Early Adequate Mycophenolic Acid Exposure is Associated with Less Rejection in Kidney Transplantation

This study examines the importance of early mycophenolic acid (MPA) exposure in the cyclosporine- and mycophenolate mofetil (MMF)-treated kidney transplant population. We prospectively evaluated 94 first solitary kidney transplant patients treated with cyclosporine (Neoral), MMF, and prednisone. Basiliximab was also given to 72 recipients. MPA exposure was measured by HPLC using a limited sampling estimate of 12 h area under the curve (AUC [0-12]) within the first week. Efficacy was determined by the occurrence of acute rejection and toxicity by the need to reduce MMF doses within the first 3 months post-transplantation. Acute rejection was observed in 14 (15%) and MMF toxicity in 27 (29%). Receiver operator curve analysis shows that MPA AUC [0-12] on day 3 was predictive of efficacy (c = 0.72, p = 0.007) but not toxicity (c = 0.57, p = 0.285). A separate analysis of only patients on basiliximab shows that the MPA AUC [0-12] on day 3 was also predictive of efficacy (c = 0.80, p = 0.01). Therefore early adequate exposure to MPA by day 3 is associated with low acute rejection but cannot predict toxicity. Adequate MPA exposure is also important with basiliximab induction therapy.     

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients

Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m² b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m² b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC_0–12) of 27.2 μg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m² b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients. Received: 7 May 2001 / Revised: 16 July 2001 / Accepted: 16 July 2001     

达利珠单抗联合环孢素A、霉酚酸酯及糖皮质激素预防肾移植后急性排斥反应

目的 观察达利珠单抗联合环孢素A、霉酚酸酯和糖皮质激素预防肾移植后急性排斥反应的有效性和安全性。方法 由15家肾移植中心参加的开放性临床试验，共纳入72例首次尸肾移植受者为研究对象，在接受环孢素A、霉酚酸酯和糖皮质激素联合应用预防肾移植后急性排斥反应的同时，给予2剂人源化达利珠单抗，首剂给予时间为术前24h内，第2剂在术后第14d给予。对入选患者密切随访，评价肾移植后3个月和6个月时急性排斥反应的发生率、严重程度以及人、肾存活率；评价该治疗方法的安全性。结果 术后3个月内有3例患者发生4次急性排斥反应，3个月及6个月的排斥反应发生率均为5．56％；人／肾6个月和1年的存活率分别为95.8％／95.8％和94．5％／94．5％；仅有1例的腹痛可能与达利珠单抗有关。结论 2剂达利珠单抗联合环孢素A、霉酚酸酯和糖皮质激素预防肾移植后的急性排斥反应安全有效。     

Fixed- or Controlled-Dose Mycophenolate Mofetil with Standard- or Reduced-Dose Calcineurin Inhibitors: The Opticept Trial

Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed-dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2-year, open-label, randomized, multicenter trial compared the efficacy and safety of concentration-controlled MMF (MMF_CC) dosing with a fixed-dose regimen in 720 kidney recipients. Patients received either (A) MMF_CC and reduced-level calcineurin inhibitor (MMF_CC/CNI_RL); (B) MMF_CC and standard-level CNI (MMF_CC/CNI_SL); or (C) fixed-dose MMF and CNI_SL (MMF_FD/CNI_SL). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (α= 0.05) of group A versus group C for treatment failure (including biopsy-proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p ≤ 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMF_CC with low-dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMF_FD, indicating potential utility of MMF_CC in CNI-sparing regimens.     

Long-Term Use of Mycophenolate Mofetil is Associated With a Reduction in the Incidence and Risk of Late Rejection

To evaluate the association of long-term continuous (minimum 1 year) mycophenolate mofetil (MMF) vs. azathioprine (AZA) therapy with the incidence of late acute rejection, we analyzed 47 693 primary renal allograft recipients reported to the United States Renal Data System between 1988 and 1998. The primary study endpoint was acute rejection beyond 1 year after transplantation. Univariate Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to investigate the risk of reaching the study endpoints. All multivariate analyses were corrected for potential confounding covariates. Mycophenolate mofetil was associated with a 65% decreased risk of developing late acute rejection as compared to AZA (RR = 0.35, CI 0.27-0.45, p < 0.001). The incidence of acute rejection episodes at 2 and 3 years post-transplantation was significantly lower in the MMF group (0.9% at 2 years, 1.1% at 3 years) than the AZA group (6.1% at 2 years, 9.3% at 3 years). In the primary vs. repeat late rejection analysis, MMF patients exhibited a decreased late acute rejection risk of 72% (RR = 0.28, p < 0.001) and 60%, respectively (RR = 0.40, p < 0.001). In African Americans, the late acute rejection risk was 70% lower in MMF patients than AZA patients (RR = 0.30, p < 0.001). Further study is indicated to determine the optimal duration of MMF therapy after renal allograft transplantation.     

Impact of mycophenolate mofetil dose posttransplantation on 12-month renal function: analysis of the MOST database

INTRODUCTION: Mycophenolate mofetil (MMF) has greatly reduced the risk of acute rejection episodes (ARE) after renal transplantation, but dose reductions/withdrawals could jeopardize long-term results. METHODS: The MOST database of "de novo" patients treated with MMF at month 1 and functioning grafts at month 12 were divided into 2 groups: groups 1, 2 g MMF at month 1 and month 12; and group 2, 2 g MMF at month 1 but MMF <2 g at month 12 to evaluate renal function glonerular filtration rate (GFR). RESULTS: In this study, 1136 patients were receiving 2 g MMF at month 1. On month 12, 645 were on 2 g (56.8%, group 1) and 431 were on <2 g (43.2%, group 2). Group 1 included younger recipients of younger donors with fewer patients with delayed graft function (DGF). Group 1 showed more ARE during month 1 and more patients who received induction. Mean Neoral daily doses at month 1/month 12 were 5.3/3.0 and 5.3/3.1 mg/kg in group 1 and group 2, respectively (P = .05 at month 12). GFR in group 1 and group 2 were 59.06 (CI 57.10-60.60) and 53.81 (CI 52-55.7) at month 1 (P < .001); 63.7 (CI 62.1-65.30) and 55.9 (CI 54.1-57.7) mL/min*1.73 m(2) at month 12 (P < .001). The mean increases in GFR between month 1 and month 12 were 4.64 and 1.94 mL/min*1.73 m(2), respectively (P < .05). A multivariate analysis also included 795 patients from the "maintenance" patient database with retrospective detailed information. The following parameters were highly predictive for good renal function at month 12: donor age younger than 60 years, recipient age younger than 60 years, immediate graft function, 12-month MMF dose = 2 g, absence of CMV infection, and 12-month Neoral dose <3 mg/kg/d. CONCLUSIONS: Maintenance of MMF dose at 2 g/d during the first year appears to facilitate the attainment of optimal renal function at 12-months after kidney transplantation.     

The pharmacokinetics of mycophenolate mofetil in Thai kidney transplant recipients

Mycophenolate mofetil, in addition to cyclosporine and prednisolone significantly reduces the rate of acute rejection. The original recommended dose of MMF is fixed at 2 g/day. However, Thai patients cannot tolerate this dose due to gastrointestinal adverse effects. So the majority of patients are maintained on MMF at doses ranging from 0.5 to 2 g/day, according to their tolerability with an acceptable rate of acute rejection episodes. This study sought to determine the steady state pharmacokinetics of MMF in Thai kidney transplant recipients on stable doses of MMF. Forty-six kidney transplant patients more than 3 months on a stable MMF dose of 0.5, 1, 1.5, and 2 g/day together with cyclosporine and prednisolone underwent a single pharmacokinetic blood sampling for 12 hours following the morning dose of MMF. The analysis of plasma concentrations of mycophenolic acid (MPA), the sole pharmacologically active metabolite of MMF, was performed by using an high performance liquid chromatography method. Sparse efficient sampling strategies were employed to optimize the blood sampling schedule. Hence, blood samples were collected at 0, 0.5, 2, 12 hours after the MMF dose. The sampling time was designed to best estimate AUC(0-tau) at steady state. The initial MPA-Bayesian estimator were used for MPA concentrations that would allow the best estimation of Vc, CLt, and Ka. In this study, there is a high interindividual variability in the AUC. The median MPA AUC was 34.3 ug.h/mL (range 14.1-65.4). Thirty-one of 45 (68.9%) patients had a MPA AUC within 20 to 40 ug.h/mL, which is the most reasonable risk: benefit ratio in terms of preventing acute rejection episodes. Forty-one of 45 (91.1%) patients had MPA AUC within 20 to 60 ug.h/mL, which is the MPA therapeutic range. The highest Pearson correlation coefficient of determination between MPA AUC and a single concentration was observed with MPA 2 hours (r = 0.622) Without a fixed dosing regimen, most Thai kidney transplant recipients who receive MMF as part of a maintenance immunosuppressive regimen have the MPA AUC within the therapeutic window. The single drug concentration that correlates well with the AUC is MPA at 2 hours postdose.     

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.     

Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination

BACKGROUND: Sirolimus (Rapamune; SRL) in combination with cyclosporine (CsA) reduces the incidence of acute rejection episodes in renal allograft recipients. This study evaluated whether renal function could be improved by elimination of CsA from an SRL-based regimen. METHODS: This phase 2, open-label, controlled, randomized study was conducted at 17 centers in the United States and Europe. Two hundred forty-six first cadaveric renal allograft recipients were enrolled, and 197 were randomized to full-dose CsA (microemulsion) plus fixed-dose SRL (2 mg/day; group A, n=97) or reduced-dose CsA plus concentration-controlled SRL (troughs 10-20 ng/mL; group B, n=100). Most patients with acute tubular necrosis-delayed graft function that resolved later than posttransplantation day 7 were not randomized but were assigned to a third group (nonrandomized, n=49) and received up to 5 mg per day of SRL as part of their individualized treatment regimen. All patients received standard doses of corticosteroids. At the end of posttransplantation month 2, eligible patients (those not treated for rejection within 3 weeks) in group B had CsA tapered and eliminated over the subsequent 4 to 6 weeks. RESULTS: At 12 months after transplantation, renal function was significantly better in the CsA-elimination arm. In patients who were on therapy and who had not experienced an acute rejection episode before month 6, serum creatinine level was significantly lower (1.38 mg/dL vs. 1.82 mg/dL, P < 0.001) and calculated glomerular filtration rate (Nankivell method) was significantly higher (73.5 mL/min vs. 57.1 mL/min, P < 0.001) in group B than in group A. In the intention-to-treat population, rates of biopsy-confirmed acute rejection at 12 months were similar between groups A and B (18.6% vs. 22.0%, respectively; P = 0.598). In addition, graft survival (92.8% and 95.0%) and patient survival (96.9% and 96.0%) rates at 12 months were not significantly different between groups A and B, respectively. Furthermore, there were no significant differences between black and nonblack recipients within treatment groups in terms of rejection rates and graft survival at 12 months. Black recipients in group B had better serum creatinine levels at 12 months compared with black recipients in group A (1.55 mg/dL vs. 2.69 mg/dL, respectively, P = 0.011), as did nonblack recipients in group B compared with nonblack recipients in group A (1.53 mg/dL vs. 1.75 mg/dL, respectively, P = 0.055). Black patients in group A had higher mean serum creatinine levels (2.69 mg/dL) than nonblack patients in group A (1.75 mg/dL, P = 0.028). Hypertension, edema, hypomagnesemia, and dyspnea were reported significantly less frequently in patients randomly assigned to undergo CsA elimination compared with patients in group A (P < 0.05); group B patients had a significantly greater (P < 0.05) incidence of abnormal liver function tests, diarrhea, hypokalemia, and thrombocytopenia. CONCLUSION: Concentration-controlled SRL with early elimination of CsA is safe and results in improved renal function. Reduced exposure to CsA does not result in a clinically significant increase in the incidence of acute rejection episodes. This is true for both black and nonblack recipients. SRL may be used to reduce the exposure of renal allograft recipients to the nephrotoxic effects of CsA.     

Comparison of transplanted kidney function in patients on two different doses of mycophenolate mofetil

INTRODUCTION: Mycophenolate mofetil (MMF), an immunosuppressant that is widely used in renal transplant recipients, is associated with several dose-dependent hematologic and gastrointestinal side effects that lead to drug dose reduction or even discontinuation. The aim of this study was to compare the renal function and acute rejection rates of kidney allograft recipients who were on two different mycophenolate mofetil doses. METHODS: In a prospective study, 59 allograft kidney recipients who were on MMF 2 g/d were randomly selected and followed for evidences of acute rejection or drug side effects. Four patients were excluded from the study due to noncompliance, graft loss, and patient loss from opportunistic infection. Of the remaining 55 patients, 22 patients (40%) underwent MMF dose reduction to 1.35 +/- 0.23 g/d due to perceived side effects or economic reasons (group 1). The mean time for this change was 4.2 +/- 2.1 months after the kidney transplantation. The remaining patients (group 2, n = 33, 60%) had no change in MMF 2 g/d drug dosage. All patients were followed for at least 30 months after transplantation. Renal function tests (blood urea and serum creatinine) were measured monthly. Statistical analysis was performed using SPSS 11.0 (Student t test). A P value < .05 was considered significant. RESULTS: The two groups were comparable regarding age, gender, other immunosuppressive medications, and the time after transplantation. There were no episodes of acute rejection in group 1 after MMF dose reduction. The renal function (blood urea or serum creatinine levels) was comparable between the two groups at the end of study (P = .846 and .610, respectively). CONCLUSION: MMF dose reduction was not associated with an increased risk of acute renal allograft rejection or impaired graft function.     

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     

Cyclosporine Sparing with Mycophenolate Mofetil, Daclizumab and Corticosteroids in Renal Allograft Recipients: The CAESAR Study

Although the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus are highly effective immunosuppressants, they are associated with serious side effects. There is great interest in immunosuppressive regimens that permit reduction or elimination of CNIs, while maintaining adequate immunosuppression and acceptable acute rejection rates. Patients (n = 536) receiving their first renal allograft were randomized to one of three immunosuppressant regimens: daclizumab, mycophenolate mofetil (MMF), corticosteroids (CS) and low-dose CsA (target trough levels of 50-100 ng/mL), weaned from month 4 and withdrawn by month 6; daclizumab, MMF, CS and low-dose CsA; or MMF, CS and standard-dose CsA. Mean GFR 12 months after transplantation (primary end point) was not statistically different in the CsA withdrawal and low-dose CsA groups (both 50.9 mL/min/1.73 m(2)) vs. the standard-dose CsA group (48.6 mL/min/1.73 m(2)). At 12 months, the incidence of biopsy-proven acute rejection was significantly higher in the CsA withdrawal group (38%) vs. the low- or standard-dose CsA groups (25.4% and 27.5%, respectively; p < 0.05). In summary, a regimen of continuous low-dose CsA with MMF, CS and daclizumab induction is a clinically safe and effective immunosuppressive regimen in renal transplant recipients.     

Pharmacodynamics of Mycophenolate Mofetil after Heart Transplantation: New Mechanisms of Action and Correlations with Histologic Severity of Graft Rejection

The primary mechanism of action in vivo of mycophenolate mofetil (MMF) is believed to be inhibition of lymphocyte proliferation. We used novel assays of lymphocyte functions (pharmacodynamics, PD) in whole blood collected from rat heart allograft recipients treated with MMF to investigate the mechanisms of action of the active metabolite of MMF, mycophenolate acid (MPA) in vivo. Allograft recipients were treated orally once daily with 3 different doses of MMF. Seven days after transplantation, blood was collected 24h after the penultimate dose and several timepoints after the last dose, after which grafts were removed for microscopic grading of rejection. Lymphocytes in whole blood samples were mitogen stimulated through calcium-dependent and -independent signaling pathways. Inhibition of PD was measured by lymphocyte proliferation and expression of several surface antigens on T cells, and was calculated as area under the time-inhibition of immune function effect curve (AUE0-24h). We found that inhibition of lymphocyte proliferation and antigen expression by MPA correlated highly with MMF-dose, MPA level and with the histologic severities of graft rejection (p <0.05). In summary, MPA suppressed lymphocyte proliferation and expression of T-cell surface antigens in whole blood collected from MMF-treated allograft recipients, thus demonstrating the multiple mechanisms of suppression of rejection on peripheral blood T cells after MMF treatment.     

Long-term follow-up of pediatric transplant recipients: mycophenolic acid trough levels are not a good indicator for long-term graft function

Abstract: Background: Mycophenolate mofetil (MMF) has the potential of decreasing acute rejection episodes early following renal transplantation. Pharmocokinetic monitoring of mycophenolic acid (MPA) trough levels is performed by many centers. MMF has also proved successful in improving long‐term graft function in patients with chronic allograft nephropathy (CAN). However, no data for long‐term monitoring of MPA in children have yet been published. Methods: MMF therapy with a dose of 600 mg/m² twice daily was initiated in 42 children (median age 9.4 yr, range 1.4–15.1) after a median period of 3.8 yr (range 1.0–10.6) post‐transplantation – according to significant increases in serum creatinine. CAN was diagnosed by renal biopsy and the amount of fibrosis was quantified with PicroSiriusRed staining. MMF therapy was combined with ciclosporin A and prednisolone. MPA‐C0‐levels, measured by high‐pressure liquid chromatography, were tested every 3 months. In 12 children a full MPA area under the curve concentration (AUC) was measured. The glomerular filtration rate (GFR) was calculated at the start of MMF therapy and 2 yr later. Results: After initiation of MMF, the calculated GFR did not decrease further in 22 children and mean GFR remained stable for 2 yr in the whole study group. There was a significant correlation between MPA levels 75 min after administration and the full AUC (r = 0.94, p < 0.001) but no correlation between trough levels and AUC (r = ?0.07, p > 0.05). The mean MPA trough level was 2.8 ± 1.3 ng/mL. The intra‐individual coefficient of variation was 2.6 ± 1.4. There was no correlation between mean MPA trough levels and GFR development after 2 yr (r = 0.03, p > 0.05). In children with an MPA level below 1.2 mg/L (n = 5), the mean GFR decline was no different to those with a higher level (p > 0.05). Conclusions: Drug monitoring of MPA trough levels had no impact on long‐term graft function in kidney recipients. MPA levels taken 75 min after administration showed a high correlation with MPA‐AUC whereas C0‐levels did not correlate. The value of C75 drug measurements for monitoring renal allograft survival will have to be judged in future studies.     

Mycophenolic acid concentrations are associated with cardiac allograft rejection.

BACKGROUND: Mycophenolate mofetil (MMF) therapy decreases the incidence of allograft rejection following solid-organ transplantation. Current dosing strategies of MMF are not routinely adjusted based on mycophenolic acid (MPA) area under the concentration-time curve (AUC), MPA trough, or free MPA (fMPA) AUC values. METHODS: To determine the clinical significance of MPA concentrations following orthotopic heart transplantation (OHT), we measured pre-dose MPA trough, MPA free fraction, an estimated MPA AUC using an abbreviated sampling schedule, and fMPA AUC in 38 consecutive patients. We measured MPA concentrations using a validated high-performance liquid chromatography method and graded endomyocardial biopsies based on the International Society for Heart and Lung Transplantation (ISHLT) grading system. RESULTS: The MPA values for the study group were as follows: MPA trough of 1.2 +/- 0.6 microg/ml; MPA free fraction of 1.9 +/- 0.4%; MPA AUC of 44.5 +/- 16. 1 microg/hour/ml; and fMPA AUC of 0.83 +/- 0.30 microg/hour/ml. We compared patients with Grade 0 (n = 22), Grade 1 (n = 13), or Grade 2/3 (n = 3). The MPA AUC values were lower in patients with Grade 2/3 than in patients with Grade 0 (26.1 +/- 6.6 vs 42.8 +/- 14.0 microg/hour/ml, p < 0.08) or Grade 1 rejection (26.1 +/- 6.6 vs 51.7 +/- 17.5 microg/hour/ml, p < 0.05). The fMPA AUC values were lower in patients with Grade 2/3 than with patients with Grade 0 (0.49 +/- 0.11 vs 0.81 +/- 0.25 microg/hour/ml, p < 0.05) or Grade 1 (0.49 +/- 0.25 vs 0.95 +/- 0.34 microg/hour/ml, p < 0.05) rejection. We noted a trend in MPA trough concentrations between patients with Grade 2/3 vs 0 (0.65 +/- 0.15 vs 1.20 +/- 0.58 microg/ml, p = 0.15) and Grade 1 (0.65 +/- 0.15 vs 1.24 +/- 0.72 microg/ml, p = 0.14) rejection. CONCLUSION: These preliminary results suggest that lower MPA AUC and fMPA AUC values are associated with cardiac allograft rejection in heart transplant recipients. Individualizing MMF dosing based on MPA determinations may minimize the risk of rejection following OHT.     

Sirolimus rescue therapy for refractory rejection in renal transplantation.

BACKGROUND: Acute renal allograft rejection episodes refractory to antilymphocyte preparations almost inevitably progress to transplantation loss. To reverse ongoing rejection processes, we administered sirolimus (RAPA) after failure of conventional immunosuppressive regimens including full courses of antilymphocyte sera. METHODS: All 36 renal transplantation recipients reported herein displayed either Grade IIB or Grade III biopsy-proven (Banff 1993 criteria) ongoing rejection episodes despite prior treatment with pulse and/or oral recycling of steroids and at least one 14- to 21-day course of murine (OKT3) or equine (ATGAM) antilymphocyte treatment. We compared the actual 12-month outcomes of two demographically similar cohorts of patients treated for refractory rejection with RAPA (Group I; n=24) or mycophenolate mofetil (MMF; Group II; n=12) added to a baseline regimen of cyclosporine (CsA)/prednisone (Pred). RESULTS: Rescue therapy reversed the renal dysfunction in 96% of patients in the RAPA group versus 67% in the MMF group (P=0.03) despite the fact that a greater fraction of patients in the RAPA (17 of 24) than the MMF group (6 of 12) had experienced two or more episodes of acute rejection before study entry and the fact that the recurrent bouts of acute rejection occurred within the first 6 months posttransplant in 94% of patients in the RAPA group compared with 50% (P=0.005) in the MMF group. Among the patients who were reversed successfully, the rates of rebound acute rejection were similar (4% vs. 8%). The mean serum creatinine values were slightly, although not significantly, lower among RAPA than MMF patients at 1, 3, 6, and 12 months: namely, 2.6 vs. 2.8, 2.8 vs. 3.2, 3.0 vs. 3.3, and 2.8 vs. 3.2 mg/dL, respectively. The 1-year patient and graft survival rates were similar: namely, 88% vs. 92% and 83% vs. 67% for the RAPA versus MMF groups. CONCLUSION: RAPA is a potent immunosuppressive agent for the treatment of refractory renal allograft rejection.     

Low-dose mycophenolate mofetil is an effective and safe treatment to permit phased reduction in calcineurin inhibitors in chronic allograft nephropathy

BACKGROUND: Chronic allograft nephropathy (CAN) is the most common cause of long-term renal-allograft dysfunction and the second most common cause of transplant loss. There are concerns that prolonged patient exposure to calcineurin inhibitors (CNIs) exacerbates or promotes the process of CAN. METHODS: In our unit, we carried out an observational study over the period 2000 to 2003 using low-dose mycophenolate mofetil (MMF) to facilitate a phased reduction in the dose of CNI in a group of patients with CAN. Low doses of MMF were chosen to minimize adverse effects and to reduce levels of CNIs without the attendant risks of under-immunosuppression. RESULTS: A step-wise reduction in mean reciprocalised creatinine was evident over the run-in period (mean 1/creatinine before MMF=0.005739-0.000083*month; R=0.77) with a step-wise monthly improvement postintroduction of MMF and dose reduction of CNI (mean 1/creatinine after MMF=0.004609+0.000049*month; R=0.74) (P<0.0001). The mean Cockroft-Gault estimated creatinine clearances were 47.1+/-24.2, 37.2+/-16.3, and 41.6+/-21.1 mL/min at time [t]=-12, t=0 and t=+12 months, respectively. Low-dose MMF therapy was well tolerated (only 7/89 patients stopped MMF because of side-effects in the first 12 months), and acute rejection was noted in only one patient. At latest follow-up, only 17 transplant losses had occurred, of which 6 patients had died with a functioning graft. CONCLUSIONS: Low-dose MMF was well tolerated and resulted in prolonged graft survival.     

Randomised open clinical trial of conversion from mycophenolate mofetil to azathioprine in cadaveric renal transplantation

Abstract Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The search for a less expensive immunosuppressive protocol has led to an open randomised clinical trial of conversion from MMF to azathioprine (Aza). A total of 28 renal allograft recipients treated with prednisone, cyclosporine, and MMF was randomised into two groups: converted (early conversion) and control (late conversion). Conversion from MMF to Aza was conducted at the end of the 4th post‐transplant month in the converted group and after the 12th month in the control. During the 20‐month observation period, biopsy‐proven acute rejection occurred more frequently in the converted than in the control group, although the difference was not statistically significant. Early conversion from MMF to Aza increased the risk of subsequent rejection in those patients who underwent at least one episode of acute rejection prior to conversion.     

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.     

Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients

BACKGROUND: Everolimus is a proliferation inhibitor designed to target chronic rejection, including prevention of acute rejection. Everolimus blocks growth factor-mediated transduction signals, preventing organ rejection by a mechanism different than that of calcineurin inhibitors and of mycophenolate mofetil (MMF). METHODS.: Everolimus (1.5 mg or 3 mg daily) was compared with MMF (2 g daily) in a randomized, multicenter, multinational, 12-month double-blind, double-dummy and 2-year open-label, phase 3 trial in de novo renal allograft recipients (n = 588) who also received cyclosporine and corticosteroids as part of a triple immunosuppressive regimen. RESULTS: At 12 months, there were no statistically significant differences between doses of 1.5 and 3 mg/day everolimus and MMF (2 g/day) in incidence of biopsy-proven acute rejection (23.2%, 19.7%, and 24.0%, respectively), graft loss (4.6%, 10.6%, and 9.2%), or death (5.2%, 4.0%, and 2.6%), respectively. Everolimus 1.5 mg/day and MMF were generally equally well tolerated. Both were better tolerated than everolimus 3 mg/day. The incidence of cytomegalovirus infection was significantly lower in patients receiving either 1.5 or 3 mg/day everolimus than in those receiving MMF (5.2% and 7.6% vs. 19.4%, respectively) (P = .001). CONCLUSIONS: Everolimus is effective in preventing acute rejection and graft loss in de novo renal allograft recipients receiving a triple immunosuppressive regimen. Prevention of acute rejection, along with reduction in cytomegalovirus infection, addresses two factors known to contribute to chronic rejection in such patients.