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So Ladies and Gentlemen,

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we know that there is a heart failure epidemic and we know that in the general population here is data from America showing that over 5 million subjects in the US have heart failure and indeed there are a lot of patients that are diagnosed with heart failure every year.

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But the issue here is if there is a heart failure epidemic and a major heart failure problem in our renal population and we have heard that there are a lot of cardio-renal problems and we’ve heard a lot already about this congestive heart failure, should we address this in CKD and particularly in dialysis population? Well, in CKD from a population-based study, as you can see here, the combination between congestive heart failure and CKD was up to 44% and this is usually underestimated and is becoming more and more prevalent and in the eye of both cardiologists and nephrologists. Mind you these are patients or individuals which are admitted to community hospitals, so they are not coming from the SOLVD studies or from other cardiovascular trials.

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If we move now to the dialysis population and we look at the data from different famous studies, the HEMO study, the USRDS study database and some other studies, we can see a fairly important consistence here and the prevalence of cardiovascular disease, of congestive heart failure amongst these ESRD patients is around 30-40%. What is much more worrying in fact, is the important incidence of congestive heart failure amongst these dialysis patients. By far congestive failure is the most important cardiovascular phenotype in incident dialysis patients. This is important because we are all talking about pre-dialysis care. In fact, we have data showing that a proper referral to a nephrological unit, to a nephrologist actually diminishes this important prevalence and incidence of CHF and we’re not talking about particular fantastic special measures as you have heard but really about proper nephrological care.

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Let’s move a little bit to see what is the natural course of this disease.

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If we look at patients which are newcomers to dialysis, we can see that there are a lot of patients, half of them which never have had and never will have congestive heart failure.

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There are a lot of patients with CHF at the beginning which will be recurrent or non-recurrent and 17% of patients will have new heart failure, de novo heart failure and we should prevent that.

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But really what is heart failure? There is a new kid on the block in the cardiological world, it’s not in the renal community yet it’s already in the cardiological world. Here are the curves of incidence, of prevalence of heart failure with preserved ejection fraction and with diminished ejection fraction. As you can see, there has been a reduction over the years, in the last years of heart failure with diminished ejection fraction, so the classical heart failure which we’ve all learned at school and there is a tremendous increase and recognition of heart failure with preserved ejection fraction. There is a reason in our patients, there is a reason in the general population but there is a particular reason in our patients and Bernard Canaud actually showed you that when the left ventricular is stiff, then the atrial volume is a good marker.

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Well this is the reason, if we compare dialysis patients with controls, we see a lot of left ventricular hypertrophy but particularly we see a lot of fibrosis and this fibrosis together with the left ventricular hypertrophy is making the heart of our patients really stiff.

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So if this is the case, what is the prevalence of the diastolic dysfunction of the heart failure with preserved ejection fraction in our patients? We really don’t know and I think this is one of the important areas of the studies to be undertaken. We have only small studies and those were not really designed to assess prevalence. We have some figures which are worrying. In fact, it’s more than 40%, is up to 60%, it’s 40% in CAPD patients and form some data which are very small and very inaccurate it’s up to 70% in the haemodialysis population.

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Now, just a word of caution because really it is important to define correctly these conditions and the time of assessment is particularly important because time assessment means preload dependence of markers, of biomarkers or echocardiographic measurements.

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If we go again to our friends cardiologists, here are the recommendations from their societies on how to diagnose diastolic heart failure and this is a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction. As you can see, they suggest, for example, some fancy invasive hemodynamic techniques which we don’t use and they don’t use. But if we leave those, then we have really the new echo-Doppler techniques and in every hospital indeed we now have the tissue Doppler which has surpassed the classical echographic techniques.

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Together with that we have a lot of biomarkers and those biomarkers are centred really on the BNP because BNP reflects, as you have heard previously, the dilatation of the left atrium. The combination of Doppler techniques and biomarkers really can differentiate between left ventricular dysfunction with preserved ejection fraction. What is really the role of BNP? You’ve heard some data on the role of BNP but of course, BNP reflects both volume overload in our patients and left ventricular dysfunction and this was one of the big issues in our patients. We really don’t know what is left ventricular dysfunction, pure left ventricular dysfunction and what is left ventricular dysfunction because of volume overload.

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This is some nice data showing that in fact, we can have a safe cut off for the NT-proBNP with a decent specificity and sensitivity and moreover, which is much more important this actually translates and differentiates between patients with volume overload and without volume overload. Of course, that it is important to know when we should measure and that there is a huge difference between the pre-dialysis conditions and the post-dialysis conditions. But it’s fair to say that if you measure this at the pre-dialysis moment, then a 4000-5000 level mark is probably a good discriminator between patients with pure left ventricular dysfunction irrespective of the volume overload.

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Now, what about asymptomatic patients with systolic function? Let’s just come back to the systolic dysfunction and you heard a lot of data from the very famous group of Carmine Zoccali. In fact, they also looked at the best marker to really describe the left ventricular systolic dysfunction because we all use left ventricular ejection fraction or the fractional shortening index and their group actually and some others demonstrated that probably the best marker to look at the diastolic dysfunction is really the change in the mid-wall fractional shortening index. This is data showing that there is a nice discriminatory difference between a cardiac event when we are looking at this important parameter of the systolic function.

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Let’s not forget that we are all clinicians and we have the old good New York Association class, the NYHA class and in this study they have compared the NYHA class value to other scores of chronic disease such as the RDSS index and the Khan index. As you can see, that just applying regular NYHA class, then we have a similar discriminatory value compared with some other indexes which are much more important.

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Let me shift gears now and let’s discuss a little bit about the significance of this love-hate relationship between the heart and the kidney. Now, there are 2 sides of this story. The side on non-dialysis and the side on dialysis. This is again from a community study because we don’t want patients from large cardiovascular trials, these are fake patients.

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This is from a community hospital database and just by dividing patients in those who have CKD irrespective of the level of GFR and those which are devoid of CKD that there is a nice difference in survival.

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To the surprise of cardiologists and few nephrologists know that actually this is important, the GFR in fact is the most powerful predictor of survival and it is far better than the NYHA class, the ejection fraction, the blood pressure, the history of myocardial infarction, so on and so forth. In fact, for a cardiologist now it is clearly demonstrable that if you have CKD, it’s the worse news possible.

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What about diastolic dysfunction as bad news for him? Well the CKD associated mortality is even worse if you compare the hazard ratio for CKD associated mortality for different left ventricular ejection fraction, you can see that in fact when the ejection fraction is preserved but you have this diastolic dysfunction phenotype, then the increase in mortality is even higher. So it’s fantastic to look for this diastolic dysfunction even in pre-dialysis patients.

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What about the love-hate relationship in dialysis patients?

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This is really very bad news, this is a horror movie because if we compare the survival of these patients, patients on dialysis with congestive heart failure, this is really worse than the worse malignancies.

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By 54 months almost everybody in fact, not almost everybody is dead. As you can see, the survival at 1 year is 49%, the survival at 3 years is just 17%. We have very few cancers with such a green prospective.

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Now if the congestive heart failure is already there, is already pre-existing when the patient starts on dialysis, then the crude death rate at 90 days, so just 90 days when some of the registry data starts kicking in, is already 12% and in the first year is 36%. It’s a huge death rate, it’s a huge death toll.

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So clearly we have to act and we have these questions to answer. What is the best renal replacement therapy? Some data about anaemia, some data about standard care and how to treat diastolic dysfunction.

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This has been a nice debate the Pros and cons of haemodialysis versus peritoneal dialysis. In this debate actually together with Wim Van Biesen we have good pros and cons dialysis versus peritoneal dialysis.

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This is data from Stack et al which has been criticised of course, but let me show you that this is in fact, more than 100.000 patients and also let me show you that the PD patients actually have a better phenotype compared to the haemodialysis patients.

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If you look at the PD patients with congestive heart failure, then to be on PD means that you are at a higher risk to die, it’s a higher risk of about 50-70% which is completely different when you don’t have congestive heart failure. This is somehow contradictory with previous data in which the risk of development of de novo, the new heart failure is much lower on PD compared to haemodialysis.

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So how do you reconcile this apparent discrepant data? Well we all know that in fact PD is heavily dependant on volume and heavily dependant on the residual renal function.

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At the start of the PD when the residual renal function is ok then PD is probably better. But then when the residual renal function, when the diuresis ends, then the heart failure kicks in and in fact, probably it’s a higher risk for those patients to be on PD.

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You’ve all heard about nocturnal haemodialysis and new studies suggesting that long hour nocturnal dialysis is better for controlling left ventricular hypertrophy. This is a very small set of data, it’s ridiculously small just 6 patients but 6 patients with congestive heart failure. Just after 3 months, as you can see there was a dramatic decrease in left ventricular mass index and there was an improvement in some of the cardiovascular parameters and particularly in the heart failure related parameters. So the conclusion was that a better clearance of certain uremic cardio-depressant toxins or vasoconstrictor toxins may be at least as important as the fluid removal.

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We all now want to put our patients on the transplant list and those patients on the transplant list are the best dialysis patients. How do we compare those patients with the really transplanted ones? Well, the patients on the waiting list are still doing worse than the transplant patients, so indeed transplantation is probably the best solution because it offers a better survival even compared to those patients that are highly selected being on the transplant list. There are several explanations. Our group performed a cross-sectional analysis looking at the stiffness comparatively between PD, HEMO and transplantation and of course, transplantation corrects the stiffness in these patients to levels which are comparable to pre-dialysis, pre-renal replacement therapy figures.

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But one other possible explanation is how transplantation really corrects the uremic toxin syndrome. This is data showing that the time to new congestive heart failure is really dependent on the quality of the renal transplant. Better the quality of your renal transplant, then you will have a far better fate in terms of not having congestive heart failure. We all have an older and aging population. Those patients are with congestive heart failure or not. Well, if the congestive heart failure is absent, then there is no difference between renal replacement therapy and the patient which is not started on a renal replacement therapy. This is when the congestive heart failure is present sorry. So this is somehow disturbing because it means that it doesn’t help those patients to be started on the current techniques, at least in terms of survival.

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So there is no difference between patients, very old patients with congestive heart failure and patients without who haven’t been started on dialysis.

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We know this data from cross-sectional observational data suggesting that the left ventricular dilatation, the de novo cardiac failure and the recurrent cardiac failure are somehow related with anaemia.

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From this observational data we thought that correcting anaemia was the final answer, the final response until this kind of data.

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In fact, suggesting that normalising hematocrit, normalising the anaemia level is actually worse in these congestive heart failure patients.

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I will end up with drug therapies.

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We all know that it’s better from registry data, from cross-sectional data, to have our patients on an ACE inhibitor or on a beta blocker, as you can see here that there is a better survival but these are not prospective studies maybe we will do studies with this kind of drugs.

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If we take wisdom for the non-dialysis population, from the CKD, from the cardiological world, there have been only a few trials there with heart failure with preserved ejection fraction and what are the lessons from those trials?

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Don’t use digoxin, there is no use for that even in patients that are not on dialysis.

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There is a suggestion that using sartans actually is better.

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Also there is a suggestion that inhibiting the renin angiotensin – is better.

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In fact, these suggestions are almost true in a trial in dialysis because this trial is non-significant ,so it’s a negative trial but this trial was not powered enough and as you can see, there is a nice difference between the group treated with a blocker of the renin angiotensin – and the other the control group. So one lesson is of course, that we have to do correctly powered trials in the renal disease.

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I will end up with the proposal of the holistic approach. What is the holistic approach? This is data from just a single centre. 200 patients and they optimised the combination for congestive heart failure therapy with beta blockers, ACE inhibitors or sartans. They had an optimal correction for the metabolic acidosis, they used the native arteriovenous fistula, a strict control of secondary hyperparathyroidism and they corrected anaemia. What they’ve seen is that in those patients in which they did all these things and they actually looked for congestive heart failure and they acted upon and then the left ventricular mass returned to normal after 1.4 years, there was a significant improvement in the cardiovascular echocardiographic parameters and what is really much more important, the survival rate was impressive, 30% for all-cause mortality and 5% for cardiovascular mortality and Charlie Herzog is going to tell you that in the States it is probably 20% in the US data.

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Now this is the list in the past 5 years for congestive heart failure trials. You’ve heard about the vasopressin antagonists and the others. There are no trials in dialysis. We have to do those trials. In fact, in congestive heart failure there are many negative trials, so we are left with a lot of promises and those promises have been discussed by the previous speakers but we have to do those trials.

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And I would conclude this by saying that CKD increases the risk for de novo congestive heart failure. That the congestive heart failure is frequent in CKD. Both the incident and the prevalent dialysis population have up to 40% of congestive heart failure. That the minor renal dysfunction is a major risk factor for a cardiovascular outcome. If you have ESRD, you are on dialysis and you have congestive heart failure, this is a fantastically negative outcome. Use proper monitoring and we have discussed and we want to hear your opinions and your experience on left atrial volume, on the mid-wall fractional shortening index, on the tissue Doppler, on the NT-proBNP, so we have now a good array to look at our patients and I think this is a fantastic leap forward because now we have the tools. If we have the tools, we can then look at the trials. Finally, the best renal replacement method is the one that ensures the best salt and volume control but the holistic approach is for sure mandatory. Thank you very much.