Prolonging Graft Survival in Kidney Transplant Recipients: Latest Strategies for Long-Term Immunosuppression Presentation 1

Transcription

1 Presentation 1 The following is a transcript from a web-based CME/CNE-certified multimedia activity. Interactivity applies only when viewing the activity online. This activity is supported by educational grants from Astellas Scientific and Medical Affairs, Inc. and Novartis Pharmaceuticals Corporation. Dr. Gaston: Hello, this is Dr. Robert Gaston from the University of Alabama at Birmingham. Welcome to this educational activity on long-term immunosuppression in renal transplantation. Joining me in this discussion today will be Dr. Arthur Matas from the University of Minnesota. The slides, transcript, audio, practice aids, and other activity features are available for download for easy access anytime, anywhere. After completing the activity, you can access the post-test and evaluation form by clicking the red Credit button. evaluation for CME/CNE credit: 1

2 Presentation 1 Disclosures Course Director and Moderator Robert S. Gaston, MD, has a financial interest/relationship or affiliation in the form of: Consultant for Astellas Pharma US, Inc. Grant/Research Support from Bristol-Myers Squibb Company and Veloxis Pharmaceuticals A/S. Advisory Board for Astellas Pharma US, Inc. Other Financial or Material Support from Journal of the American Society of Nephrology for editorial board involvement. Dr. Gaston has also received other financial material support as a speaker for a CME symposium - Sanofi. Interviewee Arthur J. Matas, MD, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from Astellas Pharma US, Inc.; Bristol-Myers Squibb; Novartis Corporation; Pfizer Inc.; and sanofi-aventis. Honoraria from Astellas Pharma US, Inc. and sanofi-aventis. Advisory Board for Bristol-Myers Squibb and Veloxis Pharmaceuticals. Medical Director Regina Janesko, MS PVI, PeerView Institute for Medical Education Regina Janesko, MS, has no financial interests/relationships or affiliations in relation to this activity. All additional planning committee members, PVI, PeerView Institute for Medical Education, Inc. staff, and Purdue University College of Pharmacy staff have no relationships to disclose. evaluation for CME/CNE credit: 2

3 Presentation 1 Selecting and Optimizing Long-Term for Kidney-Transplant Recipients BPM: beats per minute; CKD: chronic kidney disease; FSGS: focal segmental glomerulosclerosis. Dr. Gaston: Our discussion today is about immunosuppression, and it's a pleasure to have Dr. Arthur Matas with us. Like every good educational encounter, this one will begin with a clinical presentation. We have selected a patient, T.J. He is a 58-year-old African American gentleman who is receiving a deceased donor kidney transplant for chronic kidney disease due to focal glomerulosclerosis, which has been biopsy proven. He has been on dialysis approximately seven years prior to the transplant. He's a nonsmoker, a nondrinker. He is slightly overweight and has type 2 diabetes that has been controlled with diet and oral agents. Physical exam at the time of transplantation is largely unremarkable apart from his functional AV fistula in the left forearm. evaluation for CME/CNE credit: 3

4 Presentation 1 Dr. Gaston: I think in selecting immunosuppression, what are your thoughts about induction in a patient like this? Dr. Matas: We actually believe that induction is important for all patients. To us, one of the major risk factors after transplant is a rejection episode and, with induction, you decrease the risk of rejection. And I think, particularly in a person who has multiple risk factors for rejection, as this patient does, induction really ought to be used. Dr. Gaston: So we agree fully, and induction is the norm in essentially all of the patients at UAB, as well. Do you have a preference in terms of induction agents? Dr. Matas: We've always had a preference for a polyclonal agent. And currently, we're using thymoglobulin for essentially all of our patients. Dr. Gaston: Well, I think that we have taken pretty much the same approach. And we would say that we're committed to depletional induction, and some of the patients get [alemtuzumab], and some thymoglobulin. But we use that for the same reason you guys evaluation for CME/CNE credit: 4

5 Presentation 1 do, with the idea that avoiding rejection in the early post-transplant course is an essential component of choosing immunosuppressive therapies. evaluation for CME/CNE credit: 5

6 Presentation 1 CNI: calcineurin inhibitor; CVD: cardiovascular disease; HCV: hepatitis C virus; NODAT: new-onset diabetes after transplantation. Dr. Gaston: Beyond that, there are numerous other factors that can influence immunosuppression selection. Some of these are patient-derived, such as the number of the transplant, the level of pre-sensitization, ethnicity particularly African Americans in our center and the prior immunosuppressive burden that the patient has experienced. Other issues include potential for the side effect profile involving the risk for things like new-onset diabetes; other comorbidities, such as preexisting cardiovascular disease; whether or not the patient has multi-organ transplant, prior cancer, hyperlipidemia, and so on. And then finally, I think [we use] just a general approach to try and minimize the overall immunosuppressive burden. evaluation for CME/CNE credit: 6

7 Presentation 1 ER: extended release; MMF: mycophenolate mofetil; MPS: mycophenolate sodium; mtor: mammalian target of rapamycin Accessed October 29, Dr. Gaston: Arthur, how do you guys incorporate all of these variables in choosing immunosuppression beyond just the induction that we've already talked about? Dr. Matas: Certainly, in terms of maintenance therapy, we would consider risk factors in terms of immunosuppression. We actually use both CNI inhibitors, and we're more likely to use cyclosporine in a patient who has much higher risks for diabetes, whereas we're more likely to use tacrolimus in a patient in whom we're particularly worried about having a high immunologic risk, and therefore more likely to be at risk for rejection. evaluation for CME/CNE credit: 7

8 Presentation 1 CsA: cyclosporine A; KTR: kidney-transplant recipient; SRL: sirolimus; TAC: tacrolimus. 1. Kandaswamy R et al. Am J Transplant. 2005;5: Dr. Gaston: If you look at the entire sort of compendium of agents available to us, how would you choose among these agents for maintenance therapy in a patient such as we presented a few minutes ago? Dr. Matas: Well, again, although I realize and respect all the risk factors you've identified, we would tend to use diabetes and risk for rejection as the major risk factors. We've actually done a prospective randomized study comparing cyclosporine/mmf versus tacrolimus/sirolimus in a steroid-free protocol and found no real differences in outcome other than drug-specific side effects so a little bit more rejection with the cyclosporine and, with the tacrolimus/sirolimus arm of the study, we found more hyperlipidemia and more diabetes. But in terms of patient survival, graft survival, renal function, all were similar. evaluation for CME/CNE credit: 8

9 Presentation 1 GFR: glomerular filtration rate. Dr. Gaston: So the approach at our center in terms of overall immunosuppressive choices is that the primary goal is, again, built around preventing rejection, with all the other variables that we've been talking about really becoming secondary considerations in terms of risk of diabetes and addressing other comorbidities. We tend to treat patients with a fairly standard protocol that involves, after depletional induction, a combination of a calcineurin inhibitor and an antiproliferative agent with or without steroids. evaluation for CME/CNE credit: 9

10 Presentation 1 Dr. Gaston: So what would be your choice in this guy? Dr. Matas: Well, our choice in this particular patient would be influenced by the obesity and the concerns for wound problems with sirolimus. So we for sure would not use sirolimus in this patient at the beginning. In general, we avoid sirolimus early on unless there's some very specific circumstance. And again, because of the diabetes that he already has, I think, you know, you could argue either way. We would tend to use tacrolimus because of the high immunologic risk related to seven years of dialysis, being an African American, and receiving a deceased donor transplant. evaluation for CME/CNE credit: 10

11 Presentation 1 IMPDH: inosine-5 -monophosphate dehydrogenase. Dr. Gaston: At UAB, we would, after depletional induction, choose a regimen of tacrolimus, mycophenolate, and prednisone and proceed in that realm. Is there anything new in what both of our centers would consider standard approaches to immunosuppression? Dr. Matas: I think the new things have to do with minimization protocols, and they're being tested both CNI minimization and rapid discontinuation of prednisone. And I think there's data to support trying these protocols because of decreasing morbidity; not to try and increase necessary longevity of the graft, although CNI-free might do that. evaluation for CME/CNE credit: 11

12 Presentation 1 Dr. Matas: There's also another new drug that's been approved fairly recently, belatacept, which I think we're all trying to learn how to incorporate into our standard protocols. Dr. Gaston: Yeah, I think we would tend to shy away from, I would say, belatacept. We have to reconcile that as this goes forward. But I think we would be reluctant to use belatacept in this kind of a patient because of the native kidney disease and the high immunologic risk, and also the duration of dialysis as well. evaluation for CME/CNE credit: 12

13 Presentation 1 CCS: chronic low-dose corticosteroid therapy; CSWD: corticosteroid withdrawal. 1. Woodle ES et al. Ann Surg. 2008;248: Dr. Gaston: Is steroid-free immunosuppression now to be considered standard therapy? Dr. Matas: In my opinion, yes, but I recognize that some people don't agree with me. To date, no study has shown that steroid-free has any downside as long as you're comparing population to population, other than an increased risk of early rejection, which, in the meta-analyses, show a slight increased risk of easy-to-treat early rejection, but absolutely no difference in patient or graft survival or renal function at 5 years, but a clear benefit in terms of minimizing steroid-related side effects. I think you have to be careful that you compare population to population. So if you're comparing a high immunologic risk patient, they're going to be at high immunologic risk whether or not they're getting steroids. And I think it would be wrong to compare a high immunologic risk steroid-free patient to a low immunologic risk patient getting steroids. evaluation for CME/CNE credit: 13

14 Presentation 1 BCAR: biopsy-confirmed acute rejection; XL: extended-release tacrolimus. 1. Silva HT et al. Am J Transplant. 2007;7: Dr. Gaston: Studies that we've both been involved in have been fairly instrumental in documenting the importance of late acute rejection and in maintaining adequate immunosuppression over the long haul. Is there any interest in the new once-daily preparation of tacrolimus? Dr. Matas: I think that will be an important consideration. In theory, patient adherence might be better on a once-daily drug, and there are certainly some suggestions in the literature that that may be true. The problem is going to be that the patients have to take their other drugs twice a day, at least if they're taking [mycophenolate mofetil]. So the combination of once-a-day tacrolimus with a once-a-day mtor inhibitor might be a nice combination. But again, that has to be proven. Dr. Gaston: I think that achieving the right balance long term for the patients is indeed a challenge. Again, for our standard recipient, our long-term maintenance therapy is still built around tacrolimus and mycophenolate in general. evaluation for CME/CNE credit: 14

15 Presentation 1 I think for us long term, maintaining adequate immunosuppression many times is a bigger challenge than avoiding toxicity. The once-a-day tacrolimus preparations may facilitate more consistent exposure over time that's a potential benefit. But the trials to support that and thus far, I believe, the clinical experience remains to be determined. evaluation for CME/CNE credit: 15

16 Long-Term : Addressing Comorbidities and Adherence CMV: cytomegalovirus. Dr. Gaston: There are additional issues that go into selection of immunosuppressant therapy, particularly maintenance immunosuppressive therapy. These include comorbidities such as infectious complications, notably CMV, but also BK polyomavirus and Epstein-Barr virus, and also the long-term effects of immunosuppression in terms of malignancy. It's become increasingly recognized that adherence concerns really rotate around socioeconomic and patient factors and these in many ways overlap. Socioeconomic factors can be things like medication costs, limited social support, limited literacy, and even level of education. Among patient factors, the strongest variable is age. Certainly, patients with a history of psychiatric illness and ongoing substance abuse may be at risk as well. evaluation for CME/CNE credit: 16

17 IgA: immunoglobulin A; MPA: mycophenolic acid. Dr. Gaston: We'll move on to a case. And this is a patient who is a 26-year-old Caucasian woman who has received a deceased donor kidney. Her original renal disease is IgA nephropathy. She is CMV seropositive at the time of transplant, and her donor happened to be CMV seronegative. In terms of immunosuppression, she received depletional induction with antithymocyte globulin followed by a triple-therapy immunosuppression with tacrolimus, mycophenolate, and steroids. Notably, she was unable to afford viral prophylaxis and was thought to be at reasonably low risk, so she didn't undergo viral prophylaxis. Subsequently, about five months post-transplant, she developed a CMV syndrome and that caused the group caring for her to reassess her immunosuppression, particularly in view of optional therapy that included an mtor inhibitor, either everolimus or sirolimus. evaluation for CME/CNE credit: 17

18 EVR: everolimus. 1. Brennen D et al. Am J Transplant. 2011;11: Dr. Gaston: There are data that support a differential effect of these agents in terms of risk of infection and malignancy. The analysis was done by Dan Brennan, basically looking at almost 2,000 patients overall who had received a combination therapy that included calcineurin inhibitor prednisone with everolimus at a standard dose, everolimus at a bit of a higher dose, or mycophenolic acid. evaluation for CME/CNE credit: 18

19 CNI: calcineurin inhibitor; CSA: cyclosporin A; KTR: kidney-transplant recipient; SCC: squamous cell carcinoma. 1. Caroti L et al. Transplant Proc. 2012;44: Euvrard S et al. N Engl J Med. 2012;367: Dr. Gaston: Another interesting component of trying to minimize comorbidity is the impact of the mtor inhibitors on risk of malignancy. You see results from an Australian study in which patients who had recurrent squamous cell carcinomas underwent randomization either to stay on cyclosporin or to convert to everolimus. Those that converted to everolimus had dramatically reduced incidence of new squamous cell carcinomas. evaluation for CME/CNE credit: 19

20 HLA: human leukocyte antigen; TAC: tacrolimus. 1. Pascual M et al. N Engl J Med. 2002;346: Dr. Gaston: If you go to the next slide, you notice the summary of factors that we have toyed with as major causes of late allograft failure, and the feeling at the time that this article was written is that the things on the left, immunologic factors, were under very good control, and therefore the cause of late kidney graft failure must reside on the other side, with the nonimmunologic variables having to do with graft quality, hypertension, hyperlipidemia, perhaps BK virus, perhaps calcineurin inhibitor toxicity. Dr. Matas: I think that there are individual circumstances where one would consider changing immunosuppression. But again, to turn it around, the biggest risk factor that we know of for renal dysfunction long term is not taking your immunosuppression, which includes the doctors lowering your immunosuppression. So I think we have to be very, very careful. Dr. Gaston: I think the single greatest cardiovascular risk factor is also losing your allograft. evaluation for CME/CNE credit: 20

21 DeKAF: A Study of Factors That Affect Long-Term Kidney Transplant Function; DSA: donor-specific anti-hla antibody; LGF: late graft failure. 1. Gaston R et al. Transplantation. 2010;90: Dr. Gaston: We formerly thought that late allograft failure was the inalterable consequence of progressive graft dysfunction; that, in many ways, has been attributed to toxicity of immunosuppressant drugs. However, recent work has really swung the pendulum back in the other direction, that the major cause of late allograft failure likely reflects chronic immunologic injury or ongoing immunologic injury, or perhaps even episodic acute episodes of immunologic injury. But the bottom line is that we have to find ways to provide adequate immunosuppression long term. We explored that somewhat in the DeKAF study. In that study, a cohort of patients had been transplanted a mean of seven years prior to undergoing a for-cause biopsy. What was found is that patients who had evidence of activation of antibody responses were at substantial risk of graft failure, whereas those who had no evidence of either C4D or DSA on the biopsy actually did quite well over a fairly prolonged period of time. evaluation for CME/CNE credit: 21

22 Dr. Matas: The DeKAF study actually started with a number of investigators essentially saying that we don't understand late graft function, and deciding to biopsy all patients with slowly deteriorating grafts. And we were quite surprised to see a high rate of acute rejection, as well as a number of other individual entities. evaluation for CME/CNE credit: 22

23 CAD: cadaveric. 1. Gaston R et al. Transplant Proc. 1999;31:21S-23S. Dr. Gaston: One of the variables associated with difficulty in providing effective longterm immunosuppression has been the ability of patients to adhere to the regimens. We documented this in our population almost two decades ago, that the patients who identified themselves as nonadherent had dramatically increased risk of graft failure. Conversely, the patients that were presumably taking their medications had graft survival much longer than was considered typical for the entire cohort. So this link between nonadherence and ongoing immunologic injury is becoming stronger. evaluation for CME/CNE credit: 23

24 ABMR: antibody-mediated rejection; GN: glomerulonephritis; PVN: polyomavirus nephropathy. 1. Sellarés J et al. Am J Transplant. 2012;12: Dr. Gaston: This has sort of been revisited and rediscovered in some recent work. You can see data that basically shows that in patients undergoing for-cause biopsy that subsequently went on to lose their allograft. There's high risk of finding immunologic injury, predominantly antibody-mediated rejection, and, among those patients, almost half of them were overtly nonadherent. And so this link between nonadherence and ongoing immunologic injury is becoming stronger. Dr. Matas: We've studied nonadherence at our institution, and the patients who are nonadherent in the first three months are statistically significantly more likely to have late graft loss. I think you can have new-onset nonadherence late, and we see that particularly in children who have now grown to adolescence, and their nonadherence starts when they reach adolescence. evaluation for CME/CNE credit: 24

25 1. Wiebe C et al. Am J Transplant. 2012;12: Dr. Gaston: Recent work from the Winnipeg group with protocol biopsies over a 10-year period suggests that those patients who developed de novo donor-specific antibody are those at greatest risk of rejection, and among the patients who did develop de novo antibody, nonadherence was extremely common. evaluation for CME/CNE credit: 25

26 1. Prendergast M, Gaston R. Clin J Am Soc Nephrol. 2010;5: Dr. Gaston: So it seems reasonable that as we're trying to make decisions about longterm immunosuppression, that we do the best we can to try and come up with regimens that patients can adhere to. There are a number of risk factors that have been identified for nonadherence. The strongest risk factor that really cuts across numerous studies is that of youth and, again, we mentioned a bit earlier the high risk in adolescent patients. evaluation for CME/CNE credit: 26

27 1. Feldman H et al. Pharmacoepidemiol Drug Saf. 1999;8: Weng F et al. J Am Soc Nephrol. 2005;16: Claxton S et al. Clin Ther. 2001; 23: Iskedjian M et al. Clin Ther. 2002; 24: Howard A et al. AIDS. 2002;16: Diaz E et al. J Clin Psychiatry. 2004;65: Dr. Gaston: If you look at the relationship of a dosing regimen with adherence, you can find in lots of other fields studies in nontransplant patients that support simplification of dosing regimens. Medicine prescribed twice a day is taken much more faithfully than that prescribed four times a day and then once a day more faithfully than twice a day. And there's starting to emerge some studies in the transplant population that shows that patients tended to be significantly more adherent to once-daily dosing of immunosuppressants than to twice-daily dosing. That experience was broadened a bit and looked at frequency of adherence that made the gold standard being twice-daily dosing. As you went to once-daily dosing, the patients were much less likely to be nonadherent. As you went to three- to four-times-a-day dosing, they had significantly increased risk of nonadherence. How would you promote adherence? evaluation for CME/CNE credit: 27

28 Dr. Matas: I think that's hard to do. There's certainly been at least some suggestion or recommendations that switching to a once-a-day regimen might help. I think one of the real issues with nonadherence is that we don't really know if the patients don't take their medications. In fact, most of the time, because the patients live so far away, we don't even know if they're renewing their prescriptions. evaluation for CME/CNE credit: 28

29 Dr. Gaston: Certainly, as physicians, we can simplify the regimens as much as possible, but there are many behavioral interventions that may help. We have to make sure the patients are able to get their medications, reminder methods in terms of pill boxes are very popular, and then helping patients to develop routines around their medications, and also problem-solving strategies for when things are not going as they should. evaluation for CME/CNE credit: 29

30 GFR: glomerular filtration rate. Dr. Gaston: So to summarize, I think you can say these days that in terms of immunosuppression, induction is certainly the norm in the United States. I think the primary goal in choosing any immunosuppressive regimen is to prevent immunologic injury and graft failure. However, there are a number of secondary considerations. And, finally, regardless of how good the drugs are, the patients have to be able to take them, and nonadherence remains a major challenge in ensuring that our patients do well in the long run. Thanks very much for the time. evaluation for CME/CNE credit: 30

31 Narrator: This activity has been jointly sponsored by Purdue University College of Pharmacy and PVI, PeerView Institute for Medical Education. evaluation for CME/CNE credit: 31