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Heldman MR, Saullo JL, Menachem BM, Messina JA, Arif S, Steinbrink JM, Tam PC, Carugati M, Wolfe CR, Baker AW, Maziarz EK. Epidemiology of Infections in Lung Transplant Recipients Treated With Belatacept. Transpl Infect Dis 2025; 27:e14403. [PMID: 39494758 PMCID: PMC11867099 DOI: 10.1111/tid.14403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/03/2024] [Accepted: 10/14/2024] [Indexed: 11/05/2024]
Abstract
BACKGROUND Belatacept is a costimulatory blocker that can be used to prevent and treat rejection in lung transplant recipients (LuTRs). The epidemiology of infections in belatacept-treated LuTRs has not been systematically evaluated. METHODS We performed a single-center retrospective study of all adult LuTRs who received belatacept as prevention or treatment of antibody-mediated rejection (desensitization) or as part of maintenance immunosuppression from January 1, 2011, to June 30, 2022. We assessed the epidemiology of infections that occurred within 12 months following the first belatacept dose. RESULTS Fifty-two LuTRs received at least one dose of belatacept as either desensitization (n = 32) or maintenance immunosuppression (n = 20). Among 45 patients who were cytomegalovirus (CMV) donor and/or recipient seropositive, nine (20%) developed CMV infection. Seven (77%) CMV infections occurred despite valganciclovir prophylaxis and four (44%) were associated with antiviral resistance. Three (6%) LuTRs developed Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disorder (PTLD). Twenty-five (48%) LuTRs developed 43 bacterial infections and five (10%) developed proven or probable invasive fungal disease. Incidence rates of viral, bacterial, and fungal infections were similar between the desensitization and maintenance groups: incidence rate ratios (95% confidence interval) were 0.70 (0.32-1.57), 1.31 (0.70-2.46), and 2.82 (0.31-25.2), respectively. Infection/PTLD prompted belatacept discontinuation in eight (15%) patients. CONCLUSIONS In the first year after belatacept initiation, LuTRs commonly developed CMV infections, EBV+ PTLD, and bacterial infections. Multicenter collaborations are needed to better understand infection risks in LuTRs treated with belatacept.
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Affiliation(s)
- Madeleine R. Heldman
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Jennifer L. Saullo
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Brandon M. Menachem
- Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Julia A. Messina
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Sana Arif
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Julie M. Steinbrink
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Patrick C.K. Tam
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Manuela Carugati
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Cameron R. Wolfe
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Arthur W. Baker
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
| | - Eileen K. Maziarz
- Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, NC, USA
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Ortiz V, Loeuillard E. Rethinking Immune Check Point Inhibitors Use in Liver Transplantation: Implications and Resistance. Cell Mol Gastroenterol Hepatol 2024; 19:101407. [PMID: 39326581 PMCID: PMC11609388 DOI: 10.1016/j.jcmgh.2024.101407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 09/18/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, including the two most common liver tumors, hepatocellular carcinoma and cholangiocarcinoma, but their use in the peri-transplantation period is controversial. ICI therapy aims to heighten cytotoxic T lymphocytes response against tumors. However, tumor recurrence is common owing to tumor immune response escape involving ablation of CTL response by interfering with antigen presentation, triggering CLT apoptosis and inducing epigenetic changes that promote ICI therapy resistance. ICI can also affect tissue resident memory T cell population, impact tolerance in the post-transplant period, and induce acute inflammation risking graft survival post-transplant. Their interaction with immunosuppression may be key in reducing tumor burden and may thus, require multimodal therapy to treat these tumors. This review summarizes ICI use in the liver transplantation period, their impact on tolerance and resistance, and new potential therapies for combination or sequential treatments for liver tumors.
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Affiliation(s)
- Vivian Ortiz
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, Missouri.
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3
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C V, B S, M Y, C M, I T, M R, A E. A case report of a lung transplant recipient receiving belatacept in combination with low dose tacrolimus complicated by progressive multifocal leukoencephalopathy. Respir Med Case Rep 2024; 49:102028. [PMID: 38712316 PMCID: PMC11070908 DOI: 10.1016/j.rmcr.2024.102028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Accepted: 04/26/2024] [Indexed: 05/08/2024] Open
Abstract
Belatacept is a novel T-cell costimulation blockade agent that has unresolved controversy in lung transplant recipients. Belatacept has been recognized as a calcineurin sparing agent for solid organ transplant recipients after reported success in renal transplant patients, despite limited evidence in other transplant recipients. We present the first case of a lung transplant recipient receiving Belatacept, in combination with low dose calcineurin inhibitor, who developed progressive multifocal leukoencephalopathy. While Belatacept without calcineurin inhibitor has been associated with increased risk of acute rejection in solid organ transplant recipients, its infectious risk profile in combination with calcineurin inhibitor remains unclear.
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Affiliation(s)
- Vahdatpour C
- Department of Medicine, Pulmonary Hypertension Program, University of Pennsylvania, USA
| | - Saha B
- Department of Pulmonary Critical Care Medicine, University of Florida, USA
| | - Younis M
- Department of Pulmonary Critical Care Medicine, University of Florida, USA
| | - Montuoro C
- Department of Pulmonary Critical Care Medicine, University of Florida, USA
| | - Timofte I
- Department of Pulmonary Critical Care Medicine, University of Texas Southwestern, USA
| | - Rackauskas M
- Department of Surgery, Division of Thoracic Surgery, University of Florida, USA
| | - Emtiazjoo A
- Department of Pulmonary Critical Care Medicine, University of Florida, USA
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4
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Kitchens WH, Larsen CP, Badell IR. Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future. Kidney Int Rep 2023; 8:2529-2545. [PMID: 38106575 PMCID: PMC10719580 DOI: 10.1016/j.ekir.2023.08.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/01/2023] [Accepted: 08/28/2023] [Indexed: 12/19/2023] Open
Abstract
Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.
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Affiliation(s)
- William H. Kitchens
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Christian P. Larsen
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - I. Raul Badell
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
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Bos S, Pradère P, Beeckmans H, Zajacova A, Vanaudenaerde BM, Fisher AJ, Vos R. Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction. Pharmacol Rev 2023; 75:1200-1217. [PMID: 37295951 PMCID: PMC10595020 DOI: 10.1124/pharmrev.123.000834] [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: 02/03/2023] [Revised: 04/27/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023] Open
Abstract
Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplantation, and limited therapeutic options are available to slow the progressive decline in lung function. Most interventions are only temporarily effective in stabilizing the loss of or modestly improving lung function, with disease progression resuming over time in the majority of patients. Therefore, identification of effective treatments that prevent the onset or halt progression of CLAD is urgently needed. As a key effector cell in its pathophysiology, lymphocytes have been considered a therapeutic target in CLAD. The aim of this review is to evaluate the use and efficacy of lymphocyte depleting and immunomodulating therapies in progressive CLAD beyond usual maintenance immunosuppressive strategies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation, and extracorporeal photopheresis, and to explore possible future strategies. When considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for progressive CLAD patients. SIGNIFICANCE STATEMENT: Effective treatments to prevent the onset and progression of chronic lung rejection after lung transplantation are still a major shortcoming. Based on existing data to date, considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin, and total lymphoid irradiation are currently the most viable second-line treatment options. However, it is important to note that interpretation of most results is hampered by the lack of randomized controlled trials.
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Affiliation(s)
- Saskia Bos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Pauline Pradère
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Hanne Beeckmans
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Andrea Zajacova
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Bart M Vanaudenaerde
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Andrew J Fisher
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
| | - Robin Vos
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom (S.B., P.P., A.J.F.); Institute of Transplantation, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, United Kingdom (S.B., A.J.F.); Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph and Paris Saclay University, Department of Respiratory Diseases, Paris, France (P.P.); Department of CHROMETA, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), KU Leuven, Leuven, Belgium (H.B., B.M.V., R.V.); Prague Lung Transplant Program, University Hospital Motol, Department of Pneumology, Prague, Czech Republic (A.Z.); and University Hospitals Leuven, Department of Respiratory Diseases, Leuven, Belgium (R.V.)
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6
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Brugière O, Vallée A, Raimbourg Q, Peraldi MN, de Verdière SC, Beaumont L, Hamid A, Zrounba M, Roux A, Picard C, Parquin F, Glorion M, Oniszczuk J, Hertig A, Mal H, Bunel V. Conversion to belatacept after lung transplantation: Report of 10 cases. PLoS One 2023; 18:e0281492. [PMID: 36920935 PMCID: PMC10016650 DOI: 10.1371/journal.pone.0281492] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/24/2023] [Indexed: 03/16/2023] Open
Abstract
BACKGROUND Calcineurin inhibitors (CNIs) remain the cornerstone of maintenance immunosuppression (IS) after lung transplantation (LTx), although CNI-related life-threatening toxic effects may occur. Belatacept, a novel immunosuppressant that blocks a T-cell co-stimulation pathway, is a non-nephrotoxic drug indicated as an alternative to CNIs in kidney Tx. In LTx, there are only a few reports of belatacept conversion as a CNI-free or CNI-sparing IS treatment. METHODS We reviewed a series of 10 LTx recipients with conversion to a CNI-free belatacept IS regimen within the first year post-LTx (n = 7) or a belatacept/low-dose CNI combination after the first year (n = 3). RESULTS Use of belatacept was triggered by severe renal failure in 9 patients and under-IS with previous other IS-related toxicities in 1 patient. Mean estimated glomerular filtration rate after starting belatacept significantly improved at 6 months after initiation and at the last-follow-up (p = 0.006, and p = 0.002 respectively). The incidence of recurrent and/or severe acute cellular rejection (ACR) episodes was high in patients with CNI-free belatacept-based IS (n = 4/7). Chronic graft allograft dysfunction developed in 2 of 9 recipients under belatacept IS. Belatacept was stopped in 6 patients because of recurrent/severe ACR (n = 3), recurrent opportunistic infections (n = 1), center modified policy (n = 1), or other cause (n = 1). CONCLUSION Early conversion to CNI-free belatacept-based IS improved renal function in this series but was counterbalanced by a high incidence of recurrent ACR, including life-threatening episodes. Other studies are needed to better determine the indications for its use after LTx, possibly with lower immunological risk IS regimens, such as CNI-sparing belatacept.
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Affiliation(s)
- Olivier Brugière
- Service de Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | | | | | | | | | - Laurence Beaumont
- Service de Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | - Abdulmonem Hamid
- Service de Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | - Mathilde Zrounba
- Service de Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | - Antoine Roux
- Service de Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | - Clément Picard
- Service de Transplantation Pulmonaire, Hôpital Foch, Suresnes, France
| | | | | | | | | | - Hervé Mal
- Service de Pneumologie B et de Transplantation Pulmonaire, Hôpital Bichat, Paris, France
| | - Vincent Bunel
- Service de Pneumologie B et de Transplantation Pulmonaire, Hôpital Bichat, Paris, France
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Patterson CM, Jolly EC, Burrows F, Ronan NJ, Lyster H. Conventional and Novel Approaches to Immunosuppression in Lung Transplantation. Clin Chest Med 2023; 44:121-136. [PMID: 36774159 DOI: 10.1016/j.ccm.2022.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Most therapeutic advances in immunosuppression have occurred over the past few decades. Although modern strategies have been effective in reducing acute cellular rejection, excess immunosuppression comes at the price of toxicity, opportunistic infection, and malignancy. As our understanding of the immune system and allograft rejection becomes more nuanced, there is an opportunity to evolve immunosuppression protocols to optimize longer term outcomes while mitigating the deleterious effects of traditional protocols.
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Affiliation(s)
- Caroline M Patterson
- Transplant Continuing Care Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Elaine C Jolly
- Division of Renal Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Fay Burrows
- Department of Pharmacy, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - Nicola J Ronan
- Transplant Continuing Care Unit, Royal Papworth Hospital NHS Foundation Trust, Cambridge, United Kingdom
| | - Haifa Lyster
- Cardiothoracic Transplant Unit, Royal Brompton and Harefield Hospitals, Part of Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom; Kings College, London, United Kingdom; Pharmacy Department, Royal Brompton and Harefield Hospitals, Part of Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.
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8
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Kittleson MM, DeFilippis EM, Bhagra CJ, Casale JP, Cauldwell M, Coscia LA, D'Souza R, Gaffney N, Gerovasili V, Ging P, Horsley K, Macera F, Mastrobattista JM, Paraskeva MA, Punnoose LR, Rasmusson KD, Reynaud Q, Ross HJ, Thakrar MV, Walsh MN. Reproductive health after thoracic transplantation: An ISHLT expert consensus statement. J Heart Lung Transplant 2023; 42:e1-e42. [PMID: 36528467 DOI: 10.1016/j.healun.2022.10.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
Pregnancy after thoracic organ transplantation is feasible for select individuals but requires multidisciplinary subspecialty care. Key components for a successful pregnancy after lung or heart transplantation include preconception and contraceptive planning, thorough risk stratification, optimization of maternal comorbidities and fetal health through careful monitoring, and open communication with shared decision-making. The goal of this consensus statement is to summarize the current evidence and provide guidance surrounding preconception counseling, patient risk assessment, medical management, maternal and fetal outcomes, obstetric management, and pharmacologic considerations.
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Affiliation(s)
- Michelle M Kittleson
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California.
| | - Ersilia M DeFilippis
- Division of Cardiology, New York Presbyterian-Columbia University Irving Medical Center, New York, New York
| | - Catriona J Bhagra
- Department of Cardiology, Cambridge University and Royal Papworth NHS Foundation Trusts, Cambridge, UK
| | - Jillian P Casale
- Department of Pharmacy Services, University of Maryland Medical Center, Baltimore, Maryland
| | - Matthew Cauldwell
- Department of Obstetrics, Maternal Medicine Service, St George's Hospital, London, UK
| | - Lisa A Coscia
- Transplant Pregnancy Registry International, Gift of Life Institute, Philadelphia, Pennsylvania
| | - Rohan D'Souza
- Division of Maternal and Fetal Medicine, Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
| | - Nicole Gaffney
- Lung Transplant Service, Alfred Hospital, Melbourne, Australia; Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia
| | | | - Patricia Ging
- Department of Pharmacy, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Kristin Horsley
- Department of Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada
| | - Francesca Macera
- De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milan, Italy; Dept of Cardiology, Cliniques Universitaires de Bruxelles - Hôpital Erasme, Brussels, Belgium
| | - Joan M Mastrobattista
- Department of Obstetrics & Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine Houston, Texas
| | - Miranda A Paraskeva
- Lung Transplant Service, Alfred Hospital, Melbourne, Australia; Department of Medicine, Central Clinical School, Monash University, Melbourne, Australia
| | - Lynn R Punnoose
- Vanderbilt Heart and Vascular Institute, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Quitterie Reynaud
- Cystic Fibrosis Adult Referral Care Centre, Department of Internal Medicine, Hospices civils de Lyon, Pierre Bénite, France
| | - Heather J Ross
- Peter Munk Cardiac Centre of the University Health Network, Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada
| | - Mitesh V Thakrar
- Department of Medicine, Division of Respirology, University of Calgary, Calgary, Alberta, Canada
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9
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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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10
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Sharma D, Sharma N, Subramaniam KG. Curbing Proteastasis to Combat Antibody-Mediated Rejection Post Lung Transplant. INDIAN JOURNAL OF TRANSPLANTATION 2023; 17:12-15. [DOI: 10.4103/ijot.ijot_33_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 01/30/2023] [Indexed: 04/03/2023] Open
Abstract
Lung transplantation (LTx) has emerged as the treatment of choice for patients suffering from end-stage lung disease all over the past 35 years. Despite ameliorated early survival with a median survival of 6.5 years, its long-term outcomes are dissatisfactory. Although antibody-mediated rejection (AMR) remained “the Achilles heel of LTx,” yet we have not attained consensus on the optimal therapeutic approach. The aim of this review article is to address the upcoming role of proteasome inhibitor drugs in managing AMR post-LTx.
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Affiliation(s)
- Dhruva Sharma
- Department of Cardiothoracic and Vascular Surgery, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan, India
| | - Neha Sharma
- Department of Pharmacology, SMS Medical College and Attached Hospitals, Jaipur, Rajasthan, India
| | - Krishnan Ganapathy Subramaniam
- Department of Cardiothoracic and Vascular Surgery, Sri Padmavathi Children Heart Centre, Tirupati, Andhra Pradesh, India
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11
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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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12
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Grootjans H, Verschuuren EAM, van Gemert JP, Kerstjens HAM, Bakker SJL, Berger SP, Gan CT. Chronic kidney disease after lung transplantation in a changing era. Transplant Rev (Orlando) 2022; 36:100727. [PMID: 36152358 DOI: 10.1016/j.trre.2022.100727] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 08/26/2022] [Accepted: 09/10/2022] [Indexed: 10/14/2022]
Abstract
Lung transplant (LTx) physicians are responsible for highly complex post-LTx care, including monitoring of kidney function and responding to kidney function loss. Better survival of the LTx population and changing patient characteristics, including older age and increased comorbidity, result in growing numbers of LTx patients with chronic kidney disease (CKD). CKD after LTx is correlated with worse survival, decreased quality of life and high costs. Challenges lie in different aspects of post-LTx renal care. First, serum creatinine form the basis for estimating renal function, under the assumption that patients have stable muscle mass. Low or changes in muscle mass is frequent in the LTx population and may lead to misclassification of CKD. Second, standardizing post-LTx monitoring of kidney function and renal care might contribute to slow down CKD progression. Third, new treatment options for CKD risk factors, such as diabetes mellitus, proteinuria and heart failure, have entered clinical practice. These new treatments have not been studied in LTx yet but are of interest for future use. In this review we will address the difficult aspects of post-LTx renal care and evaluate new and promising future approaches to slow down CKD progression.
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Affiliation(s)
- Heleen Grootjans
- Department of Pulmonology and Tuberculosis, Lung Transplantation Program, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
| | - Erik A M Verschuuren
- Department of Pulmonology and Tuberculosis, Lung Transplantation Program, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Johanna P van Gemert
- Department of Pulmonology and Tuberculosis, Lung Transplantation Program, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Huib A M Kerstjens
- Department of Pulmonology and Tuberculosis, Lung Transplantation Program, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Stephan J L Bakker
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Stefan P Berger
- Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - C Tji Gan
- Department of Pulmonology and Tuberculosis, Lung Transplantation Program, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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13
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Iglesias M, Brennan DC, Larsen CP, Raimondi G. Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection. Front Immunol 2022; 13:926648. [PMID: 36119093 PMCID: PMC9478663 DOI: 10.3389/fimmu.2022.926648] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.
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Affiliation(s)
- Marcos Iglesias
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
| | - Daniel C. Brennan
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Christian P. Larsen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Giorgio Raimondi
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
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14
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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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15
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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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16
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Huang HJ, Schechtman K, Askar M, Bernadt C, Mittler B, Dore P, Witt C, Byers D, Vazquez-Guillamet R, Halverson L, Nava R, Puri V, Gelman A, Kreisel D, Hachem RR. A pilot randomized controlled trial of de novo belatacept-based immunosuppression following anti-thymocyte globulin induction in lung transplantation. Am J Transplant 2022; 22:1884-1892. [PMID: 35286760 PMCID: PMC9262777 DOI: 10.1111/ajt.17028] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 01/25/2023]
Abstract
The development of donor-specific antibodies (DSA) after lung transplantation is common and results in adverse outcomes. In kidney transplantation, Belatacept has been associated with a lower incidence of DSA, but experience with Belatacept in lung transplantation is limited. We conducted a two-center pilot randomized controlled trial of de novo immunosuppression with Belatacept after lung transplantation to assess the feasibility of conducting a pivotal trial. Twenty-seven participants were randomized to Control (Tacrolimus, Mycophenolate Mofetil, and prednisone, n = 14) or Belatacept-based immunosuppression (Tacrolimus, Belatacept, and prednisone until day 89 followed by Belatacept, Mycophenolate Mofetil, and prednisone, n = 13). All participants were treated with rabbit anti-thymocyte globulin for induction immunosuppression. We permanently stopped randomization and treatment with Belatacept after three participants in the Belatacept arm died compared to none in the Control arm. Subsequently, two additional participants in the Belatacept arm died for a total of five deaths compared to none in the Control arm (log rank p = .016). We did not detect a significant difference in DSA development, acute cellular rejection, or infection between the two groups. We conclude that the investigational regimen used in this study is associated with increased mortality after lung transplantation.
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Affiliation(s)
| | | | - Medhat Askar
- Department of Pathology and Laboratory Medicine, Texas A & M College of Medicine
| | - Cory Bernadt
- Department of Pathology and Immunology, Washington University in St. Louis
| | - Brigitte Mittler
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | - Peter Dore
- Division of Biostatistics, Washington University in St. Louis
| | - Chad Witt
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | - Derek Byers
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | | | - Laura Halverson
- Division of Pulmonary and Critical Care, Washington University in St. Louis
| | - Ruben Nava
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Varun Puri
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Andrew Gelman
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Daniel Kreisel
- Division of Cardiothoracic Surgery, Washington University in St. Louis
| | - Ramsey R. Hachem
- Division of Pulmonary and Critical Care, Washington University in St. Louis
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17
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Effect of MMF Immunosuppression Based on CNI Reduction on CNI-Related Renal Damage after Lung Transplantation. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:8099684. [PMID: 35126949 PMCID: PMC8808151 DOI: 10.1155/2022/8099684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/14/2021] [Accepted: 12/30/2021] [Indexed: 01/31/2023]
Abstract
In this paper, numerous effects of immunosuppressive regimen of mycophenolate mofetil (MMF) on CNI-related renal damage after lung transplantation are evaluated thoroughly. For this purpose, 110 lung transplant recipients who were treated in our hospital from March 2016 to January 2018 were randomly selected. All patients took prednisone acetate tablets or rapamycin at the same time or not at the same time. MMF is 1 g every time, twice a day, and adjusted according to the re-examination. According to the different drugs taken by 110 patients, they were divided into cyclosporine A group and tacrolimus group. Among them, 92 patients in cyclosporine A group took cyclosporine A; 18 patients in tacrolimus group took tacrolimus. The clinical data of age and gender of the two groups were collected, To observe and compare the occurrence of CNI-related renal damage in lung transplant recipients and different immunosuppressants. The CNI dosage of tacrolimus group and cyclosporine A group was compared before and after MMF. The changes of serum creatinine level and serum creatinine clearance rate were measured before MMF administration and 30, 60, and 90 days after MMF administration, to observe the complications of CNI-related renal damage after lung transplantation. Experimental results showed that there were 16 cases (14.55%) of CNI-related renal damage in lung transplant recipients and different immunosuppressants, including 10 cases (11.36%) in males, 6 cases (27.27%) in females, 11 cases (12.09%) in tacrolimus group, and 5 cases (26.32%) in cyclosporine A group. There was no significant difference between the two groups (P > 0.05). Compared with MMF before and after administration, CNI dosage of cyclosporine A group and tacrolimus group decreased significantly (P < 0.01). Compared with MMF before administration, serum creatinine level decreased and serum creatinine clearance rate increased significantly (P < 0.05). In the follow-up, 16 patients with CNI-related renal damage were found to be immune rejection before the adjustment of immunosuppression program, no complications such as immune rejection, myelosuppression, and infection occurred within 15 months after the adjustment of immunosuppression program, blood glucose increased in 3 patients within 2 years after operation, blood lipid increased in 1 patient, urea increased in 1 patient, and uric acid increased in 1 patient. MMF immunosuppressive therapy based on CNI reduction is a safe and effective immunosuppressive therapy, which can significantly reduce immune rejection, improve renal function, and play an important role in improving CNI-related renal damage after lung transplantation.
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18
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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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19
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Mejia C, Yadav A. Kidney Disease After Nonkidney Solid Organ Transplant. Adv Chronic Kidney Dis 2021; 28:577-586. [PMID: 35367026 DOI: 10.1053/j.ackd.2021.10.010] [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: 08/25/2021] [Revised: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 11/11/2022]
Abstract
Nonkidney solid organ transplants (NKSOTs) are increasing in the United States with improving long-term allograft and patient survival. CKD is prevalent in patients with NKSOT and is associated with increased morbidity and mortality especially in those who progress to end-stage kidney disease. Calcineurin inhibitor nephrotoxicity is a main contributor to CKD after NKSOT, but other factors in the pretransplant, peritransplant, and post-transplant period can predispose to progressive kidney dysfunction. The management of CKD after NKSOT generally follows society guidelines for native kidney disease. Kidney-protective and calcineurin inhibitor-sparing immunosuppression has been explored in this population and warrants a discussion with transplant teams. Kidney transplantation in NKSOT recipients remains the kidney replacement therapy of choice for suitable candidates, as it provides a survival benefit over remaining on dialysis.
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20
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Nachiappan A, Fallah T, Willert R, Chojnowski D, Deshpande C, Courtwright A. Severe Acute Cellular Rejection With High-Grade Lymphocytic Bronchiolitis Following Transition from Tacrolimus to Belatacept in a Lung Transplantation Recipient: A Case Report. Transplant Proc 2021; 54:165-168. [PMID: 34756649 DOI: 10.1016/j.transproceed.2021.08.051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/19/2021] [Accepted: 08/30/2021] [Indexed: 12/01/2022]
Abstract
This case report describes a lung transplantation recipient who developed severe acute cellular rejection with high-grade lymphocytic bronchiolitis after transition to a calcineurin-free regimen using belatacept. A 53-year-old man who had undergone lung transplantation 3 years prior developed progressive chronic kidney disease related to tacrolimus. He was transitioned off tacrolimus to belatacept to prevent the need for dialysis. He was admitted 2 months later with acute hypoxemic respiratory failure. Video-assisted thoracic surgery biopsy showed acute fibrinous and organizing pneumonia and A4B2 rejection. He subsequently developed chronic lung allograft dysfunction. This case illustrates the potential increased risk of acute rejection associated with belatacept maintenance immunosuppression.
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Affiliation(s)
- Arun Nachiappan
- Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tara Fallah
- Advanced Lung Disease and Lung Transplantation, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rebecca Willert
- Advanced Lung Disease and Lung Transplantation, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Donna Chojnowski
- Advanced Lung Disease and Lung Transplantation, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Charuhas Deshpande
- Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Andrew Courtwright
- Advanced Lung Disease and Lung Transplantation, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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21
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Non-pulmonary complications after lung transplantation: Part I. Indian J Thorac Cardiovasc Surg 2021; 38:280-289. [DOI: 10.1007/s12055-021-01223-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/23/2021] [Accepted: 06/03/2021] [Indexed: 01/15/2023] Open
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22
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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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23
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Infectious Challenges with Novel Antibody–Based Therapies. Curr Infect Dis Rep 2021. [DOI: 10.1007/s11908-021-00753-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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24
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Jing L, Chen W, Guo L, Zhao L, Liang C, Chen J, Wang C. Acute kidney injury after lung transplantation: a narrative review. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:717. [PMID: 33987415 PMCID: PMC8106087 DOI: 10.21037/atm-20-7644] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Acute kidney injury (AKI) is a commonly recognized complication after lung transplantation (LT) and is related to increased mortality and morbidity. With the improvement of survival after LT and the increasing number of lung transplant recipients, the detrimental impact of current management on renal function has become increasingly apparent. Multifarious risk factors in the perioperative setting contribute to the development of AKI, including the preoperative status and complications of the recipient, complex perioperative problems especially hemodynamic fluctuation, and exposure to nephrotoxic agents, mainly calcineurin inhibitors (CNIs) and antimicrobial drugs. Identification and minimization of the effects of these risk factors can relieve AKI severity and incidence in high-risk patients. Close monitoring of urine output and serum creatinine (sCr) levels and of specific biomarkers may promote early recognition of AKI and rapid nephrology intervention to improve outcomes. This review summarizes advances in the epidemiology, diagnostic criteria, biological markers of AKI, and further recommends appropriate treatment strategies for the long-term management of AKI related manifestations in lung transplant recipients. Future work will need to focus on developing more accurate measures of renal function and identifying patients before the occurrence of early renal damage. Combining renal protection strategies with the use of new biomarkers to develop early kidney risk identification and protection protocols is a promising idea that requires further investigation.
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Affiliation(s)
- Lei Jing
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Wenhui Chen
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Lijuan Guo
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Li Zhao
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Chaoyang Liang
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Jingyu Chen
- Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
| | - Chen Wang
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Department of Lung Transplantation, Centre of Lung Transplantation, Centre of Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China.,National Center for Respiratory Medicine, Beijing, China.,Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, Beijing, China.,National Clinical Research Center for Respiratory Diseases, Beijing, China.,WHO Collaborating Centre for Tobacco Cessation and Respiratory Diseases Prevention, Beijing, China
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25
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Sharma D, Sharma N. A potential drug in the armamentarium of post-cardiac transplantation immunosuppression: belatacept. Indian J Thorac Cardiovasc Surg 2020; 36:625-628. [PMID: 33100623 PMCID: PMC7572983 DOI: 10.1007/s12055-020-00991-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/12/2020] [Accepted: 06/19/2020] [Indexed: 10/23/2022] Open
Abstract
Undeterred by all the advancement in the field of cardiac transplantation, heart transplant rejection remained its mammoth quandary. Management of heart transplant recipients has drastically improved with current regimens of immunosuppressive drugs. The adverse effects of calcineurin inhibitors are lacking with the use of belatacept, which is a costimulation inhibitor that interferes with the interaction between CD28 on T cells and the B7 ligands on antigen-presenting cells. It was originally approved for use in renal transplant recipients but it has shown promising results in heart transplant recipients.
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Affiliation(s)
- Dhruva Sharma
- Department of Cardiothoracic & Vascular Surgery, SMS Medical College & Attached Group of Hospitals, Jaipur, India
| | - Neha Sharma
- Department of Pharmacology, SMS Medical College, Jaipur, India
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26
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Xiu MX, Liu ZT, Tang J. Screening and identification of key regulatory connections and immune cell infiltration characteristics for lung transplant rejection using mucosal biopsies. Int Immunopharmacol 2020; 87:106827. [PMID: 32791489 PMCID: PMC7417178 DOI: 10.1016/j.intimp.2020.106827] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 07/03/2020] [Accepted: 07/20/2020] [Indexed: 02/06/2023]
Abstract
This study aimed to explore key regulatory connections underlying lung transplant rejection. The differentially expressed genes (DEGs) between rejection and stable lung transplantation (LTx) samples were screened using R package limma, followed by functional enrichment analysis and protein-protein interaction network construction. Subsequently, a global triple network, including miRNAs, mRNAs, and transcription factors (TFs), was constructed. Furthermore, immune cell infiltration characteristics were analyzed to investigate the molecular immunology of lung transplant rejection. Finally, potential drug-target interactions were generated. In brief, 739 DEGs were found between rejection and stable LTx samples. PTPRC, IL-6, ITGAM, CD86, TLR8, TYROBP, CXCL10, ITGB2, and CCR5 were defined as hub genes. Eight TFs, including STAT1, SPIB, NFKB1, SPI1, STAT5A, RUNX1, VENTX, and BATF, and five miRNAs, including miR-335-5p, miR-26b-5p, miR-124-3p, miR-1-3p, and miR-155-5p, were involved in regulating hub genes. The immune cell infiltration analysis revealed higher proportions of activated memory CD4 T cells, follicular helper T cells, γδ T cells, monocytes, M1 and M2 macrophages, and eosinophils in rejection samples, besides lower proportions of resting memory CD4 T cells, regulatory T cells, activated NK cells, M0 macrophages, and resting mast cells. This study provided a comprehensive perspective of the molecular co-regulatory network underlying lung transplant rejection.
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Affiliation(s)
- Meng-Xi Xiu
- Medical School of Nanchang University, Nanchang, PR China
| | - Zu-Ting Liu
- Medical School of Nanchang University, Nanchang, PR China
| | - Jian Tang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, PR China.
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27
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van der Mark SC, Hoek RAS, Hellemons ME. Developments in lung transplantation over the past decade. Eur Respir Rev 2020; 29:190132. [PMID: 32699023 PMCID: PMC9489139 DOI: 10.1183/16000617.0132-2019] [Citation(s) in RCA: 81] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 01/30/2020] [Indexed: 12/12/2022] Open
Abstract
With an improved median survival of 6.2 years, lung transplantation has become an increasingly acceptable treatment option for end-stage lung disease. Besides survival benefit, improvement of quality of life is achieved in the vast majority of patients. Many developments have taken place in the field of lung transplantation over the past decade. Broadened indication criteria and bridging techniques for patients awaiting lung transplantation have led to increased waiting lists and changes in allocation schemes worldwide. Moreover, the use of previously unacceptable donor lungs for lung transplantation has increased, with donations from donors after cardiac death, donors with increasing age and donors with positive smoking status extending the donor pool substantially. Use of ex vivo lung perfusion further increased the number of lungs suitable for lung transplantation. Nonetheless, the use of these previously unacceptable lungs did not have detrimental effects on survival and long-term graft outcomes, and has decreased waiting list mortality. To further improve long-term outcomes, strategies have been proposed to modify chronic lung allograft dysfunction progression and minimise toxic immunosuppressive effects. This review summarises the developments in clinical lung transplantation over the past decade.
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Affiliation(s)
- Sophie C van der Mark
- Dept of Pulmonary Medicine, Division of Interstitial Lung Disease, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands
- Authors contributed equally
| | - Rogier A S Hoek
- Dept of Pulmonary Medicine, Division of Lung Transplantation, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands
- Authors contributed equally
| | - Merel E Hellemons
- Dept of Pulmonary Medicine, Division of Interstitial Lung Disease, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands
- Dept of Pulmonary Medicine, Division of Lung Transplantation, Erasmus Medical Centre Rotterdam, Rotterdam, The Netherlands
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28
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Cheng CH, Lee CF, Oh BC, Furtmüller GJ, Patel CH, Brandacher G, Powell JD. Targeting Metabolism as a Platform for Inducing Allograft Tolerance in the Absence of Long-Term Immunosuppression. Front Immunol 2020; 11:572. [PMID: 32328063 PMCID: PMC7161684 DOI: 10.3389/fimmu.2020.00572] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2019] [Accepted: 03/12/2020] [Indexed: 12/14/2022] Open
Abstract
Transplant tolerance in the absence of long-term immunosuppression has been an elusive goal for solid organ transplantation. Recently, it has become clear that metabolic reprogramming plays a critical role in promoting T cell activation, differentiation, and function. Targeting metabolism can preferentially inhibit T cell effector generation while simultaneously promoting the generation of T regulatory cells. We hypothesized that costimulatory blockade with CTLA4Ig in combination with targeting T cell metabolism might provide a novel platform to promote the induction of transplant tolerance.
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Affiliation(s)
- Chih-Hsien Cheng
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung Transplantation Institute, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Chen-Fang Lee
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Department of Liver and Transplantation Surgery, Chang-Gung Memorial Hospital, Chang-Gung Transplantation Institute, Chang-Gung University College of Medicine, Taoyuan, Taiwan
| | - Byoung Chol Oh
- Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Georg J Furtmüller
- Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Chirag H Patel
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Gerald Brandacher
- Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Jonathan D Powell
- Sidney∼Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.,Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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29
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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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30
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De Novo Belatacept in a Kidney-After-Heart Transplant Recipient. Transplant Direct 2020; 6:e515. [PMID: 32047843 PMCID: PMC6964935 DOI: 10.1097/txd.0000000000000967] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/04/2019] [Accepted: 11/08/2019] [Indexed: 11/26/2022] Open
Abstract
Renal injury almost always accompanies the multisystem organ failure that precedes cardiac transplantation and renal function is further compromised by the nephrotoxicity of calcineurin inhibitors posttransplant. Renal dysfunction in turn causes significant morbidity and mortality. The development of belatacept was motivated by need for an alternative to calcineurin-based immunosuppression, particularly in renal transplantation where the nephrotoxicity of calcineurin inhibitors reduce graft longevity and adverse cardiovascular effects of calcineurin inhibitors increase overall mortality. In 2011, the FDA approved belatacept for use in renal transplantation. Seven-year data from the multicenter randomized phase III BENEFIT trial, which compared belatacept with cyclosporine in renal transplant recipients, show belatacept therapy offers both improved renal function and 43% risk reduction for the combined endpoint of graft loss and death. At present, belatacept use is predominantly confined to renal transplant recipients; however, reports of belatacept use in other transplant settings are emerging. Here, we describe successful long-term use of belatacept in a kidney-after-heart transplant recipient and review use of belatacept in cardiothoracic and other nonrenal transplant settings.
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31
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Launay M, Guitard J, Dorent R, Prevot Y, Prion F, Beaumont L, Kably B, Lecuyer L, Billaud EM, Guillemain R. Belatacept-based immunosuppression: A calcineurin inhibitor-sparing regimen in heart transplant recipients. Am J Transplant 2020; 20:553-563. [PMID: 31452337 DOI: 10.1111/ajt.15584] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 08/12/2019] [Accepted: 08/13/2019] [Indexed: 01/25/2023]
Abstract
Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35 ± 20 mL/min/m2 were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P = .0002*) within 1 month, particularly in the early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n = 4), DSA no longer detectable (n = 1), compliance issues (n = 3), poor venous access (n = 2), multiple infections (n = 1), 1 death (fungal lung infection), and treatment failure (n = 4). Median follow-up was 24 months. Four patients developed de novo DSA (MFI<1500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring.
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Affiliation(s)
- Manon Launay
- Pharmacology and Toxicology Laboratory, Georges Pompidou European Hospital - APHP, Paris, France.,Paris-Descartes University, Paris, France
| | - Joelle Guitard
- Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Richard Dorent
- Department of Cardiac Surgery, AP-HP, Bichat-Claude Bernard Hospital, Paris, France
| | - Yoann Prevot
- Heart and Lung Transplantation, Georges Pompidou European Hospital - APHP, Paris, France
| | - Florent Prion
- Department of Cardiac Surgery, AP-HP, Bichat-Claude Bernard Hospital, Paris, France
| | - Laurence Beaumont
- Pulmonology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Foch Hospital, Suresnes, France
| | - Benjamin Kably
- Pharmacology and Toxicology Laboratory, Georges Pompidou European Hospital - APHP, Paris, France
| | - Lucien Lecuyer
- Heart and Lung Transplantation, Georges Pompidou European Hospital - APHP, Paris, France
| | - Eliane M Billaud
- Pharmacology and Toxicology Laboratory, Georges Pompidou European Hospital - APHP, Paris, France.,Paris-Descartes University, Paris, France
| | - Romain Guillemain
- Heart and Lung Transplantation, Georges Pompidou European Hospital - APHP, Paris, France
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32
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Belatacept in Solid Organ Transplant: Review of Current Literature Across Transplant Types. Transplantation 2019; 102:1440-1452. [PMID: 29787522 DOI: 10.1097/tp.0000000000002291] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Calcineurin inhibitors (CNIs) have been the backbone immunosuppressant for solid organ transplant recipients for decades. Long-term use of CNIs unfortunately is associated with multiple toxicities, with the biggest concern being CNI-induced nephrotoxicity. Belatacept is a novel agent approved for maintenance immunosuppression in renal transplant recipients. In the kidney transplant literature, it has shown promise as being an alternative agent by preserving renal function and having a minimal adverse effect profile. There are emerging studies of its use in other organ groups, particularly liver transplantation, as well as using with other alternative immunosuppressive strategies. The purpose of this review is to analyze the current literature of belatacept use in solid organ transplantation and discuss its use in current practice.
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33
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Maintenance Belatacept-Based Immunosuppression in Lung Transplantation Recipients Who Failed Calcineurin Inhibitors. Transplantation 2018; 102:171-177. [PMID: 28691954 DOI: 10.1097/tp.0000000000001873] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Traditional immunosuppressive regimens (ISR) used in lung transplantation rely on calcineurin inhibitors (CNI) that occasionally cause severe adverse reactions necessitating discontinuation. Belatacept is a novel costimulation antagonist approved for use in renal transplantation which lacks data in lung transplantation. This series aims to describe the response to belatacept ISR in 11 lung transplantation recipients after CNI failure. METHODS Single-center, retrospective medical record review of adult lung transplant recipients (LTR) before and after conversion to belatacept-based ISR. Patients were evaluated at fixed time points before and after belatacept initiation. Primary outcome was incidence of acute cellular rejection (ACR). Secondary outcomes included incidence of infection, chronic lung allograft dysfunction (CLAD) progression, death, change in mean arterial pressure, and estimated glomerular filtration rate. RESULTS Eleven LTRs received belatacept with a mean of 246 (91-1064) days of follow-up after conversion. Four were changed to belatacept for thrombotic thrombocytopenic purpura, 3 for posterior reversible encephalopathy syndrome, 2 for recurrent ACR, 1 for CLAD, and 1 for renal-sparing. ACR was not different before and after belatacept (P = 0.17). Mean estimated glomerular filtration rate was significantly higher postbelatacept (32.53 vs 45.26, P = 0.04). Mean incidence of infections (24.4% vs 16.0%, P = 0.55) and mean arterial pressure (97.5 vs 92.1 P = 0.38) were not different. Progression of CLAD occurred in 2 patients. At the end of follow-up, 7 of 11 patients were alive. CONCLUSIONS Belatacept-based ISR appear to produce reasonable results in LTRs who fail CNI-based ISR. Larger prospective trials appear warranted in lung transplantation.
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34
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Ensor CR, Goehring KC, Iasella CJ, Moore CA, Lendermon EA, McDyer JF, Morrell MR, Sciortino CM, Venkataramanan R, Wiland AM. Belatacept for maintenance immunosuppression in cardiothoracic transplantation: The potential frontier. Clin Transplant 2018; 32:e13363. [PMID: 30058177 DOI: 10.1111/ctr.13363] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 07/21/2018] [Accepted: 07/23/2018] [Indexed: 01/18/2023]
Abstract
Current immunosuppressive regimens with calcineurin inhibitors have improved the management of patients after transplantation. However, their adverse effects are linked to increased morbidity and limit the long-term survival of heart and lung transplant recipients. Belatacept, a costimulation inhibitor interfering with the interaction between CD28 on T cells and the B7 ligands on antigen presenting cells, has shown success and is currently approved for use in renal transplant recipients. Furthermore, it lacks many of the cardiovascular, metabolic, neurologic, and renal adverse of effects of calcineurin inhibitors that have the largest impact on long-term survival in cardiothoracic transplant. Additionally, it requires no therapeutic drug monitoring and is only administered once a month. Limitations to belatacept use have been observed that must be considered when comparing immunosuppression options. Despite this, maintenance immunosuppression with belatacept has the potential to improve outcomes in cardiothoracic transplant recipients, as it has with kidney transplant recipients. However, no large clinical trials investigating belatacept for maintenance immunosuppression in heart and lung transplant recipients exist. There is a large need for focused research of belatacept in cardiothoracic transplantation. Belatacept is a viable treatment option for maintenance immunosuppression, and it is reasonable to pursue more evidence in cardiothoracic transplant recipients.
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Affiliation(s)
- Christopher R Ensor
- Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | | | - Carlo J Iasella
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
| | - Cody A Moore
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
| | - Elizabeth A Lendermon
- Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - John F McDyer
- Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Matthew R Morrell
- Division of Pulmonary Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Christopher M Sciortino
- Department of Cardiothoracic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Raman Venkataramanan
- Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania
| | - Anne M Wiland
- Norvartis Pharmaceuticals Corporation, Baltimore, Maryland
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35
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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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36
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Schwarz C, Mahr B, Muckenhuber M, Wekerle T. Belatacept/CTLA4Ig: an update and critical appraisal of preclinical and clinical results. Expert Rev Clin Immunol 2018; 14:583-592. [PMID: 29874474 DOI: 10.1080/1744666x.2018.1485489] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The B7/CD28/CTLA4 signaling cascade is the most thoroughly studied costimulatory pathway and blockade with CTLA4Ig (abatacept) or its derivative belatacept has emerged as a valuable option for pharmacologic immune modulation. Several clinical studies have ultimately led to the approval of belatacept for immunosuppression in kidney transplant recipients. Areas covered: This review will discuss the immunological background of costimulation blockade and recent preclinical data and clinical results of CTLA4Ig/belatacept. Expert commentary: The development of belatacept is a major advance in clinical transplantation. However, in spite of promising results in preclinical and clinical trials, clinical use remains limited at present, in part due to increased rates of acute rejection. Recent efforts showing encouraging progress in refining such protocols might be a step toward harnessing the full potential of costimulation blockade-based immunosuppression.
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Affiliation(s)
- Christoph Schwarz
- a Division of General Surgery, Department of Surgery , Medical University of Vienna , Vienna , Austria.,b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
| | - Benedikt Mahr
- b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
| | - Moritz Muckenhuber
- b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
| | - Thomas Wekerle
- b Section of Transplantation Immunology, Department of Surgery , Medical University of Vienna , Vienna , Austria
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37
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38
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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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39
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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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40
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Kumar D, LeCorchick S, Gupta G. Belatacept As an Alternative to Calcineurin Inhibitors in Patients with Solid Organ Transplants. Front Med (Lausanne) 2017; 4:60. [PMID: 28580358 PMCID: PMC5437176 DOI: 10.3389/fmed.2017.00060] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 05/01/2017] [Indexed: 12/28/2022] Open
Abstract
The goal of immunosuppression in transplantation has shifted to improving long-term outcomes, reducing drug-induced toxicities while preserving the already excellent short-term outcomes. Long-term gains in solid organ transplantation have been limited at least partly due to the nephrotoxicity and metabolic side effects of calcineurin inhibitors (CNIs). The alloimmune response requires activation of the costimulatory pathway for T cell proliferation and amplification. Belatacept is a molecule that selectively blocks T cell costimulation. In June 2011, the U.S. Food and Drug Administration approved it for maintenance immunosuppression in kidney transplantation based on two open-label, randomized, phase III trials. Since its introduction, belatacept has shown promise in both short- and long-term renal transplant outcomes in several other trials. It exhibits a superior side effect profile compared to CNIs with a comparable efficacy. Across all solid organ transplants, the burden of chronic kidney disease, its associated cardiovascular morbidity, mortality, and inferior patient/allograft survival is a well-documented problem. In this review, we aim to discuss the evidence behind the use of belatacept in solid organ transplants as an effective alternative to CNIs for renal rescue in patients with acute and/or chronic kidney injury.
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Affiliation(s)
- Dhiren Kumar
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA, USA
| | - Spencer LeCorchick
- Division of Transplant Surgery, Virginia Commonwealth University, Richmond, VA, USA
| | - Gaurav Gupta
- Division of Nephrology, Virginia Commonwealth University, Richmond, VA, USA
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