1 Department of Internal Medicine, University of Florida College of Medicine, Gainesville, FL, USA, 2 ProSanos Corporation, La Jolla, CA, USA and 3 Roche Laboratories, Nutley, NJ, USA
Correspondence and offprint requests to: Herwig-Ulf Meier-Kriesche, MD, Division of Nephrology, University of Florida College of Medicine, 1600 SW Archer Road, Box 100224, Gainesville, FL 32610-0224, USA. E-mail: meierhu{at}medicine.ufl.edu
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Abstract |
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Methods. We analysed 5069 elderly (>65 years of age) primary renal allograft recipients treated with either MMF or AZA reported to the Scientific Registry of Transplant Recipients between 1988 and 2000, and compared rates of acute rejection, late acute rejection, graft survival, death-censored graft survival, patient survival and death with a functioning graft.
Results. In Cox proportional hazard models, MMF was associated with lower rates of late acute rejection with 12 (RR = 0.72, P = 0.11) and 24 months (RR = 0.50, P = 0.028) of continuous therapy. In univariate analysis (KaplanMeier), MMF was associated with improved patient (P = 0.0003) and graft (P<0.0001) survival vs AZA, and trends toward improved patient and graft survival in multivariate analyses.
Conclusions. These findings demonstrate the efficacy of MMF-based immunosuppression in elderly transplant recipients and do not suggest an increased risk of death compared to treatment with AZA.
Keywords: azathioprine; elderly patient; immunosuppression; mycophenolate mofetil; renal transplantation
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Introduction |
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Mycophenolate mofetil (MMF) is a potent antimetabolite, used increasingly as part of a standard triple drug immunosuppressive regimen [in combination with a calcineurin inhibitor (CNI; cyclosporine or tacrolimus) and corticosteroids] in renal transplantation. Multiple clinical studies comparing MMF to azathioprine (AZA) have demonstrated efficacy of MMF for the prevention of acute rejection episodes and treatment failures, while maintaining a good safety profile [68]. Small studies in elderly transplant recipients have reported that this population may be less susceptible to acute rejection than younger patients [9,10], but is at an increased risk of infectious complications [11,12]. It has been suggested that due to progressively impaired immune systems, elderly patients may require treatment with less intensive immunosuppressive agents [13,14], and may be more susceptible to over-immunosuppression, with sequelae including infection- and malignancy-related death. Recently, a single-centre, Australian, retrospective study reported that triple therapy with MMF was associated with reduced survival (patient and graft) compared to AZA-based triple therapy in elderly renal transplant recipients [15].
The excellent outcomes in kidney transplantation present the challenge of designing prospective studies with adequate power and follow-up to detect differences between interventions [16], especially for specific safety endpoints, such as death or, more specifically, infection- or malignancy-related death. Registries of adequate size and reporting quality can address these questions because of the potentially larger sample size and follow-up. When carefully acknowledging and accounting for potential selection biases, studies based on such registries can be of considerable value as a complement to prospective studies.
To investigate the risk-to-benefit relationship of MMF- vs AZA-based therapy in elderly renal transplant recipients, we assessed the risks of death and acute rejection using data from the Scientific Registry of Transplant Recipients (SRTR).
Patients and methods
Data from elderly (defined as age >65 years) renal transplant recipients recorded in the SRTR were analysed. Patients were included in the analysis if they received solitary, primary renal transplants between 1 October 1988 and 30 June 2000, and were discharged from the hospital on either MMF or AZA therapy. Patients were excluded from analysis if they were 65 years of age, underwent multiorgan transplant or second transplant, or if both MMF and AZA or neither MMF nor AZA were recorded as maintenance therapy at discharge. Patients were followed from initial transplantation date until the last follow-up visit available in the database, or the end study date of 31 July 2002, at which point data were censored.
The treatment course was determined by examining medications reported at discharge and subsequent follow-up visits, as recorded on the UNOS data collection forms. Discharge medications were used to classify patients into the MMF- or AZA-treatment group. Medications recorded at follow-up visits (6, 12 and 24 months post-transplantation) were used to determine post-transplantation therapy and to classify antiproliferative agent use as continuous, switched or discontinued for two follow-up periods: 12 and 24 months post-transplantation. For the purpose of this study, patients were considered to be on continuous therapy for each of the follow-up periods if the same therapy (MMF or AZA) was recorded at discharge, 6 and 12 months (12 months continuous therapy) post-transplantation, and 24 months (24 months continuous therapy) post-transplantation. Patients were considered to be switched or discontinued from discharge therapy if a different medication was recorded at any of the follow-up visits, or if both MMF and AZA were recorded as maintenance therapy during the 12- or 24-month post-transplantation periods.
The following outcomes were compared for the two treatment groups: acute rejection, graft survival, death-censored graft survival, patient survival and death with a functioning graft. The definition for an acute rejection episode was that the patient received treatment for acute rejection, as recorded on UNOS follow-up forms. To examine more accurately differences in late (i.e. beyond 1 year after transplantation) outcomes as described by Meier-Kriesche et al. [17], late acute rejection also was analysed as both 12- and 24-month minimum treatment analyses. Patients who remained on either MMF or AZA for (i) a minimum period of 12 months following transplantation, and (ii) a minimum of 24 months following transplantation were included in an intent-to-treat analysis. Patients were excluded from the minimum treatment analysis if discharge therapy was switched or discontinued during the 12- or 24-month post-transplantation periods.
Statistical analyses
Univariate KaplanMeier analysis was used to compare the MMF- and AZA-treatment groups by evaluating the fraction of patients who experienced late acute rejection, graft loss and death. P-values were calculated and log-rank tests performed to determine the statistical significance of differences between the two groups.
Cox proportional hazard models were used to investigate the independent effect of MMF on study endpoints while controlling for relevant risk factors, and to investigate the potential differences in graft loss and mortality rate between the two groups. A conditional backward elimination model was used to identify significant covariates and to reduce the model to the least amount of covariates necessary to account for potential selection biases. The multivariate analyses were corrected for seven potential confounding covariates: donor and recipient age, recipient race, degree of human leukocyte antigen (HLA) matching, living vs cadaveric donor, type of CNI used and transplant year. In the multivariate analysis for late acute rejection, a correction was made for acute rejection within the first year post-transplantation. Mean values were used for missing data. Univariate proportionality checks were performed to ensure that the Cox model assumptions were met.
A probability of type 1 error = 0.05 was considered the threshold of statistical significance. The statistical analyses were performed with SAS version 8.2 (Windows® NT version).
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Results |
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Acute rejection and late acute rejection
Acute rejection within the first 12 months post-transplantation was reported for 411 (24.0%) MMF-treated patients and 497 (28.2%) AZA-treated patients (P = 0.004). KaplanMeier analysis showed a significantly lower incidence of late acute rejection (i.e. episodes occurring beyond 1 year after transplantation) at 4 years in the MMF group compared to the AZA group [4.5% vs 17.0%, respectively (P<0.0001); Figure 1]. The Cox proportional hazard analysis (Table 2) showed that acute rejection in the first 12 months after transplantation is a strong risk factor for late acute rejection (RR = 1.31, P = 0.013). After controlling for acute rejection, MMF therapy was associated with a trend toward risk reduction (RR = 0.72, P = 0.109) for a late acute rejection episode compared to AZA therapy. In patients who had been on either MMF or AZA for at least 2 years, MMF was associated with a significantly lower incidence of late acute rejection 4 years post-transplantation (2.3 vs 12.6% for AZA; P<0.0001) and a 50% reduction (RR = 0.50, P = 0.028) in the risk of developing late acute rejection beyond 24 months post-transplantation vs AZA.
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Patient survival
KaplanMeier analysis showed a significantly higher rate of patient survival at 4 years post-transplantation in the MMF group (73.2%) compared to the AZA group [69.2% (P = 0.0003); Figure 3]. In the Cox proportional hazard analysis, no risk reduction was noted for patient death for treatment with MMF vs AZA (RR = 0.89, 95% CI 0.761.04), although a trend for improved outcomes was observed with MMF treatment. Having a living donor compared to a cadaveric donor was associated with a protective effect on patient survival (RR = 0.54, P<0.0001). Significant risk factors for patient death included having any HLA mismatch (RR = 1.21, P = 0.01), having an older donor (P<0.0001) or being an older recipient (P<0.0001).
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Subgroup analysis of living vs cadaveric donors
To determine if the benefits observed in the MMF group might be attributable to a larger proportion of living vs cadaveric donors, late acute rejection and graft and patient survival were examined by donor type for the two treatment groups. Univariate analyses showed a significantly lower incidence of late acute rejection at 4 years post-transplantation following at least 1 year of treatment in MMF vs AZA patients who received kidneys from living (3.1% vs 14.5%, respectively; P<0.0001) as well as cadaveric donors (5.0 vs 17.4%, respectively; P<0.0001). Findings were similar for acute rejection following at least 2 years of treatment [living donor: 1.7 vs 12.6% (P<0.0001) for MMF vs AZA, respectively; cadaveric donor: 2.5 vs 12.6% (P<0.0001), respectively]. MMF was associated with significantly higher rates of graft survival at 4 years compared to AZA therapy, independent of donor type [living donor: 79.4 vs 74.6% (P = 0.0143), respectively; cadaveric donor: 66.0 vs 61.6% (P = 0.0048), respectively]. Patient survival at 4 years was similar for MMF- and AZA-treated patients who received kidneys from living donors [80.4; and 78.9% (P = 0.0937), respectively]; however, a higher survival rate was observed for MMF patients (71.1%) than for AZA patients with cadaveric donors (67.8%; P = 0.018). Findings from multivariate analyses were similar to those observed for the overall study population (data not shown).
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Discussion |
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Previous reports [9,10,15] have shown a lower incidence of acute rejection in the elderly subpopulation vs the general adult population. Our study shows that the lowest rates of both early and late acute rejection were demonstrated in patients who were treated with MMF compared to patients treated with AZA. These results confirm an association between MMF and a lower incidence of acute rejection in the first year post-transplantation, and suggest for the first time, a benefit in reducing late acute rejection, beyond the first year of transplantation in elderly renal transplant patients. This is important because late acute rejection episodes are known to be associated with a higher risk for chronic allograft nephropathy and graft loss [18,19]. Furthermore, elderly patients are considered to be at a lower risk for acute rejection, but an elevated risk for death secondary to effects of overimmunosuppression. It is possible, however, that the lower risk for acute rejection in elderly renal transplant recipients might in fact be offset by the on-average, older organs transplanted into this population, which have been shown repeatedly to be associated with a higher risk for both early and late acute rejection [17].
Lower rates of acute rejection are thought generally to correlate with better overall graft survival. Data from our study suggest a possible benefit in terms of graft survival, as in the univariate analysis, there was a clear difference associated with MMF vs AZA therapy. However, this result may have been amplified, in part, by concomitant variations in possible confounding variables, as differences in graft survival observed in the multivariate analysis only came close to being significant.
MMF was also associated with better patient survival compared to AZA in the univariate analysis, but again in the multivariate analysis, the result did not reach statistical significance. As for overall graft survival, this finding could be due, in part, to the effect of confounding variables, but also possibly may be related to statistical power. These data can allow us to conclude that MMF likely did not jeopardize survival in elderly renal transplant recipients, and even provide some evidence of a potential benefit in the reduction of acute rejection and late acute rejection episodes, as well as a potential benefit of better graft survival.
The results of this study are in contrast to a recent retrospective study in which Johnson et al. [15] observed higher rates of actuarial survival at 2 years in patients treated with AZA vs MMF (100 and 87%, respectively). This finding may, in part, be explained by regional practice differences between Australia and the USA. In the USA, it was recognized relatively early that the enhanced immunosuppression conferred by MMF might be tolerated less by elderly renal transplant recipients. In a previous retrospective analysis conducted in the USA, an MMF-based regimen resulted in actuarial graft and patient survival rates at 1 year that were comparable to AZA-based regimens; however, it appeared to be associated with an increased risk of serious infections [20]. More recently, MMF has been employed largely as a CNI sparing agent, as well as to allow the possibility of lowering steroid doses. Such tailored treatment regimens are often used in elderly renal transplant recipients, who are more susceptible to infectious complications, and who more frequently receive organs that tend to be more fragile and susceptible to CNI toxicity because of advanced donor age. It is very possible, therefore, that the results of the current study reflect differences in doses and concomitant immunosuppression.
In this study, we could not analyse rates of infection, as data on non-fatal infectious complications are not reported to the SRTR. In addition, we did not feel that available data in the release of the SRTR used were adequate to analyse and draw conclusions regarding the rate of infectious deaths in this study. However, we did not observe an overall greater rate of patient death or graft loss in the MMF-treated patients, which one might expect if the serious opportunistic infection rate were relatively higher in this group.
The design of this study was meant to be as rigorous as possible in order to avoid potential positive bias for the study drug. The study design included transplant recipients from 1988 (earliest available data from the SRTR) through 2000, in order to capture as much transplant experience in the elderly sub-population. Because the clinical use of AZA has dramatically decreased (and MMF use increased) since 1997, the treatment groups are potentially reflective of transplant care from different eras. Our Cox proportional hazard model includes transplant year as a variable in effort to correct for any bias this may introduce. In addition, our analysis showed that transplant year was not a significant independent predictor for any of our study endpoints. In the stepwise elimination of variables, transplant year could be eliminated from the Cox regression model, since it was not statistically significant for any of the endpoints. In fact, excluding transplant year as a variable, resulted in no change to the conclusions of this study, with the exception that the late acute rejection endpoint for the 12-month treatment analysis did become statistically significant (RR = 0.64, P = 0.020) for MMF vs AZA treatment.
For the endpoint of late acute rejection, patients who lost their grafts, died or discontinued MMF or AZA within the first year were excluded by design. Therefore, we examined each of these as a potential source of bias. We confirmed that the overall patient and graft survival was not significantly worse in the MMF group during the first year. In addition, we investigated the impact of excluding patients who discontinued therapy. Most of the drug switching occurred from AZA to MMF, likely in the attempt to intensify immunosuppression following an acute rejection episode. As a result of excluding these patients, the AZA group at 1 year consisted of relatively low-risk patients for whom no therapy change was necessary. Therefore, we believe that the specific bias of this study design was actually against finding a beneficial effect of MMF, and that the effect we have demonstrated is as free of potential bias as is possible.
Several data limitations preclude a full description of the clinical usage pattern of MMF and AZA in conjunction with CNIs. The SRTR database contains no information about drug dosing or whether medications are discontinued between visits, and therefore we cannot determine the dose or exact duration of MMF vs AZA. Nor can any conclusions be drawn regarding CNI reduction or elimination strategies. Finally, since patients are not randomized to treatment groups, we cannot exclude a single-centre bias, if a particular treatment was preferentially used for either high- or low-risk patients at one or more transplant centres.
In summary, our analysis indicates that in elderly renal transplant recipients, MMF is associated with lower early and late acute rejection rates compared to AZA, and that the benefits of MMF-based immunosuppression in elderly renal transplant patients occur without compromising patient survival.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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