Long-Term Use of MMF Associated With Less Risk of Late Rejection
Dr. Herwig-Ulf Meier-Kriesche, Associate Professor of Medicine, University of Florida College of Medicine, Gainesville, and his colleagues assessed the incidence of late acute rejection among patients remaining on mycophenolate mofetil (MMF) immunosuppression for a minimum of 12 months after kidney transplantation. This paper was presented at the American Transplant Congress Transplant 2002 in Washington, DC, April 26 - May 1, 2002. The following is an interview with Dr. Meier-Kriesche conducted by Dr. Susan Smith, Site Editor and Program Director of Medscape Transplantation.
Dr. Smith: The authors of another study presented at this meeting concluded that in a selected group of stable renal transplant recipients, discontinuation of MMF is safe with no increased risk of acute or chronic rejection. Why do you think the results of your study are divergent from this study?
Dr. Meier-Kriesche: As you said, this study was conducted in stable renal transplant recipients, and more specifically in patients without or with mild previous acute rejection episodes. In addition, the patients withdrawn from MMF in this study had stable renal function and no proteinuria. In other words, it was a very selected low-risk category of patients. In fact, less than 41% of patients available were judged to be low risk enough to be withdrawn from MMF in this study. The study concludes that in low-risk, stable patients, MMF withdrawal and conversion to azathioprine (AZA) might be a safe option. We have published a study in Transplantation that arrives at a similar conclusion.A note of caution, however; none of these studies have gone out beyond 3 years, and the final results with regard to late chronic rejection are not yet known.
Our study addresses the overall renal transplant population, which includes high-risk and low-risk patients. Even in patients without reported rejection episodes during the first year, there seemed to be a measurable benefit in patients who had been on MMF for at least a year compared with patients on AZA. The magnitude of the benefit in this lower-risk cohort of patients was less when compared with patients who had experienced a previous rejection episode. On the other hand, in African American renal transplant recipients who have been traditionally regarded as being at high risk for acute rejection, the associative benefit of MMF vs AZA appeared to be greater. In other words, it is possible to narrow down low-risk patient populations who might benefit less from newer, more potent immunosuppressive agents, and it is in fact up to the expertise of the transplant physician to customize the immunosuppressive regimen for each patient to maximize safety, tolerability, and health economic savings.
Dr. Smith: Why are African Americans at higher risk for late rejection, and can you explain the better outcomes in African American recipients treated under this protocol?
Dr. Meier-Kriesche: The answer to the first part of the question is that it is not completely clear why African Americans are at increased risk for acute rejection. It has been shown repeatedly that African Americans have a different immunosuppressive balance in the sense that they experience more acute rejection, while on the other hand they are less prone to infectious complications of immunosuppression. For this reason, African Americans are generally treated with stronger immunosuppressive regimens as compared with their Caucasian counterparts.
Any preventative drug benefit is more pronounced in patient populations at high risk for the event that is to be prevented. Conversely, in patients at low risk for an event, the likelihood of obtaining a beneficial effect is much lower. For example, any new immunosuppressive drug is unlikely to show any benefit in patients receiving transplants from identical siblings, as the chance for acute rejection is extremely low. For this reason, African Americans and other high-risk renal transplant candidates are particularly likely to benefit from newer, more efficacious agents such as MMF.
Dr. Smith: From a cost/benefit perspective, is the higher-priced MMF justified in lieu of AZA? If so, why?
Dr. Meier-Kriesche: This is a complex question and difficult to address. Our study did not include a pharmacoeconomic analysis. However, it follows that a drug that substantially decreases the risk of acute rejection has the benefits of less antirejection therapy; less comorbidity from rejection; and less need for antirejection therapy, hospitalization, and return to dialysis, all of which incur significant costs.
Cost-benefit analyses are particularly tricky in renal transplant recipients. Contrary to what is often quoted in the medical and lay literature, kidney transplantation is a life-saving procedure. Kidney transplantation significantly increases life expectancy. (In fact, life expectancy is doubled in younger kidney transplant recipients.) Patients who return to dialysis do not die immediately, but they do eventually die prematurely. This is the tricky part, because when patients die the costs stop. Longevity, on the other hand, intrinsically increases cost. And the better drugs, which are more expensive in the long run, increase costs globally. So the question becomes, What cost do you want to put on a life saved?
Dr. Smith: What are the benefits of this type of analysis and what are the weaknesses?
Dr. Meier-Kriesche: Overall, registry analyses are beneficial because of the large sample sizes and increased power that can be achieved -- which are necessary to answer certain questions and will never be possible in clinical trials. Furthermore, registry analyses yield "real life" data vs clinical laboratory data collected under the most ideal conditions. For example, in a clinical trial, patients are compliant with the protocol, even in some cases when the study drug has significant side effects, because of intense involvement of study coordinators and data collectors. However, in the real world, this same very good drug may not be successful due to patient noncompliance.
Weaknesses of registry analyses include the retrospective design and the fact that conclusions can be made only for the time period of the study. By the time the analysis is complete, it may be outdated. In addition, there are potential selection biases and potential explanatory variables that are not captured at all or not fully captured (ie, under-reporting, inaccurate reporting).
Specifically with regard to this analysis design, a certain danger lies in the comparison of patients who have been on treatment with either agent for 1 year. Patients who have lost their grafts, died, or switched immunosuppression within the first year are excluded. We had to make sure that the overall patient and graft survival was not significantly worse in the MMF group during the first year. In addition, we had to make sure that the drug switch did not leave us with a lower-risk population at 1 year in the MMF group. Our analysis led us to believe that, in fact, the opposite is true. Most of the drug switching that occurred was from AZA to MMF, likely in the attempt to intensify immunosuppression following an acute rejection episode. As these patients were excluded, the AZA group at 1 year was composed of relatively low-risk patients in whom no switching was considered necessary. Therefore, we believe that the specific bias of this study design was actually against finding a beneficial effect of MMF, and we feel relatively comfortable in believing that the effect we were able to demonstrate is real.