A joint Congress by ERA-EDTA and ISN

MAGIC BULLET OR MULTIPLE INTERVENTIONS TO REVERSE KIDNEY DISEASE PROGRESSION?

Giuseppe Remuzzi, Bergamo, Italy

Chair: Giuseppe D'Amico, Milan, Italy

Raghu Kalluri, Boston, USA

Prof G. Remuzzi Mario Negri Institute for Pharmacological Researches Negri Bergamo Laboratories Bergamo, Italy

Slide 1

Good morning.

Slide 2

You know that chronic diseases all over the world are more important everywhere than communicable disease except for this part of the world but even there the difference is not so important already.

Slide 3

Cardiovascular disease is predicted by the degree of renal insufficiency, more renal insufficiency, more cardiovascular disease and this means that we have to make all the possible efforts in order to try to lower or prevent if you wish, the degree of progression of renal disease to terminal renal failure.

Slide 4

Interestingly, let’s take the example of diabetes, this is a very old paper but very important showing that not all patients do progress at the same rate. So ideally if you were able to slow the rate of disease progression from this rapid progression here 5 ml/min declining GFR to this very low progression 0, 2 ml/min, now you have fixed the problem of dialysis, particularly in poor countries and cardiovascular disease.

Slide 5

There are no effective drugs yet for kidney disease, CKD. We have listened to two very nice talks but so far as doctor Kalluri said we will have drugs in the future but we have patients now and what we need to do because renal transplantation is limited is actually to try and prevent renal disease progression.

Slide 6

Progression is driven by glomerular hypertension, as doctor Brenner discovered many years ago and progression.

Slide 7

One of the determinants of progression is that glomerular hypertension creates a condition of shear stress by which high glomerular pressure on podocytes, in pores of podocytes and enlarges the dimension of glomerular pore like in diabetes in this particular experiment in rats as compared to control and more protein trafficking throughout the pores to accumulate into the luminal proximal tubuli.

Slide 8

They are reabsorbed and this leads to apoptosis and phenotype changes in the cells, cells start to upregulate inflammatory genes and these translate into interstitial inflammation.

Slide 9

But this slide is very recent work from Daniela Macconi and Ariela Benigni in my group and what they did was to discover a new mechanism for progression of non-immunologically mediated renal diseases like Heymann’s kidney in rats for instance which actually appeared to be immunological. What happens when they expose proximal tubular cells in culture to albumin those cells degrade albumin and create an albumin fragment of 124 and this particular fragment 124 of albumin then is processed by proteasomes in dendritic cells.

Slide 10

Andrew Rees has given this nice title to the editorial accompanying this particular paper: Cross dendritic cells anger T cells after kidney injury, indicating this new immunological way of injury.

Slide 11

You lower the dimension of pores by losartan, Fabiola explained to you some of the effects of losartan in other systems. Losartan lowers the dimension of pores to -- glomerular capillaries and in animals this results in less proteinuria, less glomerulosclerosis and prolonged animal survival. Those are animals with superficial nephrons, genetically prone to proteinuria and glomerulosclerosis, this is a genetic defect. You uni-nephrectomise the animals, now they have very high proteinuria, impressive glomerulosclerosis, high rate of death. All of them are dead at 13 months of age and the animals who however are treated with lisinopril are protected and they -- control very impressive effect. This is true in humans. If you take patients who have non-diabetic proteinuric renal disease, progression of the disease is function of initial proteinuria, 1-3 g proteinuria at the beginning, less progression after 3 years. More than 3 g proteinuria at the beginning, more progression. In terms of decline in GFR ml/min/month.

Slide 12

Now you give an ACE inhibitor or conventional therapy, same degree of BP control and you see in those who are rapid progressors 50% protection from GFR decline and this is associated with lowering proteinuria exactly as in animals and prolonging renal survival.

Slide 13

In 10 patients in this particular study we observed after a 3 year REIN core study and a 3 year follow-up that after a given break point you see that GFR starts to increase, it’s not simply a question of preventing renal disease progression but it seems to start to be a question of kidney repair in humans. GFR increases and this is in those patients who had more anti-proteinuric benefit from ACE inhibition. Normally, in this particular study, you have 20-30% reduction in proteinuria and this is a lot in order to protect your kidney from renal disease progression but when in occasional patients who reach something like 50% reduction in proteinuria, now you can start to see after 6 years, it is a long process, it takes a long time to realise but you start to see GFR increasing.

Slide 14

Then we went back to animals and Andrea Remuzzi studying these animals who at 60 weeks of age had almost complete sclerosis in their glomeruli, this is just an example, they have re-constructed 3 dimensionally more than 100 glomeruli, an immense work but you see all those animals had glomerulosclerosis affecting almost 100% of the glomerular tuft. Now only lisinopril between 50 and 60 weeks, 10 weeks lisinopril you start reabsorption of glomerulosclerosis and they have all the mathematical things to show that that we do not have time to address in this talk.

Slide 15

Now those cells you must remember that there are cells that do these jobs and cells are probably resident progenitor cells that are on the Bowman’s capsule

Slide 16

and so on the glomeruli and what we have observed is that those cells that normally are sitting as flat cells on the Bowman’s capsule in conditions of need of kidney repair they start to acquire the phenotype of podocytes and then they can migrate into the tuft and start repairing the lesions and again I don’t have time to show you the details of that but this what we are currently working on.

Slide 17

In this same study non-diabetic chronic nephropathy we found 20 patients in which you have some reducing in proteinuria, not that much then proteinuria starts to increase again and GFR in those particular patients is not protected from decline. Number one this shows in 20 patients that if you are unable to lower proteinuria, GFR cannot protect it from decline.

Slide 18

So what happens with these patients? People said well it’s because you don’t lower BP low enough. ACE inhibitors are not good enough to lower BP, calcium channel blockers are much better. So we did another study called REIN-2. This study has a peculiarity, it is almost never quoted I don’t why, it’s in the Lancet, it’s exactly like the REIN. The Rein study is extensively quoted the REIN-2 is not. REIN-2 shows that 2 different degrees on purpose of BP control. Ramipril plus felodipine lowers BP control, more dialysis in those patients who are in the combined therapy as compared to ramipril alone. So it’s not a question of BP control, it’s a question of ACE inhibitor, lowering the dimension of pore and reducing the trafficking of proteinuria or reducing EGF binding to its receptor, as Fabiola may have suggested.

Slide 19

Then we went back to animal experiments and found that lisinopril plus ACE inhibitor is even better than ACE inhibitor alone in terms of retarding renal disease progression in Heymann nephritis.

Slide 20

We took 20 identical patients to the one who did not respond to ramipril. This is not a controlled trial, those are 20 identical patients. Now, you see proteinuria goes down beautifully and you protect and we found this experiment very meaningful.

Slide 21

The part of proteinuria reduction was confirmed by a recent metanalysis in more than 400 patients, combined therapy is better than ACE inhibitor alone, is better than ARB alone in reduction in proteinuria.

Slide 22

So this metanalysis confirms as for proteinuria the data on our 10-20 patients. But then a study has been presented in the Lancet on 20.000 patients and this study shows that also a combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens renal outcomes. So people stop me while I’m at these meeting many times, telling me, look we have learnt that combined therapy is not good for my patients.

Slide 23

So in fact those 20,000 patients are very different from my 20 patients. But the problem was were we right with 20 patients or are they right with 20.000 patients? These 20.000 patients, only 13% had microalbuminuria, there were no patients with overt proteinuria, all other patients had simply no proteinuria. There was more BP reduction in the combined therapy that may mean more decline in GFR. There was no pre-screening for ischemic kidney disease and it was a secondary outcome analysis, so there was a competition risk.

Slide 24

You see the REIN study showed that the curve does dissociate very well in terms of rate of GFR decline between conventional therapy and ramipril and the curve starts to dissociate over 1 g of proteinuria, between 1 and 2 g you see no difference, between 2 and 3 g this curve starts to dissociate and then they do dissociate beautifully. Look at the on target data, they were here. We already knew that you have no difference even in ACE inhibitor alone as for the control with conventional therapy. So these patients with such low proteinuria do not benefit even from ramipril alone. So it was not the right population of patients to start.

Slide 25

Moreover, look at the outcome, all death no difference, doubling of serum creatinine no difference, ESRD no differences, so where is the difference in the outcome? The difference is in acute dialysis. Of course with the combined therapy in those patients who were not patients with progressive renal disease but were patients with congestive heart failure. Of course, with the combined therapy you lower perfusion pressure in these particular patients and you have more acute dialysis that is less than 2 months dialysis then they recover.

Slide 26

This was taken to show that double blocking of angiotensin is associated with reverse renal outcome and people took those to understand that you should not use it progressive nephropathies. That accounted for 90% of events. End stage was no different in the treatment group.

Slide 27

So I believe the on target was out of target, difference in renal outcome was largely driven by difference in acute dialysis. Need for acute dialysis is a treatment-related event, it shows that you are taking the medication, it does not reflect disease progression.

Slide 28

If you use three drugs in animals, you can see even lower proteinuria and low glomerulosclerosis.

Slide 29

What we did was now to do the same in patients as we did in rats. We have called it Remission Clinic, 56 patients with proteinuria more than 3 g on ACE or ARB for more than 6 months were compared to reference patients retrieved form the REIN study. Those patients were perfectly matched and those were patients on REIN who despite ACE inhibitor had more than 3 g proteinuria while on ramipril for at least 6 months.

Slide 30

You see the difference between ramipril patients and the Remission Clinic using the same approach as in animals.

Slide 31

I remember that those were patients on a trial, the placebo group was even worse. This is the number of dialysis, so the result of the Remission Clinic approach, this is your control and this is the Remission Clinic to dialysis, only in 2 patients with membranous nephropathy. Well, it seems -- impressed by these data.

Slide 32

Slide 33

Now the reason for showing Stewart from so many years ago is that he kept on saying dialysis and transplantation exist and flourish as a result of failure, not of success. He told me that 30 years ago.

Slide 34

You see this is what we wanted to achieve, from this to this when I saw this paper in ‘79 and this is what we actually achieved in non-diabetic renal disease, this is done. The problem is completely different in diabetes. In diabetes you only lower ESRD and cardiovascular events if you are capable of lowering 6 months proteinuria. If you don’t lower proteinuria in patients with overt nephropathy and diabetes, losartan is even worse than placebo.

Slide 35

Of course if you are capable of lowering proteinuria and you have more proteinuria lowering with losartan, now you protect your patients from events but if after 6 months of losartan you do not lower proteinuria, in fact the evolution is even worse and the reason is that those patients die of cardiovascular disease before they need renal replacement therapy.

Slide 36

People with diabetes they do treat patients when they have overt proteinuria, like in the RENAAL study. Now you have very little effect when they have overt proteinuria.

Slide 37

Cardiovascular disease is prominent

Slide 38

and this is why you have such a tremendous increase 200% of patients with overt proteinuria and diabetes needing dialysis in the United States in the last few years.

Slide 39

The point is you have to start earlier in microalbuminuria like in the IRMA-2 study

Slide 40

or even when patients have no renal disease at all,

Slide 41

start to treat BP with ACE inhibitor and now you have the way of preventing renal disease progression in diabetes. Late is too late.

Slide 42

We have another study now in Pakistan to use Polypill with the advantage of lowering blood pressure because of this component of Polypill, lowering LDL cholesterol because of this component of Polypill and lowering aspirin activation because of this component.

Slide 43

We have many different programs around the world in order to prevent renal disease progression in the contest of the ISN

Slide 44

and recently Peter Agri was coming to us to see those people who are involved in these prevention activities around the world. Peter Agri has an interest in Malaria, he wanted by his experience with aquaporin to see whether he could manipulate that cell membrane in order to fight malaria and he was kind enough to come and see our people from developing countries working with us these days.

Slide 45

Thank you for your attention.