Mycophenolate mofetil is associated with less death with function than azathioprine in cadaveric renal transplantation
Mark A. Schnitzler1,2,,
Karen E. Craig6,
Karen E. Hardinger5,
Jeffrey A. Lowell1,3 and
Daniel C. Brennan1,4
1 Pharmaco-economic Transplant Research,
2 The Health Administration Program,
3 Department of Surgery and
4 Department of Internal Medicine, Washington University School of Medicine,
5 The Saint Louis College of Pharmacy, St Louis, MI and
6 Arkansas Children's Hospital, Little Rock, AR, USA
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Abstract
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Background. A previous study has argued that mycophenolate mofetil (MMF) is associated with a reduced incidence of death with function when compared to azathioprine (AZA) in cadaveric renal transplantation. This study was designed to verify this result because methodological issues bring these findings into question.
Methods. The data used in this study was derived from records of renal transplants performed in 1995 and 1996 as recorded in the UNOS Scientific Renal Transplant Registry and supplied by the United States Renal Data System (USRDS). Univariate and multivariate survival analysis was used to compare rates of death with function. Covariate characteristics of the donor, recipient, procedures, early outcomes and the transplant centre were considered.
Results. 12 251 recipients of cadaveric renal transplants were identified as having received either MMF or AZA, but not both. The relative risk of death with function calculated by the KaplanMeier method was 21% less for MMF patients (P=0.005). MMF had from 21% (P=0.008) to 24% (P=0.001) reductions in relative risk by multivariate methods.
Conclusions. The use of MMF is associated with a reduction in the incidence of death with a functioning graft in cadaveric renal transplantation. These results verify previous analyses.
Keywords: azathioprine; cadaveric renal transplantation; death with function; immunosuppression; mycophenolate mofetil
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Introduction
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Death with a functioning graft has become the most common cause of graft loss after renal transplantation [1]. This is due in part to the array of comorbid conditions existing in the recipient population prior to transplant combined with steady reductions in graft loss due to acute rejection and other causes because of advances in medical management and immunosuppression. However, more effective immunosuppression has brought with the reductions in acute rejection risk increased rates of complications such as infections, diabetes, hyperlipidaemia, and others, all of which may increase the risk of death with function [24].
In a randomized clinical trial, mycophenolate mofetil (MMF), compared to azathioprine (AZA), has been shown to significantly reduce the incidence of acute rejection in cadaveric renal transplant recipients [5]. There was also a trend toward superior graft survival for patients treated with MMF, however, there was no significant effect observed on patient survival. More recently, MMF has been shown in registry data to have significantly superior graft and patient survival when compared to AZA [6,7]. It has also been argued with registry data that MMF reduces death with function at 3 years post-transplant [8]. However, this analysis has an important flaw. Patients who received transplants between 1988 and 1997 were included, while MMF became available in 1995, possibly improperly attributing to MMF the benefits of improvements in medicine between the late 1980s and late 1990s. Furthermore, 3 year results were published while 3 years of follow-up was available for very few patients who received MMF. This study was designed to correct the problems with the existing analysis and verify the relative effects of MMF and AZA on death with a functioning graft in cadaveric renal transplantation.
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Materials and methods
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Data
The data used in this study was derived from records of renal transplants performed in 1995 and 1996 as recorded in the UNOS Scientific Renal Transplant Registry and supplied by the United States Renal Data System (USRDS) [9,10]. The USRDS is a joint effort of the National Institute of Diabetes and Digestive and Kidney Diseases, and the Health Care Financing Administration (HCFA). It was designed to collect, analyse and distribute data describing ESRD in the United States including: prevalence, treatment modality, survival and cost of care. For the purposes of the proposed study, the USRDS provides information for all transplants performed in the United States recorded in the UNOS renal transplant registry.
Following an intention to treat methodology, patients were considered to be MMF patients if they were discharged from their transplant hospitalization with MMF but not AZA recorded in their immunosuppression regimen. Similarly, AZA patients were required to have AZA but not MMF recorded in their immunosuppression regimen at transplant discharge. Indicator covariates were coded to measure the recorded presence of the factor with missing and unknown information included with negative responses. Missing or unknown values of continuous covariates were replaced with the mean known value. Peak panel reactive antibody (PRA) was the most commonly missing covariate and was missing in 13.7% of cases. No significant pattern of missing values was observed for MMF or AZA. These data conservation methods will tend to understate the magnitude and significance of covariate factors.
Covariate characteristics of the donor, recipient, procedures, early outcomes and the transplant centre were considered. These included: in the donor: body mass index, age, age <5 years or >55 years, race, gender, terminal serum creatinine, terminal serum creatinine >2.5 mg/dl, blood urea nitrogen >50 mg/dl, cause of death, HLA mismatches, HLA DR mismatches, CREG mismatches, positive B- or T-cell crossmatch, ABO incompatibility, Rh incompatibility, pre-treatments, infection, histories of: cigarette use, alcohol use, illegal drug use, hypertension or diabetes, non-heart beating donor, CMV serology; in the recipient: peak PRA, peak PRA >10% and >80%, body mass index, age, age >60 years, race, gender, diabetes, insulin dependence, peripheral vascular disease, chronic obstructive pulmonary disease, CMV serology, physical limitations, employment limitations, pre-transplant transfusions, pre-transplant dialysis, type of dialysis, previous pregnancies, previous kidney and/or other transplants, multi-organ recipient, kidneypancreas recipient, and characteristics of the recipient's area of residence by zip code according to the 1990 US census including: the percent of adult residents who have graduated from high school, the percent of adult residents who have received bachelor's degrees, and median income; procedures, early outcomes and transplant centre characteristics: year of transplant, cold ischaemia time, cold ischaemia time >24 h, warm ischaemia time, warm ischaemia time >60 min, antibody induction therapy, pulsutile perfusion, immunosuppression based upon cyclosporine, tacrolimus, or neither, unknown calcineurin inhibitor use, post-transplant dialysis, delayed urine production, rejection prior to transplant discharge, transplant centre volume of kidney transplants between 1990 and 1994, and transplant centre 1 year cadaveric graft survival fraction for transplants performed between 1990 and 1994.
Statistics
Differences in the characteristics of patients treated with MMF compared to AZA were tested with Student's t-test for continuous variables, Fisher's exact test for binary categorical variables, chi-square for multi-categorical variables, and the MantelHaenszel chi-square for ordered multi-categorical variables. Differences in the incidence of death with function were calculated using survival analysis techniques. Patients were considered to be at risk of death with function during the period from transplant until graft failure from a cause other than death or end of follow-up and were censored from the analysis thereafter. Univariate survival analysis was performed with the KaplanMeier methodology. Multivariate survival analysis was performed with Cox regression. Covariates were drawn from the lists of donor, recipient, procedures, early outcomes and the transplant centre characteristics noted above. All interactions between these covariates and MMF and AZA were also considered. Numerous covariates were insignificant. The inclusion of large lists of insignificant variables may produce misspecification bias [11]. To analyse this large set of covariates, given the possible problems of misspecification bias, we used stepwise variable selection methods and compared the results to models with the full list of variables. All statistical tests were two-tailed. P-values were required to be <0.05 for significance in univariate comparisons. P-values <0.01 were required for significance in multivariate models due to the large number of covariates considered.
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Results
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Between 1 January 1995 and 31 December 1996, 23 842 renal transplants were performed in the United States and subsequently recorded in the UNOS Scientific Renal Transplant Registry. Cadaveric donors accounted for 16 970 of the transplants in these 2 years. Among the recipients of cadaveric donors, 4493 did not have an indication that either MMF or AZA was used and 226 had both indicated. After restricting the sample to cadaveric kidney recipients who received MMF or AZA but not both, 12 251 subjects remained in the study.
MMF was used in 4938 patients and AZA in 7313. Significant differences by MMF compared to AZA were found for 31 characteristics (Table 1
).
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Table 1. Donor, recipient, procedural, early outcome and centre characteristics associated significantly with MMF use
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The relative risk of death with function through 3 years post-transplant was higher in AZA-treated patients (6.7%) compared to MMF-treated patients (5.3%) (P=0.005) (Figure 1
). Death rates from all causes were also higher in AZA-treated patients (10.4%) compared to MMF-treated patients (9.2%) (P=0.014). MMF is associated with a 21% reduction in unadjusted relative risk of death with function by 3 years post-transplant compared to AZA. Therefore, the number needed to treat with MMF relative to AZA to prevent one graft loss due to death with function by 3 years post-transplant is 72.

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Fig. 1. Incidence of death with a functioning graft through 1095 days (3 years) post-transplant. The incidence of death with function through 3 years post-transplant was significantly greater in patients treated with AZA (6.7%) compared to MMF (5.3%), log-rank P=0.005. Calculations were made using the KaplanMeier method accounting for censoring due to graft loss from a reason other than death and end of follow-up.
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Several multivariate Cox survival models were estimated to assess the importance of covariate factors on the observed effect of MMF on death with function. The first included only a variable indicating MMF use, verifying the KaplanMeier results, with an estimated reduction in relative risk of death with function of 21% compared to AZA (P=0.005). The second model included all of the variables listed in Methods. MMF continued to show the same effect on death with function, a reduction in relative risk of 21% of that with AZA (P=0.008). However, it is likely that this model was misspecified, with the great majority of variables highly insignificant. Therefore, stepwise selection methods were used to identify a model containing variables that have a significant relationship to death with function. In this equation, MMF reduced the relative risk of death with function by 24% compared to AZA (P=0.001). Significant covariates included: recipient age, increasing risk by 4% per year (P<0.001); need for dialysis prior to transplant discharge, increasing risk by 83% (P<0.001); recipient diabetes, increasing risk by 81% (P<0.001); pre-transplant transfusions, increasing risk by 35% (P<0.001); peripheral vascular disease, increasing risk by 59% (P=0.001); and warm ischaemia time >60 min, increasing risk by 49% (P=0.009). The effects of interactions between MMF compared to AZA and each covariate were tested collectively and individually. No interactions were found to be significant.
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Discussion
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We have verified that the use of MMF compared to AZA reduces the relative risk of death with function in cadaveric renal transplantation. The estimated effect ranged from a 21 to 24% reduction in relative risk of death with function with MMF compared to AZA. The magnitude of this effect is smaller than previous estimates ranging from 33 to 41% reductions in death with function associated with MMF [8]. The differences may be due in part to the study period of the previous study.
This study and any retrospective study of registry data, has the potential to incorrectly attribute effects to treatments. The patients in a retrospective study, such as this, have not been randomized in a controlled manner, but instead appear in the MMF and AZA groups through their selection of transplant centre and the decision of the physicians at those centres. Differences in characteristics of patients may have in part caused patients to be in either the MMF or AZA groups, as is suggested by Table 1
. Extensive control methods were used in this study accounting for a wide variety of donor, recipient, procedure, early outcome and the transplant centre characteristics including possible interactions with the choice of MMF or AZA. These controls tended to increase the estimated reduction in death with function attributable to MMF compared to AZA. While the difference is slight, it suggests that patients who received MMF in 1995 and 1996 were at a lower relative risk of death with function than AZA patients. Therefore, we expect that a randomized trial of sufficient size would show a larger effect than that estimated here. However, more than 2000 patients would need to be enrolled, randomized, and followed for 3 years to properly assess the magnitude of the expected reduction in death with function due to MMF compared to AZA. A clinical trial of such magnitude is unlikely; therefore, we will have to rely on the retrospective evidence that we have arguing that MMF reduces death with function compared to AZA.
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Acknowledgments
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The data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the the USRDS, NIDDK or the US Government. This work was funded in part by a grant from Hoffman-La-Roche.
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Notes
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Correspondence and offprint requests to: Mark A. Schnitzler, PhD, The Health Administration Program, Washington University School of Medicine, 4547 Clayton Avenue, St Louis, MI 63110, USA. Email: schnitz{at}wueconc.wustl.edu 
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Received for publication: 18. 6.02
Accepted in revised form: 8. 1.03