CME Slides Forum - J. Scoble

scobleslide

The first slide I’d like to go over with some detail is actually I think one of the most important slides in this whole area and this is a rat model of renal artery stenosis and I think what it does is so lots of doubts as to exactly what we know. The top group here just shows that if you have a rat with two normal kidneys, with time the weight, in comparison to the weight of the overall animal will decrease. So there is a relative change to the proportion of weight of the kidneys to the overall animal size. What we also know is that if we take a kidney out, there will actually be compensatory hypertrophy in the remaining kidney. Now, that we understand that fits into all our preconceived ideas. We also know from Gobe et al work from a long, long time ago, I can’t that if you put renal artery stenosis into a kidney that kidney size will go down and there will be relative compensatory hypertrophy in almost exactly the same way as if you’d done a unilateral nephrectomy. What is much less well known and completely counterintuitive is if you get to this point and remove the contralateral kidney without changing the stenosis, this kidney will hypertrophy. If you do the same as this and remove the clip from the stenotic kidney, that kidney will stop worsening in size and will stabilize and there will be no effect on the normal kidney.

If however, you do exactly the same as here but remove the clip, you have the same compensatory hypertrophy from the contralateral removal. What this says is that some of the things that we think we know about that renal artery narrowing is bad, produces hypertension and also reduces the size of the kidneys is possibly true in some instances but this suggests the mechanisms that we think we know are not clear and I think my view of the whole area is at the moment a lack of clarity. We have ideas, they’re not proven and some of the interventions are counterintuitive.

What I’d like to do is divide my talk into three. First of all, I was challenged to how to diagnose renal artery stenosis, which is a little bit difficult because I only look at pictures that are provided by other people. I’d like to talk about renovascular hypertension, focus on FMD and then what I think is the big contentious issue is atherosclerotic renal artery stenosis and the concept of atherosclerotic nephropathy.

These were great, these were wonderful days, DTPA scans, we knew why they worked, we did them, oh, it was great fun. I don’t think I’ve requested one for about 10 years now. In their time they were elegant and interesting but I don’t think there is a place for them anymore.

What is also absolutely clear to me is this is the only investigation, which will absolutely and ultimately give you the correct diagnosis of the degree of renal artery stenosis. This is an intravascular ultrasound, interestingly different context, it’s very much being used now by the aortic surgeons in terms of placement of aortic grafts, so it is in operation, the catheters are extremely expensive and can only going to be used once so this is the goal standard but we cannot use it.

What we also must be clear is what we think is the goal standard is not the goal standard on the left is a study in which individual radiologists were blinded to the same angiogram and produced a significant number of different degrees of stenosis. This has been repeated later with an interesting, almost exactly the same degree of disparity for the angiograms but a slightly greater degree of disparity for the MRI.

This has come out in the last few years, this is a metanalysis of all the studies that the group of Tan at al. could find and I think what it’s saying now is that in terms of sensitive in specificity, MR scanning is a very reasonable option but what they’ve also pointed out which wasn’t present when we first started off is that with gadolinium enhancement the figures are actually very, very good. I just put this slide in because this is sort of my view of how important it is.

This is a very nice young girl with middle aortic syndrome, neurofibromatosis, incredibly complex anatomy. Here’s an aneurysm, a stenotic lesion there another stenotic lesion there and was lost in the neurology clinic, no action was taken and someone decided to repeat the scan 11 years later and I have to say from a practising clinical nephrologist’s point of view, actually that gives extremely good imaging of what is an incredibly complex situation.

This is very atypical in that it is an atypical form of fibromuscular dysplasia even more atypical, it’s an Afrocaribean female and I would just suggest that the MR is extremely good at screening but possibly doesn’t give the detail of this very odd lesion which responded brilliantly to angioplasty.

I will just close on this part with my own personal views. I don’t think there is any real role for nuclear medicine scanning. MR angiography that is available is remarkably without its problems except for claustrophobia in some of my older patients and I think on clinical grounds if you think renal artery stenosis needs to be excluded, I think it’s perfectly reasonable for this to be performed and I think all individuals in whom we think there’s a clinical indication should be scanned. There is however one caveat and there is some argument in the literature about whether the MR will pick up the peripheral lesions in fibromuscular dysplasia and there’s certainly one paper in which they’ve suggested that in living donor assessment where FMD is really the only thing you’re looking at you should only use spiral CT scan. Certainly that is our practise we have stopped using MR for living donor assessment.

Let’s go on to this quite interesting area. This is a very nice lady who presented with some form of intracerebral bleed was found to have FMD on her carotid and we went back in retrospect and looked at her renal artery and this the beautiful beading appearance.

I think this is the best-kept secret in nephrology. It’s interesting when you get a slightly aberrant result and yet all the papers come out with exactly the same conclusion. What this says is that Cragg many years ago suggested that if you looked at all the living donors who were assessed and don’t forget these are people who are normotensive and well, there was an incidence of 4% of them had FMD and this is madness, this is terrible. But in fact Neymark later came out with a very similar study and then made it 7%. Andreoni a couple of years later came out and said it’s 4%. We’re, I think one of the biggest, well we are the biggest living donor transplant unit in the U.K. now, our number is 3%.

So interestingly fibromuscular dysplasia is more common than membranous glomerular nephropathy, it’s more common than adult polycystic kidney disease but interestingly it’s not common in the way we think it should be common in that these people in essence were normotensive when they presented. We know that the majority of involvement of renal artery FMDs in renal arteries but there are manifestations in other territories and this is the excellent review in the New England Journal. One of the big important things, points I’d like to make is that we think of it as a ring of beads, it’s not the artery is constant in size, there are like these diaphragms coming down. Our experience is once you’ve achieved angioplasty of these almost like pulling varicous veins or stripping that actually five years later the angiographic appearance is often much, much better than immediately after the procedure which is completely different from atherosclerotic disease.

What we do know here is that if you have a stenotic kidney in FMD, it will be smaller than the opposite kidney and actually possibly a little bit smaller than those with central hypertension and this can be represented as renal length or as cortical thickness. I’d like you to remember that for when we come to talk about atherosclerotic disease.

This is the excellent work of Professor Mounier-Vehier group. Once we won’t talk about the left but if you could just remember roughly what it shows. What this shows is in angioplasty for fibromuscular dysplasia, there is improvement in that kidney and if it’s unilateral, there is in fact a slight decrement in the function of the contralateral kidney, so in terms of function there’s an excellent outcome in terms of FMD.

Once more this is this excellent review by La Batide-Alanore and colleagues. But the interesting thing they didn’t actually pick up on the incidence of fibromuscular dysplasia in the general population, which is slightly bizarre. What I’d like to show you here though is that what we’re talking about is a significant incidence of cure of hypertension which is something, which I think most of us, think is wonderful and would not expect but the published series suggests that anything up to a half of patients can be cured with hypertension.

Our experience is slightly different in that what we’re finding is somebody’s been diagnosed with hypertension aged 30, we get them aged 55 and find they have FMD, the results aren’t quite so good, so what we’ve retrospectively looked back and if it’s diagnosed under 40 and angioplasty there’s often a good result, if you pick up what in retrospect was FMD which has been present for 20 years, the results are less good.

What I would have liked to draw your attention to is how closely related it is to the actual ostium of the renal arteries. This is a patch of a kidney which was taken for transplantation, the origin of the aorta seemed to be very atherosclerotic and the patch was taken off, the kidney used but if you look through here what we’re talking about in atherosclerotic disease is disease of the aorta with actually remarkably quickly into this a normal renal artery. That’s very different from the pictures I’ve shown you of FMD where there is often disease all the way to the periphery. How do we diagnose atherosclerotic renal artery stenosis?

Well, what this slide is trying to say is choose an incidence of what we know is a consequence of atherosclerosis, people going for coronary angiography, peripheral vascular disease. You will find a significant proportion of these individuals will actually have renal artery stenosis. In peripheral vascular disease it’s probably about 50%. In coronary angiography it may well be 30%, bottom one now that we’re screening people with diabetes because of the lack of worry of MR and contrast, type 2 diabetes, hypertension, creatinine greater than 160, 40% of them had renal artery stenosis.

This is data which only one member of the audience I think has seen already and this is a slightly different way of looking at it. This is the ASTRAL data of the patients enrolled. Obviously the trial is still going on and we’ll talk about that in a minute but this just shows you what the characteristics of these patients are. They’re relatively old, they’ve got hypertension both systolic and diastolic and interestingly though there are degrees of renal impairment in those entered in for trial is not enormously great and the vast majority have modest degrees of renal impairment.

That is very, very different from the data about FMD where it is always the kidney that has got stenosis, is a small kidney as we looked at before. If however, the stenosis goes to occlusion then the function of that kidney is always very poor. So, what we’re saying is the presence of renal artery narrowing in atherosclerotic disease does not determine renal function.

This is the data slightly differently put saying it’s only when you get to 100% that is occlusion that you actually get any clear change in the single kidney GFR. All these data I’ve shown you are on GFR measured in the individual kidney.

Why should this be? What I tried to show you with the histology is that you’ve got an enormous atherosclerotic plaque sitting right at the renal ostium and then suddenly you get a normal renal artery. You can actually look at hundreds and hundreds of things that can actually cause renal damage. I think the one we know most about is cholesterol embolisation. We also know that in other territories which I won’t go into today, protection devices which actually will pick up debris at the time of intervention have been shown to be very effective but I think it’s probably this which makes the interventions potentially so different and the relationship between the renal artery narrowing and the function size of that kidney so different from in FMD.

Why is this important? Alain Meyrier was just telling me about some years ago about cardiologists doing renal angioplasties in France. This is data, which shows it’s a three-fold increase in angioplasting and stenting in the United States over the last ten years. As I said at the very beginning this is very important if there was an absolute indication for this but this is on the basis of no published data.

I’ve chosen the metanalysis that Ives did, there is one other metanalysis and this shows that if you look for hypertension in the three studies that have been published with atherosclerotic disease, there is no evidence of a change in diastolic blood pressure, mean diastolic blood pressure, mean systolic blood pressure or a change in systolic blood pressure. So, I think in terms of atherosclerotic disease it is very difficult to make a clear case that renal angioplasty plays a role.

Paul Harden from Glasgow did this very nice sequential study looking at the rate of decline of kidney function before stent placement. I think the data is very nice if you look overall at the data though, you can actually see that there’s quite a variation in the way individual kidneys or individual patients respond to angioplasty.

J. Radermacher, who I met on the bus this morning, did this very, very good study and I think it supports all that we know which is that the resistive index which is a measure of parenchimal damage if there’s a high resistive index, the kidney will not do very well with angioplasty, the important thing to state though is that this was not actually the resistive index in the kidney that’s angioplasty this was the resistive index in the contralateral kidney because the resistive index in a kidney with severe stenosis is obviously going to be very low, so it’s one of the bits that people are not actually in the text but must be born in mind. The second is that because it wasn’t randomised what they showed is that people who had an excellent renal function got an excellent improvement in renal function but they didn’t need it and that yes, these people won’t do very well but moving a creatinine clearance from 60-65 is not clinically useful if you do change it from 10-15 it will be clinically useful, so although this is fitting in with all the data that we know about those who respond poorly because we haven’t randomised them, we don’t know what the change would have been otherwise and it’s in that critical group we need to look.

This is what I think certainly Phil and I have spent a large part of our life trying to do. This is the ASTRAL trial. We’re very pleased, we’ve now got 530 patients enrolled and it’s on for another 18 months. We had hoped for 1000, we’ll probably get over 700 but it’s still a very good trial and this just shows the aggregation of the enrolments.

I’d like to share two thoughts with you about this. The first is that in the last year or two years, 2 trials of protection devices, one in the heart and one in the crotted territory have been stopped by the supervising committee because of a divergence in the two arms. Our data monitoring committee have not stopped us yet which suggests that even with 530 patients there is not a staggering difference, which is very interesting. The second is and I think it’ll come out of some of the issues that I know Phil’s going to present you in one of his papers later. We all know there’s an effect of getting patients to come to the clinic. We know overall from the non-analysed data just for the overall group that the blood pressure has improved on follow-up in all the patients as an aggregate. I’ve certainly now had to, not had to, are randomising patients who I would not have randomised before. Tight renal artery stenosis in a single kidney I used to think was an absolute indication. I’ve now randomised some to doing intervention, got their cholesterol down and blood pressure controlled and they’ve done very well. So I’ve actually learnt a lot from the trials and my actual understanding of the importance of intervention is even less.

This is flash pulmonary edema, this is a nice lady who had an aortic replacement of a saphenous vein graft who ten years later presented not with renal impairment, creatinine was 150 but that wasn’t terrible but with three episodes needing ventilation, she was angioplastied and she’s not been admitted to hospital since. I think the first description of flash pulmonary edema was one of those things you read but it is an absolute clinical indication now I feel. The Pickering group first described it as subsequent analysis has shown it’s much more likely to be present in bilateral renal artery stenosis or occlusion stenosis and the response to angioplasty is much more likely to be a cure in those two groups, so I think we know a lot about it. I would exclude all these individuals from going into the trial.

I’m not sure any of you are aware of this but this is the bane of my life, we’re now, all our surgeons are doing endovascular grafting.

The study hasn’t finished but what hasn’t come out brilliantly well here though, the 30-day analysis, the stent group has 1.7% mortality, open repairs 4.7%, so there’s going to be great pressure on us to do this.

And this is the angiogram when we got to that point and you can see the covered part of the stent is here but we’ve lost that artery on that side.

There’s a very good study that has just come out about aortic stenting in which they obviously focused on the stent bit because they’re not nephrologists. It didn’t reach statistical significance I think in terms of death but the numbers were smaller than EVAR but this is the bit that got me. The deaths and deaths and complications are significant in both groups. Fascinatingly the change in creatinine with the open repair is modest and there’s a significant change of creatinine in the endovascular repair. So what I would suggest certainly now is that if you’ve got renal artery stenosis and you’re going to put an aortic stent in I think that’s now an indication in my view.

I think this is like me trying to climb mountains, every time I get to the next bit there’s another hill coming up and I never quite know when it’s going to finish.

I think this is where we are at the present time, eventually we’ll get to the top of this wonderful mountain and we’ll be able to look back and everything will make sense. There are some pointers, there are ASTRALs on going, stars starting and CORAL starting in the States but at the moment all we have is soft data to support us. If you want to ask me what do I do with the patients after atherosclerotic renal artery stenosis I have a very quick and simple answer I randomise them.

Chairman: Well thank you very much John, I think there are plenty of questions from the audience.

Question: John, you were saying the patients with Flash pulmonary edema, you will have no hesitation in stenting them, can you speculate the difference in the renovascular physiology in a group of patients who develop Flash pulmonary edema and have the same degree of stenosis as another group who never does?

Dr Scoble: I don’t know, you can only have my thoughts, the one thing I’ve found is I’ve never found any patient with Flash pulmonary edema who’s got it going round the supermarket on a Saturday afternoon. They obviously invariably go to bed without orthopnea they wake up in the middle of the night with flash pulmonary edema. The suggestion is these patients maybe the ones that have kept their dip at night in hypertension, they’re volume overloaded and it just tips them over that’s as a reasonable explanation there is in the literature at the moment.

Question: In which case wouldn’t you just treat the volume and then stent them and not stenting them?

Dr Scoble: These aren’t grossly volume-overloaded patients, they don’t have terrible LVs all I know is if you actually intervene it is a fantastic diagnosis to make.

Question: May I ask you a comment on the restrain, the present restrain on the use of ACA, ACE inhibitors in bilateral or unilateral disease, thank you?

Dr Scoble: I think that the data is not very good. There is a suggestion that if those individuals become volume deplete there are two or three case reports of them having renal artery occlusion. I’m just very conservative and have not done it. I’m aggressive about keeping their blood pressure in control, their statin, stopping them smoking and the rest. I think if you can’t control their volume status I’m just hesitant at the present time. Once more as with all of it there’s no randomised data to support that.

Question: Burnier from Lausanne. Since you are doing MRs, I am also, I wanted to ask you one question. We are more and more confronted with false positives and then when we discuss with some people they say that the MR is also very much investigator dependant, it depends also on the analysis of the people, how they do interpret the data.

Dr Scoble: I mean I think it’s a very good point. What we found with ASTRAL is that the MR has tended when we’ve had angiograms as well to overestimate by 1 degree, so 50% may not be significant when they go for an angiogram, 75% becomes 50% but once more the other way round though we don’t get any false negatives I mean so that what you’re then talking about is planning the treatment of someone with a known problem, so I’m less, I’m more comfortable with that but it does tend to slightly overestimate in our hands.

Question: You showed the metanalysis of Doctor Ives and there is another metanalysis of the same study perhaps you know NAME and it’s very interesting the result of this metanalysis nearly the same but he calculated that the cardiovascular mortality in the patients who got medical treatment was higher than in the PTA group and the result of this metanalysis I think was that the CORAL study you mentioned in the United States they have an end point a very hard end point only cardiovascular mortality and nothing else.

Dr Scoble: You know I think that’s been interesting one of CORAL and they’re going to put protection devices in. I think the problem we’re talking to John Webster the biggest improvement in blood pressure is certainly in the Scottish Newcastle trial was on entering the trial was nothing to do with the two groups and that’s always one of the difficulties I think. I mean I hope that we’ll have some data from ASTRAL, the powering of the three studies is not enormous at the present time and as you know Drastic came out with a slight reduction in numbers of agents it’s not what I think I could stand up to in epidemiology and say this is really clear evidence for intervention.

Question: Do we have cardiovascular mortality at the end point in your study?

Question: I’ve had recently two patients who might be interesting. One was a 60-year-old patient who got a vascular graft endovascularly put into him and he lost one renal, one function, one kidney. Sorry and later on he had a sharp drop in his creatinine when the remaining renal artery was stented too because the stent was partly occluding that so they put another stent in the big stent and initially they had a drop in the creatinine.

Dr Scoble: I mean we’ve had now since one of these in which they’ve gone back and tried to put the stent through the side of the stent. There’s a study in the literature, which says if that’s the case, you ought to do it at the same time. What we’ve tended to do is if there’s significant renal artery disease stent them, leave them and then they put aortic will open up above it. There’s been at least one case unfortunately where the covered part of the stent has been put over the renal arteries, which I can assure you is not very good for renal function.

Question: Well finally it turns out that the stent thing, the initial stent in the aorta had a pressure effect also on the remaining kidney and it had an effect that went into….

Dr Scoble: And also they move and they …… It’s big business for us nephrologists.

Question: What do you do with people with a low output cardiac failure who also have renal stenosis bilateral for example? I’ve had such a case, a patient with a 20…

Dr Scoble: I only do them with flash pulmonary edema or enter them into the trial unless they’re going to have an aortic stent.