EARLY VERSUS LATE STEROID WITHDRAWAL Julio Pascual, Barcelona, Spain Chairs: Ryszard Grenda, Warsaw, Poland

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1 EARLY VERSUS LATE STEROID WITHDRAWAL Julio Pascual, Barcelona, Spain Chairs: Ryszard Grenda, Warsaw, Poland Julio Pascual, Barcelona, Spain Prof. Julio Pascal Hospital del Mar Nephrology Department Barcelona, Spain Slide 1 Ladies and gentlemen, dear chairman, I'm not Julio Pascual, he unfortunately couldn't come due to family matters and asked me two days ago whether it would be possible to present his talk. So I agreed but I certainly cannot replace Julio who is a really too much of an expert in that field but again he sent me his slides so I will try to do my best. Slide2

2 It's a topic that's always hot and is always a topic that is open for discussion simply because there are no clear answers. If it were clear, there wouldn't be any reason to discuss it. Slide 3 What is the reason that steroids are used in transplantation? First of all, we all know they're used for prophylaxis, for acute rejection, they exhibit immunosuppressive effects, they are frequently or standard used in the treatment of rejections, and they are also probably useful for prevention of chronic rejection. So what is the reason to why we think we may be able to withdraw them? Because there are some side effects attached to it. Slide 4

3 In the short term there's weight gain, which is never very good, there is sometimes as what's listed here PTDM or NODAT, new onset diabetes after transplantation, it's highly associated with wound healing problems, sometimes it's GI problems and nevertheless emotional disturbances and other severe problems. There are long-term issues. The cumulative dose of steroids should not be underestimated, specifically if you talk about bone disease, osteoporosis, hypotension, the long consequences of post-transplant diabetes and also, visibility might be impacted by a cataract and psychiatric disorders. So what's the balance on that? Slide 5 Why should we consider to use steroids or stop them? To minimise adverse effects without increasing acute rejection or chronic loss of function. This would be the ideal world.

4 Slide 6 Now he actually separated his talk into two parts. The first part will be about the withdrawal of steroids in the long run, so after a month. He coined this 'late withdrawal' and I will speak about that first. The second part is about what he calls 'avoidance', which is only a few days immediately after transplantation the use of steroids and then immediate cessation. Slide 7 Now let's start with the late withdrawal. Slide 8

5 In the early days so to speak, more than 10 years ago. Bert Kasiske published his first metaanalysis, which is a compound analysis on all the randomised trials that were available then, and I think it's a very useful tool in terms of getting a clear impact or a clear answer on the intervention. What it basically shows on the outcome of acute rejection and the studies that were at that time available, I think it was clear that if you withdraw steroids in combination with cyclosporine that's an important issue, in combination with cyclosporine and CellCept, you actually had a higher risk of acute rejection which was in the range of about 10-20%. Slide 9 The meta-analysis also found a more important risk of graft loss. The risk for graft loss was increased by almost 4%. It's a relative risk, so it's not the absolute risk but still it's a huge impact on long-term outcomes. So from that point of view steroid withdrawal would not have been recommended. But again keep in mind it's more than 15 years ago because the studies that are listed here, some of them were years ago. So they were all done in combination with cyclosporine. Slide 10

6 Now, what I said initially that steroids are able to suppress the inflammatory response of the alloimmune graft you see here the Brian Nankivell protocol biopsy study showing that if you withdraw steroids in combination with cyclosporine and azathioprine, you actually experience what he calls 'subclinical acute rejection' in the range of about 60% which is actually a very high range. However, in the newer combination with tacrolimus and MMF it's actually initially high but then it weans off and at 12 months you have virtually no subclinical acute rejection in the protocol biopsies suggesting that if you use a standard immunosuppressive regimen with tacrolimus Cellcept, it might easily be possible to withdraw cyclosporine after a couple of months after transplantation. Slide 11 Now there are other control trials. Julio actually published 8 years ago 9 years ago another meta-analysis with the new trials on cyclosporine, or tacrolimus plus MMF and he actually found the same estimates. So the risk was even higher when the trials were mixed. So, the conclusion is not so clear from this meta-analysis but keep in mind again that this was published 10 years ago.

7 Slide 12 However, he did not observe the same effect on graft loss that Bert Kasiske did which is I think important. Slide 13

8 Now what he found was that some proxy markers or biomarkers for atherosclerosis such as total cholesterol were lower in the group where steroids were withdrawn. Now that's not unexpected I would say but we don't know whether this actually has an impact on for example, mortality, cardiac arrest, stroke or atherosclerotic comorbidities, that's unclear. Slide 14 Now what did the KDOQI guidelines say four years ago? Point 3.2 says if prednisolone is being used beyond the first week after transplantation, we suggest to keep it rather than withdraw it but again this was almost now more than 4 or 5 years ago, maybe this has changed. Slide 15 Now there's one meta-analysis from Julio done together with the Cochrane group in Sidney and one of my co-workers Maria Haller who is here spent the last year updating this review, data not quite available but I hope it will be next year. Slide 16

9 So what's the recommendation from their point of view? So withdrawal after the first 3-6 months is safe. If you have a patient with a low immunological risk and on immunosuppression that's basically on tacrolimus and MMF. However, with cyclosporine one experiences more rejections. It seems that with tacrolimus these problems are not so severe. You may have an impact on the cardiovascular risk profile as evidenced by the lower or decrease in cholesterol. However, nobody knows whether this actually impacts on hard outcomes. No controlled evaluation beyond 3 years is available. So it's still open to discussion. Slide 17 Now what about the very early stop of cyclosporine the so-called 'steroid avoidance strategy' which is one of the favourite protocols in the United States? Slide 18

10 A recent paper from Julio Pascual actually investigated the available 9 trials with the same design Slide 19 like a systemic review and these are the main results from the paper. Now if you have steroid avoidance protocols within the first 2 weeks, he identified 9 trials as I said, there was no impact whatsoever on hard outcomes such as death. You see the relative risk is close to 1. There was no impact on graft loss including death, which is the actual graft loss. There was no impact whatsoever on death censored or functional graft loss. However, biopsy proven acute rejections were more frequently seen before in the cyclosporine groups. So the risk was almost 2-fold but there was no statistical risk in tacrolimus. One conclusion or one lesson from this would be that obviously early acute rejections do not impact on long-term graft survival because otherwise it wouldn't have been explainable that you have a twiceincreased risk of acute rejection but no differences in graft loss. Again, other measures proxy or steroid use were beneficial but it remains to be determined what this means in the longterm. Slide 20

11 Another group or group from Arthur Matas in the United States from Minnesota, his group is using steroid withdrawal very early on for a long period of time and he published recently in the CJASN a paper where he compared the results from Minnesota on the patients that had steroid avoidance with historical controls. Now there are some issues, some statistical issues that if you use historic controls. For some people doing a randomised controlled trial in randomised people is not the same. There's also something that's called the era effect that for example that the overall mortality decreased over years for several other reasons, for people smoking, for better cars whatsoever. So it's very hard actually to compare those groups. So certainly in a univariate analysis using just Kaplan-Meier analysis. Nevertheless, what he showed is that the steroid avoidance group in the solid line compared to the historical controls Slide 21 in the dash line was not different in terms of graft survival. There was no difference in functional graft survival whether it was live donors or deceased donors. Actually, for the deceased donors he found that their sense of graft survival was actually better if steroids were withdrawn. Now the only explanation for that was probably that there was a selection bias because one would not expect that the graft survival is actually better if you withdraw the functional graft survival, if you withdraw the steroids. Slide 22

12 Now Slide 23 what is the KDIGO suggestion from 2009? Point 2.4 they suggest that in patients who are at low immunological risk and who receive induction therapy steroids could be discontinued during the first week after transplantation but again the statement says 'if they're receiving induction therapy'. It depends on what you're using. Most of the centres in the USA are using Campath now. In most of European countries Campath is not the first line induction therapy, it's usually an IL2 antagonist. Whether that's true for the IL2 antagonist, I'm not quite sure. Slide 24

13 Now what do they recommend? They would recommend, as in most of the conclusions stated, to do a randomised trial. There should be long term randomized controlled trials with adequate statistical power to detect differences in early rejection, adverse events but also in the long run. Now this probably will never happen as we know and it's very hard to power a trial to actually find the differences in long term outcomes and the real culprit with this is that it can only test one time point. You say is it possible to withdraw at week 1, 2 of month 3? And then you get a result for one time point but you still don't know when the optimal time point is. Maybe the optimal time point is at I don't know 4 months. Slide 25 This is actually a question that Maria tried to address and she used large databases where people were withdrawn at different time points. There were people that were withdrawn at 3 months, one week, two years and so on so continuous withdrawal of steroids and certainly there's usually a reason why people are withdrawn. So you have to account for that and there are statistical tools to address this issue. One is called the propensity score matching which is basically a retrospective matching of people that got withdrawn versus people that were still maintained on steroids. Then you can do what's called land marking to test for different time points whether the patients that survived until this time point had a higher risk of graft loss or a lower risk of graft loss if steroids were withdrawn. You see in the first almost year if you withdraw steroids, you have a higher risk and ---- hard outcome of actual graft

14 loss which is a combination of death and graft loss. Then after the first year that's a 6 curve the risk decreases to half predominantly because the mortality decreases somehow. I think that's a very, very interesting observation suggesting that probably it's wise to keep steroids for the first year or somewhere around the first year and then try to wean them off. Then you have the maximal protection in the first couple of months and not the long run toxicity. But again, that's an observational study with all the limitations of an observational study. Slide 26 Now what is Julio's conclusion? Steroids he says may be withdrawn in many patients without any problems. So better than a new large randomised trial he wants to have more answers to specific questions whether first of all is the dose we're using in the long run 5 mg/day of prednisolone impact on long term problems such as severe risks? Is there an immune phenotype of high responders that will develop acute or chronic rejection after withdrawal? So in other words is there a biomarker? Probably yes with DSA for example. To stimulate indirect antigen recognition de novo HLA antibodies or other alloimmune response after withdrawal that remains to be determined. Slide 27

15 Now again I gave this talk on behalf of Julio who unfortunately has a major family issue and could not come and I hope I was able to replace in somehow. Thank you very much.