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Hu J, Zhao S, Zuo M, Li CH, Yao W, Yang X, Xing W, Song P. Local-region treatment comparison following conversion therapy of hepatocellular carcinoma: a period and age-dependent analysis. Ther Adv Med Oncol 2025; 17:17588359251316665. [PMID: 40109509 PMCID: PMC11921006 DOI: 10.1177/17588359251316665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Accepted: 01/14/2025] [Indexed: 03/22/2025] Open
Abstract
Background Transarterial chemoembolization (TACE) is a potential conversion therapeutic strategy for unresectable hepatocellular carcinoma (uHCC). However, therapeutic options following conversion therapy are still controversial. Objectives This study aimed to compare the efficacy and safety of surgical resection (SR) and microwave ablation (MWA) after TACE conversion therapy for uHCC. Design A retrospective, multi-institutional study. Methods From June 2008 to October 2022, 8842 consecutive uHCC patients underwent initial TACE at 15 hospitals were identified. Among them, 1348 eligible patients who received TACE conversion therapy were included. The propensity score matching (PSM) was applied to reduce selection bias. To explore the effect of age on conversion therapy, a therapeutic factor analysis with age change was performed. The overall survival (OS) and disease-free survival (DFS) were compared using the Kaplan-Meier method with the log-rank test. Results After PSM 1:1, 542 patients in the MWA group were matched with those in the SR group. SR demonstrated better long-term survival outcomes (median OS, 10.6 vs 5.8 years, HR:1.83, 95% CI: 1.48-2.25, p < 0.001 and median DFS, 3.2 vs 2.5 years, HR: 1.27, 95% CI:1.09-1.49, p = 0.003) than MWA. There was an improvement in the 5-year DFS rate for MWA from 17.1% during 2009-2016 to 37.3% during 2017-2022, becoming comparable to the 40.8% of SR (p = 0.129). When the uHCC patients downstage met Milan criteria, the long-term OS and DFS were comparable between two groups (both, p > 0.05). SR presents an OS advantage over MWA at the age (years) of 45-54 (p = 0.036), 55-65 (p = 0.001), and >65 (p < 0.001), except <45(p = 0.140). Conclusion MWA might be acceptable as an alternative to SR in first-line therapeutic scheme after TACE conversion therapy for uHCC, especially, for the aged <45 years cohorts.
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Affiliation(s)
- Jiahui Hu
- Institute of Medical Information, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shu Zhao
- Department of Medical Oncology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, China
| | - Mengxuan Zuo
- Department of Minimal Invasive Intervention, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
| | - Chun Hui Li
- Department of general surgery, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Wang Yao
- Department of Interventional Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Province Guangdong, China
| | - Xinyu Yang
- Department of Radiology, The Tangshan Worker Hospital, Tangshan, HeBei, China
| | - WeiWei Xing
- Beijing Institute of Basic Medical Sciences, Beijing 100850, China
| | - Peng Song
- Department of Medical Oncology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Fuixing 28 Road, Beijing 100853, China
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Jagdish RK, Chappity P, Lata S. Dental and ENT Evaluation Before Liver Transplantation. J Clin Exp Hepatol 2024; 14:101431. [PMID: 38745755 PMCID: PMC11090062 DOI: 10.1016/j.jceh.2024.101431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Accepted: 04/14/2024] [Indexed: 05/16/2024] Open
Abstract
The assessment of dental and ear, nose and throat (ENT) conditions holds significant importance in the pre-transplantation evaluation for individuals undergoing liver transplantation. This evaluation aims to address concerns related to dental and ENT issues both before and after liver transplantation. These concerns include the risk of sepsis, the impact of post-transplantation immunosuppression, the detection of existing malignancies, including oral potentially malignant disorders (OPMDs), and identifying any contraindications to the transplantation procedure. However, it is worth noting that there exists a notable absence of clear guidelines and protocols in the existing literature regarding this practice. Moreover, recent studies have presented conflicting results, and concerns have arisen regarding the cost-effectiveness of these evaluations. It is crucial to perform these investigations judiciously to avoid unnecessary testing burdens and delays in placing patients on waiting lists, particularly when considering live donor liver transplantation (LDLT) evaluations. A comprehensive examination of the oral and ENT regions, in conjunction with relevant laboratory tests, can play a pivotal role in identifying and managing oral and ENT diseases before the liver transplantation procedure. Timely recognition and treatment of potential issues are essential for minimizing perioperative morbidity and mortality. There is an evident need for prospective trials and studies to further explore and establish guidelines in the critical area of dental and ENT evaluation in liver transplantation recipients. Such research efforts would contribute significantly to enhancing our understanding and management of oral and ENT conditions in the pre-transplantation setting, ultimately improving patient care and outcomes.
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Affiliation(s)
- Rakesh K. Jagdish
- Hepatology, Gastroenterology and Liver Transplant Medicine, Pan Metro Group of Hospitals, Delhi and NCR, India
| | - Preetam Chappity
- Department of Otorhinolaryngology and Head & Neck Surgery, A.I.I.M.S, Bhubaneswar, Odisha, 751019, India
| | - S. Lata
- Department of Conservative Dentistry and Endodontics, Kalinga Institute of Dental Sciences, Bhubaneswar, Odisha, 751019, India
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Arrabi L, Jan A, Hosing C, Milton DR, Yeh J. Transitioning tacrolimus to sirolimus in allogeneic hematopoietic cell transplantation. Eur J Haematol 2021; 107:634-641. [PMID: 34431142 DOI: 10.1111/ejh.13701] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 08/20/2021] [Accepted: 08/23/2021] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Calcineurin inhibitor (CNI) use for acute graft-versus-host disease (aGVHD) prophylaxis in allogeneic hematopoietic cell transplantation (allo-HCT) recipients has been associated with toxicities. Toxicities may be managed by converting CNI to sirolimus as often done in solid organ transplantation. This study aimed to characterize allo-HCT patients who completely transitioned from tacrolimus to sirolimus and evaluate the incidence of aGVHD within 100 days post-transition, overall survival (OS), and incidence of relapse. METHODS Safety and efficacy data were collected at baseline and at day 30 and 90 post-transition from tacrolimus to sirolimus and at one-year post-HCT. RESULTS Most patients who transitioned had acute leukemia, received a matched unrelated donor allo-HCT, and transitioned due to nephrotoxicity or neurotoxicity. The resolution rate was 83% and 48% in the nephrotoxicity group, 78% and 61% in the neurotoxicity group, 33% and 33% in the group that developed both nephrotoxicity and transplant-associated thrombotic microangiopathy at 30 and 90 days of assessments, respectively. Patients who transitioned before day 55 post-allo-HCT were more likely to develop new or worsening aGVHD. The one-year OS and relapse rates were 37% and 20%, respectively. CONCLUSIONS The conversion from tacrolimus to sirolimus demonstrates promising resolution of acute toxicities; however, overall mortality remains high.
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Affiliation(s)
- Linda Arrabi
- Department of Pharmacy, Henry Ford Health System, Detroit, MI, USA
| | - Anna Jan
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Chitra Hosing
- Division of Cancer Medicine, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Denái R Milton
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jason Yeh
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Abstract
INTRODUCTION Liver transplantation is a life-changing event for patients and survival following transplantation has improved significantly since the first transplantation in 1967. Following liver transplantation, patients face a unique set of healthcare management decisions including transplantation-specific complications, recurrence of primary liver disease, as well as metabolic and malignancy concerns related to immunosuppression. As more patients with liver disease receive transplantation and live longer, understanding and managing these patients will require not only transplant specialist but also local subspecialist and primary care physicians. AREAS COVERED This review covers common issues related to the management of patients following liver transplantation including immunosuppression, liver allograft dysfunction, metabolic complications, as well as routine health maintenance such as immunizations and cancer screening. EXPERT OPINION Optimizing medical care for patients following liver transplant will benefit from ensuring all providers, not just transplant specialist, have a basic understanding of the common issues encountered in the post-transplant patient. This review provides an overview of common healthcare concerns and management options for patients following liver transplantation.
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Affiliation(s)
- Nicholas Hoppmann
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham , Birmingham, Alabama, USA
| | - Omar Massoud
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham , Birmingham, Alabama, USA
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Levitsky J, Burrell BE, Kanaparthi S, Turka LA, Kurian S, Sanchez-Fueyo A, Lozano JJ, Demetris A, Lesniak A, Kirk AD, Stempora L, Yang GY, Mathew JM. Immunosuppression Withdrawal in Liver Transplant Recipients on Sirolimus. Hepatology 2020; 72:569-583. [PMID: 31721246 PMCID: PMC7217743 DOI: 10.1002/hep.31036] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 11/06/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS As conversion from calcineurin inhibitor to sirolimus (SRL), a mechanistic target of rapamycin inhibitor (mTOR-I), has been shown to enhance immunoregulatory profiles in liver transplant (LT) recipients (LTRs), mTOR-I therapy might allow for increased success of immunosuppression (IS) withdrawal. Our aim was to determine if operational tolerance could be observed in LTRs withdrawn from SRL and if blood/graft tolerance biomarkers were predictive of successful withdrawal. APPROACH AND RESULTS We performed a prospective trial of SRL monotherapy withdrawal in nonimmune, nonviremic LTRs > 3 years post-LT. SRL was weaned over ~6 months, and biopsies were performed 12 months postweaning or at concern for acute rejection. Twenty-one LTRs consented; 6 were excluded due to subclinical acute rejection on baseline biopsy or other reasons, and 15 underwent weaning (age 61.3 ± 8.8 years; LT to SRL weaning 6.7 ± 3 years). Eight (53%) achieved operational tolerance (TOL). Of the 7 who were nontolerant (non-TOL), 6 had mild acute rejection on biopsy near the end of weaning or at study end; 1 was removed from the trial due to liver cancer recurrence. At baseline preweaning, there were statistically increased blood tolerogenic dendritic cells and cell phenotypes correlating with chronic antigen presentation in the TOL versus non-TOL groups. A previously identified biopsy gene signature accurately predicted TOL versus non-TOL in 12/14 LTRs before weaning. At study end, biopsy staining revealed statistically significant increases in antigen-presenting cell:leukocyte pairings, FOXP3+ /CD4+ T cells, Tbet+ /CD8+ T cells, and lobular dendritic cells in the non-TOL group. CONCLUSIONS This study evaluated IS withdrawal directly from mTOR-I therapy in LTRs and achieved > 50% operational tolerance. Preweaning gene expression and peripheral blood mononuclear cell profiling may be useful as predictors of successful mTOR-I therapy withdrawal. NCT02062944.
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Affiliation(s)
- Josh Levitsky
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | | | | | - Laurence A. Turka
- Immune Tolerance Network, Bethesda, MD; Massachusetts General Hospital, Boston, MA
| | - Sunil Kurian
- Scripps Clinic Bio-Repository and Transplantation Research, La Jolla, California, United States
| | | | - Juan J. Lozano
- Biomedical Research Center in Hepatic and Digestive Diseases, Carlos III Health Institute, Barcelona, Spain
| | | | | | | | | | - Guang-Yu Yang
- Northwestern University Feinberg School of Medicine, Chicago, IL
| | - James M. Mathew
- Northwestern University Feinberg School of Medicine, Chicago, IL
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Gilad O, Rabinowich L, Levy S, Gotlieb N, Lubezky N, Goykhman Y, Nachmany I, Katz P, Shibolet O, Katchman H. Metabolic and Renal Effects of Mammalian Target of Rapamycin Inhibitors Treatment After Liver Transplantation: Real-Life Single-Center Experience. Transplant Proc 2020; 53:221-227. [PMID: 32650991 DOI: 10.1016/j.transproceed.2020.05.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 05/12/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors following liver transplantation (LT) are used to minimize calcineurin inhibitor (CNI)-related nephrotoxicity. Data about metabolic effects of mTOR inhibitors are still limited. AIM This study aims to determine the renal and metabolic effects of different mTOR inhibitor-based protocols in real-life LT patients. METHODS This is a retrospective cohort study of patients treated with mTOR inhibitors after LT. Demographics, treatment protocols, glomerular filtration rate (GFR), and metabolic parameters were collected over a period of 4 years. Initiation of blood pressure (BP), diabetes mellitus, and lipid medications was also noted. RESULTS Fifty-two LT recipients received mTOR inhibitors. GFR improved significantly (by 1.96 mL/min/year), with greater improvement in patients with baseline renal dysfunction (+13.3 mL/min vs +4.5 mL/min at 3 years). Conversion to an mTOR inhibitor during the first post-transplant year resulted in a more durable improvement in GFR (for 4 years vs only 1 year for later conversion).No significant weight gain or new-onset diabetes mellitus was observed. However, there was some increase in total cholesterol (+7 mg/dL) and blood pressure (+2 mm Hg during the third year and +8 mm Hg in the fourth years), followed by initiation of lipid-lowering and BP medications in 25% and 13% of patients, respectively. CONCLUSIONS Treatment with an mTOR inhibitor following LT resulted in improved kidney functions without significant negative metabolic effects such as weight gain or new-onset diabetes mellitus. This makes mTOR inhibitors a valuable immunosuppressive option in the face of the growing incidence of nonalcoholic steatohepatitis as a leading cause for LT.
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Affiliation(s)
- O Gilad
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - L Rabinowich
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - S Levy
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - N Gotlieb
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - N Lubezky
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Y Goykhman
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - I Nachmany
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - P Katz
- Devision of Surgery, Tel Aviv Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - O Shibolet
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - H Katchman
- Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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mTOR inhibitors in pediatric liver transplant recipients. Clin Res Hepatol Gastroenterol 2019; 43:403-409. [PMID: 30528864 DOI: 10.1016/j.clinre.2018.11.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 11/05/2018] [Accepted: 11/09/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients. METHODS All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed. RESULTS The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2-17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3-5.0) or 0.058 mg/kg/day (range: 0.01-0.26), and the median trough level was 5.1 μg/L (range: 1.0-15.5). After a median follow-up of 2.8 years (range: 0.2-10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function. CONCLUSION Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.
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Di Stefano C, Vanni E, Mirabella S, Younes R, Boano V, Mosso E, Nada E, Milazzo V, Maule S, Romagnoli R, Salizzoni M, Veglio F, Milan A. Risk factors for arterial hypertension after liver transplantation. JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION : JASH 2018; 12:220-229. [PMID: 29366595 DOI: 10.1016/j.jash.2018.01.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 12/29/2017] [Accepted: 01/01/2018] [Indexed: 12/11/2022]
Abstract
Arterial hypertension represents a common complication of immunosuppressive therapy after liver transplantation (LT). The aim of the study is to evaluate the prevalence and risk factors associated with hypertension after LT. From a cohort of 323 cirrhotic patients who underwent LT from 2008 to 2012, 270 patients were retrospectively evaluated, whereas 53 (16.4%) patients deceased. Hypertension was defined as blood pressure ≥140/90 mm Hg in at least two visits and/or the need for antihypertensive therapy. The prevalence of hypertension was 15% before LT and significantly increased up to 53% after LT (P < .001). Mean follow-up was 43 ± 19 months. In normotensive (NT) subjects at baseline, 35.9% developed sustained hypertension after LT, whereas 15.2% developed transient hypertension within the first month after LT, and then returned NT. The development of sustained hypertension after LT was related to the mammalian target of rapamycin inhibitor treatment (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.26-13.48; P = .02), alcoholic cirrhosis before LT (OR, 3.38; 95% CI, 1.44-8.09; P = .005), and new-onset hepatic steatosis after LT (OR, 2.13; 95% CI, 1.10-4.11; P = .02). Tacrolimus, the etiology and severity of liver disease, and other immunosuppressive regimens were not related to the development of hypertension after LT. In our cohort, the prevalence of arterial hypertension has increased up to 53% after LT, and metabolic comorbidities and immunosuppressive treatment with mammalian target of rapamycin inhibitors are the risk factors for the development of hypertension after LT.
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Affiliation(s)
- Cristina Di Stefano
- Department of Medical Sciences, Hypertension Unit, Città della Salute e della Scienza, University of Torino, Torino, Italy.
| | - Ester Vanni
- Division of Gastroenterology, Department of Medical Sciences, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Stefano Mirabella
- Liver Transplant Center, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Ramy Younes
- Division of Gastroenterology, Department of Medical Sciences, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Valentina Boano
- Division of Gastroenterology, Department of Medical Sciences, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Elena Mosso
- Division of Gastroenterology, Department of Medical Sciences, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Elisabetta Nada
- Liver Transplant Center, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Valeria Milazzo
- Department of Medical Sciences, Hypertension Unit, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Simona Maule
- Department of Medical Sciences, Hypertension Unit, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Renato Romagnoli
- Liver Transplant Center, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Mauro Salizzoni
- Liver Transplant Center, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Franco Veglio
- Department of Medical Sciences, Hypertension Unit, Città della Salute e della Scienza, University of Torino, Torino, Italy
| | - Alberto Milan
- Department of Medical Sciences, Hypertension Unit, Città della Salute e della Scienza, University of Torino, Torino, Italy
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Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients: A Guidance Report and Clinical Checklist by the Consensus on Managing Modifiable Risk in Transplantation (COMMIT) Group. Transplantation 2017; 101:S1-S56. [PMID: 28328734 DOI: 10.1097/tp.0000000000001651] [Citation(s) in RCA: 205] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.
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Abstract
Liver transplantation outcomes have significantly improved over the past few decades owing largely to the introduction of effective immunosuppression medications. Further comprehension of the unique immune microenvironment of the liver has led to the development of newer molecular targeted therapeutics. Understanding the mechanism of action and adverse effect profiles of these medications is crucial for appropriate management of posttransplant patients. In this review, the author describes the immunologic response elicited by liver transplantation, chronicles the various immunosuppressant drug classes, discusses the evidence behind their use, and evaluates the management of special subpopulations of posttransplantation patients.
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Affiliation(s)
- Renumathy Dhanasekaran
- Division of Gastroenterology and Hepatology, Stanford University, 750 Welch Road, Suite 210, Palo Alto, CA 94304, USA.
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Li LC, Hsu CN, Lin CC, Cheng YF, Hu TH, Chen DW, Lee CH, Nakano T, Chen CL. Proteinuria and baseline renal function predict mortality and renal outcomes after sirolimus therapy in liver transplantation recipients. BMC Gastroenterol 2017; 17:58. [PMID: 28427351 PMCID: PMC5399310 DOI: 10.1186/s12876-017-0611-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 04/10/2017] [Indexed: 12/16/2022] Open
Abstract
Background Chronic kidney disease is a significant complication after liver transplantation (LT), but the role of pre-existing renal insufficiency and proteinuria remains unclear among LT recipients receiving sirolimus. Methods We assessed the effects of proteinuria and baseline renal function on long-term renal and survival outcomes among 576 LT recipients who received SRL in a medical center between 2005 and 2014. Renal outcomes were the incidences of >50% reduction in their baseline estimated glomerular filtration rate and end stage kidney disease requiring renal replacement therapy. Proteinuria was identified using morning dipstick results (≥30 mg/dL) at baseline and within the first year after the initiation of SRL therapy. A Kaplan-Meier analysis was performed to estimate time to event. Factors associated with the outcomes were determined using the Cox proportional hazards model with a significance level set at P <0.05. Results During the study period, renal function deteriorated in 135 (25.3%) patients and 68 (11.8%) patients died. Persistent and new onset proteinuria contributed to a high rate of mortality and the deterioration of renal function (both log-rank tests, P <0.0001). After adjustments, new onset proteinuria within the first year after the initiation of SRL therapy increased the risk of deteriorating renal function, regardless of baseline estimated glomerular filtration rate. Moreover, pre-existing (hazard ratio = 1.91; P <0.001) and new onset diabetes (hazard ratio = 2.34; P <0.0001) were significantly associated with new onset proteinuria among SRL users. Conclusions These findings support the effective monitoring and early management of the predictable risks for proteinuria among new SRL users in order to delay the progression of renal disease.
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Affiliation(s)
- Lung-Chih Li
- Division of Nephrology, Department of Internal Medicine, Kaohsiung, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, 123, Ta Pei Road, Niao Sung District, 833, Kaohsiung, Taiwan. .,School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
| | - Chih-Che Lin
- Liver Transplant Center, Department of Surgery, Kaohsiung, Taiwan
| | - Yu-Fan Cheng
- Department of Diagnostic Radiology, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung, Taiwan
| | - Ding-Wei Chen
- Liver Transplant Center, Department of Surgery, Kaohsiung, Taiwan.,Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan
| | - Chih-Hsiung Lee
- Division of Nephrology, Department of Internal Medicine, Kaohsiung, Taiwan
| | - Toshiaki Nakano
- Liver Transplant Center, Department of Surgery, Kaohsiung, Taiwan
| | - Chao-Long Chen
- Liver Transplant Center, Department of Surgery, Kaohsiung, Taiwan
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Lipid profiles of donors and recipients of liver transplant: like father like son. Hepatol Int 2017; 11:300-305. [PMID: 28176203 DOI: 10.1007/s12072-017-9786-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2016] [Accepted: 01/17/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND/PURPOSE Dyslipidemia is common in liver transplant recipients. This retrospective study investigates whether donors play a role. METHODS Prospectively collected data of donors and recipients of deceased-donor liver transplantation (DDLT) and living-donor liver transplantation (LDLT) were reviewed. Total cholesterol, triglyceride, low-density lipoprotein, high-density lipoprotein (HDL) and fasting glucose were compared between groups. HDL ≥1.6 mmol/L at 2 years after transplant was considered the marker of a favorable post-transplant lipid profile in recipients. Univariate and multivariate analyses were performed to identify predictive factors for this marker. RESULTS There were 85 DDLTs and 80 LDLTs. LDLT donors were younger (30 vs. 50 years, p < 0.001) and lighter (58.2 vs. 63.4 kg, p = 0.008) and had a lower body mass index (21.2 vs. 23.7, p < 0.001). The DDLT group had more fatty grafts (p = 0.001) and longer cold (375 vs. 103.5 min, p < 0.001) and warm (50.5 vs. 46 min, p = 0.034) ischemia. LDLT donors had lower fasting glucose (4.85 vs. 7.21 mmol/L, p < 0.001) and triglyceride (0.87 vs. 1.22 mmol/L, p = 0.016) but higher HDL (1.58 vs. 1.39 mmol/L, p = 0.022). LDLT recipients also had higher HDL at 1 year (1.48 vs. 1.28 mmol/L, p = 0.026) and 2 years (1.43 vs. 1.21 mmol/L, p = 0.008). Fourteen (16.5%) DDLT recipients and 27 (33.8%) LDLT recipients had HDL ≥1.6 mmol/L at 2 years. On multivariate analysis, donor HDL ≥1.6 mmol/L (RR 4.311, 95% CI 1.666-11.158, p = 0.003) and recipient body mass index <24 (RR 2.753, 95% CI 1.064-7.127, p = 0.037) were the two independent predictive factors. CONCLUSION LDLT recipients had better lipid profiles than DDLT recipients. The feature of high HDL level in donors was transferred to recipients.
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Dumortier J, Dharancy S, Calmus Y, Duvoux C, Durand F, Salamé E, Saliba F. Use of everolimus in liver transplantation: The French experience. Transplant Rev (Orlando) 2016; 30:161-70. [DOI: 10.1016/j.trre.2015.12.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2015] [Accepted: 12/14/2015] [Indexed: 12/18/2022]
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Hüsing A, Kabar I, Schmidt HH. Lipids in liver transplant recipients. World J Gastroenterol 2016; 22:3315-3324. [PMID: 27022213 PMCID: PMC4806189 DOI: 10.3748/wjg.v22.i12.3315] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 01/19/2016] [Accepted: 01/30/2016] [Indexed: 02/06/2023] Open
Abstract
Hyperlipidemia is very common after liver transplantation and can be observed in up to 71% of patients. The etiology of lipid disorders in these patients is multifactorial, with different lipid profiles observed depending on the immunosuppressive agents administered and the presence of additional risk factors, such as obesity, diabetes mellitus and nutrition. Due to recent improvements in survival of liver transplant recipients, the prevention of cardiovascular events has become more important, especially as approximately 64% of liver transplant recipients present with an increased risk of cardiovascular events. Management of dyslipidemia and of other modifiable cardiovascular risk factors, such as hypertension, diabetes and smoking, has therefore become essential in these patients. Treatment of hyperlipidemia after liver transplantation consists of life style modification, modifying the dose or type of immunosuppressive agents and use of lipid lowering agents. At the start of administration of lipid lowering medications, it is important to monitor drug-drug interactions, especially between lipid lowering agents and immunosuppressive drugs. Furthermore, as combinations of various lipid lowering drugs can lead to severe side effects, such as myopathies and rhabdomyolysis, these combinations should therefore be avoided. To our knowledge, there are no current guidelines targeting the management of lipid metabolism disorders in liver transplant recipients. This paper therefore recommends an approach of managing lipid abnormalities occurring after liver transplantation.
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Waller LP, Deshpande V, Pyrsopoulos N. Hepatocellular carcinoma: A comprehensive review. World J Hepatol 2015; 7:2648-2663. [PMID: 26609342 PMCID: PMC4651909 DOI: 10.4254/wjh.v7.i26.2648] [Citation(s) in RCA: 137] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 07/30/2015] [Accepted: 11/04/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is rapidly becoming one of the most prevalent cancers worldwide. With a rising rate, it is a prominent source of mortality. Patients with advanced fibrosis, predominantly cirrhosis and hepatitis B are predisposed to developing HCC. Individuals with chronic hepatitis B and C infections are most commonly afflicted. Different therapeutic options, including liver resection, transplantation, systemic and local therapy, must be tailored to each patient. Liver transplantation offers leading results to achieve a cure. The Milan criteria is acknowledged as the model to classify the individuals that meet requirements to undergo transplantation. Mean survival remains suboptimal because of long waiting times and limited donor organ resources. Recent debates involve expansion of these criteria to create options for patients with HCC to increase overall survival.
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Incidence of cardiovascular and cerebrovascular events associated with sirolimus use after liver transplantation. Transplant Proc 2015; 47:460-4. [PMID: 25769591 DOI: 10.1016/j.transproceed.2014.11.036] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Accepted: 11/25/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Sirolimus (SRL) is an immunosuppressant often used in liver transplantation (LT) to mitigate renal insufficiency associated with calcineurin inhibitors. Sirolimus can cause hyperlipidemia, but its association with coronary artery disease (CAD) and cerebrovascular accidents (CVAs) is unclear. The purpose of this study was to assess the risk of CAD and CVAs with the use of SRL in LT recipients. METHODS We retrospectively reviewed all of our LT recipients from 2000 to 2011. Patients with multiorgan transplant, multiple liver transplants, everolimus therapy, or survival <3 months were excluded. The 803 remaining patients were divided into 3 groups: 1) 134 patients who received and tolerated SRL; 2) 604 patients who never received SRL; and 3) 65 patients who started but discontinued SRL. The primary outcome was the development of CAD or CVA beyond 4 months after transplantation with the use of time-dependent Kaplan-Meier analysis. RESULTS In group 1, there were 6 CAD and 2 CVA events; in group 2, 27 CAD and 16 CVA events; and in group 3, 10 CAD and 2 CVA events. The event-free survival for CAD/CVA at 1, 3, and 5 years was 100%, 98.1%, and 97.2% respectively for group 1; 99.7%, 98.4%, and 96.1% for group 2; and 92.3%, 92.3%, and 85.6% for group 3. On an unadjusted basis, compared with group 2, there was no difference in CAD/CVA rates in group 1 (hazard ratio [HR] 0.92; not significant), but there was an increase in group 3 (HR 2.94; P = .0019). However, on multivariate analysis, only age at transplantation (HR 1.06; P = .001) and diabetes before transplantation (P = .011) were associated with increased CAD/CVA risk. CONCLUSIONS Our analysis showed that patients receiving SRL after LT had no increased risk of CAD/CVA events compared with patients maintained on a calcineurin inhibitor. The risk of CAD/CVA should not be a factor in avoiding SRL.
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Álamo JM, Olivares C, Barrera L, Marín LM, Suarez G, Bernal C, Serrano J, Muntané J, Padillo FJ, Gómez MA. Conversion from calcineurin inhibitors to mTOR inhibitors stabilizes diabetic and hypertensive nephropathy after liver transplant. World J Transplant 2015; 5:19-25. [PMID: 25815268 PMCID: PMC4371158 DOI: 10.5500/wjt.v5.i1.19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 02/18/2014] [Accepted: 10/29/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To investigate if conversion to the mammalian target of rapamycin inhibitors (mTORi) improves renal function in diabetic and/or hypertensive liver transplant patients immunosuppressed with tacrolimus or cyclosporine.
METHODS: The study included 86 liver graft recipients immunosuppressed with mTORi treatment after orthotopic liver transplantation (OLT), including all liver recipients with worsening renal function before conversion to mTORi (n = 55 patients) and recipients with normal renal function who converted to mTORi for other reasons (n = 31 patients). We identified patients with diabetes mellitus (n = 28), arterial hypertension (n = 27), proteinuria (n = 27) and all three factors (n = 8) (some patients have hypertension and diabetes and no proteinuria). The primary endpoint was evolution in renal function defined as the development in plasma creatinine as a function of diabetes mellitus (DM), hypertension (HT) or proteinuria. We required elevated serum creatinine for at least two weeks to define renal dysfunction.
RESULTS: Only patients that converted because of renal failure with plasma creatinine levels > 1.5 mg/dL showed an improvement of renal function (2.14 to 1.77 mg/dL) (P = 0.02). Patients with DM showed no improvement of serum creatinine levels (1.31 mg/dL to 1.37 mg/dL) compared with non DM patients (1.31 mg/dL to 1.15 mg/dL) (P = 0.01), HT patients (1.48 mg/dL to 1.5 mg/dL) with non HT patients (1.21mg/dL to 1.08 mg/dL) and patients with proteinuria (1.44 mg/dL to 1.41 mg/dL) and no proteinuria (1.31 mg/dL to 1.11 mg/dL).
CONCLUSION: In OLT recipients with diabetes or hypertensive nephropathy, conversion to mTORi does not improve renal function but stabilizes plasma levels of creatinine. Proteinuria is not a contraindication to conversion to mTORi; it also stabilizes renal function. Conversion to mTORi should only be avoided in patients with diabetes, hypertension and proteinuria.
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Cuestas ML, Oubiña JR, Mathet VL. Hepatocellular carcinoma and multidrug resistance: Past, present and new challenges for therapy improvement. World J Pharmacol 2015; 4:96-116. [DOI: 10.5497/wjp.v4.i1.96] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/02/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer and the third most common cause of cancer-related death in the world. The main risk factor worldwide for this type of malignancy is chronic hepatitis caused by hepatitis B virus and hepatitis C virus infections. Advances in early detection and treatment have improved life expectancy of patients with HCC. However, this disorder remains as a disease with poor prognosis. In fact, epidemiological studies have revealed that there is an 8-mo median survival rate in patients, approximately 20% of whom survive one year while only 5% remain alive after three years. Additionally, HCC is particularly difficult to treat because of its high recurrence rate, and its resistance to conventional chemotherapy is due, among other mechanisms, to several members of the ATP-Binding Cassette protein family involved in drug transport being overexpressed. Fortunately, there is evidence that these patients may benefit from alternative molecular-targeted therapies. This manuscript intends to provide further insight into the etiology and molecular mechanisms related to HCC development and the latest therapeutic approaches to treat this malignancy. The development of effective delivery systems of antitumor drugs able to target the liver parenchyma is also assessed. Finally, the prospects in the development of more efficient drug therapies to overcome multidrug resistance are also examined.
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Shah M, Shankar A, Gee I, Nash K, Hoare M, Gibbs P, Davies S, Alexander GJM. A retrospective 15-year review: survival advantage after switching to sirolimus in hepatitis C virus infected liver graft recipients. Aliment Pharmacol Ther 2015; 41:379-92. [PMID: 25496225 DOI: 10.1111/apt.13049] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/05/2014] [Accepted: 11/21/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND The use of sirolimus-based immune suppression in liver transplantation, particularly in hepatitis C virus (HCV)-infected recipients, remains contentious. There is some evidence that sirolimus retards hepatic fibrosis, is renal sparing and may be of benefit in preventing hepatocellular carcinoma (HCC) recurrence. Sirolimus has not been adopted by many transplant centres because of persistent concerns regarding an increased risk of hepatic artery thrombosis, graft loss and death with de novo sirolimus. AIM To review the impact of switching to sirolimus monotherapy in HCV-infected liver recipients with respect to survival, graft loss and hepatic fibrosis. METHODS A retrospective review of 190 patients from a single centre undergoing first liver transplantation for HCV over 15 years. 113 patients were switched from calcineurin inhibitor (CNI)-based therapy to low-dose sirolimus monotherapy at a median of 15 months after transplantation for HCV-related fibrosis (72%), renal impairment (14%) or high-risk HCC (5%). RESULTS Patients switched to sirolimus had improved survival (P < 0.001) and slower progression to cirrhosis (P = 0.001). In patients with HCC (n = 91), sirolimus duration rather than strategy was an independent predictor of survival (P = 0.001) and extended time to HCC recurrence (33 vs. 16 months). Patients switched for renal dysfunction showed improvement in serum creatinine (140-108 μmol/L, P = 0.001). Those remaining on CNI-therapy were more likely to develop post-transplant diabetes (P = 0.03). CONCLUSION These data suggest selective switching to low-dose sirolimus monotherapy in HCV-positive liver recipients improves clinical outcome.
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Affiliation(s)
- M Shah
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge University Hospitals, Cambridge, UK
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Abstract
Advances in pharmacologic immunosuppression are responsible for the excellent outcomes experienced by recipients of liver transplants. However, long-term follow-up of these patients reveals an increasing burden of morbidity and mortality that is attributable to these drugs. The authors summarize the agents used in contemporary liver transplantation immunosuppression protocols and discuss the emerging trend within the community to minimize or eliminate these agents from use. The authors present recently published data that may provide the foundation for immunosuppression minimization or tolerance induction in the future and review studies that have focused on the utility of biomarkers in guiding immunosuppression management.
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Klintmalm GB, Nashan B. The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence. J Transplant 2014; 2014:845438. [PMID: 24719752 PMCID: PMC3955586 DOI: 10.1155/2014/845438] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 09/20/2013] [Accepted: 09/21/2013] [Indexed: 12/14/2022] Open
Abstract
Despite the success of liver transplantation, long-term complications remain, including de novo malignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.
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Affiliation(s)
- Goran B. Klintmalm
- Baylor Simmons Transplant Institute, Baylor University Medical Center, 3410 Worth Street, Suite 950, Dallas, TX 75246, USA
| | - Björn Nashan
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Medical Center Eppendorf, Martinistraβe 52, 20246 Hamburg, Germany
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Teperman L, Moonka D, Sebastian A, Sher L, Marotta P, Marsh C, Koneru B, Goss J, Preston D, Roberts JP. Calcineurin inhibitor-free mycophenolate mofetil/sirolimus maintenance in liver transplantation: the randomized spare-the-nephron trial. Liver Transpl 2013; 19:675-89. [PMID: 23775875 DOI: 10.1002/lt.23658] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Accepted: 04/08/2013] [Indexed: 12/12/2022]
Abstract
Mycophenolate mofetil (MMF) and sirolimus (SRL) have been used for calcineurin inhibitor (CNI) minimization to reduce nephrotoxicity following liver transplantation. In this prospective, open-label, multicenter study, patients undergoing transplantation from July 2005 to June 2007 who were maintained on MMF/CNI were randomized 4 to 12 weeks after transplantation to receive MMF/SRL (n = 148) or continue MMF/CNI (n = 145) and included in the intent-to-treat population. The primary efficacy endpoints were the mean percentage change in the calculated glomerular filtration rate (GFR) and a composite of biopsy-proven acute rejection (BPAR), graft lost, death, and lost to follow-up 12 months after transplantation. Patients were followed for a median of 519 days after randomization. MMF/SRL was associated with a significantly greater renal function improvement from baseline with a mean percentage change in GFR of 19.7 ± 40.6 (versus 1.2 ± 39.9 for MMF/CNI, P = 0.0012). The composite endpoint demonstrated the noninferiority of MMF/SRL versus MMF/CNI (16.4% versus 15.4%, 90% confidence interval = -7.1% to 9.0%). The incidence of BPAR was significantly greater with MMF/SRL (12.2%) versus MMF/CNI (4.1%, P = 0.02). Graft loss (including death) occurred in 3.4% of the MMF/SRL-treated patients and in 8.3% of the MMF/CNI-treated patients (P = 0.04). Malignancy-related deaths were less frequent with MMF/SRL. Adverse events caused withdrawal for 34.2% of the MMF/SRL-treated patients and for 24.1% of the MMF/CNI-treated patients (P = 0.06). The use of MMF/SRL is an option for liver transplant recipients who can benefit from improved renal function but is associated with an increased risk of rejection (but not graft loss).
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Affiliation(s)
- Lewis Teperman
- Mary Lea Johnson Richards Organ Transplant Center, New York University School of Medicine, New York, NY 10016, USA.
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Levitsky J, Mathew JM, Abecassis M, Tambur A, Leventhal J, Chandrasekaran D, Herrera N, Al-Saden P, Gallon L, Abdul-Nabi A, Yang GY, Kurian SM, Salomon DR, Miller J. Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients. Hepatology 2013; 57:239-48. [PMID: 22234876 PMCID: PMC3334454 DOI: 10.1002/hep.25579] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 12/21/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ≈ 20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4(+) CD25(+++) FOXP3(+) ) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3(+) /4(+) ); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 ± 8.0; 3.5 ± 2.1 years post-liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3(+) cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion. CONCLUSIONS TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal.
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Affiliation(s)
- Josh Levitsky
- Division of Gastroenterology & Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - James M. Mathew
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Michael Abecassis
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Anat Tambur
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Joseph Leventhal
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Dhivya Chandrasekaran
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Nancy Herrera
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Patrice Al-Saden
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Lorenzo Gallon
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Anmaar Abdul-Nabi
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Sunil M. Kurian
- The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA
| | - Daniel R. Salomon
- The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, CA
| | - Joshua Miller
- Comprehensive Transplant Center, Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Jesse Brown VA Medical Center, Chicago, Illinois
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Reigada C, de Ataide E, de Araújo F, Ramos A, Stucchi R, Eescanhoela C, Boin I. Sirolimus as Rescue Therapy After Liver Transplantation. Transplant Proc 2012; 44:2434-7. [DOI: 10.1016/j.transproceed.2012.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Manzia TM, Sforza D, Angelico R, Bellini MI, Ciano P, Manuelli M, Toti L, Tisone G. Everolimus and enteric-coated mycophenolate sodium ab initio after liver transplantation: midterm results. Transplant Proc 2012; 44:1942-5. [PMID: 22974878 DOI: 10.1016/j.transproceed.2012.06.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Everolimus (EVR) use in liver transplantation (OLT) has been prescribed with calcineurin inhibitors (CNIs), steroids, and monoclonal antibodies. The aim of our study was to evaluate the safety, feasibility, and impact on renal function of EVR ab initio, in combination with enteric-coated mycophenolate sodium (EC-MPS) without the use of induction treatment, steroids, or CNIs. PATIENTS AND METHODS We retrospective analyzed nine consecutive patients who underwent OLT at our institution. The initial dose of EVR (1.5 mg/d) was adjusted to achieve trough levels of 8 to 12 ng/mL. EC-MPS introduced at 1080 mg/d was maintained at the same dose over time. RESULTS At a mean follow-up of 21.48 (standard deviation [SD] 1.4) months from OLT, 7/9 recipients were alive with stable graft function. The 2-year patient and graft survivals were 77%. One recipient died due to cerebral hemorrhage and one, lung failure. No clinical evidence of an acute rejection episode was observed. Mean estimated glomerular filtration rate value, according to the Modification of Diet in Renal Disease formula increased from 59.5 (SD 9.89) mL/min/1.73 m(2) at OLT to 100.2 (SD 47.5) mL/min/1.73 m(2) (P = .03) after 12 months and 98.71 (SD 33.74) mL/min/1.73 m(2) (P = .03) after 24 months' follow-up. CONCLUSION A double immunosuppression therapy with EVR and EC-MPS ab initio seemed to be efficacions and safe, representing a valid alternative to CNIs to prevent renal failure after OLT.
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Affiliation(s)
- T M Manzia
- Transplant Unit, Fondazione Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy
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Lim KBL, Schiano TD. Long-term outcome after liver transplantation. ACTA ACUST UNITED AC 2012; 79:169-89. [PMID: 22499489 DOI: 10.1002/msj.21302] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Liver transplantation is a life-saving therapy for patients with end-stage liver disease, acute liver failure, and liver tumors. Over the past 4 decades, improvements in surgical techniques, peritransplant intensive care, and immunosuppressive regimens have resulted in significant improvements in short-term survival. Focus has now shifted to addressing long-term complications and improving quality of life in liver recipients. These include adverse effects of immunosuppression; recurrence of the primary liver disease; and management of diabetes, hypertension, dyslipidemia, obesity, metabolic syndrome, cardiovascular disease, renal dysfunction, osteoporosis, and de novo malignancy. Issues such as posttransplant depression, employment, sexual function, fertility, and pregnancy must not be overlooked, as they have a direct impact on the liver recipient's quality of life. This review summarizes the latest data in long-term outcome after liver transplantation.
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Singh S, Watt KD. Long-term medical management of the liver transplant recipient: what the primary care physician needs to know. Mayo Clin Proc 2012; 87:779-90. [PMID: 22763347 PMCID: PMC3498400 DOI: 10.1016/j.mayocp.2012.02.021] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 02/07/2012] [Accepted: 02/16/2012] [Indexed: 12/18/2022]
Abstract
Recognition, management, and prevention of medical complications and comorbidities after liver transplant is the key to improved long-term outcomes. Beyond allograft-related complications, metabolic syndrome, cardiovascular disease, renal dysfunction, and malignancies are leading causes of morbidity and mortality in this patient population. Primary care physicians have an important role in improving outcomes of liver transplant recipients and are increasingly relied on for managing these complex patients. This review serves to assist the primary care physician in the long-term management issues of liver transplant recipients.
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Key Words
- acei, angiotensin converting enzyme inhibitor
- arb, angiotensin receptor blocker
- ckd, chronic kidney disease
- cni, calcineurin inhibitor
- ibd, inflammatory bowel disease
- lt, liver transplant
- mmf, mycophenolate mofetil
- mtor, mammalian target of rapamycin
- nash, nonalcoholic steatohepatitis-related cirrhosis
- olt, orthotopic liver transplant
- psc, primary sclerosing cholangitis
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Affiliation(s)
| | - Kymberly D. Watt
- Correspondence: Address to Kymberly D. Watt, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905
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Proteinuria following sirolimus conversion is associated with deterioration of kidney function in liver transplant recipients. Transplantation 2012; 93:1006-12. [PMID: 22357174 DOI: 10.1097/tp.0b013e31824bbd01] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND The role of sirolimus (SRL) conversion in the preservation of kidney function in liver transplant (LT) recipients with calcineurin inhibitor (CNI) nephrotoxicity is unclear. METHODS Data on 102 LT recipients with deteriorating kidney function after CNI exposure who were later converted to SRL were retrospectively reviewed. Kidney function was assessed using serum creatinine and estimated glomerular filtration rate (eGFR) at time of conversion and serially thereafter. The primary endpoint was stabilization or improvement of kidney function as assessed by eGFR at last recorded follow-up compared with eGFR at the time of conversion. RESULT After a median (interquartile range) of 3.1 (1.6-4.5) years of follow-up, serum creatinine decreased from 1.9 ± 0.8 to 1.8 ± 0.7 mg/dL (P=0.25) and eGFR increased from 40.8 ± 16.7 to 44.3 ± 20.0 mL/min (P=0.03). During the same time period, 24-hr urinary protein excretion increased from median (interquartile range) of 72 (0-155) to 382 (169-999) mg/day (P=0.0001). Sixty-five (64%) patients achieved the primary endpoint and 37 (36%) experienced deterioration in kidney function. Independent predictors of deterioration of kidney function after SRL conversion were development of proteinuria ≥ 1000 mg/day (odds ratio [OR]: 3.3, confidence interval [CI]: 1.1-9.5 P=0.03), post-LT diabetes (OR: 4.2, CI: 1.6-11.1, P=0.004), and higher eGFR at time of conversion (OR: 1.6, CI: 1.2-2.2, P=0.003). CONCLUSION Improvement or stabilization of kidney function occurred in the majority of LT recipients converted to SRL for CNI nephrotoxicity. Proteinuria ≥ 1000 mg/day, post-LT diabetes, and higher baseline eGFR were independent predictors of kidney function loss after SRL conversion.
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30
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Optimization of the use of Calcineurin inhibitors in liver transplantation. Best Pract Res Clin Gastroenterol 2012; 26:85-95. [PMID: 22482528 DOI: 10.1016/j.bpg.2012.01.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 01/24/2012] [Indexed: 02/06/2023]
Abstract
Calcineurin inhibitors (CNIs), such as cyclosporin A and tacrolimus, are the cornerstone of maintenance immunosuppressive regimens in liver transplantation. CNIs prevent rejection by inhibition of calcineurin, via which lymphocyte proliferation and interleukin (IL)-2 production is prevented. Tacrolimus is now the first-choice immunosuppressant after liver transplantation, since it is associated with fewer episodes of rejection than cyclosporin A. In this review we will discuss interindividual differences, which influence tacrolimus metabolism. Because of these factors and the narrow therapeutic index of tacrolimus, monitoring of drug trough levels is necessary. Furthermore, we will discuss studies concerning conversion from the tacrolimus twice daily to tacrolimus once daily formulation in stable LT patients. Due to adverse effects of CNIs, such as chronic renal failure, hypertension, de novo malignancy and new-onset diabetes mellitus, CNI minimization strategies have been developed, which will be discussed too.
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31
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Kawahara T, Asthana S, Kneteman NM. m-TOR inhibitors: what role in liver transplantation? J Hepatol 2011; 55:1441-51. [PMID: 21781947 DOI: 10.1016/j.jhep.2011.06.015] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 06/28/2011] [Accepted: 06/29/2011] [Indexed: 12/11/2022]
Abstract
The development of calcineurin inhibitors (CNIs) led to marked improvements in patient and graft survival after liver transplantation (LTx). We have been left, however, with a dependence on immunosuppressive agents with nephrotoxicity, neurotoxicity, adverse impacts on cardiac risk profile, and risk for malignancy. These challenges need to be met against a dominance of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) as indications for liver transplant. Unmet needs for immunosuppression (IS) in LTx include: (1) Effective drugs that avoid CNIs toxicities. (2) Agents without adverse impact on HCV recurrence. (3) Compounds that minimize risk of HCC recurrence. New immunosuppressives will need to address the above needs while supporting patient and graft survival equivalent to those achievable with CNIs, ideally without important new toxicities. Two new classes of agents are currently in advanced clinical development: belatacept, and the mammalian target of rapamycin inhibitors (m-TORi). This manuscript will review evidence for a role for m-TORi in LTx in a range of clinical scenarios including patients with CNI nephrotoxicity or neurotoxicity, patients at risk of (or with) HCV recurrence, and patients at risk of HCC recurrence.
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Affiliation(s)
- Toshiyasu Kawahara
- Division of Transplantation, Department of Surgery, University of Alberta, Canada
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32
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Basso MS, Subramaniam P, Tredger M, Verma A, Heaton N, Rela M, Mieli-Vergani G, Dhawan A. Sirolimus as renal and immunological rescue agent in pediatric liver transplant recipients. Pediatr Transplant 2011; 15:722-7. [PMID: 22004546 DOI: 10.1111/j.1399-3046.2011.01560.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
CNI have improved the outcome of LT. However, their inherent potential to nephrotoxic and sometimes-inadequate immunosuppressive effect has lead to the usage of newer drugs like SRL. Aim of this study was to review children who received SRL. Thirty-seven (20 women) children post-LT, median age 10.4 yr (0.8-17.4) with a minimum follow-up of six months comprised the study group. Indications for SRL were biopsy-proven resistant acute allograft rejection (n = 12), early CR (n = 12), and CNI-induced nephropathy with MMF intolerance (n = 11). In two patients, the indication was the recurrence of BSEP disease in the allograft. In patients with acute rejection, AST normalized in 10/12 patients. In patients with CR, AST normalized in 6/12 patients. Those with renal impairment showed improvement in their creatinine levels from a mean baseline of 99-56.7 μm (p = 0.03) and their mean cystatin C was 1.02 after SRL. Side effects leading to discontinuation of SRL were seen in three patients. SRL was effective in rescuing patients with acute and chronic allograft rejection and improving renal function in CNI-induced nephropathy group.
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Affiliation(s)
- Maria-Sole Basso
- Paediatric Liver, GI and Nutrition Centre, Institute of Liver Studies, King's College Hospital, London, UK
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33
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Matsuda Y, Ichida T, Fukumoto M. Hepatocellular carcinoma and liver transplantation: clinical perspective on molecular targeted strategies. Med Mol Morphol 2011; 44:117-24. [PMID: 21922382 DOI: 10.1007/s00795-011-0547-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2011] [Accepted: 04/20/2011] [Indexed: 12/11/2022]
Abstract
Hepatocellular carcinoma (HCC) has an aggressive clinical course with frequent recurrence and metastasis. Orthotopic liver transplantation has been the only curative tool for unresectable HCC; therefore, recent advances in molecular targeted therapy may improve the prognosis of HCC. The multiple kinase inhibitor sorafenib and the macrolide antibiotic rapamycin are currently the most promising agents for treating unresectable HCC. A large population-based clinical trial revealed that sorafenib significantly prolonged the overall survival of HCC patients. However, subsequent clinical studies showed that sorafenib rarely reduced tumor volume and inadequately prolonged survival of patients with severe liver damage. To improve its therapeutic effect, the development of a predictive biomarker and a sorafenib-based combination is awaited. Another molecular targeting agent, rapamycin, has now been considered as a putative agent for preventing tumor recurrence in post-liver transplantation HCC patients, because it not only has immunosuppressive activity but also exerts an anti-tumor effect. In the near future, a combination of molecular targeting agents, such as sorafenib and rapamycin, may become a standard protocol for treating unresectable HCC. For specifying cases with more effective and less harmful modalities, further investigation in clinical and basic research to identify unexpected effects are needed.
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Affiliation(s)
- Yasunobu Matsuda
- Department of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Niigata 951-8518, Japan.
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34
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Kong Y, Wang D, Shang Y, Liang W, Ling X, Guo Z, He X. Calcineurin-inhibitor minimization in liver transplant patients with calcineurin-inhibitor-related renal dysfunction: a meta-analysis. PLoS One 2011; 6:e24387. [PMID: 21931704 PMCID: PMC3170329 DOI: 10.1371/journal.pone.0024387] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 08/08/2011] [Indexed: 12/13/2022] Open
Abstract
Background Introduction of calcineurin-inhibitor (CNI) has made transplantation a miracle in the past century. However, the side effects of long-term use of CNI turn out to be one of the major challenges in the current century. Among these, renal dysfunction attracts more and more attention. Herein, we undertook a meta-analysis to evaluate the efficacy and safety of calcineurin-inhibitor (CNI) minimization protocols in liver transplant recipients with CNI-related renal dysfunction. Methods We included randomized trials with no year and language restriction. All data were analyzed using random effect model by Review Manager 5.0. The primary endpoints were glomerular filtration rate (GFR), serum creatinine level (sCr) and creatinine clearance rate (CrCl), and the secondary endpoints were acute rejection episodes, incidence of infection and patient survival at the end of follow-up. Results GFR was significantly improved in CNI minimization group than in routine CNI regimen group (Z = 5.45, P<0.00001; I2 = 0%). Likely, sCr level was significantly lower in the CNI minimization group (Z = 2.84, P = 0.005; I2 = 39%). However, CrCl was not significantly higher in the CNI minimization group (Z = 1.59, P = 0.11; I2 = 0%). Both acute rejection episodes and patient survival were comparable between two groups (rejection: Z = 0.01, P = 0.99; I2 = 0%; survival: Z = 0.28, P = 0.78; I2 = 0%, respectively). However, current CNI minimization protocols may be related to a higher incidence of infections (Z = 3.06, P = 0.002; I2 = 0%). Conclusion CNI minimization can preserve or even improve renal function in liver transplant patients with renal impairment, while sharing similar short term acute rejection rate and patient survival with routine CNI regimen.
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Affiliation(s)
- Yuan Kong
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dongping Wang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yushu Shang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenhua Liang
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoting Ling
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhiyong Guo
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- * E-mail: (ZG); (XH)
| | - Xiaoshun He
- Organ Transplant Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- * E-mail: (ZG); (XH)
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Switching to sirolimus-based immune suppression after liver transplantation is safe and effective: a single-center experience. Transplantation 2011; 91:128-32. [PMID: 21452417 DOI: 10.1097/tp.0b013e3181fe131b] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Sirolimus is unlicensed for use in liver transplantation because of concerns over safety, particularly in regard to hepatic artery thrombosis and excess mortality. However, sirolimus offers potential advantages over calcineurin inhibitor-based immunosuppression, relating to its renal sparing and antiproliferative properties. METHODS A review was undertaken of 148 liver transplant patients converted to sirolimus over 10 years at a single center. RESULTS The main indications for sirolimus were renal impairment and hepatitis C virus fibrosis. One hundred eleven (75%) patients remained on sirolimus after median follow-up of 1006 days. Mean (+/-standard deviation) glomerular filtration rate improved significantly from 59+/-29 mL/min preconversion to 72+/-39 mL/min at censor point (P<0.05). Improvement in glomerular filtration rate was most marked in patients converted for renal impairment. Liver function tests remained stable or improved, particularly in patients transplanted for hepatitis C virus. Side effects attributed to sirolimus occurred in 101 (68%) patients requiring withdrawal in 20 patients (14%). Moderate increases in serum lipids were observed and controlled effectively with statins. The incidence of proteinuria increased postconversion but had no deleterious impact on renal function. No episodes of hepatic artery thrombosis were observed. CONCLUSIONS Sirolimus was safe and may improve outcome in selected patients after liver transplantation.
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36
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Duvoux C, Pageaux GP. Immunosuppression in liver transplant recipients with renal impairment. J Hepatol 2011; 54:1041-54. [PMID: 21145927 DOI: 10.1016/j.jhep.2010.12.001] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2009] [Revised: 11/27/2010] [Accepted: 12/01/2010] [Indexed: 02/06/2023]
Affiliation(s)
- C Duvoux
- Department of Hepatology and Gastroenterology, Liver Transplant Unit, Hospital Henri Mondor AP-HP, University Paris Est, Créteil, France.
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37
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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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38
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Vivarelli M, Dazzi A, Cucchetti A, Gasbarrini A, Zanello M, Di Gioia P, Bianchi G, Tamè MR, Gaudio MD, Ravaioli M, Cescon M, Grazi GL, Pinna AD. Sirolimus in liver transplant recipients: a large single-center experience. Transplant Proc 2011; 42:2579-84. [PMID: 20832548 DOI: 10.1016/j.transproceed.2010.04.045] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Accepted: 04/16/2010] [Indexed: 01/22/2023]
Abstract
Sirolimus (SRL) is a newer immunosuppressant whose possible benefits and side effects in comparison to calcineurin inhibitors (CNIs) still have to be addressed in the liver transplantation setting. We report the results of the use of SRL in 86 liver transplant recipients, 38 of whom received SRL as the main immunosuppressant in a CNI-sparing regimen. Indications for the use of SRL were: impaired renal function (n = 32), CNI neurotoxicity (n = 16), hepatocellular carcinoma (HCC) at high risk of recurrence (n = 21), recurrence of HCC (n = 6), de novo malignancies (n = 4), cholangiocarcinoma (n = 1), and the need to reinforce immunosuppression (n = 6). Among patients on SRL-based treatment, four episodes of acute rejection were observed, three of which occurred during the first postoperative month. Renal function significantly improved when sirolimus was introduced within the third postoperative month, while no change was observed when it was introduced later. Neurological symptoms resolved completely in 14/16 patients. The 3-year recurrence-free survival of patients with HCC on SRL was 84%. Sixty-two patients developed side effects that required drug withdrawal in seven cases. There was a reduced prevalence of hypertension and new-onset diabetes among patients under SRL. In conclusion, SRL was an effective immunosuppressant even when used in a CNI-sparing regimen. It was beneficial for patients with recently developed renal dysfunction or neurological disorders.
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Affiliation(s)
- M Vivarelli
- Department of Surgery and Transplantation, University of Bologna, S. Orsola Hospital, Italy.
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39
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Toso C, Patel S, Asthana S, Kawahara T, Girgis S, Kneteman NN, Shapiro AMJ, Bigam DL. The impact of sirolimus on hepatocyte proliferation after living donor liver transplantation. Clin Transplant 2011; 24:695-700. [PMID: 20002466 DOI: 10.1111/j.1399-0012.2009.01159.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND There is a lack of data on the use of sirolimus after partial liver transplantation, especially regarding its impact on post-transplant regeneration. METHODS We reviewed adult living donor transplantations, with de novo sirolimus (n = 7) and without sirolimus (n = 21). Liver biopsies were stained for KI-67, a proliferation marker. Controls included specimens with normal liver parenchyma (n = 13). RESULTS Both groups had similar demographics, graft and patient survival and complication rates. During the first six wk and over the whole first year post-transplant, the use of sirolimus was associated with lower levels of hepatocyte proliferation compared to sirolimus-free patients, (overall, 0.3 [0-7.2] vs. 3 [0-49] KI-67 positive hepatocytes per high power field, p ≤ 0.05). The levels observed in the sirolimus group were similar to those seen in non-transplanted control patients with normal parenchyma (0.2 [0-1.3], p = NS). Post-transplant hepatocyte proliferation correlated with the serum levels of sirolimus (p ≤ 0.05), but not with those of tacrolimus or with the dose of mycophenolate mofetil (p = 0.9 and 0.3, respectively). CONCLUSIONS These data suggest that sirolimus is associated with decreased post-transplant hepatocyte proliferation. The clinical significance of this observation remains to be fully determined.
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Affiliation(s)
- Christian Toso
- Department of Surgery, Section of Hepatobiliary, Pancreatic and Transplant Surgery, University of Alberta Hospital, Edmonton, AB, Canada.
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40
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Vallin M, Guillaud O, Morard I, Gagnieu MC, Mentha G, Adham M, Morelon E, Boillot O, Giostra E, Dumortier J. Tolerability of everolimus-based immunosuppression in maintenance liver transplant recipients. Clin Transplant 2010; 25:660-9. [PMID: 21158921 DOI: 10.1111/j.1399-0012.2010.01370.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The aim of this study was to evaluate the tolerability of the conversion from calcineurin inhibitor (CNI) to everolimus (ERL) in maintenance liver transplant (LT) recipients. METHODS From January 2005 to March 2008, ERL was introduced after LT as maintenance immunosuppressive therapy because of (i) de novo or recurrent cancer after LT, (ii) pre-existing liver carcinoma on the liver explant or (iii) CNI toxicity. CNI dosage was progressively reduced until discontinuation. RESULTS The study population included 94 patients, of mean age 57 ± 10. The mean delay between LT and ERL introduction was 5 ± 5 yr. After a mean follow-up of 12 ± 7 months, 70% of the patients did present at least one side effect. The mean trough level of ERL was 6 μg/L at the end of follow-up. Main side effects included hyperlipidemia (37%), dermatitis (19%), mucositis (15%), and proteinuria (18%). Biopsy-proven acute rejection occurred in 9% of patients. Global ERL discontinuation rate was 21% (16% because of side effects). CONCLUSIONS The results of our experience indicate that conversion to ERL is associated with adverse effects in 70% of patients leading to drug discontinuation in 16% (and amenable to dose reduction in the remainders). Longer follow-up periods are necessary to capture the impact of ERL fully on renal function and survival in cancer patients.
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Affiliation(s)
- Mélanie Vallin
- Liver Transplantation Unit, Edouard Herriot Hospital, Lyon, France
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41
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Masetti M, Montalti R, Rompianesi G, Codeluppi M, Gerring R, Romano A, Begliomini B, Di Benedetto F, Gerunda GE. Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function. Am J Transplant 2010; 10:2252-62. [PMID: 20486905 DOI: 10.1111/j.1600-6143.2010.03128.x] [Citation(s) in RCA: 114] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We designed a randomized trial to assess whether the early withdrawal of cyclosporine (CsA) followed by the initiation of everolimus (Evr) monotherapy in de novo liver transplantation (LT) patients would result in superior renal function compared to a CsA-based immunosuppression protocol. All patients were treated with CsA for the first 10 days and then randomized to receive Evr in combination with CsA up to day 30, then either continued on Evr monotherapy (Evr group) or maintained on CsA with/without mycophenolate mofetil (CsA group) in case of chronic kidney disease (CKD). Seventy-eight patients were randomized (Evr n = 52; CsA n = 26). The 1-year freedom from efficacy failure in Evr group was 75% versus 69.2% in CsA group, p = 0.36. There was no statistically significant difference in patient survival between the two groups. Mean modification of diet in renal disease (MDRD) was significantly better in the Evr group at 12 months (87.7 ± 26.1 vs. 59.9 ± 12.6 mL/min; p < 0.001). The incidence of CKD stage ≥ 3 (estimated glomerular filtration rate < 60 mL/min) was higher in the CsA group at 1 year (52.2% vs. 15.4%, p = 0.005). The results indicate that early withdrawal of CsA followed by Evr monotherapy in de novo LT patients is associated with an improvement in renal function, with a similar incidence of rejection and major complications.
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Affiliation(s)
- M Masetti
- Liver and Multivisceral Transplantation Center Division of Infectious Diseases, Azienda Ospedaliero-Universitaria di Modena-Policlinico, Modena, Italy.
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Introduction of Mycophenolate Mofetil in Maintenance Liver Transplant Recipients: What Can We Expect? Results of a 10-Year Experience. Transplant Proc 2010; 42:2602-6. [DOI: 10.1016/j.transproceed.2010.05.170] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2009] [Accepted: 05/19/2010] [Indexed: 01/01/2023]
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43
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Dutkowski P, De Rougemont O, Müllhaupt B, Clavien PA. Current and future trends in liver transplantation in Europe. Gastroenterology 2010; 138:802-9.e1-4. [PMID: 20096694 DOI: 10.1053/j.gastro.2010.01.030] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Philipp Dutkowski
- Department of Surgery, Swiss Hepato-Pancreatico-Biliary and Transplant Center, University Hospital Zurich, 8091 Zurich, Switzerland
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44
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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:S1-34. [PMID: 19877213 DOI: 10.1002/lt.21877] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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45
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Rogers CC, Johnson SR, Mandelbrot DA, Pavlakis M, Horwedel T, Karp SJ, Egbuna O, Rodrigue JR, Chudzinski RE, Goldfarb-Rumyantzev AS, Hanto DW, Curry MP. Timing of sirolimus conversion influences recovery of renal function in liver transplant recipients. Clin Transplant 2009; 23:887-96. [DOI: 10.1111/j.1399-0012.2009.01040.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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46
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Immunosuppression après transplantation hépatique. Presse Med 2009; 38:1307-13. [DOI: 10.1016/j.lpm.2009.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2009] [Revised: 06/05/2009] [Accepted: 06/05/2009] [Indexed: 11/17/2022] Open
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Schrader J, Sterneck M, Klose H, Lohse AW, Nashan B, Fischer L. Everolimus-induced pneumonitis: report of the first case in a liver transplant recipient and review of treatment options. Transpl Int 2009; 23:110-3. [PMID: 19497063 DOI: 10.1111/j.1432-2277.2009.00900.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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48
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Liew A, Chiang GSC, Vathsala A. Factors associated with proteinuria in renal transplant recipients treated with sirolimus. Transpl Int 2009; 22:313-22. [DOI: 10.1111/j.1432-2277.2008.00801.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
Organ transplant recipients given mammalian target of rapamycin inhibitor (mTORi) have reduced incidence of de novo posttransplant malignancies (dNPTMs). Posttransplant Kaposi's sarcoma and nonmelanotic skin malignancies (NMSC) frequently undergo remission/regression after conversion to mTORi immunosuppression (IS), especially early, small, and low-grade lesions, whereas larger, aggressive, and metastatic skin tumors are less likely to respond. mTORi-based IS is effective and well tolerated in orthotopic liver transplant patients with hepatocellular carcinoma (HCC) achieving excellent survival and disease-free intervals, particularly with extended criteria tumors, although the evidence that mTORi prevents HCC recurrence after orthotopic liver transplantation is only suggestive. Regression of metastatic HCC and other tumors and various forms of posttransplant lymphoproliferative disease have occurred after mTOR conversion. Documentation of regression/remission of other solid-organ dNPTM (colon, stomach, breast, etc.) after mTORi conversion is essentially absent with only anecdotal reports lacking follow-up data. Unfortunately, there is not a single reported prospective clinical trial powered for looking at the effect of mTORi IS in transplant recipients. Nevertheless, reduced incidence of all of dNPTMs and remission/regression of the commonest posttransplant tumors with mTOR therapy are strong reasons to expand the use of mTORi.
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Ekser B, Furian L, Baldan N, Amico A, Fabris L, Lazzarin M, Marchini F, Rigotti P. Dual kidney transplantation after liver transplantation: a good option to rescue a patient from dialysis. Clin Transplant 2009; 23:124-8. [DOI: 10.1111/j.1399-0012.2008.00903.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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