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<title>The Kidney and Calcium Homeostasis</title></titleStmt>

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<idno>lslct027</idno>

<availability><p>The British Academic Spoken English (BASE) corpus was developed at the

Universities of Warwick and Reading, under the directorship of Hilary Nesi

(Centre for English Language Teacher Education, Warwick) and Paul Thompson

(Department of Applied Linguistics, Reading), with funding from BALEAP,

EURALEX, the British Academy and the Arts and Humanities Research Board. The

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Researchers should acknowledge their use of the corpus using the following

form of words:

The recordings and transcriptions used in this study come from the British

Academic Spoken English (BASE) corpus, which was developed at the

Universities of Warwick and Reading under the directorship of Hilary Nesi

(Warwick) and Paul Thompson (Reading). Corpus development was assisted by

funding from the Universities of Warwick and Reading, BALEAP, EURALEX, the

British Academy and the Arts and Humanities Research Board. </p></availability>

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<date>01/10/2003</date><equipment><p>video</p></equipment>

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<u who="nf0369"><kinesic desc="projector is on showing slide" iterated="n"/> right <pause dur="0.7"/> okay <pause dur="1.1"/> if we can settle down we need to <pause dur="0.3"/> dash on to the next one <pause dur="12.0"/> now again some of this is going to be <pause dur="0.3"/> revision for you <pause dur="0.8"/> because # we touched upon it briefly in musculoskeletal <pause dur="0.4"/> # <pause dur="0.4"/> that was last semester i think wasn't it <pause dur="0.8"/> and <pause dur="0.3"/> it comes up again in clinical pharmacology when we look at bone diseases <pause dur="1.6"/> so it's partly revision but we're looking at it from a different aspect today <pause dur="0.6"/> so i just want to have a look at what <pause dur="0.4"/> what's normal <pause dur="0.6"/> a very quick review of calcium homeostasis <pause dur="1.3"/><kinesic desc="changes slide" iterated="n"/> # look at the tissues that are involved but obviously particularly the kidney the kidney's what we're really talking about today so although there's a multitude of tissues involved in calcium homeostasis <pause dur="0.5"/> the kidney's the one i'm concentrating on <pause dur="0.9"/> and then have a quick look at vitamin D deficiency <pause dur="0.6"/> # <pause dur="1.0"/> because that's really important when we're considering renal disease <pause dur="1.8"/> so if we look at the physiological roles of <pause dur="0.2"/> calcium <pause dur="0.7"/> we went over this last semester <pause dur="0.5"/> and in that time we were particularly talking

about <pause dur="0.2"/> bones <pause dur="0.5"/> and we're going to be <trunc>tic</trunc> particularly talking about bones in clinical pharmacology <pause dur="2.2"/> that obviously is a long term effect <pause dur="0.3"/> calcium homeostasis <pause dur="0.3"/> gone wrong <pause dur="0.6"/> will affect bones but it has a longer term <pause dur="0.5"/> # effect it's not going to happen overnight <pause dur="0.5"/> although you can see changes within a fortnight but <trunc>i</trunc> it's a long process more chronic <pause dur="0.8"/> whereas these functions that i've listed here <pause dur="0.5"/> are much more rapid and acute <pause dur="0.6"/> # in terms of the functions of the calcium <pause dur="0.4"/> obviously if you have changes in your nerve function and nerve signalling <pause dur="0.5"/> # or muscle contraction <pause dur="0.4"/> that'll happen rapidly <pause dur="0.5"/> so there are sort of kind of acute and chronic <pause dur="0.2"/> consequences of calcium homeostasis being messed up <pause dur="0.8"/> and this one i've just put here just to remind you <pause dur="0.4"/> # that one of the roles of calcium is in # blood clotting <pause dur="0.4"/> so if you've all your blood tubes or a lot of them have # E-D-T-A in that's simply to collate the calcium and stop the blood that you've taken clotting so that's why E-D-T-A's <pause dur="0.5"/> in blood tubes <pause dur="0.8"/> but

the really important thing is that the levels need to be very tightly regulated <pause dur="0.5"/> in order to ensure that all these kind of acute problems don't happen <pause dur="0.4"/> and then longer term the chronic bone problems you need to regulate your calcium levels that are circulating quite closely <pause dur="1.6"/><kinesic desc="changes slide" iterated="n"/> so this is a slide you've had this one before <pause dur="0.4"/> but just to remind you <pause dur="0.3"/> these are the plasma concentrations <pause dur="0.4"/> and this is the normal range <kinesic desc="indicates point on slide" iterated="n"/> here or roughly <pause dur="0.7"/> now these numbers that i've put up and the numbers that i've put up on a lot of my slides <pause dur="0.3"/> depending on the book you look at they will vary very slightly <pause dur="0.9"/> i've got forty-five per cent ionized here and fifty-five per cent bound <pause dur="0.4"/> what i tend to do in my numbers is trying to match <pause dur="0.3"/> what the <gap reason="name" extent="1 word"/> students get <pause dur="0.3"/> but you will find books that'll give you anywhere between forty and fifty here # and alter this accordingly <pause dur="0.6"/> it doesn't matter too much again it's roughly fifty-fifty <pause dur="0.5"/> # <pause dur="0.4"/> but i'll give you the numbers as <pause dur="0.2"/> best i can as # to match <gap reason="name" extent="1 word"/>'s but

just bear in mind <trunc>thes</trunc> they're not absolute values <pause dur="0.4"/> so <kinesic desc="indicates point on slide" iterated="n"/> this is your normal plasma concentration <pause dur="0.4"/> that's the range and it's split like this <pause dur="0.4"/> and this is important because it's only the ionized calcium <pause dur="0.3"/> that actually has an effect <pause dur="0.4"/> what you're really interested in is the amount of ionized calcium that's free in the blood <pause dur="0.4"/> or in the plasma <pause dur="0.6"/> not the calcium that is bound <pause dur="0.6"/> although that has a role to play obviously it's a storage component <pause dur="0.5"/> and the flux between bound and <pause dur="0.3"/> and free is really important <pause dur="0.4"/> and there are issues there <pause dur="0.5"/> in terms of physical function it's the ionized calcium that has a role <pause dur="1.4"/> but in terms of the kidney it's important to note this is further subdivided you've got some of it bound to plasma proteins <pause dur="0.3"/> and this is predominantly albumin <pause dur="0.3"/> and you'll see that's important in a minute <pause dur="0.6"/> # but some of it's ions so anions you've got bicarb and phosphate and citrate <pause dur="1.3"/> # <pause dur="0.3"/> and that's important because these get into the kidney <pause dur="0.8"/> but # <pause dur="1.2"/> forty-five per cent is bound to

proteins and can't be filtered <pause dur="0.9"/> and this is what we need again figures i've given you already you need a gram if you're a normal person <pause dur="0.6"/> if you're pregnant or lactating you need a bit more because obviously you're building up the bones in the child and you need to make milk so you need more calcium <pause dur="0.5"/> and if you're old you need more <pause dur="0.4"/> and you need more if you're old because you can't absorb it from your gut <pause dur="0.3"/> as efficiently <pause dur="0.7"/> so although you're taking in more as an elderly person your absorption from the gut <pause dur="0.3"/> is decreased so your actual # <pause dur="0.6"/> levels usually they're they're deficient elderly people in calcium from what we would normally <pause dur="0.3"/> count as normal levels <pause dur="2.3"/><kinesic desc="changes slide" iterated="n"/> so if we look at plasma concentrations or plasma calcium <pause dur="0.4"/> that's what i've told you <pause dur="0.5"/> that's what we're really interested in regulating is the free calcium <pause dur="1.2"/> when you send blood off to a lab <pause dur="0.4"/> it'll send it back as a total calcium concentration you'll get <pause dur="0.4"/> two-point-four or two-point-five or whatever it back as as

a number <pause dur="0.5"/> and that's your total calcium concentration <pause dur="0.5"/> and what they've done is they've corrected for albumin <pause dur="0.6"/> now okay don't get tied up this is exactly what happens <pause dur="0.5"/> # the calculation that's used but you can see they measure the the blood albumin <pause dur="0.3"/> as well as the blood calcium <pause dur="0.9"/> now this is taken something that any of you going into renal <pause dur="0.2"/> fields will find out about there's a renal registry <pause dur="0.5"/> renal medicine's quite tightly controlled in Britain <pause dur="0.4"/> and # they produce a renal registry which outlines # <pause dur="0.3"/> treatment standards how quickly you should be seen if you've got various conditions <pause dur="0.4"/> what your <pause dur="0.3"/> concentrations of various things should be et cetera it's standardized throughout the country <pause dur="0.4"/> and they also list things like <pause dur="0.3"/> how the measurements are done in different hospitals because calcium and albumin are measured differently <pause dur="0.4"/> depending on which hospital you're working in so there's different there's about three or four assays for them <pause dur="0.5"/> different hospitals use different ones <pause dur="0.6"/> and as

a consequence <pause dur="0.3"/><kinesic desc="indicates point on slide" iterated="n"/> this correction equation <pause dur="0.3"/> will vary between hospitals <pause dur="0.5"/> now this is kind of like the U-K standard in the renal registry <pause dur="0.5"/> if you measure the calcium the way they suggest and the albumin the way they suggest <pause dur="0.3"/> then this is the equation they would use <pause dur="0.5"/> however the Walsgrave <pause dur="0.4"/> just uses a completely different formula it's slightly more complicated so if you see the correction from the Walsgrave from labs <pause dur="0.3"/> and it's different to this <pause dur="0.3"/> this is why <pause dur="0.4"/> but you don't need to know it all you need to know is that you're getting back the total calcium <pause dur="0.6"/> and that's important because it can skew your results <pause dur="1.0"/> you normally know <pause dur="0.3"/> if it's a total calcium and they've corrected for albumin <pause dur="0.3"/> in a normal person that's fine <pause dur="0.4"/> # it's going to be split in a forty-five fifty-five proportions so you know roughly what your free albumin is <pause dur="0.4"/> # free calcium whether normal or not <pause dur="0.8"/> if somebody has a disease or a condition where their albumin levels <pause dur="0.3"/> are grossly abnormal <pause dur="0.4"/> that may skew the results <pause dur="0.4"/> so for

example if somebody has a very low albumin <pause dur="0.4"/> it may come back # <pause dur="0.4"/> the total may be <pause dur="0.2"/> normal <pause dur="0.4"/> but actually the amount you've got bound because your albumin's low <pause dur="0.4"/> is low so your free calcium could be significantly higher than you would <pause dur="0.3"/> normally expect <pause dur="0.5"/> so this happens with a couple of # <pause dur="0.7"/> # <pause dur="0.5"/> substances that you <pause dur="0.2"/> do lab measurements on <pause dur="0.3"/> so just bear in mind your total calcium <pause dur="0.4"/> may not a normal total calcium may not reflect a normal <pause dur="0.4"/> total # free calcium and sometimes you have to bear that in mind <pause dur="1.3"/> i've put here can we measure free <pause dur="0.2"/> we said you were interested in free why don't we measure free <pause dur="0.7"/> it's more difficult is the simple answer <pause dur="0.6"/> the assays are more variable between places and people are <pause dur="0.6"/> # <pause dur="0.3"/> seem to be very divided over this as to whether it actually gives you any great benefit in the average person <pause dur="0.3"/> if you think there's a reason why you need free particularly for that patient you might want to request it <pause dur="0.3"/> but on the whole <pause dur="0.3"/> people think for the time money and the variability it

doesn't seem to be worth <pause dur="0.5"/> # it doesn't give you a significantly better result <pause dur="1.1"/> and i've just put this here <pause dur="0.6"/> this is very low remember most of the calcium <pause dur="0.2"/> isn't within a cell <pause dur="0.2"/> and the calcium that is in a cell <pause dur="0.3"/> is complexed to calmodulin and you must keep it very low <pause dur="0.5"/> so # <pause dur="0.3"/> that's just something to bear in mind that calcium normally is not in cells at all <pause dur="1.0"/><kinesic desc="changes slide" iterated="n"/> so what happens when it goes wrong <pause dur="1.4"/><kinesic desc="changes slide" iterated="n"/> obviously you can have too much or too little <pause dur="0.6"/> so <pause dur="0.2"/> if we look at hypocalcaemia first <pause dur="0.7"/> generally <pause dur="0.3"/> and this is a big generalization this tends to be the more serious condition because it tends to be more acute <pause dur="0.6"/> and that's a big they're they're generalizations <pause dur="0.4"/> but you'll see from the hypercalcaemia slide <pause dur="0.7"/> on the whole it has more chronic # less severe effects <pause dur="0.9"/> if you haven't got enough calcium <pause dur="0.4"/> it really affects your nerves and # your signalling <pause dur="0.3"/> and the muscle function and you get # muscle cramps and tetany <pause dur="0.7"/> and long term seizures <pause dur="0.4"/> and most of you will be aware of tetany but it's quite <pause dur="0.3"/> clear to see

here in a wrist you see it in other # <pause dur="0.9"/> # <pause dur="0.7"/> tissues but the the wrist and the hand are quite normal and that's the # form that it takes basically <pause dur="0.3"/> you're unable your muscles are # contracted and you're unable to <pause dur="0.8"/> uncontract <shift feature="voice" new="laugh"/>them <pause dur="0.2"/> for want of a better word <pause dur="0.5"/> <shift feature="voice" new="normal"/> # <pause dur="0.3"/> and that's a symptom of low calcium <pause dur="0.5"/> but this is what's important <pause dur="0.4"/> you get cardiac arrhythmias <pause dur="0.8"/><kinesic desc="changes slide" iterated="n"/> and then if we look at hypercalcaemia <pause dur="0.2"/> in the contrast <pause dur="0.6"/> this tends to i said it tends to be slight and variable <pause dur="0.6"/> a lot of cases of hypercalcaemia are picked up on routine blood scans <pause dur="0.2"/> # tests <pause dur="0.4"/> so normally it sort of often occurs middle-aged women they go for a Well <trunc>wom</trunc> Well Women Clinic or Well Woman Clinic <pause dur="0.5"/> have a blood sample they measure calcium and find their calcium's quite high <pause dur="0.2"/> it is a consequence the symptoms <pause dur="0.2"/> obviously # are quite minor so <pause dur="0.4"/> you've got a <trunc>ole</trunc> whole range of G-I kind of problems <pause dur="0.4"/> they can be a bit depressed tired confused <pause dur="0.4"/> but as this is normally a # disease of middle-aged women <pause dur="0.3"/> # <pause dur="0.2"/> because they

often have a parathyroid hormone tumour which we'll see about in a bit <pause dur="0.5"/> these sort of symptoms are very similar to menopause type symptoms so you wouldn't really <pause dur="0.3"/> # pick up on them <pause dur="0.4"/> muscle weakness <pause dur="0.6"/> this is <pause dur="0.2"/> a big one <pause dur="0.7"/> if it goes on for a long time <pause dur="0.3"/> or you're severely hypercalcaemic and you've got far too much calcium <pause dur="0.3"/> the calcium <unclear>will</unclear> deposit <pause dur="0.4"/> and form # solid lumps <pause dur="0.3"/> and this either happens in the kidney and forms kidney stones which we'll see about in the next session <pause dur="0.4"/> stones aren't only made of calcium there's lots of different types of stones <pause dur="0.4"/> but some of them are made of calcium <pause dur="0.4"/> and you get ectopic calcification <pause dur="0.4"/> so you can pick up little lumps of calcium on X-rays <pause dur="0.3"/> in all sorts of places where you wouldn't expect them throughout the kidneys <pause dur="0.3"/> or throughout the body <pause dur="0.3"/> so if it goes on for a long long time you're severely hypercalcaemic that's a problem <pause dur="1.0"/> but again <pause dur="0.5"/> very hypercalcaemic <pause dur="0.7"/> very suddenly <pause dur="0.3"/> and you have cardiac problems again <pause dur="1.0"/><kinesic desc="changes slide" iterated="n"/> so that's why it's really

important if it's an acute <pause dur="0.4"/> # situation <pause dur="0.7"/> so what do you do the main aims <pause dur="0.4"/> if you've got a patient is you want to normalize their calcium <pause dur="1.4"/> so if they're hypercalcaemic and i've just put here <pause dur="0.4"/> if their levels remember the normal's about two-point-five if the levels are up here <pause dur="0.3"/> it's an emergency in terms of heart conditions <pause dur="0.6"/> # <pause dur="0.2"/> so what you do is you try to flush the calcium out of the system by giving them fluids and making them pee more <pause dur="0.6"/> and these treatments <kinesic desc="indicates point on slide" iterated="n"/> here basically refer to the bone conditions <pause dur="0.4"/> because <pause dur="0.3"/> if you're hypercalcaemic <pause dur="0.3"/> most of that calcium's coming from your bone if you remember i told you that in the second year and we'll look at that <pause dur="0.4"/> # second semester and we'll look at that in a couple of weeks' time <pause dur="0.5"/> so if you can stop the bones losing calcium that will help bring down the calcium level certainly long term <pause dur="0.4"/> so these are a more longer term treatment and they affect the bone <pause dur="0.4"/> but initially you're going to want to try and flush the calcium certainly flush it

out of the system <pause dur="1.3"/> and as i said normally it's a parathyroid tumour <pause dur="0.5"/> # ninety per cent of the cases unless they're an emergency if it's a chronic hypercalcaemia <pause dur="0.4"/> are parathyroid tumours <pause dur="0.4"/> and then you may have to consider removing all or some of the parathyroid glands <pause dur="2.2"/><kinesic desc="changes slide" iterated="n"/> if it's <trunc>hypercal</trunc> hypocalcaemia sorry hypo <pause dur="0.7"/> again you've got an acute situation or a chronic <pause dur="0.6"/> if it's acute you can simply give them calcium I-V <pause dur="0.4"/> and you give them that as # <pause dur="0.3"/> calcium gluconate <pause dur="0.6"/> if it's chronic <pause dur="0.5"/> you want to make certain they've got enough calcium in their diet <pause dur="0.3"/> and they're able to reabsorb it or absorb it from their diet properly <pause dur="0.4"/> so you give them calcium <pause dur="0.3"/> and give them vitamin D and we'll see why they need vitamin D <pause dur="0.2"/> a little later <pause dur="1.0"/><kinesic desc="changes slide" iterated="n"/> and i've just put this in P-T-H-R-P <pause dur="0.4"/> it's nothing to do with the kidney really or at least not that we know of at the moment <pause dur="0.6"/> but because it acts exactly like parathyroid hormone <pause dur="0.3"/> and we'll see the effects of that in a couple of slides <pause dur="0.3"/> it can make people

hypercalcaemic <pause dur="0.4"/> so <pause dur="0.2"/> but if often occurs when there's malignancy <pause dur="0.5"/> so hypercalcaemia and malignancy tend to go hand in hand <pause dur="0.4"/> and although there's a number of causes for that <pause dur="0.4"/> increased P-T-H-R-P can be one of them <pause dur="0.4"/> so you just bear in mind you you may need to look for this <pause dur="0.9"/> # the difference is <pause dur="0.4"/> # if you've got # <pause dur="0.2"/> hyperparathyroidism it won't affect your P-T-H-R-P production <pause dur="0.6"/> and likewise # <pause dur="0.4"/> you don't see a change in your vitamin D levels so if your vitamin D levels are normal <pause dur="0.3"/> but very high calcium <pause dur="0.5"/> # and you haven't got a parathyroid tumour it might be worth looking for a tumour elsewhere that's producing P-T-H-R-P <pause dur="1.7"/><kinesic desc="changes slide" iterated="n"/> so this is the slide i've shown you before <pause dur="0.5"/> low calcium <pause dur="0.4"/> you produce P-T-H that affects the bone <pause dur="0.2"/> and the kidney <pause dur="0.4"/> the kidney produces vitamin D <pause dur="1.5"/> which acts on the bone and the gut and the net effects are increased calcium and feedback to switch the whole system off <pause dur="0.4"/> and i've put the kidney in the middle <pause dur="0.4"/> not because i think it's the most important but it is quite pivotal to

this system <pause dur="1.1"/><kinesic desc="changes slide" iterated="n"/> and if we're looking at calcium homeostasis and the kidney <pause dur="0.3"/> it's basically got three roles <pause dur="0.7"/> phosphate i've put here because phosphate and calcium go hand in hand one goes up the other goes down and we've <pause dur="0.4"/> talked about that and that's more apparent in the bone lectures <pause dur="0.6"/> # so we're not going to discuss it today <pause dur="0.5"/> but the other thing it does is it regulates your reabsorption from your filtrate you filter all your calcium more or less <pause dur="0.3"/> into your filtrate <pause dur="0.3"/> and you want to reabsorb most of it or regulate how much of that you reabsorb <pause dur="0.4"/> so the regulation of reabsorption from the filtrate or the occurrence of it <pause dur="0.3"/> happens in the kidney <pause dur="0.6"/> and it makes vitamin D and vitamin D <pause dur="0.3"/> is really important for calcium homeostasis <pause dur="1.0"/> so if we look at this <pause dur="0.5"/> # your filtered calcium again <pause dur="0.6"/> takes all the free calcium but it also takes the calcium that's bound to the anions <pause dur="0.3"/> not the protein-bound <pause dur="0.2"/> calcium because obviously that can't be filtered through if it's bound to a protein <pause dur="0.4"/> but it does take the

ionic bound so you've got about fifty-five per cent getting into the filtrate <pause dur="0.8"/><kinesic desc="changes slide" iterated="n"/> and this is roughly what happens as you go across the nephron so here's a schematic nephron <pause dur="0.5"/> and this indicates your calcium concentrations as you go through <pause dur="0.4"/> so by the time you get into the thin <pause dur="0.6"/> descending loop of Henle nearly all of your calcium's been reabsorbed already <pause dur="0.4"/> and most of it happens here <pause dur="0.4"/> and you've got a little bit left to be reabsorbed <pause dur="0.2"/> throughout this part of the nephron <pause dur="1.0"/> so if we put that in context <pause dur="0.4"/> you've got at least sixty seventy per cent of your calcium's reabsorbed in the proximal tubule <pause dur="0.7"/> most of that happens by simple diffusion <pause dur="0.4"/> but there is some active transport <pause dur="0.2"/> but we're not going to look at that in great detail <pause dur="1.7"/> when we come down <kinesic desc="indicates point on slide" iterated="n"/> here we've got the # loop of Henle between it you get a bit more reabsorbed <pause dur="0.6"/> and the distal convoluted tubule now this is interesting because although it's only a small proportion that's reabsorbed here <pause dur="0.5"/> this is under active transport and is

regulated <pause dur="0.4"/> so this is where the P-T-H has a role it can regulate the amount of calcium reabsorbed here <pause dur="0.4"/> but you can see you're only talking of regulating a very small proportion so it's <pause dur="0.3"/> quite a fine tuning exercise in terms of maintaining your calcium levels <pause dur="0.4"/> # from your kidneys <pause dur="0.5"/> and then a little bit goes into the collecting duct <pause dur="0.3"/> and <pause dur="0.4"/> only a small per cent out in urine one to two per cent in urine <pause dur="0.4"/> and you can see here you filter <kinesic desc="indicates point on slide" iterated="n"/> this much # per day <pause dur="0.3"/> but you reabsorb ninety-eight ninety-nine per cent of that <pause dur="0.6"/> so the kidney's really important if it stops reabsorbing calcium <pause dur="0.4"/> for any reason you're going to lose your calcium really rapidly <pause dur="1.2"/><kinesic desc="changes slide" iterated="n"/> so what about vitamin D i said the kidney makes vitamin D <pause dur="0.3"/> and the reason it's really important in terms of # <pause dur="0.6"/> calcium apart from the bones is that it regulates the uptake from the gut <pause dur="0.5"/><kinesic desc="changes slide" iterated="n"/> so i'm going to # go through this quite quickly 'cause it's not a G-I lecture but <pause dur="0.5"/> you've got three ways you can take up calcium from the gut <pause dur="0.4"/> simple <pause dur="0.3"/> # transport

between cells <pause dur="1.2"/> secondly it gets absorbed in the brush border binds to binding proteins and then is extruded by this # <pause dur="0.5"/> A-T-P-ase <pause dur="1.4"/> also it goes across the brush border goes into vesicles <pause dur="0.3"/> and then # endocytosis gets rid of it at <kinesic desc="indicates point on slide" iterated="n"/> this end <pause dur="0.3"/> but the important thing to note is that <pause dur="0.3"/> # <pause dur="0.2"/> the calcium binding protein is involved in all three cases doesn't matter which mechanism's used you need a calcium binding protein <pause dur="0.4"/> to get it across the cell <pause dur="0.6"/> and this is regulated by vitamin D <pause dur="0.5"/> so vitamin D increases levels of calcium binding protein <pause dur="0.6"/> which will effectively allow you to take up more from your gut <pause dur="0.3"/> it also alters the permeability of the brush border <pause dur="0.5"/> # so it allows more <pause dur="0.3"/> # calcium to be <pause dur="0.2"/> # <pause dur="0.2"/> absorbed through the brush border of the G-I system <pause dur="0.5"/> and vitamin D has got some role to play in this regulation of the calcium-sodium exchanger <pause dur="0.5"/> so vitamin D regulates the calcium from your diet <pause dur="1.4"/><kinesic desc="changes slide" iterated="n"/> it also is important for bones we've talked about this before and we're going to <pause dur="0.3"/> so whether the

calcium stays in your bones or is released in the circulation vitamin D has a role in <pause dur="0.7"/> and # <pause dur="0.6"/> it also regulates # you know when i said P-T-H regulates that small amount of # <pause dur="0.2"/> calcium reabsorbed in the <pause dur="0.2"/> the gut <pause dur="0.6"/> # <pause dur="0.7"/> vitamin D will also regulate calcium absorption to a small amount <vocal desc="clears throat" iterated="n"/><pause dur="0.6"/> but its real importance is regulating bone <pause dur="0.3"/> and regulating calcium uptake from the gut <pause dur="0.7"/><kinesic desc="changes slide" iterated="n"/> so how do we make vitamin D and this is really important in terms of kidneys <pause dur="0.5"/> so sunlight produces <pause dur="0.5"/> somewhere between eighty and ninety per cent of our vitamin D in our sun that's why it's important to get some sunlight <pause dur="0.5"/> # <pause dur="0.2"/> while balancing that against the risk of skin cancer <pause dur="1.0"/> # we get some from our diet and here here the levels of bile salts have a role to play but again that's that's a topic beyond the urinary course <pause dur="0.7"/> and the liver activates both these precursor forms <pause dur="0.3"/> into twenty-five-hydroxy-vitamin-D-three which is largely inactive <pause dur="0.4"/> and you can store that for quite a long time <pause dur="0.6"/> and then the kidney <pause dur="0.4"/><kinesic desc="indicates point on slide" iterated="n"/> here has

another enzyme that activates it into the active form which is one-twenty-five-<pause dur="0.3"/>dihydroxy-vitamin-D-three <pause dur="0.5"/> and as clinicians you'll get used to calling it calcitriol <pause dur="0.8"/> i try and use that but i i tend to use its real name 'cause obviously that's what i use in research all the time <pause dur="0.6"/> and these are the two enzymes that are involved <pause dur="0.5"/> they're both hydroxylases the liver has twenty-five-hydroxylase <pause dur="0.3"/> and the kidney has one-alpha-hydroxylase <pause dur="0.3"/> it's got a much longer name but that'll do for you <pause dur="0.7"/><kinesic desc="indicates point on slide" iterated="n"/> this one # is not regulated and depends on substrate concentrations <pause dur="0.5"/><kinesic desc="indicates point on slide" iterated="n"/> this one is very tightly regulated so you can see defects in either the liver <pause dur="0.3"/> or the kidney <pause dur="0.3"/> will affect your ability to make vitamin D <pause dur="2.7"/><kinesic desc="changes slide" iterated="n"/> so what's important <pause dur="0.3"/> i've just told you that the activity of the twenty-five-hydroxylase isn't regulated <pause dur="0.4"/> so if you want to see if somebody is deficient in vitamin D or not <pause dur="0.3"/> you can measure the twenty-five-hydroxy-vitamin-D-three levels the circulating substrate form <pause dur="0.5"/> and that'll tell you <pause dur="0.4"/> # <pause dur="0.4"/> their vitamin

D status <pause dur="0.3"/> <vocal desc="clears throat" iterated="n"/> <pause dur="2.6"/> the one-alpha-hydroxylase conversely <pause dur="0.3"/> very tightly regulated only works when you need the active form of vitamin D <pause dur="0.5"/> and that's because <pause dur="0.3"/> the vitamin <trunc>d</trunc> the active form of vitamin D <pause dur="0.3"/> is so good at <pause dur="0.4"/> # <pause dur="0.3"/> increasing levels of calcium in your blood <pause dur="0.3"/> if you have too much active vitamin D you become hypercalcaemic <pause dur="0.4"/> very rapidly <pause dur="0.5"/> and i do touch on this very briefly in the clinical pharmacology lecture <pause dur="0.8"/> # <pause dur="0.8"/> so it's very tightly regulated and i've just put here <pause dur="0.3"/> all the textbooks will tell you it's only in the kidney <pause dur="0.4"/> absolute rubbish couple of years ago we found out that this enzyme now <pause dur="0.6"/> all the tissues more or less in the body not <pause dur="0.3"/> not every single one but the vast majority are able to make vitamin D <pause dur="0.4"/> don't know why yet <pause dur="0.3"/> and we don't know what regulates it yet but # <pause dur="0.9"/> five years down the line textbooks will be different <pause dur="0.9"/> and that's just the normal ranges for your information i'm not going to dwell on that but you can see you've got far greater amounts of twenty-five versus

one-twenty-five-D-three <pause dur="1.8"/> so what happens why is the kidney important <pause dur="0.4"/> apart from regulating the levels of calcium in your blood <pause dur="0.4"/> # people with kidney disease can't make vitamin D <pause dur="1.3"/> that's sometimes because their kidneys are not functioning at all # they have no effect whatsoever but if the kidneys are just not working quite as well as normal <pause dur="0.3"/> then their ability to make vitamin D will be attenuated <pause dur="0.4"/><vocal desc="clears throat" iterated="n"/> <pause dur="1.3"/><kinesic desc="changes slide" iterated="n"/> if they can't make vitamin D <pause dur="0.3"/> obviously they become vitamin D deficient <pause dur="0.4"/> you don't absorb calcium from your gut <pause dur="0.5"/> you don't reabsorb it from your bone and you become hypocalcaemic <pause dur="0.6"/> this then activates the parathyroid glands to produce P-T-H <pause dur="0.8"/> the P-T-H <pause dur="0.6"/> then <pause dur="0.7"/> will act on bone to release calcium <pause dur="0.5"/> but it will also try and act on the kidney to stimulate vitamin D production <pause dur="0.2"/> but remember your kidneys are knackered for one reason or another <pause dur="0.4"/> so the vitamin D production doesn't go up <pause dur="0.7"/> so you're still hypocalcaemic <pause dur="0.2"/> because there's no vitamin D <pause dur="0.4"/> so the only place the P-T-H can act is on the bone <pause dur="0.6"/> so

the bone P-T-H system kind of goes into overdrive <pause dur="0.3"/> you reabsorb more and more and more bone to try and normalize your calcium levels <pause dur="0.4"/> the consequences are <pause dur="0.5"/> you get really bad bone disease <pause dur="0.8"/> # <pause dur="1.2"/> and that <pause dur="0.2"/> if it's caused because of # <pause dur="0.2"/> kidney disease it's known as renal osteodystrophy <pause dur="0.4"/> in terms of phenotype it's very similar to osteoporosis <pause dur="0.6"/> # and this is a real problem <pause dur="0.4"/> this secondary hyperparathyroidism <pause dur="0.5"/> so the the <pause dur="0.3"/> parathyroid glands <pause dur="0.3"/> don't switch off 'cause there's no vitamin D to act as a negative feedback <pause dur="0.5"/> it's almost impossible to normalize your calcium plasma calcium levels <pause dur="0.3"/> so that doesn't feed back to switch off P-T-H production <pause dur="0.3"/> and the gland goes into overdrive producing more and more P-T-H <pause dur="0.3"/> which only acts on the bone <pause dur="0.4"/> so you get severe bone disease <pause dur="0.4"/> and this is a real problem with anybody with renal disease <pause dur="0.9"/><kinesic desc="changes slide" iterated="n"/> so these are the things to take home this is revision <pause dur="0.7"/> calcium homeostasis basically you've got three main hormones we haven't talked about calcitonin today <pause dur="0.4"/> <unclear>i'll</unclear> do

in a couple of weeks <pause dur="0.5"/> and # <pause dur="0.6"/> three tissues <pause dur="0.3"/> # four tissues sorry you've got gut and bone put there together <pause dur="0.4"/> so four tissues three hormones <pause dur="0.9"/> this is important to remember later in the the module doesn't come up now <pause dur="0.5"/> but the most of the calcium that you eat <pause dur="0.4"/> we excrete <pause dur="0.6"/> whereas nearly all of the phosphate that you ingest <pause dur="0.2"/> we retain <pause dur="0.8"/> # or you absorb rather you don't <pause dur="0.2"/> retain it you absorb it so when you're looking at the <pause dur="0.2"/> G-I uptake <pause dur="0.4"/> most calcium <pause dur="0.5"/> is excreted straightaway in faeces whereas all the phosphate is absorbed <pause dur="0.3"/> and that will become apparent why that's important later on <pause dur="1.2"/> okay so the kidney's important 'cause it reabsorbs most of the filtered calcium and makes vitamin D <pause dur="0.7"/> and vitamin D we've just gone over <pause dur="1.5"/><kinesic desc="changes slide" iterated="n"/> a hyperparathyroidism <pause dur="1.0"/> now this is # <pause dur="0.5"/> something that comes up in the group work and something you'll get used to <pause dur="0.4"/> as you go through the module <pause dur="0.8"/> but there's three forms of hyperparathyroidism <pause dur="0.8"/> now remember i said most # <pause dur="0.2"/> hypercalcaemia presents with a sort of middle-aged

woman <pause dur="0.5"/> # in a routine blood test and she's probably got a tumour <pause dur="0.9"/> now that's primary hyperparathyroidism <pause dur="0.4"/> the parathyroid glands <pause dur="0.3"/> are producing too much P-T-H on their own <pause dur="0.9"/> now in that case <pause dur="0.4"/> you have # <pause dur="0.4"/> too much P-T-H <pause dur="0.4"/> the kidneys respond normally producing more vitamin D <pause dur="0.5"/> # the bones respond to release calcium <pause dur="1.1"/> that all produces an increase in calcium in the plasma <pause dur="0.4"/> but because it's coming from a tumour there's no negative feedback system working <pause dur="0.6"/> so you go on and on <pause dur="0.2"/> producing more calcium <pause dur="0.5"/> # hence hypercalcaemia <pause dur="1.2"/> and that's <pause dur="0.2"/> relatively simple you can whip some of the parathyroids out <pause dur="2.1"/> secondary hyperparathyroidism was the one we've just talked about where the system can't work <pause dur="0.4"/> so there's no negative feedback so the parathyroid glands go on producing <pause dur="0.4"/> # P-T-H <pause dur="0.5"/> and eventually they # become desensitized as we'll see <pause dur="0.7"/> now this is i've put vitamin D deficiency here but it's usually is a consequence of renal disease it's not somebody who's just not <pause dur="0.5"/> # <pause dur="0.4"/> vitamin D deficient

and developing rickets it's a renal problem really <pause dur="0.5"/> and in that case you've got low or normal plasma calcium whereas they're high here <pause dur="1.0"/> and the last one is tertiary hyperparathyroidism <pause dur="0.4"/> and this is really quite specialized <pause dur="0.5"/> # this is a # <pause dur="0.6"/> consequence of renal disease <pause dur="0.6"/> but it's a # <pause dur="0.2"/> a continuation of secondary hyperparathyroidism <pause dur="0.6"/> when there's no feedback <pause dur="0.3"/> # to switch the parathyroid glands off they go on producing P-T-H <pause dur="0.6"/> and they become insensitive to calcium levels and vitamin D the receptor levels drop <pause dur="0.6"/> they also sometimes become hyperplastic so you get more cells <pause dur="0.4"/> # bigger parathyroid glands <pause dur="0.3"/> producing more P-T-H <pause dur="0.4"/> so the consequences are completely unregulated P-T-H production <pause dur="0.6"/> remember you've got kidneys that can't respond normally <pause dur="0.6"/> # <pause dur="0.4"/> so you get # <pause dur="0.2"/> loads and loads and loads of reabsorption from your bone so you get really bad bone disease <pause dur="0.3"/> but in that case as well you usually

have high plasma calcium <pause dur="0.7"/> but <pause dur="0.2"/> this <trunc>h</trunc> plasma calcium which would normally shut off P-T-H production can't because the gland's lost all its natural <pause dur="0.5"/> # <pause dur="0.5"/> mechanisms for feedback <pause dur="1.7"/> oh i'll leave that slide up at the end in a minute 'cause i realize you haven't got that one 'cause that was an addition <pause dur="0.6"/><kinesic desc="changes slide" iterated="n"/> this one at the end i'm not going through it's kind of a pictorial representation of secondary hyperparathyroidism <pause dur="0.5"/> and the problems associated with kidney disease <pause dur="0.6"/> it's # <pause dur="0.3"/> it's really important you know calcium homeostasis # goes up the creek if you've kidney disease <pause dur="0.7"/> so that's all i've got to say now # <pause dur="0.4"/> 'cause i know we're running slightly probably any questions either come and see me or see me in the group work <pause dur="0.5"/><kinesic desc="changes slide" iterated="n"/> and # i'll just leave that one up for you to copy down <pause dur="0.4"/> while i get <gap reason="name" extent="2 words"/> sorted out for the next lecture

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