Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation

BACKGROUND: In simultaneous kidney-pancreas (SPK) transplantation, manifestations of renal allograft rejection typically become evident before those of pancreatic rejection. This study compared mycophenolate mofetil (MMF) and azathioprine (AZA) in prevention of renal rejection after primary SPK transplantation. METHODS: In an open-label, randomized, multicenter study, patients received MMF 1.5 g twice daily (n=74) or AZA 1-3 mg/kg daily (n=76) for 1 year after transplantation. The incidence of rejection was assessed at 6 months. Adverse events were tracked through 1 year. Survival data are reported through 2 years. RESULTS: At 6 months, efficacy results for MMF vs. AZA patients, respectively, were the following: rejection (27% vs. 39%); rejection or death (34% vs. 42%); rejection, graft loss, death, or premature withdrawal (i.e., treatment failure; 41% vs. 55%). Six-month efficacy trends favored MMF, and time to rejection or treatment failure was significantly longer when compared with AZA (P=0.049). One-year efficacy results for MMF vs. AZA patients, respectively, were the following: treatment of renal rejection (35% vs. 47%); renal allograft loss or death (9% vs. 12%); pancreas allograft loss or death (15% vs. 14%). Five MMF patients (7%) and four (5%) in the AZA group died. More MMF than AZA patients developed opportunistic infections (54% vs. 38%), but the pathogens did not differ. CONCLUSIONS: Trends for most efficacy parameters favored MMF over AZA, and time to renal allograft rejection or treatment failure was statistically significantly longer for MMF. The use of MMF in the treatment of SPK recipients is a useful advance.     

Effects of azathioprine and mycophenolate mofetil-immunosuppressive regimens on the erythropoietic system of renal transplant recipients

INTRODUCTION: Azathioprine (AZA) and mycophenolate mofetil (MMF) are major immunosuppressants used to prevent rejection following renal transplantation. Bone marrow suppression is a potential adverse effect of these agents manifesting itself as leukopenia, thrombocytopenia, and anemia. The aim of this study was to compare the effects of AZA versus MMF immunosuppressive regimens on the erythropoietic system of renal transplant recipients within 6 months after transplantation. METHODS: Eighty kidney allograft recipients who were on AZA (n = 40) or MMF (n = 40) plus cyclosporine and prednisolone were enrolled in this study. Hematologic parameters included red blood cell counts, hemoglobin (Hb), hematocrit, mean corpuscular volume, mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) and were measured before and at 1 week, as well as 1 and 6 months posttransplantation. Plasma erythropoietin level was measured at the end of 6 months. Statistical analysis was performed with Student t test; a P value less than .05 was considered significant. RESULTS: There was no significant difference between the two groups regarding red blood cell counts. High Hb level was noted at 1 and 6 months posttransplantation among patients who received MMF. MCH and MCHC were higher among patients on MMF compared with those on AZA at 1 week and 1 month posttransplant. Although the mean plasma erythropoietin levels in AZA-treated patients were higher than those of MMF-treated patients, the trend did not reach statistical significance (P = .066). CONCLUSION: MMF administration was apparently associated with a higher level of hemoglobin compared with AZA among renal allograft recipients with good graft function at 6 months posttransplantation.     

Mycophenolate mofetil vs azathioprine in a large population of elderly renal transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to decrease acute rejection episodes after kidney transplantation, and has been associated with better graft and patient survival vs azathioprine (AZA). Previous studies reported a higher risk of death due to infection in elderly recipients treated with MMF-based immunosuppression. 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 (Kaplan-Meier), 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.     

Increased incidence of allograft rejection in stable heart transplant recipients after late conversion from mycophenolate mofetil to azathioprine.

Mycophenolate mofetil (MMF) is a safe and effective immunosuppressive agent in kidney and liver transplantation. Preliminary studies also support its use in heart transplantation. However, the cost of MMF is substantially greater than azathioprine (AZA), the current alternative. Since the majority of rejection episodes occur within the first few months of transplantation, using MMF early after transplantation and subsequently converting to AZA, after the risk of rejection has diminished, might be cost-effective. In order to evaluate the safety of such a strategy in heart transplant recipients, we reviewed the rejection profiles of a group of patients who were converted from MMF to AZA late after transplantation. Forty-three stable patients on chronic MMF therapy as part of an open-label, long-term safety study were converted to either commercially available MMF (CellCept) or AZA, at the conclusion of the study. Demographic variables, rejection histories before and after conversion, and immunosuppressive regimens were examined. Twenty-three patients were continued on commercial MMF and 20 were converted to AZA therapy. The average duration of MMF therapy prior to conversion was 41 months in each group. Baseline demographics were similar in the two groups. Treated allograft rejection occurred in 10 of 20 patients converting to AZA, as compared to only 1 of 23 patients remaining on MMF; p = 0.002. Additionally, mean scores (1-5 scale) for the three biopsies before and after conversion favored continued MMF therapy (1.5+/-0.6 before and 1.2+/-0.4 after conversion in MMF group vs. 1.3+/-0.5 before and 1.7+/-0.9 after conversion to AZA; p = 0.02). No allograft loss occurred as a result of conversion. These data suggest that conversion from MMF to AZA, even late after transplantation, can be associated with allograft rejection. The costs associated with these rejection episodes (the additional immunosuppressive agents, endomyocardial biopsies, and physician visits) may exceed the potential cost savings of converting stable heart transplant recipients from MMF to AZA.     

New immunosuppressive treatment in kidney transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has been successfully introduced into clinical practice with evident benefits for renal transplant recipients. SUBJECTS AND METHODS: To evaluate some clinical results of MMF introduction, two groups of subjects underwent cadaveric renal transplants over the last 3 years and were retrospectively investigated. The first group (AZA group) contained 40 subjects (26 males and 14 females) on triple-drug therapy with steroids, cyclosporine and azathioprine (AZA). The second group (MMF group) contained 25 patients ( 19 males and 6 females) on the same regime with steroids and cyclosporine but MMF was administered as a third drug instead of AZA. The AZA group received renal transplant after a mean dialytic time of 32 +/- 19 months and the AZA group's dialytic time was 39.9 +/- 17 months. Clinical data, collected after a minimum 12 months observational period included a crude mortality rate and survival analysis recognized by Kaplan-Meyer curve, creatinine, creatinine clearance, rejection episodes and major clinical events such as infections and acute tubular necrosis. RESULTS: One subject died in each group. For kidney graft survival, Kaplan Meyer survival analysis showed a mean survival time of 1170.04 days in the AZA group vs 845 in the MMF group without statistical significance. Graft survival demonstrated 5:40 (12.5%) graft losses in the AZA group vs no kidney transplant loss in the MMF group (the only deceased patient had a well functioning kidney). The curve of graft cumulative proportion survival analysis demonstrated a more improved survival in the MMF group, but this difference did not reach a statistical significance (p = 0.07). Acute rejection episodes in the AZA group were 37.5% vs. 20% in the MMF group. In both groups, CMV infection was successfully treated with specific antiviral agents. CONCLUSIONS: MMF represents an important step towards induction and maintenance of immunosuppression. Our experience in a relatively small cohort investigated in a single center, demonstrates encouraging results regarding graft survival in comparison to those detected in conventional triple drug therapy. Surprisingly, in spite of stronger immunosuppressive treatment, the prevalence of CMV infections was not statistically different in the MMF versus the AZA group.     

Safe conversion of mycophenolate mofetil to azathioprine in kidney transplant recipients with sirolimus-based immunosuppression

Aim:   Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The long-term use of MMF may bring increased risk of for infection and malignancy and also increased cost of transplantation. The search for minimization of immunosuppressive protocol has led to an open randomized clinical trial of conversion from MMF to azathioprine (AZA).
Methods:   A total of 50 kidney allograft recipients treated with prednisone, sirolimus and MMF were randomized into two groups: converted (AZA group) and continuing (MMF group). The average duration of MMF therapy prior to conversion was 43 months in each group. Inclusion criteria included: patients with serum creatinine levels of less than 200 µmol/L; no past history of acute vascular rejection or recent acute rejection 6 months before randomization; and normal liver function tests.
Results:   Baseline demographics were similar in the two groups. During the 12 month observation period, there were no acute rejection episodes in either group. There were no significant differences in overall patient or graft survival or function. AZA-treated patients had a lower incidence of gastrointestinal complications ( P  = 0.03). Daily cost reduction in the AZA group was more than $US8.79/day per patient.
Conclusion:   In general, replacing MMF with AZA in stable renal transplant recipients is well tolerated and was cost effective with no increased risk of rejection. As the this study was on relatively small samples, larger and longer follow-up studies will be needed to confirm these expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.     

Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil.

BACKGROUND: Several multinational controlled clinical trials have shown that triple therapy immunosuppressive regimens which include mycophenolate mofetil (MMF), cyclosporin A (CSA) and steroids (S) are superior compared with conventional regimens which include azathioprine (AZA), CSA and S, mainly because MMF reduces the rate of acute rejection episodes in the first 6 months after kidney transplantation. Post-marketing studies are useful to evaluate the general applicability and costs of MMF-based immunosuppressive regimens. METHODS: Based on the excellent results of the published controlled clinical trials, we have changed the standard triple therapy immunosuppressive protocol (AZA+CSA+S) to an MMF-based regimen (MMF+CSA+S) at our centre. To analyse the impact of this change in regimen, we have monitored 6-month patient and graft survival, rejection rate, serum creatinine and CSA levels, as well as the costs of the immunosuppressive and anti-rejection treatments, in 40 consecutive renal transplant recipients (MMF group) and have compared the data with 40 consecutive patients transplanted immediately prior to the change in regimen (AZA group). RESULTS: Recipient and donor characteristics were similar in the AZA and MMF groups. Patient survival (37/40; 92.5% in the AZA group vs 38/40; 95% in the MMF group), graft survival (36/40 vs 36/40; both 90%) and serum creatinine (137+/-56 vs 139+/-44 micromol/l) after 6 months were not significantly different. However, the rate of acute rejection episodes (defined as a rise in creatinine without other obvious cause and treated at least with pulse steroids) was significantly reduced with MMF from 60 to 20% (P=0.0005). The resulting cost for rejection treatment was lowered 8-fold (from sFr. 2113 to 259 averaged per patient) and the number of transplant biopsies was lowered > 3-fold in the MMF group. The cost for the immunosuppressive therapy was increased 1.5-fold with MMF (from sFr. 5906 to 9231 per patient for the first 6 months). CONCLUSIONS: The change from AZA to MMF resulted in a significant reduction in early rejection episodes, resulting in fewer diagnostic procedures and rehospitalizations. The optimal long-term regimen in terms of patient and pharmacoeconomic benefits remains to be defined.     

Mycophenolate mofetil in pediatric renal transplantation

INTRODUCTION: Since kidney transplantation is the therapy of choice for children with end-stage renal disease (ESRD), we investigated the effects of mycophenolate mofetil (MMF) in pediatric renal transplantation. METHODS AND SUBJECTS: Two hundred sixteen children received renal transplants between 1985 and 2003: 100 patients received MMF with cyclosporine and prednisolone (cases), and 116 patients, azathioprine with cyclosporine and prednisolone (controls). RESULTS: The MMF group (100 patients) showed better graft survival and function than the AZA group (116 patients). Patients who received MMF immediately after transplantation experienced less graft loss and acute rejection episodes in the first 3 months after transplantation (P < .05). Patients who received MMF at the time of diagnosis of chronic rejection had stable renal function and remarkably better graft survival than those with chronic rejection who received AZA instead of MMF (P < .05). CONCLUSION: This study suggests that MMF may stop persistent graft dysfunction in chronic rejection, improving graft survival in the short and long terms posttransplantation.     

Six-year follow-up of azathioprine and mycophenolate mofetil use during the first 6 months of renal transplantation

Long-term follow-up examination to test whether therapy with mycophenolate mofetil (MMF) or azathioprine (AZA) during the first year translates into different graft or patient survival and graft function is important. Therefore, 6-year follow-up data of a group of 80 consecutive renal transplant recipients were analyzed. The first group of 40 patients was treated with AZA, cyclosporine and prednisone and the second group with MMF, cyclosporine and prednisone for the first 6 months. Graft failure rates were compared during follow-up. Creatinine, inverse slope of creatinine (delta/creatinine) and 24-hour proteinuria at 6 years post transplantation were compared. The Kaplan-Meier analyses for death-censored and non-censored graft failure showed no difference between the groups. Creatinine values at 6 years for the AZA Group were 139 +/- 36 micromol/l (95% CI 125.9-151.2 micromol/l) and for the MMF Group 149 +/- 52 micromol/l (95% CI 133.9-164.9 micromol/l). Delta/creatinine and 24-hour proteinuria at 6 years did not differ between the two groups. We conclude that an initial 6-month treatment with MMF as opposed to AZA reduced the early rejection rate, but did not result in superior long-term graft function or survival after 6 years of follow-up observation.     

肾移植患者术后早期应用霉酚酸酯的临床观察

目的 观察肾移植术后早期不同剂量霉酚酸酯（ＭＭＦ）与环孢素Ａ（ＣｓＡ）和泼尼松（Ｐｒｅｄ）联用预防急性排斥反应的效果及安全性。方法 将６４例肾移植患者分为３组,分别给予ＭＭＦ２．０ｇ／ｄ（Ａ组）、１．５ｇ／ｄ（Ｂ组）及Ａｚａ ５０～１００ｍｇ／ｄ（Ｃ组）,每组均联用ＣｓＡ及Ｐｒｅｄ（剂量相同）。观察肾移植术后６个月内急性排斥反应的发生率、移植肾功能及药物的副作用。结果 Ａ、Ｂ、Ｃ组急性排斥反应的发     

Mycophenolate mofetil versus azathioprine therapy is associated with a significant protection against long-term renal allograft function deterioration

BACKGROUND: To evaluate the association of long-term continuous mycophenolate mofetil (MMF) versus azathioprine (AZA) therapy and renal allograft function, as measured by the slope of reciprocal creatinine, we analyzed 49,666 primary renal allograft recipients reported to the United States Renal Data System between October 31, 1988 and June 30, 1998. METHODS: The primary study endpoint was defined as a greater than 20% decrease below a 6-month baseline of 1/serum creatinine (SCr) (slope of reciprocal creatinine) at or beyond 1 year after transplantation. A secondary endpoint was defined as reaching an SCr value greater than 1.6 mg/dL. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. Multivariate analyses were corrected for potential confounding covariates. RESULTS: According to the Cox proportional hazard model, 12-month continued therapy of MMF versus AZA was associated with a protective effect against declining renal function, as measured by the slope of reciprocal creatinine (relative risk [RR]=0.84, confidence interval 0.78-0.91, P<0.001). For 24-month continued therapy of MMF versus AZA, MMF was associated with a further decreased risk for a decline in renal function (RR=0.66, confidence interval=0.57-0.77, P<0.001). Furthermore, MMF was associated with a protective effect against reaching the SCr threshold of 1.6 mg/dL (RR=0.80, P<0.001) beyond 12 months posttransplantation. CONCLUSIONS: Continuous use of MMF versus AZA was associated with a protective effect against declining renal function beyond 1 year after transplantation. Further study is needed to confirm that continued MMF therapy is protective against long-term deterioration in renal function.     

Conversion of azathioprine to mycophenolate mofetil and chronic graft failure progression

The purpose of the study was to evaluate the impact of conversion from azathioprine (AZA) to mycophenolate mofetil (MMF) on graft function in 35 renal transplant recipients with chronic allograft nephropathy (CAN). The immunosuppressive regimen originally consisted of AZA, cyclosporine (CsA), and prednisone (Pr). At the onset of the study (mean period = 39 posttransplant months), a graft biopsy was performed on all patients who were randomly divided into group 1 (n = 17) in whom MMF was introduced instead of AZA. The remaining 18 subjects (group 2) were maintained on the previous regimen. Two periods were analyzed: period I: 12 months before, and period II: 12 months after biopsy and therapy conversion. Graft function was assessed monthly by measurements of the 24-hour creatinine clearance (CCr). Analysis of variance (ANOVA) was used to compare the differences in CCr and proteinuria between the two groups. No difference was observed in the baseline characteristics, in the incidence of delayed graft function and acute rejection, or in the mean CsA dose. Pathohistological analysis revealed advanced CAN in the majority of patients in both groups. The morphological changes negatively correlated with graft function. The graft function showed parallel deterioration in the two groups; no significant difference was observed in the mean CCr values in the periods studied. Proteinuria was similar for both groups throughout the study. Conversion of AZA to MMF in recipients with CAN, albeit safe, was without significant benefit on the progression of chronic graft failure over the period of a year.     

Clear benefit of mycophenolate mofetil-based triple therapy in reducing the incidence of acute rejection after living donor renal transplantations.

BACKGROUND: According to a pooled analysis of three randomized clinical studies concerning the prevention of acute rejection in cadaveric renal transplantation, mycophenolate mofetil (MMF) proved superior to azathioprine or placebo in conjunction with cyclosporine (CsA) and steroids. MMF-treated patients showed reduced incidence and severity of acute rejection, similar graft survival, and better graft function over 12 months. However, the multicenter trials did not include the Asian recipients of living donor kidneys. METHODS: To assess the efficacy of MMF as the third component of a triple therapy in addition to CsA-Neoral and steroids in living donor renal transplantation recipients in Asians, a total of 100 recipients were randomized to receive CsA-Neoral and steroids (control group, n=50), or MMF-based triple therapy (1.0 g of MMF twice daily from postoperative day 2, MMF group, n=50). The dosing plan for Neoral and steroids was essentially same between groups. During 12 months of follow-up, we compared the incidence of acute rejection, adverse events such as infections, and 12-month actual graft and patient survival. RESULTS: The graft and patient survival at 1 year was excellent in both groups: 96/98% in the control group and 98/100% in the MMF group, respectively. MMF significantly reduced the proportion of patients with at least one episode of acute rejection (34% in the control group vs. 14% in the MMF group), cumulative incidence of acute rejection episodes (46% vs. 16%), and requirement of antilymphocyte antibody (21.7% vs. 12.5%). In the MMF group, viral infection such as herpes zoster or chicken pox was more prevalent than in the control group. CONCLUSIONS: Like cadaveric renal transplantation, this open clinical trial showed MMF to be effective in reducing the incidence and severity of acute rejection if used in conjunction with Neoral and steroids after living donor renal transplantation in Asian ethnicity.     

Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection.

BACKGROUND: Although the use of mycophenolate mofetil (MMF) has reduced the incidence of acute rejection in heart and kidney allograft recipients, its role in lung transplantation remains controversial. Therefore, we conducted a randomized, prospective, open-label, multicenter study in lung transplant recipients to determine whether MMF decreases episodes of acute allograft rejection when compared with azathioprine (AZA). METHODS: Between March of 1997 and January of 1999, 81 consecutive lung transplant recipients from two centers were prospectively randomized to receive cyclosporine, corticosteroids, and either 2 mg/kg per day of AZA or 1 g twice daily of MMF. The primary study endpoint was biopsy-proven acute allograft rejection over the first 6 months posttransplant. Secondary endpoints included clinical rejection, cytomegalovirus (CMV) infection, adverse events, and survival. Surveillance bronchoscopies were performed at 1, 3, and 6 months, or if clinically indicated. Pathologists interpreting the biopsy results were blinded to the randomization. Results were analyzed according to intention-to-treat. Between group comparisons of means and proportions were made by using two sample t tests and Fisher's exact tests, respectively. Six-month survival was calculated by the Kaplan-Meier method and compared by the log rank test. RESULTS: Thirty-eight patients were prospectively randomized to receive AZA, and 43 MMF. The incidence of biopsy proven grade II or greater acute allograft rejection at 6 months was 58% in the AZA group and 63% in the MMF group (P=0.82). The 6-month survival rates in the MMF and AZA groups were 86% and 82%, respectively (P=0.57). Rates of CMV infection and adverse events were not significantly different between the two groups. CONCLUSIONS: Acute rejection rates and overall survival at 6 months are similar in lung transplant recipients treated with either MMF- or AZA-based immunosuppression.     

Conversion from mycophenolate mofetil to azathioprine in high-risk renal allograft recipients on cyclosporine-based immunosuppression

OBJECTIVE: In a randomized control trial of mycophenolate mofetil (MMF) versus azathioprine (AZA) with cyclosporine and steroids, we demonstrated that MMF reduced acute rejection (AR) among renal allograft recipients (RTX) who were of low to moderate risk. However, 10% had AR when converted from MMF to AZA at 6 months, postrenal transplantation (RT). Two clinical markers, abnormal serum creatinine (SCr) and proteinuria at 6 months, post-RT, were associated with AR postconversion. The present study examined the safety of such conversion in selected high-risk RTX at 1 year of MMF therapy. METHODS: Thirteen high-risk RTX receiving MMF for either high panel reactive antibody (n = 9) or following AR (n = 4), with normal SCr and no proteinuria at 1 year, were selected for conversion. The incidence of AR, adverse events, and renal parameters (SCr, creatinine clearance, proteinuria) at 6 months postconversion was evaluated. Eight high-risk RTX who did not meet these selection criteria were retrospectively reviewed and used as controls. RESULTS: Renal parameters (SCr 123 +/- 26 vs 129 +/- 27 mumol/L; pre- vs postconversion) were not significantly different; no episodes of AR or proteinuria were documented. Azathioprine was discontinued in two patients due to leukopenia. In the control group, one patient had graft loss from chronic rejection, whereas one developed posttransplant lymphoproliferative disease necessitating MMF withdrawal. CONCLUSION: These results suggest that selective conversion from MMF to AZA after 1 year is safe, even in high-risk RTX. Normal SCr and absence of proteinuria are good screening parameters to identify patients at low risk for AR following such conversion.     

Effect of mycophenolate mofetil on long-term outcomes in African american renal transplant recipients

African American renal transplant recipients have poorer graft survival. A study using the United States Renal Data Registry documented an improvement in graft survival for patients who took mycophenolate mofetil (MMF) compared with azathioprine (AZA). This analysis did not address the impact of MMF on African American renal transplant recipients. The present study aimed to quantify potential beneficial effects of MMF therapy on long-term renal allograft survival in African Americans. With the use of the United States Renal Data Registry, all adult Caucasian and African American patients who had received a primary renal transplant between 1988 and 1997 were analyzed by Kaplan-Meier analysis and Cox proportional hazard models. Primary study end points were death with a functioning graft and graft failure censored for death. A total of 57,926 patients were studied. For African Americans, 3-yr patient survival was 96.3 versus 93.2% (P<0.001) for MMF and AZA, respectively. Three-yr death-censored graft survival for African Americans was 85.8 versus 75.1% (P<0.001) for MMF and AZA, respectively. For Caucasians, 3-yr patient survival was 97.3 versus 93.2% for MMF and AZA, respectively. Three-yr death-censored graft survival for Caucasians was 90.1 versus 86.4% (P<0.001) for MMF and AZA, respectively. By multivariate analysis, MMF was associated with a significant reduction in the relative risk for all study end points in African Americans. MMF therapy is associated with both improved patient and death-censored graft survival in African American renal transplant recipients. This benefit is comparable to the benefit of MMF in Caucasian renal transplant recipients.     

Randomized study on the conversion of treatment with cyclosporine to azathioprine or mycophenolate mofetil followed by dose reduction

BACKGROUND: The introduction of cyclosporine (CsA) in kidney transplantation has improved early graft survival. However, its long-term use is associated with impairment of renal function and increased cardiovascular risk factors. To avoid CsA-related long-term adverse effects, patients were converted to either azathioprine (AZA) or mycophenolate mofetil (MMF) 1 year after transplantation. METHODS: Between September 1995 and January 1997, 64 stable renal transplant recipients on CsA and prednisone treatment were included in a prospective, randomized study. Patients were randomized for conversion of CsA to 2 mg/kg AZA (n=30) or 1 g of MMF twice daily (n=34). All patients remained on low-dose steroids. To decrease the total immunosuppressive load, a dose reduction in MMF and AZA was performed at 4 and again at 8 months after conversion. Mycophenolic acid trough levels were measured at regular intervals. RESULTS: After conversion, a decrease in serum creatinine was found for both groups: for MMF, 132 to 109 micromol/L (P=0.016); and for AZA, 123 to 112 micromol/L (P<0.0001). After conversion, more acute rejections occurred in the AZA group (11/30) compared to the MMF group (4/34) (P=0.04). Dose reduction of MMF to 500 mg twice daily and of AZA to 1.0 mg/kg elicited three rejections in both groups. The incidence of side effects and infections were similar. CONCLUSION: Discontinuation of CsA spared renal function. In patients converted to MMF significantly less rejections occurred compared to patients converted to AZA. Furthermore, dose reduction of both AZA and MMF is possible in the majority (72%) of the patients.     

Efficacy of mycophenolate mofetil versus azathioprine after renal transplantation: a systematic review

INTRODUCTION: Our objective was to evaluate the efficacy of mycophenolate acid (MMF) versus azathioprine (AZA) after renal transplantation. MATERIALS AND METHODS: The following electronic databases were searched: Medline, Embase, Cochrane library, and Chinese Biomedicine database (CBM). Randomized controlled trials (RCTs) were subjected to Revman 4.11 for statistical analyses. RESULTS: Twenty-three RCTs were identified to compare MMF and AZA for antirejection, prophylaxis after renal transplantation. The data showed that MMF (2 g/d) was more beneficial than AZA to improve graft and long-term patient survivals, but there was no statistical differences between MMF (3 g/d) and AZA. Whether at 6 months or at 1 year after renal transplantation, the use of MMF (2 g/d) or MMF (3 g/d) markedly reduced the incidence of biopsy-proven rejection. CONCLUSION: Compared with AZA, MMF is a more potent immunosuppressive drug, that is more efficient in reducing the incidence of acute rejection episodes after renal transplantation. MMF can improve the graft and patient survival rate. The 2 g per day dosage is more acceptable.     

Analysis of a single-center experience with mycophenolate mofetil based immunosuppression in renal transplantation

Purpose. Acute rejection continues to be a major clinical issue in renal transplantation. Three large multicenter trials have demonstrated a 50% decline in biopsy‐proven rejection when mycophenolate mofetil (MMF) was given to renal transplant recipients with corticosteroids and cyclosporine. The purpose of this study was to compare the 6‐month outcome of renal transplant recipients using MMF and non‐MMF based immunosuppression protocols over a 4‐year period at a single center.
Methods. This retrospective study analyzed three patient groups defined by their immunosuppression protocol. The first group included patients who received a quadruple immunosuppression regimen of antilymphocyte induction (ATG), cyclosporine (CYA), azathioprine (AZA), and corticosteroids (CCS), and were transplanted between October 1993 and May 1995 (AZA group). The second group included patients who received a triple immunosuppression regimen of CYA, MMF, and CCS, and were transplanted between June 1995 and May 1996 (MMF group). The third group included patients who were transplanted between January 1997 and December 1997, and received an immunosuppression regimen of CYA and MMF with a reduced CCS dosing schema (reduced steroid group (RST)). Data were collected from a retrospective review of inpatient and outpatient clinical records.
Results. A total of 325 patients were included in the study (106 AZA, 106 MMF, 113 RST). The demographic characteristics of the three groups were similar; however, the mean donor age for the AZA group was 40±15.1 years versus 33±14.1 years and 34±13.1 years for the MMF and RST groups, respectively (p<0.043). The incidence of acute, biopsy‐proven rejection at 6 months was significantly less in the MMF group when compared with the AZA group [16 (15.1%) versus 35 (33%) patients, p=0.002]. However, the incidence of acute, biopsy‐proven rejection in the RST group (35 patients, 31%) was similar to that of the AZA group. Kaplan–Meier estimates for the cumulative incidence of acute rejection demonstrated a significant difference between the MMF group and the other two groups (p=0.0059). The AZA group had more severe rejection as demonstrated by the more frequent use of antilymphocyte therapy for rejection treatment (68.4% episodes) compared with the MMF (38.9%) and RST (47.6%) groups. After 6 months of follow‐up, 11 patients had lost their grafts (8, AZA; 1, MMF; 2, RST). One patient died in each of the AZA and RST groups due to hemorrhage and a pulmonary embolus, respectively. Four AZA patients were diagnosed with a malignancy (three post‐transplant lymphoproliferative disorder, one squamous skin cell carcinoma) compared with 2 MMF patients (prostate cancer, basal skin cell carcinoma) and no RST patients. Herpes zoster was the only infection that occurred more frequently in the MMF group (p=0.03). No other differences in infection rates were noted among the three groups. The initial length of hospital stay declined significantly over the 4‐year study period [11±4.3 d (AZA), 7.0±4.0 d (MMF), 6.2±3.3 d (RST), p<0.001]. Total number of hospital days for the first 6 months also followed a similar declining pattern. Despite using intravenous cyclosporine immediately post‐transplant in the MMF and RST groups, the incidence of delayed graft function was similar among the three groups. Average serum creatinine at 1 month was significantly lower in the MMF group (p=0.008), but no difference was noted at 3 and 6 months when compared with the AZA and RST groups.
Conclusion. This retrospective analysis indicates that MMF is an effective immunosuppressant. Decreased length of stay and less steroid resistant rejections with MMF is favorable for decreased hospital costs. However, the rebound in rejection rate with the RST group suggests that further study is needed to define the optimal use of this agent in combination with others to maximize effectiveness and minimize negative side effects.     

Short-term combination of mycophenolate mofetil with cyclosporine as a therapeutic option for renal transplant recipients: A prospective,multicenter, randomized study

BACKGROUND: Mycophenolate mofetil (MMF), compared to azathioprine (AZA), reduces acute rejection and treatment failure in cyclosporine (CsA) and steroid regimens, but its effect on graft survival is unproven from prospective studies and prolonged use is costly. This study evaluated the efficacy and tolerability of replacing MMF by AZA after 3 months. METHODS: This 28 center, prospective, 12-month, parallel group, open-label study, randomized patients to three groups with microemulsion formulation of CsA (ME-CsA) and steroids as baseline therapy. Group 1 (n=158) received MMF for 3 months, replaced by AZA for 9 months; group 2 (n=162) received MMF for 12 months; and group 3 (n=157) received AZA for 12 months. RESULTS: Treatment failure and the cumulative rate of acute rejection were significantly lower in the MMF groups compared with the AZA group (P=0.007 and P=0.03, respectively). Graft loss, death, and safety profiles of all three treatments were similar over 12 months, as were mean serum creatinine levels. Switching from MMF to AZA did not affect treatment failure. No patient in group 1 experienced a recurrent rejection after month 3, one patient died, and nine patients experienced first rejection episodes. Most rejections (6/9) were steroid-sensitive and histologically mild. CONCLUSIONS: Replacement of MMF by AZA after 3 months of therapy with ME-CsA and steroids provides comparable efficacy and safety profiles to continuous MMF over 12 months. Although apparently a cost-effective option, long-term studies are required to assess the benefit/risk ratio of this therapy switch in different patient subpopulations.