Slide 1

Thank you.

Slide 2

So more than 100 years ago Professor Goodhart at the Guy’s hospital had a lecture discussing chronic parenchymatous nephritis.

Slide 3

And at this time he already understood that outcome of these patients was not so importantly affected by any kind of therapy. His idea was that this was because there was no drug that was able to interfere with the loss of albumin in their urine.

Slide 4

So more than 100 years ago there was this intuition of a key role of albumin in the progression of renal disease and then we had the landmark study by Anderson and co-workers from the group of Barry Brenner in Boston showing that if you have a drug able to reduce proteinuria such as an angiotensin converting enzyme inhibitor as compared to conventional antihypertensive therapy, you can prevent sclerosis and progression of renal damage.

Slide 5

This was the hypothesis that all of us know very well on the mechanisms of progression of renal disease reduction in renal mass, reduction in number of nephrons, hypertension, transmission of the hypertension to the capillary network, increased also in diabetes by the loss of upregulation, increased permeability of the glomerular barrier to macromolecules, proteinuria and scarring.

Slide 6

Actually, when you have glomerular hypertension and an increase in the mechanical strain to the glomerular barrier, you have from one side a loss of podocytes, from the other side you have an activation of the renin-angiotensin system, upregulation of angiotensin II and angiotensin II receptor that all of them, both mechanisms might increase the pore dimension of the glomerular barrier and this might cause proteinuria.

Slide 7

Actually, if you infuse angiotensin II in perfused kidneys, you see that angiotensin II is able to directly increase the glomerular barrier permeability to polysaccharides of different radius, as you can see as compared to vehicle.

Slide 8

These very large polysaccharides have the dimension, let’s say of albumin and IgG, so this is a possible mechanism explaining the permeability effect of angiotensin on the glomerular barrier.

Slide 9

And in experimental diabetes you have that intracapillary hypertension is associated with a shift of the distribution of the radius of the pores that cross the glomerular barrier to the left, to the right and you have the appearance of very large pores that are completely permeant to plasma macromolecules and proteins. This is important because whenever you have an increased traffic of protein through the glomerular barrier, you have an accumulation of protein at the tubular level, in particular at the proximal tubular level and this might trigger a sequence of events resulting in fibrogenesis and sclerosis.

Slide 10

So, from one point of view proteinuria is just a marker of disease because urinary protein loss in urine has no pathogenetic role but the proteins that are reabsorbed at the tubular level they are those that have a deleterious effect to the kidney. So proteinuria is a marker of protein traffic and scarring. This might explain why in human experimental animals we also have an important inflammation at the interstitium that is close to the area of sclerosis and that is associated with renal function loss.

Slide 11

If we affected the urinary protein loss with drugs that ameliorate the selectivity of the glomerular barrier, for instance, with an angiotensin II receptor antagonist but the same can be documented with ACE inhibitors, you can shift the distribution of the pores across the glomerular barrier to the left and you have the disappearance of these very large and permeant pores that cross the glomerular barrier.

Slide 12

This is associated with the prevention of proteinuria that is a characteristic of diabetic nephropathy not only human but also in animals and protection against the development of glomerulosclerosis. About ten years ago we showed that this applies also to humans.

Slide 13

If you use very low doses, 2.5 mg/day of enalapril that do not change the systemic blood pressure you see and the glomerular hemodynamics, you see a reduction in proteinuria, albumin, IgG fractional clearance and there is a remarkable reduction of what we call the shunt pathway that are actually those very large pores that are completely permeant to plasma macromolecules. So this data suggested a direct effect of drugs that inhibited the renin-angiotensin system on the permeability of better selectivity of the glomerular barrier.

Slide 14

Later we had the landmark trial by Ed Lewis and co-workers showing that these drugs, an ACE inhibitor at comparable blood pressure control as compared conventional therapy are able to reduce by about 50% the progression to end-stage renal disease or doubling of serum creatinine. This effect is achieved with a remarkable reduction in urinary protein.

Slide 15

So there is an association between the antiproteinuric effect and the renoprotection at comparable blood pressure control. In the REIN study more recently, we found that in patients with non-diabetic chronic renal disease severe proteinuria at baseline, more than 3 grams was associated with a faster GFR decline as compared to patients with less severe proteinuria. In this group the ACE inhibitor was extremely effective in reducing the rate of GFR decline and protection, conserved protection against kidney function loss. Again, the beneficial effect of the ACE inihibitor was achieved with proteinuria reduction but at comparable blood pressure control as compared to conventional therapy.

Slide 16

This finding might have a major relevance in my opinion because we know that proteinuria is a strong predictor of end-stage renal disease also in the general population. These are more than 100.000 patient subjects followed in Japan. You see that the appearance of proteins is associated with a remarkable increase in the risk of end-stage renal disease. But we know also from the data of the UKPDS study that proteinuria is a risk factor not only for end-stage renal disease but also for mortality.

Slide 17

These are type II diabetic patients with micro and macroalbuminuria and you see they have 2-3 times more mortality as compared to normoalbuminuric that have the same life expectancies of subjects without diabetes. Those that have proteinuria and renal insufficiency have a dramatic excess of cardiovascular mortality. So, reducing proteinuria and preventing proteinuria maybe not only renoprotective but also cardioprotective.

Slide 18

You see from this data from the HOPE study showing that if you have a patient with renal insufficiency and albuminuria, this patient has a risk to die of cardiovascular events that is higher than a patient who previously had a coronary artery disease. So, a kidney marker, a marker of kidney dysfunction is a strong predictor of cardiovascular mortality as compared to a previous cardiovascular disease.

Slide 19

So nephrologists are actually those who see patients with the highest cardiovascular risk. If we reduce proteinuria, these are data from the RENAAL study, you have that not only you reduce the risk of end-stage renal disease but also you reduce the risk of cardiovascular events and the risk of heart failure. This was achieved by losartan in the RENAAL study.

Slide 20

We know that both ACE inhibitors, captopril or ramipril in the REIN study and angiotensin II receptor antagonists such as valsartan and besartan in type II diabetes nephropathy are able to reduce the risk of end-stage renal disease by about 40-50% with ACE inhibitors, about 20-30% with angiotensin II receptor antagonists. None of these drugs, however is able to provide full protection from progression.

Slide 21

The strategies that have been suggested to increase the beneficial effect of these drugs is to use them in combination since they act on the renin-angiotensin system at two different levels and combined together they may have a synergistic antiproteinuric and renoprotective effect.

Slide 22

Indeed, in animals if you in severe Heymann nephritis, if you use an angiotensin II receptor antagonist and ACE inhibitor together, you have a more effective reduction of proteinuria as compared to ACE inhibitor alone and more protection from development of glomerulosclerosis as compared to ACE inhibitor alone. So, in animals there is the evidence that combined therapy by the 2 agents might increase the proteinuric effect and the renoprotective effect.

Slide 23

Actually, these are recent data by Andrea Remuzzi and co-workers from our laboratories. It is also possible that with this approach we can not only prevent or slow the progression of experimental chronic renal disease but also to achieve a regression of structural changes. These are the distributions of the glomeruli in animals that at 25 weeks have a given proportion of glomeruli with at least 25% of sclerosis. If we follow this animal for 40 weeks, the proportion of these glomeruli with glomerulosclerosis is increasing as well as all the others. But you see here this proportion is decreasing not only as compared to this but also to this. So, we have data showing that actually you can achieve a regression of sclerosis with dual RAS blockade, at least in experimental animals.

Slide 24

Does this apply also to humans? Mogenson evaluated the effect of combined candesartan-lisinopril therapy in patients with type II diabetes and microalbuminuria and he showed a reduction in albuminuria that was more effective with the combination. In this study however, there was also more blood pressure reduction, so it is impossible to say whether the beneficial effect is related to ACE inhibition, RAS inhibition or to more blood pressure reduction. So, this was an open question.

Slide 25

We addressed this in a study, an acute study in patients with non-diabetic renal disease comparing the antiproteinuric effect of valsartan, benazepril and their combination at elevated doses in order to have the same blood pressure reduction in the 3 treatment groups. As you can see, with the combination there was more proteinuria reduction than with the 2 agents alone at comparable blood pressure control.

Slide 26

Recently, the COOPERATE study evaluated whether this antiproteinuric effect was actually renoprotective in the long-term. This trial compared ACE inhibition, angiotensin receptor antagonist and their combination at comparable blood pressure control less than 130/80 of blood pressure in subjects with non-diabetic chronic renal disease.

Slide 27

And they showed that the combination was associated with a renoprotective effect against the development of end-stage renal disease that was superior to that of the 2 agents used alone and again at comparable blood pressure control. Interestingly the extent of proteinuria reduction in the short-term was the strongest predictor of protection against the development of end-stage renal disease regardless of the treatment arm.

Slide 28

So can we increase the beneficial effect of combined RAS inhibition on proteinuria and protection of kidney disease? One strategy that has been suggested is to intensify the blood pressure control.

Slide 29

We explored this possibility in the REIN II study. One group of patients with non-diabetic renal disease was on ramipril and the same doses we used in the REIN. In another group was added felodipine in order to have a more effective blood pressure control, less than 130/80, here the target was 90.

Slide 30

When we went to see the data however, we found that the risk of end-stage renal disease in the two groups was identical. It was identical despite more blood pressure reduction in the combination therapy. Of interest also proteinuria was identical in the 2 groups. So, in this study we were able to reduce the blood pressure but we were not able to reduce proteinuria and we did not have a superior renoprotective effect of the combination as compared to ACE inhibition alone.

Slide 31

Why this? One possible explanation is that we know from clearance studies that dihydropyridinic calcium channel blockers, in this case felodipine in type II diabetic nephropathy, for instance, increases the permeability of the glomerular barrier to polysaccharides, neutrodextrans and we know now that when you have this effect, this implies that you have an increased ultrafiltration plasma proteins to the glomerular level.

Slide 32

So our interpretation of these findings is that if you have an increased ultrafiltration of protein, you have an increase in the toxicity, in the renal toxicity of ultrafiltered proteins that might upset the potential benefit of more blood pressure reduction.

Slide 33

To test this we went to see other trials exploring the role of blood pressure control. All of you are aware of this data from ‘95 from the MDRD trial showing that in subjects with more effective blood pressure control regardless of the GFR at baseline you have a more effective reduction in the rate of GFR decline. This shows clearly that more blood pressure reduction, more renoprotection.

Slide 34

Another study from Ed Lewis in type I diabetic nephropathy showed that more effective blood pressure reduction, more effective reduction in proteinuria as compared to subjects in usual blood pressure controls. This study was not powered to evaluate the outcomes but was able to document a more reduction in proteinuria with more effective blood pressure. So, this data suggests that blood pressure is protective but let’s give a look, a closer look at this data.

Slide 35

In the MDRD trial there was a higher proportion of subjects given ACE inhibitors among those with intensified blood pressure control as compared to those with low blood pressure control.

Slide 36

In the diabetic nephropathy study I showed you before there was a much higher proportion of patients on high dose ACE inhibitors as compared to the proportion in those with less intensified blood pressure control. In other words, this data suggests that the superior effect associated with blood pressure reduction actually was driven by a more effective inhibition of the renin-angiotensin system.

Slide 37

On this line are the data, for instance, from the AASK trial showing that despite more effective blood pressure control in Afro-Americans with nephrosclerosis you have the same rate of GFR decline and in these two treatment groups the use of ACE inhibitors was identical. So, the only difference was the blood pressure.

Slide 38

On the same line the ABCD trial in type II diabetic subjects with a very strong difference in blood pressure failed to document a differing in the rate of creatinine clearance decline and in albuminuria. Again, if you don’t have difference in the use of ACE inhibitors or angiotensin receptor antagonists, it does not seem that intensified blood pressure control has a specific renoprotective effect.

Slide 39

So, our data and our idea is that it’s actually proteinuria reduction that is the key component of renoprotective therapy.

Slide 40

And that we should set up strategies aimed to achieve the best reduction in proteinuria that we can achieve.

Slide 41

For instance, using different approaches including also the use of statins that in animals reduce proteinuria in particular in rats given also ACE inhibitors and angiotensin II receptor antagonists and these drugs might prevent glomerulosclerosis and reduce glomerulosclerosis to levels similar to those of control.

Slide 42

This is why in our clinic we have set up what we have called remission clinic in which we put together all these strategies, ACE inhibition, angiotensin II receptor antagonists, diuretics and statins and intensified blood pressure control and whenever it is possible also the use of aldosterone antagonists pending on serum potassium.

Slide 43

We targeted the therapy to these targets blood pressure 120, low proteinuria and optimised control of lipid and metabolic profile.

Slide 44

You can see that with this approach you can achieve complete remission of proteinuria in a good number of patients that have heavy proteinuria despite standard ACE inhibition therapy. This is associated with stabilisation of renal function in the long term. This does not apply to all patients of course, it is about 2/3 of patients. We know in type II diabetes it’s much more difficult to achieve this target.

Slide 45

These are only 5 patients in which we were able to achieve complete remission and stabilisation.

Slide 46

There were other patients in which we were able only to reduce proteinuria but not normalise proteinuria and these patients continue to progress. This is a major problem because when you have type II diabetes and overt nephropathy, you have very high risk patients and to slow progression in these patients is very difficult.

Slide 47

Probably we have to change our target. Our target of treatment should not be end-stage renal disease.

Slide 48

We know that these patients every year for one of them progressing to end-stage renal disease, 5 die of cardiovascular complication. So actually they do not go to dialysis not because they are protected but rather because they die before.

Slide 49

So, I think that the nephrologists in particular – with diabetes should start working on the possibility to prevent nephropathy rather than treat it when it is already overt.

Slide 50

And to do this we have had several studies evaluating the possibility to intervention at the stage of microalbuminuria and very recently the data from BENEDICT at the stage of normoalbuminuria. We can do prevention in diabetes because we know the history of diabetes over time, we know that we can start even at the stage of normoalbuminuria to achieve renoprotection.

Slide 51

Again, in the BENEDICT study a comparable blood pressure control, ACE inhibition alone or combined to verapamil reduced the risk of microalbuminuria in type II diabetes subjects with normoalbuminuria by about 50%. This was an effect specific for ACE inhibition not mediated by more blood pressure reduction.

Slide 52

And so this is my conclusion. I think that a new agenda for kidney doctors will be for the future preventing nephropathy with the final aim to limit cardiovascular events and death. I thank you for your attention.