nf0440: if you're all ready to start [0.6] thank you [0.9] okay so we're 
looking about how you concentrate your urine so we're going to look at 
osmolarity and urine concentration [1.3] and then we're going to look at water 
reabsorption and what actually regulates your water reabsorption from the 
nephron [0.8] and this brings us on to the loop of Henle in the counter current 
er [0.2] system [0.9] now you might remember that from A-level and hate it but 
hopefully i'm going to explain it to you [0.4] but it's really quite important 
to that you actually understand the principle behind it [0.4] i know it says in 
your workbook you're not covering it that's because namex don't see any point 
in teaching it [0.4] but i'm sorry everybody clinicians [0.2] and myself think 
it's vital at this end so you do get taught it [1.2] and then we're just going 
to finish up with what happens when it goes wrong [0.4] and the two clinical 
conditions [0.5] and these are actually covered in case studies so [0.2] we 
skip over the er clinical conditions we're just [0.4] 
not too much detail in the lecture because you get them in case studies to 
actually look at them in more depth [2.1] so if we have a look at [0.4] urine 
production first off then [1.6] so this is your you've got a huge flexibility 
in how much urine you do or don't produce [0.4] so you've got a minimum of 
about [0.3] point-twenty-five er point-two-five mls per minute [0.5] and a 
maximum of twenty-five [0.6] but twenty-five's a hell of a lot of urine if 
you've got somebody producing twenty-five mls of urine a minute [0.5] 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 [2.4] normal urine production [0.4] most 
of you probably peeing somewhere between about fifteen-hundred and two mls a 
day [0.7] 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 [0.8] now this is [0.2] 
kind of an important number because if you were producing two litres of urine a 
day [0.4] and you'll see why on the next couple of slides [0.3] that 
actually means you're er peeing out isotonic urine compared to blood plasma [0.
6] and that doesn't matter to us er [0.2] if your kidneys are operating 
normally that's no problem [0.4] but if you're a renal patient with some 
impaired function [0.4] er [0.3] drinking two litres and therefore peeing two 
litres kind of [0.4] takes the strain off the kidney really so [0.4] if you've 
got somebody with impaired renal function [0.4] two litres becomes more 
important [1.3] and most of you will know this already [0.3] you make more 
urine during the day than you do at night [0.4] 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 [0.8] and if you're [0.
2] 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 [0.4] you e-
, excrete more salts during the day [0.2] and you pee more urine during the day 
[0.9] now obviously this might change if you're a shift worker if you work 
nights [0.3] your system's going to readjust to it [0.4] because you actually 
produce more water during the day [0.3] because of what you do because of 
eating [0.3] and metabolism [0.6] so if you're er [0.7] on the reverse system 
because you're a night worker then you're going to be metaboli-, [0.2] meta-, 
metabolically more active during the night [0.3] so you're going to pee during 
the night because effectively their days are just reversed [0.4] but normal day 
shift workers [0.5] we make more urine in the day than we do at night [1.6] and 
this is just important here we're going to talk about A-D-H later antidiuretic 
hormone [0.9] but the amount of solutes you excrete per day is fixed [0.3] 
depending on your intake and what you need to get rid of [0.4] it's the amount 
of water in your urine that varies which is why the osmolarity has to vary [0.
6] you don't change your concentration the amount the quantity of solutes that 
you want to excrete [1.4] so if we just look at how flexible it is [0.4] this 
blue bar here [0.5] that's your plasma osmolarity remember i said [0.7] week 
before last or [0.2] whichever week it was w-, session one or two [0.3] your 
plasma osmolarity has to stay very fixed it's it's very narrow band [0.3] 
around about two-hundred-and-eighty milliosmoles [0.8] in contrast your urine 
can [0.3] have this great range [0.9] although it looks like it can make it [0.
2] er more concentrated [0.3] relative to dilution actually it's a tenfold 
dilution it can manage because it can er produce thirty milliosmoles [0.2] er 
of urine er it has can be that dilute [0.6] this is er [0.8] a concentration 
that's only four times the value of plasma but it's a huge range [2.1] now you 
can actually work out [0.2] the concentration of your [0.3] er [1.2] osmolarity 
of your urine if you want to [0.7] and this is what we averagely excrete a day 
about six-hundred milliosmoles of salt solutes [0.4] er on an average normal 
diet over here [0.3] and therefore you can just put the numbers into this 
equation and come up with er [0.3] these simple answers so that if you excrete 
fifteen-hundred mls of urine [0.4] then the concentration of urine's going to 
be that [0.3] 
obviously if you excrete double the amount of urine it's less [0.4] er so i've 
just put that in [0.4] for you to know about [1.2] but this is important we're 
not going to most of what we're going to talk about today is how you regulate 
water [0.3] via hormones and osmosis et cetera [1.0] but the solute 
concentration will [0.2] alter your alter er your urine excretion [0.4] on its 
own independent of antidiuretic hormone and anything else that's going on [1.1] 
so [0.5] just to get the the units up here [0.2] come like that but just 
remember that a kilogram of water [0.3] is a thousand mls therefore you're 
actually talking of the molarity effectively it's just that osmolarity comes 
with slightly different units [0.8] so remember i said a normal person needs to 
excrete on an average diet six-hundred milliosmoles [0.9] and then that's your 
maximum urine concentration of twelve-hundred [0.3] so that means to excrete 
that during the day [0.3] you have to pass five-hundred mls of urine [1.3] if 
for some reason [0.4] you want to get rid of this num-, this amount of salt [0.
5] 
depending on your diet or various other conditions [0.9] the maximum urine 
concentration's still only twelve-hundred [0.4] so in this case you have to er 
pee fifteen-hundred mls [0.3] and that is totally independent of whatever else 
is going on if your solute concentration goes up [0.4] you will need to pass 
more urine if nothing else changes [2.5] and i've just said that [0.8] so let's 
have a look what actually happens to water in the nephron [0.5] so here we have 
your hundred-and-eighty litres of filtrate per day [0.5] but you only get rid 
of one per cent which is one-point-eight here [0.2] or fifteen-hundred mls that 
sort of [0.2] er quantity [1.7] now these two regions of the nephron [0.3] get 
rid of somewhere between eighty-five and ninety per cent of the water they 
reabsorb it [0.6] and this is done passively there's no regulation whatsoever 
[0.5] now although [0.3] er from the diuretics lecture with namex if you can 
remember [0.3] you can modify [0.3] the absorption of water in these parts of 
the nephron [0.3] that's a drug action normally you don't regulate 
it whatsoever [0.3] you just simply reabsorb [0.3] passively [0.3] all this 
amount of water [2.0] but this is what we're going to look at [0.2] this part 
of the nephron the collecting duct [0.3] you regulate the amount of water that 
you reabsorb [0.8] and that's the bit that we're actually going to look at the 
control of [0.4] so you only have control of a small amount of your filtrate [0.
3] i haven't actually done the numbers but [0.2] most of that hundred-and-
eighty litres is going to be reabsorbed here [0.6] relatively under no control 
whatsoever [0.3] you only have control over the small proportion the sort of 
ten per cent that actually gets to this part of the nephron [1.9] so how does 
the er collecting duct regulate water reabsorption [1.5] 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 [0.5] it's also called vasopressin and the abbreviation's A-V-
P [0.3] that's simply 'cause we've got an arginine in the human form of 
vasopressin [0.8] 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 [2.0] and the water transport in the collecting duct 
is also passive [0.6] so if it's passive you need water channels you need 
something physically for the water to move through [0.7] so in response to 
antidiuretic hormone so [0.3] antidiuretic it's going to stop you peeing it's 
going to make you conserve water [0.5] you get water channels er transported 
into the er [0.6] ch-, er the cells of the the membrane of the tubule cells [0.
6] and we'll see exactly how [0.2] in a [0.2] bit later [0.9] but you also need 
something else water's not going to move on its own [0.5] you need an osmotic 
gradient [0.4] so you need there to be a difference in the concentration of the 
[0.4] er solutes in the filtrate [0.4] compared to the concentration of solutes 
in the interstitial er [0.4] tissues surrounding the nephron [0.7] so you need 
to produce it [0.5] so you have there's two things you have to have you have to 
have a very dilute urine [0.4] 
going into the collecting duct [0.7] and you need to have this osmotic gradient 
which is produced by the counter current system [0.5] and i've just put down 
here A-D-H also activates the urea [0.2] er transporter [0.4] and you'll see 
why that has a slight relevance later but don't get tied up on that [1.9] so if 
we have a look at these water channels first we're going to take our [0.2] s-, 
ways through we're going to look first at the water transport and antidiuretic 
hormone [0.4] and then we're going to look at the generation of the osmotic 
gradient [0.5] so it's at least five of them at the moment [0.5] four of them 
are in the kidney [0.6] er [0.4] the [0.2] the type one [0.3] is in the 
proximal tubule [0.3] and in the loop of Henle and this is what [0.2] er [0.2] 
is involved in the unregulated water transport it simply flows through the A-Q 
[0.3] A-P-Q-one [1.2] er three and four are also in the collecting duct [0.4] 
er but these are in the basolateral membrane so that's the [0.2] interstitial 
tissue [0.2] er [0.9] border with the tubule lumen remember [0.3] you've got a 
kidney tubule cell water has to go into it [0.4] and 
out of it [0.5] so these ones here are actually the er [0.3] aquaporins that 
control the water release from the tubule cells back into the circulation [0.9] 
and these are the ones we're interested in [0.4] the aquaporins two [0.4] and 
these are the aquaporins that go into the lumenal membranes that's the side 
where the filtrate is [0.4] and they control the loss of water or [0.5] er from 
the filtrate [0.4] into the er eventually into the bloodstream [0.8] so it's 
the A-P-Q-twos we're talking about today [1.5] so what's antidiuretic hormone 
[3.4] it's a very small peptide [0.7] er [0.3] and in terms of i've i've put 
down here details [0.5] but for your interest [0.2] it's made in the 
hypothalamus [0.5] and it's released from the pituitary so you've got the 
hypothalamus and the pituitary involved one makes it [0.3] and one releases it 
[0.4] and that's important [0.4] 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 [1.9] so how do we control its release [1.0] the main 
mechanism by regulating A-D-H 
release [0.4] is in the hypothalamus [0.4] and it has osmoreceptors up here 
which detect changes in plasma osmolarity [0.9] so if the plasma osmolarity 
goes up that means it becomes more concentrated [0.4] you want to dilute your 
plasma so you want to retain water [0.5] you actually release A-D-H from the 
pituitary [0.6] and this will then have the effect on the kidney [1.0] er [0.3] 
you can see here you've also got this is er [0.2] obviously a diagram taken 
from the textbook you've got a thirst centre up here [0.3] so the osmoreceptors 
not only control A-D-H release which is what we're looking at today [0.3] but 
they also regulate your thirst [0.3] so you've got the two aspects if you 
become water depleted or your plasma osmolarity goes up [0.4] you release A-D-H 
to regulate water reabsorption [0.3] or stop its loss from the kidney [0.5] but 
you also stimulate your thirst reflex so you drink more so you're putting more 
fluid in as well [1.0] er [0.2] 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 [0.4] and 
they respond to blood volume and they can also release A-D-H so that [0.5] if 
you've got a large blood volume [0.2] so you want to lose some water they 
switch off A-D-H synthesis [0.3] or release and vice versa [0.5] er but that's 
not part of [0.2] this module [1.5] 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 [0.5] so you can see here [0.3] just above two-hundred-and-eighty [0.
3] you suddenly see this er increase in [0.4] er A-D-H release [0.4] and this 
is actually what we've normally got because our plasma osmolarity varies 
between about two-hundred-and-eighty and [0.7] three-hundred if it has to it 
doesn't it's happier nearer to two-hundred-and-eighty [0.4] we actually always 
have some A-D-H circulating you would expect to find A-D-H in normal people [0.
4] but you can see [0.4] 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 [0.4] up to three-hundred-and-ten is actually a relatively small change [0.
4] you get er er a rapid increase in A-D-H release [1.8] so how does it work [0.
5] so here's your er [0.4] tubule er er cell of the collecting duct [0.4] so 
this side is the lumen so this is where the urine is now in the collecting duct 
[0.4] and this is the blood side [0.6] but remember when talking about blood it 
actually goes out of the tubule cell [0.3] into the interstitial fluid and then 
into the blood er [0.3] vessel [0.4] and that'll become [0.2] even more 
apparent as we go through today [0.8] so you've got vasopressin receptors on 
the er cell surface [0.8] obviously they pick up er circulating levels of A-D-H 
[0.6] and i've just put down here these are V-two receptors [0.4] A-D-H also is 
a vasoconstrictor [0.6] in which case it acts via V-one receptors to modulate 
er vasoconstrictions primarily in the skin [0.4] but in other parts of the er 
body as well [0.5] and if it's acting as a vasoconstrictor it uses V-one type 
receptors [0.7] and they signal fi-, through phospholipase C [1.1] whereas 
these V-two 
receptors which are in the kidney [0.4] er [0.2] as we'll see now signal via 
cyclic A-M-P [0.7] and they also have er [0.4] a lower level of er [0.8] 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 [1.6] so here you go so [0.4] the A-D-H 
binds to the receptors cyclic A-M-P release [0.4] pro-, er [0.4] P-K-C 
activation and protein phosphorylation that's ec-, your standard er [0.7] 
activation pathway [1.2] what the protein phosphorylation does [0.3] is it then 
allows these [0.3] inactive water channels er aquaporins [0.3] to be 
translocated to the membrane [1.6] once they're inserted in the membrane this 
then allows water to move from the urine [0.6] into the cell [0.7] and you 
notice i'm actually talking about urine now because it's into the collecting 
system so it's urine [0.3] not filtrate so we're actually concentrating our 
urine [0.3] we're not concentrating our filtrate [0.7] so the water moves in [0.
8] protein phosphorylation also longer term [0.3] regulates the er 
transcription of the aquaporin gene [0.4] so er if you 
have continued stimulation here you'll get aquaporin synthesis which again then 
allows more [0.4] er water transport to occur [2.7] and if we look at what 
happens to the er permeability of the tubules [0.4] so you can see here 
remember i said the proximal [0.4] er tubule and we've got it split here into 
two the proximal convoluted and the proximal straight [0.6] and the thin 
descending loop of Henle [0.4] they've got a huge capacity to er reabsorb water 
passively by osmosis [0.5] whereas these regions so you've got the thin [0.2] 
ascending loop and the thick ascending loop [0.4] and parts of the distal 
nephron and the collecting system [0.3] this is the cortical collecting duct [0.
5] er are able to absorb small amounts of water whereas the inner medullary 
collecting duct [0.4] has no water absorption normally [0.6] but under the 
control of A-V-P [0.3] you can see both of these two [0.7] er collecting duct 
regions er [0.5] the ability to reabsorb water increases dramatically [3.1] 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 [0.5] but what do [0.4] er [0.2] what's actually detected so 
you've got changes here of plasma osmolarity [0.8] if you get alterations in 
your extracellular volume [0.5] therefore you're becoming dehydrated that will 
also er [0.5] change its er [0.4] release so in this case if you become 
dehydrated [0.3] you want to retain water [0.3] so you produce A-D-H which 
stops water secretion [0.6] thirst [0.5] 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 [0.3] and if you are sick [0.3] you lose water and lose 
er [0.3] fluid volume from you so it kind of er [0.4] as a precaution [0.4] and 
also some drugs [0.4] down here [0.9] 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 [0.4] that might be why [0.8] so if we look at inhibition 
of its release which will cause a fluid loss because you're not er causing 
reabsorption [1.2] again [0.3] 
plasma osmolarity [0.5] and then one we all know about alcohol [0.5] drink too 
much alcohol you have to go to the loo constantly [0.7] and er [0.6] happens a 
lot particularly to boys with pints i have to say [0.3] and the cold as well 
you go out in the cold weather you end up peeing more than normal or you want 
to [0.3] and stress will have an effect so they're they're the er [0.7] er [0.
6] physiological stimuli that actually alter [0.3] A-D-H release [1.4] okay so 
we've looked at the er [0.2] insertion of water channels into the tubular 
membrane under the control of A-D-H [0.4] what about the concentration of an 
osmotic gradient [1.0] so if we look here so this is like a cross section 
you've got cortex outer medulla [0.5] inner medulla [0.4] and you can see if 
you look at sodium and chloride they're almost the same [0.4] but they go up so 
there's much higher concentrations in the medulla than in the cortex [0.4] and 
urea goes up [0.5] and it's these three the combination of these three sodium 
chloride and urea [0.4] that actually makes the inner medulla of the cor-, of 
the kidney [0.4] very 
concentrated osmoticallywise [0.3] so that's what generates an osmotic 
difference [0.6] so how do we do this [3.9] so there's a number of mechanisms 
if we look at urea first [1.4] now remember urea's freely filtered [0.4] so 
everything that's circulating would potentially be filtered so that's a hundred 
per cent goes into the er [0.5] nephron [1.3] of that fifty per cent is 
reabsorbed early on in the proximal tubule so you've got fifty per cent of your 
[0.3] total urea concentration going into the nephron down here [2.1] when that 
goes it goes all the way round gets right round to the collecting duct [0.4] 
and it's reabsorbed so [0.4] er [1.0] and you've got seventy per cent of that 
remaining fifty per cent so the seventy per cent here is reabsorbed [0.2] goes 
into the medulla [0.5] because you remember this is all interstitial space 
between these parts of the nephron [0.9] but some of that is then secreted back 
into the kidney so if you remember urea's one of those strange substances [0.4] 
it's filtered here [0.5] it's reabsorbed here and here [0.3] and it's also 
secreted so you've got b-, all three of the main mechanisms of er [0.5] urine 
production going on with urea [0.9] so of this seventy per cent that it 
secretes into the medulla [0.4] some of that is then taken back up into the 
nephron [0.7] and sixty per cent [0.5] so you can see you've got ten per cent 
difference between what you reabsorb and what you put back into the nephron [0.
6] and that ten per cent [0.3] stays in the medulla [0.5] and because er and it 
creates er a concentration gradient so you'll have less urea at this region [0.
3] and more urea down here and you can see [0.4] er [0.5] you get ten per cent 
in your [0.2] er [0.4] medulla [0.2] you retain that [0.2] that's part of your 
osmotic concentration gradient [0.7] 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 [0.5] but it's this small percentage here that remains in the 
medulla [0.6] that's important [2.5] okay [0.4] loop of Henle did you all do 
this at A-level [1.7] no [0.4] yes [0.8] did you understand it [2.2] [laughter] 
[laugh] [0.3] 
i think that's probably a pretty mixed response [0.7] hopefully you will 
[laughter] at the end of this [0.2] can't guarantee it there's always books or 
you can come and ask me [0.7] but hopefully i'll take you through it [1.8] now 
this is absolutely vital without a loop of Henle [0.3] we would not be able to 
concentrate our urine [0.3] we'd be peeing out as much as we m-, er [0.3] we 
filter [1.1] now it's only present in birds and mammals [0.6] so we're the only 
er species [0.2] er birds and mammals that are able to actually concentrate 
their urine anything else [0.4] what they filter is what they pass as urine [0.
9] and that's because we have loops of Henle [1.3] so if we didn't do anything 
[0.2] 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 [0.3] three-
hundred millimol-, milliosmoles [0.5] and that's a hundred-and-eighty litres a 
day [0.3] so if we didn't concentrate it at all [0.3] we'd lose a hundred-and-
eighty litres a day which is about seven-point-five litres an hour [0.3] you'd 
be
sitting on the loo constantly [0.6] apart from the fact you couldn't drink 
enough to replace all the water you were losing [1.7] so you have to split the 
loop of Henle into three sections for this to work [0.9] and this is [0.2] this 
is what the c-, sections consid-, er together actually do but don't worry about 
that [0.5] so you have the thin [0.6] descending loop [0.9] and this is 
permeable to water [0.7] and slightly permeable to sodium and chloride but it's 
the permeability to water that's important [1.1] if we look at the er [0.3] 
thin ascending loop [0.8] it's impermeable to water and there's a little bit of 
salt and water transport here as well [0.4] er s-, er sorry [0.3] sodium 
chloride transport [1.2] but the thick ascending loop is what's important as 
well [0.6] you can see here it has sodium and chloride reabsorption but it's 
completely impermeable to water [0.7] so you have to remember this side is 
permeable to water [0.9] this part isn't [0.7] but this part transports your 
sodium and your chloride [1.3] so if we have a look so this is basically [0.2] 
reiterates what i've said [0.3] so 
there's your water transport and if you take a section here [0.7] you can see 
so this is the lumen so this is the side where the filtrate is [0.5] and that 
has that takes up [0.4] it's got the sodium er [0.4] the potassium-two-chloride 
sodium pump [0.4] which takes up [0.6] er all of these ions [0.4] the energy 
for that comes from the sodium potassium A-T-P-ase [0.7] but the net effect of 
this is that it transports sodium out [0.8] and chloride goes out through this 
channel [0.7] so you take up [0.2] er sodium and chloride [0.4] from the er 
filtrate [0.4] and you put it into the interstitial [0.5] tissue surrounding 
the nephron [1.3] okay [0.6] so this is the counter current mechanism so this 
is [0.2] this is your loop of Henle [0.2] thin bits [0.3] thick bits [1.1] 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 
[0.4] what the number down here should be or what the number up there should be 
[1.5] so you have to remember [1.0] this part [0.3] is permeable to water [0.8] 
er this part isn't permeable to 
water [0.3] but has sodium pumps [0.3] okay [0.8] so this is what would happen 
if nothing happened [0.3] you've got if i just go back one minute [0.4] if 
nothing happened here this is water coming in [0.3] and you have to also 
imagine this is static urine obviously the urine's flowing through your nephron 
continuously [0.3] but you have to take snapshots at it to imagine how the 
system works [0.4] so if nothing happened [0.5] three-hundred milliosmoles in 
[0.2] i know it should be two-hundred-and-eighty but it's much neater to use 
three-hundred for illustration purposes [0.5] so this is isotonic filtrate 
coming in [0.5] and if nothing happened whatsoever you'd have isotonic filtrate 
going out [1.5] flick through those [0.8] okay [1.2] so this is what happens 
those the sodium pumps in this part of the er loop of Henle switch on [0.4] and 
they pump sodium chloride [0.3] out into the medulla [0.7] and what they do 
their aim is to keep a two-hundred milliosmole difference between the filtrate 
coming round here [0.4] and the concentration in the medulla [0.7] so they s-, 
they switch on these pumps [0.3] so the medulla becomes concentrated [0.3] 
compared to the filtrate that's in the loop of Henle [1.2] now if you remember 
[0.5] this part of the loop of Henle is permeable to water [0.8] so [0.3] at 
the moment in this situation you have [0.3] dilute [0.3] filtrate here [0.4] 
compared to the interstitial flui-, fluid concentration [0.6] so water flows 
from [0.5] a high concentration of water [0.4] into a lower concentration to 
try and equal it out [0.3] so water will flow [0.4] from here [0.5] into there 
[0.4] which will make this more concentrated [0.8] is that clear [0.3] which is 
what happens here [0.5] so then you end up with sort of one cycle of urine 
moving round [0.4] you've got [0.3] dilute urine here compared to this part of 
the loop of Henle [0.6] and [0.2] compared to when we started here where it 
would have been three-hundred you've now got a t-, er [0.7] increased 
concentration in the medulla [0.9] 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 [2.4] pumps pump [0.6] 
sodium out so that you get a two-hundred er [0.2] milliosmole difference [0.7] 
this part of the nephron says hang on a minute i'm too conc-, i'm too dilute 
now compared to the medulla [0.3] and water moves from that thin ascending er 
descending loop [0.5] into the medulla [0.2] to equalize it so again [0.6] the 
concentration in the thin descending loop [0.4] equals that in the medulla [0.
6] whereas the thick ascending loop [0.5] is a two-hundred milliosmole 
difference making this urine [0.3] or this filtrate more dilute [0.7] and 
that's it that's all that happens [0.7] the consequences of this are [0.5] that 
filtrate coming in here [0.3] is isoosmotic to your plasma [0.3] so two-hundred-
and-eighty [1.1] by the time it gets down here [0.4] your filtrate er [0.3] has 
become more concentrated because it's losing water all the way down here to try 
and equalize the difference between the medulla [0.4] and the filtrate 
osmolarity [0.6] and then when it goes up here [0.2] salt is pumped out which 
means you have dilute urine [0.5] c-, er filtrate coming out [0.5] so you have 
a difference at the top 
wi-, compared to filtrate in [0.4] and filtrate out it's more dilute [1.3] is 
that all clear [0.7] anybody want me to go over it again [2.1] okay [0.4] i'll 
take your silence as that's all right and [0.4] if you don't understand it ask 
me later [1.1] okay so we've now developed [0.4] what we've got now is we've 
got lots of solutes in the medulla [0.4] and they get more and more 
concentrated [0.2] the nearer the er [0.3] tip of the medulla that you get to 
[0.9] now if you had normal blood flow if you had simply er a straight blood 
vessel [0.4] going from the cortex through the medulla [0.4] and into the sort 
of collecting region the the pelvis or the kidney [0.6] it's going to wash all 
those solutes out because er [0.4] the water in the solute concentration is 
simply going to er [0.2] er equalize as the blood vessel go-, travels down 
through the medulla [0.3] and all that hard work by the loop of Henle is 
completely obliviated [0.4] or alleviated [1.1] so remember the blood system's 
set up differently in the kidney from what you'd normally expect [1.4] so we 
have the [0.2] vasa recta remember i mentioned this right 
back in the first er [0.2] microstructure lecture [0.5] and these are very 
specialized blood vessels [0.3] and they parallel the er loops of Henle [1.2] 
and they've got very low blood f-, er flow if you remember i mentioned that 
although the kidney has [0.3] an extremely high blood flow for the size of the 
organ [0.6] you only get five per-, [0.2] to ten per cent of this actually 
going into the medulla so that's one of the way they conserve this osmotic 
gradient [0.3] is not to put too much blood in the medulla and it's set just i-,
un-, [0.4] er a high enough flow rate so that you can deliver the nutrients 
and remove what you have to from the medulla [0.7] and they're also in this 
hairpin arrangement [1.0] so just to remind you they look like this [0.4] so 
you remember you have these er [0.5] bigger vessels coming in [0.4] and this is 
the er a medullary pyla-, pyramid here [0.5] so the blood vessels come in and 
they kind of go along [0.4] the cortex-medulla [0.3] border [0.6] and then you 
get these loops [0.2] branching off the vasa recta which follow round [0.4] the 
long loops of Henle [0.6] 
remember some of the er nephrons have long loops and some have short loops [0.
4] er when we're talking about concentration of urine [0.3] it's the juxta-, er 
medullary nephrons that are important they're the ones with the very long loops 
of Henle [0.5] and they have these blood vessels that parallel them [0.3] 
around [1.7] so this is how the vasa recta works [0.3] now remember this is 
slightly different from the er [0.2] nephron [0.4] because this is a capillary 
[0.4] so it's semi-permeable [0.2] and doesn't have the pumps and the 
impermeability to water that the nephron has so this is a semi-permeable 
membrane now [0.5] permeable to both solutes and water [0.9] so here we have [0.
3] this is the cortex this is the blood coming in [0.4] at er isoosmotic to 
your filtrate [0.2] at this stage [0.6] and but remember in the medulla we've 
now built up this concentration gradient so it's dilute at the tip [0.5] and 
more concentrated at the bottom [0.8] and as the er blood flows in down here [0.
5] what happens is that [0.4] from the er [0.4] dilute [0.3] filtrate you lose 
water because [0.3] 
it's simple diffusion the water wants to try and equate the balance and [0.5] 
it's effectively [0.4] concentrated water in the filtrate so it flows to a 
region of low water concentration so it flows [0.3] out of dilute filtrate [0.
4] into concentrated medulla [0.6] and likewise the solutes do the opposite 
there's lots of solutes here [0.4] not so many here [0.2] so to try and er 
equilibrate that solutes move in [0.6] now this is what i was saying if it was 
a straight er [0.6] capillary that then just went on out down here [0.5] all 
you've done is negate this er concentration gradient you've built up [1.1] but 
it's again it's arranged like er [0.9] the loop o-, the loop of Henle is and 
its counter current system [0.4] so this is what would happen [0.4] so it 
becomes more concentra-, your blood becomes more concentrated in here as it 
flows down to the tip of the hairpin [0.4] and somewhere round here it reach-, 
equi-, er a point of equili-, er equilibration between the [0.4] concentration 
in the blood and the concentration in the medulla [1.1] but as it then flows 
back up [0.4] 
it's going up through a more dilute system [0.5] and [0.4] 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 [0.6] so here [0.4] you've got 
more solute than you have in the medulla so the solutes go out back into the 
medulla [0.5] and likewise [0.3] the water from the medulla [0.2] flows in to 
try and compensate [0.5] so the net effect here is that although you l-, lose 
water here and gain solutes which is what you don't want [0.5] because it's a 
hairpin and goes back up again [0.3] the opposite happens on this er [0.9] er 
er [0.2] this direction [0.5] and you actually end up [0.3] with just a small 
difference between your [0.3] concentration of your blood going in and the 
concentration of your blood le-, [0.3] leaving [0.3] and that maintains [0.3] 
the concentration gradient in the medulla [1.0] it also does one really other 
important things 'cause if you remember from stones urea [0.4] and sodium and 
chloride they're all things 
that can crystallize out [0.6] so if you had a lot of urea [0.5] and sodium and 
chloride just sitting in your medulla doing nothing statically they'd 
crystallize and form er [0.2] crystals in the medulla [0.4] and stop it working 
properly [0.9] if you imagine you've got a loop of Henle here [0.3] and you've 
got urea going into this space and then [0.2] into here and then out again it 
kind of keeps the circulation system going between the nephron and the blood 
system and the medulla [0.4] and that circulation prevents any precipitation 
occurring of the salts that you've got in the medulla [0.5] because this is 
quite a high [0.3] you're talking of twelve fourteen-hundred [0.4] er conce-, 
osmotic concentration here so that's quite concentrated [0.6] and they would 
precipitate [0.7] so here you go so this is what you end up with you've got a 
[0.3] osmotic gradient as you go through the medulla [0.9] and the thing that a-
, then allows to happen [1.2] you've got this osmotic gradient here and this is 
your collecting duct going through it [0.6] A-D-H is being 
stimulated to insert water channels here [0.6] and because they work by osmosis 
[0.4] the water can then flow from the collecting duct [0.4] back into the 
medulla [0.3] and that then obviously gets taken away [0.4] er [0.5] back into 
the blood supply and into the sys-, er body [0.5] so that's how it works [1.5] 
okay [0.8] so that's the physiology [1.0] what happens when it all goes wrong 
[0.5] and you get some [0.4] er diseased state [0.4] well basically you're 
either going to make too dilute or too concentrated a urine [0.4] that's all 
that happens [1.4] so this is the first condition we're going to look at this 
is a syndrome of inappropriate secretion of A-D-H [0.4] means you're secreting 
A-D-H when you shouldn't do [0.7] it's an antidiuretic hormone it's going to 
stop you concentrating your urine [0.3] so your blood volume is going to go up 
and you're [0.2] going to become fluid overloaded [0.9] so i've put up here 
this is normally what happens it's often [0.4] er a pituitary tumour which is 
secreting A-D-H [0.4] or you get them from er [0.3] ectopic sites some [0.5] 
cancer remember a lot of these tumours 
a lot of cancers produce hormones they're not supposed to [0.5] you get 
parathyroid hormone related peptide produced by [0.4] er breast cancer [0.2] er 
tumours of breast cancer origin [0.4] again some of them produce A-D-H [1.3] 
likewise sometimes you obviously if you have a pituitary tumour [0.4] and that 
metastasizes [0.2] it's the same cell type so that also would account for A-D-H 
being produced [0.9] so what are the signs and symptoms [0.5] remember i said 
you were going to get fluid lo-, overloaded but this is [0.3] only regulating 
your water reabsorption [0.2] doesn't affect your sodium [0.7] so you become 
hyponatraemia [0.6] er or dis-, you develop hyponatraemia [0.3] so that's low 
sodium concentration in your blood [0.7] and that's simply because the sodium 
has been diluted [1.0] if you look at the total body sodium of these people 
it's exactly what you would expect it's normal [0.5] but because they've 
retained more water [0.3] you've diluted the sodium [0.4] so when you send off 
[0.9] i don't know ten mls or whatever to a lab and it 
comes back as a [0.4] molarity of your sodium concentration [0.6] you're going 
to think their sodium is low [1.4] now that has effect because low sodium will 
er [0.6] have effects on your system's physiological systems and we do look at 
these er [0.9] actually one of the case studies today is er [0.5] she's got low 
sodium [0.7] er [0.7] but remember it's diluted [0.2] your actual blood body 
sodium isn't low but you've diluted what you've got [1.6] again [0.5] er if 
you've got too much er [0.5] A-D-H your urine's going to become too 
concentrated when you're not expecting it to become concentrated [0.5] and 
again the sodium's going to be high in your urine so these are s-, kind of the 
classic symptoms [0.3] the hyponatraemic [0.6] the urine's concentrated [0.2] 
and the urine sodium's quite high [2.1] and what are the causes [0.7] i've er 
i've listed them here [0.5] 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 [0.7] or an 
inflammatory response [0.5] or drugs or stress that's kind of an easier way of 
remembering the causes 
of [0.5] er [1.4] syndrome of er A-D-H release [0.7] but if we look here [0.4] 
obviously [0.2] you make and release it from the pituitary and hypothalamus [0.
3] so any lesions in that region can have problems [0.5] inflammatory diseases 
generally will cause A-D-H release or can do [0.3] but obviously if they're in 
the brain that that's er more likely [0.7] and there's a whole range of other 
things [1.2] problems with the lungs also er [0.2] tend to cause er A-D-H 
release [0.4] C-O-P-D is a classic symptom where you get A-D-H release [0.5] er 
and that makes it even worse because if they've got chronic obstructive er lung 
disease already [0.3] 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 [0.6] and tumours and particularly the small cell type in in 
lungs are [0.2] are bad [1.1] and then also er [0.4] certain drugs [0.8] so 
okay they've got mixed action so i've put a whole load here [0.3] there's far 
far far more drugs than i've listed here but these are com-, some of the common 
ones [0.6] 
oxytocin's important [0.4] because that happens when you give oxytocin quite 
often to pregnant women if you're inducing labour [0.4] and you have to bear in 
mind the effect that will have on their fluid system so [0.4] sometimes you may 
be inducing labour because of pre-eclampsia the last thing you want to do [0.3] 
by giving them oxytocin [0.3] is to cause fluid retention as well so you have 
to be careful [0.4] when you give oxytocin that the person's [0.3] or monitor 
their fluid load [0.4] er [0.2] carefully [0.6] er Ecstasy as well [0.5] people 
who take Ecstasy have a problem with fluid er loss they tend to retain it and 
become very oedematous [0.4] and that's acting probably via A-D-H [0.6] and 
then just down here post-operatively [0.5] obviously that's quite specialized 
but [0.6] the case varies and this trauma would also go in there [0.5] a sudden 
fluid loss may sometimes activate [0.3] A-D-H [0.3] now it may not because if 
you lose blood you're losing isoosmotic [0.4] er fluid [0.5] so you're not 
altering the ratio of er [0.5] the plasma osmolarity you might be getting low 
plasma volume 
but the osmolarity of it is normal [1.0] 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 [0.5] so sometimes 
by giving glucose [0.4] you're er going to exacerbate the fluid overload [0.3] 
that's already been caused by A-D-H release [0.8] er [0.4] and H-I-V people [0.
2] the people that are H-I-V positive they have [0.2] problems about a third of 
them [0.5] er produce er A-D-H [0.7] so just bear that in mind [1.4] so what's 
the consequences the basic consequences are you end up with too much water [0.
8] er so we've talked about having low plasma sodium [0.5] sometimes you get 
oedema [0.5] sometimes you don't because this fluid overload is primarily a 
circulatory problem [0.5] so the fluid overload is still in the blood vessels 
and in your blood volume [0.5] but obviously sometimes that has the knock-on 
effect of oedema [0.7] so if somebody [0.4] you suspect somebody of having S-R 
S-I-A-D-H [0.5] and they haven't got oedema it doesn't rule it out but 
they may have [0.8] 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 [1.6] okay so that's if you have too much 
A-D-H so you retain fluid what happens if you have the opposite condition [0.4] 
you can't concentrate your urine and you lose loads of water [0.7] and this is 
called diabetes insipidus [0.3] and this is why i keep stressing the importance 
when you answer a question [0.8] particularly in this module but generally it's 
a habit you should get into you have to [0.5] be careful that you tell me which 
tal-, [0.2] type of diabetes you're going to be talking about because [0.4] er 
diabetes mellitus has effects on the kidney [0.6] 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 [2.0] so there's two 
conditions so you basically have central [0.3] or nephrogenic er [0.5] diabetes 
insipidus [1.0] and what they 
refer to obviously [0.5] nephrogenic is er a condition that refers to problems 
with the kidney [0.5] and central [0.3] 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 [0.4] so if it's central 
it's a problem with the [0.3] synthesis and release [0.3] if it's nephrogenic 
it's a problem with the kidneys being able to respond [1.1] so here [0.2] 
symptoms are obvious polyurea [0.4] they produce loads and loads of urine [0.3] 
the consequences are they have to drink lots to try and compensate for this [0.
6] now remember these are symptoms of diabetes mellitus as well somebody comes 
in saying they're [0.5] 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 [0.8] but obviously if 
they're drinking lots and peeing lots [0.3] no glucose in their urine [0.3] you 
might start thinking about other forms [0.5] and they're going 
to have er [0.7] a low pa-, a plasma os-, a low urine osmolarity because 
they're passing lots out [2.2] okay so what's the defects so i've talked about 
this so [0.2] central's a problem with the brain you either don't make it [0.3] 
or you can't secrete it [0.6] so the obvious cause is allow for something like 
trauma or injury or infection [0.5] and inflammation that are going to affect 
your pituitary hypothalamic [0.2] er function [1.7] or nephrogenic now 
nephrogenic it simply means you you're producing A-D-H correctly [0.3] as your 
body wants it [0.4] but your sa-, your kidneys can't respond to it [0.5] and 
there's a number of reasons for this they could be [0.2] congenital there are 
people who have congenital problems [0.4] but also an infection or an 
obstruction can do it [0.7] you might lack the receptor [0.4] er or you can't 
form or translocate aquaporins obviously this isn't something that tends to 
happen [0.4] late in life this is a [0.6] problem that will have been with you 
a congenital problem from birth [1.5] er [0.4] sometimes i've just put down 
here [0.4] if it's a problem 
with aquaporin translocation remember cyclic A-M-P is important in this [0.3] 
so things that interfere with the cyclic A-M-P signalling pathway [0.4] may 
well interfere with er A-D-H signalling [0.3] and therefore interfere with er 
aquaporin translocation so [0.3] if they're on drugs that you know might 
inhibit that kind of pathway [0.4] that might er also be a cause of it [1.9] 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 [0.4] so you do what's called a water deprivation test [0.8] so 
here we have along the bottom [0.5] er [0.2] or at least up the up the side 
here we've got er urine osmolarity [0.6] and this is A-D-H concentration [0.5] 
i'm sorry i've cut off the units i have no idea what A-D-H is actually measured 
in [0.4] er but this is A-D-H along here [1.7] so er [0.6] if somebody a normal 
person [1.0] 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 [1.6] sorry i can't remember it's er in the 
textbook but ignore that 'cause it's totally irrelevant for the actual er [0.6] 
what i'm going to tell you [0.3] but this is a normal person here [0.5] so [0.
3] as their A-D-H [0.2] rises [0.4] yeah it must be A-D-H as their A-D-H rises 
[0.5] their urine osmolarity [0.5] er [0.4] changes as well er sorry their 
normal osmolarity changes [0.7] you give somebody A-D-H by injection [0.7] 
they're going to stop their urine osmolarity increasing because you start to [0.
3] retain [0.3] er [1.8] water [0.4] okay [0.4] so this is a person who's not 
drinking remember water deprivation test [0.4] so if you're not drinking your 
plasma osmolarity will go up [0.7] okay [1.0] you give them [0.2] A-D-H [0.8] 
and they're going to stop their plasma osmolarity increasing because although 
they want to [0.4] carry on because they're still not drinking [0.4] the A-D-H 
will cause them to [0.4] retain water [1.3] okay is that clear on my second 
time round [0.7] okay so this is somebody with er [1.0] er one of the forms or 
both forms of diabetes insipidus you don't know which to this point [0.3] so 
you deprive them of water [0.6] they still pee a lot of 
urine [0.4] so their plasma osmolarity will not increase it doesn't go up at 
all if you notice [0.5] they just still er maintain their er dilute plasma [1.
2] you give them A-D-H okay [0.7] so if it's somebody who has a defect in the 
brain who can't make or secrete A-D-H [0.3] you give it to them [0.3] they 
respond as normal [0.3] remember they've got very er [0.4] dilute urine here [0.
5] er you give them this [0.3] and they concentrate their plasma rather 
concentrate their plasma [0.6] to er [0.3] as you would expect from A-D-H [1.7] 
if you give er somebody with nephrogenic A-D-H [0.3] they have absolutely no 
way of responding to it so you don't see any change in the response whatsoever 
[1.2] okay [0.3] so this is the way you can tell them apart [0.3] deprive 
somebody of water [0.5] then give them er an A-D-H injection [0.5] if you see a 
change in the [0.2] er urine osmolarity [0.6] then they've responded to A-D-H 
[0.4] and they've got central [0.2] diabetes insipidus [0.6] you give them er 
an injection of A-D-H and they've got a problem with their kidney [0.4] you see 
absolutely no change [0.3] yep sorry 
sm0441: 
with the [0.2] nephrogenic form do they hypersecrete A-D-H [0.2] do they have 
like a lot of A-D-H in their blood that 
nf0440: yep 
sm0441: they start to respond to [0.7] 
nf0440: probably yes [0.3] er if you were to actually measure their A-D-H they 
will be producing lots because they're trying to [0.2] er [0.3] concentrate 
their urine so they're [0.3] they're overproducing [0.2] to try and compensate 
but of course it has no effect [0.4] wherever the defect is [2.4] but you 
normally having said they [0.5] it's not [0.3] you wouldn't normally just 
measure their A-D-H as a diagnostic er [0.3] tool it's a clue but you would 
normally do a water deprivation test [3.2] okay [0.8] so just to reiterate [0.
3] the important factors [2.9] the length of the loop of Henle is important [0.
5] the longer the length of the loop of Henle [0.4] the more concentrating 
ability you've got [0.7] 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 [0.6] but those 
are the ones that are actually important for forming the osmotic gradient 
within the medulla [2.6] you've got the rate of sodium reabsorption so those 
sodium pumps that are working in the thick ascending loop of Henle [0.6] the 
more efficiently they work [0.3] the more the higher the osmotic [0.2] er 
concentration in the medulla's going to be so if you inhibit those from working 
for some reason [0.5] you don't develop such an osmotic [0.2] gradient [0.3] 
and don't reabsorb so much water [0.5] so [0.3] er some diuretics [0.3] 
interfere with these pumps [1.9] 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 [0.5] 
alters that will also alter your er [0.7] ability to er [0.7] reabsor-, to 
create the osmotic gradient and therefore reabsorb water [2.7] the flow rate [0.
7] if you've got very high filtrate flow rate [0.3] through the loop of Henle 
[0.4] it's going to wash everything through the loop [0.5] more quickly [0.3] 
than all the er functions can actually er the counter current mechanism can 
work properly [0.6] so if it flows too quickly 
through like you've got a really high G-F-R [0.5] er you don't develop a very 
good er counter current system [0.6] the osmotic gradient is not as strong as 
it could be [0.4] therefore you tend not to concentrate your urine so well so 
you would produce dilute urine in that case [2.3] and the protein content of 
diet [0.9] remember urea comes from protein it's a breakdown product [0.5] so 
in theory if you have a high protein diet [0.5] there's high urea in the blood 
[0.6] so that's more urea that can go into the er medulla [0.5] and in theory 
that increases the osmotic potential and there is some evidence that people 
with high protein diets do concentrate their urine [0.5] more efficiently than 
people with low protein diets [0.9] having said that and we're not talking 
about it yet in the module [0.4] but if you've got renal failure [0.4] remember 
one of the things you look for is an increased in the urea in the er blood [0.
4] and the plasma because you can't filter it and you can't deal with the urea 
properly [0.3] so if 
you've got kidney disease or kidney failure [0.3] you might actually want to 
consider limiting the protein diet and certainly people [0.4] with er [0.4] end-
stage renal failure have a low protein diet because they can't get rid of the 
urea [0.6] so [0.2] normal people there's some evidence that if you eat lots of 
protein [0.4] you'll concentrate your urine more and pee less [1.0] and then 
you want the osmotic potential of the tubule cells so you obviously you need 
antidiuretic hormone or A-V-P [0.4] to be present to allow the water 
reabsorption to occur [0.3] so you've basically got the length of the tubule [0.
4] the flow rate [0.3] and then the efficiency at how the water moves out of 
the f-, [0.3] ur-, er filtrate or urine into the er [0.6] kidney [0.3] and the 
efficiency of the sodium pumps and the counter current mechanism [1.2] and 
that's it [0.5] 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 [1.2] 
so i just want to remind you next week's acid-base balance [0.5] and this kind 
of fits in 
with your respiratory module [0.3] so i think you do a bit of acid-base 
tomorrow it's not kind of [0.8] i've looked at it in the module booklet and 
it's not kind of listed as acid-base [0.4] but you do do some [0.3] carb-, er 
some [0.3] tomorrow [0.5] and there is some following on from the urinary 
module next week so [0.4] this week's respiratory [0.2] and next week's 
respiratory kind of fit in slightly [0.4] with the er kidney acid-base because 
the two of them work together the lungs and the kidney to regulate it so [0.8] 
er [0.2] group work starts about quarter to eleven ten to eleven [0.4] okay and 
if you've got any questions at all [0.3] come and see me