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Jiménez-Romero C, Justo Alonso I, Caso Maestro O, Manrique Municio A, García-Sesma Á, Calvo Pulido J, Cambra Molero F, Loinaz Segurola C, Martín-Arriscado C, Nutu A, Marcacuzco Quinto A. Indications and Long-Term Outcomes of Using Mycophenolate Mofetil Monotherapy in Substitution for Calcineurin Inhibitors in Liver Transplantation. Transpl Int 2025; 38:13790. [PMID: 40060933 PMCID: PMC11886422 DOI: 10.3389/ti.2025.13790] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 01/27/2025] [Indexed: 05/13/2025]
Abstract
Switching the use of calcineurin inhibitors (CNIs), as basal immunosuppression in liver transplantation (LT) patients, for that of mycophenolate mofetil monotherapy (MMF-MT) is currently considered a good measure in recipients with chronic kidney disease (CKD) and other CNI-related adverse effects. We analyzed a retrospective cohort series of 324 LT patients who underwent long-term follow-up and were switched from CNI immunosuppression to MMF-MT due to CKD and other CNI-related adverse effects (diabetes, hypertension, infection). The median time on MMF-MT was 78 months. The indication for MMF-MT was CKD alone or associated with CNI-related adverse effects in 215 patients, diabetes in 61, hypertension in 42, and recurrent cholangitis in 6. Twenty-four (7.4%) patients developed non-resistant acute rejection post-MMF-MT, and 48 (14.8%) patients experienced MMF-related adverse effects, with MMF-MT withdrawn in only 8 (2.5%) patients. In the comparison between the pre-MMF-MT period and the last outpatient review, using a repeated measures model and taking each patient as its own comparator, we demonstrated a significant increase in GFR and significant decrease in creatinine and ALT values, remaining the other variables (diabetes, hypertension, and hematological and AST) within similar levels. Five-year survival post-MMF-MT conversion was 75.3%. MMF-MT significantly improved renal function, was well tolerated, and had a low rejection rate.
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Affiliation(s)
- Carlos Jiménez-Romero
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Iago Justo Alonso
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Oscar Caso Maestro
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Alejandro Manrique Municio
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Álvaro García-Sesma
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Jorge Calvo Pulido
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Félix Cambra Molero
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Carmelo Loinaz Segurola
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | | | - Anisa Nutu
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
| | - Alberto Marcacuzco Quinto
- Unit of Hepato-Pancreato-Biliary Surgery and Abdominal Organ Transplantation, Doce de Octubre University Hospital, Madrid, Spain
- Department of Surgery, Faculty of Medicine, Complutense University, Madrid, Spain
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Herrero JI, Cuervas-Mons V, Gómez-Bravo MÁ, Fabregat J, Otero A, Bilbao I, Salcedo MM, González-Diéguez ML, Fernández JR, Serrano MT, Jiménez M, Rodrigo JM, Narváez I, Sánchez G. Prevalence and progression of chronic kidney disease after a liver transplant: a prospective, real-life, observational, two-year multicenter study. REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS 2018; 110:538-543. [DOI: 10.17235/reed.2018.5431/2017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Hwang S, Song GW, Jung DH, Park GC, Ahn CS, Moon DB, Ha TY, Kim KH, Lee SG. Intra-individual variability of mycophenolic acid concentration according to renal function in liver transplant recipients receiving mycophenolate monotherapy. Ann Hepatobiliary Pancreat Surg 2017; 21:11-16. [PMID: 28317040 PMCID: PMC5353912 DOI: 10.14701/ahbps.2017.21.1.11] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 01/20/2017] [Accepted: 01/25/2017] [Indexed: 01/01/2023] Open
Abstract
BACKGROUNDS/AIMS Mycophenolate mofetil (MMF) has wide inter- and intra-individual variability of mycophenolic acid (MPA) after liver transplantation (LT). On this study, we aimed to analyse the intra-individual variability of MPA concentration in stable adult LT recipients receiving MMF monotherapy and develop a method to determine the target level in the situation of wide intra-individual variability. METHODS This retrospective cross-sectional study included 30 LT recipients. All patients received MMF monotherapy at a dose of 500 mg twice daily for ≥2 years and were divided into two groups based on renal function. MPA concentration-associated values were presented as mean with standard deviation and coefficient of variation (CV). RESULTS The normal renal function group (n=15) showed a mean 12-hour MPA concentration of 2.5±0.5 µg/ml (range, 1.8±0.5 to 3.6±0.7 µg/ml) and a mean CV of 20.4±7.7% (range, 8.7% to 39.4%). In the renal dysfunction group (n=15), the 12-hour MPA concentration fluctuated more widely with a mean value of 3.7±0.9 µg/ml (range, 2.8±0.8 to 5.1±1.2 µg/ml) and a mean CV of 24.5±4.9% (range, 17.1% to 37.5%). The 12-hour MPA concentration was significantly higher in the renal dysfunction group, as compared to the normal renal function group (p=0.001); whereas, the CV was not significantly different between the two groups (p=0.093). CONCLUSIONS We determined the inter- and intra-individual variability of 12-hour MPA concentration after LT. The results suggested that therapeutic drug monitoring of MPA is necessary due to the inter-individual and intra-individual variability of MMF pharmacokinetics, especially in LT recipients with renal dysfunction.
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Affiliation(s)
- Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Gil-Chun Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chul-Soo Ahn
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Tae-Yong Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Park YH, Hwang S, Song GW, Jung DH, Ahn CS, Kim KH, Moon DB, Ha TY, Park GC, Kim N, Lee SG. Correlation between mycophenolic acid blood level and renal dysfunction in stable liver transplant recipients receiving mycophenolate monotherapy. Transplant Proc 2015; 46:811-5. [PMID: 24767354 DOI: 10.1016/j.transproceed.2013.12.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Revised: 11/30/2013] [Accepted: 12/11/2013] [Indexed: 10/25/2022]
Abstract
PURPOSE Mycophenolate mofetil (MMF) is frequently used after liver transplantation (OLT). Mycophenolic acid (MPA) metabolites are eliminated primarily via the kidneys. If renal function declines, clearance is significantly impaired. The aim of this study was to reveal the renal function-dependent changes of MPA level in stable adult OLT recipients receiving MMF monotherapy. METHODS Sixty-five OLT recipients were selected from our OLT database of >3500 cases. All had undergone MMF monotherapy with a daily MMF dose of 1000 mg or 1500 mg for more than 2 years, primarily because they could not tolerate calcineurin inhibitors. Their clinical profiles, including MPA therapeutic drug monitoring (TDM) and renal function, were analyzed as a cross-sectional study. RESULTS For the group treated with 1000 mg MMF (n = 40), the 12-hour MPA trough level was 1.20 ± 0.35 μg/mL with serum creatinine (Cr) level ≤1.4 mg/dL in 13 patients; it was 2.78 ± 1.19 μg/mL with Cr >1.4 mg/dL in 16 patients not undergoing hemodialysis and 3.83 ± 0.87 μg/mL in 11 patients undergoing hemodialysis (P < .001). For the group treated with 1500 mg MMF (n = 25), the MPA trough level was 2.23 ± 0.99 μg/mL with Cr ≤1.4 mg/dL in 6 patients; it was 2.81 ± 0.99 μg/mL with Cr >1.4 mg/dL in 18 patients not undergoing hemodialysis and 3.5 μg/mL in 1 patient undergoing hemodialysis (P = .21). CONCLUSIONS Considering the potential therapeutic range of MPA, the suggested MMF dosage for Korean adult OLT recipients requiring hemodialysis may be set around 1000 mg per day. We suggest adjusting the MMF dosage on an individualized basis according to the results of MPA TDM, particularly for patients with markedly impaired renal function.
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Affiliation(s)
- Y-H Park
- Department of Surgery, Inje University Haeundae Paik Hospital, Busan, Korea
| | - S Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - G-W Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - D-H Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - C-S Ahn
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - K-H Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - D-B Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - T-Y Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - G-C Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - N Kim
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
| | - S-G Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Detección precoz, prevención y manejo de la insuficiencia renal en el trasplante hepático. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:480-91. [DOI: 10.1016/j.gastrohep.2013.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 11/06/2013] [Accepted: 11/12/2013] [Indexed: 12/19/2022]
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Dopazo C, Bilbao I, Castells LL, Sapisochin G, Moreiras C, Campos-Varela I, Echeverri J, Caralt M, Lázaro JL, Charco R. Analysis of adult 20-year survivors after liver transplantation. Hepatol Int 2014; 9:461-70. [PMID: 25788182 PMCID: PMC4473278 DOI: 10.1007/s12072-014-9577-x] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Accepted: 08/21/2014] [Indexed: 02/07/2023]
Abstract
Background Liver transplantation (LT) is the treatment of choice for chronic and acute liver failure; however, the status of long-term survivors and allograft function is not well known. Aim To evaluate the clinical outcome and allograft function of survivors 20 years post-LT, cause of death during the same period and risk factors of mortality. Methods A retrospective study was conducted from prospective, longitudinal data collected at a single center of adult LT recipients surviving 20 years. A comparative sub-analysis was made with patients who were not alive 20 years post-transplantation to identify the causes of death and risk factors of mortality. Results Between 1988 and 1994, 132 patients received 151 deceased-donors LT and 28 (21 %) survived more than 20 years. Regarding liver function in this group, medians of AST, ALT and total bilirubin at 20 years post-LT were 33 IU/L (13–135 IU/L), 27 (11–152 IU/L) and 0.6 mg/dL (0.3–1.1 mg/dL). Renal dysfunction was observed in 40 % of patients and median eGFR among 20-year survivors was 64 mL/min/1.73 m2 (6–144 mL/min/1.73 m2). Sixty-one percent of 20-year survivors had arterial hypertension, 43 % dyslipidemia, 25 % de novo tumors and 21 % diabetes mellitus. Infections were the main cause of death during the 1st year post-transplant (32 %) and between the 1st and 5th year post-transplant (25 %). After 5th year from transplant, hepatitis C recurrence (22 %) became the first cause of death. Factors having an impact on long-term patient survival were HCC indication (p = 0.049), pre-transplant renal dysfunction (p = 0.043) and long warm ischemia time (p = 0.016); furthermore, post-transplant factors were diabetes mellitus (p = 0.001) and liver dysfunction (p = 0.05) at 1 year. Conclusion Our results showed the effect of immunosuppression used during decades on long-term outcome in our LT patients in terms of morbidity (arterial hypertension, diabetes mellitus, dyslipidemia and renal dysfunction) and mortality (infections and hepatitis C recurrence).
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Affiliation(s)
- C Dopazo
- Department of HBP Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Paseo Vall d´Hebron 119-129, 08035, Barcelona, Spain,
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Castillo RF, García Rios MDC, Peña Amaro P, García García I. Progression of alterations in lipid metabolism in kidney transplant recipients over 5 years of follow-up. Int J Clin Pract 2014; 68:1141-6. [PMID: 24852888 DOI: 10.1111/ijcp.12465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Alterations in lipid metabolism frequently affect kidney transplant recipients and contribute to the onset of metabolic and cardiovascular diseases that threaten graft integrity. The purpose of this research study was to investigate the pattern of hyperlipidaemia and its progression, as well as to study potential risk factors in kidney transplant recipients. METHODS In this study, 119 kidney transplant recipients of both sexes were monitored over a period of 5 years in our posttransplant clinic. During this period, all patients had pretransplant and posttransplant blood tests to measure levels of the following: total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL) and triglycerides. Furthermore, the subjects were also weighed and their height measured. Their body mass index was then calculated using the weight (kg)/height (m(2) ) formula. RESULTS In the 5 years following the transplant, the patients experienced a significant increase in the levels of their biochemical markers as well as in their BMI. Consequently, a greater number suffered from dyslipidaemia, diabetes and hypertension. CONCLUSIONS Kidney transplants can often trigger hyperlipidaemia, as reflected in higher levels of total cholesterol, low-density lipoproteins and high-density lipoproteins. The results of our study also showed that despite statin therapy, the patients had higher triglyceride levels, which made them more vulnerable to diabetes, hypertension, cardiovascular disease and graft rejection.
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Affiliation(s)
- R F Castillo
- Faculty of Health Sciences, University of Granada, Granada, Spain
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Chen H, Chen B. Clinical mycophenolic acid monitoring in liver transplant recipients. World J Gastroenterol 2014; 20:10715-10728. [PMID: 25152575 PMCID: PMC4138452 DOI: 10.3748/wjg.v20.i31.10715] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 06/03/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
In liver transplantation, the efficacy of mycophenolate mofetil (MMF) has been confirmed in clinical trials and studies. However, therapeutic drug monitoring for mycophenolic acid (MPA) has not been fully accepted in liver transplantation as no long-term prospective study of concentration controlled vs fixed-dose prescribing of MMF has been done. This review addressed MPA measurement, pharmacokinetic variability and reasons of this variation, exposure related to acute rejection and MMF-associated side effects in liver transplant recipients. Limited sampling strategies to predict MPA area under the concentration-time curve have also been described, and the value of clinical use needs to be investigated in future. The published data suggested that a fixed-dosage MMF regimen might not be suitable and monitoring of MPA exposure seems helpful in various clinical settings of liver transplantation.
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Limited Sampling Model for Advanced Mycophenolic Acid Therapeutic Drug Monitoring After Liver Transplantation. Ther Drug Monit 2014; 36:141-7. [DOI: 10.1097/ftd.0b013e3182a37a1e] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Pérez T, Segovia R, Castro L, Roblero JP, Estela R. Conversion to everolimus in liver transplant patients with renal dysfunction. Transplant Proc 2012; 43:2307-10. [PMID: 21839260 DOI: 10.1016/j.transproceed.2011.06.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Calcineurin inhibitor (CNI) immunosuppressive therapy post-liver transplantation (OLT) is important to reduce graft rejection episodes. However, these drugs show important side effects, particularly renal dysfunction (RDF). Changing from CNI to a nonnephrotoxic drug, as mammalian target of rapamycin (mTOR) inhibitor may solve the problem. Our objective was to evaluate renal function (RF) among liver transplant patients initially receiving CNI, among whom the patients with RDF were converted completely or partially to an mTOR inhibitor like everolimus (EVE). We performed a prospective study in liver transplant patients from 2000 to 2009. Creatinine levels and creatinine clearances (Cockroft-Gault) expressed as mean values ± standard deviations were measured pre- and postswitch for comparisons using Wilcoxon nonparametric tests. Six patients were converted fully or partially to EVE. Their mean age at the moment of introducing the new therapy was 52.2 ± 13.6 years (range = 28-60). Immunosuppression time prior to switching from CNI to EVE was 23.8 ± 26.6 months (range = 6-70). Postconversion follow-up was 25.8 ± 16.5 months (range = 8-42). All patients showed improvement in RF. The creatinine level improvement was significant (P = .03) namely, from a mean of 2.26 ± 0.49 to 1.21 ± 0.57 mg/dL. Glomerular filtration rate improved from a mean of 40 ± 15.13 to 72.60 ± 17.3 mL/min/m(2) (P = .03). Conversion from CNI to EVE improved creatinine concentrations and creatinine clearances with long-term effects free of graft rejection.
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Affiliation(s)
- T Pérez
- Liver and Gastroenterology Unit, Hospital San Borja-Arriarán, University of Chile, Medical School, Santiago, Chile
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Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial. Transplantation 2011; 92:923-9. [PMID: 21832958 DOI: 10.1097/tp.0b013e31822d880d] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNIs) play the key role in immunosuppressive protocols yet are often associated with numerous side effects. Renal insufficiency, hypertension, hyperglycemia, and increased risk of secondary malignancy are major problems in short- and long-term follow-up of liver transplant patients. Mycophenolate mofetil (MMF) has proved to be a potent immunosuppressive agent free of the CNI-associated side effects. PATIENTS AND METHODS One hundred fifty patients who received liver transplantation at our institution (1998-2003) were prospectively randomized: 75 patients continued CNI standard therapy, 75 patients were switched to MMF monotherapy, and follow-up was 5 years. Incidence of rejection, renal complication, cardiovascular, neurological and gastrointestinal adverse effects, and diabetes and malignancy development was recorded. Graft biopsies were performed every 2 to 3 years. RESULTS No significant difference regarding the incidence of acute rejection was detected. A trend to higher rejection frequency was apparent in the MMF monotherapy group. Chronic rejection was absent; organ and patient survival were identical in the two groups. No significant difference occurred concerning the incidence of cardiovascular, gastrointestinal or neurological adverse effects, or the development of malignancies. Renal function improved significantly in patients with renal insufficiency when patients treated with CNI were switched to MMF monotherapy. CONCLUSION MMF monotherapy may serve as safe long-term immunosuppression after liver transplantation for a subgroup of patients. Especially for patients with renal insufficiency MMF offers immunosuppression without the risk of nephrotoxicity.
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Kriss M, Sotil EU, Abecassis M, Welti M, Levitsky J. Mycophenolate mofetil monotherapy in liver transplant recipients. Clin Transplant 2011; 25:E639-46. [PMID: 22007615 DOI: 10.1111/j.1399-0012.2011.01512.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
INTRODUCTION Complete conversion of calcineurin inhibitor (CNI) immunosuppressant therapy to non-nephrotoxic agents such as mycophenolate mofetil (MMF) is controversial, but may be safe in selected patients, although appropriate protocols and long-term benefits of conversion are not well reported. METHODS We analyzed all liver transplant (LT) recipients at our institution who were converted from CNI-based therapy to MMF monotherapy because of renal dysfunction (n = 23) and compared them with patients remaining on CNI-based therapy (n = 23). Renal function, rejection episodes, and markers of CNI-related comorbidities (lipid profile, blood pressure, and glycosylated hemoglobin) were noted. RESULTS Overall, serum creatinine (SCr) and calculated glomerular filtration rate improved on MMF monotherapy. This improvement was significant when compared with patients who remained on CNI-based therapy. Improvement was most pronounced in patients with milder renal dysfunction (SCr <2.2 mg/dL prior to conversion) (n = 14) with decrease in SCr from 1.63 ± 0.29 to 1.34 ± 0.26 mg/dL (p = 0.02) at last follow-up. Five patients on MMF monotherapy (21.7%) progressed to end-stage renal disease (ESRD), while only two (8.7%) had rejection episodes following conversion. Clinical markers of CNI-related comorbidities also improved. MMF monotherapy was well tolerated. CONCLUSION In summary, our data support the safety and efficacy of CNI to MMF monotherapy conversion.
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Affiliation(s)
- Michael Kriss
- Department of Medicine, Northwestern University, Chicago, IL 60611, USA
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Cantarovich M, Brown NW, Ensom MHH, Jain A, Kuypers DRJ, Van Gelder T, Tredger JM. Mycophenolate monitoring in liver, thoracic, pancreas, and small bowel transplantation: a consensus report. Transplant Rev (Orlando) 2011; 25:65-77. [PMID: 21454066 DOI: 10.1016/j.trre.2010.12.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 12/07/2010] [Indexed: 12/21/2022]
Abstract
Assessing the value of mycophenolic acid (MPA) monitoring outside renal transplantation is hindered by the absence of any trial comparing fixed-dose and concentration-controlled therapy. However, in liver and thoracic transplantation particularly, clinical trials, observational studies with comparison groups, and case series have described MPA efficacy, exposure/efficacy relationships, pharmacokinetic variability, and clinical outcomes relating to plasma MPA concentrations. On the basis of this evidence, this report identifies MPA as an immunosuppressant for which the combination of variable disposition, efficacy, and adverse effects contributes to interindividual differences seemingly in excess of those optimal for a fixed-dosage mycophenolate regimen. Combined with experiences of MPA monitoring in other transplant indications, the data have been rationalized to define circumstances in which measurement of MPA concentrations can contribute to improved management of mycophenolate therapy in nonrenal transplant recipients.
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Affiliation(s)
- Marcelo Cantarovich
- Multi-Organ Transplant Program, McGill University Health Center, 687 Pine Avenue West (R2.58), Montreal, Quebec, Canada
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Goralczyk AD, Schnitzbauer A, Tsui TY, Ramadori G, Lorf T, Obed A. A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT. BMC Surg 2010; 10:15. [PMID: 20380712 PMCID: PMC2858131 DOI: 10.1186/1471-2482-10-15] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2009] [Accepted: 04/09/2010] [Indexed: 01/13/2023] Open
Abstract
Background Immunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. Methods/Design A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT. Discussion This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial. Trial registration number NCT00890253 (clinicaltrials.gov)
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Affiliation(s)
- Armin D Goralczyk
- Department of General and Visceral Surgery, University Medical Center Göttingen, Göttingen, Germany.
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Hwang S, Lee SG, Ahn CS, Kim KH, Moon DB, Ha TY, Song GW, Jung DH, Choi NK, Kim KW, Yu YD, Park GC, Park PJ, Choi YI. A clinical assessment of mycophenolate drug monitoring after liver transplantation. Clin Transplant 2010; 24:E35-42. [PMID: 20070319 DOI: 10.1111/j.1399-0012.2009.01166.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Recent findings have suggested the clinical utility of therapeutic drug monitoring (TDM) in patients treated with mycophenolate mofetil (MMF). AIM To assess whether routine mycophenolic acid (MPA) TDM is beneficial and how to utilize it. METHODS A series of short-term prospective studies on TDM for MPA and/or tacrolimus was performed at a large-volume center. RESULTS The 673 adult liver transplants were divided into four groups based on immunosuppressive regimens as tacrolimus monotherapy (n = 369), tacrolimus-MMF therapy (n = 270), MMF-minimal tacrolimus therapy (n = 17), and MMF monotherapy (n = 17). There was a significant difference of tacrolimus concentration between the groups receiving tacrolimus monotherapy and tacrolimus-MMF therapy during the first two yr (at two yr: 8.4 +/- 2.7 vs. 6.3 +/- 2.6 ng/mL; p < or = 0.002). MMF-minimal tacrolimus therapy and MMF monotherapy were applied after first three months and MPA levels ranged from 1.8 to 5.3 microg/mL. Correlation between MMF dosage and MPA concentration showed wide interindividual variations (n = 304, r(2) = 0.271, p < 0.001), in which r(2) was fluctuating from 0.056 to 0.213 according to the post-transplant period over five yr; wide intraindividual variation was also observed during the first two months (n = 12, r(2) < 0.2, p > 0.195). About 10% of patients were classified as poor MMF absorber and excluded from MMF usage. Mean MPA level leading to successful MMF monotherapy or MMF-minimal tacrolimus therapy was > or =1.0 microg/mL in 87% and >2.0 microg/mL in 56.5%. CONCLUSION MPA TDM-based MMF dosage adjustment enabled us to administer MMF more confidently than categorical dosing. MPA TDM appears to be a useful tool to cope with the wide pharmacokinetic variability of MMF after liver transplantation.
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Affiliation(s)
- Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Charlton MR, Wall WJ, Ojo AO, Ginès P, Textor S, Shihab FS, Marotta P, Cantarovich M, Eason JD, Wiesner RH, Ramsay MA, Garcia-Valdecasas JC, Neuberger JM, Feng S, Davis CL, Gonwa TA. Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation. Liver Transpl 2009; 15:S1-S34. [PMID: 19877213 DOI: 10.1002/lt.21877] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Efficacy and safety of mycophenolate mofetil monotherapy in liver transplant patients with renal failure induced by calcineurin inhibitors. Transplant Proc 2009; 40:2985-7. [PMID: 19010168 DOI: 10.1016/j.transproceed.2008.09.017] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To assess the efficacy and safety of mycophenolate mofetil (MMF) monotherapy in liver transplant recipients with renal failure secondary to the use of calcineurin inhibitors (CNIs). MATERIALS AND METHODS Thirty-one patients on MMF monotherapy with creatinine levels >1.3 mg/dL, previously immunosuppressed with CNIs and MMF, were analyzed. Conversion was started in patients with no acute or chronic rejection episodes and stable liver chemistry. CNI doses were reduced by 25% every 2 to 3 months, or to 50% if the dose was lower than 1 mg/d of tacrolimus or 50 mg/d of cyclosporine. Different variables were recorded from the time that conversion to monotherapy was decided, on the discontinuation day of the calcineurin inhibitor, and during the follow-up. RESULTS Mean times from transplant to conversion ranged from 14 to 186 months. The minimum follow-up time in monotherapy was 12 months. Renal function improved at 6 months in 70% of cases and at 12 months in 69.6%. Patients with no renal function improvement maintained stable creatinine values. There were no rejection episodes, graft losses, or deaths. No leukopenia occurred, and triglyceride and uric acid values improved. CONCLUSIONS MMF monotherapy is a safe alternative in patients with posttransplant renal failure secondary to the use of CNIs. Renal function improvement was achieved in almost 70% of patients at 12 months, and creatinine values were maintained in all other patients. The risk of rejection due to the slow tapering of CNIs is minimum.
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Biselli M, Vitale G, Gramenzi A, Riili A, Berardi S, Cammà C, Scuteri A, Morelli MC, Grazi GL, Pinna AD, Andreone P, Bernardi M. Two yr mycophenolate mofetil plus low-dose calcineurin inhibitor for renal dysfunction after liver transplant. Clin Transplant 2009; 23:191-198. [PMID: 19210525 DOI: 10.1111/j.1399-0012.2009.00965.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
We assessed the efficacy and outcome of low through level of calcineurin inhibitors (CNI) and introducing mycophenolate mofetil (MMF) in liver transplant (LT) patients with CNI-related renal dysfunction. Thirty LT patients were converted to combined therapy and compared with 30 patients used as a contemporary control group receiving CNI only. The two groups were matched for sex, age, months after LT, immunosuppressive treatment, creatinine level, presence of diabetes and calculated glomerular filtration rate (GFR) via Cockroft-Gault method. After two years, in the MMF serum creatinine decreased from 1.65 mg/dL (range 1.33-3.5) to 1.4 mg/dL (range 0.9-4.7) (p = 0.002) and GFR increased from 51 mL/min (range 18.9-72.2) to 57.6 mL/min (range 16-92.2) (p < 0.001), whereas the controls not showed any improvement. The logistic regression models employing improvement of creatinine and GFR of at least 10% with respect to baseline as dependent variables showed the use of MMF (p = 0.004 and p = 0.019, respectively) as the only statistically significant parameter. Multiple linear regression analysis identified only MMF as independent predictor of Deltacreatinine and DeltaGFR (p = 0.002 and p < 0.001, respectively). No rejection episode was observed (three in controls). This study demonstrates the medium-term efficacy and safety of MMF plus low dose CNI in reducing nephrotoxicity in LT recipients.
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Affiliation(s)
- Maurizio Biselli
- Semeiotica Medica, Dipartimento di Medicina Clinica, Universitàdi Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy
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