WESTERN EUROPE: THE CHALLENGE OF AN “OLDER AND SICKER” POPULATION

Francesco Locatelli, Lecco, Italy

Chair: Adrian Covic, Iasi, Romania

Netar P. Mallick, Manchester

Prof. F. Locatelli Dipartimento Nefro-Urologico Ospedale "A. Manzoni" Lecco, Italy

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Slide 1

Thank you Adrian, Sir Mallick, Ladies and Gentlemen. It’s a great pleasure to be here to discuss this topic.

Slide 2

I think that we have a sort of agenda of my presentation, so we’ll try to discuss several points, point by point in order to try to have some answers to the different questions.

Slide 3

As Professor Zoccali underlined before we have to start with the increasing number of incident of dialysis patients.

Slide 4

And just to have an idea we’ll start with the Lombardy Registry. You can see here now we have more or less 170 patients starting dialysis each year and the situation has dramatically increased, if you just compare 1994 where the number of the patients was 115. So I think that the situation is really, absolutely important.

Slide 5

If you are looking at the situation in the United States, you can see here the number of the patients per million population is 340. Comparing the data with the Lombardy Registry, when we have 68 patients for million population in 1985 and in the United States the number was 125 really we thought it was impossible, this number was absolutely enormous, impossible to reach and now you can see here that the situation of the Lombardy in 2003 is with 172 patients much more than the number of the patients in the United States in 1985. So I’m a little bit worried about the fact that in the near future we’ll reach probably the same number of the patients that the United States have reached now. So I think that this is something very important to take into consideration and to try and discuss.

Slide 6

But the real problem is what can we do to manage the chronic kidney disease progression to end-stage renal disease?

Slide 7

So we are very aware of the fact that we have the JAFAR, the previous slide was related to the Jafar trial underlying the fact that ACE inhibitors are able to slow down the progression of chronic kidney disease.

Slide 8

But in the Lancet this metanalysis was published that in some way was toning down the optimistic point of view to try to slow down the progression of chronic kidney disease considering that the trials in favour of this inhibitor were in some way balanced by the ALLHAT study that was for sure dominating this metanalysis. So again this situation is not clear at all because I think that when we have a metanalysis with so many patients inside 24,000 while for the other trial the number is rather small, it’s very difficult to have a conclusion because this metanalysis has just underlined the results of the ALLHAT study without any new information on the field.

Slide 9

But very recently we have looked, just to have an idea, at the paper published in KI about the possibility to slow down the progression of kidney disease in the community-dwelling elderly patients. This was a cohort of 10,000 subjects, 65 years, 66 years old or older. We know which is the decline of the renal function over 2 years.

Slide 10

As you can see here, there is a different situation according to the different GFR. The progression of the disease was in a different group in patients with GFR between 60 and 90 was just 0.6 ml/min in females without diabetes but you can see here the number according to the different epidemiological situation. Of course, when the progression was higher in the patient population between 30 and 60 and of course, in cases of baseline creatinine clearance, GFR less than 30 the progression was higher going from 1.8 in females without diabetes to 3.2 in males with diabetes. But you can see here that looking at the use of ACE inhibitors and Angiotensin 2 receptor antagonists the situation is striking because the percentage of these drugs in the patient population between 60-90 was just 35, while it was 65 in the patient population with GFR less than 30.

Slide 11

So, of course, the interpretation could be different according to the different points of view. So my editorial comment to the situation was to underline that for sure, there is an increase in the number of the patients affected by chronic kidney disease that are elderly and for sure, we have a very small percentage of the patients that really progress to end-stage renal disease while there are many patients that die before the stage of end-stage renal disease is reached and this is largely due to the cardiovascular disease. For sure this underscores the urgent need for cardiovascular prevention even more important even the renoprotection particularly among the elderly patient population with chronic kidney disease.

Slide 12

Of course, according to the number of the ACE inhibitors/Angiotensin II receptor blockers that we saw in the previous slides, my comment was that this raises the question of whether we should reconsider the role of renin-angiotensin system blockade as a means of protecting against the progression of chronic kidney disease, at least in the context of the elderly population because the situation is completely different with glomerulonephritis as Professor Zoccali underlined before because in the elderly population the burden of overt proteinuric nephropathies is believed to be lower than in other populations and for sure, there is the risk of the potential deterioration of the renal function because these patients, for sure, are not selected as in the trial for the prevention of renal atherosclerotic lesions and very often they are using together diuretics and non-steroidal anti-inflammatory drugs. This is an important point.

Slide 13

So in my view it can likewise be argued that the epidemiological surveys should be analysed more cautiously because maybe we are, according to some comments, we have too often claimed that the reduction in the number of patients reaching end-stage renal disease was due to the increasing administration of ACE inhibitors and angiotensin II receptor blockers particularly in the elderly population.

Slide 14

But considering our comment we received this letter to our editorial comment underlining that of course there is the possibility of the bias of selections but an alternative explanation maybe that angiotensin II receptor blockers in general and the increased use of diuretics in the population with more progressive renal disease led to hemodynamic-mediated declines in GFR. So, of course, the point of view could be completely different but it is, for sure, I would like to underline that it is not so clear that we’ll have the possibility to reduce the progression of chronic kidney disease in the elderly population using the new drugs.

Slide 15

So I think that we need, for sure, to have a prospective randomised trial in this patient population because the data that are available are related to glomerulonephritis, proteinuric patients where we did a selection for avoiding to enrol patients with possibly stenotic artery disease, particularly related to renal artery disease. So I think that this is very important practice also because we should remember, for example, the lesson of the RALES study about the risk of hyperkalemia in this patient population when the results of the clinical trial are translated in every day clinical practice. So I think that is a very important point to take into consideration. Clearly I’m not against the use of ACE inhibitors or angiotensin II receptor blockers but I would like to underline that it is not easy to translate the results of the younger patient population with proteinuric disease to the present end-stage renal disease population we have to deal with in everyday clinical practice.

Slide 16

For sure, you should consider, for example, in the Lombardy that the number of glomerulonephritis has for sure is declining year by year while the number of vascular disease is increasing, as was the problem of the diabetic patient population.

Slide 17

So, for sure, dialysis population is every year an older and sicker population.

Slide 18

And you can see, for example, these old slides underline the so-called ageing index in our population and just in 1983 you can see here the number of patients between 20 and 44 were absolutely the same and maybe even a little bit higher but the number of patients more than 64 years old.

Slide 19

You can see here for example the age of incident dialysis patients is now we have the majority of the patients starting dialysis older than 65 years, you can see here and the mean age of the patients, the incident patients is 66 years.

Slide 20

So I think that is something very important to take into consideration and the same is true around Europe because, of course, Adrian will discuss about the East part of Europe but, of course, here you can see in France the percentage of the patients with more than 65 you can see here is very important. The same in Germany, in Italy we’ve already discussed the problem. In Italy the general population is very old, so we have more or less the same problem and the same is true also in Spain. So it’s not just a problem related to the single country but it’s the same problem around Europe.

Slide 21

You can see here the cardiovascular condition among the new dialysis patients in the United States and the congestive heart failure, for sure, is present at least in more than 30% of the population and coronary artery disease in 25% of the patient population with myocardial infarction very close to 9, peripheral vascular disease 14% and central cerebrovascular system problems are more or less 10%. So all together we have very, very important comorbidities in our patient population.

Slide 22

Also in Lombardy, you can see the number of congestive heart disease is increasing year by year just to demonstrate that the problem is absolutely the same around the world.

Slide 23

And here, for example, we have an idea of the prevalence of occult coronary artery stenosis in the patient at initialisation of dialysis and considering 30 stage 5 CKD patient with no previous history of angina or myocardial infarction, you can see that the prevalence of the stenosis was very important with the coronary artery stenosis with 1 vessel affecting more than 62% of the patients and 2 vessels were present in 25 and 3 vessels atherosclerotic lesions representing more than 12% of the patient population.

Slide 24

Also the diabetic problem, the problem of the diabetic nephropathy where in general diabetes is increasing everywhere particularly, for example, you can see it’s very well known the situation in the United States but what is dramatically increasing is the situation in Germany and also in Italy the situation is much, much worse than it was 20 years ago. 20 years ago we had just 7 patient % in our population now we are very close 20% for the incident patients and 16% for the prevalent patients. So I think that it’s a very important problem.

Slide 25

Also considering the DOPPS study and the prevalence of cardiovascular disease around the world, you can see here that the problem related to the vascular disease is the green bar in Europe is absolutely important, is very close to the United States while the situation in Japan is much, much better but just to have an idea that the real problem of the vascular disease.

Slide 26

Normally, you are not aware of this problem because if you look, for example, at this randomised controlled study, membrane permeability outcome that was just closed now, at the baseline the number of the patients with vascular complications, coronary artery disease, congestive heart failure or peripheral vascular disease was absolutely low and just to have an idea we compared the same countries enrolled in the MPO study, you can see this was a randomisation of the patients in the real practice, clinical practice, you can see that the percentage of the patients with complications is much, much higher.

Slide 27

Here, just to have an idea, we’ll have a look at the presentation that was here in Glasgow about the ORAMA trial comparing the East and West situation.

Slide 28

You can see here, anticipating maybe a little bit the presentation of Dear Adrian, I don’t know if you are discussing this point but I would like to underline the difference in age between the 2 groups, 64 versus 55 and the percentage of the patients with diabetes was 38 in Western Europe and 16 in Eastern Europe. So I think that is the major difference together of course with the use of beta-blockers was 48 in Western Europe versus 42.

Slide 29

So just to have an idea that the situation is rather different in the different countries, so also was in some way the difference in the underlying disease, for example, in Western countries the percentage of GN is much higher while it was the opposite for diabetes as you can see here is very clear. So I think that the situation is really different in the different countries according to the previous tradition, the previous economical situation and the present economical situation too.

Slide 30

But what do we have to do to try to improve the dialysis outcome of our patients?

Slide 31

I think it’s not very easy because we know, for example, that an increase in the haemoglobin level was not successful and the Besarab trial clearly demonstrated that it is impossible to improve the outcome of our patients trying to normalise the haemoglobin level of our patient population, even if there is some discussion about the results of this trial considering what was in patients with cardiovascular disease and 67% of grafts in the control group and 66 or 67 were more or less. So the number of the grafts was impressive that is absolutely not in agreement with the data we have in Europe where the percentage of the grafts normally is less than 5%.

Slide 32

So I think there are factors to be discussed in this situation also because strangely enough for the same level of haemoglobin the mortality was much higher in the group randomised to the normalisation.

Slide 33

So I think there is something to discuss but the message is clear, at least in patients with graft and cardiac disease, not to try to normalise the haemoglobin level and in any case the Parfrey trial that was a randomised, double-blinded trial in patients with very a recent start of hemodialysis in absence of symptomatic cardiac disease and left ventricular dilatation have as a primary outcome the left ventricular volume index again separating the haemoglobin level in the two groups.

Slide 34

The control group maintained to 11 and the experimental group was randomised to reach 13 g/dL.

Slide 35

You can see here the difference between the two groups but unfortunately, no possibility to improve the cardiac situation in this patient population.

Slide 36

While there was just an effect on quality of life.

Slide 37

So I think that the primary end point of ameliorating the cardiac disease was absolutely unsuccessful in hemodialysis patients. So I think that, as we heard before during the presentation of Kai-Uwe Eckardt about the recent publication of the K/DOQI guidelines I think there is no reason for increasing the haemoglobin level in our patient population, at least not more than 13. Here we have the data from Cice.

Slide 38

We published the paper on the effect of carvedilol with the possibility to increase the survival in our patient population with beta-blockers.

Slide 39

And I have also this data demonstrating that using angiotensin II receptor antagonists added to the ACE inhibitors there was the possibility to reduce the cardiovascular mortality.

Slide 40

And the hospitalisation related to the congestive heart failure. So I was impressed with it because while the majority of the trial in the membrane, in the use of haemoglobin and so on was negative, the trials using beta-blockers and angiotensin II receptor antagonists were absolutely positive in this patient population.

Slide 41

You can see here also this study, this is a Japanese trial that is not very strong from a methodological point of view but in any case it’s supporting the Cice data that the use of angiotensin II receptor antagonists are able to increase the survival in the patient population on dialysis in different countries.

Slide 42

So I think that is a confirmation, it is not strong but in any case this is a confirmation of the fact that the approach using these drugs could be very useful in this patient population.

Slide 43

But at the same time Christoph Wanner published in the New England Journal of Medicine the results of the use of statins in patients with type 2 diabetes on dialysis.

Slide 44

And unfortunately, you have to trust me the effect of statins was negative, absolutely negative.

Slide 45

No effects of statins.

Slide 46

And of course, looking at the causes of death in the dialysis patient population we have a very large percentage, the yellow part of the cardiac disease.

Slide 47

But looking at the effect of the cardiovascular disease we have 5% of stroke and 43% of cardiac disease.

Slide 48

But that is a very important point 27% of these causes of mortality are related to cardiac arrest and arrhythmias, so the possibility to improve this patient population using statins is related just to the acute myocardial infarction or the other cardiovascular disease and in percentage this is less, this is for sure approximately no more than 10% of the other causes of mortality.

Slide 49

We also have some data suggesting that considering that the population is getting older and older that in patients more than 65 years old that might be using drugs that without calcium for controlling hyperphosphatemia, this is the subanalysis of the DCOR trial where there is some possibility to improve the survival in this patient population but unfortunately, this is just a secondary analysis and the primary end point was absolutely negative.

Slide 50

So what can I say in conclusion? For sure we have the situation in Western Europe where the dialysis patients are getting older and older and we have a patient with a lot of comorbidities including cardiovascular disease and diabetes, for sure, this is the major problem. So I think that we should have a multifactorial therapeutical approach in order to try to improve the outcome in our patients and particularly, we have, now we need trials for proving the efficacy of the standard drugs also in this patient population and particularly, as far as the prevention of the cardiovascular events because we are very well aware of the fact that now the prevalence in chronic kidney disease patients of the elderly subjects with no proteinuric nephropathies may raise the question  of whether we really need a large-scale renin-angiotensin system blockade in order to be sure that these drugs are really useful in slowing down the progression of chronic kidney disease and the cardiac disease without creating new problems related to the general applicability of these drugs in everyday clinical practice. Thank you for your attention.