inflammation that are going to affect your pituitary hypothalamic 
er function or nephrogenic now nephrogenic it simply means you you're producing 
A-D-H correctly as your body wants it but your sa-, your kidneys can't respond 
to it and there's a number of reasons for this they could be congenital there 
are people who have congenital problems but also an infection or an obstruction 
can do it you might lack the receptor er or you can't form or translocate 
aquaporins obviously this isn't something that tends to happen late in life 
this is a problem that will have been with you a congenital problem from birth 
er sometimes i've just put down here if it's a problem 
with aquaporin translocation remember cyclic A-M-P is important in this so 
things that interfere with the cyclic A-M-P signalling pathway may well 
interfere with er A-D-H signalling and therefore interfere with er aquaporin 
translocation so if they're on drugs that you know might inhibit that kind of 
pathway that might er also be a cause of it so this is what you do you're going 
to want if you've got somebody you're pretty certain has got diabetes insipidus 
you're going to want to know which form they've got so you do what's called a 
water deprivation test so here we have along the bottom er or at least up the 
up the side here we've got er urine osmolarity and this is A-D-H concentration 
i'm sorry i've cut off the units i have no idea what A-D-H is actually measured 
in er but this is A-D-H along here so er if somebody a normal person i'm sorry 
i'm telling you it's A-D-H i think i might be wrong now i think that could be 
hours sorry i can't remember it's er in the 
textbook but ignore that 'cause it's totally irrelevant for the actual er what 
i'm going to tell you but this is a normal person here so as their A-D-H rises 
yeah it must be A-D-H as their A-D-H rises their urine osmolarity er changes as 
well er sorry their normal osmolarity changes you give somebody A-D-H by 
injection they're going to stop their urine osmolarity increasing because you 
start to retain er water okay so this is a person who's not drinking remember 
water deprivation test so if you're not drinking your plasma osmolarity will go 
up okay you give them A-D-H and they're going to stop their plasma osmolarity 
increasing because although they want to carry on because they're still not 
drinking the A-D-H will cause them to retain water okay is that clear on my 
second time round okay so this is somebody with er er one of the forms or both 
forms of diabetes insipidus you don't know which to this point so you deprive 
them of water they still pee a lot of 
urine so their plasma osmolarity will not increase it doesn't go up at all if 
you notice they just still er maintain their er dilute plasma you give them A-D-
H okay so if it's somebody who has a defect in the brain who can't make or 
secrete A-D-H you give it to them they respond as normal remember they've got 
very er dilute urine here er you give them this and they concentrate their 
plasma rather concentrate their plasma to er as you would expect from A-D-H if 
you give er somebody with nephrogenic A-D-H they have absolutely no way of 
responding to it so you don't see any change in the response whatsoever okay so 
this is the way you can tell them apart deprive somebody of water then give 
them er an A-D-H injection if you see a change in the er urine osmolarity then 
they've responded to A-D-H and they've got central diabetes insipidus you give 
them er an injection of A-D-H and they've got a problem with their kidney you 
see absolutely no change yep sorry 
sm0441: 
with the nephrogenic form do they hypersecrete A-D-H do they have like a lot of 
A-D-H in their blood that 
nf0440: yep 
sm0441: they start to respond to 
nf0440: probably yes er if you were to actually measure their A-D-H they will 
be producing lots because they're trying to er concentrate their urine so 
they're they're overproducing to try and compensate but of course it has no 
effect wherever the defect is but you normally having said they it's not you 
wouldn't normally just measure their A-D-H as a diagnostic er tool it's a clue 
but you would normally do a water deprivation test okay so just to reiterate 
the important factors the length of the loop of Henle is important the longer 
the length of the loop of Henle the more concentrating ability you've got and 
there's remember i said to you it's the juxta-, er medullary er nephrons that 
are important there's only fifteen per cent of your nephrons are of this strain 
this type but those 
are the ones that are actually important for forming the osmotic gradient 
within the medulla you've got the rate of sodium reabsorption so those sodium 
pumps that are working in the thick ascending loop of Henle the more 
efficiently they work the more the higher the osmotic er concentration in the 
medulla's going to be so if you inhibit those from working for some reason you 
don't develop such an osmotic gradient and don't reabsorb so much water so er 
some diuretics interfere with these pumps er obviously if you've got changes in 
the er G-F-R so your rate of sodium chloride delivery to that part of the 
nephron alters that will also alter your er ability to er reabsor-, to create 
the osmotic gradient and therefore reabsorb water the flow rate if you've got 
very high filtrate flow rate through the loop of Henle it's going to wash 
everything through the loop more quickly than all the er functions can actually 
er the counter current mechanism can work properly so if it flows too quickly 
through like you've got a really high G-F-R er you don't develop a very good er 
counter current system the osmotic gradient is not as strong as it could be 
therefore you tend not to concentrate your urine so well so you would produce 
dilute urine in that case and the protein content of diet remember urea comes 
from protein it's a breakdown product so in theory if you have a high protein 
diet there's high urea in the blood so that's more urea that can go into the er 
medulla and in theory that increases the osmotic potential and there is some 
evidence that people with high protein diets do concentrate their urine more 
efficiently than people with low protein diets having said that and we're not 
talking about it yet in the module but if you've got renal failure remember one 
of the things you look for is an increased in the urea in the er blood and the 
plasma because you can't filter it and you can't deal with the urea properly so 
if 
you've got kidney disease or kidney failure you might actually want to consider 
limiting the protein diet and certainly people with er end-stage renal failure 
have a low protein diet because they can't get rid of the urea so normal people 
there's some evidence that if you eat lots of protein you'll concentrate your 
urine more and pee less and then you want the osmotic potential of the tubule 
cells so you obviously you need antidiuretic hormone or A-V-P to be present to 
allow the water reabsorption to occur so you've basically got the length of the 
tubule the flow rate and then the efficiency at how the water moves out of the 
f-, ur-, er filtrate or urine into the er kidney and the efficiency of the 
sodium pumps and the counter current mechanism and that's it oh and the 
medullary blood flow obviously if you've got very high blood flow going through 
the vasa recta it will still wash stuff out so i just want to remind you next 
week's acid-base balance and this kind of fits in 
with your respiratory module so i think you do a bit of acid-base tomorrow it's 
not kind of i've looked at it in the module booklet and it's not kind of listed 
as acid-base but you do do some carb-, er some tomorrow and there is some 
following on from the urinary module next week so this week's respiratory and 
next week's respiratory kind of fit in slightly with the er kidney acid-base 
because the two of them work together the lungs and the kidney to regulate it 
so er group work starts about quarter to eleven ten to eleven okay and if 
you've got any questions at all come and see me