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.     

Mycophenolate mofetil in combination with reduction of calcineurin inhibitors for chronic renal dysfunction after liver transplantation.

The purpose of the study was to introduce mycophenolate mofetil (MMF) in liver transplant recipients with renal dysfunction to decrease calcineurin inhibitor (CNI) dosages without increasing rejection risk. In this prospective, multicenter, randomized study, chronic CNI-related renal dysfunction was defined by an increase in serum creatinine with values >140 micromol/L and <300 micromol/L. Patients were randomized in 2 groups. Study group: combination of MMF (2 to 3 g/day) and reduced dose of CNI >or=50% of initial dose; control group: no MMF, but with the ability to reduce CNI doses, but not below 75% of initial dose. Fifty-six patients were included, 27 in the study group and 29 in the control group. In the study group, there was a significant decrease in serum creatinine values, from 171.7 +/- 24.2 micromol/L at day 0 to 143.4 +/- 19 micromol/L at month 12 and a significant increase in creatinine clearance, from 42.6 +/- 10.9 mL/min to 51.7 +/- 13.8 mL/min. No rejection episode was observed in the study group. In the control group, there was no improvement of renal function, assessed by the changes in serum creatinine values, from 175.4 +/- 23.4 micromol/L at day 0 to 181.6 +/- 63 micromol/L at month 12, and in creatinine clearance, from 42.8 +/- 12.8 mL/min to 44.8 +/- 19.7 mL/min. The differences between the 2 groups were significant: P = 0.001 for serum creatinine, and P = 0.04 for creatinine clearance. In conclusion, the introduction of MMF combined with the reduction of at least 50% of CNI dose allowed the renal function of liver transplant recipients to significantly improve at 1 year, without any rejection episode and without significant secondary effects.     

Mycophenolate mofetil (Cellcept) in pediatric renal transplantation

Mycophenolate mofetil (MMF) was introduced in pediatric renal transplantation almost 10 years ago. In several pediatric studies, MMF has been associated with improved graft survival and improved renal function with standard immunosuppression of steroids and calcineurin inhibitors (CNI). Both drugs are associated with significant negative effects including influence on growth, blood pressure, glucose metabolism, and also cosmetic side effects. Reduction of CNI was possible with MMF without increased rejection, improving blood pressure and renal function. Information is accumulating that steroid-sparing protocols including CNI are also associated with clinical improvement. Recent reports are positive in the pediatric population using the combination of induction with interleukin-2-receptor antagonists and mTOR inhibitors to spare steroids and CNI. Therefore MMF remains a mainstay of immunosuppressive protocols in the pediatric renal transplantation.     

Mycophenolate mofetil monotherapy in liver transplantation

Aim

Calcineurin inhibitors (CI) are associated with significant morbidity in transplant recipients. The aim of this study was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) monotherapy in liver transplantation (LT).

Methods

We analysed 32 patients (24 males, 8 female, of mean age 55.7 years) who underwent LT between 1994 and 2003. In 29 patients immunosuppressive therapy was cyclosporine; in three patients it was tacrolimus. Eleven patients were submitted for LT due to hepatitis B cirrhosis; eight for hepatitis C cirrhosis, six for alcoholic cirrhosis, and seven for other diseases. In these patients, MMF was added gradually, simultaneously reducing the dosage of CI up to complete withdrawal. We considered the efficacy (decrease in serum creatinine) and the incidence of complications (acute and chronic rejection, leukopenia, diarrhea).

Results

Patients were converted to MMF after a median of 50 months after LT. MMF monotherapy was started after a median of 9 months in association with CI. Indications for switch to MMF monotherapy were adverse effects of CI (renal disfunction in 30 patients) and de novo tumoral evidence after LT in two patients. Median dosage of MMF was 750 mg twice daily (500-1500 mg). There was a statistically significant decrease in serum creatinine levels (2.02-1.7 mg/dL; P = .0001). Side effects were: leukopenia in five of 32 patients (15.6%), diarrhea in four of 32 patients (12.5%), and one acute rejection.

Conclusion

MMF monotherapy improved renal function and was not associated with a significant risk of allograft rejection. Side effects were mild with dose regimens up to 750 mg twice daily.     

Mycophenolate mofetil added to immunosuppression after liver transplantation – first results

Mycophenolate mofetil (MMF) has been used successfully as an immunosuppressive agent after kidney and heart transplantation, but experience with MMF after liver transplantation is still limited. Between August 1995 and January 1996, we treated 20 patients with MMF after orthotopic liver transplantation in an open, prospective study. Five out of eight patients with acute rejection and one patient with early chronic rejection showed a complete response after MMF was added to the immunosuppression. Three patients with chronic rejection did not improve, one died, and two have stable graft function at present. In eight patients who suffered from toxicity, a reduction in the dosage of tacrolimus was attempted with simultaneous MMF therapy. One patient died due to multiple organ failure. Liver function improved completely in one other patient, and partially in three patients after adding MMF. In the remaining three patients, a reduced dosage of tacrolimus or cyclosporin, together with MMF, reduced toxicity, not significantly. In conclusion, MMF appears to be a safe and potentially useful adjuvant immunosuppressive agent for rescue and maintenance therapy. Received: 15 August 1996 Accepted: 6 December 1996     

Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation

BACKGROUND: Calcineurin inhibitors (CNIs) are the first-line immunosuppressive agents administered after liver transplantation, but they cause renal impairment. Two recent randomized trials report cellular rejection and liver graft loss when mycophenolate mofetil (MMF) monotherapy was used as a renal-sparing agent. Our experience with MMF in the same setting but with longer follow-up is described. METHODS: In 45 patients with serum creatinine more than 120 micromol/L or creatinine clearance less than 50 mL/min, 2 g MMF per day was administered (median 29 months, 1-49 months) either as monotherapy (with all other immunosuppression withdrawn in 1 month) in 16 patients (group I) or in combination with low-dose CNI (trough tacrolimus 相似文献   

Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation

Mycophenolate mofetil (MMF) significantly decreases acute rejection rates after renal transplantation, but intolerance often occurs, leading to dose reduction. The clinical effect of MMF dose reduction has not been clearly established. This study determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close surveillance on such patients.     

Diaphragmatic dysfunction after pediatric orthotopic liver transplantation

BACKGROUND: Pediatric orthotopic liver transplantation (OLT) has a low mortality. Some children, however, have an adverse outcome defined as a prolonged ventilatory support requirement and protracted pediatric intensive care unit (PICU) stay. The aim of this study was to determine if that adverse outcome related to the child's condition pre-OLT and/or the development of a pleural effusion or diaphragmatic dysfunction. METHODS: The study included 210 children with a median age at transplantation of 45.5 months (range 0.2-252 months). Fourteen had undergone retransplantation. The duration of ventilatory support (intermittent positive pressure ventilation [IPPV]) and PICU admission and development of a pleural effusion and/or diaphragmatic dysfunction were documented for each child. The patients were divided into three groups according to whether they had acute liver failure (ALF), chronic liver disease at home (CHOM), or chronic liver failure sufficiently ill to be in the hospital awaiting transplantation (CHOSP). RESULTS: The 36 children with ALF were of similar age to the 138 CHOM and 36 CHOSP children but required longer IPPV (P<0.0001) and PICU stay (P<0.0001). Overall, 17 children developed diaphragmatic dysfunction and 138 pleural effusions; affected children required longer IPPV and PICU stay (P<0.01). Regression analysis demonstrated that diaphragmatic dysfunction, but not pleural effusion development, was associated with prolonged ventilation (P<0.01) and protracted PICU stay (P<0.05). Other risk factors were ALF (P<0.01), retransplantation (P<0.01), and young age (P<0.05). CONCLUSION: Diaphragmatic dysfunction adversely influences PICU morbidity after OLT. Early assessment of diaphragmatic function, and if necessary aggressive management, might improve outcome.     

The renal benefit of mycophenolate mofetil after liver transplantation

Haywood S, Abecassis M, Levitsky J. The renal benefit of mycophenolate mofetil after liver transplantation.
Clin Transplant 2011: 25: E88–E95. © 2010 John Wiley & Sons A/S. Abstract: Background: The risk and benefit of adding mycophenolate mofetil (MMF) to a standard immunosuppressive regimen at the time of liver transplantation (LT) is not well described. Methods: We performed a retrospective case–control analysis comparing one‐yr outcomes of all LT recipients at our institution treated with post‐operative tacrolimus (TAC), MMF, and steroids vs. TAC and steroids. Results: A total of 101 LT recipients (50:51 case:control) were analyzed. Despite more renal dysfunction at LT, the MMF + TAC group had similar serum creatinine (Cr) and glomerular filtration rate (GFR) as the TAC group one‐yr post‐LT. In this time period, Cr decreased (1.57–1.22 mg/dL, p = 0.04) and GFR increased (57.5–65.1 mL/min per 1.73 m², p = 0.05) in the MMF + TAC group, while Cr increased (1.11–1.35, p < 0.01) and GFR declined (73.5–60.1, p < 0.001) in the TAC group. These findings occurred without a difference in absolute rejection episodes, hospitalizations, infections, deaths, or time to above events (p > 0.05). Subgroup analysis of patients stratified by pre‐transplant renal dysfunction (Cr ≥ 1.2 mg/dL) supported the previous. MMF was reasonably well tolerated with a low rate of discontinuation. Conclusions: The use of adjunctive MMF immediately after LT may protect against calcineurin inhibitor nephrotoxicity, potentially without the need for dose reduction or increased risk of adverse events.     

Mycophenolate mofetil decreases antibody production after cardiac transplantation.

New immunosuppressive drugs are extensively being investigated for their effect on T-cell immunity, with far less being known about their effect on the humoral immune response. In view of the experimental and clinical evidence that humoral immunity contributes to acute and chronic rejection, we investigated post-transplant production of anti-vimentin and anti-HLA antibodies in 86 patients who were part of a worldwide clinical trial for mycophenolate mofetil in cardiac transplantation. The results demonstrate that patients taking MMF instead of azathioprine generated significantly fewer de novo anti-vimentin antibodies.     

Chronic renal dysfunction late after liver transplantation

With the increasing success of liver transplantation, more patients are developing late complications such as renal dysfunction. The goal of the current study was to assess the prevalence of renal dysfunction years after liver transplantation and to identify patients at risk for the development of this complication. Of the 527 liver transplantations performed at our institution between April 1990 and October 1998, 353 had pretransplantation and posttransplantation glomerular filtration rate (GFR) determinations by iothalamate clearance. From this entire group, 198 patients had actual 4-year follow-up and 52 had actual 6-year follow-up. In addition, 191 of these patients had intensive follow-up with GFR measurements pretransplantation and at 1 and 3 years posttransplantation (complete follow-up group). All patients received either tacrolimus- or cyclosporine-based immunosuppression. The overall mean GFR levels in both of these groups was acceptable and was not different in cyclosporine- versus tacrolimus-based immunosuppressive regimens. Renal dysfunction was progressive, with 27.5% of patients in the intensive group having a GFR < 40 mL/min/body surface area 5 years after transplantation. GFR pretransplantation did not correlate well with late renal function; however, GFR at 1 year identified patients with subsequent renal dysfunction. The cumulative incidence of renal failure for the entire group was 6.25% at 7 years and 10% at 10 years. Renal dysfunction is a major late complication after liver transplantation. The GFR at 1 year correlates best with late renal function. Patients with a low GFR at 1 year (< 40 mL/min/BSA) are a high-risk group that might benefit from early therapeutic interventions aimed at preventing subsequent renal failure. (Liver Transpl 2002;8:916-921.)     

肝移植术后慢性肾功能损伤的危险因素分析

目的 探讨影响肝移植术后慢性肾功能损伤(CRD)的危险因素.方法 回顾性分析2007年1月至2008年1月于中国人民武装警察部队总医院接受肝移植术后生存时间＞3年的101例患者的临床资料,应用MDRD公式计算术前以及术后1、3年的肾小球滤过率(GFR).根据术后GFR是否＜60 ml/min将患者分为CRD组(16例)和对照组(85例).采用x2检验或t检验对可能影响肝移植术后肾功能的16项危险因素(性别、年龄、高血压、糖尿病、肌酐、尿素氮、他克莫司浓度、术前GFR、热缺血时间、冷缺血时间、国际标准化比值、TP、TBil、ALT、AST、ALP)进行单因素分析,将差异有统计学意义的因素进行Logistic多因素回归分析.结果 101例肝移植患者手术前GFR为(103±22) ml/min,其中3例患者术前GFR＜60 ml/min;101例患者肝移植术后l、3年GFR分别为(91 ±22) ml/min和(83 ± 21) ml/min,其中7例患者肝移植术后1年GFR＜ 60 ml/min,16例患者术后3年GFR＜ 60 ml/min.单因素分析结果表明:高血压、糖尿病、肌酐、尿素氮、他克莫司浓度和术前GFR是肝移植术后CRD的危险因素(x2=9.400,21.917,f =51.024,91.620,41.381,99.000,P＜0.05).多因素分析结果表明:高血压、糖尿病和术前GFR是肝移植术后CRD的独立危险因素(OR=65.438,17.903,0.911,P＜0.05).结论 GFR降低和手术前合并高血糖和高血压是肝移植术后CRD的危险因素.     

Use of mycophenolate mofetil as rescue therapy after pediatric liver transplantation

BACKGROUND: Mycophenolate mofetil (MMF) has been increasingly used after liver transplantation (LT) in adults. We report our preliminary experience with MMF as rescue therapy after pediatric LT. METHODS: A total of 19 children received MMF for 21 indications. Median age at LT was 30 months (range 7-149). The median initial oral dose of MMF was 23 mg/kg/day (range 12-43) orally. Median follow-up after initiation of MMF therapy was 642 days (range 229-1606). RESULTS: 1) Efficacy: MMF was indicated for rejection or insufficient immunosuppression in 16 cases, with normalization of both liver function tests and liver histology in 10 (62%). MMF was successfully used in one patient with post-LT immmune hepatitis and one patient with corticodependence. In three patients with renal function impairment, MMF allowed reduction of cyclosporine A or tacrolimus blood levels, without subsequent rejection. 2) Tolerance: Six patients (32%) experienced eight side effects, mainly gastrointestinal and hematological, which resolved after cessation of MMF in five cases and dose reduction in three. One case of posttransplant lymphoproliferative disease (PTLD) occurred under MMF therapy (5.2%). Four patients had EBV primary infection, while under MMF therapy, without subsequent PTLD. Three patients had CMV primary infection, and five CMV reactivation, under MMF therapy. Seven remained asymptomatic, and one presented with CMV enteritis. CONCLUSIONS: These preliminary results suggest that MMF is an effective and safe immunosuppressant in pediatric LT recipients. Its use is hampered by frequent gastrointestinal and hematological side-effects. MMF does not seem to increase the risk of PTLD nor CMV disease.