Slide 1

Mr Chairman thank you. So the canvas has been painted by two experts. What I’ll try to share with you is just to add the fine touches to this painting just to try to make it a complete and maybe a masterful piece.

Slide 2

Now, I’m going to touch on a different subject because we all talk about adults and in fact, we all talk about very old adults. That’s the kind of patient we all treat but we have to be aware that we also have kids and adolescents coming to dialysis and this is maybe a particular subject. I’m going to touch with you about this issue and in fact, the cardiac mortality and morbidity is huge and I want to point out this is well known and another interpretation of this very famous slide is that in fact if you are really very old, the difference in mortality between the general population and ESRD is not very high. This is a one hundred times difference when you are an adolescent with ESRD and this shows that particularly the issue of stiffness and of cardiovascular mortality and morbidity has to be watched out and applied to the younger population.
Now, this is still an unclear area and I’m going to touch with you various subjects. I’m going to have an overview on the established cardiovascular abnormalities. I’m going to discuss a little bit about the different methods of evaluating stiffness and you have heard a lot about this today. I’m going to discuss with you about the prognostic significance of arterial stiffness in children to describe the vascular pathology in CKD in children and adolescents and to go beyond ESRD because this is not just a disease of CKD.

Slide 3

Now, children offer a unique opportunity to study the cardiovascular impact of uraemia unobscured by aging and comorbidities. I agree with Jacques Blacher. I have the same slide of Gerard, what does it mean? Does it mean we have a lot of influences that we can’t dissect really the impact of uraemia? The EUTox group tries to find out the impact really of uraemia but we are quite a long way and in children we have a lot of cardiomiopathy not maybe so much as high as in adults as in old ESRD subjects but still it’s a significant amount.

Slide 4

We have the same sort of picture with kids and adolescents having normal hearts, dilated hearts, hearts with just concentric or eccentric cardiomiopathy. So, really the same sort of picture as in adults but the percentages are, of course, different. I would say that the percentage of LVH is just a little bit lower than in adults and in old subjects but you’d expect that.

Slide 5

Now, let’s go to the non-invasive methods for the evaluation of vascular function. One big difference and let me state it from the very beginning is the size and also the way the system, the arterial tree has developed. It’s not just the same, the heart is different, the length of the arteries is different and of course, the material is different and I’m going to touch with you the fact that we have always to look at the endothelial function measurements and to assess both the endothelial function and the arterial stiffness.

Slide 6

You have all seen the pulse wave velocity, this is actually an example of how the pulse wave velocity is performed. When this performed it is related to an ECG gated signal just to measure the difference in time as this has been explained and exemplified by Doctor Blacher but it also takes into consideration the actual size of the body, so the actual length of the body. So, we have really to think of kids and of their sizes as well.

Slide 7

To look at stiffness also we can look at compliance and really at elastance and stiffness and both those two parameters are in fact, a ratio between the volume or the area or the length which is in here and really the other term of the equation is pressure.

Slide 8

How can we measure this? Now we have very good systems and in fact, in young children and in adolescents it’s even easier because we can use the high definition echotracking devices and in kids it’s particularly easy to use an ultrasound probe, you obtain very good results in looking at the vessels. You don’t have usually the same difficulties as in older adults and you can directly measure the pressure at that particular site by using Millar instruments and the Aplanation tonometry and of course, you can relate the two and then you will have the famous diameter pressure curve and in fact, this is a way of expressing the stiffness or the compliance.

Slide 9

Now, you have heard again about the pulse wave analysis and the way that pharmacologically we can manipulate the contour of these waves and really look at the function.

Slide 10

And Gerard London discussed with you the use of nitroglycerin and in fact, we can use some other drugs. For example, we can use β mimetics really to look at the endothelial dependent function. So in fact, with a pulse wave analysis we can really look in the endothelial function testing not only with the flow mediated vasorelaxations. So, we have really the tools to look in depth at the arterial system in this particular population. But whenever we do that we have really to think of what is normal because particularly with some of these measurements we have to use developments that have been related or have been developed for the adult population.

Slide 11

For example, with a SphygmoCor device the transfer function has been developed mainly in the adult population and the question is does this always apply to children? In fact, the only thing we have is really to rely on large epidemiological data and this is one of this data showing that in very young subjects and here it stops at age 20 you can see that in fact, and here it goes a little bit to a lower age, you obtain a negative augmentation index. In fact we have different values for this and we have to refer to this normative.

Slide 12

Another important question which hasn’t been touched by my two previous speakers is about the reproducibility of these measurements, do we have a perfect tool in our hands? Can we use this tool repeatedly enough in different populations really to draw significant conclusions in the longitudinal, studies for example, in the interventional studies? The answer is definitely yes in adults and as you can see here, in the younger population from different areas, from different countries and in fact, this is a highly reproducible method.

Slide 13

Now, this is just a slide showing you a crude, a very crude comparison between the different methods. In fact, it’s a question of availability and a question of the experience of the person who is performing this. I would probably advocate the use of the tonometry devices because really they are simple to use, you can use them at the bedside, they are quite cheap actually and they offer quite reproducible measurements and also you can perform the entire range of evaluation from pulse wave velocity, pulse wave analysis and as I’ve shown you, the endothelial function and dysfunction.

Slide 14

Is it enough? In fact, I believe that it is not. If really we have to assess the arterial tree and the vascular pathology of our patients, we really have to look at the entire spectrum and the vascular calcifications are very important and this has been shown in the two previous talks. We have several methods of assessing those. We have also to look at the cardiac calcifications and we have different methods, we have the x-rays, we have the very nice echograms now and of course, we have the multi-slice or the EBCT.

Slide 15

We really have to look at the intima-media thickness and with all of those we have a full picture of what is vascular pathology. Now, of course when we have all this spectrum of evaluation, the proper question and this has been addressed partially by my previous speakers is which one is the most relevant? Should we use all of them? Should we use some of them? Which one offers the best information for us.

Slide 16

Another way of looking at this slide from Gerard London is really that in fact, the aortic pulse wave velocity and the calcification scores as you can see here in red and in black are the two most relevant diagnostic tools. That’s why I’m somehow advocating the use of two and it’s so simple in all the populations. On top of that, as I’m going to show you as well, they’re bringing complementary information and in fact one is related to the other.

Slide 17

Now, we had augmentation index, we had pulse wave velocity and we heard the debate they are not the same thing. Of course, the augmentation index is related to pulse wave velocity and is related to many other things. We can have both of course for sure because both are derived with the same machine, with the same tool but are there any differences in children? Please look at these 2 graphs which show completely different ways of behaving for the augmentation index and the pulse wave velocity with time and with age. So that in this particular paper if you look at the influence of 10 years of aging, you will see that both in males and in females the impact is greater for the younger population for the augmentation index, for example it’s a + 9 impact of a 10 years aging and it’s a very small impact of the pulse wave velocity in this particular population. Compared for example, with this older population this is almost + 1.5, 1.4  in a let’s say 10 median pulse wave velocity that would be 15% up to 20% and this is a very small impact for the augmentation index. So in fact if you are older, it’s far better to look at the pulse wave velocity. If you are younger guy, if you are a child then the impact in terms of mortality and morbidity data is probably much more important if you look at the augmentation index. Of course, you have to look at the two and really to take into account the whole spectrum.

Slide 18

Now, a lot has been said as well about the prognostic values of the pulse wave velocity, of the stiffness in the general population. This is another slide showing the same thing and in fact, describing the fact that the pulse wave velocity is probably the most important predictor and has the highest prognostic value in the general population. I have to point out in fact again that we don’t have the same quality, the same strength of data in the lower end of age of the spectrum.

Slide 19

This shows that in the ESRD, the typical ESRD population the pulse wave velocity is a fantastic prognostic marker, the augmentation index is a fantastic prognostic marker. So I’m going to ask you all what is the problem with these slides? First, just to have a joke with you it’s just coming from one centre, it’s coming from the population of Gerard London. Of course, we have the same data from the Soji data, the Soji group but this is somehow different, it’s an Asian, it’s  Japanese population.

Slide 20

So in fact, our group looked at the same kind of data. The reason behind that was that we have a different population, we have a younger population with a different comorbidity impact, with a different comorbidity index. In fact, in a younger dialysis population the impact is a little bit different and I’m showing you just data on augmentation index and as you can see here we divided the population by augmentation tertiles and there is not such a tremendous difference between the highest augmentation index or the highest pulse wave velocity and the lowest tertile. So, in the younger population and this is by I think ten years younger than the typical Gerard London’s population which again is really younger than the typical dialysis population the impact, the prognostic impact of the augmentation index and maybe of the pulse wave velocity is not as high as that so, again maybe a word of caution.

Slide 21

I’m going to move now to the crude facts of ESRD in children and their impact on the vascular tree. We have some indirect evidence and this indirect evidence comes from the very good study, the LERIC study which is the Late Effects of Renal Insufficiency in Children. In fact, this is not a study performed in children because in fact the authors looked at all the 249 Dutch patients which started renal replacement therapy at the age 0-14, so way before the study was preformed. There were some 187 patients alive and this was a retrospective analysis and of course, the mortality risk as you can see was hugely increased, it was in the same range as I showed you in the second slide. It’s in fact 30 times more than in the age matched controls, there were a lot of cardiovascular deaths. There was a lot of LVH and stiffness was increased compared to the matched controls and was related to the left ventricular abnormalities.

Slide 22

Are you convinced? In fact probably not because as you can see for example, in this particular study the intima-media thickness in an ESRD population was almost similar to the matched controls. This was because some of the patients died or this was because it was a retrospective study. This is clearly not direct evidence.

Slide 23

We have only two studies with direct evidence.

Slide 24

And in fact, one of the studies comes from our group and what we did we took the entire dialysis children population from an entire region and we were lucky enough that because of the lack of transplantation facilities there were children that were unfortunately kept a long time on dialysis.

Slide 25

What we’ve seen in this population of very young kids, we’ve seen that the pulse wave velocity was by 22% higher and the augmentation index in fact, was hugely increases as you can see here almost by 250% more than in a very well matched control population. I may remind you that again in this age range the augmentation index is the one which is much more influenced by age but still this is a huge difference compared to the control population.

Slide 26

Interestingly enough there was no impact of a dialysis session because we looked at all these parameters before the dialysis session and after the dialysis session and as you can see, there was no impact whatsoever of a dialysis session on the stiffness and the augmentation index parameters.

Slide 27

What were the consequences in this study? Well, the left ventricular mass index in the dialysis children correlated only with the augmentation index and there was no relationship found with the pulse wave velocity or with the other indexes of the vascular pathology.

Slide 28

This was confirmed in fact, by another study, another direct evidence and this study was a larger study and this study also had the quality and the advantage of looking at a full spectrum of renal disease. So, they looked at dialysis, they looked at controls but also they looked at a predialysis population. The suggestion from this study in fact that there is a continuum, the stiffness and the augmentation index are worse, if you go to the CKD pre-dialysis population and then it’s becoming even worse on dialysis.

Slide 29

Now, of course, the question is if we transplant quickly enough or if we transplant anyway does this prevent? I think that this is another important question because somebody asks here what are the means of influencing the stiffness’ Should we use statins? Should we use sevelamer? Should we use ACE inhibitors? Should we use transplantation? Is transplantation the best method of reducing stiffness? Well, actually in kids it is reducing the stiffness but not tremendously, there is still some residual stiffness which is increased compared to the controls. Surprisingly enough and the authors couldn’t really explain this difference is that when you receive a graft from a cadaveric donor, then your stiffness parameters are worse even if your renal function is similar to the moment when you receive a graft a live donor.

Slide 30

Now, in children what are the determinants of the arterial stiffness? In adults we have a lot of data and of course, we have the usual suspects which are age, which are height, demographic parameters and you have heard the vascular calcifications and the calcium-phosphate metabolism.

Slide 31

What about the children? Well, we have some data from kids in non-renal populations and the risk score is really a composite score of blood pressure, of lipid abnormalities of age and so on. If we look at this composite risk score of the systolic blood pressure or just some markers of development, you can see that in fact, those are determinants related to stiffness and they remain determinants even when you adjust for multiple things.

Slide 32

In kids as well we have age, blood pressure and these are the references, the length of the dialysis and the type of renal replacement therapy but many, many authors are really putting forward the abnormalities in the mineral metabolism and mineral disorders.

Slide 33

Other than that you have really the usual suspects in the children population compared to the adult population.

Slide 34

In our study we looked to the same determinants and there was a difference in relation to the parameters. So, there were some parameters related to augmentation index and other parameters related to pulse wave velocity as you can see the augmentation index and you would expect that is much more related to the demographic data to age to height to weight. In fact, pulse wave velocity in this profoundly sickened population kids which were quite a long time on ESRD and on dialysis you can see the main parameters are related to phosphorous and calcium-phosphate metabolism and this is in contrast to the control population from our study where pulse wave velocity was of course related to the age, height and weight.

Slide 35

In this model the age was in fact, was the only major predictor of augmentation index and it explained almost 60% of the variance in augmentation index. On the other hand for pulse wave velocity phosphate and phosphate control was the only really determinant of the pulse wave velocity and it explained pretty much of the variance in pulse wave velocity almost 1/3 of the variance.

Slide 36

Why is this so? Well we have this classic study now and classic slide. This is presented everywhere these days which showed for the very first time that you can have  vascular calcification even at the very early ages in adolescents and from that moment on actually evidence kept accumulating.

Slide 37

And this is just a slide summarising the data showing that you have different populations and in these different populations you basically have this sort of picture where you have some patients without any calcifications but you have some patients with really tremendous calcifications even at a very early age.

Slide 38

Well, what about intima-media thickness? Remember in the LERIC study there was no difference and this was explained by the authors that a lot of patients were transplanted or died so it was a bias. Well, in our study we looked also at the intima-media thickness and similar to other studies and in fact, this is really the result, the dialysis population of children and young adolescents will have a higher intima-media thickness so profound abnormalities.

Slide 39

And again as shown by Litwin and co-workers this is related again to indexes of vascular calcification of phosphate and calcium metabolism.

Slide 40

I’m going now to shift to the last part of my presentation to ideas and facts beyond ESRD because it is beyond ESRD but however, you’ll see from this other population we are going to recruit the patients with CKD in adulthood and there is a lot of endothelial dysfunction which is demonstrated in infants, in children and in young adults with low birth weight and also some abnormalities in the synthesis of elastin and decreased compliance and  I’m going to refer to that.

Slide 41

This is a nice study because in this study they had 3 beautiful groups. One group was of children who had a low birth weight but they came to life at the proper age. The other one was of premature children but with normal birth weight and in fact the last group, the group of controls.

Slide 42

We now know more about this relationship that low birth weight is related to CKD and that low birth weight is related to hypertension. There are some very nice data out with endothelial dysfunction and of course, with arterial stiffness. We can argue here both ways that hypotension, vascular function, endothelial dysfunction will promote CKD and CKD can promote those 3 abnormalities.

Slide 43

These are the 3 groups and as you can see, that in premature children with normal birth weight you have really the same indices as the control group, the normal children. In the low birth weight you have a higher pulse wave velocity and in fact, the pulse wave velocity is related to the Z score of birth weight. So I have to put forward to you that actually in this particular subgroup we should probably have pulse wave velocity as a mandatory tool of investigating these children at regular intervals and maybe to intervene with some measures.

Slide 44

Diabetes is another population and very early as you can see, there is a huge difference in arterial stiffness when we compare patients with diabetes even with early onset diabetes and with diabetes which has been going on for a short time.

Slide 45

But it’s not only diabetes because in this other study you can see that they’ve compared the non-obese insulin insensitive children, the obese insulin sensitive and in fact the only groups that show a higher stiffness are those groups with insulin resistance.

Slide 46

Can I do something? I have to address in my last two slides this idea because we’ve all heard about stiffness. Is this something which we can’t influence?

Slide 47

I’m not going to refer to adults we can discuss a lot about that, in kids we can do two very good things. First of all, we can look at the obesity which now is becoming a pandemic in kids. As you can see here that there is an important relationship between the way the pulse wave velocity changes related to the way the weight in children changes. So, if we manage to decrease the weight in children, the pulse wave velocity is going to be fantastically improved.

Slide 48

The other thing is sports and exercise and here is very nice quite recent data showing that in fact, if we have a good cardiorespiratory fitness, physical activity then the arterial stiffness is going to be influenced and there are some very nice data also in adults maybe the two other speakers can comment on that as well which can influence even our ESRD population.

Slide 49

I will conclude this data showing you that in fact, CKD and ESRD determine significant arterial wall structural abnormalities even at very young ages. When vascular wall is not affected by age-related atherosclerosis and arterial sclerosis. This is a very important issue because this somehow brings the message that uraemia per se is a disease and actually supports the data from Doctor Blacher that arterial stiffness is a stiffness related to uraemia and it is a nephrological disease. Look for augmentation index in born small and obese kids and obese adolescents and really we need consensus on calcium phosphate and on different treatments and I think that really the calcium-phosphate story has the most impact on arterial rigidity and through arterial rigidity it’s a tremendous impact on cardiac and cardiovascular morbidity.
So in the end I would say and probably as a conclusion to this symposium save the vessels and not the heart. Thank you very much.

Slide 50

Chairman: Thank you very much Doctor Covic actually as you said this is a very nice conclusion but we have time just for one burning question please.

Question: Very nice presentation. I have just two remarks. Concerning intima-media thickness which is usually normal in these patients as Adrian very nicely showed but vessels are dilated, they have an outward remodelling so if you measure not the intima-media thickness but intima-media cross-sectional area it will be increased.

Prof. Covic: It’s true we did that and actually it’s highly dilated compared to kids.

Question: The second point which was very nicely illustrated that underlines is the role of in babies at least of the body size, the height. If you analyse augmentation index with age and Adrian has shown that it increases till the age of 60 and remains stable but in young babies, the augmentation in newborns until 2, 3, 4, 5 years usually augmentation index is high. It was very nicely shown by Australians and this is due to the fact that they are not tall, they measure 50, 60, 70 cm and body height is low and augmentation index is high. So what you said is very important always consider another index which is associated with augmentation, its body size.

Prof. Covic: Yes one of my conclusions to this symposium, you’re right would be the fact that really we have to look at augmentation index and pulse wave velocity are always done with the same sort of measurements so that’s very simple in fact but then also look at the vascular calcification plus intima-media thickness and these four parameters probably you have the entire story of the vascular pathology.

Chairman: So thank you Professor Covic, thanks to the audience, thank to our wonderful lecturerers and we do hope we have got a better insight to all these parameters for the risk in ESRD population. Thank you very much.