Slide 1

Mr Chairman, Ladies and Gentlemen thank you for inviting me here to represent at last the children. I will discuss some problems. I will use Scandinavian and Finnish data as we are here in Stockholm but the trends seen there are similar to the – data and so on.

Slide 2

Now, many of the problems that we have in children are similar to the ones that we have discussed already for the adult population. One of the big problems is the availability of treatment for all ages in the world for treatment of ESRD and for renal transplantation.
In many places the small children are still excluded from active treatment even though the results are very good. The individualised immunosuppression that has been also discussed by the previous speakers is a question that is even more important, if you have a small child because you have to balance between enough immunosuppression and not in the long run having side effects of your immunosuppression.
I think one thing that we don’t know exactly how important it is for the small children are the cardiovascular diseases they may have because of the treatment they have early and then especially in the teenagers one problem is compliance.

Slide 3

Now if we look at the childhood population in the more developing countries, we see a lot of glomerulonephritis, we see HUS and so on when we have more infections there. In the developed world in children there are the obstructive uropathies that are everywhere, one of the most important causes of terminal renal failure and congenital diseases, they vary depending on the country where you come from or the part of the world, how common they are.

Slide 4

Now here if we look at the data from the Nordic countries representing about 400-500 children that have been followed for the last 20 years, you can see that there are some difference in our Nordic countries. You see that about 60% of the children that are transplanted are over 7 years of age but if you look at the younger age group, you see a marked difference. In Sweden and Norway about 20% of the small are represented by children under 2 years of age. In Finland 31% are under 2 years of age and this is of course, to a great extent because of the Finnish type of congenital nephrosis that is more common in our countries than anywhere else in the world. So we have been forced to specialise on dialysis in very small children and also on transplantation in very small children.
But surprisingly in Denmark there is only 1% which means there mustn’t be a very specialised centre for treatment of very young children. So depending on where you come from you have different possibilities to come into treatment.

Slide 5

Now, if we look at patient survival, almost everywhere and with every protocol in childhood the patient survival is very good over 90%. Here you can see the Helsinki data represented by about 200 children and you see 72 of them are less than 5 years of age but still the survival even though it’s the worst one but there’s no statistical difference is comparable to that of the older children. The children that have been lost in this age group are as reported from other centres also mainly because of co-morbidity. They had heart failure or they had some central nervous system disease, so it was not because of the renal problems that they died.

Slide 6

Now, everywhere also with many different protocols that we have at hand we can reach a very good graft survival here represented by the living related recipients over the 5 years and this represents about 20 years of experience in the Scandinavian countries.

Slide 7

Now, if we compare again, our different Scandinavian countries, we can see that there are some differences and this is also globally seen. You can see that living related donors are very common in Norway and Sweden and then we come again to my home country where most of the children get a cadaver donor. So there are differences in policy. The reason for this is perhaps that the results of our cadaver donors have not been so much worse than in the living related donor ones so that we haven’t had such a big motivation to actively talk for living related donation but as pointed out by the previous speakers, our cadaver donors are getting older and older and 15 years ago the mean age of the cadaver donors was about 35, 36 years because the younger ones were collected to the children but now the mean age is 45 years. So if you give a kidney that is very old to a child that is less than 2 years of age, that might be a problem.

Slide 8

Now today we have a lot of different immunosuppressants, we have antibodies, calcineurin inhibitors and antiproliferative agents and steroids. It’s very fashionable to use the strongest medication here. But the experience from different centres is that as long as you know how to use your immunosuppression, the results are really comparable. In my centre we use IL-2 receptor molecule antibodies, cyclosporine, azathioprine and steroids and then we individualise the immunosuppression as I’m going to tell you a little bit later depending not only on protocol biopsies but also on the renal function because we regularly measure the GFR and those together decide how to proceed in the future with the immunosuppression. So we have to individualise it to avoid the side effects and to still get enough immunosuppression.

Slide 9

Now one problem that also is seen in the – data is that the graft survival in the teenagers is worse than in the younger ones and here is the problem partly of compliance that is a very hard problem in my experience the only thing you can do is to support them and hope that they become responsible adults and once they do that then they take their medication and then the situation is stable but that is certainly a problem that we have with our young recipients.

Slide 10

Now, one problem that has also been discussed by the previous speakers is the one of progressive loss of renal function and as also pointed out before there are immunological factors, the match, the immunosuppression, possible infection that the patients may have that may cause a reduction in renal function in the long run. But then we also have the non-immunological factors that also have been addressed, the immunosuppression, the side effects of the calcineurin inhibitors. We have the graft age and then the special perhaps paediatric problem that has been addressed by the Stanford group during the last years is also the size of the kidney compared with the size of the recipient.

Slide 11

A request from our department showed in 2000 that when we compared the absolute GFR of the patients who were less than 2 years of age when they got their kidney and most of them got an adult kidney, they didn’t have an increase in their absolute GFR with age. Whereas, the older patients who got an adult kidney they had an increase in their GFR. The Stanford group has shown that if you put an adult kidney into a small child, you don’t get enough perfusion of the kidney and you get a defect there and that influences it in the long run and with aggressive fluids you can increase the renal blood flow and you can also influence the outcome of the kidney in the long run.
So here when we changed, this is actually here you can see the results from Helsinki between the GFR in the kidneys after transplantation and after 1 and a half years and these are measured GFRs not calculated, if you use the calculated ones you get better results. So these are measured ones and you can see that the mean GFR during the first one and a half years was that and then here we introduced some things, we introduced a protocol biopsy at 3 months and GFR measurements at 3 months. We saw some kind of immunoactivation in 30% of our patients and we did treat many of them. We also gave excessive fluids to the young ones. Through this intervention you can see that we were able these are the results of the children between 2000 and 2005 there are about 30 children in each of these groups, so you can really influence renal function with these measures. Of course, it’s a little bit hard to say what’s the influence of the young ones who got more fluids and what’s the influence of the protocol biopsies that were treated.

Slide 12

Now, with a reduction of renal function and also because of the immunosuppression, in children after renal transplantation as in adults you have the problem of hypertension, you have high cholesterols, you may have bone diseases and you may have growth failure that is a problem in our child population.

Slide 13

So one problem that I think we need to focus on and especially in the children if they are very young is the cardiovascular disease after renal transplantation. We know from adult studies that the mortality is about 10-20 times higher than in the normal population. The reasons for these vascular changes that develop after renal transplantation are many, partly they are because of vascular calcifications that may develop because of problems in the calcium phosphate balance, with problems with the vitamin D, if we have a high calcium and phosphate balance, we will get vascular calcifications in the media. We will also have problems that are caused by a high blood pressure, by immunosuppression, by the calcineurin inhibitor changes that have been demonstrated here and we know that many patients prior to transplantation, during dialysis and after transplantation have high lipid values which may contribute to the vascular defects. We don’t actually know how severe or common these are in children because it hasn’t really been studied in the long run.

Slide 14

Here you can see 300 patients who got a re-kidney or a liver or heart transplantation in Helsinki. They have been followed with lipid measurements from transplantation and here you can see that 50% of the patients during the first 5 years had high triglyceride values. You can see that they’re not extremely high. Here you have the normal with 1 and they are about double, it’s the same for all the organs. 40% also have a high LDL cholesterol. They seem to have a high cholesterol absorption and a low synthesis but 30% of our patients, renal patients have 3 metabolic risk factors for cardiovascular disease, so obviously they are more prone to that.
The values are not very high with the immunosuppression that we use which is very low dose every other day corticosteroids, for example, compared with other protocols. We don’t wean our patients off but we give them very little.
We could see that proteinuria, obesity, genetic predisposition meaning a high lipid -- prior to transplantation, age and high cyclosporine were risk factors for these lipid abnormalities.

Slide 15

Well what can I do? I think the most important thing is to propagate for a healthy life-style with weight control and active motion habits to restrict saturated fat and cholesterol and have an abundant intake of polyunsaturated fats.

Slide 16

Now, what about the changes in the skeleton? We have also been following with DEXA our patients from the beginning and our orthopaedic went through and looked at 200 of our transplanted patients, 230 of those had a renal transplantation and you could see that 38% of them had some type of fracture after transplantation and 61% of those were vertebral. So here you can see in the control populations how this is fracture free interval and you can see that the transplanted patients were much more prone to fractures and especially vertebral fractures not so much other fractures.

Slide 17

Here you can just see the growth of the patients and you see a growth spurt in all of them. Predisposing factors to fractures were male sex, older age and a higher body mass index also liver transplantation and in the patients who had fractures already prior to transplantation. So especially the vertebrae are important to follow after that. We are using bisphosphonates in some of the patients but we don’t know yet if that has an influence in the long run.

Slide 18

Growth is important for children and now that we can treat chronic renal failure better we can see that the height at transplantation has been increasing during the years everywhere in the world. It’s important to treat chronic renal failure aggressively and to see that you don’t have too much immunosuppression, especially the steroids.

Slide 19

One interesting observation coming from Hanover is that the living related donor-recipients seem to grow, this is cm per year and they seem to grow better than the ones who got a cadaver donor. They speculated that because graft function was better in the beginning the cadaver donors may have had some cytokine production that would have influenced the bone but I think there are technical problems with this study so we cannot really be sure if that holds true.
Growth hormone treatment is effective, that has been shown in several studies and increases growth. So considering growth after renal transplantation early diagnosis and aggressive treatment of chronic renal failure is of utmost importance. If the patients are short, one should give growth hormone prior to transplantation because otherwise there may be some problems with the immunoactivation. We have not seen that and individualised immunosuppression meaning low dose or low steroids are important. Here just to show the Finnish patients here you can see 85% grew well and those who got growth hormone also caught up during the next 5 years after renal transplantation.

Slide 20

Now, about shortage of donors. We can see that in Europe cadaver donors per million population.

Slide 21

Spain is famous for using most of them and there is a big variation.

Slide 22

To address this problem in Finland where we mostly use cadaver donors we have introduced a donor action programme that has been effective in many countries of the world. You’re probably familiar with that and it is where the centres do a medical record review. They go through all their deceased people and see if they have been used for donation or not and then there is a hospital attitude survey and as in many countries when we introduced this all over Finland our donors were increased with 50% but you have to keep reminding the people of the importance of this because otherwise the system does not work.

Slide 23

So today with many immunosuppressive protocols we can have quite good results. This young man had a urethral valve he has been on dialysis form birth. Here he is at 1 year of age with normal growth. He got a kidney at the age of 2, he is now 6. So we have to see that we maximise his treatment so he has a good future without any complications. Thank you.

Slide 24

Chairman: Doctor Holmberg I think that you said that you give steroids alternates? You give steroids on alternate days instead of withdrawing? Which is the proportion of paediatric centres nowadays that withdraw steroids as protocol, in paediatric?

Prof Holmberg: The proportion of centres that withdraw steroids? I don’t think there is any exact data of that but my guess would be that about 50% try to do it and some succeed but most of them who use them use them every day. We’ve always used every other day and we switch at 3-6 months.

Chairman: Any other questions? If not Doctor Holmberg thank you very much for this very clear presentation and to the audience for its active participation. Thank you very much.