Slide 1

Thank you very much.

Slide 2

I think that my task is much, much easier considering that many topics have already been discussed but I think that one of the most important points to underline is the exclusion of chronic kidney disease patients from clinical trials. I think that this is why looking at the information we have in the literature, you can see that the percentage of the patients excluded from end-stage renal disease is approximately 80% and in any case also in chronic kidney disease we have 74% of the patients excluded for the trial.

Slide 3

But you know that the starting point of the story was the MDRD trial where we realised that when we are starting the antihypertensive treatment, there is always a reduction in GFR. I think that it is important to take into consideration this point particularly now that we have to deal with very fragile people, the older people. So I think that this starting point is something to take into consideration even though we are very aware of the fact that later on we have a very great advantage in reducing the blood pressure values in our patient population. But I think that the situation is much more important now considering that the population is getting older and older.

Slide 4

So, we have the possibility to see the side effects of lowering maybe too quickly the blood pressure values.

Slide 5

But just from the patient’s point of view I think that it is important to know which is the potential advantage of reducing the blood pressure values. You can see from this post hoc analysis of the MDRD trial just reducing the blood pressure value from the two different groups, the higher group was 107, the other one 92 you can see that starting with a GFR of 40 ml/min, you can save more than 1 year free of dialysis just following these patients for 8-9 years.

Slide 6

So, I think the advantage of reducing the blood pressure values is very clear and what is even more strange in some ways but in any case important that looking at these patients 10 years later the effect of reducing the blood pressure during the trial was still persistent. You can see here the difference between the patient in the usual blood pressure value and the control value was important after more than 10 years is a sort of imprinting that the patients receive in order to be able to control the blood pressure values and in this way to reduce the progression of chronic kidney disease.

Slide 7

But also the information we receive from this follow up of the MDRD trial is related to the fact that even after 10 years, more than 10 years the effect of proteinuria is of paramount importance because in order to see a very major effect, a statistically significant effect, you should have a proteinuria of at least 1-3 g/24 hours, while it is very difficult to have in the top of the slide the significant effects of the drug when the proteinuria is very small. I think it is the message that in some way Dick and Luis before underlined very well in their presentations but I think that my task is to try to underline the difficulties now we have to translate the results of the trial with patients with very large proteinuria in that the majority of the present patients are normally with elevated blood pressure values but their proteinuria in many situations is very low indeed.

Slide 8

I think that this is something that you should take into consideration when we analyse the trial, so the follow up of the MDRD was suggesting that it is important to start the treatment as early as possible and of course, we fully agree on that but I think that it is impossible to give a demonstration of that just showing that when you start later of course, 10 years later 96% of the patients have reached the end point.

Slide 9

So, I think that it is almost impossible to tell the difference between the effective treatment and the start of treatment and standard treatment, if say the majority of the patients reach the end point. But of course, we are aware that the target of the blood pressure now with the publishing and updating the guidelines but what is important to underline that even 4 years ago it was very clear that in patients with diabetic renal disease you should reach a very low goal in controlling blood pressure values. At the same time, you should underline very clearly that adding on top benazepril to the standard, this was ACE inhibitor benazepril to the standard treatment, of course, we have the possibility to delay the need of dialysis of almost 4 years.

Slide 10

So, of course, this is not related to the ACE inhibitor per se because the control of blood pressure was much, much better in the benazepril group but this is in any case important for underlining that it doesn’t matter which is the mechanism, in any case adding an ACE inhibitor, as very well was underlined in the previous presentation, is able to delay the need of dialysis of almost 4 years starting from 40 ml/min and following the therapy for 10 years. But I think that analysing the data we can have very important information. Of course, using ACE inhibitors is important for reducing the progression of the disease. So, for example, analysing the patient with proteinuria between 1-3 g/24 hours, you can see here very clearly that the effect of ACE inhibitors is very important in delaying the need of dialysis. The effect is still present in the red lines when the treatment is performed in patients with proteinuria of more than 3g/24 hours.

Slide 11

But in the same time these figures clearly underline that the effect of proteinuria in the progression of disease is even more important than the treatment with ACE inhibitors. You can see here that the patients treated with ramipril in the red line is for sure the progression is sure much, much faster than in the patients with proteinuria between 1-3 g /24 hours. I think that it is important to see the difference between the ramipril group and the patients in the standard antihypertensive therapy. You can see that the progression of disease is faster in patients treated with ACE inhibitors, if the proteinuria is very high. So I think the message that was very well discussed before is that ACE inhibitors are not enough, you should in any case try to take into consideration as your goal the effect of reducing proteinuria.

Slide 12

We analysed in the AIPRI trial the effect of the control group, so this is a standard hypertensive therapy and the patient was treated with ACE inhibitors in this case was ramipril and looking at the effect of the proteinuria. So you can see here at the same level the blood pressure values the effect of ACE inhibitor was better than the control group, so there is an effect related to the blood pressure controls in the ACE inhibitors group but also there is a specific effect of the drug that is not so impressive but in any case is important.

Slide 13

So I think that is the major point of any kind of trial because there is a long discussion between is there a specific effect of the drug or is there just the reduction of the blood pressure values? I think that the presentation of Dick was very clear in underlining that both factors are of paramount importance.

Slide 14

This is because my topic was to take into consideration the metanalysis and I think that it’s very important to remember that in this metanalysis for sure, the Jafar metanalysis considering 11 trials together with approximately 1860 patients, you can see the end point in the ACE inhibitors was 7.4 % and in the control group 11.6%. I think that Dick very well underlined that we are not to be happy of the fact that we are able to reduce the number of end points but in any case, we have still a lot of work to do in order to try to better control these patients which in any case are progressing even when they are treated with ACE inhibitors. So, I think that is something important to take into consideration but considering that the previous speakers were underlining the advantages of this kind of therapy, but I think that it is important also to put some caution in treating these kinds of patients because this metanalysis was clearly underlining the advantage of reducing the blood pressure values.

Slide 15

You can see here as a reference having 110-119, you can see here there is still the possibility to increase the risk, if the blood pressure is lower. Of course, this is an association, there are many possibilities, many interpretations related to the cardiac disease of the patient but in any case, the suggestion of this metanalysis to be careful in reducing too much, too much I would like to underline the blood pressure values in this patient population not to aim for blood pressure, systolic blood pressure values lower than 110.

Slide 16

Again just for reinforcing the message of Dick, you can clearly see that the proteinuria in the metanalysis was for sure much lower in the ACE inhibitor group than in the control group suggesting that at least, a large part of the effect was related to the control of proteinuria. Further underlining this problem, you can see how important it is to control the blood pressure values when the proteinuria is equal to or more than 1 g/24 hours.

Slide 17

You can see here if you don’t control the blood pressure value when the systolic blood pressure is equal to or more than 160, you can see the relative risk is impressive having a reference value this one again between 110 and 119, you can see you have more or less 8 times the risk of the progression of the disease but in any case even at the level of 130 and 140, you can see that the relative risk is 3, 4 times higher than in the control group and again of course, particularly when we have a proteinuria equal to or more than 1 g/24 hours, there is a clear association between increasing risk and too low blood pressure values. So, I think please try to take into consideration to treat these patients as low as possible as Dick suggested but not too low.

Slide 18

Of course, the relationship between proteinuria and the advantage of the treatment with ACE inhibitors, the effect of ACE inhibitors is very clear when you have a very important proteinuria, we have the possibility to reduce the relative risk of progression of 80%. While when the proteinuria is decreasing step by step, you are reducing the potential advantage of using ACE inhibitors and when the proteinuria is less than 1 g/24 hours, you can see here that step by step the effect of ACE inhibitors is decreasing with the possibility it might be not to have such a large effect as expected in patients with proteinuria.

Slide 19

But I think that what is important to know in any case is that the number of the patients to be treated in order to try to save an event and analysing the data of according again to metanalysis we have to treat 21 patients in order to try to save one event or doubling the serum creatinine in this patient population and if you want to avoid the risk of dialysis or transplantation or death, of course the number of the patients to be treated is 26.

Slide 20

So I think that normally we are discussing all the large advantages of this kind of treatment but we should absolutely be aware of the fact that there is a lot of work to do in order to try to better preserve the renal function of our patient population because the unmet needs for these patients I think that Dick’s presentation was very clear in underlining the fact that we did get good results but we have a lot of work to do in order to try to improve the situation of this population.

Slide 21

One of the major questions we received during the meeting is: but is it possible to use ACE inhibitors even in the very late phase of the chronic kidney disease? I think this Chinese paper was important in trying to reply to this question because as you can see here in this Chinese study we have 2 groups, one group with plasma creatinine between 1.5 and 3 and the second group with plasma creatinine between 3.1 and 5. Of course, this was exactly the study we published with AIPRI  trial so the design was absolutely the same using benazipril. You can see here they treated the patient without any randomisation because they considered the result of our study strong enough to not randomise this kind of patient. What is important to underline that in this patient population the acute renal failure was present in 3 patients and hyperkalemia just in 1 patient but I think that I would like to underline that this are the side effects in a selected population, selected doctors, selected centres. So the general applicability of these results should be in any case very careful. In the patients with a plasma creatinine between 3.1 they randomised the patients but in any case you can see here the number of the acute renal failure doubled and 4 times more, of course, 1 versus 4 we have hyperkalemia but in any case they randomised the patients to ACE inhibitors and the standard antihypertensive therapy with a follow up of 3.4 years. You can see here this is the result of the group 1 treated with benazepril and you can see the survival was, of course, much better for the other group and this is just underlining the fact that the prognosis is much better when you had the patients with much preserved renal function but in any case even in this patient population with a very high level of plasma creatinine, you can see here the effect of benazepril ACE inhibitor in protecting the renal function was important indeed. So this trial is underlining the fact that you can use the ACE inhibitors also in very advanced phases of chronic kidney disease but, of course, you should be very careful following very correctly the patient in order to avoid the risk of acute renal failure and hyperkalemia.

Slide 22

But several times it was underlined the possibility to have a combined therapy and I would like to underline that the COOPERATE trial was important in demonstrating as is general opinion in treating hypertension that you’re not to stay, we have a single drug increasing the dosage and maybe also increasing the side effects while the combination of the two drugs you can see here is very important in reducing the end points.

Slide 23

Again, I think that this factor was reached at the same level of the control of blood pressure values while the proteinuria was much, much lower in the combination therapy.

Slide 24

So, I think that is another important message in order to have another step for better controls in the follow up of our patients.

Slide 25

You can see making the same analysis that we did before about the number of the patients to be treated in order to avoid an event, you can see here that the final conclusion of this trial is that you have just to treat 8 patients for 3 years in order to avoid an event. So, combining the two drugs together in this trial we diminished the number of the patients from more than 20 to just 8 patients. I think that is very important because that is underlining that this combination is very useful.

Slide 26

We know already the results of RENAAL and the IDNT trial underlining the possibility to reduce the progression of diabetic II nephropathy, but I think that is another important point to underline that amlodipine was effective as placebo. So in case you need a calcium channel blocker to better control the blood pressure values there is no risk as in the past was several times underlined in many presentations about the fact that maybe calcium channel blockers were worsening the renal function and increasing the proteinuria. I think the message of this trial is that angiotensin II receptor blockers are important but also you can in case use the combination with calcium channel blockers in order to better control the blood pressure values.

Slide 27

But of course, not all the metanalyses are very good and we have to deal also with --- metanalysis and this is exactly an example of because the major point of metanalysis should be to have a sort of homogenous number of the trial but you can see here this metanalysis is clearly dominated for the older trial and analysing the number of the patients in the control group was 27000 and 24 000 were coming from the older trial. The same is true analysing the intervention group you can see 11 000 patients here as a whole and 9 000 were coming from the older trial. So this is I used to say that this is sort of chicken with some potatoes around. So the conclusion of the metanalysis --- is just the conclusion of the results of the old trial. But I think that in any case it’s important to take into consideration that nowadays probably we have to deal with a completely different population than in the past. Of course, we have some young people with proteinuria, glomerulonephritis and for this patient population I think the treatment should be the same as in the past we underlined very clearly but we have no trials in the elderly patient on the effect of the treatment in slowing down the progression of renal disease.

Slide 28

For example, we have this cohort study from Canada and you can see here that the progression of the disease in this patient population in 2 years was absolutely very slow, very low.

Slide 29

And you can see here females without diabetes the progression when the GFR was between 60 and 90 was very, very small, only 0.6 ml/min/year but in any case even when the renal function was less than 30 ml/min you can see here the progression was really very slow. Of course, it was faster in males with diabetes but in any case we have many people with the progression of renal disease was very, very low.

Slide 30

You can see here there should be great caution in analysing the database because in this case there is a clear association between the use of ACE inhibitors and the progression of the disease. So, I think that the message of the association was that ACE inhibitors maybe could be associated with the faster progression but in reality of course, the interpretation is very clear the other side around you use ACE inhibitors in patients who are the most progressive for sure. There is no discussion about it. But in any case analysing the change in GFR in this patient population, you can see here the percentage of the patients with no progression at all in these groups. So, I think that also the progression of between 1 and 0.5 ml/min was very important, the percentage was important in the different groups in the patients with let me say very well preserved renal function but also in the patients with very advanced chronic kidney disease.

Slide 31

So I think that the question mark in this situation is how to manage these patients according to the present data available in the literature?

Slide 32

Of course, we have a discussion that was the editorial comment that I published in this paper underlining the fact, of course, that you have to take into consideration the role of the renin-angiotensin system in this patient population at least in the context of such an elderly population. Of course, we have to take into consideration that normally the proteinuria is lower in this patient population and we have the risk of having a renal stenotic atherosclerotic lesion and of course, these patients normally use diuretics not steroidal anti-inflammatory drugs that in this patient population could be very, very dangerous.

Slide 33

Of course considering the situation all together you should take into consideration that preventing the cardiovascular disease is also a major problem, so you should balance the situation and give these patients the treatment but to be very cautious particularly in the early phases of the treatment.

Slide 34

But you know, I thought it was strong enough in underlining the risk of this kind of therapy but we received a letter saying that an alternative explanation will be that blocking the renin-angiotensin system and the increase of diuretics in this group led to a hemodynamic mediated decline in the glomerular filtration rate.

Slide 35

So I feel that debate is very strong and many, many nephrologists are reluctant in using ACE inhibitors in this patient population but of course, I think you should be very balanced to be aware of the risk particularly, now that we want to use together ACE inhibitors, angiotensin II receptor antagonist, maybe blocking the aldosterone system and some patients particularly the elderly patients are taking aspirin, non-steroidal anti-inflammatory drugs, so the risk of hyperkalemia is very important because you should remember the general application of the results of the RALES trial and the risk of hyperkalemia in this patient population when applied to everyday clinical practice.

Slide 36

Also the comments about the fact that the number of the patients going to dialysis is decreasing was in some ways attributed to the effect of ACE inhibitors but you should consider it analysing the data of the US registry that the number of the patients going on dialysis is decreasing for the population more than 80 years old.

Slide 37

So, I think that is an important message to take into consideration because we are very aware of the fact that the majority of the patients die before reaching the need for dialysis. This is true in the early phases of the chronic kidney disease where the risk of dieing is more than 20% higher than the risk of going on to dialysis.

Slide 38

But also in the very advanced chronic kidney disease you can see the risk of the end-stage renal disease is above all than the risk to go on to dialysis. I think that this is the same analysing the recent data published in JASN. I think you have more or less the same situation it doesn’t matter the race of the patient, the risk is for example, for the cardiovascular event, you can see here is absolutely of paramount importance.

Slide 39

So in conclusion for sure we know that nowadays hypertensive kidney disease together with type II diabetic nephropathy is for sure the leading cause of end-stage renal disease and these diseases normally are affecting the elderly patients and is characterised by very low or absent proteinuria. So I think that the data we have in the literature about the effect of ACE inhibitor angiotensin II inhibitors blockers is in someway impossible to automatically translate the results of this trial in this elderly population. I think that in any case you should consider the great advantage of this drug in preventing the cardiovascular disease, so the message is we have to use these drugs but to be very cautious particularly in the fragile population that we have to deal with nowadays.

Slide 40

Thank you for your attention.