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Masuda S, Lemaitre F, Barten MJ, Bergan S, Shipkova M, van Gelder T, Vinks S, Wieland E, Bornemann-Kolatzki K, Brunet M, de Winter B, Dieterlen MT, Elens L, Ito T, Johnson-Davis K, Kunicki PK, Lawson R, Lloberas N, Marquet P, Millan O, Mizuno T, Moes DJAR, Noceti O, Oellerich M, Pattanaik S, Pawinski T, Seger C, van Schaik R, Venkataramanan R, Walson P, Woillard JB, Langman LJ. Everolimus Personalized Therapy: Second Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Ther Drug Monit 2025; 47:4-31. [PMID: 39331837 DOI: 10.1097/ftd.0000000000001250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Accepted: 06/09/2024] [Indexed: 09/29/2024]
Abstract
ABSTRACT The Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology established the second consensus report to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice 7 years after the first version was published in 2016. This version provides information focused on new developments that have arisen in the last 7 years. For the general aspects of the pharmacology and TDM of EVR that have retained their relevance, readers can refer to the 2016 document. This edition includes new evidence from the literature, focusing on the topics updated during the last 7 years, including indirect pharmacological effects of EVR on the mammalian target of rapamycin complex 2 with the major mechanism of direct inhibition of the mammalian target of rapamycin complex 1. In addition, various concepts and technical options to monitor EVR concentrations, improve analytical performance, and increase the number of options available for immunochemical analytical methods have been included. Only limited new pharmacogenetic information regarding EVR has emerged; however, pharmacometrics and model-informed precision dosing have been constructed using physiological parameters as covariates, including pharmacogenetic information. In clinical settings, EVR is combined with a decreased dose of calcineurin inhibitors, such as tacrolimus and cyclosporine, instead of mycophenolic acid. The literature and recommendations for specific organ transplantations, such as that of the kidneys, liver, heart, and lungs, as well as for oncology and pediatrics have been updated. EVR TDM for pancreatic and islet transplantation has been added to this edition. The pharmacodynamic monitoring of EVR in organ transplantation has also been updated. These updates and additions, along with the previous version of this consensus document, will be helpful to clinicians and researchers treating patients receiving EVR.
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Affiliation(s)
- Satohiro Masuda
- Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan
| | - Florian Lemaitre
- Université de Rennes, CHU Rennes, Inserm, EHESP, IRSET-UMR S 1085, Rennes, France
- INSERM, Centre d'Investigation Clinique 1414, Rennes, France
- FHU SUPPORT, Rennes, France
| | - Markus J Barten
- Department of Cardiac and Vascular Surgery, University Heart and Vascular Center Hamburg, Hamburg, Germany
| | - Stein Bergan
- Department of Pharmacology, Oslo University Hospital and Department of Pharmacy, University of Oslo, Norway
| | | | - Teun van Gelder
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Sander Vinks
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- NDA Partners, A Propharma Group Company, Washington District of Columbia
| | | | | | - Mercè Brunet
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Brenda de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maja-Theresa Dieterlen
- Laboratory Management Research Laboratory, Cardiac Surgery Clinic, Heart Center Leipzig GmbH, University Hospital, Leipzig, Germany
| | - Laure Elens
- Integrated Pharmacometrics, Pharmacogenetic and Pharmacokinetics Research Group (PMGK) Louvain Drug for Research Institute (LDRI), Catholic University of Louvain, (UCLouvain), Brussels, Belgium
| | - Taihei Ito
- Department of Organ Transplant Surgery; Fujita Health University School of Medicine, Toyoake Aichi, Japan
| | - Kamisha Johnson-Davis
- University of Utah Health Sciences Center and ARUP Laboratories, Salt Lake City, Utah
| | - Pawel K Kunicki
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | - Roland Lawson
- University of Limoges, Inserm U1248, Pharmacology & Transplantation, Limoges, France
| | - Nuria Lloberas
- Nephrology Department, Hospital Universitari de Bellvitge-Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
| | - Pierre Marquet
- University of Limoges, Inserm U1248, Pharmacology & Transplantation, Limoges, France
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, France
| | - Olga Millan
- Pharmacology and Toxicology Laboratory, Biochemistry and Molecular Genetics Department, Biomedical Diagnostic Center, Hospital Clinic of Barcelona, University of Barcelona, IDIBAPS, CIBERehd, Spain
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Ofelia Noceti
- National Center for Liver Transplantation and Liver Diseases, Army Forces Hospital, Montevideo, Uruguay
| | - Michael Oellerich
- Department of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
| | - Smita Pattanaik
- Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| | - Tomasz Pawinski
- Department of Drug Chemistry, Pharmaceutical and Biomedical Analysis, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland
| | | | - Ron van Schaik
- Department of Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, the Netherlands
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, School of Pharmacy and Department of Pathology, Starzl Transplantation Institute, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Phil Walson
- University Medical School, Göttingen, Germany
| | - Jean-Baptiste Woillard
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, Limoges, France; and
| | - Loralie J Langman
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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Iturbe-Fernández D, de Pablo Gafas A, Mora Cuesta VM, Alonso Moralejo R, Quezada Loaiza CA, Pérez González V, López-Padilla D, Cifrián JM. Everolimus Treatment for Chronic Lung Allograft Dysfunction in Lung Transplantation. Life (Basel) 2024; 14:603. [PMID: 38792624 PMCID: PMC11123303 DOI: 10.3390/life14050603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 03/20/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
Our study aims to evaluate the effect of everolimus treatment on lung function in lung transplant (LT) patients with established chronic lung allograft dysfunction (CLAD). METHODS This retrospective study included LT patients in two reference LT units who started everolimus therapy to treat CLAD from October 2008 to October 2016. We assessed the variation in the maximum forced expiratory volume in the first second (FEV1) before and after the treatment. RESULTS Fifty-seven patients were included in this study. The variation in the FEV1 was -102.7 (149.6) mL/month before starting everolimus compared to -44.7 (109.6) mL/month within the first three months, +1.4 (63.5) mL/month until the sixth month, and -7.4 (46.2) mL/month until the twelfth month (p < 0.05). Glomerular filtrate remained unchanged after everolimus treatment [59.1 (17.5) mL/min per 1.73 m2 at baseline and 60.9 (19.6) mL/min per 1.73 m2, 57.7 (20.5) mL/min per 1.73 m2, and 57.3 (17.8) mL/min per 1.73 m2, at 1, 3, and 6 months, respectively] (p > 0.05). Everolimus was withdrawn in 22 (38.6%) patients. The median time to withdrawal was 14.1 (5.5-25.1) months. CONCLUSIONS This study showed an improvement in FEV1 decline in patients with CLAD treated with everolimus. However, the drug was withdrawn in a high proportion of patients.
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Affiliation(s)
- David Iturbe-Fernández
- Lung Transplant Unit, Pulmonary Medicine Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; (V.M.M.C.); (J.M.C.)
| | - Alicia de Pablo Gafas
- Lung Transplant Unit, Pulmonary Medicine Department, Doce de Octubre University Hospital, 28041 Madrid, Spain; (A.d.P.G.); (R.A.M.); (C.A.Q.L.); (V.P.G.)
| | - Víctor Manuel Mora Cuesta
- Lung Transplant Unit, Pulmonary Medicine Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; (V.M.M.C.); (J.M.C.)
| | - Rodrigo Alonso Moralejo
- Lung Transplant Unit, Pulmonary Medicine Department, Doce de Octubre University Hospital, 28041 Madrid, Spain; (A.d.P.G.); (R.A.M.); (C.A.Q.L.); (V.P.G.)
| | - Carlos Andrés Quezada Loaiza
- Lung Transplant Unit, Pulmonary Medicine Department, Doce de Octubre University Hospital, 28041 Madrid, Spain; (A.d.P.G.); (R.A.M.); (C.A.Q.L.); (V.P.G.)
- CIBER Respiratory Diseases (CIBERES), Carlos III Health Institute, 28029 Madrid, Spain
| | - Virginia Pérez González
- Lung Transplant Unit, Pulmonary Medicine Department, Doce de Octubre University Hospital, 28041 Madrid, Spain; (A.d.P.G.); (R.A.M.); (C.A.Q.L.); (V.P.G.)
| | - Daniel López-Padilla
- Pulmonary Medicine Department, Gregorio Marañón University Hospital, 28007 Madrid, Spain
| | - José M. Cifrián
- Lung Transplant Unit, Pulmonary Medicine Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; (V.M.M.C.); (J.M.C.)
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Bansal S, Rahman M, Ravichandran R, Canez J, Fleming T, Mohanakumar T. Extracellular Vesicles in Transplantation: Friend or Foe. Transplantation 2024; 108:374-385. [PMID: 37482627 DOI: 10.1097/tp.0000000000004693] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2023]
Abstract
The long-term function of transplanted organs, even under immunosuppression, is hindered by rejection, especially chronic rejection. Chronic rejection occurs more frequently after lung transplantation, termed chronic lung allograft dysfunction (CLAD), than after transplantation of other solid organs. Pulmonary infection is a known risk factor for CLAD, as transplanted lungs are constantly exposed to the external environment; however, the mechanisms by which respiratory infections lead to CLAD are poorly understood. The role of extracellular vesicles (EVs) in transplantation remains largely unknown. Current evidence suggests that EVs released from transplanted organs can serve as friend and foe. EVs carry not only major histocompatibility complex antigens but also tissue-restricted self-antigens and various transcription factors, costimulatory molecules, and microRNAs capable of regulating alloimmune responses. EVs play an important role in antigen presentation by direct, indirect, and semidirect pathways in which CD8 and CD4 cells can be activated. During viral infections, exosomes (small EVs <200 nm in diameter) can express viral antigens and regulate immune responses. Circulating exosomes may also be a viable biomarker for other diseases and rejection after organ transplantation. Bioengineering the surface of exosomes has been proposed as a tool for targeted delivery of drugs and personalized medicine. This review focuses on recent studies demonstrating the role of EVs with a focus on exosomes and their dual role (immune activation or tolerance induction) after organ transplantation, more specifically, lung transplantation.
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Affiliation(s)
- Sandhya Bansal
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ
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Halitim P, Tissot A. [Chronic lung allograft dysfunction in 2022, past and updates]. Rev Mal Respir 2023; 40:324-334. [PMID: 36858879 DOI: 10.1016/j.rmr.2023.01.025] [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: 09/21/2022] [Accepted: 01/24/2023] [Indexed: 03/03/2023]
Abstract
INTRODUCTION While short-term results of lung transplantation have improved considerably, long-term survival remains below that achieved for other solid organ transplants. CURRENT KNOWLEDGE The main cause of late mortality is chronic lung allograft dysfunction (CLAD), which affects nearly half of the recipients 5 years after transplantation. Immunological and non-immune risk factors have been identified. These factors activate the innate and adaptive immune system, leading to lesional and altered wound-healing processes, which result in fibrosis affecting the small airways or interstitial tissue. Several phenotypes of CLAD have been identified based on respiratory function and imaging pattern. Aside from retransplantation, which is possible for only small number of patients, no treatment can reverse the CLAD process. PERSPECTIVES Current therapeutic research is focused on anti-fibrotic treatments and photopheresis. Basic research has identified numerous biomarkers that could prove to be relevant as therapeutic targets. CONCLUSION While the pathophysiological mechanisms of CLAD are better understood than before, a major therapeutic challenge remains.
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Affiliation(s)
- P Halitim
- Service de pneumologie et soins intensifs, Hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, 75015 Paris, France; Service de pneumologie, CHU de Nantes, l'Institut du thorax, Nantes Université, Inserm, Center for Research in Transplantation and Translational Immunology, UMR 1064, 44093 Nantes cedex, France
| | - A Tissot
- Service de pneumologie, CHU de Nantes, l'Institut du thorax, Nantes Université, Inserm, Center for Research in Transplantation and Translational Immunology, UMR 1064, 44093 Nantes cedex, France.
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Narula T, Martin AK, Asif AA, Fritz AV, Li Z, Erasmus DB, Alvarez F, Thomas M. Outcomes of Lung Transplantation in Patients With Combined Pulmonary Fibrosis and Emphysema: A Single-Center Experience. Transplant Proc 2023; 55:449-455. [PMID: 36849338 DOI: 10.1016/j.transproceed.2023.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 12/24/2022] [Accepted: 01/24/2023] [Indexed: 02/27/2023]
Abstract
BACKGROUND Combined pulmonary fibrosis and emphysema (CPFE) is a distinct clinical entity that can progress to end-stage lung disease. Patients with CPFE may develop pulmonary hypertension and face a predicted 1-year mortality of 60%. Lung transplantation is the only curative therapeutic option for CPFE. This report describes our experience after lung transplantation in patients with CPFE. METHODS This retrospective, single-center study describes short- and long-term outcomes for adult patients who underwent lung transplant for CPFE. RESULTS The study included 19 patients with explant pathology-proven diagnosis of CPFE. The patients were transplanted between July 2005 and December 2018. Sixteen recipients (84%) had pulmonary hypertension before transplant. Of the 19 patients, 7 (37%) had primary graft dysfunction at 72 hours post-transplant. 1-, 3-, and 5-year freedom from bronchiolitis obliterans syndrome was 100%, 91% (95% CI, 75%-100%), and 82% (95% CI, 62%-100%), respectively. One-, 3-, and 5-year survival was 94% (95% CI, 84%-100%), 82% (95% CI, 65%-100%), and 74% (95% CI, 54%-100%), respectively. CONCLUSION Our experience demonstrates the safety and feasibility of lung transplant for patients with CPFE. Significant morbidity and mortality without lung transplant coupled with favorable post-transplant outcomes merit prioritization of CPFE in the Lung Allocation Score algorithm for lung transplant candidacy.
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Affiliation(s)
- Tathagat Narula
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida.
| | - Archer K Martin
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, Florida
| | - Abuzar A Asif
- Internal Medicine, University of Illinois College of Medicine, Peoria, Illinois
| | - Ashley V Fritz
- Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, Florida
| | - Zhuo Li
- Department of Biostatistics, Mayo Clinic, Jacksonville, Florida
| | - David B Erasmus
- Division of Allergy, Pulmonary, and Critical Care Medicine and The Vanderbilt Lung Institute
| | | | - Mathew Thomas
- Department of Cardiothoracic Surgery, Mayo Clinic, Jacksonville, Florida
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Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial. Liver Transpl 2023; 29:184-195. [PMID: 36668691 DOI: 10.1097/lvt.0000000000000003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/15/2022] [Indexed: 01/22/2023]
Abstract
The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC.
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Ivulich S, Paul E, Kirkpatrick C, Dooley M, Snell G. Everolimus Based Immunosuppression Strategies in Adult Lung Transplant Recipients: Calcineurin Inhibitor Minimization Versus Calcineurin Inhibitor Elimination. Transpl Int 2023; 36:10704. [PMID: 36744051 PMCID: PMC9894878 DOI: 10.3389/ti.2023.10704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 01/02/2023] [Indexed: 01/21/2023]
Abstract
Everolimus (EVE) provides an alternative to maintenance immunosuppression when conventional immunosuppression cannot be tolerated. EVE can be utilized with a calcineurin inhibitor (CNI) minimization or elimination strategy. To date, clinical studies investigating EVE after lung transplant (LTx) have primarily focused on the minimization strategy to preserve renal function. The primary aim was to determine the preferred method of EVE utilization for lung transplant recipients (LTR). To undertake this aim, we compared the safety and efficacy outcomes of EVE as part of minimization and elimination immunosuppressant regimens. Single center retrospective study of 217 LTR initiated on EVE (120 CNI minimization and 97 CNI elimination). Survival outcomes were calculated from the date of EVE commencement. On multivariate analysis, LTR who received EVE as part of the CNI elimination strategy had poorer survival outcomes compared to the CNI minimization strategy [HR 1.61, 95% CI: 1.11-2.32, p=0.010]. Utilization of EVE for renal preservation was associated with improved survival compared to other indications [HR 0.64, 95% CI: 0.42-0.97, p=0.032]. EVE can be successfully utilized for maintenance immunosuppression post LTx, particularly for renal preservation. However, immunosuppressive regimens containing low dose CNI had superior survival outcomes, highlighting the importance of retaining a CNI wherever possible.
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Affiliation(s)
- Steven Ivulich
- The Alfred Hospital, Melbourne, VIC, Australia,Centre for Medication Use and Safety, Monash University, Melbourne, VIC, Australia,*Correspondence: Steven Ivulich,
| | - Eldho Paul
- Public Health and Preventative Medicine, Monash University, Melbourne, VIC, Australia
| | - Carl Kirkpatrick
- Centre for Medication Use and Safety, Monash University, Melbourne, VIC, Australia
| | - Michael Dooley
- The Alfred Hospital, Melbourne, VIC, Australia,Centre for Medication Use and Safety, Monash University, Melbourne, VIC, Australia
| | - Greg Snell
- The Alfred Hospital, Melbourne, VIC, Australia
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Schmucki K, Hofmann P, Fehr T, Inci I, Kohler M, Schuurmans MM. Mammalian Target of Rapamycin Inhibitors and Kidney Function After Thoracic Transplantation: A Systematic Review and Recommendations for Management of Lung Transplant Recipients. Transplantation 2023; 107:53-73. [PMID: 36508646 PMCID: PMC9746343 DOI: 10.1097/tp.0000000000004336] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/18/2022] [Accepted: 07/19/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) after lung transplantation is common and limits the survival of transplant recipients. The calcineurin inhibitors (CNI), cyclosporine A, and tacrolimus being the cornerstone of immunosuppression are key mediators of nephrotoxicity. The mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus, are increasingly used in combination with reduced CNI dosage after lung transplantation. METHODS This systematic review examined the efficacy and safety of mTOR inhibitors after lung transplantation and explored their effect on kidney function. RESULTS mTOR inhibitors are often introduced to preserve kidney function. Several clinical trials have demonstrated improved kidney function and efficacy of mTOR inhibitors. The potential for kidney function improvement and preservation increases with early initiation of mTOR inhibitors and low target levels for both mTOR inhibitors and CNI. No defined stage of CKD for mTOR inhibitor initiation exists, nor does severe CKD preclude the improvement of kidney function under mTOR inhibitors. Baseline proteinuria may negatively predict the preservation and improvement of kidney function. Discontinuation rates of mTOR inhibitors due to adverse effects increase with higher target levels. CONCLUSIONS More evidence is needed to define the optimal immunosuppressive regimen incorporating mTOR inhibitors after lung transplantation. Not only the indication criteria for the introduction of mTOR inhibitors are needed, but also the best timing, target levels, and possibly discontinuation criteria must be defined more clearly. Current evidence supports the notion of nephroprotective potential under certain conditions.
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Affiliation(s)
- Katja Schmucki
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Department of Internal Medicine, Cantonal Hospital Graubünden, Chur, Switzerland
| | - Patrick Hofmann
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Department of Internal Medicine, Cantonal Hospital Graubünden, Chur, Switzerland
| | - Thomas Fehr
- Department of Internal Medicine, Cantonal Hospital Graubünden, Chur, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Ilhan Inci
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
- Department of Thoracic Surgery, Zurich University Hospital, Zurich, Switzerland
| | - Malcolm Kohler
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Macé M. Schuurmans
- Division of Pulmonology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
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Gottlieb J, Fischer B, Schupp JC, Golpon H. Calcineurin-inhibitor free immunosuppression after lung transplantation - a single center case-control study in 51 patients converted to Mechanistic Target of Rapamycin (mTOR) inhibitors. PLoS One 2023; 18:e0284653. [PMID: 37200246 DOI: 10.1371/journal.pone.0284653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 04/05/2023] [Indexed: 05/20/2023] Open
Abstract
BACKGROUND Data on calcineurin-inhibitor (CNI) free immunosuppression after lung transplantation (LTx) are limited. Aim of this study was to investigate CNI-free immunosuppression using mechanistic target of rapamycin (mTOR) inhibitors. METHODS This retrospective analysis was performed at a single center. Adult patients after LTx without CNI during the follow-up period were included. Outcome was compared to those LTx patients with malignancy who continued CNI. RESULTS Among 2,099 patients in follow-up, fifty-one (2.4%) were converted median 6.2 years after LTx to a CNI-free regimen combining mTOR inhibitors with prednisolone and an antimetabolite, two patients were switched to mTOR inhibitors with prednisolone only. In 25 patients, malignancies without curative treatment options were the reason of the conversion, with a 1-year survival of 36%. The remaining patients had a 1-year survival of 100%. Most common non-malignant indication was neurological complications (n = 9). Fifteen patients were re-converted to a CNI-based regimen. The median duration of CNI-free immunosuppression was 338 days. No acute rejections were detected in 7 patients with follow-up biopsies. In multivariate analysis, CNI-free immunosuppression were not associated with improved survival after malignancy. The majority of patients with neurological diseases improved 12 months after conversion. Glomerular filtration rate increased by median 5 (25 and 75% percentiles -6; +18) ml/min/1.73 m2. CONCLUSIONS mTOR inhibitor based CNI-free immunosuppression may be safely performed in selected patients after LTx. This approach was not associated with improved survival in patients with malignancy. Significant functional improvements were observed in patients with neurological diseases.
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Affiliation(s)
- Jens Gottlieb
- Respiratory Medicine, Hannover Medical School, Hannover, Germany
- German Center for Lung Research (DZL), Hannover, Germany
| | - Bettina Fischer
- Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - Jonas C Schupp
- Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - Heiko Golpon
- Respiratory Medicine, Hannover Medical School, Hannover, Germany
- German Center for Lung Research (DZL), Hannover, Germany
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Swanson KJ. Kidney disease in non-kidney solid organ transplantation. World J Transplant 2022; 12:231-249. [PMID: 36159075 PMCID: PMC9453292 DOI: 10.5500/wjt.v12.i8.231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 04/07/2022] [Accepted: 07/11/2022] [Indexed: 02/05/2023] Open
Abstract
Kidney disease after non-kidney solid organ transplantation (NKSOT) is a common post-transplant complication associated with deleterious outcomes. Kidney disease, both acute kidney injury and chronic kidney disease (CKD) alike, emanates from multifactorial, summative pre-, peri- and post-transplant events. Several factors leading to kidney disease are shared amongst solid organ transplantation in addition to distinct mechanisms unique to individual transplant types. The aim of this review is to summarize the current literature describing kidney disease in NKSOT. We conducted a narrative review of pertinent studies on the subject, limiting our search to full text studies in the English language. Kidney disease after NKSOT is prevalent, particularly in intestinal and lung transplantation. Management strategies in the peri-operative and post-transplant periods including proteinuria management, calcineurin-inhibitor minimization/ sparing approaches, and nephrology referral can counteract CKD progression and/or aid in subsequent kidney after solid organ transplantation. Kidney disease after NKSOT is an important consideration in organ allocation practices, ethics of transplantation. Kidney disease after SOT is an incipient condition demanding further inquiry. While some truths have been revealed about this chronic disease, as we have aimed to describe in this review, continued multidisciplinary efforts are needed more than ever to combat this threat to patient and allograft survival.
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Affiliation(s)
- Kurtis J Swanson
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN 55414, United States
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Nelson J, Alvey N, Bowman L, Schulte J, Segovia M, McDermott J, Te HS, Kapila N, Levine DJ, Gottlieb RL, Oberholzer J, Campara M. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation. Pharmacotherapy 2022; 42:599-633. [DOI: 10.1002/phar.2716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/29/2022] [Accepted: 04/08/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Joelle Nelson
- Department of Pharmacotherapy and Pharmacy Services University Health San Antonio Texas USA
- Pharmacotherapy Education and Research Center University of Texas Health San Antonio San Antonio Texas USA
- Department of Pharmacy, Pharmacotherapy Division, College of Pharmacy The University of Texas at Austin Austin Texas USA
| | - Nicole Alvey
- Department of Pharmacy Rush University Medical Center Chicago Illinois USA
- Science and Pharmacy Roosevelt University College of Health Schaumburg Illinois USA
| | - Lyndsey Bowman
- Department of Pharmacy Tampa General Hospital Tampa Florida USA
| | - Jamie Schulte
- Department of Pharmacy Services Thomas Jefferson University Hospital Philadelphia Pennsylvania USA
| | | | - Jennifer McDermott
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health Grand Rapids Michigan USA
- Department of Medicine, Michigan State University College of Human Medicine Grand Rapids Michigan USA
| | - Helen S. Te
- Liver Transplantation, Center for Liver Diseases, Department of Medicine University of Chicago Medical Center Chicago Illinois USA
| | - Nikhil Kapila
- Department of Transplant Hepatology Duke University Hospital Durham North Carolina USA
| | - Deborah Jo Levine
- Division of Critical Care Medicine, Department of Medicine The University of Texas Health Science Center at San Antonio San Antonio Texas USA
| | - Robert L. Gottlieb
- Baylor University Medical Center and Baylor Scott and White Research Institute Dallas Texas USA
| | - Jose Oberholzer
- Department of Surgery/Division of Transplantation University of Virginia Charlottesville Virginia USA
| | - Maya Campara
- Department of Surgery University of Illinois Chicago Chicago Illinois USA
- Department of Pharmacy Practice University of Illinois Chicago Chicago Illinois USA
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12
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Evans RA, Walter KS, Lobo LJ, Coakley R, Doligalski CT. Pharmacotherapy of chronic lung allograft dysfunction post lung transplantation. Clin Transplant 2022; 36:e14770. [PMID: 35801376 DOI: 10.1111/ctr.14770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 05/30/2022] [Accepted: 07/05/2022] [Indexed: 11/30/2022]
Abstract
Chronic lung allograft dysfunction (CLAD) remains the primary cause of death in lung transplant recipients (LTRs) in spite of improvements in immunosuppression management. Despite advances in knowledge regarding the pathogenesis of CLAD, treatments that are currently available are usually ineffective and delay progression of disease at best. There are currently no evidence-based guidelines for the optimal treatment of CLAD, and management varies widely across transplant centers. Additionally, there are minimal publications available to summarize data for currently available therapies and outcomes in LTRs. We identified the major domains of the medical management of CLAD and conducted a comprehensive search of PubMed and Embase databases to identify articles published from inception to December 2021 related to CLAD in LTRs. Studies published in English pertaining to the pharmacologic prevention and treatment of CLAD were included; highest priority was given to prospective, randomized, controlled trials if available. Prospective observational and retrospective controlled trials were prioritized next, followed by retrospective uncontrolled studies, case series, and finally case reports if the information was deemed to be pertinent. Reference lists of qualified publications were also reviewed to find any other publications of interest that were not found on initial search. In the absence of literature published in the aforementioned databases, additional articles were identified by reviewing abstracts presented at the International Society for Heart and Lung Transplantation and American Transplant Congress annual meetings between 2010-2021. This document serves to provide a comprehensive review of the literature and considerations for the prevention and medical management of CLAD. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Rickey A Evans
- Department of Pharmacy, University of Kentucky Healthcare, Lexington, KY, USA
| | - Krysta S Walter
- Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA
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13
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Abstract
Rejection is a major complication following lung transplantation. Acute cellular rejection (ACR), and antibody-mediated rejection (AMR) are risk factors for the subsequent development of chronic lung allograft dysfunction and worse outcomes after transplantation. Although ACR has well-defined histopathologic diagnostic criteria and grading, the diagnosis of AMR requires a multidisciplinary diagnostic approach. This article reviews the identification, clinical and pathologic features of, and therapeutic options for ACR and AMR.
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Affiliation(s)
- Deborah J Levine
- Division of Pulmonary and Critical Care Medicine, University of Texas Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
| | - Ramsey R Hachem
- Division of Pulmonary and Critical Care Medicine, Washington University in St. Louis, 4523 Clayton Avenue, Mailstop 8052-0043-14, St Louis, MO 63110, USA.
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14
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Safety of Inhaled Amphotericin B Lipid Complex as Antifungal Prophylaxis in Lung Transplant Recipients. Antimicrob Agents Chemother 2022; 66:e0028322. [PMID: 35506698 DOI: 10.1128/aac.00283-22] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Inhaled formulations of amphotericin B are the most widely used antifungal prophylactic agents in lung transplant recipients, yet there are limited data on their safety. We performed a single-center retrospective cohort study of 603 consecutive patients who underwent lung transplantation between 2012 and 2017 and received antifungal prophylaxis with inhaled amphotericin B lipid complex (iABLC) from the day of transplantation until hospital discharge. Of 603 patients, 600 (99.5%) received ≥1 dose of iABLC, and 544 (90.2%) completed the recommended prophylactic course. In total, 4,128 iABLC doses (median, 5; range, 1 to 48 per patient) were administered; 24 patients received >3 months of therapy. Only one (0.2%) patient discontinued therapy due to a drug-attributable adverse event. During the first posttransplant year, 80 (13.3%) patients died (median time to death, 171 days; interquartile range [IQR], 80 to 272 days), and 3,352 (median, 6 per patient) lung biopsies were performed; 414 (68.7%) patients developed biopsy-proven acute cellular rejection. One-year adverse events in our cohort of lung transplant recipients treated with iABLC during transplant hospitalization matched national outcomes for rejection, graft loss, and death. iABLC is a safe and well-tolerated antifungal prophylactic agent in lung transplant recipients.
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15
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Terada Y, Takahashi T, Hachem RR, Liu J, Witt CA, Byers DE, Guillamet RV, Kulkarni HS, Nava RG, Kozower BD, Meyers BF, Pasque MK, Patterson GA, Kreisel D, Puri V. Clinical Features and Outcomes of Unplanned Single Lung Transplants. J Thorac Cardiovasc Surg 2022; 164:1650-1659.e3. [DOI: 10.1016/j.jtcvs.2022.01.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 01/01/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022]
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16
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Subramani MV, Pandit S, Gadre SK. Acute rejection and post lung transplant surveillance. Indian J Thorac Cardiovasc Surg 2022; 38:271-279. [PMID: 35340687 PMCID: PMC8938213 DOI: 10.1007/s12055-021-01320-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 12/09/2021] [Accepted: 12/16/2021] [Indexed: 12/05/2022] Open
Abstract
Purpose The purpose of this review is to summarize the current evidence on the evaluation and treatment of acute rejection after lung transplantation. Results Despite significant progress in the field of transplant immunology, acute rejection remains a frequent complication after transplantation. Almost 30% of lung transplant recipients experience at least one episode of acute cellular rejection (ACR) during the first year after transplant. Acute cellular rejection, lymphocytic bronchiolitis, and antibody-mediated rejection (AMR) are all risk factors for the subsequent development of chronic lung allograft dysfunction (CLAD). Acute cellular rejection and lymphocytic bronchiolitis have well-defined histopathologic diagnostic criteria and grading. The diagnosis of antibody-mediated rejection after lung transplantation requires a multidisciplinary approach. Antibody-mediated rejection may cause acute allograft failure. Conclusions Acute rejection is a risk factor for development of chronic rejection. Further investigations are required to better define risk factors, surveillance strategies, and optimal management strategies for acute allograft rejection.
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Affiliation(s)
| | - Sumir Pandit
- Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
| | - Shruti Kumar Gadre
- Department of Pulmonary and Critical Care Medicine, Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue A-90, Cleveland, OH 44195 USA
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17
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Five-Year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients. Transplantation 2022; 106:1867-1874. [DOI: 10.1097/tp.0000000000004095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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18
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A survey of use of mTOR inhibitors in patients with lymphangioleiomyomatosis listed for lung transplant. Respir Med 2022; 195:106779. [DOI: 10.1016/j.rmed.2022.106779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/06/2022] [Accepted: 02/17/2022] [Indexed: 11/17/2022]
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19
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Wiseman AC. CKD in Recipients of Nonkidney Solid Organ Transplants: A Review. Am J Kidney Dis 2021; 80:108-118. [PMID: 34979161 DOI: 10.1053/j.ajkd.2021.10.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 10/25/2021] [Indexed: 12/14/2022]
Abstract
Chronic kidney disease (CKD) after solid organ transplant is a common clinical presentation, affecting 10% to 20% of liver, heart and lung transplant recipients and accounting for approximately 5% of the kidney transplant waiting list. The causes of CKD are different for different types of transplants and are not all, or even predominantly, due to calcineurin inhibitor toxicity, with significant heterogeneity particularly in liver transplant recipients. Many solid organ transplant recipients with advanced CKD benefit from kidney transplantation, but have a higher rate of death while waitlisted and higher mortality following transplant than the general kidney failure population. Recent organ allocation policies and proposals have attempted to address the appropriate identification and prioritization of candidates in need of a kidney transplant, either simultaneous with or following non-kidney transplant. Future research should focus on predictive factors for individuals identified at high risk for progression to kidney failure and death, and strategies to preserve kidney function and minimize the CKD burden in this unique patient population.
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20
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Immunosuppression in Lung Transplantation. Handb Exp Pharmacol 2021; 272:139-164. [PMID: 34796380 DOI: 10.1007/164_2021_548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Immunosuppression in lung transplantation is an area devoid of robust clinical data. This chapter will review the history of immunosuppression in lung transplantation. Additionally, it will evaluate the three classes of induction, maintenance, and rescue immunosuppression in detail. Induction immunosuppression in lung transplantation aims to decrease incidence of lung allograft rejection, however infectious risk must be considered when determining if induction is appropriate and which agent is most favorable. Similar to other solid organ transplant patient populations, a multi-drug approach is commonly prescribed for maintenance immunosuppression to minimize single agent drug toxicities. Emphasis of this review is placed on key medication considerations including dosing, adverse effects, and drug interactions. Clinical considerations will be reviewed per drug class given available literature. Finally, acute cellular, antibody mediated, and chronic rejection are reviewed.
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21
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de Souza AR, Dos Santos TAGM, Von Jakitsch CB, de Sant'Anna ALGG, de Claudio JCM, Branco JNR, Giovanazzi RSD, Junior NAH, Pimentel WDS, da Costa SACM, Girones P, Machado RC. Mammalian Target of Rapamycin Inhibitors Vs Calcineurin Inhibitors in Chronic Graft Rejection After Lung Transplantation: A Systematic Review and Meta-Analysis. Transplant Proc 2021; 53:3056-3064. [PMID: 34785027 DOI: 10.1016/j.transproceed.2021.09.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 08/24/2021] [Accepted: 09/22/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND The number of lung transplantations has been rising constantly. However, use of this therapeutic resource is limited by several issues that are difficult to resolve, such as chronic graft rejection and complications secondary to immunosuppression. METHODS This systematic review compared mammalian target of rapamycin (mTOR) inhibitor immunosuppression associated with low-dose calcineurin inhibitors with isolated calcineurin inhibitor immunosuppression on the new-onset chronic rejection development and mortality 12 months after lung transplantation. Three controlled randomized clinical trials (SHITRIT, NOCTET, and 4EVERLUNG) were selected from electronic databases. RESULTS Meta-analysis of the data at 12 months postintervention showed that only 4EVERLUNG assessed chronic graft rejection, with a higher incidence in the control group; however, the difference was not statistically significant (P = .197). Significant data were related to an increase in the number of adverse events (P = .0064) and improved renal function (P < .0001) in the mTOR inhibitor-based scheme. The other outcomes indicated a trend toward greater risk of death and acute graft rejection with the use of mTORs. CONCLUSIONS The researchers suggest considering the use of mTOR inhibitors, whose greatest benefit is felt by patients with renal dysfunction, in association with the use of calcineurin inhibitors, because of the imminent risk of death among patients with renal failure.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Puri Girones
- Hospital Universitari i Politècnic La Fe, Valencia, Spain
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22
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Tedesco-Silva H, Saliba F, Barten MJ, De Simone P, Potena L, Gottlieb J, Gawai A, Bernhardt P, Pascual J. An overview of the efficacy and safety of everolimus in adult solid organ transplant recipients. Transplant Rev (Orlando) 2021; 36:100655. [PMID: 34696930 DOI: 10.1016/j.trre.2021.100655] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 09/17/2021] [Accepted: 09/17/2021] [Indexed: 12/15/2022]
Abstract
As the risk of graft loss due to acute rejection has declined, the goal of post-transplant management has switched to long-term preservation of organ function. Minimizing calcineurin inhibitor (CNI)-related nephrotoxicity is a key component of this objective. Everolimus is a mammalian target of rapamycin inhibitor/proliferation-signal inhibitor with potent immunosuppressive and anti-proliferative effects. It has been widely investigated in large randomized clinical studies that have shown it to have similar anti-rejection efficacy compared with standard-of-care regimens across organ transplant indications. With demonstrated potential to facilitate the reduction of CNI therapy and preserve renal function, everolimus is an alternative to the current standard-of-care CNI-based regimens used in de novo and maintenance solid organ transplantation recipients. Here, we provide an overview of the evidence from the everolimus clinical study program across kidney, liver, heart, and lung transplants, as well as other key data associated with its use in CNI reduction strategies in adult transplant recipients.
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Affiliation(s)
| | - Faouzi Saliba
- AP-HP_Hôpital Paul Brousse, Hepato-Biliary Centre, Villejuif, France; Université Paris-Saclay, INSERM Unit 1193, France
| | - Markus J Barten
- Department of Cardiovascular Surgery, University Heart Center Hamburg, Hamburg, Germany
| | | | - Luciano Potena
- Heart Failure and Transplant Program, Cardiology Unit, IRCCS Policlinico di Sant'Orsola, Bologna, Italy
| | - Jens Gottlieb
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | | | | | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Barcelona, Spain.
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23
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Induction and maintenance immunosuppression in lung transplantation. Indian J Thorac Cardiovasc Surg 2021; 38:300-317. [DOI: 10.1007/s12055-021-01225-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/04/2021] [Accepted: 06/13/2021] [Indexed: 10/20/2022] Open
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24
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Sekulovski M, Simonska B, Peruhova M, Krastev B, Peshevska-Sekulovska M, Spassov L, Velikova T. Factors affecting complications development and mortality after single lung transplant. World J Transplant 2021; 11:320-334. [PMID: 34447669 PMCID: PMC8371496 DOI: 10.5500/wjt.v11.i8.320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/15/2021] [Accepted: 06/28/2021] [Indexed: 02/06/2023] Open
Abstract
Lung transplantation (LT) is a life-saving therapeutic procedure that prolongs survival in patients with end-stage lung disease. Furthermore, as a therapeutic option for high-risk candidates, single LT (SLT) can be feasible because the immediate morbidity and mortality after transplantation are lower compared to sequential single (double) LT (SSLTx). Still, the long-term overall survival is, in general, better for SSLTx. Despite the great success over the years, the early post-SLT period remains a perilous time for these patients. Patients who undergo SLT are predisposed to evolving early or late postoperative complications. This review emphasizes factors leading to post-SLT complications in the early and late periods including primary graft dysfunction and chronic lung allograft dysfunction, native lung complications, anastomosis complications, infections, cardiovascular, gastrointestinal, renal, and metabolite complications, and their association with morbidity and mortality in these patients. Furthermore, we discuss the incidence of malignancy after SLT and their correlation with immunosuppression therapy.
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Affiliation(s)
- Metodija Sekulovski
- Department of Anesthesiology and Intensive care, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Bilyana Simonska
- Department of Anesthesiology and Intensive care, University Hospital Lozenetz, Sofia 1407, Bulgaria
| | - Milena Peruhova
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
| | - Boris Krastev
- Department of Clinical Oncology, MHAT Hospital for Women Health Nadezhda, Sofia 1330, Bulgaria
| | | | - Lubomir Spassov
- Department of Cardiothoracic Surgery, University Hospital Lozenetz, Sofia 1431, Bulgaria
| | - Tsvetelina Velikova
- Department of Clinical Immunology, University Hospital Lozenetz, Sofia 1407, Bulgaria
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25
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McPheeters CM, Lorenz D, Burcham PK, Barger CD, Bhandari B, Bauldoff GS, Truelove DB, Nunley DR. Calcineurin Inhibitor-Based Maintenance Immunosuppression in Lung Transplant Recipients: Optimal Serum Levels for Managing Acute Rejection and Renal Function. Transplant Proc 2021; 53:1998-2003. [PMID: 34253383 DOI: 10.1016/j.transproceed.2021.05.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 04/24/2021] [Accepted: 05/04/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND Although effective for curtailing alloimmune responses, calcineurin inhibitors (CNIs) have an adverse-effect profile that includes nephrotoxicity. In lung transplant (LTx) recipients, the optimal serum levels of the CNI tacrolimus necessary to control alloimmune responses and minimize nephrotoxicity are unknown. METHODS This retrospective, single-center study reviewed tacrolimus whole blood trough levels (BTLs), grades of acute cellular rejection (ACR), acute rejection scores, and creatinine clearance (CrCl) obtained in LTx recipients within the first year after their transplant procedure. Comparisons were made between the first 90 days post LTx (when tacrolimus BTLs were maintained >10 µg/L) and the remainder of the post-LTX year (when BTLs were <10 µg/L). RESULTS Despite tacrolimus mean BTLs being higher during the first 90 days post LTx compared with the remainder of the first post-LTx year (10.4 ± 0.3 µg/L vs 9.5 ± 0.3 µg/L, P < .0001) there was no association with lower grades of ACR (P = .24). The intensity of ACR (as determined by acute rejection scores) did not correlate with tacrolimus mean BTLs at any time during the first posttransplant year (P = .79). During the first 90 days post LTx there was a significant decline in CrCl and a correlation between increasing tacrolimus mean BTLs and declining CrCl (r = -0.26, P = .03); a correlation that was not observed during the remainder of the year (r = -0.09, P = .52). CONCLUSIONS In LTx recipients, maintaining BTLs of the CNI tacrolimus >10µg/L did not result in superior control of acute rejection responses but was associated with declining renal function.
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Affiliation(s)
- Chelsey M McPheeters
- Department of Pharmacy, University of Louisville Healthcare, Louisville, Kentucky
| | - Douglas Lorenz
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, Kentucky
| | - Pamela K Burcham
- Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Christopher D Barger
- Department of Pharmacy, University of Louisville Healthcare, Louisville, Kentucky
| | - Bikash Bhandari
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, Kentucky
| | | | - Daniel B Truelove
- Department of Pharmacy, University of Tennessee Medical Center, Knoxville, Tennessee
| | - David R Nunley
- Pulmonary, Critical Care & Sleep Medicine, The Ohio State University, Columbus, Ohio.
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26
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Desensitization and management of allograft rejection. Curr Opin Organ Transplant 2021; 26:314-320. [PMID: 33938468 DOI: 10.1097/mot.0000000000000878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE OF REVIEW Chronic lung allograft dysfunction (CLAD) limits the success of lung transplantation. Among the risk factors associated with CLAD, we recognize pretransplant circulating antibodies against the human leukocyte antigens (HLA), acute cellular rejection (ACR) and antibody-mediated rejection (AMR). This review will summarize current data surrounding management of desensitization, ACR, AMR, and CLAD. RECENT FINDINGS Strategies in managing in highly sensitized patients waiting for lung transplant include avoidance of specific HLA antigens and reduction of circulating anti-HLA antibodies at time of transplant. Several multimodal approaches have been studied in the treatment of AMR with a goal to clear circulating donor-specific antibodies (DSAs) and to halt the production of new antibodies. Different immunosuppressive strategies focus on influence of the host immune system, particularly T-cell responses, in order to prevent ACR and the progression of CLAD. SUMMARY The lack of significant evidence and consensus limits to draw conclusion regarding the impact of specific immunosuppressive regimens in the management of HLA antibodies, ACR, and CLAD. Development of novel therapeutic agents and use of multicenter randomized clinical trials will allow to better define patient-specific treatments and improve the length and quality of life of lung transplant recipients.
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27
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Bush A. Azithromycin is the answer in paediatric respiratory medicine, but what was the question? Paediatr Respir Rev 2020; 34:67-74. [PMID: 31629643 DOI: 10.1016/j.prrv.2019.07.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 07/30/2019] [Indexed: 02/07/2023]
Abstract
The first clinical indication of non-antibiotic benefits of macrolides was in the Far East, in adults with diffuse panbronchiolitis. This condition is characterised by chronic airway infection, often with Pseudomonas aeruginosa, airway inflammation, bronchiectasis and a high mortality. Low dose erythromycin, and subsequently other macrolides, led in many cases to complete remission of the condition, and abrogated the neutrophilic airway inflammation characteristic of the disease. This dramatic finding sparked a flurry of interest in the many hundreds of macrolides in nature, especially their anti-inflammatory and immunomodulatory effects. The biggest subsequent trials of azithromycin were in cystic fibrosis, which has obvious similarities to diffuse panbronchiolitis. There were unquestionable improvements in lung function and pulmonary exacerbations, but compared to diffuse panbronchiolitis, the results were disappointing. Case reports, case series and some randomised controlled trials followed in other conditions. Three trials of azithromycin in preschool wheeze gave contradictory results; a trial in pauci-inflammatory adult asthma, and a trial in non-cystic fibrosis bronchiectasis both showed a significant reduction in exacerbations, but none matched the dramatic results in diffuse panbronchiolitis. There is clearly a huge risk of antibacterial resistance if macrolides are used widely and uncritically in the community. In summary, Azithromycin is not the answer to anything in paediatric respiratory medicine; the paediatric respiratory community needs to refocus on the dramatic benefits of macrolides in diffuse panbronchiolitis, use modern - omics technologies to determine the endotypes of inflammatory diseases and discover in nature or synthesise designer macrolides to replicate the diffuse panbronchiolitis results. We must now find out how to do better!
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Affiliation(s)
- Andrew Bush
- Professor of Paediatrics and Paediatric Respirology, Imperial College Consultant Paediatric Chest Physician, Royal Brompton & Harefield NHS Foundation Trust, National Heart and Lung Institute, UK; Paediatric Chest Physician, Royal Brompton Harefield NHS Foundation Trust, UK.
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28
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Abstract
Lung transplantation is a viable option for those with end-stage lung disease which is evidenced by the continued increase in the number of lung transplantations worldwide. However, patients and clinicians are constantly faced with acute and chronic rejection, infectious complications, drug toxicities, and malignancies throughout the lifetime of the lung transplant recipient. Conventional maintenance immunosuppression therapy consisting of a calcineurin inhibitor (CNI), anti-metabolite, and corticosteroids have become the standard regimen but newer agents and modalities continue to be developed. Here we will review induction agents, maintenance immunosuppressives, adjunctive therapies and other strategies to improve long-term outcomes.
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Affiliation(s)
- Paul A Chung
- Division of Pulmonary and Critical Care, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
| | - Daniel F Dilling
- Division of Pulmonary and Critical Care, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA
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29
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Greer M, Werlein C, Jonigk D. Surveillance for acute cellular rejection after lung transplantation. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:410. [PMID: 32355854 PMCID: PMC7186718 DOI: 10.21037/atm.2020.02.127] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Acute cellular rejection (ACR) is a common complication following lung transplantation (LTx), affecting almost a third of recipients in the first year. Established, comprehensive diagnostic criteria exist but they necessitate allograft biopsies which in turn increases clinical risk and can pose certain logistical and economic problems in service delivery. Undermining these challenges further, are known problems with inter-observer interpretation of biopsies and uncertainty as to the long-term implications of milder or indeed asymptomatic episodes. Increased risk of chronic lung allograft dysfunction (CLAD) has long been considered the most significant consequence of ACR. Consensus is lacking as to whether this applies to mild ACR, with contradictory evidence available. Given these issues, research into alternative, minimal or non-invasive biomarkers represents the main focus of research in ACR. A number of potential markers have been proposed, but none to date have demonstrated adequate sensitivity and specificity to allow translation from bench to bedside.
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Affiliation(s)
- Mark Greer
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany.,Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), German Centre for Lung Research (DZL), Hannover, Germany
| | | | - Danny Jonigk
- Biomedical Research in End-Stage and Obstructive Lung Disease (BREATH), German Centre for Lung Research (DZL), Hannover, Germany.,Institute for Pathology, Hannover Medical School, Hannover, Germany
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30
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Bry C, Hubert D, Reynaud-Gaubert M, Dromer C, Mal H, Roux A, Boussaud V, Claustre J, Le Pavec J, Murris-Espin M, Danner-Boucher I. Pregnancy after lung and heart-lung transplantation: a French multicentre retrospective study of 39 pregnancies. ERJ Open Res 2019; 5:00254-2018. [PMID: 31687369 PMCID: PMC6819984 DOI: 10.1183/23120541.00254-2018] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 07/29/2019] [Indexed: 11/30/2022] Open
Abstract
Pregnancy after lung and heart–lung transplantation remains rare. This French study deals with change in lung function after a pregnancy and the maternal and newborn outcomes. We retrospectively included 39 pregnancies in 35 women aged >20 years. Data on patients, course of pregnancies and newborns were collected from nine transplantation centres. Mean age at time of pregnancy was 28 years. Cystic fibrosis affected 71% of patients. Mean±sd time between transplantation and pregnancy was 63±44 months. 26 births occurred (67%) with a mean term of 36 weeks of amenorrhoea and a mean birthweight of 2409 g. Prematurity was observed in 11 cases (43%). Forced expiratory volume in 1 s was 83.9% of predicted before pregnancy and 77.3% of predicted 1 year after the end of pregnancy (p=0.04). 10 patients developed chronic lung allograft dysfunction after delivery. Nine patients died at a mean±sd time after transplantation of 8.2±7 years and a mean±sd time after pregnancy of 4.6±6.5 years. These data show that pregnancy remains feasible in lung and heart–lung transplant recipients, with more frequent maternal and newborn complications than in the general population. Survival in this cohort appears to be similar to the global survival observed in lung transplant recipients. Planned pregnancy and multidisciplinary follow-up are crucial. Pregnancy in lung and heart–lung recipients remains rare but possible. There is a significant decrease in FEV1 pre- and post-pregnancy, but overall outcomes are reassuring. Specialised, multidisciplinary follow-up is necessary.http://bit.ly/31iXxov
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Affiliation(s)
- Charlotte Bry
- Service de Pneumologie, CHU de Nantes, Nantes, France
| | | | - Martine Reynaud-Gaubert
- Centre de Ressource et de Compétences de la Mucoviscidose Adulte, Equipe de Transplantation Pulmonaire, CHU Nord, Marseille, France
| | - Claire Dromer
- Service de Pneumologie, CHU de Bordeaux, Bordeaux, France
| | - Hervé Mal
- Service de Pneumologie, Hôpital Bichat-Claude Bernard, Paris, France
| | - Antoine Roux
- Service de Pneumologie, Hôpital Foch, Suresnes, France
| | - Véronique Boussaud
- Service de Pneumologie, Hôpital Européen Georges Pompidou, Paris, France
| | - Johanna Claustre
- Clinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, CHU de Grenoble, Grenoble, France
| | - Jérôme Le Pavec
- Service de Chirurgie Thoracique et Vasculaire, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France
| | - Muriel Murris-Espin
- CRCM Adulte, Service de Pneumologie-Allergologie, CHU de Toulouse, Toulouse, France
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31
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Yun JSW, Yap T, Martyres R, Kern JS, Varigos G, Scardamaglia L. The association of mycophenolate mofetil and human herpes virus infection. J DERMATOL TREAT 2019; 31:46-55. [DOI: 10.1080/09546634.2019.1572864] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jenny Sung Won Yun
- Departments of Dermatology, Royal Melbourne Hospital, Victoria, Australia
- Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Victoria, Australia
| | - Tami Yap
- Departments of Dermatology, Royal Melbourne Hospital, Victoria, Australia
- Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Victoria, Australia
- Melbourne Dental School, University of Melbourne, Victoria, Australia
| | - Raymond Martyres
- Departments of Dermatology, Royal Melbourne Hospital, Victoria, Australia
- Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Victoria, Australia
| | - Johannes S. Kern
- Departments of Dermatology, Royal Melbourne Hospital, Victoria, Australia
| | - George Varigos
- Departments of Dermatology, Royal Melbourne Hospital, Victoria, Australia
- Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Victoria, Australia
| | - Laura Scardamaglia
- Departments of Dermatology, Royal Melbourne Hospital, Victoria, Australia
- Faculty of Medicine, Dentistry and Health Science, University of Melbourne, Victoria, Australia
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32
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Hachem RR. The role of the immune system in lung transplantation: towards improved long-term results. J Thorac Dis 2019; 11:S1721-S1731. [PMID: 31632749 DOI: 10.21037/jtd.2019.04.25] [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] [Indexed: 12/21/2022]
Abstract
Over the past 35 years, lung transplantation has evolved from an experimental treatment to the treatment of choice for patients with end-stage lung disease. Beyond the immediate period after lung transplantation, rejection and infection are the leading causes of death. The risk of rejection after lung transplantation is generally higher than after other solid organ transplants, and this necessitates more intensive immunosuppression. However, this more intensive treatment does not reduce the risk of rejection sufficiently, and rejection is one of the most common complications after transplantation. There are multiple forms of rejection including acute cellular rejection, antibody-mediated rejection, and chronic lung allograft dysfunction. These have posed a vexing problem for clinicians, patients, and the field of lung transplantation. Confounding matters is the inherent effect of more intensive immunosuppression on the risk of infections. Indeed, infections pose a direct problem resulting in morbidity and mortality and increase the risk of chronic lung allograft dysfunction in the ensuing weeks and months. There are complex interactions between microbes and the immune response that are the subject of ongoing studies. This review focuses on the role of the immune system in lung transplantation and highlights different forms of rejection and the impact of infections on outcomes.
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Affiliation(s)
- Ramsey R Hachem
- Division of Pulmonary & Critical Care, Washington University in St. Louis School of Medicine, St. Louis, MO, USA
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33
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Parulekar AD, Kao CC. Detection, classification, and management of rejection after lung transplantation. J Thorac Dis 2019; 11:S1732-S1739. [PMID: 31632750 DOI: 10.21037/jtd.2019.03.83] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Rejection is a major complication following lung transplantation. Acute cellular rejection, lymphocytic bronchiolitis, and antibody-mediated rejection (AMR) are all risk factors for the subsequent development of chronic lung allograft dysfunction (CLAD). Acute cellular rejection and lymphocytic bronchiolitis have well defined histopathologic diagnostic criteria and grading. Diagnosis of AMR requires a multidisciplinary approach. CLAD is the major barrier to long-term survival following lung transplantation. The most common phenotype of CLAD is bronchiolitis obliterans syndrome (BOS) which is defined by a persistent obstructive decline in lung function. Restrictive allograft dysfunction (RAS) is a second phenotype of CLAD and is associated with a worse prognosis. This article will review the diagnosis, staging, clinical presentation, and treatment of acute rejection, AMR, and CLAD following lung transplantation.
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Affiliation(s)
- Amit D Parulekar
- Section of Pulmonary, Critical Care, and Sleep, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Christina C Kao
- Section of Pulmonary, Critical Care, and Sleep, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
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34
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Gottlieb J, Neurohr C, Müller‐Quernheim J, Wirtz H, Sill B, Wilkens H, Bessa V, Knosalla C, Porstner M, Capusan C, Strüber M. A randomized trial of everolimus-based quadruple therapy vs standard triple therapy early after lung transplantation. Am J Transplant 2019; 19:1759-1769. [PMID: 30615259 PMCID: PMC6590654 DOI: 10.1111/ajt.15251] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 12/04/2018] [Accepted: 12/27/2018] [Indexed: 01/25/2023]
Abstract
Calcineurin inhibitor (CNI) therapy after lung transplantation increases risk of kidney failure. Early everolimus-based quadruple low CNI immunosuppression may improve renal function without compromising efficacy or safety. A prospective, randomized, open-label, 12-month multicenter trial was conducted at 8 German sites. Patients 3-18 months after lung transplantation were randomized (1:1), stratified by baseline estimated glomerular filtration rate (eGFR). In the quadruple low CNI regimen, patients received everolimus (target trough level 3-5 ng/mL) with reduced CNI (tacrolimus 3-5 ng/mL or cyclosporine 25-75 ng/mL) and a cell cycle inhibitor plus prednisone. In the standard triple CNI regimen, patients received tacrolimus (target trough level >5 ng/mL) or cyclosporine (>100 ng/mL) and a cell cycle inhibitor plus prednisone. Of the 180 patients screened, 130 were randomized: 67 in the quadruple low CNI group and 63 in the standard triple CNI group. The primary endpoint (eGFR after 12 months) demonstrated superiority of the quadruple low CNI regimen: 64.5 mL/min vs 54.6 mL/min for the standard triple group (least squares mean, analysis of covariance; P < .001). Key efficacy parameters (biopsy-proven acute rejection, chronic lung allograft dysfunction, and death) and safety endpoints were similar between both groups. Quadruple low CNI immunosuppression early after lung transplantation was demonstrated to be efficacious and safe. Clinical trials registry: ClinicalTrials.gov NCT01404325.
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Affiliation(s)
- Jens Gottlieb
- Department of Respiratory MedicineHannover Medical SchoolHannoverGermany,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH)Member of the German Center for Lung Research (DZL)HannoverGermany
| | - Claus Neurohr
- Grosshadern Medical Clinic and Policlinic VLMU Munich University HospitalMunichGermany
| | | | - Hubert Wirtz
- Internal Medicine/Department of PneumologyLeipzig University HospitalLeipzigGermany
| | - Bjoern Sill
- Department of Cardiovascular SurgeryHamburg‐Eppendorf University HospitalHamburgGermany
| | - Heinrike Wilkens
- Internal Medicine VUniversity Hospital of SaarlandHomburg SaarGermany
| | - Vasiliki Bessa
- Department of PneumologyRuhrlandklinikWest German Center for Lung TransplantationUniversity Hospital EssenUniversity Duisburg‐EssenEssenGermany
| | - Christoph Knosalla
- Department of Cardiothoracic and Vascular SurgeryGerman Heart Institute BerlinDZHK (German Center for Cardiovascular Research)BerlinGermany
| | | | | | - Martin Strüber
- Department of Cardiothoracic SurgeryNewark Beth Israel Medical CenterChildren's Hospital of New JerseyNewarkNew Jersey
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35
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Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant 2019; 38:493-503. [PMID: 30962148 DOI: 10.1016/j.healun.2019.03.009] [Citation(s) in RCA: 612] [Impact Index Per Article: 102.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/18/2019] [Indexed: 02/06/2023] Open
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36
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Glanville AR, Verleden GM, Todd JL, Benden C, Calabrese F, Gottlieb J, Hachem RR, Levine D, Meloni F, Palmer SM, Roman A, Sato M, Singer LG, Tokman S, Verleden SE, von der Thüsen J, Vos R, Snell G. Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant 2019; 38:483-492. [PMID: 31027539 DOI: 10.1016/j.healun.2019.03.008] [Citation(s) in RCA: 196] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/18/2019] [Indexed: 02/07/2023] Open
Affiliation(s)
- Allan R Glanville
- Lung Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia
| | | | - Jamie L Todd
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University, Durham, North Carolina, USA
| | | | - Fiorella Calabrese
- Department of Cardiothoracic and Vascular Sciences, University of Padova Medical School, Padova, Italy
| | - Jens Gottlieb
- Department of Respiratory Medicine, Hannover Medical School, Member of the German Center for Lung Research, Hannover, Germany
| | - Ramsey R Hachem
- Division of Pulmonary & Critical Care, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Deborah Levine
- Pulmonary Disease and Critical Care Medicine, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA
| | - Federica Meloni
- Department of Respiratory Diseases Policlinico San Matteo Foundation & University of Pavia, Pavia, Italy
| | - Scott M Palmer
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University, Durham, North Carolina, USA
| | - Antonio Roman
- Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Masaaki Sato
- Department of Thoracic Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Lianne G Singer
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Sofya Tokman
- Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA
| | | | - Jan von der Thüsen
- Department of Pathology, University Medical Center, Rotterdam, The Netherlands
| | - Robin Vos
- University Hospital Gasthuisberg, Leuven, Belgium
| | - Gregory Snell
- Lung Transplant Service, The Alfred Hospital, Melbourne, Victoria, Australia
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37
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Abstract
Lung transplantation provides a realistic hope of improved survival and enhanced quality of life. However, outcomes can be disappointing, meaning many decisions are highly controversial. Practice is largely based on expert opinion and there is a dearth of high-level evidence. Not surprisingly, this leads to centre-specific practices that may vary considerably in controversial areas. The aim of this review, therefore, is to explore some of those domains and present the available evidence. As the science of lung transplantation approaches its fifth decade, we are only now reaching a critical mass of clinicians and scientific researchers to enable adequately powered studies to assist in informing our approach to some of these controversies. Lung transplantation provides a realistic hope of improved survival and enhanced quality of life. However, outcomes can be disappointing, meaning many decisions are highly controversial. Better evidence is desperately needed.http://ow.ly/Dl4N30maYV9
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Affiliation(s)
- David Abelson
- The Lung Transplant Unit, St Vincent's Hospital, Sydney, Australia
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38
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Kelsh SE, Girgis R, Dickinson M, McDermott JK. Everolimus Use for Intolerance or Failure of Baseline Immunosuppression in Adult Heart and Lung Transplantation. Ann Transplant 2018; 23:744-750. [PMID: 30348935 PMCID: PMC6248067 DOI: 10.12659/aot.910952] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background Everolimus can be utilized after heart or lung transplantation to reduce calcineurin inhibitor associated nephrotoxicity, due to cell cycle inhibitor adverse effects, and as adjunct therapy for rejection, cardiac allograft vasculopathy, and bronchiolitis obliterans syndrome. Material/Methods A single-center, retrospective cohort study was conducted including 51 adult heart transplant patients (n=32) and lung transplant patients (n=19) started on everolimus due to immunosuppressive therapy intolerance or failure, between 2010 and 2017. Everolimus indication, response, efficacy, and tolerability were assessed. Results Everolimus was most commonly initiated due to leukopenia/neutropenia (n=17, 33%) or renal dysfunction (n=13, 25%). Leukopenia/neutropenia resolved in 76% of patients (13 out of 17 patients). Renal function (GFR) increased 7.4 mL/min from baseline to 3 months after everolimus initiation (P=0.011). The most common adverse effects were edema (n=23, 45%) and hyperlipidemia (n=25, 49%). A high discontinuation rate was observed (n=21, 41%), mostly from edema. Conclusions Everolimus might be beneficial in heart and lung transplant patients with leukopenia or neutropenia and lead to modest, short-term renal function improvement. Patient selection is crucial because adverse effects frequently lead to everolimus discontinuation.
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Affiliation(s)
- Shelby E Kelsh
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health, Grand Rapids, MI, USA
| | - Reda Girgis
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health, Grand Rapids, MI, USA.,Department of Medicine, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA
| | - Michael Dickinson
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health, Grand Rapids, MI, USA.,Department of Medicine, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA
| | - Jennifer K McDermott
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health, Grand Rapids, MI, USA.,Department of Medicine, Michigan State University, College of Human Medicine, Grand Rapids, MI, USA
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39
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Abstract
Purpose of the review The number of lung transplantations performed worldwide continues to increase. There is a growing need in these patients for more effective immunosuppressive medications with less toxicity. Recent findings This review article summarizes the recent studies and developments in lung transplant immunosuppression. Novel immunosuppressive medications and strategies used in other solid organ transplantations are being trialed in lung transplantation. This includes the use of co-stimulation blockers like belatacept and mTOR inhibitors like everolimus. Calcineurin sparing regimens have been described in an attempt to minimize nephrotoxicity. Assays to measure the bioactivity of immunosuppressive medications to determine the global immune competence, such as Immuknow assay and Gamma interferon response are gaining traction. Summary Immunosuppression in lung transplant is evolving with the development of newer drugs and promising strategies to optimize immunosuppression. Further studies with multicenter randomized trials are required to increase the strength of the evidence.
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40
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Saldanha IJ, Akinyede O, Robinson KA. Immunosuppressive drug therapy for preventing rejection following lung transplantation in cystic fibrosis. Cochrane Database Syst Rev 2018; 6:CD009421. [PMID: 29921013 PMCID: PMC6513212 DOI: 10.1002/14651858.cd009421.pub4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND For people with cystic fibrosis and advanced pulmonary damage, lung transplantation is an available and viable option. However, graft rejection is an important potential consequence after lung transplantation. Immunosuppressive therapy is needed to prevent episodes of graft rejection and thus subsequently reduce morbidity and mortality in this population. There are a number of classes of immunosuppressive drugs which act on different components of the immune system. There is considerable variability in the use of immunosuppressive agents after lung transplantation in cystic fibrosis. While much of the research in immunosuppressive drug therapy has focused on the general population of lung transplant recipients, little is known about the comparative effectiveness and safety of these agents in people with cystic fibrosis. This is an update of a previously published review. OBJECTIVES To assess the effects of individual drugs or combinations of drugs compared to placebo or other individual drugs or combinations of drugs in preventing rejection following lung transplantation in people with cystic fibrosis. SEARCH METHODS We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the potentially eligible study. We also searched the www.clinicaltrials.gov registry and the World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP) to obtain information on unpublished and ongoing studies.Date of latest search: 29 May 2018. SELECTION CRITERIA Randomised and quasi-randomised studies. DATA COLLECTION AND ANALYSIS We independently assessed the studies identified from our searches for inclusion in the review. Should eligible studies be identified and included in future updates of the review, we will independently extract data and assess the risk of bias. We will use GRADE to summarize our results through a summary of findings table for each comparison we present in the review. MAIN RESULTS While five studies addressed the interventions of interest, we did not include them in the review because the investigators of the studies did not report any information specific to people with cystic fibrosis. Our attempts to obtain this information have not yet been successful. We will include any provided data in future updates of the review. AUTHORS' CONCLUSIONS The lack of currently available evidence makes it impossible to draw conclusions about the comparative efficacy and safety of the various immunosuppressive drugs among people with cystic fibrosis after lung transplantation. A 2013 Cochrane Review comparing tacrolimus with cyclosporine in all lung transplant recipients (not restricted to those with cystic fibrosis) reported no significant difference in mortality and risk of acute rejection. However, tacrolimus use was associated with lower risk of broncholitis obliterans syndrome and arterial hypertension and higher risk of diabetes mellitus. It should be noted that this wider review contained only a small number of included studies (n = 3) with a high risk of bias. Additional randomised studies are required to provide evidence for the benefit and safety of the use of immunosuppressive therapy among people with cystic fibrosis after lung transplantation.
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Affiliation(s)
- Ian J Saldanha
- Center for Evidence Synthesis in Health, Department of Health Services, Policy, and Practice, Brown University School of Public Health, 121 South Main Street, Box G-S121-8, Providence, Rhode Island, USA, 02912
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41
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Abstract
Immunosuppressive therapy is arguably the most important component of medical care after lung transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term allograft function. However, the benefits of immunosuppressive therapy must be balanced against the side effects and major toxicities of these medications. Immunosuppressive agents can be classified as induction agents, maintenance therapies, treatments for acute rejection and chronic rejection and antibody directed therapies. Although induction therapy remains an area of controversy in lung transplantation, it is still used in the majority of transplant centers. On the other hand, maintenance immunosuppression is less contentious; but, unfortunately, since the creation of three-drug combination therapy, including a glucocorticoid, calcineurin inhibitor and anti-metabolite, there have been relatively modest improvements in chronic maintenance immunosuppressive regimens. The presence of HLA antibodies in transplant candidates and development of de novo antibodies after transplantation remain a major therapeutic challenge before and after lung transplantation. In this chapter we review the medications used for induction and maintenance immunosuppression along with their efficacy and side effect profiles. We also review strategies and evidence for HLA desensitization prior to lung transplantation and management of de novo antibody formation after transplant. Finally, we review immune tolerance and the future of lung transplantation to limit the toxicities of conventional immunosuppressive therapy.
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Affiliation(s)
- Luke J Benvenuto
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
| | - Michaela R Anderson
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
| | - Selim M Arcasoy
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
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42
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Jaamei N, Koutsokera A, Pasquier J, Mombelli M, Meylan P, Pascual M, Aubert JD, Manuel O. Clinical significance of post-prophylaxis cytomegalovirus infection in lung transplant recipients. Transpl Infect Dis 2018; 20:e12893. [PMID: 29603543 DOI: 10.1111/tid.12893] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 03/19/2018] [Accepted: 03/20/2018] [Indexed: 12/16/2022]
Abstract
Cytomegalovirus (CMV) disease has been associated with the development of chronic lung allograft dysfunction (CLAD) after transplantation. However, the relevance of CMV replication occurring after the discontinuation of antiviral prophylaxis on the development of CLAD has not been fully established. Patients who underwent lung transplantation during 2004-2014 were included. All patients received antiviral prophylaxis for 3-6 months, followed by monitoring of CMV replication during the first year post-transplantation (preemptive therapy). Risk factors for the development of CLAD were assessed by Cox models. A linear regression model with an interaction coefficient between time and CMV infection was used to evaluate the influence of CMV infection on the evolution of FEV1 . Overall, 69 patients were included, 30/69 (43%) patients developed at least 1 episode of significant CMV infection, and 8/69 (11.5%) patients developed CMV disease. After a median follow-up of 3.67 years, 25/69 (36%) patients developed CLAD and 14/69 (20%) patients died. In the univariate Cox analysis, significant CMV infection (HR 1.177, P = .698), CMV disease (HR 1.001, P = .998), and duration of CMV replication (HR 1.004, P = .758) were not associated with CLAD. Only bacterial pneumonia tended to be associated with CLAD in the multivariate model (HR 2.579, P = .062). We did not observe a significant interaction between CMV replication and evolution FEV1 (interaction coefficient 0.006, CI 95% [-0.084 to 0.096], P = .890). In this cohort of lung transplant recipients receiving antiviral prophylaxis and monitored by preemptive therapy post-prophylaxis, CMV infection did not have impact on long-term allograft lung function.
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Affiliation(s)
- Nikta Jaamei
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Angela Koutsokera
- Division of Pneumology, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Jérôme Pasquier
- Institute for Social and Preventive Medicine, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Matteo Mombelli
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.,Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Pascal Meylan
- Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Manuel Pascual
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - John-David Aubert
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.,Division of Pneumology, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Oriol Manuel
- Transplantation Center, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.,Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
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43
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Salman J, Jansson K, Siemeni T, Sommer W, Knoefel AK, Ahrens L, Nakagiri T, Ius F, Tudorache I, Kruse B, Thissen S, Jonigk D, Strüber M, Haverich A, Warnecke G, Avsar M. Role for primary immunosuppression with everolimus after pulmonary transplantation. Transpl Immunol 2018; 49:12-19. [PMID: 29588160 DOI: 10.1016/j.trim.2018.03.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 03/15/2018] [Accepted: 03/21/2018] [Indexed: 12/31/2022]
Affiliation(s)
- J Salman
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany.
| | - K Jansson
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Th Siemeni
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - W Sommer
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - A-K Knoefel
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - L Ahrens
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - T Nakagiri
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - F Ius
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - I Tudorache
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - B Kruse
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - S Thissen
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - D Jonigk
- Institute for Pathology, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - M Strüber
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - A Haverich
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - G Warnecke
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - M Avsar
- Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany
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44
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Abstract
Immunosuppression management after lung transplantation continues to evolve, with an increasing number of agents available for use in various combinations allowing for more choice and individualization of immunosuppressive therapy. Therapeutic developments have led to improved outcomes including lower acute rejection rates and improved survival. However, a one size fits all approach for any immunosuppressive strategy may not be best suited to the individual patient and ultimately patient specific factors must be considered when designing the immunosuppressive regimen. Recipient factors including age, race, co-morbidities, immunologic risk, genetic polymorphisms, concomitant and previous pharmacotherapy, and overall immunosuppression burden should be considered. There are several significant drug-drug interactions with select immunosuppressive agents utilized in lung transplant pharmacotherapy that must be considered when choosing and devising a dosing strategy for an individual immunosuppressive agent. Herein, considerations for immunosuppression management in the individual patient will be reviewed.
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Affiliation(s)
- Jennifer K McDermott
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health, Grand Rapids, Michigan.,Michigan State University College of Human Medicine, Grand Rapids, Michigan
| | - Reda E Girgis
- Michigan State University College of Human Medicine, Grand Rapids, Michigan
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45
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Van Herck A, Verleden SE, Vanaudenaerde BM, Verleden GM, Vos R. Prevention of chronic rejection after lung transplantation. J Thorac Dis 2017; 9:5472-5488. [PMID: 29312757 DOI: 10.21037/jtd.2017.11.85] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Long-term survival after lung transplantation (LTx) is limited by chronic rejection (CR). Therapeutic strategies for CR have been largely unsuccessful, making prevention of CR an important and challenging therapeutic approach. In the current review, we will discuss current clinical evidence regarding prevention of CR after LTx.
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Affiliation(s)
- Anke Van Herck
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Stijn E Verleden
- Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Bart M Vanaudenaerde
- Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Geert M Verleden
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
| | - Robin Vos
- Department of Respiratory Diseases, University Hospitals Leuven, Leuven, Belgium.,Department of Chronic Diseases, Metabolism & Ageing (CHROMETA), Division of Respiratory Diseases, KU Leuven, Leuven, Belgium
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46
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Abstract
Despite advances in immunosuppression over the past 25 years, acute cellular rejection remains a common complication early after lung transplantation. Although acute cellular rejection has often not resulted in clinical signs or symptoms of allograft dysfunction, it has been widely recognized as a strong independent risk factor for the development of chronic rejection, emphasizing its clinical significance. In recent years, the role of humoral immunity in lung rejection has been increasingly appreciated, and antibody-mediated rejection is now recognized as a form of rejection that may result in allograft failure.
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Affiliation(s)
- Ramsey R Hachem
- Division of Pulmonary and Critical Care, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8052, St Louis, MO 63110, USA.
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47
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Schwarz S, Jaksch P, Klepetko W, Hoetzenecker K. Immunosuppression after lung transplantation: the search for the holy grail continues. J Thorac Dis 2017; 9:1412-1414. [PMID: 28740645 DOI: 10.21037/jtd.2017.04.66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Affiliation(s)
- Stefan Schwarz
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Peter Jaksch
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Walter Klepetko
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Konrad Hoetzenecker
- Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
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48
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Abstract
In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged.
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49
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Recent Advances in Mammalian Target of Rapamycin Inhibitor Use in Heart and Lung Transplantation. Transplantation 2016; 100:2558-2568. [DOI: 10.1097/tp.0000000000001432] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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50
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Strueber M, Warnecke G, Fuge J, Simon AR, Zhang R, Welte T, Haverich A, Gottlieb J. Everolimus Versus Mycophenolate Mofetil De Novo After Lung Transplantation: A Prospective, Randomized, Open-Label Trial. Am J Transplant 2016; 16:3171-3180. [PMID: 27104933 DOI: 10.1111/ajt.13835] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Revised: 03/27/2016] [Accepted: 04/16/2016] [Indexed: 01/25/2023]
Abstract
The role of mammalian target of rapamycin (mTOR) inhibitors in de novo immunosuppression after lung transplantation is not well defined. We compared Everolimus versus mycophenolate mofetil in an investigator-initiated single-center trial in Hannover, Germany. A total of 190 patients were randomly assigned 1:1 on day 28 posttransplantation to mycophenolate mofetil (MMF) or Everolimus combined with cyclosporine A (CsA) and steroids. Patients were followed up for 2 years. The primary endpoint was freedom from bronchiolitis obliterans syndrome (BOS). The secondary endpoints were incidence of acute rejections, infections, treatment failure and kidney function. BOS-free survival in intention-to-treat (ITT) analysis was similar in both groups (p = 0.174). The study protocol was completed by 51% of enrolled patients. The per-protocol analysis shows incidence of bronchiolitis obliterans syndrome (BOS): 1/43 in the Everolimus group and 8/54 in the MMF group (p = 0.041). Less biopsy-proven acute rejection (AR) (p = 0.005), cytomegalovirus (CMV) antigenemia (p = 0.005) and lower respiratory tract infection (p = 0.003) and no leucopenia were seen in the Everolimus group. The glomerular filtration rate (GFR) decreased in both groups about 50% within 6 months. Due to a high withdrawal rate, the study was underpowered to prove a difference in BOS-free survival. The dropout rate was more pronounced in the Everolimus group. Secondary endpoints indicate potential advantages of Everolimus-based protocols but also a potentially higher rate of drug-related serious adverse events.
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Affiliation(s)
- M Strueber
- Richard DeVos Heart & Lung Transplant Program, Frederik Meijer Heart & Vascular Institute, Grand Rapids, MI.
| | - G Warnecke
- Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.,German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany
| | - J Fuge
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - A R Simon
- Department of Heart and Lung Transplantation/VAD, Royal Brompton & Harefield NHS Foundation Trust, London, United Kingdom
| | - R Zhang
- Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - T Welte
- German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany.,Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
| | - A Haverich
- Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.,German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany
| | - J Gottlieb
- German Centre of Lung Research (DZL/BREATH), Hannover Medical School, Hannover, Germany.,Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
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