Slide 1

Mr Chairman, Ladies and Gentlemen. First of all, I would like to thank the organisers for giving me the opportunity to share some data with you on this topic which I might confess is rather difficult tailoring immunosuppression in chronic allograft nephropathy.

Slide 2

This is a typical case and this is what happens in everyday clinics that when we look at a patient and we see that serum creatinine remains stable, everyone is happy and confident but when serum creatinine begins to rise we begin to doubt and to think about the possibility to perform a biopsy.

Slide 3

And when we decide to do a biopsy sometimes we look at a picture that is like this.

Slide 4

By looking at this picture with these many lesions in the vessels, in the tubular interstitium we realised that lesions were too advanced, the biopsy was done too late and probably, there is not much to do for this patient.

Slide 5

This situation that happens nearly every day in every hospital is the situation that justifies this question, is there a new look for this old problem?

Slide 6

We have learned in the last, I would say 15 years many things about the natural history of chronic allograft nephropathy thanks to studies of protocol biopsies and if I had to summarise which is or which are the main important points we have learnt, the first one is that tubular interstitial chronic lesions progress following more or less an exponential curve.

Slide 7

So that the major progression of chronic lesions occurs early after transplantation during the first few months. The second important concept is that in studies of serial protocol biopsies while chronic lesions progress in all renal compartments, serum creatinine remains stable suggesting that at these early stages of the disease histological progression of damage is not reflected in clinical data.

Slide 8

So, that from this situation we can easily understand that if this is the progression of the incidence of chronic allograft nephropathy, the opportunities to modify the natural history of the process but here at the end of this process the opportunities are less.

Slide 9

So, that from these important pieces of knowledge we can understand that it makes sense to try prevention in chronic allograft nephropathy, even early treatment makes sense but for these approaches we need an important tool which are protocol biopsies and it seems also from the knowledge we have nowadays that late treatment makes not much sense.

Slide 10

But we are speaking about tailoring and tailoring means that the tailor has to design and to make clothes for different persons for big, for small persons, for smart for more casual persons, so that each client needs clothes and if this is tailoring and this is the definition of tailoring, then we have to make an important assumption in the case of chronic allograft nephropathy.

Slide 11

The assumption in order to assume that we can tailor immunosuppression is the assumption that we are able to define different types of chronic allograft nephropathy. If there were a type I, type II, type III, type IV, then we can envision that it would be a treatment one for type I, treatment 2, treatment 3 and this is the concept of tailoring.

Slide 12

Let us see whether how far we are from this concept and let us review for this purpose the lessons learnt from protocol biopsy studies.

Slide 13

From protocol biopsy studies we have learnt that when we classify patients as having chronic allograft nephropathy under protocol biopsy or not having this condition, there is beyond doubt that the presence of chronic allograft nephropathy defined as the presence of tubular interstitial chronic lesions is associated with a poorer outcome and this is a very consistent finding in the literature.

Slide 14

But in studies in which the authors have wondered whether specific lesions are always associated to outcome it has been also observed that when we classify patients having chronic allograft nephropathy, as those having tubular interstitial chronic lesions with or without transplant vasculopathy, transplant vasculopathy implies a much poorer prognosis than patients having only tubular interstitial chronic lesions and this data suggests that there are some specific forms from the histological point of view of presentations of chronic allograft nephropathy and stable grafts that are associated with different outcomes.

Slide 15

An important recent piece of information is related to subclinical rejection. In a recent study last year it was for the first time clearly demonstrated that the presence of subclinical rejection is associated with allograft survival at approximately 10 years of follow up. But now recently in the last 2 years 3 papers, 3 large studies have presented a similar result that is that when we classify patients as having chronic allograft nephropathy on the one hand and patients having chronic allograft nephropathy associated to subclinical rejection on the other, the presence or the coincidence of these two lesions in the same biopsy is also associated with a much poorer prognosis suggesting that this combination of chronic and inflammatory lesions implies a different entity with its own prognosis.

Slide 16

More recently, it has been suggested also that when we classify chronic allograft nephropathy as plain or normal chronic allograft nephropathy and chronic allograft nephropathy associated with transplant glomerulopathy, the prognosis between these 2 entities is different despite there is only one report suggesting this possibility and I must confess that this observation is less consistent than the previous ones.

Slide 17

So just to summarise, epidemiological studies done with protocol studies suggest that it might be possible to distinguish different histological patterns that have a different clinical behaviour, that have a different prognosis and this is the classical chronic allograft nephropathy the so-called chronic allograft nephropathy type a according to the Banff criteria which is characterised by tubular atrophy and interstitial fibrosis and anything else. Then there is the chronic allograft nephropathy with transplant vasculopathy, with intimal thickening. There might be a new entity coming or a new entity which is the association between tubular interstitial chronic lesions and subclinical rejection and these other suggestions that have come recently to the literature and that have been validated by other groups.

Slide 18

If there are different patterns associated with different prognoses, we might suggest that it could be that there are also different treatments for these conditions and just to cut a long story short it has been suggested that in the classical tubular interstitial lesion this is mainly dependent on nephrotoxicity. It has also been suggested that when there is subclinical rejection over chronic lesions, there is a problem related to enhanced cellular immunity or inadequate immunosuppression and in these two last situations which are more complex it has been suggested that cellular, especially humoral or inadequate immunosuppression are playing a role.

Slide 19

So let’s briefly review one by one these entities what do we know about or which evidence we have about different mechanisms leading to different lesions.

Slide 20

With regards to the presence of tubular atrophy and interstitial fibrosis in this study in which all patients started with sirolimus, cyclosporine, prednisone they were randomised at 3 months to withdraw cyclosporine in one group or continue with cyclosporine.

Slide 21

When cyclosporine was withdrawn at 3 years, the severity of chronic lesions was less in patients not receiving any more CNIs but if you look at this data with more detail we realise that the major benefit of withdrawing cyclosporine was observed in the tubular interstitial compartment and not so clearly  in other compartments.

Slide 22

Similar results and there are many studies that could be quoted here were obtained in this study in which patients received from the beginning of transplantation either cyclosporine or sirolimus and patients receiving sirolimus had less chronic lesions but the major benefit was once more observed in the interstitial tubular compartment.

Slide 23

So, that this data suggests that these patients might benefit, if they show in the protocol biopsy tubular interstitial lesions and anything else may benefit from CNI withdrawal or minimisation.

Slide 24

What do we know about chronic allograft nephropathy associated to transplant vasculopathy or chronic vascular lesions?

Slide 25

I must confess that in this regard cardiologists know much more than we nephrologists thanks to the use of a very powerful tool to evaluate vascular lesions like this intravascular ultrasound that allows to quantify along a coronary artery the severity of intima thickening but cardiologists have observed that in a randomised trial that the use of statins delays the progression of transplant vasculopathy and this effect is associated with a better graft survival.

Slide 26

Also cardiologists using intravascular ultrasound have been shown that immunosuppressive treatment modulates the progression of transplant vasculopathy.

Slide 27

And just to show this in this study in which patients received everolimus or azathioprine associated with cyclosporine prednisone in the first group of patients progression of transplant vasculopathy was much slower than in patients receiving the less powerful immunosuppressive schedule. This data might be interpreted that first, a more powerful immunosuppression is associated with less progression of intima thickening and also it might be another alternative explanation that the anti-proliferative effect of everolimus or sirolimus might also contribute to the delay in the progression of transplant vasculopathy.

Slide 28

In the kidney the role of statins to prevent progression of lesions is a matter of debate. There was the very well known ALERT study in which statins were introduced at 5 years and there was no benefit in graft survival. But there are also some epidemiological studies that suggest the contrary and in this large Spanish study, an epidemiological and retrospective study in which statins introduced at the first year for any reason were considered as a predictive variable it was observed that patients receiving statins from the beginning of transplantation had less graft loss than patients that did not receive statins.

Slide 29

We have to consider this data with caution because this is an epidemiological study.

Slide 30

But in a recently preformed prospective trial in which patients were as in the case of the heart randomised from the beginning of transplantation to receive statins or placebo, this is a multicentric double blinded placebo controlled study, it was observed that while in the donor biopsy the proportion of patients presented chronic vascular lesions was the same, patients receiving fluvastatin chronic vascular lesions progressed less than in patients receiving placebo in a similar way as it has been previously described in heart.

Slide 31

Unfortunately, at present the idea or the point whether immunosuppression modulates progression of intimal thickening is not available at the moment. So finally this data suggests that in the case of transplant vasculopathy patients might benefit from these kinds of treatments.

Slide 32

Let us now consider what we know about the combination of chronic allograft nephropathy and subclinical rejection.

Slide 33

As I mentioned, subclinical rejection associated with chronic allograft nephropathy implies a poorer prognosis than subclinical rejection alone or the chronic allograft nephropathy alone and we do not understand very well why things are like this but there are at least two possible explanations.

Slide 34

The first one is that in patients with subclinical rejections already displaying chronic lesions the activity of the infiltrate might be more intense than in patients only presenting subclinical rejection. In this case these patients might benefit from increased immunosuppression but there is also an alternative explanation.

Slide 35

This is that in patients with subclinical rejection taking place on an already diseased kidney that has chronic lesions, these patients will have reduced capacity for tissue repair and accordingly these patients may benefit from decreased nephrotoxicity.

Slide 36

I must say that in the case of transplant glomerulopathy observed in protocol biopsies we do not know many things. It is true that in indication biopsy studies the presence of transplant glomerulopathy is associated with humoral response.

Slide 37

But for example, in the only study performed in protocol biopsies in which a large series of cases, about 500 protocol biopsies were stained with C4d, C4d positive patients did not have a poorer allograft survival than C4d negative patients and accordingly this is an area that deserves more investigation.

Slide 38

Accordingly, the treatment if this entity just we can suggest that humoral response must be targeted but honestly there is no more information to go forward in this suggestion.

Slide 39

So just let me summarise what we have said. We have suggested that epidemiological studies performing protocol biopsies allow to classify chronic allograft nephropathy in different subsets according to the presence of either inflammation, vascular damage or glomerular damage. This data suggests that the main factors associated with these lesions are different and accordingly we began to envision that these different patterns or histological patterns of chronic allograft nephropathy might benefit from different therapeutical approaches. I mentioned that in this first case CNI withdrawal or minimisation might be an approach. In this case these patients might benefit from increasing immunosuppression and at the same time decreasing nephrotoxicity which is a quite difficult exercise. In these patients there is some evidence that statins and increasing immunosuppression might have a benefit and according to data obtained in indication biopsies these patients might benefit especially from targeting humoral response.

Slide 40

But I want to just to remark that this is just a hypothesis that might guide and facilitate the design of proper clinical trials in order to check whether these hypotheses are true or not.

Slide 41

Thank you very much for your attention.