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.     

Tacrolimus and mycophenolate mofetil as first line immunosuppression after lung transplantation

The optimal maintenance therapy after lung transplantation remains to be established. The aim of this study was to analyse the impact of tacrolimus and mycophenolate mofetil (MMF) as first line immunosuppression on long-term survival and Bronchiolitis Obliterans Syndrome (BOS). From January 1996 through December 2006, all 155 recipients receiving tacrolimus and MMF as maintenance immunosuppression were included in this study. Tacrolimus and MMF was discontinued in 36 patients (23.2%). The overall survival rates were 91.6% at 6 months, 86.4% at 1 year, 74.9% at 3 years, 60.3% at 5 years and 32.4% at 10 years. The overall freedom from acute rejection was 74.6%, 63.2% and 59.4% at 1, 3, and 5 years respectively. The overall BOS-free survival was 95.6% at 1 year, 88.4% at 3 years, 69.5% at 5 years and 30.5% at 10 years. The development of BOS ≥ 1 was associated with a significantly increased risk of death and reduced long-term survival. The combination of tacrolimus and MMF offers safe and reliable maintenance immunosuppression after lung transplantation. However, substantial improvements of long-term survival and freedom from BOS might only be achieved by a change in organ allocation policies and patient management beyond differential immunosuppressive protocols.     

Elective withdrawal of mycophenolate mofetil in renal transplant recipients treated with mycophenolate mofetil, cyclosporine, and prednisone

In a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection. Received: 24 November 1999 Revised: 11 May 2000 Accepted: 18 December 2000     

Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine.

There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial.     

Comparison of long-term actual renal allograft survival in mycophenolate mofetil and azathioprine-based triple drug immunosuppression protocols

INTRODUCTION: The use of mycophenolate mofetil (MMF) in renal transplantation results in a 50% lower incidence of acute rejection compared to azathioprine (AZA). However, the graft survival reports are conflicting: the European trial and US database analysis suggest better survival with MMF, an observation that was not seen in the US and tricontinental studies. METHODS: We retrospectively reviewed our single-center experience (60% African-Americans) comparing the serum creatinine (SCr) values and 3-year actual graft survival with MMF versus AZA-based immunosuppression. Group I included patients transplanted between January 1990 and December 1992 on cyclosporine (CSA), AZA, and steroids; group II subjects, from January 1996 to December 1998 on CSA, MMF, and steroids. We analyzed SCr and all causes of graft losses at 3, 6, 12, 18, 24, and 36 months posttransplantation. RESULTS: The patient demographics were similar in both groups as was the mean SCr values at different times. The time-group interaction for SCr, the Kruskal-Wallis test for SCr for different categories (<1.5, 1.5 to 2.0, 2.0 to 2.5, and >2.5 mg/dL) and the all-cause graft loss between the two groups were not significantly different. CONCLUSION: Our results failed to show better long-term actual graft survival despite the 6-year interval between the two groups. These findings agree with the results of the United States and the tricontinental studies. A lower incidence of acute rejection early after transplantation observed with MMF may not always translate into a long-term benefit, possibly due to the influence of nonimmunological factors, such as hypertension, calcineurin inhibitor toxicity, more frequent cytomegalovirus infections, and increased attempts to withdraw steroids using MMF-based protocols.     

Comparison of enteric-coated mycophenolate sodium with mycophenolate mofetil in living renal allograft transplantation

OBJECTIVE: Enteric-coated mycophenolate sodium (MPS) has been developed to decrease the GI side effects of mycophenolate mofetil (MMF). We did a retrospective analysis of 112 patients to compare the safety and efficacy of enteric coated MPS vs MMF in living renal transplantation. METHODS: Patients were divided into two groups. Group A who received MPS [Novartis, Basel, Switzerland] [1.08-1.44 g/d] included 53 patients of mean age 33.5 +/- 11.9 yrs, and M:F gender ratio 37:15 with a mean donor age of 43.2 +/- 9.9 years. Group B who received MMF [1.5-2.0 g/d] included 59 subjects of mean age 33.2 +/- 9.9 yrs and M:F gender ratio 57:6, with a mean donor age of 41.4 +/- 10.9 years. All patients received cyclosporine and prednisolone in addition to mycophenolate. Mean follow-up in the two groups was 11.6 +/- 7.0 and 12.6 +/- 8.5 months, respectively. RESULTS: There were 11 (20.7%) rejection episodes in Group A and 12 (20.3%) rejection episodes in Group B (P = NS). Incidence of CMV disease was 9.61% and 10.1%, and of other infections, 88.7% and 74.7% in Groups A and Group B, respectively [P = NS]. The incidence of GI (18.9% & 20.3%) and hematologic toxicities (9.4% & 5.1%) were similar in the groups. Patient and graft survivals in Group A were 91.9% & 86.6%, and in Group B was 91.3% & 91.3%, respectively [P = NS]. CONCLUSION: Mycophenolate sodium is an alternative immunosuppressant to mycophenolate mofetil in kidney transplant recipients with a similar efficacy and safety profile.     

Renal function and safety of heart transplant recipients switched to mycophenolate mofetil and low-dose cyclosporine

BACKGROUND: We evaluated cyclosporine (CSA) dose reduction and mycophenolate mofetil (MMF) treatment versus maintained CSA dosage and azathioprine (AZA) in HTX regarding renal function and safety from CSA nephrotoxicity (creatinine > 1.7 mg/dL). METHODS: Fourteen recipients (group 1: 12 men, 2 women) with CSA-based immunosuppression (plus azathioprine and/or steroids) were started on 2000 mg MMF/d. Azathioprine was discontinued and CSA tapered to trough whole blood levels of 70 to 120 microg/L. Ten recipients (group 2: seven men, three women) were maintained on their CSA dosages. Creatinine clearance, serum creatinine, uric acid, urea nitrogen, and rejection were monitored. RESULTS: Mean age was 58 (range 44 to 69 years) and 48 years (range 24 to 61 years) in groups 1 and 2, respectively. In group 1 creatinine fell from 2.7 +/- 0.8 to 1.9 +/- 0.5 mg/dL (baseline vs control 2: P =.001); uric acid and urea nitrogen remained constant. CSA levels decreased from 173 +/- 56 to 110 +/- 33 microg/L (P =.02). In group 2 creatinine (2.4 +/- 0.7 vs 2.3 +/- 0.5 mg/dL), uric acid, urea nitrogen, and CSA levels remained constant. Comparison between groups showed higher creatinine clearance (50 +/- 18 vs 29 +/- 14 mL/min; group 1 vs group 2: P =.02), lower CSA levels (110 +/- 33 vs 161 +/- 35 microg/L; P <.001) and a trend toward lower serum creatinine (1.9 +/- 0.5 vs 2.3 +/- 0.5 mg/dL, P =.077). There were two rejections >/= 1B according to ISHLT in the study and four in the control group. Two deaths occurred in each group. CONCLUSIONS: Conversion from AZA to MMF after CSA reduction improves creatinine clearance in HTX recipients and reduces serum creatinine. No negative effect on patient safety was identified by rejection rate or survival.     

Primary immunosuppression with tacrolimus and low-dose mycophenolate mofetil in renal transplant recipients

Both tacrolimus and mycophenolate mofetil (MMF) are potent immunosuppressive agents used in combination for prevention of acute rejection in renal transplantation. We studied the efficacy and safety of tacrolimus/MMF-based primary immunosuppression as well as their pharmacokinetics (PK) in Chinese renal transplant recipients. Oral tacrolimus was initiated at about 0.2 mg/kg/d, dose which was adjusted to achieve target trough levels of 10 to 20 ng/mL at 3 months and 5 to 10 ng/mL thereafter. The patients also received MMF (0.5 g bid) and prednisolone. PK profiles were studied at 1 week, and 1, 3, and 6 months posttransplant. Blood samples were taken at 0 (predose), 20, 40, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose for each profile. Plasma MPA and whole blood tacrolimus levels were determined by HPLC and EMIT methods respectively. Eight patients were studied with mean follow-up of 16.1 +/- 2.4 months. One patient (12.5%) experienced a borderline acute rejection episode. Both 1-year graft and patient survival rates were 100%. Posttransplant diabetes, diarrhea, and hand tremor occurred in 12.5%, 12.5%, and 37.5%, respectively. No patient had an opportunistic infection. Tacrolimus trough concentrations showed a fair correlation with AUC(0-12h) (R(2) = 0.587). Mean MPA AUC values at 1, 3, and 6 months were 40.5 +/- 9.4, 44.4 +/- 17.3, and 57.2 +/- 20.7 mug*h/mL, respectively (P = .0486, n = 7). In conclusion, primary immunosuppression with tacrolimus, low-dose MMF (0.5 g bid), and prednisolone is effective and safe with adequate systemic MPA exposure in renal transplant recipients.     

Immunosuppression with cyclosporine A and mycophenolate mofetil after penetrating high-risk keratoplasty: a retrospective study

BACKGROUND: Graft-prognosis after penetrating high-risk keratoplasty has improved considerably with the use of systemic immunosuppressive medications. In this retrospective investigation we analyzed the long-term results of 417 high-risk keratoplasties with systemic immunosuppression (cyclosporine A [CsA] or mycophenolate mofetil [MMF]). METHODS: A total of 417 high-risk keratoplasties with postoperative systemic immunosuppression were evaluated retrospectively: CsA has been given in 252 keratoplasties since 1987, aiming at blood trough levels of 120 to 150 ng/mL. Systemic MMF at a daily dose of 2 x 1 g was administered in 149 surgical procedures. After 16 high-risk keratoplasties, combined systemic immunosuppression with CsA and MMF was administered. Systemic immunosuppression was scheduled for 6 to 12 months. All patients received fluocortolone 1 mg/kg body weight per day, tapered over 3 weeks, and topical prednisolone acetate 1%, tapered over 5 months. RESULTS: Rejection-free graft survival after 1 year was 75% in the CsA group and 89% in the MMF group; 60% of the grafts in the CsA group and 72% of the grafts in the MMF group were rejection-free 3 years postoperatively (Kaplan-Meier log-rank test P=0.03). Clear graft survival after 1 and 3 years was 92% and 77% (CsA) and 96% and 87% (MMF), respectively. The MMF-treated patients showed fewer side effects than the CsA-treated patients. The side effects attributable to both drugs were reversible. CONCLUSIONS: We found a statistically significant, stronger effect of MMF compared with CsA in preventing immune reactions after high-risk keratoplasty, despite a shorter MMF administration compared with CsA. Both systemic immunosuppressants were shown to have comparable potency regarding clear graft survival and were well tolerated.     

De novo immunosuppression with sirolimus and tacrolimus in heart transplant recipients compared with cyclosporine and mycophenolate mofetil: a one-year follow-up analysis

BACKGROUND: Limited data exist regarding the safety and efficacy of sirolimus in combination with a calcineurin inhibitor in heart transplant recipients. METHODS: From January 2001 to June 2002, 31 de novo heart transplant recipients (treatment group) received a combination of sirolimus, tacrolimus, low-dose rabbit antithymocyte globulin, and glucocorticoids. Outcomes, such as actuarial survival, rate of rejection, incidence of infection, probability of developing diabetes mellitus, renal function, platelet and white blood cell counts, and incidence of coronary artery disease at 1 year, were compared with a cohort of 25 patients (control group) who underwent transplantation primarily in 2000 and in early 2002 treated with cyclosporine, mycophenolate mofetil, and glucocorticoids. All patients were followed up for at least 12 months. RESULTS: Kaplan-Meier actuarial 1-year survival rates were equivalent between groups (97% for the treatment group and 88% for the control group), as was freedom from allograft rejection (48% and 42% for treatment and control groups, respectively). No cases of transplant arteriopathy were noted within the first posttransplantation year. Renal function was not significantly affected in either group. There was a striking increased incidence of mediastinitis in the treatment group (19%) versus 0% in the control group (P = .02). Tacrolimus-sirolimus therapy was associated with a nearly 11-fold increased incidence of new-onset diabetes mellitus as well (P = .004). CONCLUSION: Tacrolimus, sirolimus, and steroids (following low-dose rabbit antithymocyte globulin) were associated with an increased incidence of mediastinitis and posttransplantation diabetes mellitus. No obvious long-term benefit on survival, arteriopathy, or renal function was noted.     

Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate mofetil versus cyclosporine (Neoral) with mycophenolate mofetil after cadaveric kidney transplantation

BACKGROUND: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation. METHODS: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year. RESULTS: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups. CONCLUSIONS: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.     

Pharmacokinetics of daclizumab and mycophenolate mofetil with cyclosporine and steroids in renal transplantation

Daclizumab and mycophenolate mofetil (MMF) decrease the incidence of acute allograft rejection. This double-blind, randomized, placebo-controlled trial was performed primarily to assess the pharmacokinetics of MMF in an immunosuppressive regimen incorporating daclizumab. At five centers, 75 renal transplant recipients were randomized 2:1 to receive either daclizumab 1 mg/kg or placebo pre-transplantation and every other week, for a total of five doses. All patients received cyclosporine, steroids, and MMF. Levels of mycophenolic acid (MPA), its glucuronide metabolite, and daclizumab were measured after dosing on days 28 and 56. Safety parameters evaluated included: adverse events, laboratory abnormalities, infections, patient/graft survival, incidence of lymphoproliferative disorders, and incidence of acute rejection at 12 months. The concomitant administration of daclizumab and MMF had no effect on the pharmacokinetics of MPA: AUC(0-8) values (microg h/mL +/- SD) on day 28 were 30.1 +/- 13.3 for daclizumab-treat patients vs. 31.1 +/- 12.4 for placebo and on day 56, 37.7 +/- 18.2 for daclizumab-treated patients vs. 35.7 +/- 14.0 for placebo. Adverse events were similar between the two groups. Acute rejection at 12 months occurred in 14% of patients receiving daclizumab and 20% of patients receiving placebo. The coadministration of daclizumab did not result in a pharmacokinetic interaction with MPA, the active metabolite of MMF.     

Initial experience with sirolimus and mycophenolate mofetil for renal rescue from cyclosporine nephrotoxicity after heart transplantation

Calcineurin inhibitors (CNIs) have become the cornerstone of immunosuppressive regimens following heart transplantation, but their use is associated with nephrotoxicity. We evaluated a CNI elimination protocol in 14 patients with renal impairment at 48.3 +/- 36.0 months after heart transplantation. The mean serum creatinine was 321 +/- 107 micromol/L; cyclosporine (n=13) or tacrolimus (n=1) was discontinued with sirolimus commenced immediately, initially aiming for a target trough level of 16 (12 to 20) ng/mL. If patients were not receiving mycophenolate (MMF) this was initiated at 1 g bid. The transfer period was covered with a tapering course of corticosteroids. In addition to monitoring clinical status, hematology, biochemistry, and sirolimus levels, graft function was assessed by echocardiography, ECG, and, where indicated, endomyocardial biopsy. Renal function improved in 12 patients (with 6 having a greater than 40% decrease in serum creatinine), remained unchanged in 1, and deteriorated in 1. Two patients who were converted at 15 and 139 months after transplantation experienced grade 3A rejection. One patient experienced a fall in ejection fraction without histologic evidence of rejection. Sirolimus was discontinued in three patients because of side effects: bone marrow suppression, presumed lymphocytic pneumonitis, and generalized acneform rash complicated by an axillary abcess; 50% of patients continue on sirolimus. In conclusion, withdrawal of CNIs after heart transplantation resulted in an improvement in renal function in most patients: 43% experienced a substantial improvement. CNI elimination protocols need to be refined to reduce the risk of breakthrough rejection and to minimize side effects while protecting renal function after heart transplantation.