nf0369: right okay if we can settle down we need to dash on to the next one now 
again some of this is going to be revision for you because er we touched upon 
it briefly in musculoskeletal er that was last semester i think wasn't it and 
it comes up again in clinical pharmacology when we look at bone diseases so 
it's partly revision but we're looking at it from a different aspect today so i 
just want to have a look at what what's normal a very quick review of calcium 
homeostasis er 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 the kidney's the 
one i'm concentrating on and then have a quick look at vitamin D deficiency er 
because that's really important when we're considering renal disease so if we 
look at the physiological roles of calcium we went over this last semester and 
in that time we were particularly talking 
about bones and we're going to be tic-, particularly talking about bones in 
clinical pharmacology that obviously is a long term effect calcium homeostasis 
gone wrong will affect bones but it has a longer term er effect it's not going 
to happen overnight although you can see changes within a fortnight but i-, 
it's a long process more chronic whereas these functions that i've listed here 
are much more rapid and acute er in terms of the functions of the calcium 
obviously if you have changes in your nerve function and nerve signalling er or 
muscle contraction that'll happen rapidly so there are sort of kind of acute 
and chronic consequences of calcium homeostasis being messed up and this one 
i've just put here just to remind you er that one of the roles of calcium is in 
er blood clotting so if you've all your blood tubes or a lot of them have er 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 in blood tubes but 
the really important thing is that the levels need to be very tightly regulated 
in order to ensure that all these kind of acute problems don't happen and then 
longer term the chronic bone problems you need to regulate your calcium levels 
that are circulating quite closely so this is a slide you've had this one 
before but just to remind you these are the plasma concentrations and this is 
the normal range here or roughly now these numbers that i've put up and the 
numbers that i've put up on a lot of my slides depending on the book you look 
at they will vary very slightly i've got forty-five per cent ionized here and 
fifty-five per cent bound what i tend to do in my numbers is trying to match 
what the namex students get but you will find books that'll give you anywhere 
between forty and fifty here er and alter this accordingly it doesn't matter 
too much again it's roughly fifty-fifty er but i'll give you the numbers as 
best i can as er to match namex's but 
just bear in mind thes-, they're not absolute values so this is your normal 
plasma concentration that's the range and it's split like this and this is 
important because it's only the ionized calcium that actually has an effect 
what you're really interested in is the amount of ionized calcium that's free 
in the blood or in the plasma not the calcium that is bound although that has a 
role to play obviously it's a storage component and the flux between bound and 
and free is really important and there are issues there in terms of physical 
function it's the ionized calcium that has a role 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 and this is predominantly albumin and you'll see that's 
important in a minute er but some of it's ions so anions you've got bicarb and 
phosphate and citrate er and that's important because these get into the kidney 
but er forty-five per cent is bound to 
proteins and can't be filtered and this is what we need again figures i've 
given you already you need a gram if you're a normal person 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 and if you're 
old you need more and you need more if you're old because you can't absorb it 
from your gut as efficiently so although you're taking in more as an elderly 
person your absorption from the gut is decreased so your actual er levels 
usually they're they're deficient elderly people in calcium from what we would 
normally count as normal levels so if we look at plasma concentrations or 
plasma calcium that's what i've told you that's what we're really interested in 
regulating is the free calcium when you send blood off to a lab it'll send it 
back as a total calcium concentration you'll get two-point-four or two-point-
five or whatever it back as as 
a number and that's your total calcium concentration and what they've done is 
they've corrected for albumin now okay don't get tied up this is exactly what 
happens er the calculation that's used but you can see they measure the the 
blood albumin as well as the blood calcium now this is taken something that any 
of you going into renal fields will find out about there's a renal registry 
renal medicine's quite tightly controlled in Britain and er they produce a 
renal registry which outlines er treatment standards how quickly you should be 
seen if you've got various conditions what your concentrations of various 
things should be et cetera it's standardized throughout the country and they 
also list things like how the measurements are done in different hospitals 
because calcium and albumin are measured differently depending on which 
hospital you're working in so there's different there's about three or four 
assays for them different hospitals use different ones and as 
a consequence this correction equation will vary between hospitals now this is 
kind of like the U-K standard in the renal registry if you measure the calcium 
the way they suggest and the albumin the way they suggest then this is the 
equation they would use however the Walsgrave just uses a completely different 
formula it's slightly more complicated so if you see the correction from the 
Walsgrave from labs and it's different to this this is why but you don't need 
to know it all you need to know is that you're getting back the total calcium 
and that's important because it can skew your results you normally know if it's 
a total calcium and they've corrected for albumin in a normal person that's 
fine er it's going to be split in a forty-five fifty-five proportions so you 
know roughly what your free albumin is er free calcium whether normal or not if 
somebody has a disease or a condition where their albumin levels are grossly 
abnormal that may skew the results so for 
example if somebody has a very low albumin it may come back er the total may be 
normal but actually the amount you've got bound because your albumin's low is 
low so your free calcium could be significantly higher than you would normally 
expect so this happens with a couple of er er substances that you do lab 
measurements on so just bear in mind your total calcium may not a normal total 
calcium may not reflect a normal total er free calcium and sometimes you have 
to bear that in mind i've put here can we measure free we said you were 
interested in free why don't we measure free it's more difficult is the simple 
answer the assays are more variable between places and people are er seem to be 
very divided over this as to whether it actually gives you any great benefit in 
the average person if you think there's a reason why you need free particularly 
for that patient you might want to request it but on the whole people think for 
the time money and the variability it 
doesn't seem to be worth er it doesn't give you a significantly better result 
and i've just put this here this is very low remember most of the calcium isn't 
within a cell and the calcium that is in a cell is complexed to calmodulin and 
you must keep it very low so er that's just something to bear in mind that 
calcium normally is not in cells at all so what happens when it goes wrong 
obviously you can have too much or too little so if we look at hypocalcaemia 
first generally and this is a big generalization this tends to be the more 
serious condition because it tends to be more acute and that's a big they're 
they're generalizations but you'll see from the hypercalcaemia slide on the 
whole it has more chronic er less severe effects if you haven't got enough 
calcium it really affects your nerves and er your signalling and the muscle 
function and you get er muscle cramps and tetany and long term seizures and 
most of you will be aware of tetany but it's quite clear to see 
here in a wrist you see it in other er er tissues but the the wrist and the 
hand are quite normal and that's the er form that it takes basically you're 
unable your muscles are er contracted and you're unable to uncontract them for 
want of a better word er and that's a symptom of low calcium but this is what's 
important you get cardiac arrhythmias and then if we look at hypercalcaemia in 
the contrast this tends to i said it tends to be slight and variable a lot of 
cases of hypercalcaemia are picked up on routine blood scans er tests so 
normally it sort of often occurs middle-aged women they go for a Well wom-, 
Well Women Clinic or Well Woman Clinic have a blood sample they measure calcium 
and find their calcium's quite high it is a consequence the symptoms obviously 
er are quite minor so you've got a ole-, whole range of G-I kind of problems 
they can be a bit depressed tired confused but as this is normally a er disease 
of middle-aged women er because they 
often have a parathyroid hormone tumour which we'll see about in a bit these 
sort of symptoms are very similar to menopause type symptoms so you wouldn't 
really er pick up on them muscle weakness this is a big one if it goes on for a 
long time or you're severely hypercalcaemic and you've got far too much calcium 
the calcium will deposit and form er solid lumps and this either happens in the 
kidney and forms kidney stones which we'll see about in the next session stones 
aren't only made of calcium there's lots of different types of stones but some 
of them are made of calcium and you get ectopic calcification so you can pick 
up little lumps of calcium on X-rays in all sorts of places where you wouldn't 
expect them throughout the kidneys or throughout the body so if it goes on for 
a long long time you're severely hypercalcaemic that's a problem but again very 
hypercalcaemic very suddenly and you have cardiac problems again so that's why 
it's really 
important if it's an acute er situation so what do you do the main aims if 
you've got a patient is you want to normalize their calcium so if they're 
hypercalcaemic and i've just put here if their levels remember the normal's 
about two-point-five if the levels are up here it's an emergency in terms of 
heart conditions er so what you do is you try to flush the calcium out of the 
system by giving them fluids and making them pee more and these treatments here 
basically refer to the bone conditions because if you're hypercalcaemic 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 er second semester and we'll look at that in 
a couple of weeks' time so if you can stop the bones losing calcium that will 
help bring down the calcium level certainly long term so these are a more 
longer term treatment and they affect the bone but initially you're going to 
want to try and flush the calcium certainly flush it 
out of the system and as i said normally it's a parathyroid tumour er ninety 
per cent of the cases unless they're an emergency if it's a chronic 
hypercalcaemia are parathyroid tumours and then you may have to consider 
removing all or some of the parathyroid glands if it's hypercal-, hypocalcaemia 
sorry hypo again you've got an acute situation or a chronic if it's acute you 
can simply give them calcium I-V and you give them that as er calcium gluconate 
if it's chronic you want to make certain they've got enough calcium in their 
diet and they're able to reabsorb it or absorb it from their diet properly so 
you give them calcium and give them vitamin D and we'll see why they need 
vitamin D a little later and i've just put this in P-T-H-R-P it's nothing to do 
with the kidney really or at least not that we know of at the moment but 
because it acts exactly like parathyroid hormone and we'll see the effects of 
that in a couple of slides it can make people 
hypercalcaemic so but if often occurs when there's malignancy so hypercalcaemia 
and malignancy tend to go hand in hand and although there's a number of causes 
for that increased P-T-H-R-P can be one of them so you just bear in mind you 
you may need to look for this er the difference is er if you've got er 
hyperparathyroidism it won't affect your P-T-H-R-P production and likewise er 
you don't see a change in your vitamin D levels so if your vitamin D levels are 
normal but very high calcium er 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 so 
this is the slide i've shown you before low calcium you produce P-T-H that 
affects the bone and the kidney the kidney produces vitamin D which acts on the 
bone and the gut and the net effects are increased calcium and feedback to 
switch the whole system off and i've put the kidney in the middle not because i 
think it's the most important but it is quite pivotal to 
this system and if we're looking at calcium homeostasis and the kidney it's 
basically got three roles phosphate i've put here because phosphate and calcium 
go hand in hand one goes up the other goes down and we've talked about that and 
that's more apparent in the bone lectures er so we're not going to discuss it 
today but the other thing it does is it regulates your reabsorption from your 
filtrate you filter all your calcium more or less into your filtrate and you 
want to reabsorb most of it or regulate how much of that you reabsorb so the 
regulation of reabsorption from the filtrate or the occurrence of it happens in 
the kidney and it makes vitamin D and vitamin D is really important for calcium 
homeostasis so if we look at this er your filtered calcium again takes all the 
free calcium but it also takes the calcium that's bound to the anions not the 
protein-bound calcium because obviously that can't be filtered through if it's 
bound to a protein but it does take the 
ionic bound so you've got about fifty-five per cent getting into the filtrate 
and this is roughly what happens as you go across the nephron so here's a 
schematic nephron and this indicates your calcium concentrations as you go 
through so by the time you get into the thin descending loop of Henle nearly 
all of your calcium's been reabsorbed already and most of it happens here and 
you've got a little bit left to be reabsorbed throughout this part of the 
nephron so if we put that in context you've got at least sixty seventy per cent 
of your calcium's reabsorbed in the proximal tubule most of that happens by 
simple diffusion but there is some active transport but we're not going to look 
at that in great detail when we come down here we've got the er loop of Henle 
between it you get a bit more reabsorbed and the distal convoluted tubule now 
this is interesting because although it's only a small proportion that's 
reabsorbed here this is under active transport and is 
regulated so this is where the P-T-H has a role it can regulate the amount of 
calcium reabsorbed here but you can see you're only talking of regulating a 
very small proportion so it's quite a fine tuning exercise in terms of 
maintaining your calcium levels er from your kidneys and then a little bit goes 
into the collecting duct and only a small per cent out in urine one to two per 
cent in urine and you can see here you filter this much er per day but you 
reabsorb ninety-eight ninety-nine per cent of that so the kidney's really 
important if it stops reabsorbing calcium for any reason you're going to lose 
your calcium really rapidly so what about vitamin D i said the kidney makes 
vitamin D and the reason it's really important in terms of er calcium apart 
from the bones is that it regulates the uptake from the gut so i'm going to er 
go through this quite quickly 'cause it's not a G-I lecture but you've got 
three ways you can take up calcium from the gut simple er transport 
between cells secondly it gets absorbed in the brush border binds to binding 
proteins and then is extruded by this er A-T-P-ase also it goes across the 
brush border goes into vesicles and then er endocytosis gets rid of it at this 
end but the important thing to note is that er the calcium binding protein is 
involved in all three cases doesn't matter which mechanism's used you need a 
calcium binding protein to get it across the cell and this is regulated by 
vitamin D so vitamin D increases levels of calcium binding protein which will 
effectively allow you to take up more from your gut it also alters the 
permeability of the brush border er so it allows more er calcium to be er 
absorbed through the brush border of the G-I system and vitamin D has got some 
role to play in this regulation of the calcium-sodium exchanger so vitamin D 
regulates the calcium from your diet it also is important for bones we've 
talked about this before and we're going to so whether the 
calcium stays in your bones or is released in the circulation vitamin D has a 
role in and er it also regulates er you know when i said P-T-H regulates that 
small amount of er calcium reabsorbed in the the gut er vitamin D will also 
regulate calcium absorption to a small amount but its real importance is 
regulating bone and regulating calcium uptake from the gut so how do we make 
vitamin D and this is really important in terms of kidneys so sunlight produces 
somewhere between eighty and ninety per cent of our vitamin D in our sun that's 
why it's important to get some sunlight er while balancing that against the 
risk of skin cancer er 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 and the liver activates both these precursor forms into twenty-
five-hydroxy-vitamin-D-three which is largely inactive and you can store that 
for quite a long time and then the kidney here has 
another enzyme that activates it into the active form which is one-twenty-five- 
dihydroxy-vitamin-D-three and as clinicians you'll get used to calling it 
calcitriol 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 and these are the two 
enzymes that are involved they're both hydroxylases the liver has twenty-five-
hydroxylase and the kidney has one-alpha-hydroxylase it's got a much longer 
name but that'll do for you this one er is not regulated and depends on 
substrate concentrations this one is very tightly regulated so you can see 
defects in either the liver or the kidney will affect your ability to make 
vitamin D so what's important i've just told you that the activity of the 
twenty-five-hydroxylase isn't regulated so if you want to see if somebody is 
deficient in vitamin D or not you can measure the twenty-five-hydroxy-vitamin-D-
three levels the circulating substrate form and that'll tell you er their 
vitamin 
D status the one-alpha-hydroxylase conversely very tightly regulated only works 
when you need the active form of vitamin D and that's because the vitamin d-, 
the active form of vitamin D is so good at er increasing levels of calcium in 
your blood if you have too much active vitamin D you become hypercalcaemic very 
rapidly and i do touch on this very briefly in the clinical pharmacology 
lecture er so it's very tightly regulated and i've just put here all the 
textbooks will tell you it's only in the kidney absolute rubbish couple of 
years ago we found out that this enzyme now all the tissues more or less in the 
body not not every single one but the vast majority are able to make vitamin D 
don't know why yet and we don't know what regulates it yet but er five years 
down the line textbooks will be different 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 so what happens why is the kidney important apart from 
regulating the levels of calcium in your blood er people with kidney disease 
can't make vitamin D that's sometimes because their kidneys are not functioning 
at all er they have no effect whatsoever but if the kidneys are just not 
working quite as well as normal then their ability to make vitamin D will be 
attenuated if they can't make vitamin D obviously they become vitamin D 
deficient you don't absorb calcium from your gut you don't reabsorb it from 
your bone and you become hypocalcaemic this then activates the parathyroid 
glands to produce P-T-H the P-T-H then will act on bone to release calcium but 
it will also try and act on the kidney to stimulate vitamin D production but 
remember your kidneys are knackered for one reason or another so the vitamin D 
production doesn't go up so you're still hypocalcaemic because there's no 
vitamin D so the only place the P-T-H can act is on the bone so 
the bone P-T-H system kind of goes into overdrive you reabsorb more and more 
and more bone to try and normalize your calcium levels the consequences are you 
get really bad bone disease er and that if it's caused because of er kidney 
disease it's known as renal osteodystrophy in terms of phenotype it's very 
similar to osteoporosis er and this is a real problem this secondary 
hyperparathyroidism so the the parathyroid glands don't switch off 'cause 
there's no vitamin D to act as a negative feedback it's almost impossible to 
normalize your calcium plasma calcium levels so that doesn't feed back to 
switch off P-T-H production and the gland goes into overdrive producing more 
and more P-T-H which only acts on the bone so you get severe bone disease and 
this is a real problem with anybody with renal disease so these are the things 
to take home this is revision calcium homeostasis basically you've got three 
main hormones we haven't talked about calcitonin today i'll do 
in a couple of weeks and er three tissues er four tissues sorry you've got gut 
and bone put there together so four tissues three hormones this is important to 
remember later in the the module doesn't come up now but the most of the 
calcium that you eat we excrete whereas nearly all of the phosphate that you 
ingest we retain er or you absorb rather you don't retain it you absorb it so 
when you're looking at the G-I uptake most calcium is excreted straightaway in 
faeces whereas all the phosphate is absorbed and that will become apparent why 
that's important later on okay so the kidney's important 'cause it reabsorbs 
most of the filtered calcium and makes vitamin D and vitamin D we've just gone 
over a hyperparathyroidism now this is er something that comes up in the group 
work and something you'll get used to as you go through the module but there's 
three forms of hyperparathyroidism now remember i said most er hypercalcaemia 
presents with a sort of middle-aged 
woman er in a routine blood test and she's probably got a tumour now that's 
primary hyperparathyroidism the parathyroid glands are producing too much P-T-H 
on their own now in that case you have er too much P-T-H the kidneys respond 
normally producing more vitamin D er the bones respond to release calcium that 
all produces an increase in calcium in the plasma but because it's coming from 
a tumour there's no negative feedback system working so you go on and on 
producing more calcium er hence hypercalcaemia and that's relatively simple you 
can whip some of the parathyroids out secondary hyperparathyroidism was the one 
we've just talked about where the system can't work so there's no negative 
feedback so the parathyroid glands go on producing er P-T-H and eventually they 
er become desensitized as we'll see 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 er vitamin D deficient 
and developing rickets it's a renal problem really and in that case you've got 
low or normal plasma calcium whereas they're high here and the last one is 
tertiary hyperparathyroidism and this is really quite specialized er this is a 
er consequence of renal disease but it's a er a continuation of secondary 
hyperparathyroidism when there's no feedback er to switch the parathyroid 
glands off they go on producing P-T-H and they become insensitive to calcium 
levels and vitamin D the receptor levels drop they also sometimes become 
hyperplastic so you get more cells er bigger parathyroid glands producing more 
P-T-H so the consequences are completely unregulated P-T-H production remember 
you've got kidneys that can't respond normally er so you get er loads and loads 
and loads of reabsorption from your bone so you get really bad bone disease but 
in that case as well you usually 
have high plasma calcium but this h-, plasma calcium which would normally shut 
off P-T-H production can't because the gland's lost all its natural er 
mechanisms for feedback 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 this one 
at the end i'm not going through it's kind of a pictorial representation of 
secondary hyperparathyroidism and the problems associated with kidney disease 
it's er it's really important you know calcium homeostasis er goes up the creek 
if you've kidney disease so that's all i've got to say now er 'cause i know 
we're running slightly probably any questions either come and see me or see me 
in the group work and er i'll just leave that one up for you to copy down while 
i get namex sorted out for the next lecture