Slide 1

Thank you very much Phil and José and thank you to the scientific committee for the opportunity to speak here at ERA-EDTA. I’m going to try and draw some of these themes together and I’m going to talk to you about trying to treat the heart and the kidney at the same time. As you’ve already heard, there isn’t an enormous amount of enthusiasm for active intervention with angioplasty.

Slide 2

Now, I come from London but it doesn’t matter where I come from, we’ve got renovascular disease all round the world, certainly all round Europe and all round the world it’s reported to a variable degree. But I hope it isn’t going to be a subject that’s going to make you all fall asleep. I think it’s a testament to the previous two speakers that many people in the audience are still awake and I hope at the end of my talk even more will be awake. But it is a frustrating subject renovascular disease because as we’ve already heard, the truth is we know that some of it is out there, we do not know though how many people have it precisely, we don’t know the best screening technique, we don’t know if we screen people, whether finding out they’ve got renovascular disease is of any use because we can’t even agree on what the therapy might be. So I sometimes feel with renovascular disease it’s a series of ever decreasing circles, I’m just spiralling into uncertainty. In the end you have to look for your wise council in various different places and I suspect we’ll all have our different authority figure to look for.

Slide 3

I don’t think any of the three of us here are like Master Yoda but in the end we don’t have the evidence but as Phil pointed out ASTRAL and then maybe later the other trial that’ll begin to tell us some of the important answers to the important questions that faces in the clinic. But anyway the medical side of things surely you’re going to tell me this is pretty obvious stuff. What am I going to fill the next 28 minutes with? Apart from about 104 slides.

Slide 4

Now, it’s pretty easy you say, medical treatment? Let’s get on with it we know how to treat blood pressure, we know how to treat cholesterol, you know we could just say look here’s some nice bit of water, maybe it’s outside here in the seafront in Barcelona, let’s just jump in, let’s use this, let’s use that, we don’t really need any evidence it’s pretty obvious stuff.

Slide 5

Well, maybe but sometimes you shouldn’t be jumping into a stream when you don’t know where it will end up. So some medical issues are not necessarily going to be followed by an obvious and predictable outcome. What we do know though as you’ve already heard from Johannes particularly is the survival of patients with renovascular disease is dismal. Very simply that’s because for atherosclerotic disease these are patients with chronic kidney disease and they have atherosclerosis. That’s a double negative and that produces, as I’ll show you in a moment, a serious impact on the mortality.

Slide 6

So here are a variety of studies which basically show 5 year survivals, variable but poor and Phil showed you that if they get on to dialysis, it’s absolutely dismal, it’s even worse than the majority and the reason for these deaths isn’t in fact end stage renal failure, it’s our old friends coronary atherosclerosis, left ventricular hypertrophy, acute myocardial infarction and sudden death.

Slide 7

We’re familiar with these in the general population and in all of the patients whom we see with chronic kidney disease.

Slide 8

So our patients as we know have an atherosclerotic burden in the coronary, the cerebral and the peripheral vascular tree and the renovascular tree as well. We can’t assume that because they have renovascular disease due to atherosclerosis there will be overt atherosclerosis elsewhere but I think it will be a brave individual who would assume complete normality in all these other vascular areas and as you’ve heard drive by stenting cardiologists can find only too much work to do. We are treating older subjects, subjects with hypertension, dyslipidemia as we’ve heard from Johannes often smokers they’ve got chronic kidney disease. As well as the atherosclerotic side of the equation increasingly people feel amongst them have been working with cardiologists and we have increasing numbers of people with heart failure due to ischemia, hypertension, anaemia which I’ll say something about at the end and fluid problems.

Slide 9

Target-organ damage where it’s been looked for in the atherosclerotic artery in the renal artery stenosis is very common. This study by Losito published in the American Journal of Hypertension 11 years ago shows us with 96 patients comparing 46 with hypertension and an abdominal aortic aneurism and 46 with atherosclerotic arterial stenosis they had angiography and sonography basically LVH was present in 33% with ARAS compared to 11% with hypertension. Abnormal kidney function of course, was much more common in atherosclerotic disease than with hypertension. So worse hearts, worse kidneys.

Slide 10

But surely there are some certainties here we can start with. Surely we need to aim to reduce the blood pressure. Yes I accept that we all struggle with that. Many of the patients present with intractable or refractory hypertension so by definition we’re all struggling against that particular problem. But as you know, there are many drugs and many classes of antihypertensives. Are they an equivalent? We can aim to improve the dyslipidemia, certainly we hope to benefit the heart, we aim to improve the brain and there are data which we won’t go into today that suggests that treating lipid dyslipidemia may benefit the kidney. We can use a statin for that and we have aspirin.

Slide 11

But we must be honest, if you look at the published data blood pressure control in this group of patients except if they heart failure when they never had hypertension in the first place blood pressure control is often very poor. This is despite the use of beta blockers, alpha blockers, calcium channel blockers, diuretics, vasodilators and so on and so forth. Please also bear in mind, I think something we all must become much more familiar with and that is this older, sicker, frailer population is at great risk of developing type II diabetes and our choice of antihypertensives may play a role in whether they do develop frank diabetes or not. If they do, we haven’t done them any favours. I’ll come back to that later.
Heart failure is common and ACEs and ARBS are under-utilised. You know as well as I do that whenever you look for outcomes whether it’s acute myocardial infarction, stenting post CABG in chronic disease patients their outcomes are much worse and that’s very often because good common sense interventions and therapies are under-utilised in chronic kidney disease. Why? There are complex reasons for this but it’s unfortunately a fact.

Cholesterol by contrast to blood pressure control and heart failure is much more easily controlled.

Slide 12

Now, I think we need to look a little further at the context. You know from the Kaiser Permanente study published in the New England Journal of Medicine three years ago, we have this graded relationship with cardiovascular outcomes and GFR such that as you can see once you go into CKD stage III, you have a huge increment in terms of your GFR impact on mortality and here it is written out here. What you’ll find, of course, is most of our patients end up with CKD stage III. Congestive cardiac failure is common in the presence of chronic kidney disease and diabetes and massively increases mortality. These are the rates for diagnosis with CKD mortality with and without diabetes and here you add in the effect of congestive heart failure. So, these things come in groups; heart failure, hypertension, dyslipidemia and chronic kidney disease. In congestive cardiac failure the most powerful predictor of outcome is not the drug you use or the intervention, it’s actually what your starting GFR is. It is that powerful a risk factor to intervene.

Slide 13

A very nice study recently has looked at the interaction between cardiovascular disease and chronic kidney disease and you can see that they are basically additive. Here are the hazard ratios for patients with chronic kidney disease, the very few of them who don’t have cardiovascular disease. Here are the hazard ratios for patients without chronic kidney disease but do have cardiovascular disease and here is the group of people we are talking about today.

Slide 14

Those with atherosclerotic renal artery stenosis, often CKD stage III, they also have the cardiovascular disease and their hazard ratios are the worst of all.

Slide 15

You can see the interaction there in this bar between CKD+ and cardiovascular+ that’s a big study from the ARIC study. If you’re looking at what happens to our patients, you’ve already heard it because Phil has gone into that, Johannes has gone into that, they don’t reach dialysis, they die, they die of cardiovascular problems.

Slide 16

So if you’re looking here at a 5% sample of the 98-99 Medicare population of 1 million people, let’s look at what happens to these people and what you find is that the stroke rate 8 here is vastly in excess of the end stage renal failure rate. So these patients will get cardiovascular disease first and end stage renal failure second. So while we may obsess about the state of their renal arteries we have to be mindful of the fact that what will kill these patients is cardiac problems.

Slide 17

This is an adaptation of some work by Keith published in the archives of Internal Medicine. CKD stage III patients followed for 5 years. 24% died, 1% reached dialysis.

Slide 18

We can look at that again. This is CKD stage II, III and IV. It’s only when you get to IV that you get a large number of people progress, all of these patients I’m afraid are going to stay stable or end up dying of a heart attack or a stroke.

Slide 19

But again we have the answer to this don’t we? If you think back to some of the big large intervention studies that have been done in the last 15 years we’ve known for example, from HOPE, and Johannes has reanalysed HOPE for kidney failure patients that if you use ramipril, you can achieve cardio protection. It’s a little bit controversial as to whether it’s a pleiotropic effect or the effect of blood pressure reduction but you can see it.

Slide 20

You can also see it with perindropil in the EUROPA.

Slide 21

And you can see it too with trandolapril and the effect is very much there in patients with an eGFR of less than 60 precisely the group that we’re talking about.

Slide 22

But now we have a little bit of a problem. If you remember Johannes’ case report from the British Medical Journal from 2003 Brammer et al you have a dilemma because on the one hand we know the treatments for the heart disease and that is what will kill the patients but there is something of a block and that’s a slight pun, a block in terms of using ACEs or ARBs which we know to be useful for the cardiovascular side but for the renal side.

Slide 23

So are ACE inhibitors absolutely contraindicated every time? Can we say that angiotensin receptors are really bad or should we actually be using them a lot more? I think this is where I’ll spend a few more moments just debating this whether we’re treating one or both.

Slide 24

The answer’s beautifully shown in that Brammer case that Johannes showed us and that’s pretty obvious now and I’m glad he showed that and I want the slide Johannes later. Here is a patient of mine who had bilateral renal artery stenosis presented with acute renal failure produced by ACE inhibitors because he was being treated for heart failure, there’s the angiogram, we stented him and just like that case he did very well from the heart and the kidney point of view.

Slide 25

But how many of us routinely would prescribe or use an ACE inhibitor to treat tension in these difficult hypertension groups? If you look at these patients and look at the indications for ACEs or ARBs, hypertension often they’ve got diabetes. Cardiovascular disease burden, proteinuria I’ll say a little more about in a moment, renal ischemia and scarring, they all have that Phil has shown us that from his very nice imaging work, LVH and problems with arterial distensibility.

Slide 26

All of these, 1, 2, 3, 4, 5, 6, 7 all of these are indications for ACE inhibitors.

Slide 27

What data do we have about the use of ACE inhibitors in this particular high risk population? There are two or three studies that are worth looking at. Tullis et al published now 8 years ago looking at the number of high grade stenosis, looking at the blood pressures here systolic and diastolic. First of all they showed that with high grade stenosis there was more hypertension.

Slide 28

But in the patients taken as a whole, if they could tolerate an ACE inhibitor, the blood pressure control was definitely better than if they couldn’t. You could actually impinge on their blood pressure by 10 mmHg in a way that beta blockers, calcium channel blockers and diuretics could not and I think that’s an important thing because the relationship between blood pressure and cardiovascular risk is linear at this level.

Slide 29

If you’re looking even after you adjust for the severity of the renal artery stenosis and the other treatments, you still get an effect particularly in the more severe cases with renal artery stenosis. So these are patients given ACE inhibitors deliberately and their blood pressures come down and provided their creatinine doesn’t go ridiculously high I think this is a way forward and I routinely use this approach but of course, I check I’ll come to the checking later.

Slide 30

There’s more clues that ACE may be useful Losito et al published a study 7 years ago perspectively recruited 67 patients, they’re old not many diabetics they had renal artery stenosis, they were hypertensive on drugs and he ACE-genotyped them.

Slide 31

Here are the characteristics just draw your attention to their blood pressure 162/88.

Slide 32

So they did not have good blood pressure control on existing therapy

Slide 33

And what he found was that if you follow them up for 5 years, their double DD, the D genotype conferred an adverse outcome regardless of treatment.

Slide 34

If we just go on to the next one Losito’s group has followed up various previous studies and this was published in NDT in 2005.

Slide 35

They took 190 patients again with poor blood pressure control, some of them diabetic, chronic renal failure, CKD stage III and some dyslipidemia.

Slide 36

Here are the medical characteristics of these patients, you can see the blood pressures, they invasively treated 136 the criteria for doing this are not clear and medically treated the others.

Slide 37

What you can see is the invasive treatment was effective at reducing their blood pressure, the medical treatment less so. Relatively few came to end stage renal failure and the effect on the creatinine was pretty similar. But what was interesting was in the medical group the use of an ACE inhibitor conferred a very significant survival advantage for the patient. So again there is some evidence that if the patient can tolerate an ACE inhibitor in this context, you’ll get better blood pressure control and it may impinge usefully on survival.

Slide 38

A word about proteinuria.

Slide 39

We all know the risk that proteinuria brings for mortality, cardiovascular disease mortality, coronary disease mortality and CCF mortality. A very important risk factor for renal disease and for cardiovascular disease.

Slide 40

We know from the BENEDICT study for example, if we use trandolapril in diabetics, we can prevent people getting into the microalbuminuric and the macroalbuminuric range. So it’s using a nephroprotection as well as the other beneficial actions of an ACE inhibitor in this stage.

Slide 41

We know from a re-working of the RENAAL study that patients who respond with a drop in their proteinuria of more than 30% from their baseline have a more favourable cardiovascular outcome and a more favourable heart failure outcome. So we can also select the patients who may respond well and those with heavy proteinuria if we do not treat them for their proteinuria we’re missing a serious risk factor.

Slide 42

Second slide form Star Wars, what about metabolic syndrome?

Slide 43

Just to come back to my point, this is a compendium of all the recent studies, not all only up to 2004 that have looked at new blood pressure reducing agents versus old ones, the old ones generally like beta blockers and thiazides are adverse metabolically and are more likely to be associated with new onset diabetes mellitus type II. The meta-analysis clearly shows that you’ve got about a third increase over your basal risk, if you’re treated with old fashioned blood pressure reducing drugs compared to modern drugs without the metabolic side effect. Giving somebody diabetes is not something I think is a good thing to do.

Slide 44

So for this part of the talk I think ACE inhibitors are important, likely to be a benefit to the patient’s heart, brain and kidney. Getting a lower blood pressure is key. ACEs are key at delivering lower blood pressure, reducing proteinuria and I don’t think renovascular patients are very different from all of CKD. They have the advantage of being metabolically neutral and if you use those that are off patent, they don’t have to be very expensive either.

Slide 45

There are many other risk factors beyond blood pressure, we haven’t time to go through them all.

Slide 46

Lipid reduction is important. You know form huge trials and meta-analyses the benefit on cardiovascular and total mortality for cholesterol reduction and yet in renal disease how many of us use statins regularly?

Slide 47

Well, we’re confused again we’ve got the spiral of despair because we have trials saying this and trials saying that.

Slide 48

From this USRDS we have 2 morbidity and mortality outcome study which is a registry derived study, what we can see is a survival benefit for statin users with CKD.

Slide 49

But we also know in type II diabetics on dialysis that statins didn’t have any beneficial impact.

Slide 50

I think in the end what you’ve got to go back to is the fact that in the general population and in the studies although they don’t include people with serious renal disease they do take some people with minor renal disease.

Slide 51

I think there’s increasingly good evidence that lipid reduction reduces proteinuria, reduces progression and will impact beneficially on cardiovascular outcomes.

Slide 52

It doesn’t matter where your cholesterol is from this reworking of the HPS heart protection study you get equal benefit even if your cholesterol starts quite low.

Slide 53

So I think that’s a given. What we are hoping to do of course is to stabilise plaque and prevent the formation of thrombus.

Slide 54

And I think there’s again nothing different about renovascular patients they’ve got diffuse atherosclerosis they should receive the same therapy.

Slide 55

Other risk factors.

Slide 56

Inflammation is one, we don’t yet have a particularly good intervention apart from statins to reduce inflammation but as you may have heard this morning from Mark Pepys’ excellent plenary lecture, it’s going to be very interesting when we have CRP manipulating drugs maybe to change the impact that CRP might have on acute or chronic renal injury.

Slide 57

Equally there are very interesting things to do with endothelial function and ADMA but again we haven’t got very good interventions, we’re not good at reducing homocysteine very well with vitamin therapy at the moment. But in time this pathway which at the moment acts as a very powerful surrogate marker for adverse outcome we maybe able to control more effectively.

Slide 58

Oxidative stress I think is very, very important particularly for patients with advanced kidney disease and this is another area where in time we’ll have agents that work. We already have one called N-acetylcysteine but we don’t use that in a systematic way.

Slide 59

So to bring my talk really to a conclusion our patients really have various ways to end their days, I’ve called one of them a renal road to ruin and it starts with the risk factors down here, blood pressure, cholesterol, obesity, smoking and diabetes, they get microalbuminuria, proteinuria, CKD III, IV, and V and they have a renal disaster.

Slide 60

On this side they have the same risk factors, endothelial dysfunction rather than microalbuminuria, LVH rather than proteinuria, they have a heart attack rather then get to CKD stage IV and V but the outcomes are just as dismal either way round.

Slide 61

What we have is ACEs and statins to try and drive the direction this way, what they have is all these other mechanisms apart form these risk factors that are busy driving the mechanism that way. At the minute what we can do, if I can get my bills to work properly is the minute we can do some of the things to target these and we can use those I think we need these to take us on to the next level in terms of interventions. Yes, it will be difficult for sure to use ACE inhibitors in this very high risk group, for example, is going to be a little bit of a tortuous path. We’re going to have to monitor these patients frequently we can’t just discharge them to GPs or primary care people, we’ll need to be looking at them frequently to look at their creatinine, look at their proteinuria, look at the other factors.

Slide 62

These are very high risk patients, they need very, very high targeted intensive medical therapy.

Slide 63

So to bring my talk to a conclusion medical therapy I think should be targeted at reducing cardiovascular risk. I think if you do that, the renal risk will look after itself mainly. I would advocate ACEs and ARBs as part of the blood pressure reducing picture. I want to get my patients under 140/90 and under 130/80 if they have significant proteinuria, we can debate whether that’s half a gram or a gram. Use of statins I think should be ubiquitous and I would want to get their cholesterol lower than 4 and if it was lower than 4 to start with I’d want to get it lower than 4 even more so. Aspirin I think is easy we have no evidence for it but it’s not likely to be harmful. I haven’t really said much about anaemia but these patients with heart failure, diabetes, with hypertension, with CKD they’re going to have mild to moderate anaemia. Don’t ignore it we have to screen for that, we have to correct it. I’m a firm believer in getting the haemoglobin up to 11-12. Whether any of these agents, spironolactone very good at reversing fibrosis, the new direct inhibitors of renin synthesis that are coming on the market, whether we should use antioxidants to target some of these other things this is for another day. We don’t even know whether to angioplasty these patients yet let alone whether we should be using some clever or fancy drugs. So that’s my take on medical therapy trying to protect the heart and the kidney simultaneously with drugs that we’re pretty well all familiar with.

Slide 64

I hope then I’ve given you this sort of feeling now that you can go out there and do some good and fight the dark side of people who say there’s nothing we can do, the nihilists.

Slide 65

I hope very much that I haven’t produced this status in you and I hope in fact you’ve found the whole session very much more interesting and it leaves you being a bit more like this. Thank you very much for your attention.

Slide 66

Chairman: Thank you David for your very energetic communication. I’m sure that you have maintained us awake. Any questions in the room please? Johannes.

Question: David a great talk. I would like to support your idea of treating patients with renal artery stenosis with ACE inhibitors and controlling their GFR and if it goes up, then you stop.

Dr Goldsmith: You stop or reinvestigate.

Question: Twenty years ago there was a paper in the American Journal of Medicine by Smith et al at a time when there was a clear contraindication showing that they work better, there are some people who increase in serum creatinine but with other drugs there’s also sometimes an increase in serum creatinine when you lower blood pressure.

Dr Goldsmith: Yes absolutely just the blood pressure lowering effect alone can increase creatinine temporarily.

Question: So, it’s not solely dependent on the inhibition of the renin system.

Dr Goldsmith: I agree completely with that. Surely this is not so uncontroversial. Everybody in the audience would agree although I know coffee beckons.

Question: Can I just ask a little supplementary question to the one that Doctor Mann has just asked you? Do you feel that every single patient with renovascular disease ought to be receiving an ACE or an ARB?

Dr Goldsmith: I actually think it should be part of what we’re doing for our patients. If Phil you can get blood pressure control, that I have defined as 140/90 or 130/80 with proteinuria and you can tackle the proteinuria and they don’t have an absolute indication for an ACE, then in that situation I think the argument for an ACE over another therapy is the least powerful although I think it’s not negligible.

Question: Unless there’s LV dysfunction.

Dr Goldsmith : Yes, but if you’ve got LV dysfunction you’ve got another reason to use an ACE. If you don’t use an ACE or try or maybe stent them or keep the arteries open I think what you’re doing is you’re being kind to the kidney and killing their hearts. This is the big danger I feel of under employing effective medication.

Question: So to take that a stage further and this might be a key message. Would you feel that if a patient in whom you definitely wanted to use an ACE or ARB with renovascular disease who had proteinuria. If they had renal dysfunction associated, would you then make that an indication to perform angioplasty stenting?

Dr Goldsmith: Well, my practice is actually to do that where the indication for the ACE is very strong and the discussion with the cardiologist it’s usually that way round. They’ve got an awful LV either systolic or diastolic function and the cardiologist says I’m sorry but each time we take them off the therapy they do very badly. We need somehow to get them on this therapy then absolutely I would say well in that case what I can do is we can do an angioplasty and stent and we can hope in the right hands with a low side effect profile this maybe better. Of course it would be nice to have an outcome study and I know that ASTRAL has nested within it a subgroup analysis to look at the impact of ACE treatment or not, hasn’t it Phil? So, we’ll get some further high impact, high population yield information about whether the small studies by Losito et al and other people are actually going to be born out in a randomised controlled study.

Question: Ok thank you.

Chairman: Ok thank you to all the speakers and the Co-chairman and also the audience.