Slide 1

Thank you very much Pepe. It’s a pleasure to be here and what I will be talking about is chronic kidney disease in a hypertension unit just to avoid overlapping with the following speakers. Well, the answer to the question which is present in the title of my presentation is directly no because I’ll try to show you that nowadays with a relevance of chronic kidney disease and in particular with an increased cardiovascular risk accompanying we need to control blood pressure and we need ancillary properties of antihypertensive drugs in order to make sure that we protect both cardiovascular and renal. This slide summarises what Victor Dzau described initially in ‘91 which is the cardiovascular continuum. Nowadays, this is the cardiorenal continuum and from the clinical point of view we can distinguish 3 different stages in this continuum. The first one is that in which we only see risk factors and these risk factors, I’m going to show you how these factors are common for the kidney and for the cardiovascular. So the same factors are damaging the kidney and damaging the cardiovascular in the hypertensive population.
The second stage is that in which if we look forward in an adequate way we find the presence of target organ damage in the hypertensive population and chronic kidney disease is a very important part of this target organ damage. Once chronic kidney disease develops, new risk factors arrive, risk factors which depend on the presence of chronic renal failure and these risk factors provoke an increased velocity of progression in cardiovascular and in renal disease. As you can see, with the passage from the first to the second atherosclerosis is more and more important and then comes the third stage in which this target organ damage becomes symptomatic in the case of the kidney, in general this third stage is characterised in particular by the presence of proteinuria that as you know is an excellent predictor of cardiovascular risk and you know very well that this is a very important predictor of what is going to happen to the kidney.
Finally, eventually the patient gets to end-stage renal disease and death which can’t be considered as similar because without dialysis if the patient gets to end-stage renal disease, he will die.
You see here 3 words: prevent, regress and retard which is relevant because depending on the stage the best we can do is retard, regress or prevent.

Slide 2

Well, the relevance of chronic kidney disease beyond what happens in the kidney is what happens with the cardiovascular of the patients. This inverted triangle represents the three stages. Number one, cardiovascular risk factors, the highest, a lot of people are included here. Number 2, target organ damage is present and undetected, the number of people is lower. Number 3, those with advanced cardiovascular and renal disease, the numbers are smaller. Here the cost that you see here is the highest but then the most important thing or one of the most important things we can do in clinical practice is to detect the presence of chronic kidney disease in any patient, independently of whether he’s hyper or normotensive or whatever because it will allow us to classify them as at least being in a stage 2 or maybe in a stage 3. The important point is that if you look at here percentage of events, 3 in 4 take place in patients which theoretically are classified as being a stage 1 and 2. In particular, if we classify them as having chronic kidney disease, patients will be here or will be here and nowadays we know that intervention has to be the best one for patients in a stage 2 and in a stage 3. When I refer to the first one, I refer to an integral coverage of cardiovascular and renal risk.

Slide 3

This slide contains data showing you that when we move from the whole general population of hypertensive to inside in which we included patients with one or more risk factors to HOPE which is the epicentre of cardiovascular risk and to what happens in a hypertension unit, you see that the degree of renal involvement preferred to serum creatinine or to estimated creatinine clearance goes up with increasing cardiovascular risk so both are connected. Remember that the two main causes of end-stage renal disease are diabetes and hypertension and I don’t need to tell you how relevant these are for cardiovascular disease.

Slide 4

Well, you don’t need to read this list but these are markers for cardiovascular or chronic kidney disease or risk factors and they are exactly the same. So, if someone has or we detect the classical cardiovascular risk factors, pay attention because that patient is at a higher risk to develop chronic kidney disease. Then genetics is in charge of differentiating who are those patients who finally will develop chronic kidney disease and eventually, will get to end-stage renal disease.

Slide 5

So I will review with you some of the concepts in these three stages, the stage in which we can retard, Dick is going to come later on with data referred to the big trials which have been conducted in renal disease for sure, I only want to remind you that all the things that we know in general take place including patients with renal diseases and proteinuria, otherwise we cannot come to a conclusion because the time needed to come to a conclusion about the evolution of renal failure is too long.

Slide 6

But anyway these two studies have been seminal in order to say that we need suppression of the renin-angiotensin system to protect the kidney in diabetics and the difference has been very significant but look at this, the decay in GFR per year, there is still some room to do something else so maybe the capacity to really do more is relatively small but talking about the need of controlling blood pressure in these patients there’s no doubt.

Slide 7

But the need for a better suppression of the renin-angiotensin system we are looking for this and this is an example, the COOPERATE study, you know it very well, a combination of ACE plus ARB did better than any of the two.

Slide 8

So this is in the case of patients with proteinuria. What happens in those without? This is data from our unit, here you see the evolution during more than 7 years, so the time required to see differences in those without proteinuria or with small amounts of protein in the urine might be some of those who had microalbuminuria but you see that when we have used an ACE inhibitor and these are data we published in Hypertension 6-7 years ago for the renal outcome there is a clear difference. In other words, the presence of suppression, if the time lapse is long enough, it is also good.

Slide 9

There is some confusion which has been induced by the fact that examining renal function in big trials in hypertension like ALLHAT or INSIGHT or whatever, has come to create some confusion because it seems that suppression of the system is not good apparently according to the data from ALLHAT but this data you must consider that the analysis is not adequate to consider an estimated GFR to see what happens in renal outcome maybe it’s not the best way to do it. Considering the evolution to end-stage renal disease the number in those studies has been really very, very small. During this stage when advanced cardiovascular and renal disease is present, the control of blood pressure is extremely relevant. You see this data from VALUE study a difference of 3.8 mm/Hg during the first 3 months of the study drove enormously the number of cardiovascular events in favour of amlodipine because the control of blood pressure was better. So, a small difference accounted for the very much increased prevalence of cardiovascular events and death.

Slide 10

So no doubt that controlling blood pressure is important but when the cardiovascular disease is advanced and you have data in heart failure in post-MI but you have data in patients with a high risk like HOPE or EUROPA or a relatively high risk as in PEACE in which the administration of an ACE inhibitor was very positive for the cardiovascular. These patients of PEACE, HOPE and EUROPA the risk of those with chronic kidney disease or proteinuria is as high or even higher. So no doubt that you need to control blood pressure but you need to suppress the system. If you prefer to consider that for the kidney blood pressure is enough that’s ok, no problem but for the cardiovascular you need ACE inhibitors or ARBs. On the contrary, this is my opinion you need suppression of the system both for the renal and for the cardiovascular continuum.

Slide 11

Second stage, regression is possible, regression of microalbuminuria in this stage is very important.

Slide 12

LIFE study showed that, Ibsen published in Hypertension, that the decrease in microalbuminuria impedes the progression to cardiovascular events and death so by decreasing microalbuminuria we are protecting the cardiovascular but we also see that we can impede as Hans Parving demonstrated in the IRMA study the progression to overt diabetic nephropathy and even more we can consider and MARVAL was a nice example that we can try to normalise the albumin excretion of our patients. We don’t know exactly what happens with normalisation but my intuition says that if I normalise the albumin excretion of this patient this will be good.

Slide 13

But what is important is that long-term follow up of these patients you see here the data from the LIFE study and you see here the capacity of losartan and atenolol to decrease albumin excretion but it seems to get exhausted with time so the disease progresses anyhow. So we need blood pressure control but probably the best argument in favour of improving suppression of the system is this, with time we will probably need better suppression.

Slide 14

So the up-titration of ARBs this is the example of Hans Parving, 900 mg of irbesartan are better but many other examples are available. So long-term evolution of microalbuminuria is telling us that probably a better suppression will be required.

Slide 15

Now, I will move to renal function. This is data from the HOT study we published in JASN and for the first time I think we used the magic number of 60 ml/min and those who were on this exhibited for all these cardiovascular events a clearly increased risk. This has been repeatedly shown in many other studies in hypertensive patients.

Slide 16

This is data that will appear published next month, in the VALUE study we performed a head to head comparison between the MDRD formula and Cockroft-Gault. In Europe you know and in particular in the cardiovascular field Cockroft-Gault has been used for most papers published looking at cardiovascular outcome in the presence of renal disease. In the VALUE study we showed that the MDRD formula for primary end point MI, congestive heart failure in particular not for a stroke but for these three MDRD was significantly better by its capacity to predict the future development of cardiovascular events and death indicating that this is the correct formula to be used.

Slide 17

Well, what happens when we follow our patients with arterial hypertension and they develop finally, or they cross the line of 60 ml/min? These are data from the unit and you see that those in whom we saw that measured creatinine clearance with 24 hours during collection, chronic kidney disease developed with time, the percentage of cardiovascular events was 40% as compared to 13% during the follow up which was around 12 years by mean.

Slide 18

So a long-term follow up indicates a cross in the line is important. These are data we published in JASN and in the same paper we could see that those receiving an ACE inhibitor the cardiovascular outcome was significantly better as compared to those who did not. So, here again suppression of the system was good as you saw to prevent the decay in renal function but also to prevent the development of cardiovascular events.

Slide 19

These are data from the PEACE study. The PEACE study has shown the relevance of chronic kidney disease for cardiovascular outcome and therapy with suppression of the system. Those patients in whom estimated GFR was above 60 you see that there was no difference between trandolapril and placebo but you see that for those below 60 the ACE inhibitor did significantly better indicating again that the situation of chronic kidney disease is particularly suitable in order to suppress the system but the same has been shown for statins and the same has been shown in the HOT study when we analyse the effect of aspirin for those with chronic kidney disease. Aspirin prevented in particular the development of myocardial infarction.

Slide 20

Now we arrive to prevent, prevent is the best, if we prevent in an adequate way the development of target organ damage, we will retard the cardiovascular and the cardiorenal continuum.

Slide 21

No doubt that Giuseppe Remuzzi showed in the BENEDICT study the relevance of primary prevention of microalbuminuria. Other studies are marching on and we will know more about this. Let me remind you something, arterial hypertension is a disease of peripheral resistance as it was defined this many years ago.

Slide 22

These are data from Ernesto Schiffrin and you see here that equal blood pressure levels hypertensives or diabetics with hypertension, you see that blood pressure is equal but the change in resistance arterioles obtained by gluteal fat biopsy, you see that the wall: lumen ratio is significantly more damaged in those with diabetes and hypertension as compared to those with hypertension alone and for sure as compared to controls.

Slide 23

But I can imagine that resistance arterioles in the gluteal fat are not too far away from the number of arterioles that are present in the kidney which are a bunch of arteries. Remember 1/5 of the total peripheral resistance is dependent on the kidney. Then, regression of these changes is very important and so suppression of the system has been shown to be really good to suppress this.

Slide 24

You see here data with olmesartan in this case showing that they regress the changes and they come back to a situation of wall: lumen ratio in this arteriole similar to that of the controls indicating that we have done the best. For sure these changes in my opinion can be applied to the kidney.

Slide 25

What else? Suppression of the system in this stage has been shown in humans to change in a positive way all the proinflammatory factors in blood like C-reactive protein, TNF-alpha, IL-6 or MCP-1, so indicating that we are doing something good probably for impeding the development or progression of atherosclerosis.

Slide 26

But at the same time changing oxidative stress is good Emma – published this data and this is a renal excretion of isoprostane PGF 2 alpha which is a marker of oxidative stress in the kidney and you see that suppression of the system decreases it, so in this initial stage I would say that’s important.

Slide 27

What else? Metabolic syndrome and cardiometabolic risk is more and more known and the relevance of this for hypertensive patients is well recognised nowadays. This is data from our unit, data that will be published in the Journal of Clinical Hypertension. Those with and without metabolic syndrome equal blood pressure control but 3 years later what happens? There has always been a positive change in microalbuminuria because 90% of our patients are on an ACE or an ARB but look at this. Those with metabolic syndrome, 1 in 4 present microalbuminuria as compared to only 1 in 10 in those without metabolic syndrome and the percentage of those developing new onset diabetes significantly higher. So we need to do something else. Maybe this could be a new occasion to really improve suppression of the system considering also that in these patients we need an integral protection of cardiovascular and renal and maybe new drugs that are coming could be positive for this.

Slide 28

So considering the type of therapy in these initial stages is relevant because when you see those patients with metabolic syndrome or prediabetes, you see here the difference in value between amlodipine and valsartan to prevent development of new onset diabetes and this is a new objective of great prevalence for the future. Same data in a study George Bakris published this in Diabetic Care even if we consider the combination maybe there could be a differences and the combination of an ACE or and ARB plus a calcium channel blocker could be significantly better.

Slide 29

This is the development of new onset diabetes and you see that the yellow columns are the combination of an ARB plus a diuretic, significantly worse in percentage as compared to the combination of an ACE plus a calcium channel blocker. So maybe all these are targets that we need to do the best that we can in order to regress or to prevent in this case the development of renal and cardiovascular damage and of course, the development of new onset diabetes.

Slide 30

This is the last of my slides. So allover the cardiovascular continuum we need to do two things. We need to control blood pressure and we need to suppress the system. But you see our capacity to see which are the good effects of this are limited here but at their highest in the initial stages. I took profit from this slide that Alberto Zanchetti published in the Journal of Hypertension where you see that the earlier we start the therapy, the better will be the outcome of our patients. So coming back to the question, no doubt the question is totally useless nowadays, we need both, to control blood pressure and to take profit from any ancillary properties of the different drugs and in particular, suppression of the renin-angiotensin system. Thank you very much.