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Fernández J, Blasi A, Hidalgo E, Karvellas CJ. Bridging the critically ill patient with acute to chronic liver failure to liver transplantation. Am J Transplant 2024; 24:1348-1361. [PMID: 38548058 DOI: 10.1016/j.ajt.2024.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 03/16/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024]
Abstract
Liver transplantation (LT) has emerged as an effective therapy for severe forms of acute-on-chronic liver failure (ACLF), an entity characterized by the development of multiorgan failure and high short-term mortality. The aim of critical care management of ACLF patients is to rapidly treat precipitating events and aggressively support failing organs to ensure that patients may successfully undergo LT or, less frequently, recover. Malnutrition and sarcopenia are frequently present, adversely impacting the prognosis of these patients. Management of critical care patients with ACLF is complex and requires the participation of different specialties. Once the patient is stabilized, a rapid evaluation for salvage LT should be performed because the time window for LT is often narrow. The development of sepsis and prolonged organ support may preclude LT or diminish its chances of success. The current review describes strategies to bridge severe ACLF patients to LT, highlights the minimal evaluation required for listing and the currently suggested contraindications to proceed with LT, and addresses different aspects of management during the perioperative and early posttransplant period.
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Affiliation(s)
- Javier Fernández
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS and CIBERehd, Spain; EF Clif, EASL-CLIF Consortium, Barcelona, Spain.
| | - Annabel Blasi
- Anesthesiology Department, Hospital Clínic, and University of Barcelona, Spain
| | - Ernest Hidalgo
- Hepatolobiliary Surgery Department, Hospital Vall d'Hebron, Barcelona, Spain
| | - Constantine J Karvellas
- Department of Critical Care Medicine, University of Alberta, Edmonton, Canada; Division of Gastroenterology (Liver Unit), University of Alberta, Edmonton, Canada
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2
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Fuochi E, Anastasio L, Lynch EN, Campani C, Dragoni G, Milani S, Galli A, Innocenti T. Main factors influencing long-term outcomes of liver transplantation in 2022. World J Hepatol 2023; 15:321-352. [PMID: 37034235 PMCID: PMC10075010 DOI: 10.4254/wjh.v15.i3.321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 11/24/2022] [Accepted: 02/22/2023] [Indexed: 04/11/2023] Open
Abstract
Liver transplant (LT) outcomes have markedly improved in the recent decades, even if long-term morbidity and mortality are still considerable. Most of late deaths are independent from graft function and different comorbidities, including complications of metabolic syndrome and de novo neoplasms, seem to play a key role in determining long-term outcomes in LT recipients. This review discusses the main factors associated with late mortality and suggests possible strategies to improve long-term management and follow-up after liver transplantation. In particular, the reduction of drug toxicity, the use of tools to identify high-risk patients, and setting up a multidisciplinary team also for long-term management of LT recipients may further improve survival after liver transplantation.
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Affiliation(s)
- Elisa Fuochi
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Lorenzo Anastasio
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Erica Nicola Lynch
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Claudia Campani
- Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy
| | - Gabriele Dragoni
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
- Department of Medical Biotechnologies, University of Siena, Siena 53100, Italy
| | - Stefano Milani
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Andrea Galli
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
| | - Tommaso Innocenti
- Gastroenterology Research Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50134, Italy
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3
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Kniepeiss D, Rosenkranz AR, Fickert P, Schemmer P. [Update: Immunosuppression in organ transplantation]. Dtsch Med Wochenschr 2022; 147:1199-1212. [PMID: 36070738 DOI: 10.1055/a-1716-8031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
Abstract
Immunosuppression is an essential prerequisite for successful transplantation. In order to reduce the sometimes-considerable side effects, combination therapies with different agents are used. This article aims to provide an up-to-date overview of immunosuppression after liver and kidney transplantation.
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4
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[Kidney failure after liver transplantation]. Nephrol Ther 2022; 18:89-103. [PMID: 35151596 DOI: 10.1016/j.nephro.2021.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/11/2021] [Accepted: 11/06/2021] [Indexed: 02/06/2023]
Abstract
One third of cirrhotic patients present impaired kidney function. It has multifactorial causes and has a harmful effect on patients' morbi-mortality before and after liver transplant. Kidney function does not improve in all patients after liver transplantation and liver-transplant recipients are at high risk of developing chronic kidney disease. Causes for renal dysfunction can be divided in three groups: preoperative, peroperative and postoperative factors. To date, there is no consensus for the modality of evaluation the risk for chronic kidney disease after liver transplantation, and for its prevention. In the present review, we describe the outcome of kidney function after liver transplantation, and the prognostic factors of chronic kidney disease to determine a risk stratification for each patient. Furthermore, we discuss therapeutic options to prevent kidney dysfunction in this setting, and highlight the indications of combined liver-kidney transplantation.
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5
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Lim SY, Wang R, Tan DJH, Ng CH, Lim WH, Quek J, Syn N, Nah BKY, Wong ETY, Huang DQ, Vathsala A, Siddiqui MS, Fung J, Muthiah MD, Tan EXX. A meta-analysis of the cumulative incidence, risk factors, and clinical outcomes associated with chronic kidney disease after liver transplantation. Transpl Int 2021; 34:2524-2533. [PMID: 34714569 DOI: 10.1111/tri.14149] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/19/2021] [Accepted: 09/29/2021] [Indexed: 12/15/2022]
Abstract
Chronic kidney disease (CKD) remains a relatively common complication after liver transplantation (LT), and significantly impacts overall survival. We sought to assess the cumulative incidence, risk factors and mortality associated with post-LT CKD. CKD was defined as eGFR <60 ml/min/1.73 m2 as estimated by the Modified Diet in Renal Disease (MDRD) formula. Single-arm meta-analysis was done to evaluate the cumulative incidence of CKD at 1-, 3-, and 5-year timepoints post-LT. Risk factors for CKD were evaluated using hazard ratios (HR). Twenty-one studies involving 44 383 patients were included. Cumulative incidence of stage 3-5 CKD was 31.44% (CI 0.182-0.447), 36.71% (CI 0.188-0.546), and 43.52% (CI 0.296-0.574) at 1, 3, and 5 years after LT, respectively. Stage 5 CKD cumulative incidence increased from 0.274% (CI 0.001-0.005) at 1 year to 2.06% (CI 0.009-0.045) at 5 years post-LT. Age, female sex, diabetes, and peri-operative acute kidney injury (AKI) were significant risk factors for CKD. Stage 4-5 CKD was associated with a decrease in overall survival (HR 3.23, 95% CI 1.74-5.98, P < 0.01). CKD after LT is relatively common, and is associated with significantly reduced overall survival. Identification of patients at high risk of developing CKD allows physicians to prophylactically use renal-sparing immunosuppression which may be crucial in achieving desirable clinical outcomes.
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Affiliation(s)
- Sze Yinn Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Renaeta Wang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Darren Jun Hao Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Cheng Han Ng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Wen Hui Lim
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jingxuan Quek
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Nicholas Syn
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Benjamin Kai Yi Nah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Emmett Tsz-Yeung Wong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Center for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Daniel Q Huang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Center for Organ Transplantation, National University Health System, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Anantharaman Vathsala
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Center for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mohammad Shadab Siddiqui
- Division of Gastroenterology and Hepatology, Virginia Commonwealth University, Richmond, VA, USA
| | - James Fung
- Division of Gastroenterology and Hepatology, Department of Medicine, Queen Mary Hospital, Hong Kong, Hong Kong
| | - Mark D Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Center for Organ Transplantation, National University Health System, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
| | - Eunice Xiang-Xuan Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Center for Organ Transplantation, National University Health System, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
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Noble J, Terrec F, Malvezzi P, Rostaing L. Adverse effects of immunosuppression after liver transplantation. Best Pract Res Clin Gastroenterol 2021; 54-55:101762. [PMID: 34874845 DOI: 10.1016/j.bpg.2021.101762] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 08/30/2021] [Indexed: 01/31/2023]
Abstract
After solid organ transplantation the cornerstone of immunosuppression is based on calcineurin inhibitors (CNIs), mostly tacrolimus. However, CNIs have a very narrow therapeutic window. The most important and serious side-effects of CNIs are nephrotoxicity, high blood pressure, post-transplant diabetes mellitus (PTMD), i.e., new-onset diabetes after transplantation (NODAT), dyslipidemia, and modification to the cardiovascular-risk profile. In this review, we will focus on tacrolimus-related toxicities in the setting of liver transplantation.
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Affiliation(s)
- Johan Noble
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, Grenoble University Hospital, Grenoble, France
| | - Florian Terrec
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, Grenoble University Hospital, Grenoble, France
| | - Paolo Malvezzi
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, Grenoble University Hospital, Grenoble, France
| | - Lionel Rostaing
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, Grenoble University Hospital, Grenoble, France; Grenoble Alpes University, Grenoble, France.
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Abstract
One-third of patients with cirrhosis present kidney failure (AKI and CKD). It has multifactorial causes and a harmful effect on morbidity and mortality before and after liver transplantation. Kidney function does not improve in all patients after liver transplantation, and liver transplant recipients are at a high risk of developing chronic kidney disease. The causes of renal dysfunction can be divided into three groups: pre-operative, perioperative and post-operative factors. To date, there is no consensus on the modality to evaluate the risk of chronic kidney disease after liver transplantation, or for its prevention. In this narrative review, we describe the outcome of kidney function after liver transplantation, and the prognostic factors of chronic kidney disease in order to establish a risk categorization for each patient. Furthermore, we discuss therapeutic options to prevent kidney dysfunction in this context, and highlight the indications of combined liver–kidney transplantation.
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8
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Abstract
Liver transplantation (LT) has revolutionized outcomes for cirrhotic patients. Current liver allocation policies dictate patients with highest short-term mortality receive the highest priority, thus, several patients become increasingly ill on the waitlist. Given cirrhosis is a progressive disease, it can be complicated by the occurrence of acute-on-chronic liver failure (ACLF), a syndrome defined by an acute deterioration of liver function associated with extrahepatic organ failures requiring intensive care support and a high short-term mortality. Successfully bridging to transplant includes accurate prognostication and prioritization of ACLF patients awaiting LT, optimizing intensive care support pre-LT, and tailoring immunosuppressive and anti-infective therapies post-LT. Furthermore, predicting futility (too sick to undergo LT) in ACLF is challenging. In this review, we summarize the role of LT in ACLF specifically highlighting (a) current prognostic scores in ACLF, (b) critical care management of the ACLF patient awaiting LT, (c) donor issues to consider in transplant in ACLF, and (d) exploring of recent post-LT outcomes in ACLF and potential opportunities to improve outcomes including current care gaps and unmet research needs.
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Interleukin-2 receptor antibody induction with early low dose tacrolimus preserves post-liver transplant renal function in at risk individuals. JOURNAL OF LIVER TRANSPLANTATION 2021. [DOI: 10.1016/j.liver.2021.100028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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Gastaca M, Ruiz P, Bustamante J, Martinez-Indart L, Ventoso A, Fernandez JR, Palomares I, Prieto M, Testillano M, Salvador P, Senosiain M, Suárez MJ, Valdivieso A. Early tacrolimus exposure does not impact long-term outcomes after liver transplantation. World J Hepatol 2021; 13:362-374. [PMID: 33815678 PMCID: PMC8006083 DOI: 10.4254/wjh.v13.i3.362] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 12/27/2020] [Accepted: 03/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Tacrolimus trough levels (TTL) during the first weeks after liver transplantation (LT) have been related with long-term renal function and hepatocellular carcinoma recurrence. Nevertheless, the significance of trough levels of tacrolimus during the early post-transplant period for the long-term outcome is under debate
AIM To evaluate the effect of TTL during the first month on the long-term outcomes after LT.
METHODS One hundred fifty-five LT recipients treated de novo with once-daily tacrolimus were retrospectively studied. Patients with repeated LT or combined transplantation were excluded as well as those who presented renal dysfunction prior to transplantation and/or those who needed induction therapy. Patients were classified into 2 groups according to their mean TTL within the first month after transplantation: ≤ 10 (n = 98) and > 10 ng/mL (n = 57). Multivariate analyses were performed to assess risk factors for patient mortality.
RESULTS Mean levels within the first month post-transplant were 7.4 ± 1.7 and 12.6 ± 2.2 ng/mL in the ≤ 10 and > 10 groups, respectively. Donor age was higher in the high TTL group 62.9 ± 16.8 years vs 45.7 ± 17.5 years (P = 0.002) whilst mycophenolate-mofetil was more frequently used in the low TTL group 32.7% vs 15.8% (P = 0.02). Recipient features were generally similar across groups. After a median follow-up of 52.8 mo (range 2.8-81.1), no significant differences were observed in: Mean estimated glomerular filtration rate (P = 0.69), hepatocellular carcinoma recurrence (P = 0.44), de novo tumors (P = 0.77), new-onset diabetes (P = 0.13), or biopsy-proven acute rejection rate (12.2% and 8.8%, respectively; P = 0.50). Eighteen patients died during the follow-up and were evenly distributed across groups (P = 0.83). Five-year patient survival was 90.5% and 84.9%, respectively (P = 0.44), while 5-year graft survival was 88.2% and 80.8%, respectively (P = 0.42). Early TTL was not an independent factor for patient mortality in multivariate analyses.
CONCLUSION Differences in tacrolimus levels restricted to the first month after transplant did not result in significant differences in long-term outcomes of LT recipients.
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Affiliation(s)
- Mikel Gastaca
- Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Patricia Ruiz
- Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Javier Bustamante
- Department of Hepatology Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Lorea Martinez-Indart
- Department of Bioinformatics and Statistics Platform, Biocruces Bizkaia Health Research Institute, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Alberto Ventoso
- Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - José Ramón Fernandez
- Department of Hepatology Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Ibone Palomares
- Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Mikel Prieto
- Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Milagros Testillano
- Department of Hepatology Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Patricia Salvador
- Department of Hepatology Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Maria Senosiain
- Department of Hepatology Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Maria Jesus Suárez
- Department of Hepatology Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
| | - Andres Valdivieso
- Department of HPB Surgery and Liver Transplantation Unit, Hospital Universitario Cruces, Bilbao 48903, Spain
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Lassailly G, Dumortier J, Saint-Marcoux F, El Amrani M, Boulanger J, Boleslawski E, Millet G, Ningarhari M, Truant S, Canva V, Goria O, Boillot O, Louvet A, Mathurin P, Lebuffe G, Pruvot FR, Marquet P, Dharancy S. Real life experience of mycophenolate mofetil monotherapy in liver transplant patients. Clin Res Hepatol Gastroenterol 2021; 45:101451. [PMID: 32536555 DOI: 10.1016/j.clinre.2020.04.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Mycophenolate mofetil (MMF) monotherapy following liver transplantation (LT) remains controversial due to a risk of acute rejection. The aim of this study was to report the largest multicenter experience of the use a MMF monotherapy guided by therapeutic drug monitoring using pharmacoslope modeling and Bayesian estimations of the MPA inter-dose AUC (BEAUCMPA) before withdrawing calcineurin inhibitors (CNI) and to evaluate the benefit of MMF monotherapy. METHODS MMF daily doses were adjusted to reach the BEAUCMPA target of 45μg.h/mL. Then CNI were withdrawn and patients were followed on liver test and clinical outcomes. MAIN FINDINGS From 2000-2014, in 2 transplantation centers, 94 liver transplant recipients received MMF monotherapy 6.5±4 years after LT. The mean BEAUCMPA was 45.5±16μg.h/mL. During follow-up, 4 patients experienced acute rejection (4%). During the first year, estimated glomerular filtration rate (eGFR) improved from 46.2±10.5 to 49.1±11.5mL/kg/min (P=0.025). Benefit persisted at year 5. In patients with metabolic syndrome, eGFR did not improve. CONCLUSION MMF monotherapy regimen appears usually safe and beneficial, with low risk of acute rejection and eGFR improvement. Therapeutic drug monitoring strategy seemed useful by identifying 14% of patients with low MMF exposure.
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Affiliation(s)
- Guillaume Lassailly
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Jerome Dumortier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Franck Saint-Marcoux
- Département de Pharmacologie Toxicologie, CHU Limoges, Limoges, Inserm UMR 850, Université Limoges, Limoges, France
| | - Medhi El Amrani
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Juliette Boulanger
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Emmanuel Boleslawski
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Guillaume Millet
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Massih Ningarhari
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Stephanie Truant
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Valérie Canva
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Odile Goria
- Département d'Hépato-gastroentérologie, Hôpital Charles Nicolle, CHU Rouen, Rouen, France
| | - Olivier Boillot
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices civils de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Alexandre Louvet
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Philippe Mathurin
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France
| | - Gilles Lebuffe
- Département d'Hépato-gastroentérologie, Hôpital Charles Nicolle, CHU Rouen, Rouen, France
| | - François-René Pruvot
- Département de Chirurgie Digestive et de Transplantation, pole médico-chirurgical, Hôpital Huriez CHU Lille, Université de Lille, Lille, France
| | - Pierre Marquet
- Département de Pharmacologie Toxicologie, CHU Limoges, Limoges, Inserm UMR 850, Université Limoges, Limoges, France
| | - Sébastien Dharancy
- Maladies Appareil Digestif, pole médico-chirurgical, Hôpital Huriez CHU Lille, Inserm U995, Université de Lille, France.
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12
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Saliba F, Dharancy S, Salamé E, Conti F, Eyraud D, Radenne S, Antonini T, Guillaud O, Guguenheim J, Neau-Cransac M, Demartin E, Lasailly G, Duvoux C, Sobesky R, Coilly A, Tresson S, Cailliez V, Boillot O, Pageaux GP, Samuel D, Calmus Y, Dumortier J. Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry. Liver Transpl 2020; 26:1465-1476. [PMID: 32869469 DOI: 10.1002/lt.25879] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/12/2020] [Accepted: 06/28/2020] [Indexed: 12/14/2022]
Abstract
Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR <60 mL/minute/1.73 m2 and was maintained in those with baseline eGFR ≥60 mL/minute/1.73 m2 . Among patients with chronic kidney disease (CKD; baseline eGFR <60 mL/minute/1.73 m2 ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12 months after transplantation (mid-conversion) experienced improvement in eGFR (≥60 mL/minute/1.73 m2 ) at month 36. Only 20.9% and 17.4% among those converted beyond 12 months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60 mL/minute/1.73 m2 ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs.
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Affiliation(s)
- Faouzi Saliba
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Sébastien Dharancy
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Ephrem Salamé
- Service de Chirurgie Hépato-Biliaire et Digestive, Hôpital Trousseau, Centre Hospitalier Universitaire Tours, Tours, France
| | - Filoména Conti
- Service de Chirurgie Digestive et Hépato-Biliaire, AP-HP Hôpital Pitié Salpêtrière, Transplantation Hépatique, Paris, France
| | - Daniel Eyraud
- Département d'Anesthésie-Réanimation, Service de Chirurgie Digestive et Hépato-Biliaire et de Transplantation Hépatique, Groupe Hospitalier Pitié Salpêtrière, Paris, France
| | - Sylvie Radenne
- Service de Chirurgie Digestive et Transplantation Hépatique, Hôpital la Croix Rousse, Lyon, France
| | - Térésa Antonini
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Olivier Guillaud
- Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France
| | - Jean Guguenheim
- Département de Chirurgie Digestive et Transplantation Hépatique, Hôpital Archet, University of Nice Sophia Antipolis, Nice, France
| | - Martine Neau-Cransac
- Unité de Chirurgie Hépato-Biliaire et de Transplantation Hépatique, Hôpital Magellan, Centre Hospitalier Universitaire Bordeaux, Pessac, France
| | - Eléonora Demartin
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Guillaume Lasailly
- Service d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire de Lille, Lille, France
| | - Christophe Duvoux
- Service d'Hépato-Gastro-Entérologie, AP-HP Hôpital Henri Mondor, Créteil, France
| | - Rodolphe Sobesky
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Audrey Coilly
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Sylvie Tresson
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Valérie Cailliez
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Olivier Boillot
- Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France
| | - Georges Philippe Pageaux
- Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Didier Samuel
- Centre Hépato-Biliaire, AP-HP Hôpital Paul Brousse, INSERM, Unité 1193, Université Paris Saclay, Villejuif, France
| | - Yvon Calmus
- Service de Chirurgie Digestive et Hépato-Biliaire, AP-HP Hôpital Pitié Salpêtrière, Transplantation Hépatique, Paris, France
| | - Jérôme Dumortier
- Unité de Transplantation Hépatique, Hôpital Edouard Herriot, Lyon, France
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13
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Kniepeiss D, Rosenkranz AR, Fickert P, Schemmer P. Update: Immunsuppression bei Organtransplantationen. TRANSFUSIONSMEDIZIN 2020. [DOI: 10.1055/a-1238-3285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
ZusammenfassungDie Immunsuppression ist eine wesentliche Grundvoraussetzung für eine erfolgreiche Transplantation. Zur Reduktion der teils beträchtlichen Nebenwirkungen werden Kombinationstherapien mit unterschiedlichen Wirkstoffen durchgeführt. Dieser Beitrag soll einen aktuellen Überblick zur Immunsuppression nach Leber- und Nierentransplantation geben.
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14
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Renal disease in the allograft recipient. Best Pract Res Clin Gastroenterol 2020; 46-47:101690. [PMID: 33158468 DOI: 10.1016/j.bpg.2020.101690] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 01/31/2023]
Abstract
Chronic renal failure after liver transplantation (LT) is significantly more frequent than after lung or heart transplantation and it results in an increased short and long-term mortality. Renal impairment may occur before LT (functional or due to preexisting parenchymal kidney disease), in the peri-operative period or later after LT. The number of patients with renal failure after LT has increased due to the liver allocation based on MELD and to the more liberal use of higher risk grafts. Calcineurin inhibitor (CNI) nephrotoxicity is the most important cause of renal dysfunction but is a modifiable factor. Strategy to prevent CNI-associated nephrotoxicity is post-op CNI minimization by induction therapy and reduced dose and/or delayed introduction of CNI in combination with mycophenolate mofetil (MMF) or everolimus with no penalty in term of rejection. With everolimus, usually started one month after LT, a drastic minimization of CNI is possible and this results in superior kidney function until at least 3 years follow up. At the moment of renal impairment a drastic reduction of CNI dose together with the introduction of MMF results in an improvement in GFR at 6 to 2 years with a low rate of acute rejection. However, secondary prevention fails to normalize renal function in most of the patients once e GFR <60 ml/min/1.73m2ml.
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15
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Park J, Jeong J, Choi HJ, Shim JW, Lee HM, Hong SH, Park CS, Choi JH, Chae MS. Role of thrombocytopenia in risk stratification for acute kidney injury after living donor liver transplantation. Platelets 2020; 32:453-462. [PMID: 32299264 DOI: 10.1080/09537104.2020.1754377] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
The aim of our study was to investigate pre and intraoperative clinical factors, including platelet count, which could inform risk stratification of early acute kidney injury (AKI) after living donor liver transplantation (LDLT). Additionally, the impact of severe thrombocytopenia on AKI risk was assessed using a propensity score (PS)-matched analysis. In total, 591 adult patients who underwent LDLT between January 2009 and December 2018 at our hospital were retrospectively analyzed. Early postoperative AKI was determined based on the KDIGO criteria, and 149 patients (25.2%) developed AKI immediately after surgery. In a multivariate analysis, a lower preoperative platelet count was significantly associated with early postoperative AKI, together with diabetes mellitus, lower hourly urine output, and longer graft ischemic time; furthermore, a decrease in platelet count was correlated with AKI severity. After adjusting for the PS, the probability of AKI was significantly (1.9-fold) higher in patients with severe thrombocytopenia than in those without severe thrombocytopenia. Patients with thrombocytopenia showed a higher postoperative incidence of AKI and a higher requirement for dialysis than those without thrombocytopenia. The platelet count can easily be obtained via regular blood analysis of patients scheduled for LDLT and can be used to identify patients at risk for AKI.
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Affiliation(s)
- Jaesik Park
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Jangsu Jeong
- Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Ho Joong Choi
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Surgery, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Jung-Woo Shim
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Hyung Mook Lee
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Sang Hyun Hong
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Chul Soo Park
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Jong Ho Choi
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
| | - Min Suk Chae
- Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Anesthesiology and Pain Medicine, Seocho-gu, Seoul, Korea (The Republic Of)
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16
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Colombo D, Zullo A, Simoni L, Zagni E. The SURF (Italian observational study for renal insufficiency evaluation in liver transplant recipients): a post-hoc between-sex analysis. BMC Nephrol 2019; 20:475. [PMID: 31870321 PMCID: PMC6929500 DOI: 10.1186/s12882-019-1656-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 12/03/2019] [Indexed: 12/15/2022] Open
Abstract
Background Female sex has been reported as an independent predictor of severe post-liver transplantation (LT) chronic kidney disease. We performed a by sex post-hoc analysis of the SURF study, that investigated the prevalence of renal impairment following LT, aimed at exploring possible differences between sexes in the prevalence and course of post-LT renal damage. Methods All patients enrolled in the SURF study were considered evaluable for this sex-based analysis, whose primary objective was to evaluate by sex the proportion of patients with estimated Glomerular Filtration Rate (eGFR) < 60 ml/min/1.73m2 at inclusion and follow-up visit. Results Seven hundred thirty-eight patients were included in our analysis, 76% males. The proportion of patients with eGFR < 60 mL/min/1.73 m2 was significantly higher in females at initial study visit (33.3 vs 22.8%; p = 0.005), but also before, at time of transplantation (22.9 vs 14.7%; p = 0.0159), as analyzed retrospectively. At follow-up, such proportion increased more in males than in females (33.9 vs 26.0%, p = 0.04). Mean eGFR values decreased over the study in both sexes, with no significant differences. Statistically significant M/F differences in patient distribution by O’Riordan eGFR levels were observed at time of transplant and study initial visit (p = 0.0005 and 0.0299 respectively), but not at follow-up. Conclusions Though the limitation of being performed post-hoc, this analysis suggests potential sex differences in the prevalence of renal impairment before and after LT, encouraging further clinical research to explore such differences more in depth.
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Affiliation(s)
- Delia Colombo
- Novartis Farma S.p.A, Largo Umberto Boccioni, 21040, Origgio, VA, Italy
| | | | | | - Emanuela Zagni
- Novartis Farma S.p.A, Largo Umberto Boccioni, 21040, Origgio, VA, Italy.
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17
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Once-daily prolonged-release tacrolimus versus twice-daily tacrolimus in liver transplantation. J Am Pharm Assoc (2003) 2019; 59:816-823.e2. [PMID: 31521585 DOI: 10.1016/j.japh.2019.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/30/2019] [Accepted: 08/02/2019] [Indexed: 12/27/2022]
Abstract
OBJECTIVE For patients who have received a kidney transplant, studies have shown that once-daily prolonged-release tacrolimus (TAC) has similar efficacy and safety to standard twice-daily dosing. The purpose of this study was to perform a meta-analysis to compare the effectiveness and safety of daily TAC (TAC qd) versus standard twice-daily TAC (TAC bid) administration in liver transplantation (LT). DESIGN Meta-analysis. SETTING AND PARTICIPANTS We systematically searched the PubMed/MEDLINE, Web of Science, and Cochrane Library databases for studies comparing outcomes of LT patients who received TAC qd versus TAC bid. OUTCOME MEASURES Results were reported as odds ratios (ORs) with 95% CIs. RESULTS Six studies, which included 5179 LT recipients (TAC qd = 951; TAC bid = 4228) were included in the analysis. The TAC qd group had a low 1-year graft loss rate (OR 0.70 [95% CI 0.54-0.91], P = 0.008) and lower rate of biopsy-proven acute rejection (BPAR) at 90 days (OR 0.46 [95% CI 0.24-0.89], P = 0.02) compared with the TAC bid group. There was no significant difference in 1-year mortality or the incidence of adverse events after LT between the 2 groups. CONCLUSIONS Current evidence suggests that TAC qd is safe and effective for LT patients during the first year after transplantation. Longer-term follow-up studies are necessary to determine if TAC qd is safe and effective beyond the first year after LT.
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18
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Bardou FN, Guillaud O, Erard-Poinsot D, Chambon-Augoyard C, Thimonier E, Vallin M, Boillot O, Dumortier J. Tacrolimus exposure after liver transplantation for alcohol-related liver disease: Impact on complications. Transpl Immunol 2019; 56:101227. [PMID: 31351125 DOI: 10.1016/j.trim.2019.101227] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 07/16/2019] [Accepted: 07/21/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Alcohol-related liver disease (ALD) is one of the main indications for liver transplantation (LT). For 20 years, tacrolimus (Tac) is the cornerstone immunosuppressive drug used after LT and is very efficient for the prevention of rejection. Nevertheless, the major drawback of long-term use of Tac is the risk for developing dose-dependent adverse effects. OBJECTIVE The aim of the present study was to assess the impact of Tac exposure (trough concentrations and concentration/dose (C/D) ratio) during the first year after LT, on short- and long-term complications after LT for ALD. METHODS All patients who underwent a LT for ALD at Lyon Edouard Herriot Hospital from October 1990 to September 2010, and who were treated with Tac for at least one year after LT, were analyzed. RESULTS The study population consisted in 251 patients, mean age 53.4 ± 7.3 years, and followed during 11.6 ± 4.8 years. Post-LT complications included severe infectious events (44.6%), malignancies (41.4%), arterial hypertension (49.4%) dyslipidemia (44.2%), diabetes (18.7%) and cardiovascular events (15.5%). De novo hypertension, cardiovascular event, CMV infection, non-melanoma skin cancers and HCC recurrence after transplantation were significantly associated with higher Tac trough blood concentration. In addition, Tac fast-metabolizers (defined as C/D < 1.8) had significantly more impaired renal function at 1, 5, and 10 years and more cardiovascular events, PTLD, diabetes and hypertension than slow-metabolizers. CONCLUSION Our results strongly support that, in addition to blood trough concentrations, Tac metabolism, as estimated by the simple C/D ratio, could be an efficient parameter in daily practice to identify LT patients at risk to develop long term general complications of Tac.
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Affiliation(s)
- Franck-Nicolas Bardou
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Olivier Guillaud
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Domitille Erard-Poinsot
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | | | - Elsa Thimonier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Mélanie Vallin
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France
| | - Olivier Boillot
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France
| | - Jérôme Dumortier
- Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.
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19
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International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients. Transplantation 2019; 102:727-743. [PMID: 29485508 DOI: 10.1097/tp.0000000000002147] [Citation(s) in RCA: 178] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Effective immunosupression management is central to achieving optimal outcomes in liver transplant recipients. Current immunosuppression regimens and agents are highly effective in minimizing graft loss due to acute and chronic rejection but can also produce a substantial array of toxicities. The utilization of immunosuppression varies widely, contributing to the wide disparities in posttransplant outcomes reported between transplant centers. The International Liver Transplantation Society (ILTS) convened a consensus conference, comprised of a global panel of expert hepatologists, transplant surgeons, nephrologists, and pharmacologists to review the literature and experience pertaining to immunosuppression management to develop guidelines on key aspects of immunosuppression. The consensus findings and recommendations of the ILTS Consensus guidelines on immunosuppression in liver transplant recipients are presented in this article.
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20
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Leiskau C, Rajanayagam J, Pfister ED, Goldschmidt I, Junge N, Karch A, Lerch C, Richter N, Lehner F, Schrem H, Baumann U. Side effects and efficacy of renal sparing immunosuppression in pediatric liver transplantation-A single center matched cohort study. Pediatr Transplant 2018; 22:e13207. [PMID: 29729061 DOI: 10.1111/petr.13207] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/31/2018] [Indexed: 11/29/2022]
Abstract
Immunosuppressive combination therapy with MMF can reduce CNI associated nephrotoxicity. We investigated effectiveness and safety of de novo MMF-tacrolimus based immunosuppression after pLTx. Patients after pLTx receiving immunosuppression with MMF/tacrolimus (MMF/TAC) were compared to retrospectively selected age- and diagnosis-matched patients with tacrolimus monotherapy (TAC) and cyclosporine/prednisolone therapy (CSA) (19 patients each, n = 57). Effectiveness, renal function and side effects were analyzed for 1 year after pLTx. Tacrolimus reduction in combination therapy (0.7 μg/L over the year) was lower than aspired (2 μg/L). Acute BPAR occurred equally in MMF/TAC and TAC groups (31.6% each), being slightly higher in CSA group (42.1%; OR = 1.5; 95% CI = 0.42-5.44; P = .5). GFR deteriorated comparably in all 3 groups (P < .01 each) without significant differences between the groups. Septicemia was detected significantly more often in MMF/TAC (73.6%) than in TAC (31.6%) (OR 4.17; 1.07-16.27; P = .04). EBV reactivation occurred more often in CSA patients (84.2%) than in MMF/TAC (47.4%; OR 5.16; 0.98-27.19; P = .05) and TAC patients (52.6%; OR 8.16; 1.48-44.89; P = .02) the same was true for other viral infections (47.4% (CSA) vs 15.8% (TAC); OR 4.21; 0.95-18.55; P = .05). Our study does not provide additional evidence for a benefit of initial use of MMF/TAC over TAC regarding renal function, but raises concerns regarding a potentially increased risk of serious infections under MMF/TAC compared to TAC monotherapy at equivalent renal outcome; our study is, however, limited by the minor CNI reduction in combination therapy.
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Affiliation(s)
- Christoph Leiskau
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Jeremy Rajanayagam
- Department of Gastroenterology and Nutrition, Royal Children's Hospital, Melbourne, Australia
| | - Eva-Doreen Pfister
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Imeke Goldschmidt
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Norman Junge
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - André Karch
- Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Christian Lerch
- Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,Division of Pediatric Nephrology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Nicolas Richter
- General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Frank Lehner
- General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Harald Schrem
- Core Facility Quality Management & Health Technology Assessment in Transplantation, Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany.,General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.,Birmingham Children´s Hospital, Liver Unit and University of Birmingham, Institute of Immunology and Immunotherapy, UK
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21
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Satapathy SK, Joglekar K, Molnar MZ, Ali B, Gonzalez HC, Vanatta JM, Eason JD, Nair SP. Achieving Sustained Virological Response in Liver Transplant Recipients With Hepatitis C Decreases Risk of Decline in Renal Function. Liver Transpl 2018; 24:1040-1049. [PMID: 29573131 DOI: 10.1002/lt.25059] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Revised: 02/28/2018] [Accepted: 03/10/2018] [Indexed: 12/15/2022]
Abstract
The effect of antiviral therapy (AVT) on kidney function in liver transplantation (LT) recipients has not been well described despite known association of hepatitis C virus (HCV) infection with chronic kidney disease (CKD). We compared the incidence of CKD and end-stage renal disease (ESRD) in 204 LT recipients with HCV based on treatment response to AVT. The mean estimated glomerular filtration rate (eGFR) at baseline (3 months after LT) was similar in the sustained virological response (SVR; n = 145) and non-SVR group (n = 59; 69 ± 21 versus 65 ± 33 mL/minute/1.73 m2 ; P = 0.27). In the unadjusted Cox proportional regression analysis, the presence of SVR was associated with an 88% lower risk of CKD (hazard ratio, 0.12; 95% confidence interval [CI], 0.05-0.31) and 86% lower risk of ESRD (odds ratio, 0.14; 95% CI, 0.05-0.35). Similar results were found after adjusting for propensity score and time-dependent Cox regression analyses. The estimated slopes of eGFR based on a 2-stage mixed model of eGFR were calculated. Patients with SVR had a less steep slope in eGFR (-0.60 mL/minute/1.73 m2 /year; 95% CI, -1.50 to 0.30; P = 0.190) than recipients without SVR (-2.53 mL/minute/1.73 m2 /year; 95% CI, -3.99 to -1.07; P = 0.001), and the differences in the slopes were statistically significant (P = 0.026). In conclusion, in LT recipients with chronic HCV infection, achieving SVR significantly lowers the risk of decline in renal function and progression to ESRD independent of the AVT therapy used.
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Affiliation(s)
- Sanjaya K Satapathy
- Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN.,Departments of Surgery, University of Tennessee Health Science Center, Memphis, TN
| | - Kiran Joglekar
- Departments of Medicine, University of Tennessee Health Science Center, Memphis, TN
| | - Miklos Z Molnar
- Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN.,Departments of Surgery, University of Tennessee Health Science Center, Memphis, TN.,Departments of Medicine, University of Tennessee Health Science Center, Memphis, TN.,Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary
| | - Bilal Ali
- Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN.,Departments of Gastroenterology, University of Tennessee Health Science Center, Memphis, TN
| | - Humberto C Gonzalez
- Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN.,Departments of Surgery, University of Tennessee Health Science Center, Memphis, TN
| | - Jason M Vanatta
- Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN.,Departments of Surgery, University of Tennessee Health Science Center, Memphis, TN
| | - James D Eason
- Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN.,Departments of Surgery, University of Tennessee Health Science Center, Memphis, TN
| | - Satheesh P Nair
- Division of Transplant Surgery, Methodist University Hospital Transplant Institute, Memphis, TN.,Departments of Surgery, University of Tennessee Health Science Center, Memphis, TN
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22
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Lower tacrolimus trough levels in the late period after living donor liver transplantation contribute to improvements in long-term clinical outcomes. Hepatobiliary Pancreat Dis Int 2018; 17:204-209. [PMID: 29807766 DOI: 10.1016/j.hbpd.2018.05.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 05/10/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Previous studies have emphasized the need to reduce tacrolimus (TAC) trough levels in the early post-liver transplantation (LT) period. However, whether late-period TAC trough levels influence the long-term outcomes of liver recipients is not clear. METHODS We enrolled 155 adult liver recipients survived more than 3 years after living donor liver transplantation because of non-malignant liver diseases. The maintenance immunosuppressive regimens were TAC monotherapy and combined therapy with mycophenolate mofetil. Patients were divided into three groups according to their late-period TAC trough levels: < 3 ng/mL group, 3-5 ng/mL group, and >5 ng/mL group. The complications and adverse effects of TAC were analyzed. RESULTS Each group showed similar rejection, graft loss and mortality. Patients achieved the < 5 ng/mL state in less than 4 years had fewer new-onset diabetes, hyperlipidemia, de novo malignancies, and hepatitis B virus recurrence; the complications of renal dysfunction and hypertension rates were the same among these 3 groups. CONCLUSIONS Collectively, our findings indicated that lower TAC trough levels in the late period of liver transplantation are safe, improve the long-term outcomes.
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23
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Short- and Long-term Outcomes of De Novo Liver Transplant Patients Treated With Once-Daily Prolonged-Release Tacrolimus. Transplant Direct 2017; 3:e207. [PMID: 28894794 PMCID: PMC5585423 DOI: 10.1097/txd.0000000000000722] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 07/08/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Tacrolimus is the key immunosuppressive drug for liver transplantation. Once-daily prolonged-release tacrolimus (TAC-PR) exhibits good drug adherence but has difficulty controlling the trough level in the early phase of liver transplantation. The aim of this study was to compare the feasibility and efficacy of immediately starting oral TAC-PR versus traditional twice-daily tacrolimus (TAC-BID) in de novo liver transplantation recipients. METHODS The study included 28 patients treated with conventional TAC-BID and 60 patients treated with TAC-PR (median follow-up 70.5 months). Short-term and long-term outcomes were compared. RESULTS Patient characteristics were similar except for the incidence of hepatocellular carcinoma and type of graft. Dose adjustment was more frequently required for TAC-PR than TAC-BID (73.3% vs 42.9%, P = 0.006), but trough levels of TAC during the first 3 months after liver transplantation were controlled well in both groups. The rate of acute cellular rejection and long-term renal function were similar in both groups. In both groups, renal function worsened during the first 6 months after transplantation and remained stable until the end of the follow-up period. The 1-year, 3-year, and 5-year survival rates were 96.4%, 85.7%, and 85.7% for TAC-BID and 96.7%, 94.8%, and 94.8% for TAC-PR, respectively. The overall survival curve for TAC-PR was not inferior to that of TAC-BID. CONCLUSIONS The TAC-PR protocol was feasible and effective with strict adjustment.
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24
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Wong TC, Lo CM, Fung JY. Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation. Expert Opin Emerg Drugs 2017; 22:123-136. [PMID: 28503959 DOI: 10.1080/14728214.2017.1330884] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection. Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored. Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.
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Affiliation(s)
- Tiffany Cl Wong
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - Chung-Mau Lo
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
| | - James Yy Fung
- a Department of Surgery, Department of Medicine , Queen Mary Hospital, The University of Hong Kong , Hong Kong , Hong Kong S.A.R
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Abstract
BACKGROUND The use of calcineurin inhibitor (CNI)-based immunosuppressive regimens following liver transplantation (LTx) has improved the outcomes of the recipients. However, CNI has nephrotoxicity and causes short- and long-term renal complications. The progressive structural changes can be irreversible in the long-term, leading to chronic kidney dysfunction. The present review was to evaluate the different strategies of CNI application to renal function in liver recipients. DATA SOURCES PubMed database was searched for relevant articles in English on the issue of immunosuppressive regimen and kidney injury that related to early minimization of CNI after LTx. RESULTS Total avoidance of CNI from post-LTx immunosuppressive regimens has been associated with unacceptable high rates of acute, steroid resistant rejections; late conversion from CNI to non-nephrotoxic immunosuppressant failed to recover renal function. Early CNI minimization and conversion to non-nephrotoxic immunosuppressant, although had no effect on patient survival rates, improved glomerular filtration rate. The combination of everolimus (a mammalian target of rapamycin inhibitor) and tacrolimus not only maintains immunosuppressive efficacy but also minimizes kidney injury. CONCLUSIONS Up to now, protocols entirely avoiding CNI have not passed the primary safety endpoint of patient and graft survival, as well as the FDA mandated endpoint of biopsy proven acute rejection. Thus, early CNI minimization after LTx is the most rational approach preserving post-transplant renal function.
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Gastaca M, Valdivieso A, Bustamante J, Fernández JR, Ruiz P, Ventoso A, Testillano M, Palomares I, Salvador P, Prieto M, Montejo M, Suárez MJ, de Urbina JO. Favorable longterm outcomes of liver transplant recipients treated de novo with once-daily tacrolimus: Results of a single-center cohort. Liver Transpl 2016; 22:1391-400. [PMID: 27434676 DOI: 10.1002/lt.24514] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 05/31/2016] [Accepted: 06/21/2016] [Indexed: 12/15/2022]
Abstract
The once-daily prolonged-release formulation of tacrolimus has been recently related with significant graft and patient mid-term survival advantages; however, practical information on the de novo administration after liver transplantation and longterm outcomes is currently lacking. This study is a 5-year retrospective analysis of a single-center cohort of liver transplant recipients treated de novo with once-daily tacrolimus (April 2008/August 2011). The study cohort consisted of 160 patients, including 23 with pretransplant renal dysfunction, with a median follow-up of 57.6 months (interquartile range, 46.6-69.0). Tacrolimus target trough levels were 5-10 ng/mL during the first 3 months after transplant, reducing progressively to <7 ng/mL after the first posttransplant year. Once-daily tacrolimus was withdrawn in 35 (21.8%) patients during follow-up, mostly due to renal dysfunction and/or metabolic syndrome. The biopsy-proven acute rejection rate was 12.5% with no cases of steroid-resistant rejection. The cumulative incidence of de novo diabetes, hypertension, and dyslipidemia were 16.9%, 31.2%, and 6.5%, respectively. Hepatocellular carcinoma recurrence rate was 2.8%. Renal function remained stable after the sixth month after transplant with a mean estimated glomerular filtration rate of 77.7 ± 19.6 mL/minute/1.73 m(2) at 5 years. None of our patients developed chronic kidney disease stage 4 or 5. Patient survival at 1, 3, and 5 years was 96.3%, 91.9%, and 88.3%, respectively. Overall survival of patients with Model for End-Stage Liver Disease (MELD) score > 25 points was not significantly different. In conclusion, our study suggests that immunosuppression based on de novo once-daily tacrolimus is feasible in routine clinical practice, showing favorable outcomes and outstanding longterm survival even in patients with high MELD scores. Liver Transplantation 22 1391-1400 2016 AASLD.
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Affiliation(s)
- Mikel Gastaca
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Bilbao, Spain. .,University of the Basque Country, Leioa, Spain.
| | - Andrés Valdivieso
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Bilbao, Spain.,University of the Basque Country, Leioa, Spain
| | - Javier Bustamante
- Liver Diseases Unit, Cruces University Hospital, Bilbao, Spain.,University of the Basque Country, Leioa, Spain
| | | | - Patricia Ruiz
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Bilbao, Spain
| | - Alberto Ventoso
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Bilbao, Spain
| | | | - Ibone Palomares
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Bilbao, Spain
| | | | - Mikel Prieto
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Bilbao, Spain
| | - Miguel Montejo
- Infectious Diseases Unit, Cruces University Hospital, Bilbao, Spain.,University of the Basque Country, Leioa, Spain
| | - María J Suárez
- Liver Diseases Unit, Cruces University Hospital, Bilbao, Spain
| | - Jorge Ortiz de Urbina
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Bilbao, Spain
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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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28
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Inoue Y, Soyama A, Takatsuki M, Hidaka M, Kinoshita A, Natsuda K, Baimakhanov Z, Kugiyama T, Adachi T, Kitasato A, Kuroki T, Eguchi S. Does the development of chronic kidney disease and acute kidney injury affect the prognosis after living donor liver transplantation? Clin Transplant 2016; 30:518-27. [PMID: 26865166 DOI: 10.1111/ctr.12715] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2016] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND AIMS Chronic kidney disease (CKD) and acute kidney injury (AKI) have been discussed as complications following living donor liver transplantation (LDLT). The aim of this study was to clarify the relationships among CKD, AKI, and the prognosis after LDLT. METHODS This study included 118 patients who underwent LDLT in our department. A low eGFR (<60 mL/min/1.73 m(2) ) was regarded to indicate CKD. AKI 1 and AKI 2 were characterized by an increase in the serum creatinine level of 0.5 and 1.0 mg/dL, respectively, within one wk after LDLT. We investigated the risk factors for and the relevance of CKD and AKI on the prognosis. RESULTS AKI 1 was associated with sepsis and intra-operative bleeding (p = 0.0032, p = 0.001). AKI 2 was associated with sepsis and hepatitis C infection (p < 0.001, p = 0.027). A pre-operative eGFR of 60-89 and diabetes were the risk factors for the development of CKD in POY 2 (p = 0.018, p = 0.002). AKI 2, sepsis, and diabetes were the risk factors for the patient death within one yr after LDLT (p = 0.010, p = 0.002, p = 0.022). AKI 2 and sepsis were the risk factors for death within two yr after LDLT (p = 0.005, p = 0.018). CONCLUSIONS Recognizing the risk factors and careful management for preventing both AKI and CKD may improve the prognosis of patients following LDLT.
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Affiliation(s)
- Yusuke Inoue
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Ayaka Kinoshita
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Koji Natsuda
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Zhassulan Baimakhanov
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tota Kugiyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Amane Kitasato
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tamotsu Kuroki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Song JL, Gao W, Zhong Y, Yan LN, Yang JY, Wen TF, Li B, Wang WT, Wu H, Xu MQ, Chen ZY, Wei YG, Jiang L, Yang J. Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation. World J Gastroenterol 2016; 22:2133-2141. [PMID: 26877618 PMCID: PMC4726686 DOI: 10.3748/wjg.v22.i6.2133] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 10/26/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the impact of minimum tacrolimus (TAC) on new-onset diabetes mellitus (NODM) after liver transplantation (LT).
METHODS: We retrospectively analyzed the data of 973 liver transplant recipients between March 1999 and September 2014 in West China Hospital Liver Transplantation Center. Following the exclusion of ineligible recipients, 528 recipients with a TAC-dominant regimen were included in our study. We calculated and determined the mean trough concentration of TAC (cTAC) in the year of diabetes diagnosis in NODM recipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value for predicting NODM 6 mo after LT was identified using a receptor operating characteristic curve. TAC-related complications after LT was evaluated by χ2 test, and the overall and allograft survival was evaluated using the Kaplan-Meier method. Risk factors for NODM after LT were examined by univariate and multivariate Cox regression.
RESULTS: Of the 528 transplant recipients, 131 (24.8%) developed NODM after 6 mo after LT, and the cumulative incidence of NODM progressively increased. The mean cTAC of NODM group recipients was significantly higher than that of recipients in the non-NODM group (7.66 ± 3.41 ng/mL vs 4.47 ± 2.22 ng/mL, P < 0.05). Furthermore, NODM group recipients had lower 1-, 5-, 10-year overall survival rates (86.7%, 71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P < 0.05) and allograft survival rates (92.8%, 84.6%, and 75.7% vs 96.1%, 91%, and 86.1%, P < 0.05) than the others. The best cutoff of mean cTAC for predicting NODM was 5.89 ng/mL after 6 mo after LT. Multivariate analysis showed that old age at the time of LT (> 50 years), hypertension pre-LT, and high mean cTAC (≥ 5.89 ng/mL) after 6 mo after LT were independent risk factors for developing NODM. Concurrently, recipients with a low cTAC (< 5.89 ng/mL) were less likely to become obese (21.3% vs 30.2%, P < 0.05) or to develop dyslipidemia (27.5% vs 44.8%, P <0.05), chronic kidney dysfunction (14.6% vs 22.7%, P < 0.05), and moderate to severe infection (24.7% vs 33.1%, P < 0.05) after LT than recipients in the high mean cTAC group. However, the two groups showed no significant difference in the incidence of acute and chronic rejection, hypertension, cardiovascular events and new-onset malignancy.
CONCLUSION: A minimal TAC regimen can decrease the risk of long-term NODM after LT. Maintaining a cTAC value below 5.89 ng/mL after LT is safe and beneficial.
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30
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Milongo D, Bascands JL, Huart A, Esposito L, Breuil B, Moulos P, Siwy J, Ramírez-Torres A, Ribes D, Lavayssière L, Del Bello A, Muscari F, Alric L, Bureau C, Rostaing L, Schanstra JP, Kamar N. Pretransplant urinary proteome analysis does not predict development of chronic kidney disease after liver transplantation. Liver Int 2015; 35:1893-901. [PMID: 25515948 DOI: 10.1111/liv.12763] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 12/10/2014] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Chronic kidney disease (CKD) is a common complication after liver transplantation. Kidney biopsies cannot be easily performed before liver transplantation to predict patients at high risk for CKD. The aim of our study was to determine whether pre-, peri- and post-transplant factors, as well as peptides present in preliver transplant urine samples were associated with loss in kidney function at 6 months post-transplantation using proteome analysis. METHODS Eighty patients who underwent a liver transplantation and that had pretransplant glomerular filtration rate (GFR) value of ≥60 mL/min/1.73 m² (MDRD) were included in the study. RESULTS GFR decreased significantly after transplantation. At month 6 post-transplantation, 40 patients displayed a CKD, i.e. eGFR of <60 mL/min/1.73 m², while the other 40 patients did not. Although thousands of peptides were identified, none was significantly associated with the development of CKD at 6 months after liver transplantation. Moreover, using a urinary peptidome classifier to detect preexisting CKD, no difference was found in CKD scores between the 2 groups. After analysis of a large number of pre-, peri- and post-transplant parameters, viral hepatitis as a cause for liver transplantation was the sole independent predictive factor for CKD. No difference in peptides with differential urinary abundance between patients who received a graft for virus related liver disease vs. all other causes of liver disease was observed. CONCLUSION Urinary peptidome analysis before liver transplantation failed to identify a peptide pattern associated with the development of CKD at 6 months after liver transplantation.
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Affiliation(s)
- David Milongo
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Jean-Loup Bascands
- U1048, Institut of Cardiovascular and Metabolic Disease, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Antoine Huart
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Laure Esposito
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Benjamin Breuil
- U1048, Institut of Cardiovascular and Metabolic Disease, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Institut of Cardiovascular and Metabolic Disease, Plateau de Protéomique des Liquides Biologiques, Toulouse, France
| | | | - Justyna Siwy
- Mosaiques Diagnostics GmbH, Hannover, Germany.,Charite-Universitatsmedizin Berlin, Berlin, Germany
| | | | - David Ribes
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Laurence Lavayssière
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Fabrice Muscari
- Université Toulouse III Paul-Sabatier, Toulouse, France.,Department of Surgery and Liver Transplantation, Toulouse, France
| | - Laurent Alric
- Internal Medecine-Digestive Department, CHU Purpan, Toulouse, France.,UMR 152, IRD, Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Christophe Bureau
- Université Toulouse III Paul-Sabatier, Toulouse, France.,Department of Hepatology, Federation Digestive, CHU Purpan, Toulouse, France
| | - Lionel Rostaing
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France.,IFR-BMT, INSERM U1043, CHU Purpan, Toulouse, France
| | - Joost P Schanstra
- U1048, Institut of Cardiovascular and Metabolic Disease, Institut National de la Santé et de la Recherche Médicale (INSERM), Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,Université Toulouse III Paul-Sabatier, Toulouse, France.,IFR-BMT, INSERM U1043, CHU Purpan, Toulouse, France
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Adams DH, Sanchez-Fueyo A, Samuel D. From immunosuppression to tolerance. J Hepatol 2015; 62:S170-85. [PMID: 25920086 DOI: 10.1016/j.jhep.2015.02.042] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 02/25/2015] [Accepted: 02/28/2015] [Indexed: 12/14/2022]
Abstract
The past three decades have seen liver transplantation becoming a major therapeutic approach in the management of end-stage liver diseases. This is due to the dramatic improvement in survival after liver transplantation as a consequence of the improvement of surgical and anaesthetic techniques, of post-transplant medico-surgical management and of prevention of disease recurrence and other post-transplant complications. Improved use of post-transplant immunosuppression to prevent acute and chronic rejection is a major factor in these improved results. The liver has been shown to be more tolerogenic than other organs, and matching of donor and recipients is mainly limited to ABO blood group compatibility. However, long-term immunosuppression is required to avoid severe acute and chronic rejection and graft loss. With the current immunosuppression protocols, the risk of acute rejection requiring additional therapy is 10-40% and the risk of chronic rejection is below 5%. However, the development of histological lesions in the graft in long-term survivors suggest atypical forms of graft rejection may develop as a consequence of under-immunosuppression. The backbone of immunosuppression remains calcineurin inhibitors (CNI) mostly in association with steroids in the short-term and mycophenolate mofetil or mTOR inhibitors (everolimus). The occurrence of post-transplant complications related to the immunosuppressive therapy has led to the development of new protocols aimed at protecting renal function and preventing the development of de novo cancer and of dysmetabolic syndrome. However, there is no new class of immunosuppressive drugs in the pipeline able to replace current protocols in the near future. The aim of a full immune tolerance of the graft is rarely achieved since only 20% of selected patients can be weaned successfully off immunosuppression. In the future, immunosuppression will probably be more case oriented aiming to protect the graft from rejection and at reducing the risk of disease recurrence and complications related to immunosuppressive therapy. Such approaches will include strategies aiming to promote stable long-term immunological tolerance of the liver graft.
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Affiliation(s)
- David H Adams
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, University of Birmingham and Queen Elizabeth Hospital, Edgbaston Birmingham B152TT, United Kingdom
| | - Alberto Sanchez-Fueyo
- Institute of Liver Studies, MRC Centre for Transplantation, King's College London, London SE5 9RS, United Kingdom
| | - Didier Samuel
- AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire; Inserm, Research Unit 1193; Université Paris-Sud, Villejuif F-94800, France.
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Detección precoz, prevención y manejo de la insuficiencia renal en el trasplante hepático. GASTROENTEROLOGIA Y HEPATOLOGIA 2014; 37:480-91. [DOI: 10.1016/j.gastrohep.2013.11.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 11/06/2013] [Accepted: 11/12/2013] [Indexed: 12/19/2022]
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Jia JJ, Lin BY, He JJ, Geng L, Kadel D, Wang L, Yu DD, Shen T, Yang Z, Ye YF, Zhou L, Zheng SS. ''Minimizing tacrolimus'' strategy and long-term survival after liver transplantation. World J Gastroenterol 2014; 20:11363-11369. [PMID: 25170223 PMCID: PMC4145777 DOI: 10.3748/wjg.v20.i32.11363] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Revised: 03/20/2014] [Accepted: 04/23/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the effect of the ‘‘minimizing tacrolimus’’ strategy on long-term survival of patients after liver transplantation (LT).
METHODS: We conducted a retrospective study of 319 patients who received LT between January 2009 and December 2011 at the First Affiliated Hospital of Zhejiang University School of Medicine. Following elimination of ineligible patients, 235 patients were included in the study. The relationship between early tacrolimus (TAC) exposure and survival period was analyzed by Kaplan Meier curves. Adverse effects related to TAC were evaluated by the χ2 test. Routine monitoring of blood TAC concentration (TC) was performed using the PRO-TracTM II Tacrolimus Elisa Kit (Diasorin, United States).
RESULTS: Of 235 subjects enrolled in the study, 124 (52.8%) experienced adverse effects due to TAC. When evaluating mean TC, the survival time of patients with a mean TC < 5 ng/mL was significantly shorter than that in the other groups (911.3 ± 131.6 d vs 1381.1 ± 66.1 d, 911.3 ± 131.6 d vs 1327.3 ± 47.8 d, 911.3 ± 131.6 d vs 1343.2 ± 83.1 d, P < 0.05), while the survival times of patients with a mean TC of 5-7, 7-10 and 10-15 ng/mL were comparable. Adverse effects due to TAC in all four groups were not significantly different. When comparing the standard deviation (SD) of TC among the groups, the survival time of patients with a SD of 2-4 was significantly longer than that in the other groups (1388.8 ± 45.4 d vs 1029.6 ± 131.3 d, 1388.8 ± 45.4 d vs 1274.9 ± 57.0 d, P < 0.05), while in patients with a SD < 2 and SD > 4, the survival time was not statistically different. Adverse effects experienced in all three groups were not statistically different. In Cox regression analysis, male patients and those with a primary diagnosis of benign disease, mean TC > 5 ng/mL and TC SD 2-4 had better outcomes.
CONCLUSION: The early ‘‘minimizing tacrolimus’’ strategy with a mean TC of 5-10 ng/mL and SD of 2-4 was beneficial in terms of long-term survival after LT.
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Kuramitsu K, Fukumoto T, Iwasaki T, Tominaga M, Matsumoto I, Ajiki T, Ku Y. Long-term Complications After Liver Transplantation. Transplant Proc 2014; 46:797-803. [DOI: 10.1016/j.transproceed.2013.11.047] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 11/05/2013] [Indexed: 12/11/2022]
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35
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Utsumi M, Umeda Y, Sadamori H, Nagasaka T, Takaki A, Matsuda H, Shinoura S, Yoshida R, Nobuoka D, Satoh D, Fuji T, Yagi T, Fujiwara T. Risk factors for acute renal injury in living donor liver transplantation: evaluation of the RIFLE criteria. Transpl Int 2014; 26:842-52. [PMID: 23855657 DOI: 10.1111/tri.12138] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Revised: 02/25/2013] [Accepted: 06/10/2013] [Indexed: 12/16/2022]
Abstract
Acute renal injury (ARI) is a serious complication after liver transplantation. This study investigated the usefulness of the RIFLE criteria in living donor liver transplantation (LDLT) and the prognostic impact of ARI after LDLT. We analyzed 200 consecutive adult LDLT patients, categorized as risk (R), injury (I), or failure (F), according to the RIFLE criteria. ARI occurred in 60.5% of patients: R-class, 23.5%; I-class, 21%; and F-class, 16%. Four patients in Group-A (normal renal function and R-class) and 26 patients in Group-B (severe ARI: I- and F-class) required renal replacement therapy (P < 0.001). Mild ARI did not affect postoperative prognosis regarding hospital mortality rate in Group A (3.2%), which was superior to that in Group B (15.8%; P = 0.0015). Fourteen patients in Group B developed chronic kidney disease (KDIGO stage 3/4). The 1-, 5- and 10-year survival rates were 96.7%, 90.6%, and 88.1% for Group A and 71.1%, 65.9%, and 59.3% for Group B, respectively (P < 0.0001). Multivariate analysis revealed risk factors for severe ARI as MELD ≥ 20 [odds ratio (OR) 2.9], small-for-size graft (GW/RBW <0.7%; OR 3.1), blood loss/body weight >55 ml/kg (OR 3.7), overexposure to calcineurin inhibitor (OR 2.5), and preoperative diabetes mellitus (OR 3.2). The RIFLE criteria offer a useful predictive tool after LDLT. Severe ARI, defined beyond class-I, could have negative prognostic impact in the acute and late postoperative phases. Perioperative treatment strategies should be designed and balanced based on the risk factors for the further improvement of transplant prognosis.
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Affiliation(s)
- Masashi Utsumi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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Blé M, Aguilera V, Rubín A, García-Eliz M, Vinaixa C, Prieto M, Berenguer M. Improved renal function in liver transplant recipients treated for hepatitis C virus with a sustained virological response and mild chronic kidney disease. Liver Transpl 2014; 20:25-34. [PMID: 24115296 DOI: 10.1002/lt.23756] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Accepted: 09/11/2013] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) is associated with renal complications. We aimed to determine whether a sustained virological response (SVR) was associated with improvements in renal function (RF) in liver transplant (LT) recipients treated for HCV. Changes in RF were compared 1, 3, and 5 years after therapy as a function of the stage of chronic kidney disease (CKD) before treatment (BT). Variables associated with renal dysfunction [RD; 4-variable Modification of Diet in Renal Disease (MDRD-4) value 60 mL/minute] at the last follow-up (LFU) were evaluated for all treated LT patients with a minimum follow-up of at least 1 year since the end of treatment (EOT; n = 175). There were 99 patients with stage 2 CKD BT (MDRD-4 value 60-89 mL/minute/1.73 m(2) ), and an improvement in RF was observed more frequently among SVR patients versus nonresponders (NRs). The median changes in the MDRD-4 values BT to 1, 3, and 5 years after treatment were -0.5, 4.5, and 9.4 mL/minute for the SVR patients and -1, -0.3, and -1.5 mL/minute for the NRs (P = 0.61, P = 0.06, and P = 0.004, respectively). RD was present in 31% of the patients at the LFU at a median of 3.8 years after EOT (range 1-9 years). The follow-up did not differ between SVR patients and NRs. RD was present at the LFU in 19% of SVR patients versus 40% of NRs (P = 0.002). In the multivariate analysis, RD at the LFU was associated with NRs [relative risk (RR) 3.8, 95% confidence interval (CI) = 1.3-11.23, P = 0.01], EOT MDRD-4 values (RR = 1.022, 95% CI = 1.001-1.04, P = 0.04), and female sex (RR = 5.6, 95% CI = 1.84-17.5, P = 0.002). In conclusion, SVR leads to improved RF in HCV-infected LT recipients with stage 2 CKD BT.
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Affiliation(s)
- Michel Blé
- Liver Transplantation and Hepatology Unit, La Fe Hospital, Valencia, Spain; Network Center for Biomedical Research in Hepatic and Digestive Diseases, Spain
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Kelly DA, Bucuvalas JC, Alonso EM, Karpen SJ, Allen U, Green M, Farmer D, Shemesh E, McDonald RA. Long-term medical management of the pediatric patient after liver transplantation: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl 2013; 19:798-825. [PMID: 23836431 DOI: 10.1002/lt.23697] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2013] [Accepted: 06/15/2013] [Indexed: 12/15/2022]
Affiliation(s)
- Deirdre A Kelly
- Liver Unit, Birmingham Children's Hospital, National Health Service Trust, Birmingham, United Kingdom.
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Boyer O, Noto C, De Serre NPM, Gubler MC, Dechaux M, Goulet O, Niaudet P, Lacaille F. Renal function and histology in children after small bowel transplantation. Pediatr Transplant 2013; 17:65-72. [PMID: 22882667 DOI: 10.1111/j.1399-3046.2012.01767.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
CKD is a frequent long-term complication after SBTx. CNIs are a well-known factor, but probably not the only cause. We assessed the incidence, risk factors, and severity of CKD in 27 children with SBTx (15 combined liver/SBTx) and prednisone/TAC-based maintenance immunosuppression. Median follow-up was seven yr (3-21). A renal biopsy was performed in 14 patients, 1-18 yr post-SBTx. A reduced GFR was observed in 17 children (63%) during the follow-up with none requiring dialysis. CNI toxicity was observed in 11/14 biopsies, as early as two yr post-transplant, and could occur with a normal mGFR. The dose of TAC was reduced by 50% in 13 patients with CKD and/or significant kidney histological lesions, and six were also given MMF. This led to a significant improvement in renal function: mGFR normalized in eight patients and improved or stabilized in five. No rejection occurred. At last follow-up, 37% had CKD stage 2 and 15% had CKD stage 3. In conclusion, CKD is frequent in children after SBTx and probably multifactorial. Less nephrotoxic immunosuppressive protocols may improve mGFR and should be further considered. The kidney histology helps in designing personalized immunosuppression strategies for patients.
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Affiliation(s)
- Olivia Boyer
- Pediatric Nephrology Unit, Reference Center for Hereditary Renal Diseases in Children and Adolescent (MARHEA), Paris, France
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Rodríguez-Perálvarez M, Germani G, Darius T, Lerut J, Tsochatzis E, Burroughs AK. Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2012; 12:2797-814. [PMID: 22703529 DOI: 10.1111/j.1600-6143.2012.04140.x] [Citation(s) in RCA: 128] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
We hypothesized that current trough concentrations of tacrolimus after liver transplantation are set too high, considering that clinical consequences of rejection are not severe while side effects are increased.We systematically reviewed 64 studies (32 randomized controlled trials and 32 observational studies) to determine how lower tacrolimus trough concentrations than currently recommended affect acute rejection rates and renal impairment. Among randomized trials the mean of tacrolimus trough concentration during the first month was positively correlated with renal impairment within 1 year (r = 0.73; p = 0.003), but not with acute rejection, either defined using protocol biopsies (r = -0.37; p = 0.32) or not (r = 0.11; p = 0.49). A meta-analysis of randomized trials directly comparing tacrolimus trough concentrations (five trials for acute rejection [n = 957] and two trials for renal impairment [n = 712]) showed that "reduced tacrolimus" trough concentrations (<10 ng/mL) within the first month after liver transplantation were associated with less renal impairment at 1 year (RR = 0.51 [0.38-0.69]), with no significant influence on acute rejection (RR = 0.92 [0.65-1.31]) compared to "conventional tacrolimus" trough levels (>10 ng/mL). Lower trough concentrations of tacrolimus (6-10 ng/mL during the first month) would be more appropriate after liver transplantation. Regulatory authorities and the pharmaceutical industry should allow changes of regulatory drug information.
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Affiliation(s)
- M Rodríguez-Perálvarez
- The Royal Free Sheila Sherlock Liver Centre and University Department of Surgery, UCL, and Royal Free Hospital, Pond Street, London, UK
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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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Abstract
BACKGROUND Increased blood pressure (BP) is common after liver transplantation. However, there is scarce information on its control. METHODS In this prospective, cross-sectional, multicenter study, we determined BP according to the recommended international standards in 921 liver transplant patients during one routine outpatient visit to assess their grade of control of BP. At the time of the study, 490 patients had been previously diagnosed with arterial hypertension and were receiving antihypertensive treatment, and 431 were not previously diagnosed as hypertensive. RESULTS In the hypertensive group, arterial hypertension was uncontrolled (BP >140/90 mm Hg [>130/80 in diabetics]) in 158 (32%) patients and controlled in 332 (68%) patients. In a multivariate analysis, only diabetes was identified as a significant predictor of uncontrolled hypertension. Among patients not previously diagnosed as hypertensive, BP was increased in 106 (25%) and normal in 325 (75%). On multivariate analysis, the only variable independently associated with increased BP in this group was metabolic syndrome. CONCLUSION BP is not adequately controlled in a noticeable percentage of liver transplant patients, especially in subjects with diabetes or metabolic syndrome.
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Kamar N, Maaroufi C, Guilbeau-Frugier C, Servais A, Meas-Yedid V, Tack I, Thervet E, Cointault O, Esposito L, Guitard J, Lavayssière L, Panterne C, Muscari F, Bureau C, Rostaing L. Do kidney histology lesions predict long-term kidney function after liver transplantation? Clin Transplant 2012; 26:927-34. [PMID: 22774805 DOI: 10.1111/j.1399-0012.2012.01682.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2012] [Indexed: 11/29/2022]
Abstract
Histological renal lesions observed after liver transplantation are complex, multifactorial, and interrelated. The aims of this study were to determine whether kidney lesions observed at five yr after liver transplantation can predict long-term kidney function. Ninety-nine liver transplant patients receiving calcineurin inhibitor (CNI)-based immunosuppression, who had undergone a kidney biopsy at 60±48 months post-transplant, were included in this follow-up study. Kidney biopsies were scored according to the Banff classification. Estimated glomerular filtration rate (eGFR) was assessed at last follow-up, that is, 109±48 months after liver transplantation. eGFR decreased from 92±33 mL/min at transplantation to 63±19 mL/min after six months, to 57±17 mL/min at the kidney biopsy, to 54±24 mL/min at last follow-up (p<0.0001). At last follow-up, only three patients required renal replacement therapy. After the kidney biopsy, 13 patients were converted from CNIs to mammalian target of rapamycin inhibitors, but no significant improvement in eGFR was observed after conversion. Elevated eGFR at six months post-transplant and a lower fibrous intimal thickening score (cv) observed at five yr post-transplant were the two independent predictive factors for eGFR≥60 mL/min at nine yr post-transplant. Long-term kidney function seems to be predicted by the kidney vascular lesions.
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Affiliation(s)
- Nassim Kamar
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, Toulouse, France.
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Prokai A, Fekete A, Pasti K, Rusai K, Banki NF, Reusz G, Szabo AJ. The importance of different immunosuppressive regimens in the development of posttransplant diabetes mellitus. Pediatr Diabetes 2012; 13:81-91. [PMID: 21595806 DOI: 10.1111/j.1399-5448.2011.00782.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Solid-organ transplantation is the optimal long-term treatment for most patients with end-stage organ failure. After solid-organ transplantation, short-term graft survival significantly improved (1). However, due to chronic allograft nephropathy and death with functioning graft, long-term survival has not prolonged remarkably (2). Posttransplant immunosuppressive medications consist of one of the calcineurin inhibitors in combination with mycophenolate mofetil (MMF) or azathioprine (Aza) and steroids. All of them have different adverse effects, among which posttransplant diabetes mellitus (PTDM) is an independent risk factor for cardiovascular (CV) events and infections causing the death of many transplant patients and it may directly contribute to graft failure (3). According to the criteria of the American Diabetes Association (4), diabetes mellitus (DM) is defined by symptoms of diabetes (polyuria and polydipsia and weight loss) plus casual plasma glucose concentration ≥ 11.1 mmol/L or fasting plasma glucose (FPG) ≥ 7.0 mmol/L or 2-h plasma glucose level ≥ 11.1 mmol/L following oral glucose tolerance test (OGTT). This metabolic disorder occurring as a complication of organ transplantation has been recognized for many years. PTDM, which is a combination of decreased insulin secretion and increased insulin resistance, develops in 4.9/15.9% of liver transplant patients, in 4.7/11.5% of kidney recipients, and in 15/17.5% of heart and lung transplants [cyclosporine A (CyA)/tacrolimus (Tac)-based regimen, respectively] (5). Risk factors of PTDM can be divided into non-modifiable and modifiable ones (6), among which the most prominent is the immunosuppressive therapy being responsible for 74% of PTDM development (7). Emphasizing the importance of the PTDM, numerous studies have determined the long-term outcome. On the basis of these studies, graft and patient survival is tendentiously (8) or significantly (9, 10) decreased for those developing PTDM.
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Affiliation(s)
- A Prokai
- 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary
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Mycophenolate mofetil monotherapy in liver transplantation: 5-year follow-up of a prospective randomized trial. Transplantation 2011; 92:923-9. [PMID: 21832958 DOI: 10.1097/tp.0b013e31822d880d] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Calcineurin inhibitors (CNIs) play the key role in immunosuppressive protocols yet are often associated with numerous side effects. Renal insufficiency, hypertension, hyperglycemia, and increased risk of secondary malignancy are major problems in short- and long-term follow-up of liver transplant patients. Mycophenolate mofetil (MMF) has proved to be a potent immunosuppressive agent free of the CNI-associated side effects. PATIENTS AND METHODS One hundred fifty patients who received liver transplantation at our institution (1998-2003) were prospectively randomized: 75 patients continued CNI standard therapy, 75 patients were switched to MMF monotherapy, and follow-up was 5 years. Incidence of rejection, renal complication, cardiovascular, neurological and gastrointestinal adverse effects, and diabetes and malignancy development was recorded. Graft biopsies were performed every 2 to 3 years. RESULTS No significant difference regarding the incidence of acute rejection was detected. A trend to higher rejection frequency was apparent in the MMF monotherapy group. Chronic rejection was absent; organ and patient survival were identical in the two groups. No significant difference occurred concerning the incidence of cardiovascular, gastrointestinal or neurological adverse effects, or the development of malignancies. Renal function improved significantly in patients with renal insufficiency when patients treated with CNI were switched to MMF monotherapy. CONCLUSION MMF monotherapy may serve as safe long-term immunosuppression after liver transplantation for a subgroup of patients. Especially for patients with renal insufficiency MMF offers immunosuppression without the risk of nephrotoxicity.
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Tsapenko M, El-Zoghby ZM, Sethi S. Renal histological lesions and outcome in liver transplant recipients. Clin Transplant 2011; 26:E48-54. [DOI: 10.1111/j.1399-0012.2011.01542.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Saliba F, Dharancy S, Lorho R, Conti F, Radenne S, Neau-Cransac M, Hurtova M, Hardwigsen J, Calmus Y, Dumortier J. Conversion to everolimus in maintenance liver transplant patients: a multicenter, retrospective analysis. Liver Transpl 2011; 17:905-13. [PMID: 21384525 DOI: 10.1002/lt.22292] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Data on the conversion of patients to everolimus after liver transplantation are sparse. A multicenter, retrospective study followed 240 maintenance liver transplant patients to analyze the current indications for everolimus conversion, the employed regimens and exposure levels, and the impact on efficacy and safety. The mean time from transplantation to the introduction of everolimus was 4.9 ± 5.2 years. The mean everolimus trough level was 7.3 ± 4.1 ng/mL at month 1 and 8.1 ± 4.7 ng/mL at month 12. At 12 months, 61.6% of the patients were no longer receiving calcineurin inhibitor (CNI) therapy. The mean estimated glomerular filtration rate (eGFR) according to the Cockcroft-Gault formula was 64.2 ± 30.0 mL/minute on day 0 and 68.4 ± 32.5 mL/minute at month 12 (P = 0.007). Among patients with baseline serum creatinine levels ≥ 130 μmol/L, the eGFR values were 44.3 ± 15.7 mL/minute on day 0 and 53.7 ± 26.0 mL/minute at month 12 (P = 0.003). Four patients (1.6%) developed mild or moderate biopsy-proven acute rejection. Adverse events led to everolimus discontinuation in 12.9% of the patients. After the initiation of everolimus, the mean white blood cell count decreased significantly, and the total cholesterol and triglyceride levels increased significantly. In this retrospective analysis of the largest cohort of maintenance liver transplant patients analyzed after their conversion to everolimus, more than 60% of the patients were kept free of CNIs with a very low risk of acute rejection and with an acceptable safety profile. Randomized trials in which maintenance liver transplant patients are switched to everolimus in response to clinical indications or preemptively are warranted.
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Affiliation(s)
- Faouzi Saliba
- Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris-Sud, Villejuif, France.
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Evidence for the immunosuppressive potential of calcineurin inhibitor-sparing regimens in liver transplant recipients with impaired renal function. J Transplant 2011; 2011:483728. [PMID: 21785695 PMCID: PMC3139187 DOI: 10.1155/2011/483728] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 05/09/2011] [Indexed: 12/19/2022] Open
Abstract
Patients requiring liver transplantation (LT) frequently experience renal insufficiency (RI), which affects their survival. Although calcineurin inhibitor-sparing immunosuppressive regimens (CSRs) are well known to prevent RI, the immune state in recipients receiving CSR remains to be intensively investigated. Among 60 cases of living-donor LT at our institute, 68% of the patients had none to mild RI (non-RI group) and 32% of the patients had moderate to severe RI (RI group). The RI group received a CSR comprising reduced dose of tacrolimus, methylprednisolone, and mycophenolate mofetil, while the non-RI group received a regimen comprising conventional dose of tacrolimus and methylprednisolone. One year after LT, the mean estimated glomerular filtration rate (eGFR) in the RI group had significantly improved, although it was still lower than that of the non-RI group. Serial mixed lymphocyte reaction assays revealed that antidonor T-cell responses were adequately suppressed in both groups. Thus, we provide evidence that CSR leads to improvement of eGFR after LT in patients with RI, while maintaining an appropriate immunosuppressive state.
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Kamar N, Guilbeau-Frugier C, Servais A, Tack I, Thervet E, Cointault O, Esposito L, Guitard J, Lavayssiere L, Muscari F, Bureau C, Rostaing L. Kidney histology and function in liver transplant patients. Nephrol Dial Transplant 2011; 26:2355-2361. [DOI: 10.1093/ndt/gfq718] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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One thousand consecutive primary liver transplants under tacrolimus immunosuppression: a 17- to 20-year longitudinal follow-up. Transplantation 2011; 91:1025-30. [PMID: 21378604 DOI: 10.1097/tp.0b013e3182129215] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Tacrolimus has proven to be a potent immunosuppressive agent in orthotopic liver transplantation (OLT). The aim of this study is to examine its long-term efficacy and safety. METHODS AND RESULTS One thousand consecutive primary OLTs performed between August 1989 and December 1992 and maintained under tacrolimus-based immunosuppression were followed up until January 2009. Patient and graft survivals with corresponding causes of death and retransplantation, maintenance immunosuppression, and adverse effects were examined. The study population includes 600 males and 400 females comprising 166 children, 630 adults, and 204 seniors. The mean follow-up was 17.83 (range, 16.1-19.50) years. The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively. At the last follow-up, 442 patients were alive; 133 (77.1%) children, 265 (34.5%) adults, and 44 (16.1%) seniors (P=0.0001). After the first post-OLT year, cardiopulmonary events, recurrence of primary disease, and malignancy were the main causes of death. Overall, 183 recipients underwent retransplants; mainly for primary nonfunction, hepatic artery thrombosis, and recurrent primary disease, 180 required dialysis, and 45 underwent kidney transplant. A total of 97.7% of the survivors were on tacrolimus and 26.2% were also receiving adjunctive immunosuppressants at the last follow-up. CONCLUSIONS The overall 20-year actuarial patient and graft survivals were 35.8% and 32.6%, respectively, with significantly better survival among children. Age-related complications, recurrence of primary disease, and malignancy were the major causes of late graft loss. Graft loss related to immunologic reasons was rare. The prevention of recurrent disease and newer immunosuppressive regimen will further improve these results.
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Inmunosupresión en el trasplante hepático: pautas renoprotectoras. GASTROENTEROLOGIA Y HEPATOLOGIA 2011; 34:422-7. [DOI: 10.1016/j.gastrohep.2010.12.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Accepted: 12/19/2010] [Indexed: 01/19/2023]
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