nm0454: er now my name's namex i'm a consultant nephrologist which means i'm a kidney doctor and i'm going to give you two talks this morning er both about forty-five minutes according to your books it should be glomerular disease then diabetes but just to confuse you we're doing it the other way round so we're going to do diabetes first and then glomerular disease and er last time i was asked to hand out handouts before the talk so i'm going to submit to your er your ways if you want to spread them around okay right sit down shush shush shush diabetes diabetic nephropathy actually can i have one of the handouts i might need to er refresh my memory thank nm0454: okay now why are we interested in diabetes and diabetic nephropathy you know by now my talk's interactive so if you don't answer i'll start picking on people so why are we interested in diabetes and diabetic nephropathy is it just because you have an exam on the subject okay come on sm0455: increases nm0454: anybody sm0455: morbidity and mortality nm0454: sorry nm0454: increases morbidity and mortality nm0454: yeah very good so diabetes is very bad for you it's also very common how common is it sf0456: think it's one in five nm0454: speak up sf0456: one in five nm0454: one in five well actually in some bits of the world you're right in some bits of Australia New Zealand and other countries it's it is probably one in five but it's it's probably about two per cent of the general population in the U-K five per cent of blacks and Asians so it makes it with schizophrenia rheumatoid disease one of the commonest chronic diseases and therefore er just by chance one or two of you in this room should have diabetes okay so it's a very common disease er you need to know a lot about it and that's going to be one of the themes of this talk the second talk is about rare diseases that you ha-, know have to know a lot about because it's in your exam but not just not because it's biologically more common or more important so diabetes is very common diabetic nephropathy is quite rare why why do you think it's quite rare lady at the end sf0457: er nm0454: if you don't know guess sf0457: because it takes a long time to get to that stage nm0454: yeah very good i mean that's exactly the answer because it takes a very long time to get it and what implication er does that have for most most blacks and Asians why why is that such if you forget everything else that i'm going to say this morning just remember what this lady said so diabetic nephropathy takes a long time to get and why is that so important sf0458: sf0457: they tend to get it earlier nm0454: well they tend to get it earlier but not that early anybody else sf0459: do they not get treated nm0454: they're not get they don't get treated and it gets missed and why does why does chronic diabetes and diabetic nephropathy get missed it's not a trick question why do diseases get missed in general sm0460: 'cause they're asymptomatic nm0454: it's asymptomatic and that's the problem so both diabetes and diabetic nephropathy and many other complications of diabetes are asymptomatic these are so-called silent killers like hypertension and this is the problem with them they're very common they're very lethal and you'll miss them unless you look for them so there's some facts there down for you on the sheet er i've said at the top eighteen per cent of patients in the U-K on dialysis have diabetes and that's true from the latest data generally you go to renal-reg-dot- com where all British data is accumulated fascinating for us nerdy nephrological types er so it's a common cause of a rare disease which makes it rare but nonetheless it's going to be the focus of the talk this morning er let's get back to basics as John Major once said and let's get into a few definitions so er i've got a definition of diabetic nephropathy down there for you as you can see it's a rather vague one it's i'll read it out to you it's a usually progressive renal disease secondary to diabetes and what's wrong with that definition why is it so difficult to define gentleman there why why is it so difficult to define something like diabetic nephropathy sm0461: it presents in very different forms it can present in many different ways and can have many different causative nm0454: very good sm0461: nm0454: very good so it can present in many different ways there are many different forms there are many different causes and when you've got a complicated disease like that it's not like a myocardial infarction which you can define in terms of a C-K rise dropped T typical symptom signs this is a vague concept and i'll explain a bit later on why it's such a vague concept one of the more fundamental reasons why diabetic nephropathy is difficult to define is 'cause diabetes is difficult to define let's have a go gentleman here have a go at er defining diabetes sm0462: er which one do you want nm0454: er either or all speak up so everybody can hear sm0462: it's when the pancreas isn't producing insulin nm0454: or sm0462: or when the s-, tissues aren't responsive to insulin nm0454: very good that's actually probably the best definition i've heard from a a medical student it's er almost impossible to define i mean there are definitions which are nice simple ones a fasting blood sugar of over ss: seven nm0454: seven and a random of over ss: eleven nm0454: eleven okay so that's a nice simple one put it in the bo-, put it in the back of your brains useful in clinical practice at a deeper level of course diabetes is very difficult to define er and the gentleman there has probably come out with a pretty good one you know it's trouble with pancreas er you know either the pancreas doesn't make enough insulin or you can't respond to insulin if you want to have another go at defining it the typical group of symptoms and signs with a variety of causes associated with pancreatic trouble it's getting a bit vague now my definition i'm running out of steam it's it's just impossible to define er in any concrete way because you've got gestational diabetes pregnancy-related diabetes is that diabetes it doesn't make you blind ten years later it's diabetes while you've got it so it is a very very difficult thing to define and it's quite interesting actually that one of the diseases that affects your whole course renal eyes heart everything is actually almost impossible to define and we could be defining it all wrong b-, what is the problem with the definition of diabetes related to absolute levels of of blood sugar what's the problem with that it's nice in a box back of the brain simple let us assume demonstrate it in the exams sf0463: there's lots of variation in the range anyway nm0454: yeah there's a lot of normal variation very good so by now you should realize that all normal ranges are a load of rubbish they're all based on er the standard normal distribution so this could be height blood sugar et cetera et cetera and all normal ranges we take usually are two standard deviations from the mean so we say a normal blood sugar is what four to six and diabetes is a fastingness of seven or a random of over eleven but there's always going to be tail end Charlie who's quite normal who doesn't have diabetes but is has diabetes by a number definition and the other reason why it's so difficult to define of course is that the complications of diabetes are really the complications of what sm0464: persistent hyperglycaemia nm0454: speak up sm0464: persistent hyperglycaemia nm0454: er yeah yeah okay you're right but but what what what constellation of diseases large vessel diseases is the main problem with diabetes or one of the main problems with ss: nm0454: speak up sm0465: ischaemic heart disease nm0454: yeah ischaemic heart a part of atheroma and there is a danger of course that the large vessel complications of diabetes today we're going to talk about a small vessel complication of diabetes diabetic nephropathy but the large vessel complication of diabetes are atheroma and it's not impossible of course that we've all got our Venn diagrams mixed up and the atheroma Venn diagram is overlapping with the diabetes Venn diagram and of course it does 'cause diabetes does this but it's also possible that people with ischaemic heart disease people with disease who happen to have a blood sugar of eight what's eight it's in the middle are labelled as having diabetes causing atheroma and i think there is so much overlap in what we now call Syndrome X which is this loose constellation of diabetes ageing hypertension atheroma eating chips et cetera et cetera it is very very grey now nonetheless i've hopefully laid out a few rules for you a few simple rules but don't think about it's like most things in medicine if you think about it in too much detail it's all wrong and it's too complicated so just think about it simply okay so diabetes is difficult to define and therefore diabetic nephropathy is difficult to define but we have to work on some definitions we've talked a bit about er the prevalence already now how common is diabetic nephropathy on the sheet there i've put a few numbers for you i've said that forty per cent of people with IDDM and five per cent of people with NIDDM get diabetic nephropathy er again there's a lot of problem with all these numbers who's heard of hea-, of of linear bias any mathematicians in the room tell me about linear bias come on there's one of you deep down there [laughter] i know you read maths textbooks every night [laughter] this thick you love it [laugh] come on linear bias well linear bias this is i wasn't going to talk about it this morning but i was thinking about it in the car on the way here and i s-, er almost certainly decided to destroy my own talk linear bias affects the whole of medicine particularly chronic diseases but there are er some important there is some importance for acute diseases too okay so we've got these numbers we say X per cent of the population have Y A per cent of the population have B ten years later fifty per cent have cancer fifty per cent are dead where do these numbers come from where do they come from how do we develop these numbers lady on the end here sf0457: er nm0454: it's not a trick question if we said you know if i said to you fifty per cent of the population have diabetes where do you think that number comes from sf0457: observing population nm0454: very good yes observing population cross-sectional analysis okay so taking a large population a hundred people a thousand people and and finding out who has diabetes but that's wrong isn't it because that's a snapshot it doesn't really tell you about the disease in the community and what you need to know in terms of how common is the disease now how common the disease was and how common the disease will be is actually nearly impossible to define so for example diabetes we could take time X in the past nineteen-sixty-one when i was born long time ago er we define diabetes in a certain way and at that point we do a cross-sectional study and we say that one per cent of the population has diabetes time goes on and we say diabetes is bad for you and leads to complications it leads to X per cent of people getting diabetic nephropathy that's why i was thinking about it in the car on the way here X per cent of people forty per cent of IDDMs five per cent of NIDDMs getting the complications which must be over ten years by definition that's also on your sheets and so they're getting the complications there so that's bad for you because if you wait long enough you'll get the complication of diabetes then something else might happen you may get away from small to large vessel complications then you may die and then people can't do studies on you when you're dead but from that passage of time we draw all the conclusions that based all of our knowledge but remember most of the analysis is done at various times it's cross-sectional data about a linear disease and it could all be wrong these are not the same patients society has changed the planet has changed the universe has changed in that time and our definitions of chronic disease so the definition of rheumatoid arthritis might be quite different then from then and if you think about it most chronic diseases have this problem with linear bias and the bias leads to what wh-, what does it make researchers do lady there in the blue researchers who don't understand linear bias what do they what what what is the danger that they do sf0466: nm0454: what happens as you get older hair falls out go grey everything goes floppy what happens to your brain as you get older what do old what do me and namex talk about when when we're out of here we're sick of you lot [laughter] you're always late moaning your mobiles are on what are we mo-, what are we what do we moan about anybody sm0467: how it used to be nm0454: how things used to be yeah the golden age [laughter] when things were better when medical students wore ties and had briefcases the good old days when we were good at football we won the World c-, ah yeah we won a World Cup earlier [laughter] i hope you all watched it er yeah we talk about the good old days the bygone era the golden age when things were good and it's all claptrap isn't it it's all claptrap it's just me and namex getting older it's your and you're getting older too and it's linear bias again we're talking about some bygone era which never existed you know because time moves on and all of our conclusions that we draw about ourselves and society and diabetes and diabetic nephropathy have the problem of linear bias in them 'cause all you need to do is change the definition from say four to six for diabetes to four to seven or rheumatoid arthritis in another way to completely change the whole of Western medicine and and the knowledge that we pass on to you how do we get rid of it we can't get rid of it actually because it's it's it's part of time it's part of the course of the universe and it it is impossible to get rid of and so the best we can come out with is generalizations made from cross-sectional studies the important thing from your perspective is to know that it goes on and therefore you should be nice and cynical about any form of i-, information any form of statistics that anybody puts in front of you so let's er throw away the rule book and er move on so we've got to give you some numbers er we've said er that er diabetic nephropathy does exist it's a small vessel complication of diabetes it's much more common in IDDMs but IDDM is a much rarer disease than NIDDM so by definition therefore far more people with NIDDM and that's where the problem lies get diabetic nephropathy and most of our patients in namex the typical namex patient is a late middle-aged fat Asian or black NIDDM [laughter] who presents late and that is the problem they present late as the gentleman said earlier it is an asymptomatic disease okay onset of the disease er most of the small vessel complications of diabetes come on after ten years so tell me some small vessel complications gentleman on the end there other than diabetic nephropathy small vessel sm0468: don't know nm0454: lady next to him sf0469: er is retinopathy nm0454: retinopathy okay there's another one which is usually classed as a small vessel any anybody else know neuropathy neuropathy er anything small is a usually a small vessel complication large vessel are com-, are complications of atheroma brain peripheral vascular disease of the heart er cu-, that's all rubbish though isn't it i mean i mean it doesn't take a a rocket scientist to work out that big blood vessels get smaller don't they and branch off in capillaries et cetera so er the whole classification of the complications of diabetes of small and large vessels is completely arbitrary 'cause what's small and what's large but nonetheless we do attempt to classify it in that way clearly most patients will have problems with both and that's very important for diabetic nephropathy because as well as having diabetic nephropathy a small vessel complication lady there with the baseball cap what else do you think might affect the kidney as well as problems with the small vessels sf0470: nm0454: speak up sorry sf0470: nm0454: i can't hear you sorry nm0454: i don't know [laughter] nm0454: okay lady next to her what else might affect the kidney in diabete-, other than the small vessel complications sf0471: large vessels nm0454: large vessels such as the sf0471: renal artery nm0454: renal artery okay and so er if you've had diabetes for over ten years you've usually got trouble in the large vessels and trouble in the small vessels er so diabetic nephropathy pure diabetic nephropathy is extremely unusual and most people have both and in fact there are other renal complications of diabetes they're listed down there for you just to er read a few of them out papillary necrosis which has other causes anyone like to tell me some other cause of papillary necrosis not fair as i'm sure you don't have a lecture on papillary necrosis fascinating disease actually the the papilli remember are part of a drainage system of the kidney these are the papilli and they can fall off papillary necrosis sickle cell disease okay sickle cell disease and diabetes are two of the most important causes of of er papillary necrosis in this country but worldwide probably analgesic nephropathy are probably er as important in the developed country okay so diabetes can affect the kidney in many ways renal vascular diabetic nephropathy papillary necrosis recurrent urinary tr-, tract infections are more likely to get contrast nephropathy after er an angiogram of any type one of the fascinating things about diabetic nephropathy and in fact all the complications of diabetes is the W question why followed by the H question which is how so you tell me how does diabetes damage the eyes the kidneys the nerves lady with the blue there third from the end sf0472: er nm0454: if you don't know give me a can you give me a calculated guess what what do you think the metabolic abnormalities in in diabetes might be sf0472: there's lots of under pressure if you're going to have cirrhosis nm0454: very good i'm glad you said that actually 'cause the obvious thing to say is what you're obviously not a a lady of the obvious [laughter] what is what is the obvious thing to say diabetes is characterized by quite ss: nm0454: hyper ss: glycaemia nm0454: glycaemia and so the most likely cause of all the trouble is hyperglycaemia but there's a lot of research going on into the and of course nobody knows and the whole research department i don't know if it's a particular interest of of of nf0473: me nm0454: of er namex or or or er research all over the U-K in physiology departments er is obviously is is i-, to these questions the why and the how questions how does diabetes do it of course nobody knows and a lot of research is now orientated towards pressure and it may be that the effects of blood pressure on small vessels are probably more important than hyperglycaemia there's lots of other theories insulin growth hormone cytokines just goes on and on and on Brian Williams who's a professor of medicine in Leicester his whole research is oriented towards this area but it is quite interesting er that we haven't actually come that far since er Banting and Best who who were Banting and Best let's pick on somebody else lady in the black top there who were Banting and Bess sf0474: they nm0454: have you heard of them sf0474: discovered insulin nm0454: very good okay so even if you didn't know good [laughter] calculated guess er and er they they discovered well i don't know if they d-, discovered insulin they they they refined it perhaps er and er this story which i'm sure you're all familiar with of a medical student and a and a surgeon who were put on the task of finding out what was the trouble in diabetes was it insulin could they refine insulin one of them i can't remember which one does anybody know Banting or Best one of them developed diabetes knew they were going to die 'cause in the the States they couldn't get a patent on insulin went off on a world tour er there were no mobiles no texting no e-mails he just assumed he was going to die on his world tour and then the other one refined insulin so had to have a ring round all the bars of Vienna and Paris you know find this drunken medical student [laughter] er and er just get them back get him back and say actually we've cracked it we've got insulin and here's an injection and they lived happily ever after no he lived for many years er n-, anybody know anybody know which one it was can't remember okay look it up Banting and Best er but we haven't actually come that much further since Banting and Best because we haven't answered the the W and the H questions for diabetic nephropathy or any of the complications of diabetes and these are incredibly important questions because it's pretty unlikely we're going to be able to get at the factor that causes diabetes but we might be able to turn off some of the complications of diabetes if namex can crack it in her in in in her lifetime okay bit of pathology er i know your course doesn't emphasize pathology and certainly i'm not going to emphasize it either because when i was a medical student they axed the pathology course which i thought was one of the best things they ever did er but you do need to know a little about it and er there are some characteristic findings of diabetic nephropathy we don't to be honest normally do a kidney biopsy on somebody with suspected diabetic nephropathy so in other words if they have renal problems and diabetes we assume by and large that it is diabetic nephropathy er and that can be a dangerous assumption if you were to do a renal biopsy at the earliest stages you do see some characteristic abnormalities you see expansion of the mesangium you see er enlargement of the glomerular basement membrane but these are really non-specific and can be seen in other nephropathies such as membranous nephropathy there is a more specific lesion which all medical students know called the Kimmelstiel-Wilson lesion er and this is part of a so- called nodular glomerulosclerosis and it has a characteristic er lumpy appearance er i deliberately haven't brought any slides of it along er because that's going to be one of your tasks after this talk to go out and find out what a Kimmelstiel-Wilson lesion looks like and er if you're really interested find out who Kimmelstiel and Wilson were but again it's not that specific to diabetes and there are other renal diseases such as light chain deposition disease and other causes of these lumps of er sclero-, of nodular glomerulosclerosis okay so i've talked a bit about the pathogenesis we don't know the answers to the the how and the why question er having destroyed all your ideas of diabetes diabetic nephropathy linear bias the definition of disease statistics et cetera er i've put a nice little table in there for you 'cause then you can go away and assume that is completely correct and you can er regurgitate that the so-called Mogensen classification of diabetic nephropathy er i don't know how useful it is but it is something that i would expect you to know about er and it Mogensen in nineteen can't remember when it was eighty-two came up with this classification of four stages of diabetic nephropathy and i just want to go through those briefly with you er the first stage is perhaps one of the most interesting one and er i i've got no idea how they found this information out but apparently at the early stage of diabetic nephropathy you go through a hyperfiltration stage which is very similar to the first trimester of pregnancy er do you know namex nf0473: no nm0454: does anybody know have you done any research into diabetes for previous degrees no ah yes you do one of you knows you're just not telling me the the er i d-, i don't know how they found out and obviously they they had a very accurate way of measuring G-F-R in the earlier stages of diabetes and we're talking you know the first couple of years of diabetes er and if you measure G- F-R at this stage apparently it is increased 'cause the kidney hyperfiltrates and apparently actually enlarges there are very few causes of of renal enlargement does anybody know any others apart from diabetes sm0475: removal of the other kidney nm0454: yeah very good actually yeah absolutely removal of the other kidney any any any any other that's about the only guaranteed thing course nobody knows the mechanism of how your body knows you've lost a kidney and how it knows to enlarge the other one other causes of er of of a lar-, l-, enlarging kidneys sf0476: tumour nm0454: speak up sf0476: tumour nm0454: tumour yeah no yes a bit i mean you get a big lump the whole kidney itself doesn't enlarge sf0477: cysts nm0454: cyst yes polycystic kidney disease but it c-, the actual renal tissue doesn't enlarge but sort of and sort of sm0478: hypertension nm0454: hyper-, no no ameloid ameloid is a characteristic cause of so-, enlarging kidneys and some you were half right lymphoma and leukaemia er if they directly infiltrate the kidney can cause the kidneys to enlarge but there are relatively few causes er of of a large kidney er and most of them are impossible to detect as the changes are so small and you need very accurate er ultrasound technology okay the second stage it starts to get a bot-, bit more interesting the glomerular disease that i've described the if you were to do a biopsy at that point the mesangial enlargement the thickening of the glomerular basement membrane er starts happening er the patient is unaware of this the G-F-R is still more than it was there's still no protein in the urine they still have normal blood pressure and er the creatinine is is still normal er this is er a very important stage and er and and i think that we we very often or or too often maybe this is what Mogensen was getting at in his classification think about stage three as the starting point in diabetes diabetic nephropathy which is the micro albin-, albuminuria stage tell me about microalbuminuria gentleman at the back there with the green on the on the right tell me about microalbuminuria or microalbuminuria can't say it sm0479: er nm0454: have you heard of the concept sm0479: no but it's er nm0454: i'll tell you what it is and this when i was a student i thought it was small albumin molecules sm0479: that's what i said as well nm0454: yeah [laughter] ah it's not actually ask somebody else two ladies at the back there what what do you think micro-, have you heard of the phrase microalbuminuria sf0480: is it just an amount of protein nm0454: speak up yep sf0480: it's amount of protein in the blood nm0454: yeah yeah anybody want to expand on that sm0481: does it mean you can see it in a microscope but not nm0454: no no i mean that's what i used to think isn't it it's not such a silly answer sm0482: 'cause there's some albumin in the bl-, in in the blood nm0454: no it's microalbuminuria so it's in the urine sm0483: is it just small quantity of small amounts of microalbumin nm0454: very good small amounts of albumin in the urine and very small amounts which cannot be detected by stick-, dipstick testing are present in the early stage of diabetic nephropathy er in my second talk i'm going to talk more about dipstick testing and the reliability and unreliability of dipstick testing er and the importance of it is it's said to be the forerunner of full-blown diabetic nephropathy but it's more important than that because it's possibly the forerunner of all the small and large vessel complications of diabetes and possibly also the complications the large vessel complications of diabetes in a non-diabetic in other words atheroma in somebody who doesn't have diabetes and there is evidence from the the Framingham study that microalbuminuria is one of the most important things you can measure in a human being when they're twenty if you want to find out whether they're going to be alive when they're forty er and it seems that the kidney can in some way show you know what's going to happen in the rest of your life er and so if you have significant amounts of microalbuminuria yours at your earlier stage you know smoke you might as well enjoy it it's very bad news microalbuminuria just anybody tell me about the Framingham study what's the Framingham study lady at the front have you heard of it sf0484: no nm0454: lady next to her very important study landmark study still going on i'm going to pick on you again what sf0485: i don't know either nm0454: any anybody anybody Framingham study sm0486: it's a big study in America where nm0454: yep sm0486: it s-, started since nineteen-sixty-four or something like that and it nm0454: yes sm0486: it's been following a group of people living in Framingham nm0454: yes sm0486: for different diseases nm0454: yes absolutely okay so there's a small study er does he know all the stuff this bloke [laughter] well er er proud of you er and it it's an attempt to get rid of linear bias i mean i don't think they realized that when they set i-, set it up small town on the east coast shush east coast of the United States in Framingham where they took a cohort of people who traditionally didn't tend to move too much from Framingham a bit like Coventry people [laughter] they just stay there basically miserable might as well stay here and nowhere else to go and the train's rubbish but the er and f-, for the people of Framingham tend to stay around it's not that large a group it's in the tens of thousands of people rather than hun-, and that's maybe also one of the reasons why the study worked and is still ongoing and they've been followed since the sixties and and and a lot of what we teach you about er the pathogenesis and the cause of atheroma and diabetes all comes from the Framingham study there's a massive website that's all about the Framingham study they're publishing papers every week er and and and and much o-, o-, of of traditional Western medicine actually comes from Framingham i don't think the people of Framingham realize that and what we know about microalbuminuria i don't know how they had the foresight in the early sixties to start looking for very small amounts of protein in the urine but they did and er and and this is a a very er clever idea the reason i emphasize the first two stages is that i think that if we're going to do anything about diabetic nephropathy and anything about the other complications the retinopathy it's before Framingham it's before microalbuminuria it's when they're normal it's when they are the IDDMs are four are six are ten years old then you start them on an ACE inhibitor then you do what you need to do to stop them from getting any complications not when they're twenty not when they're thirty but there lies the rub because the majority of patients i said are NIDDMs and they present late they've had a blood sugar of eight for five years of nine for another five years then it's picked up on routine testing and it's all over by then the eyes are starting to go they they're in stage three more likely stage four of diabetic nephropathy there's nothing you can do so if you want to really help diabetics i think it's it's premicroalbuminuria or at least at microalbuminuria stage and this is true for the not just for the kidneys but for the eyes and all the other complications okay so can we isolate specific patients to focus on well not really er race er black and Asian people are more likely to get the small vessel complications that they're more likely to get diabetes and they're more likely to get the bad diabetes there are strong genetic factors which er are probably polygenic and haven't really been worked out but there are certainly patients who are born with a predisposition to develop bad diabetes and this is one this is the counter-argument for being a touchy-feely person going out in the community starting all black and Asian people on an ACE inhibitor as soon as they're born a-, and that studies such as that have been done there were some islands on the north coast of Australia where people just couldn't get away and they put entire communities with and without er diabetes on ACE inhibitors and this is one of the few things you can do for a diabetic and they've dramatically reduced the dialysis rates the mortality cardiac mortality er look it up northern Australia islands diabetic nephropathy er you'll find loads and loads of papers er and they're actually fascinating studies where you take an entire community and reduce their glomerular capillary pressure and see what happens and a lot happens the reason i emphasize this is i think that racial and family er predisposition to developing bad diabetes is probably the most important factor and that of course we can do nothing about you can't change your parents and it does seem that forty per cent or so of diabetics get bad diabetes including the eyes the kidneys et cetera and so if you were a cynic you'd say well why bother for those forty per cent 'cause they're buggered anyway er but nonetheless i think we have to er adopt a positive approach and try and treat the hundred er not not just the sixty er glycaemic control oh God i've got to tell you about this haven't i this is one of the things that i've i've i i have to tell you about because you you'll be expected to regurgitate it but i don't particularly believe in myself er what's the Judaeo- Christian method of controlling people [laughter] sm0487: nm0454: Islamic as well come on bit of politics how lady here how do we control people in the Judaeo-Christian way sf0488: you have one partner nm0454: yeah yeah okay fair enough yeah i'm talking more about society how do we control society sf0488: well you don't marry your cousin you don't have children family [laugh] nm0454: mm yeah but a bit broader politics [laughter] cynicism i want sm0489: indoctrination nm0454: sorry sm0489: indoctrination nm0454: indoctrination sm0490: fear nm0454: fear ah fear [cough] that's how we control people in the Judaeo- Christian way isn't it fear the stick and the carrot er and if you're a good boy what happens sm0491: you're rewarded nm0454: you go to heaven [laughter] good things happen if you're a bad boy or girl it's very bad isn't it so if you're a good boy you get rewarded by stuff you do good things you don't eat chips you don't go to McDonalds you don't smoke you don't have God it's boring isn't it [laughter] and if you're a bad boy you do all those things and then bad things happen you have diabetes you get fat you eat chips and you go to McDonalds and it all goes horribly wrong and the problem with the Judaeo-Christian-Islamic method of controlling people is we extended it to medicine of course because you know we're part o-, of this culture we can't get away from it so and this is true of all chronic diseases whether it's rheumatoid arthritis schizophrenia you're a bad boy you didn't take your tablets you didn't have electric shocks to the head you didn't have injections once a month so what's going to happen you go out you go kill people that's bound to happen er and we have linked it to diabetes as well and the classic way we've linked it is glycaemic control and for years decades it has been assumed that if the blood sugar is the bad thing in diabetes which it probably isn't it's probably the blood pressure er then if you have tight diabetic control you can prevent the complications and this was dogma in Western medicine for for decades er until what what landmark study not many studies you need to know about in detail but there are a couple in diabetes anybody the D-C-C-T in nineteen-ninety-one New England Journal of Medicine the U-K-P-D- S B-M-J the Lancet look these up very important studies if you ever get me in a viva i'll ask you about them the reference the page number [laughter] the exact number of patients in each study i will not forget okay so don't come across me in a viva and don't know both studies sideways those are landmark studies er and the bottom line is that the first study attempted to address the Judaeo- Christian concept of tight diabetic control leads to good result in IDDMs and the U-K-P-D-S done in the U-K did the same in NIDDMs and both studies i'm not going into them in detail today have been interpreted or misinterpreted as being positive er in that the patients who achieved tight diabetic control had less complications and they did to an extent but the end points were all soft such as can anybody think of a soft end point in diabetic nephropathy or eye disease let's pick on somebody else gentleman there if you were do a s-, design a study of does tight diabetic control prevent the complications and you wanted to look at the complications of diabetes such as nephropathy or eye disease what what would be a possible soft end point that you could look at er i i wishy-washy end point difficult to define and prove anybody else ladies up lady in the white there soft end point diabetes sf0492: disturbance in vision nm0454: yeah disturbance in vision would be a good one proteinuria rate of decline of renal failure lots just think about it there's lots of soft end points and the soft end points were affected by tight diabetic control so there is some evidence of tight diabetic control but er if you look at the studies and i stress i will ask you about them if i ever meet you in a viva er and i will create hell if you don't know about them er the hard end points weren't there death dialysis chop your legs off blindness they weren't there there was no significant improvement in the hard end points now you can say er back to linear bias well what does that what does that matter that you don't stop people from from dying er er and you don't er chop their legs off if you can delay chopping their legs off by a year then that's a good thing obviously but that wasn't proven either er because the study didn't really incorporate this problem of linear bias into it now but these are the best studies that we have and they are landmark studies and and you should know about them okay er they well probably several hundred people's life work so i shouldn't knock them too much er you know these were tens of thousands of patients putting them in in into into both studies and they are the the best data that we have but look at them critically as just out of interest apart from get away from my ideas of the Judaeo-Christian method of controlling people what what wh-, why why do you think who do you think set up the studies and why lady there the in the black jumper who do you think sf0493: er nm0454: would an old cynic like me set up a study sf0493: er nm0454: who would set up such a study and why sf0493: i guess people that can er didn't believe that er it had a difference nm0454: so either the the the knockers like me or more likely sf0493: people trying to prove it nm0454: the believers sf0493: yeah nm0454: and who are the believers sf0494: drug companies sm0495: pharmaceutical companies nm0454: pharmaceutical companies yeah ah there's a cynic that's what i like to hear [laughter] excellent i know i know where to get the cynical pharmaceutical companies yeah diabetologists it's their raison d'être you know if tight diabetic control doesn't lead to good outcomes what's the point of a diabetologist don't tell other people don't tell all these professors Professor and everybody don't tell them don't even mention my name i didn't exist don't exi-, i wasn't here but you know it's their raison d'être and it may not be true now you can s-, you can be just as cynical about kidney medicine as well renal units well i've come back from Australia drop it in the conversation [laughter] i visted a a renal unit in in north-west Australian there were no nephrologists there they don't need one they worked it out themselves and a forty-bedded dialysis is run by nurses and G-Ps so you know do we need nephrologists maybe not and it's quite interesting actually slight aside i i asked one of the G-Ps er h-, how how she knows so much about er er dialysis and kidney transplantation she said well mate i've got a bit of paper and she showed it's absolutely brilliant she showed so we had a bit of paper on the wall and the whole of nephrology was er summarized on one single bit of paper and it was absolutely brilliant you know creatinine goes up put them on the whirly they've got oedema put them on the whirly diabetes it's probably diabetic nephropathy put them on the whirly and [laughter] er and it was all there one bit of paper and i thought my whole specialty [laughter] on one bit of paper this is terrible er but the same can be said of of of of most specialties you know what is the the point of us er i don't know that's not for for for me to judge okay er treatment treatment so we talked about some treatments that er might work could work should work in fact let's be a bit less cynical and think about what we can do well we can only do what we can do we can only do what what what powers are given to us what drugs are given to us and the important thing in diabe-, diabetic nephropathy is to rationalize the problems to rationalize the problems in an early stage and attempt to do something about it even if it's all claptrap at least it gives the patient something to do the sort of things you can do you can achieve tight diabetic control that's what the D-C-C-T and U-K-P-D-S that's what i think they really showed they showed it was possible and nobody had ever shown it was possible tight diabetic control as shown by H-B-A-one-C you can get the blood pressure down you can favour ACE inhibitors and ACE antagonists these things do work they do affect soft end points at the later stages if you have people with advanced complicated diabetes diabetic retinopathy it's going to get a bit vague later diabetic nephropathy prepare them for dialysis diabetic legs not much you can do send them to Mr namex er but there are things we can do at these earlier stages and wi-, to those of you who are going to be G-Ps it's very important to recognize these early stages and do something about them don't be a cynical Dr namex don't wait till their legs fall off go blind try to prevent that stage if you can okay so i don't particularly want to talk about the the treatment of end-stage renal failure which is the final stage of diabetic nephropathy in any great detail today other than to say that it exists the treatment's for them really the same as for non-diabetic diseases dialysis peritoneal dialysis haemodialysis transplantation kidney alone transplants what i would like to leave you with is some thoughts for the future in terms of the treatment of of diabetic nephropathy until namex can crack it and we can sort out the the how and the why question we have to go back to a bit of our old agricultural medicine which is chopping things out of other people and putting them into other people and the modern treatment for diabetic nephropathy in an IDDM wh-, wh-, why would it not work in a NIDDM it's a kidney pancreas transplant why would that not work in a NIDDM sf0496: because the tissues will have been nm0454: what's sf0496: nm0454: what's the difference between IDDM and NIDDM in terms of the the the the the the the underlying problem shush listen sf0497: 'cause in a NIDDM it's more of the tissues being non-receptive nm0454: very good okay so in IDDM you don't make it in NIDDM you can't respond to it and therefore if you put a new kidney pancreas into somebody it won't it work won't make any difference they won't respond to it and it can sometimes be quite difficult to tell the difference between IDDM and NIDDM because younger people are getting fatter linear bias again the things aren't as good as they used to be but you know people are getting fatter actually and er and er even even if you chuck out linear bias and with it diabetes is getting more complicated so we now see people in their thirties fat people with diabetes and it's sometimes quite difficult to tell whether they're a new IDDM er or an insulin-requiring NIDDM er you can measure what can you measure one biochemical test which is useful sm0498: insulin nm0454: yes C-peptides are quite good at at er differentiate them so we don't normally do it because usually er it it is it is clinically obvious so the problem with combined kidney pancreas transplantation is it's only good for a few fit usually white IDDMs so it isn't the saviour of the free world it isn't the saviour o-, of diabetes and in Coventry i've established a link with Guy's which is one of the units in the U- K which does kidney pancreases and we have er a couple of patients on their waiting list and one has has er received a kidney pancreas transplant er about six months ago and she now has a normal blood sugar and normal kidney function hoorah er her hair's falling out due to tacrolimus her face is fat due to prednisolone and she was beautiful and now she isn't but she's got normal kidney function and er she doesn't have diabetes she's also oh yeah she's had to spend six months living in London which she didn't want to do but er the the it is possible er they are being done not in any great numbers i mean Guy's last year did about twelve and you know they're covering a lot of the a lot of the United Kingdom so in statistical terms it's as important er or less important than a heart transplant about two- hundred heart transplants done in the U-K every year er so what about the future future er pancreatic islet transplantation has been tried in the U-K before er didn't really work i was in in the early nineties and we tried it and it all went horribly wrong er so we we aborted a programme quite early er s-, there's a group in Canada who's come up with a new protocol and er various units in the U-K are starting to copy that now and the idea is you graft pancreatic islet cells in the laboratory and inject them into where does anybody know where we inject them into sm0499: liver nm0454: into the liver and er they spread through the liver and other organs and form little er pancreases little islets of of Langerhans er so that may be the future of stem cell research there are some advances in the near future which i think will come through things like inhaled insulin er but there are some small things which which are coming through i don't personally feel that we're going to er be treating diabetes much better than Banting and Best until somebody clever [laugh] like namex er actually cracks the the how and the why question i think our our treatments are still er agricultural okay that's it on diabetes have a ten minute break before you go any questions on diabetes and then w-, when you come back it'll be glomerular disease any questions diabetes sm0499: yes nm0454: diabetic nephropathy if you're shy come down the front okay sf0470: er i just want to know like why would you give insulin to a type two diabet-, diabetic patient nm0454: do you know i i i thought that when i was a student i couldn't work it out sf0470: i don't understand it nm0454: why you'd give insulin sf0470: i don't see how nm0454: why you'd give insulin no wh-, why would er i suppose because somebody tried it once and it worked i mean conventionally NIDDMs we start off on agents such as sulphonylureas as you know biguanides there's this new group called the glitazones we're using acarbose but it seems to me that the that the the pancreas sort of gets worn out and you you you keep stimulating it you know er some of the drugs work by stimulating the pancreas some by er er reducing the insensitivity to insulin but eventually it seems to you know you you're you're bashing away at the pancreas and then it wears out then we don't have anything else to do 'cause the blood sugar's still rising a-, and and so a somebody somewhere along the line tried insulin but you're right it shouldn't work really all i c-, sf0470: but typically you do nm0454: yeah sf0470: you do do that nm0454: i mean i all i can think of is it's some supersaturated system and if you you know give enough i mean some NIDDMs need large doses er sf0470: yes nm0454: that that that it you can break through the lack of responsiveness to it's not a very good answer sf0470: but you still do that practically you do do that nm0454: yeah practically so you know if you achieve good diabetic control and by that i mean a an H-B-A-one-C of less than eight say and you know er most blood sugars you know in the normal range or just above the normal range with tablets then that would be fine er if you didn't few patients are just controlled by diet alone if you didn't you'd add insulin sf0470: yeah nm0454: and 'cause quite a few patients are on both actually sf0470: yeah nm0454: we just don't know i mean you know we can say that if you you know you do biopsies you see this thickening of the glomerular basement membrane you see er proliferation in the mesangium but you know but but what leads to that and why that leads to er proteinuria we don't know i mean i'm going to talk about it a bit in the second talk about there are some various theories about why er proteinuric diseases happen er well it isn't obvious is it really you know sm0500: it's all about glycosylation of the basement nm0454: yeah sm0500: nm0454: i mean you you you you you may know more about it than than i do but i i i er i er and you know chip in in the second talk i don't think we know but all you can say is that a high blood sugar does seem to be associated reason we don't understand with proteinuria and and and that eventually if untreated leads to renal failure nf0473: the photocopier's broken so i think that's nm0454: okay nf0473: so i'll come back when i've done them so nm0454: okay right nf0473: we'll do them sm0500: so nm0454: right so sm0500: you could just say nm0454: in simple terms i mean what i tell a patient what i m-, is is is that that i-, is is the high blood sugar somehow damages er and i i draw them diagrams o-, o-, of glomeruli and things and and if they the more articulate patient i i i would actually i think in one of my previous talks i talked about the kidney being a tube i'll i'll talk about that in in in the second in my second talk you know and i'd actually do like draw glomeruli and and draw er the the capillary the the the intraglomerular capillary and say somehow the blood sugar damages the wall and makes sort of holes in the wall and protein which normally passes through the kidney then falls out you know i wi-, i'll talk about a bit in that second talk er but somehow you know the high blood sugar somehow leads to proteinuria and that eventually sm0501: nm0454: yeah that's going to be er sm0501: nm0454: er that's the spare one that's yours yeah okay i've not really answered your question but [laughter] it's it's because we don't it's 'cause we don't know sf0502: do you get a decreased G-F-R does it nm0454: eventually yeah that's the stage f-, oh it's on the previous as-, that's the stage four it's when the G-F-R goes down and then your creatinine starts to rise sf0502: so first it affects the er the nephron and then it affects the vessels nm0454: well it it it affects really diabetes affects the large vessels in simple old old bog standard atheroma sf0502: yeah nm0454: and the small vessels in this other way which we don't understand sf0502: oh yeah nm0454: and and and both lead to the renal impairment traditionally you're not told that renovascular disease is part of diabetic nephropathy sf0502: mm-hmm nm0454: but i think it must be i don't because you can't define the size of a blood vessel you know the big ones the small one sm0503: yeah nm0454: do you want to ask a question or sm0503: i've actually i think first of all do you know who actually published er nm0454: er no the i think they were both published without authors sm0503: right nm0454: so er and and so if you look up D-C-C-T on the Internet you get hun-, thousands of of of of er papers i think it was nineteen-ninety-one New England Journal and the the the nineteen-ninety-one i think or could be three er the the the er U-K-P-D-S was about nineteen-ninety-nine and two-thousand and that was published in several stages er and it and then you know i mean i know i'm cynical about it but it it is the best information we've got and er which is er why we and er when i'm even though i'm cynical with you lot i'm not completely cynical with patients because if you if you give them my old linear bias spiel and and Judaeo- Christian model of controlling the world you know that basically removes all hope from the patient sm0501: yeah nm0454: and that i wouldn't recommend you know because you mustn't ever remove hope from a patient 'cause their only hope is that you either get rid of their diabetes or or or or at least you control it