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Audio interviews and conversations covering all things nephrology
Highlighting the lack of randomized controlled trials in the area. So we had 15 studies in total, and these studies, they compared rather high variability of different treatment regimens.
Speaker 2:Thank you for joining us. It is IASEN's pleasure to present the latest episode of the Global Kidney Care podcast on systematic review on evaluating interventions for minimal change disease in adults with nephrotic syndrome. This episode is hosted by Edmund Chung, Cochrane and kidney transplant knowledge translation and dissemination editor. ISN thanks him and the Cochrane and kidney transplant for their collaboration.
Speaker 3:So, welcome everyone. And thanks for joining us on this podcast, through the International Society of Nephrology. My name is Edmund Chung. I'm the Cochrane Kidney and Transplant Group Knowledge Translation and Dissemination Editor. And today I've got two authors of a recent Cochrane systematic review, evaluating interventions for a minimal change disease in adult nephrotic syndrome.
Speaker 3:So we have Elizabeth Hodson, as well as who's the senior author on this review, as well as Corollis Azucatis, who's the first author. And please correct me with my pronunciation, Corollus.
Speaker 1:No, that sounds quite well for what I'm used to.
Speaker 3:Yeah, perfect. Thank you. Excellent. And definitely feel free to chime in at any time. But I thought I'd just start off by introducing the condition that I'm sure our audience is very familiar with.
Speaker 3:Minimal change disease is a cause for primary nephrotic syndrome. It's the third most common cause of primary nephrotic syndrome in adults behind membranous nephropathy and focal segmental glomerulosclerosis. And even though the pathogenesis of the disease remains incompletely understood, there's definitely a role for the immune system, particularly T cells and now even maybe B cell dysfunction. So traditionally immunosuppression such as corticosteroids has featured largely in the treatment of minimal change disease. But in terms of alternative treatments, this has been largely based off studies in children with steroid sensitive nephrotic syndrome, including calcium neuroin inhibitors, mycophenolate, cyclophosphamide, even most recently rituximab, which is a CD20 monoclonal antibody.
Speaker 3:However, I guess the summary of the harms and benefits of these treatments in adults with minimal change disease has not been, well summarized in general. And hence, there was an initiative from the Cochrane Kidney and Transplant Group to summarize the totality of this evidence. The review that we'll highlight is actually an update of an original Cochrane review in 2008 that Elizabeth Hodson was also involved in. So I hand over to Elizabeth just to, I guess, set the groundwork for why the Cochrane group decided to engage in this topic and and maybe a brief introduction of the initial study in 2008 before launching into a discussion about this 2022 update.
Speaker 4:Thank you, Edmund. This review was updated as part of a generalized update of reviews that was carried out before the publication of the 2021 KD Go guidelines for glomerulonephritis. And the original review was published in 2008. And at that time, there were only three randomized controlled trials identified, all looking at steroid treatment and coming up with no real conclusions. But it did not appear that steroids were particularly effective.
Speaker 4:The review that we did, there were some more studies but still a disappointingly low number of randomized controlled trials in this condition with only 15 identified overall with any interventions, which included seven sixty nine participants, not all of whom could be evaluated in analyses. So we went on from there, and I think probably Corollis might like to talk a little bit about what we found.
Speaker 1:Thank you, Elizabeth, for the introduction to our work. Indeed, the number of studies that we could analyse wasn't that high, highlighting the lack of randomised controlled trials in the area. So we had 15 studies in total. And these all studies, they compared rather high variability of different treatment regimens. As you mentioned, Edmund, indeed corticosteroids were considered to be the mainstay treatment.
Speaker 1:But if we look at the evidence point of view, there were only a few studies that analyzed corticosteroids in a randomized controlled trial fashion, namely two studies that compared them with no treatment with a very low patient number and very low certainty evidence that did not show effect actually, but the certainty of evidence was very low, including both adverse events and how the primary endpoint was reached. The other two studies looked at the IV steroids plus oral steroids versus oral steroids alone, And again, suffered from low patient numbers and failed to show any superiority, any of the treatment modalities. I think what's also important to point out that we lack studies that would compare or try to establish different steroid protocols in steroid sensitive disease. So we had only comparisons of steroid versus no treatment, or IV plus oral versus oral only. So the majority of studies actually came from those that, from that part that compared calcineurin inhibitors with or without steroids, with oral steroids alone.
Speaker 1:And here we had the highest certainty of evidence in our meta analysis, which reached the moderate level. And what we found with this moderate certainty evidence is that there seems to be little or no difference when you compare calcineurin inhibitors with or without oral steroids to oral steroids alone in terms of reaching complete remission or reducing relapse rate, and this comes with moderate certainty of evidence. But the important point is that treatment employing calcineurin inhibitors appears to reduce the number and the frequency of adverse events, and mostly those associated with glucocorticoid steroid treatment, which is obesity, Cushing's syndrome, and acne. And the number of events in all trials that analysed this was quite low. So the evidence certainty is also low.
Speaker 1:But this is probably the main finding that CNIs, with or without steroids compared to oral steroids alone, although it doesn't seem to affect the occurrence, the frequency of complete remission or relapses, it appears to reduce the number of steroid associated adverse events. As speaking about other treatments, there were two studies on mecophenolic acid with a low certainty of evidence also suggesting little to no benefit. And unfortunately, one of the promising therapies that we have also introduced, rituximab, we had no studies so far, no study results, I would say, so far to be analysed, as there are two randomised controlled trials ongoing, and we're still awaiting for the results that would be very important in terms of establishing best treatment options for the disease. So I think that would be the general summary of our main findings.
Speaker 3:Excellent. Thank you for very detailed kind of background, Elizabeth, and as well as summarizing the results of this current study, COROLIS. I guess in terms of we've already established that there are definitely gaps in the knowledge base. How do you think that this current study will influence treatment decisions, do you think, in the treatment of adults with minimal change disease? And either Corollis or Elizabeth or Friedrichs?
Speaker 4:I'll have a go at that first. I'm not sure to what extent it will influence it because I imagine that most clinicians have already moved from a regimen of corticosteroids alone to tacrolimus or cyclosporine together with steroids. I would have thought they've already moved to that regimen. I would point out that I'm a pediatric nephrologist, not an adult nephrologist, so don't actually know what they would do, but I would think that that's what they do. I would also think they're probably trying mycophenolate on a similar basis, although in the few trials that we saw, we didn't find any differences between the two regimens.
Speaker 4:And I would also think that although there are no randomized controlled trials completed and published for rituximab, that people are already using rituximab in this condition on the basis that it's a difficult condition to treat. It's associated with a lot of morbidity and mortality. And any efforts to get patients into remission should tried. But everybody is now working entirely on observational studies and case series rather than randomised controlled trials, which is very disappointing.
Speaker 3:Excellent. No, I definitely would agree. And Coralis, any additional thoughts?
Speaker 1:I think that the only thing that I could probably add is that, well, our findings are in line with the latest KEDIGO recommendations on minimal change disease that say that calcineurin inhibitors plus steroids would be the preferable option in those susceptible to steroid induced complications. And this is supported by the evidence that although there may be no major effects on the achieving primary outcomes such as remission, but we can definitely with this regimen reduce steroid associated toxicity. So that's the only thing that-
Speaker 3:Excellent. And I definitely, as an adult nephrologist, but relatively early in my career, I do know that this condition relapses quite often and the cumulative dose of steroids is very apparent in terms of the complications that come with it as patients continue to experience disease relapse. So calcium neuroinhibitors are definitely the agents we tend to go to second line. And if not, yet persist with to try to induce or at least maintain remission. And some of us don't even remove them to prevent the very frequent relapses.
Speaker 3:So it's good to know that at least it's as effective in terms of our randomised controlled trials in moderate certainty evidence compared to corticosteroids alone, and that it most likely reduces the steroid associated complications.
Speaker 4:I think we can just say, though, that the data from randomized controlled trials comes largely from patients being treated in their initial episode or from their first relapse. There weren't any studies looking at patients who'd had several relapses.
Speaker 3:And do you think that it would be important to stay focused in this area or given that this is relatively rare disease that any form of randomized controlled trials including all comers would be necessary moving forward?
Speaker 4:I think the latter, except that you would need to stratify the data, which would mean you'd need a whole lot more enrollments. So, it'd be difficult studies to do. From what we could see, there was really no attempt to do international studies in this condition. I think that would be largely because it's not a particularly common condition. And there are a whole lot of other more considered more important studies to be done with randomized controlled trials.
Speaker 4:The other problem, of course,
Speaker 1:is
Speaker 4:that except for rituximab, or even that, these are all legacy treatments, and there would be no funding for these from pharmaceutical companies. So if you were going to get funding for these sort of studies, you'd need to get from research organizations and funding bodies from within governments. Which is that's always a problem for conditions that are not very common and don't have really obvious new treatments.
Speaker 3:Yeah, definitely. Well, it sounds like that there are many challenges in this field to developing a better evidence base. So if I may, I guess, entice you both with a hypothetical. If there were funding available and understanding that this is a relatively rare condition where hopefully international collaboration is necessary, If there was just one trial you could pick in terms of the ideal trial to take it to the next step, what would it be?
Speaker 4:I'll let Carolus have a go at that one first.
Speaker 1:I think that's quite a difficult question, but some of the aspects that would be important were already touched upon. So first of all is looking at different subsets of patients, which requires, as Elizabeth mentioned, enrolling sufficient number of patients into the trial. So, it would have to have a design that would allow for this considering the relatively low frequency of the disease. So this should be a multicenter international collaboration. And indeed, a very important thing would be not only looking at the treatment of first episode, which was the predominant or first relapse, but looking at those, as you mentioned, Edmund, yourself, with the frequently relapsing course where accumulated doses of steroids become a problem and where we're interested in reducing both relapse rates and increasing time to relapse.
Speaker 1:So that would be one point, stratification and sufficient number of patients. And I think that one of the important things would be probably if we would have the results from rituximab studies, at least that would be a bit easier because we should look for newer therapies that would allow maybe to omit steroid use at all, or at least and in an ideal scenario would also be more effective. Hopefully, after the rituximab studies, I could say that I will be able to say that these should be the studies with a large number of patients treated with rituximab, that would appear to be more effective, but we don't know yet. So it's difficult for me. Otherwise, all the things like standardisation, really defining steroid regimens to the detail and knowing exactly how the patients receive it, controlling for concomitant medication use and so on.
Speaker 1:But maybe Elizabeth can elaborate on this further, I think.
Speaker 4:I would agree with everything that Carolus has said. It would need to be an international study. There may be some new methodology in the development of randomized controlled trials that could used most of it I'm not familiar with but that would allow more people to be entered in the trial, perhaps sequentially. But currently, based on what we know, I think the most likely comparison would have to be a CNI with prednisone compared with rituximab or other medications similar to rituximab. And using normal RCT methodology, it would certainly have to be a large international study.
Speaker 4:And that sort of study, however important, would be very difficult to fund, I'm afraid.
Speaker 3:No. Definitely. But I think it's still important to highlight the need for Yeah. International collaboration, which hopefully through the ISN will stimulate our community to hopefully engage with this important disease, albeit a rare one.
Speaker 1:Yeah, absolutely.
Speaker 3:I guess from an adult nephrologist perspective, do you think that it would be possible to combine the pediatric cohort and adult cohort? Or because it's uncommon to biopsy the pediatric cohort, This would be a challenging scenario.
Speaker 4:I wouldn't think that you would want to put pediatric and adults in together. I think the diseases might look the same on biopsy, but they behave slightly differently. And particularly the adverse events are much more a problem with the adult disease than with pediatric disease. And I think it would be very hard to get families, children, to take part in that sort of study when there are already many pediatric studies looking at the medications that we currently have. Really new medications that might be different, but at the moment the medications that we have I don't think it would be justified to try and have children and adults in the same study.
Speaker 1:Yeah, I completely agree to Elizabeth, and it's first probably, despite the similar clinical presentation or histological presentation, these are two different entities. And children have their own peculiarities in terms of response to treatment susceptibility to side effects. And indeed, the evidence base in pediatric nephrotic syndrome is much more established. Thus, we have a little bit of different questions that we're aiming to answer at this point than to those that we just discussed for the adult disease, which is still how should we best treat even the first episode or the frequently relapsing ones.
Speaker 3:Absolutely. Unfortunately, despite these differences would you highlight, we may still be as adult nephrologists looking at the paediatric realm when it comes to how to provide management for our patients. So are there any closing remarks that you guys wanted to make? Otherwise, I think this has been an insightful discussion about this Cochrane review and hopefully it stimulates not just better practice, but also a desire to conduct high quality research into the future with international collaboration.
Speaker 4:I think that's what I would say is that the disease in adults just justifies good, well designed, adequately powered studies in this group of patients. We haven't got those to date.
Speaker 1:I can only say the same. I hope that this work might be a stimulation highlighting the need of trials and highlighting what Elizabeth very well pointed out.
Speaker 3:Well, you for first of all completing an important systematic review in this space, as well as summarising it and hopefully guiding our community forward. I'd like to thank everyone for their time and hope everyone got something out of this podcast.