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Keywords:

  • Graft survival;
  • late acute rejection;
  • long-term outcomes;
  • patient survival

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described.

To investigate the risk of LAR (rejection ≥6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation.

Kaplan–Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6–12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001).

Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

With advances in immunosuppression, graft and patient survival rates have significantly increased since 1995 (1). This improvement has largely been the result of more accurate diagnoses, more potent immunosuppressive agents and improved post-operative care. In this setting, clinical practice has evolved toward minimization and withdrawal protocols, in an attempt to avoid complications of immunosuppression like nephrotoxicity, infection and malignancy. Maintenance immunosuppression is largely empiric, and is often given with the assumption that all grafts have a similar risk of rejection. This practice may lead to delayed rejection episodes, as late acute rejection (LAR) has been generally associated with sub-therapeutic levels of immunosuppression (2,3).

The majority of acute cellular rejection episodes occur early, usually within 6 weeks post-transplantation. Early episodes usually resolve with anti-rejection treatment, and are not associated with clinically significant architectural changes or graft loss (4). Compared to early rejection, late episodes occur in a smaller percentage of recipients (5), and with important sequelae, such as exposure to more immunosuppression, and the potential for increased risk of late complications (5,6). Some risk factors for late rejection have been identified, such as underlying liver disease (6,7), noncompliance and sub-therapeutic levels of calcineurin inhibitors (CNIs) (2,3). Yet, the role of specific immunosuppressive regimens in LAR has not been fully investigated.

The efficacy of mycophenolate mofetil (MMF) administered in combination with cyclosporine and corticosteroids for reduction of acute rejection has been demonstrated relative to azathioprine (8). In addition, MMF used in a triple-drug regimen (MMF with tacrolimus and corticosteroids) has been shown to decrease acute rejection rates, as compared to a double-drug regimen (tacrolimus and corticosteroids) (9). In clinical practice, MMF often is discontinued within 4 to 6 months following transplantation, despite growing evidence that this is an efficacious and safe regimen over the long term (9,10).

To examine the impact of continuous (long-term) maintenance immunosuppression including MMF, we used data from the Scientific Registry of Transplant Recipients (SRTR) to analyze LAR, and the impact of LAR episodes on graft and patient survival, for patients undergoing primary liver transplantation. Because tacrolimus has replaced cyclosporine as the CNI of choice for liver transplantation in the United States in recent years (11), we compared outcomes in patients who received tacrolimus-based immunosuppression with and without MMF. Due to previous reports (5) that recipients with viral cause of underlying liver disease were at reduced risk for but increased consequence of LAR, we analyzed LAR outcomes in the subset of patients with hepatitis C, hepatitis B and nonviral disease.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Data reported to the SRTR, September 2004 release for patients between the ages of 18 and 80 years who underwent primary, single-organ, liver transplantation in the United States between June 1, 1995, and April 30, 2004, were analyzed. Only patients who were discharged from the hospital on tacrolimus-based immunosuppression therapy (i.e. tacrolimus and corticosteroids) with or without MMF were included in the analysis. Continuous treatment was determined based on whether a patient was recorded as being on the same treatment regimen at discharge and at 6-month follow-up visit (6 months continuous therapy) or at discharge, and at 6 and 12 month follow-ups (12 months continuous therapy). Patients were included who were discharged on MMF + tracrolimus + steroids or tacrolimus + steroids, and who continued to receive original discharge immunosuppression 6 months (n = 9646; MMF + Tac + steroids = 4154, Tac + steroids = 5492) and 12 months (n = 4709; MMF + Tac + steroids = 1497, Tac + steroids = 3212) post-transplant. Rates of LAR, defined as an episode of rejection that occurred beyond 6 months post-transplantation, were determined and compared between the treatment groups. A patient was determined to have a rejection episode if it was recorded that the patient received treatment for rejection since the last follow-up visit. Effects of immunosuppression treatment on time to LAR were also examined for 6-month continuous-therapy sub-populations; hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) and nonviral disease (n = 5740) were sub-groups of interest. Relative risks on outcomes were analyzed using Kaplan–Meier analyses and Cox proportional hazard models correcting for demographic and clinical covariates.

Patients who received cyclosporine or other nontacrolimus immunosuppression at discharge were excluded from the analysis (6520 patients). Follow-up data were obtained 6 and 12 months post-transplantation, and annually thereafter, up to June 30, 2004, or as long as data were available.

In the 12-month continuous-therapy population, late graft and patient survival rates were determined for groups based on the presence (or absence) and timing of a rejection episode (i.e. early rejection, occurring between 0 and less than 6 months post-transplantation; and LAR, occurring between 6 and 12 months post-transplantation). Differences between groups were compared using the log-rank test. Cox proportional hazard models were used to investigate the independent effects of multiple covariates on graft and patient survival.

Categorical covariates were transformed into sets of binary variables, with one variable from each set omitted to represent the reference group. Patients with missing data were included in the analysis, but missing values were imputed as follows: race (n = 8) was replaced with other race, pre-transplant serum creatinine (n = 391) was replaced with serum creatinine <2 mg/dL, pre-transplantation hospitalization status (n = 17) was replaced with not hospitalized and donor age (n = 11) was replaced with mean donor age. The September 2004 release of the SRTR did not contain all data required for calculation of Model for End Stage Liver Disease or Child-Pugh scores; therefore, hospitalization status at the time of listing (i.e. in the intensive care unit [ICU], hospitalized or not hospitalized) was used as an estimate of pre-transplant liver disease severity. Demographic and baseline clinical characteristic data were summarized with descriptive statistics. A p-value of less than 0.05 was used to determine statistical significance. All analyses were performed using SAS Release 8.2 (SAS Institute, Cary, NC, USA; Windows XP).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Patient population

A total of 9646 patients (4154 MMF, tacrolimus and steroids; 5492 tacrolimus and steroids) between the ages 18 and 78 years (mean age 50.5 ± 10.1) were included in the study. The population was predominantly male (63.8%) and Caucasian (87.2%). The two treatment groups were well matched in terms of recipient and donor characteristics (Table 1). Only a small percentage of patients underwent live donor transplantation (7.5% MMF, tacrolimus and steroids; 3.9% tacrolimus and steroids). Mean length of follow-up was 2.7 years for patients who received MMF, tacrolimus and steroids and 3.6 years for patients treated with tacrolimus and steroids alone; maximum length of follow-up was 8.0 and 8.4 years, respectively. The study included 3356 patients with HCV (1402 MMF, tacrolimus and steroids; 1954 tacrolimus and steroids). Demographic and clinical characteristics for the sub-group of patients with HCV and nonviral disease were similar to the overall study population (data not shown). HBV recipients (n = 550) were represented by a higher proportion of male (78.2%) and other race (e.g. Asian, American Indian and other) (35.6%), compared to the HCV and nonviral groups. More HBV recipients had severe disease, indicated by pre-transplantation ICU stay (23.3%) (data not shown).

Table 1.  Demographic and baseline clinical characteristics
VariableMMF + tacro + steroids (n = 4154)Tacro + steroids (n = 5492)p-value
Recipient
 Age (years)
  Mean ± SD50.2 ± 10.050.8 ± 10.20.005
  Minimum1818 
  Maximum7778 
 Gender
  Female1524 (36.7%)1970 (35.9%)0.408
  Male2630 (63.3%)3522 (64.1%) 
 Race
  Caucasian3597 (86.6%)4812 (87.6%)0.135
  African American300 (7.2%)336 (6.1%)0.031
  Other race257 (6.2%)344 (6.3%)0.877
 Weight (kg; mean ± SD)83.4 ± 19.380.9 ± 17.9<0.001
 Pre-transplant liver disease
  HCV1402 (33.7%)1954 (35.6%)0.062
  HBV210 (5.1%)340 (6.2%)0.017
  Nonviral disease2542 (61.2%)3198 (58.2%)0.003
 Pre-transplant serum creatinine ≥2 mg/dL385 (9.3%)380 (6.9%)<0.001
 Pre-transplant hospitalization status
  In ICU667 (16.1%)707 (12.9%)<0.001
  Hospitalized560 (13.5%)897 (16.3%)<0.001
  Not hospitalized2927 (70.5%)3888 (70.8%)0.723
 Length of follow-up (years)
  Mean2.73.6<0.001
  Median2.03.0 
  Maximum8.08.3 
Donor
 Age (years)
  Mean ± SD38.6 ± 17.138.5 ± 17.20.824
  Minimum31 
  Maximum9084 
 Gender
  Female1646 (39.6%)2188 (39.8%)0.831
  Male2508 (60.4%)3304 (60.2%) 
 Type
  Deceased3842 (92.5%)5276 (96.1%)<0.001
  Living312 (7.5%)216 (3.9%) 

LAR in recipient sub-populations who received 6 months continuous therapy

Hepatitis C:  Freedom from LAR was significantly higher for HCV-infected recipients whose treatment included MMF at discharge compared to treatment with tacrolimus and steroids alone (p = 0.001), with 4-year freedom from rejection rates of 87.0% versus 81.3%, respectively (Figure 1A). Cox regression analysis demonstrated that MMF at discharge contributed independently to a reduction in the risk of LAR (hazard ratio [HR]= 0.75, p = 0.003). The strongest risk factor (and only statistically significant factor) for LAR in patients with HCV was whether the patients experienced early rejection within the first 6 months post-transplantation (HR = 3.83, p < 0.001). Receiving a transplant in a later year was associated with a reduced risk for LAR (HR = 0.86, p = 0 < 0.001). Being an older recipient showed a trend toward a reduced risk for LAR (HR = 0.90 per decade, p = 0.073), but this result did not reach statistical significance (Table 2).

image

Figure 1. Kaplan-Meier analysis of freedom from LAR in liver transplant recipients with hepatitis C (A), hepatitis B (B) and with nonviral liver disease (C) following 6 months continuous treatment with MMF, tacrolimus and corticosteroids or tacrolimus and corticosteroids alone.

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Table 2.  Cox regression analysis: Selected1 covariates for LAR in hepatitis C, hepatitis B and nonviral disease liver transplant sub-populations
Variable (reference group)Hepatitis CHepatitis BNonviral disease
HR95% CIpHR95% CIpHR95% CIp
  1. 1Other variables included in the multivariable model (and reference group) were pre-transplant ICU stay, hospitalized (not hospitalized); cytomegalovirus (CMV) +D/−R, +D/+R, −D/+R (−D/−R), donor age 21–30 years (0–20 years), donor age 31–40 years (0–20 years), donor age 41–50 years (0–20 years), donor age 51–60 years (0–20 years), donor age >60 years (0–20 years); cold ischemia time (CIT) ≥2 hours (CIT < 12 hours). Variables that violated the proportionality assumption were eliminated.

Treatment at discharge
 MMF + tacrolimus + steroids (tacarolimus + steroids)0.750.62–0.910.0030.530.29, 0.960.0360.870.75, 0.990.041
Recipient factors
 Recipient age (per 10 years)0.900.81, 1.100.0740.840.68, 1.040.1080.920.87, 0.970.003
 African American race (Caucasian/other)0.890.61, 1.300.5461.100.50, 2.410.8041.861.51, 2.28<0.001
 Pre-transplant serum creatinine ≥2 mg/dL (serum creatinine <2 mg/dL)0.780.52, 1.150.2081.550.75, 3.220.2391.140.91, 1.430.253
 Acute rejection in first 6 months post-transplant (no rejection)3.833.18, 4.61<0.0013.482.05, 5.91<0.0013.342.93, 3.81<0.001
Transplant factors
 Transplant year (per year, 1995 + 96)0.860.82, 0.90<0.0010.750.66, 0.85<0.0010.880.86, 0.91<0.001

Hepatitis B:  Freedom from LAR was significantly higher for HBV-infected recipients whose treatment included MMF at discharge compared to treatment with tacrolimus and steroids alone (p = 0.001), with 4-year freedom from rejection rates of 92.6% versus 81.8%, respectively (Figure 1B). Cox regression analysis demonstrated that MMF at discharge contributed independently to a reduction in the risk of LAR (HR = 0.53, p = 0.036). The strongest risk factor (and only statistically significant factor) for LAR in patients with HBV was whether the patients experienced early rejection within the first 6 months post-transplantation (HR = 3.48, p < 0.001). Receiving a transplant in a later year was associated with a reduced risk for LAR (HR = 0.75, p = 0 < 0.001). Being an older recipient was associated with a trend toward a reduced risk for LAR (HR = 0.84 per decade, p = 0.108), but this result did not reach statistical significance (Table 2).

Nonviral:  Freedom from LAR was significantly greater for nonviral disease recipients whose treatment included MMF at discharge compared to treatment with tacrolimus and steroids alone (p < 0.001), with 4-year freedom from rejection rates of 82.7% versus 79.3%, respectively (Figure 1C). Cox regression analysis demonstrated that MMF at discharge contributed independently to a reduction in the risk of LAR (HR = 0.87, p = 0.041). Similar to the HCV and HBV groups, the strongest risk factor for LAR in patients with nonviral disease was whether the patients experienced early rejection within the first 6 months post-transplantation (HR = 3.34, p < 0.001). African American recipient race was also associated with a statistically significant risk of experiencing LAR (HR = 1.86, p < 0.001). Receiving a transplant in a later year was associated with a reduced risk for LAR (HR = 0.88, p = 0 < 0.001), as was being an older recipient (HR = 0.92 per decade, p = 0.003) (Table 2).

Acute rejection within the first year post-transplantation

The addition of MMF at discharge to tacrolimus and steroids was associated with significantly lower rates of acute rejection compared to tacrolimus and steroids alone within the HCV, HBV and nonviral diagnostic groups. The rates of rejection for MMF + Tac + steroids versus Tac + steroids groups were 12.8% versus 14.8% within the first 6 months post-transplantation, respectively; p < 0.001, and 3.3% versus 4.2% between 6 and 12 months post-transplantation. The rates within the first year post transplantation were 16.1% versus 19.0%; p < 0.001. Results were similar within the HCV, HBV and nonviral disease sub-groups (data not shown).

Late graft and patient survival in recipient sub-populations who received 12 months continuous therapy

Late graft survival (graft survival beyond 1 year post-transplantation) was significantly lower at 4 years post-transplant for patients who experienced LAR 6–12 months post-transplantation compared to patients who experienced early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001) (Figure 2). Cox regression analysis confirmed that LAR was an independent risk factor for late graft loss (HR = 1.99, p < 0.001), and had a greater impact than multiple rejection episodes (in both the 0–6 and 6–12 month period) (HR = 1.50, p = 0.012). Acute rejection in the first 6 months was not associated with an increased risk for late graft loss (HR = 0.99, p = 0.942). Donor age >31, underlying liver disease, pre-transplant serum creatinine ≥2 mg/dL and African American recipient race were significant risk factors for late graft loss (Table 3).

image

Figure 2. Kaplan–Meier estimates of graft survival, by timing of rejection episode.

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Table 3.  Cox regression analysis: Covariates for late graft loss and patient death, occurring >1 year post-transplantation
Variable (reference group)Graft lossPatient death
HR95% CIpHR95% CIp
Timing of rejection episode
 Early acute rejection 0–6 months post-transplantation (no rejection)0.990.75, 1.310.9420.980.72, 1.330.897
 Early and LAR 0–6 months and 6–12 months post-transplantation (no rejection)1.501.09, 2.070.0121.431.002, 2.030.048
 LAR 6–12 months post-transplantation (no rejection)1.991.50, 2.66<0.0011.981.47, 2.68<0.001
Treatment at discharge
 MMF + tacrolimus + steroids (tacrolimus + steroids)0.910.75, 1.100.340.880.71, 1.090.256
Recipient factors
 Recipient age (per 10 years)1.010.93, 1.100.7511.091.001, 1.190.048
 African American race (Caucasian/other)1.371.01, 1.850.0401.350.97, 1.880.072
 In ICU (not hospitalized)1.020.81, 1.280.8891.010.79, 1.290.933
 Hospitalized (not hospitalized)1.130.92, 1.390.2591.110.89, 1.380.355
 Pre-transplant serum creatinine ≥2 mg/dL (serum creatinine <2 mg/dL)1.481.13, 1.940.0041.591.21, 2.100.001
 Pre-transplant diabetes (no diabetes)1.180.95, 1.460.1251.251.01, 1.560.043
 CMV negative donor to positive recipient (CMV negative donor to negative recipient)0.990.77, 1.290.9961.060.80, 1.400.694
 CMV positive donor to negative recipient (CMV negative donor to negative recipient)1.150.89, 1.480.2621.260.96, 1.650.093
 CMV positive donor to positive recipient (CMV negative donor to negative recipient)0.930.73, 1.180.5570.980.76, 1.280.902
Cause of underlying liver disease
 HCV (noncholestatic)1.601.25, 2.05<0.0011.501.15, 1.950.002
 HBV (noncholestatic)1.150.76, 1.740.4940.960.61, 1.540.879
 Alcoholic cirrhosis (noncholestatic)1.411.08, 1.830.0101.521.16, 1.990.002
 Malignancy (noncholestatic)3.062.10, 4.46<0.0013.102.09, 4.60<0.001
 Cholestatic (noncholestatic)0.880.66, 1.180.4030.870.64, 1.190.380
Donor factors
 Donor age ≤10 (11–20 years)0.800.35, 1.840.6020.900.39, 2.070.809
 Donor age 21–30 (11–20 years)1.050.79, 1.400.7321.020.75, 1.390.886
 Donor age 31–40 years (11–20 years)1.411.07, 1.850.0131.260.94, 1.690.115
 Donor age 41–50 years (11–20 years)1.331.01, 1.740.0421.310.98, 1.740.066
 Donor age 51–60 years (11–20 years)1.551.17, 2.070.0021.421.05, 1.920.023
 Donor age >60 years (11–20 years)2.221.68, 2.94<0.0012.201.65, 2.95<0.001
Transplant factors
 Cold ischemia time (CIT) ≥12 hours (CIT < 12 hours)0.960.76, 1.210.7411.010.80, 1.280.921
 Transplant year (per year, 1995 + 1996)1.030.97, 1.090.3071.050.99, 1.120.127

Results for late patient survival (patient survival beyond 1 year post-transplantation) were similar to those in graft survival. Late survival was significantly lower at 4 years post-transplant for patients who experienced LAR 6–12 months post-transplantation compared to patients who experienced early rejection (79.6% vs. 87.9%, p < 0.001) and no rejection (89.0%, p < 0.001). Cox regression analysis confirmed that LAR was an independent risk factor for late death (HR = 1.98, p < 0.001), and had a greater impact than multiple rejection episodes (in both the 0–6 and 6–12 month period) (HR = 1.43, p = 0.048). Acute rejection in the first 6 months was not associated with an increased risk for late death (HR = 0.98, p = 0.897). Donor age >51, underlying liver disease, pre-transplant serum creatinine ≥2 mg/dL and pre-transplant diabetes were significant risk factors for late patient death (Table 3).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

This study is the first to demonstrate an association between a reduced incidence and risk of LAR and a minimum of 6 months continuous treatment with MMF in combination with tacrolimus and steroids in liver transplant recipients. Lower LAR rates were present in patients treated with MMF + Tacro + steroids, in all pre-transplant diagnostic groups studied (i.e. HCV, HBV and nonviral disease), compared to patients treated with Tacro + steroids. In this study, LAR occurred at a rate of approximately 2.5–5% per year, between 1 and 4 years post-transplantation, suggesting this is a post-transplant complication that occurs with a reasonable frequency. This is similar to previous reports of the incidence of LAR (12).

Based on prior observations that underlying liver disease contributes to the risk of developing LAR (5–7), we analyzed sub-populations based on pre-transplant diagnosis of HCV, HBV and nonviral liver disease. A retrospective analysis by Ramji et al. in western Canada found viral cause of underlying liver disease to be associated with a reduced risk for LAR (5). We confirmed this observation, but observed that significantly reduced rates of LAR were found only in the HCV and HBV sub-populations (compared to nonviral diagnoses) that received 6 months continuous treatment with MMF + tacrolimus + steroids. In contrast to the western Canadian experience, we found approximately equivalent rates of LAR in the HCV and HBV sub-populations, compared to nonviral diagnoses, in the 2-drug treated recipients. A possible explanation for this difference is that the Canadian study included transplants between 1989 and 2000, during which time, care of the viral post-transplant recipient and immunosuppression options were different.

LAR is important to avoid for reasons including the psychological setback for patients, the need for biopsy and potential hospitalization and the need for increased monitoring of liver function tests. In addition, it may be desirable to avoid the exposure to increased immunosuppression (i.e. bolus corticosteroid therapy), especially in the HCV sub-population, in which it has been associated with an increased risk of HCV recurrence (13–16). However, the data on whether LAR actually promotes chronic rejection and late graft loss have been mixed. In a retrospective study of 375 liver transplants, Mor and colleagues found LAR episodes responded equally to steroids as compared to early acute rejection, but steroid-resistant rejection responded less well to treatment with OKT3. Despite this finding, chronic rejection rates in the two groups were similar, and graft survival rates were not assessed (6). In the western Canadian experience, Ramji found an increased risk for chronic rejection in the LAR population (compared to no LAR), but could not detect differences in rates of disease recurrence, retransplantation or death, and hypothesized that this may have been a result of the small sample size. Contrary to these findings, Anand et al. have found LAR episodes to be associated with statistically significant increases in rates of graft loss, which correlated best with certain histological features on biopsy (2). In this retrospective analysis of the U.S. transplant population between 1995 and 2004, we did find that LAR contributed independently to the risk of late graft loss suggesting that LAR should be a clinical concern.

Risk factors for LAR were also assessed. The single greatest risk factor for development of LAR was whether a patient experienced early rejection, regardless of whether the patient was transplanted for viral or nonviral liver disease. In nonviral recipients only, African American recipient race was also associated with a statistically significant increased risk for LAR. Importantly, our analysis differs from previous studies by focusing on recipients in the modern era of immunosupprssion in the United States, when tacrolimus and MMF became widely used for maintenance therapy. We found that receiving a transplant in later years and continuous treatment for a minimum of 6 months with MMF in conjunction with tacrolimus and steroids resulted in a significantly reduced risk of LAR.

In interpreting findings from this retrospective analysis of registry data from the SRTR, the following caveats must be considered. The most obvious limitation of this study is the inability to make any claims regarding dosing of the treatments compared. The SRTR database does not contain information on drug dosing. Furthermore, as a continuous therapy analysis based on immunosuppression at hospital discharge and at subsequent follow-up visits, we can only approximate duration of therapy. It is possible that a patient discontinued, and then re-started a particular drug between visits. These results represent the best approximation of continuous therapy that can be derived from the database. We cannot determine any effects that might be attributable to continuation, tapering or withdrawal of tacrolimus or corticosteroids, or noncompliance on the part of the patient. A potential source of bias is the fact that the 2-drug group had slightly longer follow-up than the 3-drug group, thus the 2-drug group may have had a greater opportunity to experience graft loss or patient death simply because longer follow-up data were available. However, we feel that the statistical methods used in the late rejection analysis (i.e. Kaplan–Meier analysis) sufficiently accounted for the slightly longer mean follow-up in the 2-drug group, and that the benefits of the using all available data (i.e. not limiting the sample to patients with 2-year follow-up to make the groups equal in terms of follow-up increases the power and decreases the chance of selection bias) outweighs a benefit of cutting the sample.

Another important potential source of bias in this study involves the contribution of differences in practice by individual transplant centers. It could be that maintenance immunosuppression with triple-drug therapy is more commonly used at more experienced transplant centers, thus resulting in more favorable outcomes in the MMF group. Information on individual transplant centers was not available for this study. Controlling for transplant center experience could be beneficial in the interpretation of findings in future analyses.

Another consideration regarding this analysis relates to the accuracy and completeness of registry data. A recent study demonstrated that aggregate patient survival data reported to Organ Procurement and Transplantation Network (OPTN) by individual transplant centers was accurate compared to OPTN data supplemented by mortality data from the Social Security Death Master File (17,18). Completeness of data from OPTN is determined by comparing expected follow-up to reported follow-up reports and, where appropriate, the SRTR uses supplemental sources to try to provide more complete follow-up data. Information on the cause of graft loss was missing for more than half of the recipients who had graft loss, in both the 2- and 3-drug groups. The ability to compare the causes of graft loss between the drug groups may have illuminated some potential differences between the two drug groups and generated hypothesis as to the effects of a 3- versus 2-drug regimen on graft loss. Thus we are limited in the conclusions that can be made regarding the mechanistic effects that a 2- versus 3-drug regimen may have on graft loss. Finally, individual reporting bias by transplant centers may result in under-reporting or over-reporting of outcomes; however, it is reasonable to expect that this would occur equally for both treatment groups compared in this study and, therefore, would not affect overall implications of the data.

In summary, continuous treatment with MMF in conjunction with tacrolimus and steroids was associated with a decreased risk of LAR, in patients with HCV, HBV and nonviral disease, and may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The data reported here have been supplied by the United Network for Organ Sharing, and University Renal Research and Education Association under contract with the Department of Health and Human Services for the SRTR. The interpretation and reporting of these data are the responsibility of the authors and do not represent an official policy or interpretation of the U.S. Government or any of its representatives. This work was presented in part at the 2005 American Transplant Congress Annual Meeting, Seattle, WA, and the 11th Annual Congress of the International Liver Transplantation Society, Los Angeles, CA. The analyses reported here were conducted in ProSanos Corporation facilities, and were funded by Roche Laboratories, Inc. Dr. Lake receives grant support from and serves as an advisor to Roche Laboratories, Inc., Astellas Pharma Inc., Wyeth Pharmaceuticals, Genzyme Corporation, Bristol-Myers Squibb, Sanofi-Synthelabo Inc., Novartis, Vital Therapies and the Sharing Life Foundation. Dr. Wiesner serves as an advisor to Roche Laboratories, Inc., Astellas Pharma Inc. and Wyeth Pharmaceuticals. Dr. Lake and Dr. Wiesner serve as consultants to ProSanos Corporation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References