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Rosso G, Salvadori M. De novo malignancies after kidney transplantation. GIORNALE DI CLINICA NEFROLOGICA E DIALISI 2024; 36:87-92. [DOI: 10.33393/gcnd.2024.3362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Cancer is the second cause of death in kidney transplant patients in most Western countries. The excess risk of cancer after kidney transplantation is two to three times higher than in the age and sex matched general population. Once cancer develops, the outcome is generally poor, particularly for melanoma, renal cell carcinoma and post-transplant lymphoproliferative disorder.A multidisciplinary approach for screening, prevention, diagnosis and treatment of neoplastic disease after kidney transplantation is necessary.
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2
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Bredewold OW, Moest WT, de Fijter JW, Meijers E, Bruchfeld A, Skov K, Svensson MHS, Chan J, Mjornstedt L, Sorensen SS, Fellstrom B, Feltkamp MCW, van Zonneveld AJ, Rotmans JI. Attenuation of Torque teno viral load over time in kidney transplantation recipients treated with calcineurin inhibitors is mitigated after conversion to belatacept. J Med Virol 2024; 96:e29905. [PMID: 39228322 DOI: 10.1002/jmv.29905] [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: 06/12/2024] [Revised: 08/23/2024] [Accepted: 08/27/2024] [Indexed: 09/05/2024]
Abstract
Torque Teno Virus (TTV) is a non-pathogenic anellovirus, highly prevalent in healthy populations. Variations in its viral load have been associated with states of diminished immunity, as occurs after organ transplantation. It is hypothesized that TTV-load might be used as a diagnostic tool to guide prescription and dosing of immunosuppressive drugs. Not much is known about the effects of combined immunosuppressive drugs on TTV replication in renal transplantation. Belatacept was introduced to counter side-effects of calcineurin inhibitors (CNI). It was never widely adopted, mainly because its association with increased risk of rejection. To investigate the differential effects of a regimen based on calcineurin inhibitors versus belatacept on TTV-loads, we measured TTV-levels in 105 patients from two randomized controlled trials in kidney transplant recipients (KTRs). We observed that time after transplantation was inversely related to TTV-levels of patients that remained on a CNI-containing regime, whereas this decline over time was diminished after conversion to belatacept. In addition, a correlation with tacrolimus-trough levels and age were found. Our study is the first report on the impact of conversion from CNI to belatacept on TTV-levels in KTR. In conclusion, the time-related decline in TTV-levels is mitigated after conversion from CNI to belatacept.
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Affiliation(s)
- O W Bredewold
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
| | - W T Moest
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
| | - J W de Fijter
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
- Department of Nephrology, Antwerp University Medical Center, Edegem, Belgium
| | - E Meijers
- Department of Medical Microbiology and Infection Control, Leiden University Center for Infectious diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - A Bruchfeld
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - K Skov
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - M H S Svensson
- Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark
- Department of Nephrology, Akershus University Hospital, Lorenskog, Norway
| | - J Chan
- Department of Nephrology, Akershus University Hospital, Lorenskog, Norway
| | - L Mjornstedt
- Transplantation Institute, Sahlgrenska University Hospital, Goteborg, Sweden
| | - S S Sorensen
- Department of Nephrology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - B Fellstrom
- Department of Medical Science, Renal Unit, University Hospital, Uppsala, Sweden
| | - M C W Feltkamp
- Department of Medical Microbiology and Infection Control, Leiden University Center for Infectious diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - A J van Zonneveld
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
| | - J I Rotmans
- Department of Internal Medicine (Nephrology), Leiden University Medical Center, Leiden, The Netherlands
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3
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Poudel S, Gupta S, Saigal S. Basics and Art of Immunosuppression in Liver Transplantation. J Clin Exp Hepatol 2024; 14:101345. [PMID: 38450290 PMCID: PMC10912712 DOI: 10.1016/j.jceh.2024.101345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 01/09/2024] [Indexed: 03/08/2024] Open
Abstract
Liver transplantation is one of the most challenging areas in the medical field. Despite that, it has already been established as a standard treatment option, especially in decompensated cirrhosis and selected cases of hepatocellular carcinoma and acute liver failure. Complications due to graft rejection, including mortality and morbidity, have greatly improved over time due to better immunosuppressive agents and management protocols. Currently, immunosuppression in liver transplant patients makes use of the best possible combinations of effective agents to achieve optimal immunosuppression for long-term graft survival. Induction agents are no longer used routinely, and the aim is to provide minimal immunosuppression in the maintenance phase. Currently available immunosuppressive agents are mainly classified as biological and pharmacological agents. Though the protocols may vary among the centers and over time, the basics of effective use usually remain similar. Most protocols use the combination of multiple agents with different mechanisms of action to reduce the dose and minimize the side effects. Along with the improvement in operative and perioperative techniques, this art of immunosuppression has contributed to the recent progress made in the outcomes of liver transplants. In this review, we will discuss the various types of immunosuppressive agents currently in use, the different protocols of immunosuppression used, and the art of optimal use for achieving maximum immunosuppression without increasing toxicity. We will also discuss the practical aspects of various immunosuppression regimens, including drug monitoring, and briefly discuss the concepts of immunosuppression minimization and withdrawal.
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Affiliation(s)
- Shekhar Poudel
- Fellow Transplant Hepatology, Centre for Liver and Biliary Sciences, Max Super Specialty Hospital, Saket, New Delhi, India
| | - Subhash Gupta
- Liver Transplant and Gastrointestinal Surgery, Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - Sanjiv Saigal
- Principal Director and Head, Transplant Hepatology, Centre for Liver and Biliary Sciences, Max Super Specialty Hospital, Saket, New Delhi, India
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Moein M, Dvorai RH, Li BW, Fioramonti PJ, Schilsky JB, Thankachan R, Yang C, Saidi RF, Shahbazov R. Early conversion to belatacept-based immunosuppression regimen promotes improved long-term renal graft function in kidney transplant recipients. Transpl Immunol 2023; 80:101882. [PMID: 37392898 DOI: 10.1016/j.trim.2023.101882] [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: 03/23/2023] [Revised: 06/12/2023] [Accepted: 06/28/2023] [Indexed: 07/03/2023]
Abstract
BACKGROUND Belatacept has been demonstrated as an effective alternative immunosuppressant in kidney transplant recipients. This study focuses on outcomes of early and late conversion to Belatacept-based immunosuppression after kidney transplant. MATERIALS AND METHODS This retrospective analysis of a prospectively collected database included all adult kidney transplants patients at SUNY Upstate Medical Hospital from 1 January 2014 to 30 December 2022. Early conversion was defined as all conversions done at <6 months after kidney transplantation, and late conversion to belatacept was defined as conversion at >6 months after kidney transplantation. RESULTS Out of 61 patients included in this study, 33 patients (54%) were in the early conversion group, and 28 patients (46%) were in the late conversion group. The mean eGFR in the early conversion group was 26.73 ± 16.26 ml/min/1.73 m2 before conversion to belatacept, which improved to 45.3 ± 21.01 ml/min/1.73 m2 at one-year post-conversion (p = 0.0006). Furthermore, eGFR changes in the late conversion group were insignificant, with 46.30 ± 15.65 ml/min/1.73 m2 before conversion to belatacept, and 44.76 ± 22.91 ml/min/1.73 m2 after one year of follow-up (p = 0.72). All four biopsy-proven allograft rejections in the early conversion group were acute T-cell-mediated rejections (ATMR). In the late conversion group, out of three biopsy-proven rejections, one was chronic antibody-mediated rejection (CAMR), one was ATMR, and one was mixed ATMR/CAMR. All four patients with ATMR rejection received mycophenolic acid (MPA) as part of their immunosuppressive regimen, and none received tacrolimus. The one-year post-conversion allograft survival rate in early and late conversion groups was 100%. However, the one-year post-conversion patient survival rate was 90.9% in the early conversion group and 100% in the late conversion group (P = 0.11). CONCLUSIONS Early post-transplant conversion to belatacept can improve the eGFR more meaningful when compared to late conversion. Patients who receive belatacept and MPA rather than tacrolimus may have increased rates of T-cell-mediated rejection.
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Affiliation(s)
- Mahmoudreza Moein
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Reut Hod Dvorai
- Department of Pathology and Laboratory Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Benson W Li
- Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - P J Fioramonti
- Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Juliana B Schilsky
- Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Reeba Thankachan
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Christine Yang
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Reza F Saidi
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Rauf Shahbazov
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA.
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Vincenti F, Budde K, Grinyo J, Rostaing L, Kirk AD, Larsen CP. Open letter to Bristol Myers Squibb: Belatacept; we aren't done yet. Am J Transplant 2023; 23:1483-1484. [PMID: 37394381 DOI: 10.1016/j.ajt.2023.05.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 05/08/2023] [Accepted: 05/22/2023] [Indexed: 07/04/2023]
Affiliation(s)
- Flavio Vincenti
- Division of Transplant Surgery, University of California, San Francisco, California, USA.
| | - Klemens Budde
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Josep Grinyo
- Division of Nephrology, University of Barcelona, Barcelona, Spain
| | - Lionel Rostaing
- Department of Nephrology, Université Grenoble Alples, Saint-Martin- d'hères, France
| | - Allan D Kirk
- Department of Surgery, Duke University, Durham, North Carolina, USA
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Malahe SRK, van Kampen JJA, Manintveld OC, Hoek RAS, den Hoed CM, Baan CC, Kho MML, Verjans GMGM. Current Perspectives on the Management of Herpesvirus Infections in Solid Organ Transplant Recipients. Viruses 2023; 15:1595. [PMID: 37515280 PMCID: PMC10383436 DOI: 10.3390/v15071595] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/12/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Solid organ transplant recipients (SOTRs) are at high risk of human herpesvirus (HHV)-related morbidity and mortality due to the use of immunosuppressive therapy. We aim to increase awareness and understanding of HHV disease burden in SOTRs by providing an overview of current prevention and management strategies as described in the literature and guidelines. We discuss challenges in both prevention and treatment as well as future perspectives.
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Affiliation(s)
- S Reshwan K Malahe
- Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Erasmus MC Transplant Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Jeroen J A van Kampen
- Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Olivier C Manintveld
- Erasmus MC Transplant Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Department of Cardiology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Rogier A S Hoek
- Erasmus MC Transplant Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Department of Pulmonary Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Caroline M den Hoed
- Erasmus MC Transplant Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Erasmus MC Transplant Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Marcia M L Kho
- Department of Internal Medicine, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Erasmus MC Transplant Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Georges M G M Verjans
- Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- HerpeslabNL, Department of Viroscience, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
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Stenger EO, Watkins B, Rogowski K, Chiang KY, Haight A, Leung K, Qayed M, Raghunandan S, Suessmuth Y, Kean L, Horan J. Abatacept GVHD prophylaxis in unrelated hematopoietic cell transplantation for pediatric bone marrow failure. Blood Adv 2023; 7:2196-2205. [PMID: 36724508 PMCID: PMC10196963 DOI: 10.1182/bloodadvances.2022008545] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 11/28/2022] [Accepted: 11/28/2022] [Indexed: 02/03/2023] Open
Abstract
Hematopoietic cell transplantation (HCT) is the only readily available cure for many life-threatening pediatric nonmalignant diseases (NMD), but most patients lack a matched related donor and are at higher risk for graft-versus-host disease (GVHD). Use of abatacept (Aba) to target donor T-cell activation has been safe and effective in preventing GVHD after unrelated donor (URD) HCT for malignant diseases (Aba2 trial). Our primary objective was to evaluate the tolerability of Aba added to standard GVHD prophylaxis (cyclosporine and mycophenolate mofetil) in pediatric patients with NMD undergoing URD HCT. In this single-arm, single-center phase 1 trial, 10 patients receiving reduced intensity or nonmyeloablative conditioning underwent URD HCT. Immune reconstitution was assessed longitudinally via flow cytometry and compared to pediatric patients on Aba2. Nine patients successfully engrafted, with 1 primary graft rejection in the setting of inadequate cell dose; secondary graft rejection occurred in 1 patient with concurrent cytomegalovirus viremia. Two deaths occurred, both unrelated to Aba. One patient developed probable posttransplant lymphoproliferative disease, responsive to rituximab and immune suppression withdrawal. No patients developed severe acute or chronic GVHD, and 8 patients were off systemic immunosuppression at 1 year. Immune reconstitution did not appear to be impacted by Aba, and preservation of naïve relative to effector memory CD4+ T cells was seen akin to Aba2. Thus, 4 doses of Aba were deemed tolerable in pediatric patients with NMD following URD HCT, with encouraging preliminary efficacy and supportive immune correlatives in this NMD cohort.
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Affiliation(s)
- Elizabeth O. Stenger
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Benjamin Watkins
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Kelsey Rogowski
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Kuang-Yueh Chiang
- Division of Pediatric Hematology/Oncology, University of Toronto/The Hospital for Sick Children, Toronto, Canada
| | - Ann Haight
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Kathryn Leung
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Muna Qayed
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Sharmila Raghunandan
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Yvonne Suessmuth
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
| | - Leslie Kean
- Division of Pediatric Hematology/Oncology, Dana-Farber/Boston Children’s Hospital, Boston, MA
| | - John Horan
- Division of Pediatric Hematology/Oncology, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, GA
- Division of Pediatric Hematology/Oncology, Dana-Farber/Boston Children’s Hospital, Boston, MA
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Moein M, Gao SX, Martin SJ, Farkouh KM, Li BW, Ball AS, Dvorai RH, Saidi RF. Conversion to Belatacept in kidney transplant recipients with chronic antibody-mediated rejection (CAMR). Transpl Immunol 2023; 76:101737. [PMID: 36379374 DOI: 10.1016/j.trim.2022.101737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 10/20/2022] [Accepted: 11/05/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND The costimulatory inhibitor Belatacept (Bela) has been shown to be an effective alternative in several clinical situations, including chronic antibody-mediated rejection, calcineurin toxicity, and de novo alloantibody formation. To further explore the usefulness of Belatacept under various clinical scenarios, we performed a retrospective analysis of a prospective database of all recipients who had a BPAR diagnosis of CAMR and were converted to a Belatacept maintenance immunosuppression regimen after kidney transplantation. MATERIAL AND METHOD We conducted a retrospective analysis of a prospectively collected database of all kidney transplants adult patients at SUNY Upstate Medical Hospital from 1 January 2013 to 31 December 2021. Our inclusion criteria were the patients who have been diagnosed with CAMR according to their renal biopsy based on the 2013 Banff criteria. The primary objective was to compare the kidney viability and function using GFR between the two interest groups and finally compare the outcomes. RESULTS A total of 48 patients met our inclusion criteria based on the kidney biopsy result, which showed chronic antibody-mediated graft rejection (CAMR). Nineteen patients (39.6%) were converted to the Belatacept, and we continued the previous immunosuppression regimen in 29 patients (60.4%). The mean time from the transplant date to the diagnosis of CAMR was 1385 days in the Belatacept group and 914 days for the non-Belatacept group (P = 0.15). The mean GFR comparison at each time point between the groups did not show a significant difference, and Belatacept did not show superiority compared to the standard immunosuppression regimen in terms of kidney function preservation. 1 (5.2%) patient from the Belatacept group and 1 (3.4%) patient from the non-Belatacept group had a biopsy-proven acute rejection (BPAR) after CAMR confirmation, and it was comparable (P = 0.76). De novo synthesis of the DSA rate was 12.5% in the Belatacept group and 15% In the non-Belatacept group, which was comparable. (P = 0.90). The patient survival rate was 100% in both groups. CONCLUSIONS We conclude that compared to the standard Tacrolimus/MMF/Prednisone regimen, Belatacept did not significantly benefit in preserving the GFR in long-term follow-ups and stabilizing the DSA production, which is one of the main factors resulting in chronic graft failure.
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Affiliation(s)
- Mahmoudreza Moein
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Shuqi X Gao
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Samuel J Martin
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Katie M Farkouh
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Benson W Li
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Angela S Ball
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Reut Hod Dvorai
- Department of Pathology and Laboratory Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Reza F Saidi
- Department of Surgery, Division of Transplantation, SUNY Upstate Medical University, Syracuse, NY, USA.
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9
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Bredewold OW, Chan J, Svensson M, Bruchfeld A, de Fijter JW, Furuland H, Grinyo JM, Hartmann A, Holdaas H, Hellberg O, Jardine A, Mjörnstedt L, Skov K, Smerud KT, Soveri I, Sørensen SS, Zonneveld AJV, Fellström B. Cardiovascular Risk Following Conversion to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: A Randomized Clinical Trial. Kidney Med 2022; 5:100574. [PMID: 36593877 PMCID: PMC9803830 DOI: 10.1016/j.xkme.2022.100574] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Rationale & Objective In kidney transplant recipients (KTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. Our objective was to compare the calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a validated model developed for KTRs. Study Design Prospective, randomized, open-label, parallel-group, investigator-initiated, international multicenter trial. Setting & Participants KTRs aged 18-80 years with a stable graft function (estimated glomerular filtration rate > 20 mL/min/1.73 m2), 3-60 months after transplantation, treated with tacrolimus or cyclosporine A, were eligible for inclusion. Intervention Continuation with a CNI-based regimen or switch to belatacept for 12 months. Outcomes Comparison of the change in the estimated 7-year risk of major adverse CV events and all-cause mortality, changes in traditional markers of CV health, as well as measures of arterial stiffness. Results Among the 105 KTRs randomized, we found no differences between the treatment groups in the predicted risk for major adverse CV events or mortality. Diastolic blood pressure, measured both centrally by using a SphygmoCor device and peripherally, was lower after the belatacept treatment than after the CNI treatment. The mean changes in traditional cardiovascular (CV) risk factors, including kidney transplant function, were otherwise similar in both the treatment groups. The belatacept group had 4 acute rejection episodes; 2 were severe rejections, of which 1 led to graft loss. Limitations The heterogeneous baseline estimated glomerular filtration rate and time from transplantation to trial enrollment in the participants. A limited study duration of 1 year. Conclusions We found no effects on the calculated CV risk by switching to the belatacept treatment. Participants in the belatacept group had not only lower central and peripheral diastolic blood pressure but also a higher rejection rate. Funding The trial has received a financial grant from Bristol-Myers Squibb. Trial Registration EudraCT no. 2013-001178-20.
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Affiliation(s)
- Obbo W. Bredewold
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands,Address for Correspondence: Obbo W. Bredewold, MD, Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Joe Chan
- Department of Renal Medicine, Akershus University Hospital, Lørenskog, Norway
| | - My Svensson
- Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
| | - Annette Bruchfeld
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden,Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden
| | - Johan W. de Fijter
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Hans Furuland
- Department of Medical Science, Renal Unit, University Hospital, Uppsala, Sweden
| | - Josep M. Grinyo
- Department of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Anders Hartmann
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Hallvard Holdaas
- Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway
| | - Olof Hellberg
- Department of Internal Medicine, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Alan Jardine
- Department of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Lars Mjörnstedt
- Division of Transplantation, Department of Surgery, Sahlgrenska University Hospital, Göteborg, Sweden
| | - Karin Skov
- Department of Renal Medicine, Aarhus University Hospital, Denmark
| | | | - Inga Soveri
- Department of Medical Science, Renal Unit, University Hospital, Uppsala, Sweden
| | - Søren S. Sørensen
- Department of Nephrology, Copenhagen University Hospital, Copenhagen, Denmark
| | | | - Bengt Fellström
- Department of Medical Science, Renal Unit, University Hospital, Uppsala, Sweden
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10
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Schaenman J, Rossetti M, Pickering H, Sunga G, Wilhalme H, Elashoff D, Zhang Q, Hickey M, Reddy U, Danovitch G, Reed EF, Bunnapradist S. Preservation of Antiviral Immunologic Efficacy Without Alloimmunity After Switch to Belatacept in Calcineurin Inhibitor-Intolerant Patients. Kidney Int Rep 2022; 8:126-140. [PMID: 36644348 PMCID: PMC9832066 DOI: 10.1016/j.ekir.2022.10.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/18/2022] [Accepted: 10/10/2022] [Indexed: 11/09/2022] Open
Abstract
Introduction Belatacept has shown potential for prevention of rejection after kidney transplantation, given its demonstration of reduced nephrotoxicity in combination with absence of significant incidence of rejection. However, concerns have been raised regarding increased risk of viral infection. Methods We set out to explore the impact of the switch to belatacept on alloimmune and antiviral immunity through the study of patients switched from calcineurin inhibitor (CNI) to belatacept within 3 months of kidney transplantation compared with a matched cohort of control patients on a CNI-based regimen. Results After the switch to belatacept, immune phenotyping demonstrated a decrease in naive and an increase in terminally differentiated effector memory (TMRA) T cells, with no significant difference compared with control patients. Donor-specific immune response, measured by intracellular cytokine staining (ICS), did not change significantly either by single or double cytokine secretion, but it was associated with the appearance of donor-specific antibody (DSA) in the control but not the belatacept cohort (P = 0.039 for naive and P = 0.002 for TMRA subtypes). Increased incidence of de novo DSA development was observed in the control group (P = 0.035). Virus-specific immune response, as measured by ICS in response to cytomegalovirus (CMV) or Epstein-Barr virus (EBV), was similar in both groups and stable over time. Conclusion We found that belatacept use was associated with an absence of alloreactivity without impact on immune phenotype, while preserving the antiviral immune response, for patients switched from a CNI-based regimen. In parallel, the antiviral immune response against CMV and EBV was preserved after the belatacept switch (clinicaltrials.gov: NCT01953120).
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Affiliation(s)
- Joanna Schaenman
- Division of Infectious Disease, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Maura Rossetti
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Gemalene Sunga
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Holly Wilhalme
- Department of Medicine Biostatistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - David Elashoff
- Department of Medicine Biostatistics Core, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Qiuheng Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Michelle Hickey
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Uttam Reddy
- Division of Kidney Transplantation, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Gabriel Danovitch
- Division of Kidney Transplantation, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
| | - Suphamai Bunnapradist
- Division of Kidney Transplantation, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA,Correspondence: Suuphamai Bunnapradist, 200 UCLA Medical Plaza, Suite 565, Los Angeles, CA 90095, USA.
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11
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Naesens M, Budde K, Hilbrands L, Oberbauer R, Bellini MI, Glotz D, Grinyó J, Heemann U, Jochmans I, Pengel L, Reinders M, Schneeberger S, Loupy A. Surrogate Endpoints for Late Kidney Transplantation Failure. Transpl Int 2022; 35:10136. [PMID: 35669974 PMCID: PMC9163814 DOI: 10.3389/ti.2022.10136] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/18/2022] [Indexed: 12/13/2022]
Abstract
In kidney transplant recipients, late graft failure is often multifactorial. In addition, primary endpoints in kidney transplantation studies seek to demonstrate the short-term efficacy and safety of clinical interventions. Although such endpoints might demonstrate short-term improvement in specific aspects of graft function or incidence of rejection, such findings do not automatically translate into meaningful long-term graft survival benefits. Combining many factors into a well-validated model is therefore more likely to predict long-term outcome and better reflect the complexity of late graft failure than using single endpoints. If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes following kidney transplantation, then the surrogate endpoint for graft failure in clinical trial settings needs clearer definition. This Consensus Report considers the potential benefits and drawbacks of several candidate surrogate endpoints (including estimated glomerular filtration rate, proteinuria, histological lesions, and donor-specific anti-human leukocyte antigen antibodies) and composite scoring systems. The content was created from information prepared by a working group within the European Society for Organ Transplantation (ESOT). The group submitted a Broad Scientific Advice request to the European Medicines Agency (EMA), June 2020: the request focused on clinical trial design and endpoints in kidney transplantation. Following discussion and refinement, the EMA made final recommendations to ESOT in December 2020 regarding the potential to use surrogate endpoints in clinical studies that aim to improving late graft failure.
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Affiliation(s)
- Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Luuk Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Rainer Oberbauer
- Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | | | - Denis Glotz
- Paris Translational Research Center for Organ Transplantation, Hôpital Saint Louis, Paris, France
| | | | - Uwe Heemann
- Department of Nephrology, Technical University of Munich, Munich, Germany
| | - Ina Jochmans
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Liset Pengel
- Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
| | - Marlies Reinders
- Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Stefan Schneeberger
- Department of General, Transplant and Thoracic Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Alexandre Loupy
- Paris Translational Research Center for Organ Transplantation, Hôpital Necker, Paris, France
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12
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Abstract
Cancer is an important outcome after kidney transplantation because it is the second leading cause of death in most Western countries. The excess risk of cancer after transplantation is approximately two to three times higher than the age- and sex-matched general population, driven largely by viral- and immune-related cancers. Once cancer develops, outcomes are generally poor, particularly for those with melanoma, renal cell carcinoma, and post-transplant lymphoproliferative disease. More importantly, effective screening and treatment strategies are limited in this high-risk population. In this review, we begin with a patient's journey that maps the experience of living with a kidney transplant and understand the patient's knowledge, education, and experience of cancer in the context of transplantation. The epidemiology and burden of cancer in recipients of kidney transplants, along with the up-to-date screening and treatment strategies, are discussed. We also focus on the current understanding of optimal care for recipients of kidney transplants who are living with cancer from the patients' perspectives.
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Affiliation(s)
- David Al-Adra
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Talal Al-Qaoud
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Kevin Fowler
- The Voice of the Patient, Inc., Columbia, Missouri
| | - Germaine Wong
- Sydney School of Public Health, University of Sydney, Sydney, New South Wales, Australia
- Centre for Kidney Research, Kids Research Institute, The Children’s Hospital at Westmead, Westmead, New South Wales, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Westmead, New South Wales, Australia
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13
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Karadkhele G, Duneton C, Garro R, Badell IR, Pearson TC, Larsen CP, Hogan J. Temporal trends and current use of de novo belatacept in kidney transplant recipients in the United States. Clin Transplant 2021; 36:e14531. [PMID: 34757651 DOI: 10.1111/ctr.14531] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 11/03/2021] [Accepted: 11/05/2021] [Indexed: 12/20/2022]
Abstract
The adoption of de novo belatacept in kidney transplant (kTx) recipients was hampered by an increased risk of acute cellular rejection (ACR) with variation in adopted belatacept based immunosuppressive therapies across centers. We used data from the Scientific Registry of Transplant Recipients (SRTR) to evaluate the temporal trends in belatacept use and describe the associated induction and maintenance regimens in US adult kTx recipients transplanted between June 2011 and December 2018. The number of patients receiving de novo-belatacept based immunosuppressive therapy increased from .74% in 2011 to 3.11% in 2016. In 2016, 66/207 centers used de novo belatacept-based regimen with 3.03% using it in over 50% of their patients. The use of T-cell depleting agents increased with time. Since 2012, the rate of calcineurin inhibitor (CNI) use in combination with belatacept remained stable around 50% and ∼30% remained under belatacept/CNI combination at 1-year post-transplantation. The adoption of belatacept as de novo immunosuppressive regimen has been slow and its use remains low in the United States. Various regimens have been used to modulate the risk of ACR. Further studies evaluating the long-term outcomes of these regimens and assessing their safety especially with regard to the risk of infection are needed.
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Affiliation(s)
- Geeta Karadkhele
- Emory Transplant Center, Department of Surgery, Emory School of medicine, Atlanta, Georgia, USA
| | - Charlotte Duneton
- Emory Transplant Center, Department of Surgery, Emory School of medicine, Atlanta, Georgia, USA.,Pediatric Nephrology Department, Robert Debré Hospital, APHP, Paris, France
| | - Rouba Garro
- Pediatric Nephrology Division, Department of Pediatrics, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Idelberto Raul Badell
- Emory Transplant Center, Department of Surgery, Emory School of medicine, Atlanta, Georgia, USA
| | - Thomas C Pearson
- Emory Transplant Center, Department of Surgery, Emory School of medicine, Atlanta, Georgia, USA
| | - Christian P Larsen
- Emory Transplant Center, Department of Surgery, Emory School of medicine, Atlanta, Georgia, USA
| | - Julien Hogan
- Emory Transplant Center, Department of Surgery, Emory School of medicine, Atlanta, Georgia, USA.,Pediatric Nephrology Department, Robert Debré Hospital, APHP, Paris, France
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14
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Shoor S. Risk of Serious Infection Associated with Agents that Target T-Cell Activation and Interleukin-17 and Interleukin-23 Cytokines. Infect Dis Clin North Am 2021; 34:179-189. [PMID: 32444009 DOI: 10.1016/j.idc.2020.02.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Co-stimulatory T-cell inhibitors are used in the treatment of rheumatoid arthritis and to prevent rejection of renal transplants. Inhibitors of the intereukin (IL-17) cytokine are indicated for psoriasis, psoriatic arthritis and ankylosing spondylitis and anti- IL-23 drugs for psoriasis. Serious infections occur in 4.2% to 25.0% of co-stimulatory inhibitors and 1.0% to 2.0% with IL-17 or IL-23 inhibitors. Underlying disease, steroid dose greater than 7.5 to 10.0 mg, and comorbidities influence risk in individual patients. Opportunistic infections or reactivation of tuberculosis are rare.
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Affiliation(s)
- Stanford Shoor
- Stanford University, 1000 Welch Road Suite 203, Palo Alto, CA 94304, USA.
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15
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Kuhn C, Lang BM, Lörcher S, Karolin A, Binet I, Beldi G, Golshayan D, Hadaya K, Mueller TF, Schaub S, Immer F, Stampf S, Koller M, Sidler D. Outcome of kidney transplantation from very senior donors in Switzerland - a national cohort study. Transpl Int 2021; 34:689-699. [PMID: 33529392 DOI: 10.1111/tri.13836] [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: 11/20/2020] [Revised: 12/18/2020] [Accepted: 01/29/2021] [Indexed: 11/29/2022]
Abstract
Kidney transplantation from older and marginal donors is effective to confront organ shortage. However, limitations after transplantation of kidneys from very marginal kidney donors remain unclear. We compared patient and graft outcome, achieved allograft function and quality of life of renal transplantations from Very Senior Donors (VSD, defined as donors aged 70 years and older) with Senior Donors (SD, aged 60-70 years) and Regular Donors (RD, aged younger than 60 years) in Switzerland. We evaluated the outcome of 1554 adult recipients of deceased donor kidney transplantations from 05/2008 to 12/2019; median follow-up was 4.7 years. Failure-free survival (freedom from graft loss or death), glomerular filtration rate (eGFR), and quality of life at 12 months were analyzed for RD (reference group, n = 940), SD (n = 404), and VSD (n = 210). Failure-free survival decreased with increasing donor age, mainly attributable to premature graft loss. Still, overall 5-year failure-free survival reached 83.1%, 81.0%, and 64.0% in the RD, SD, and VSD subgroups, respectively. eGFR 12 months post-transplantation was significantly higher in RD compared with SD and VSD. The acceptance rate of donor candidates for kidney TPL was 78% for the entire cohort (87% for RD, 79% for SD, and 56% for VSD). Deceased donor kidney transplantation from donors aged 70 years or older is associated with an inferior, yet acceptable failure-free outcome, with sustained quality of life.
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Affiliation(s)
- Christian Kuhn
- Klinik für Nephrologie und Hypertonie, Inselspital, Bern, Switzerland
| | - Brian M Lang
- Klinik für Transplantationsimmunologie und Nephrologie, Universitätsspital Basel, Basel, Switzerland.,Swiss Transplant Cohort Study (STCS), Basel, Switzerland
| | - Sylvia Lörcher
- Klinik für Nephrologie und Hypertonie, Inselspital, Bern, Switzerland
| | - Andrea Karolin
- Klinik für Nephrologie und Hypertonie, Inselspital, Bern, Switzerland
| | - Isabelle Binet
- Klinik für Nephrologie und Transplantationsmedizin, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Guido Beldi
- Klinik für Viszerale Chirurgie und Medizin, Inselspital, Bern, Switzerland
| | - Délaviz Golshayan
- Centre de Transplantation d'organes et Service de Néphrologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Karine Hadaya
- Service de Néphrologie et Hypertension, Hôpitaux Universitaires Genève, Genève, Switzerland
| | - Thomas F Mueller
- Klinik für Nephrologie, Universitätsspital Zürich, Zürich, Switzerland
| | - Stefan Schaub
- Klinik für Transplantationsimmunologie und Nephrologie, Universitätsspital Basel, Basel, Switzerland
| | | | - Susanne Stampf
- Klinik für Transplantationsimmunologie und Nephrologie, Universitätsspital Basel, Basel, Switzerland.,Swiss Transplant Cohort Study (STCS), Basel, Switzerland
| | - Michael Koller
- Klinik für Transplantationsimmunologie und Nephrologie, Universitätsspital Basel, Basel, Switzerland
| | - Daniel Sidler
- Klinik für Nephrologie und Hypertonie, Inselspital, Bern, Switzerland
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16
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Ding M, He Y, Zhang S, Guo W. Recent Advances in Costimulatory Blockade to Induce Immune Tolerance in Liver Transplantation. Front Immunol 2021; 12:537079. [PMID: 33732228 PMCID: PMC7959747 DOI: 10.3389/fimmu.2021.537079] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 01/12/2021] [Indexed: 01/25/2023] Open
Abstract
Liver transplantation is an effective therapy for end-stage liver disease. However, most postoperative patients must take immunosuppressive drugs to prevent organ rejection. Interestingly, some transplant recipients have normal liver function and do not experience organ rejection after the withdrawal of immunosuppressive agents. This phenomenon, called immune tolerance, is the ultimate goal in clinical transplantation. Costimulatory molecules play important roles in T cell-mediated immune responses and the maintenance of T cell tolerance. Blocking costimulatory pathways can alter T cell responses and prolong graft survival. Better understanding of the roles of costimulatory molecules has facilitated the use of costimulatory blockade to effectively induce immune tolerance in animal transplantation models. In this article, we review the state of the art in costimulatory pathway blockade for the induction of immune tolerance in transplantation and its potential application prospects for liver transplantation.
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Affiliation(s)
- Mingjie Ding
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Yuting He
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
| | - Wenzhi Guo
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Open and Key Laboratory of Hepatobiliary & Pancreatic Surgery and Digestive Organ Transplantation at Henan Universities, Zhengzhou, China.,Zhengzhou Key Laboratory of Hepatobiliary & Pancreatic Diseases and Organ Transplantation Medicine, Zhengzhou, China
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17
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Purnajo I, Beaumont JL, Polinsky M, Alemao E, Everly MJ. Trajectories of health-related quality of life among renal transplant patients associated with graft failure and symptom distress: Analysis of the BENEFIT and BENEFIT-EXT trials. Am J Transplant 2020; 20:1650-1658. [PMID: 31874117 DOI: 10.1111/ajt.15757] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 12/05/2019] [Accepted: 12/08/2019] [Indexed: 01/25/2023]
Abstract
Understanding the correlation between transplant symptoms, health-related quality of life (HRQoL), and graft outcomes is needed to support patient-focused drug development and posttransplant management. A post-hoc analysis of patient-reported outcomes from the Phase III belatacept trials was conducted in order to investigate the interrelationship between trajectories of HRQoL, symptom experience, and allograft outcomes. HRQoL and symptom experience were evaluated using Short-Form 36 Survey (SF-36) and Modified Transplant Symptom Occurrence and Distress Scale (MTSOSD-59R), respectively. HRQoL was captured in 831 eligible renal transplant patients at baseline, 12, 24, and 36 months posttransplant. Following transplantation, patients reported improvements in all SF-36 subscales compared to baseline. Latent class analysis revealed four trajectories in perceived general health, which were associated with graft failure after adjustment. Compared to patients with good perceived health, patients with fair and poor perceived health had 4.7 (95% confidence interval [CI] 1.5-14.8, P < .01) and 19.8 (95% CI 5.9-66.0, P < .01) times the risk of graft failure, respectively. Using multinomial logistic regression, different sets of symptoms were associated with perceived general health at baseline and 12 months posttransplant. The study supports monitoring HRQoL and symptom experience to capture each patient's health perspective, improve drug development, and optimize posttransplant management.
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Affiliation(s)
- Intan Purnajo
- Terasaki Research Institute, Los Angeles, California
| | | | | | - Evo Alemao
- Bristol Myers Squibb, Princeton, New Jersey
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18
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Carrión-Barberà I, Fajardo M, Danias G, Tsapepas D, Gartshteyn Y, Fernandez H, Askanase A. Belatacept in kidney transplant patients with systemic lupus erythematosus. Lupus Sci Med 2019; 6:e000355. [PMID: 31908816 PMCID: PMC6928461 DOI: 10.1136/lupus-2019-000355] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Revised: 10/31/2019] [Accepted: 12/07/2019] [Indexed: 11/04/2022]
Abstract
Objectives Lupus nephritis (LN) requires renal replacement therapy in 10%-30% of patients. About 30% of these patients receive a kidney transplant. Belatacept is a second-generation, selective, T-cell co-stimulator blocker (inhibits cytotoxic, T-lymphocyte antigen 4, CTLA-4) used as an alternative to calcineurin inhibitors (CNI) for maintenance regimens after kidney transplantation. The pathogenic relevance of CTLA-4 inhibition and the favourable cardiovascular profile of belatacept make it an attractive therapeutic option in systemic lupus erythematosus (SLE). Intravenous administration of belatacept ensures therapeutic adherence. Methods This retrospective, single-centre study evaluates the outcomes of LN kidney transplant recipients treated with belatacept for reasons not related to SLE at the Columbia University Lupus and Renal Transplant Cohort. Results Belatacept was started in six patients on CNI regimens at 15.5±17.1 months following transplantation for LN. In five patients, creatinine levels stabilised 6 months after belatacept, one returned to haemodialysis due to CNI toxicity and pyelonephritis and one relisted for a kidney transplant following acute cellular rejection and cortical necrosis. Five patients are followed for extrarenal lupus; no extrarenal manifestations were documented in the other two patients. Data on SLE disease activity pre-belatacept and post-belatacept were available and scored in three patients using the SLE Disease Activity Index Glucocorticosteroid Index (SLEDAI-2KG), which accounts for clinical and laboratory manifestations, as well as steroid dose. Mean SLEDAI-2KG decreased from 13 to 7.6. Conclusion Belatacept in LN kidney transplant recipients may decrease extrarenal manifestations, attenuate CNI toxicity and stabilise allograft function, providing a better alternative to CNI regimens. Furthermore, these data suggest that belatacept, although initiated for reasons not related to SLE, might have a beneficial effect in SLE.
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Affiliation(s)
| | - Melissa Fajardo
- Department of Nephrology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA
| | - George Danias
- Department of Rheumatology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA
| | - Demetra Tsapepas
- Department of Nephrology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA
| | - Yevgeniya Gartshteyn
- Department of Rheumatology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA
| | - Hilda Fernandez
- Department of Nephrology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA
| | - Anca Askanase
- Department of Rheumatology, NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York, USA
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19
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Allen UD, Preiksaitis JK. Post-transplant lymphoproliferative disorders, Epstein-Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13652. [PMID: 31230381 DOI: 10.1111/ctr.13652] [Citation(s) in RCA: 213] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 06/19/2019] [Indexed: 02/06/2023]
Abstract
PTLD with the response-dependent sequential use of RIS, rituximab, and cytotoxic chemotherapy is recommended. Evidence gaps requiring future research and alternate treatment strategies including immunotherapy are highlighted.
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Affiliation(s)
- Upton D Allen
- Division of Infectious Diseases, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.,Research Institute, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.,Institute of Health Policy, Management & Evaluation, University of Toronto, Toronto, ON, Canada
| | - Jutta K Preiksaitis
- Division of Infectious Diseases, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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20
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Knechtle SJ, Shaw JM, Hering BJ, Kraemer K, Madsen JC. Translational impact of NIH-funded nonhuman primate research in transplantation. Sci Transl Med 2019; 11:eaau0143. [PMID: 31292263 PMCID: PMC7197021 DOI: 10.1126/scitranslmed.aau0143] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 12/13/2018] [Indexed: 12/23/2022]
Abstract
The National Institutes of Health (NIH) has long supported using nonhuman primate (NHP) models for research on kidney, pancreatic islet, heart, and lung transplantation. The primary purpose of this research has been to develop new treatments for down-modulating or preventing deleterious immune responses after transplantation in human patients. Here, we discuss NIH-funded NHP studies of immune cell depletion, costimulation blockade, regulatory cell therapy, desensitization, and mixed hematopoietic chimerism that either preceded clinical trials or prevented the human application of therapies that were toxic or ineffective.
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Affiliation(s)
- Stuart J Knechtle
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
| | - Julia M Shaw
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Bernhard J Hering
- Schulze Diabetes Institute, Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
| | - Kristy Kraemer
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
| | - Joren C Madsen
- Center for Transplantation Sciences and Division of Cardiac Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
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21
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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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22
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Leibler C, Matignon M, Moktefi A, Samson C, Zarour A, Malard S, Boutin E, Pilon C, Salomon L, Natella PA, Durrbach A, Robert T, Canoui-Poitrine F, Grimbert P. Belatacept in renal transplant recipient with mild immunologic risk factor: A pilot prospective study (BELACOR). Am J Transplant 2019; 19:894-906. [PMID: 30582270 DOI: 10.1111/ajt.15229] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 11/21/2018] [Accepted: 12/06/2018] [Indexed: 01/25/2023]
Abstract
The benefit of belatacept on antibody-mediated rejection (ABMR) incidence after kidney transplant with preformed donor-specific antibodies (DSAs) has never been assessed. Between 2014 and 2016, we conducted a multicenter prospective clinical trial with 49 patients to determine kidney allograft outcome in recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000) treated with belatacept (BELACOR trial). Immunosuppressive strategy included antithymocyte globulin, belatacept, mycophenolate mofetil, and steroids. An ancillary control group was designed retrospectively, including patients fulfilling the same inclusion criteria treated with calcineurin inhibitors. In BELACOR group, no patient exhibited acute ABMR, patient and allograft survival at 1 year was 100% and 95.4%, respectively, and the estimated glomerular filtration rate was 53.2 mL/min/1.73 m2 . However, the 12-month incidence of acute T cell-mediated rejection was 25.4% (14.5% to 42.4%). Comparison with the control group showed significantly higher T cell-mediated rejection incidence only in the BELACOR group (P = .003). Considering the DSAs, the outcome was similar in the 2 groups except a significantly higher number of patients displayed a complete disappearance of class II DSAs in the BELACOR group (P = .001). Belatacept was not associated with an acute ABMR increased risk and may be considered as immunosuppressive strategy in transplant recipients with preformed DSAs (maximal mean fluorescence intensity 500 to 3000). Prospective randomized trials are needed to confirm these results.
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Affiliation(s)
- Claire Leibler
- Assistance Publique-Hôpitaux de Paris, Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France.,Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Créteil, France
| | - Marie Matignon
- Assistance Publique-Hôpitaux de Paris, Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France.,Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Créteil, France
| | - Anissa Moktefi
- Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Créteil, France.,Assistance Publique-Hôpitaux de Paris, Pathology Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France
| | - Chloé Samson
- Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Créteil, France
| | - Anissa Zarour
- Assistance Publique-Hôpitaux de Paris, Public Health Department/Clinical Research Unit (URC-Mondor), Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France
| | - Stéphanie Malard
- Assistance Publique-Hôpitaux de Paris, Laboratoire Régional d' Histocompatibilité, Hôpital Saint Louis, Paris, France
| | - Emmanuelle Boutin
- Assistance Publique-Hôpitaux de Paris, Public Health Department/Clinical Research Unit (URC-Mondor), Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France.,Assistance Publique-Hôpitaux de Paris, Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Caroline Pilon
- Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Créteil, France
| | - Laurent Salomon
- Assistance Publique-Hôpitaux de Paris, Urology Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France
| | - Pierre-André Natella
- Assistance Publique-Hôpitaux de Paris, Public Health Department/Clinical Research Unit (URC-Mondor), Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France
| | - Antoine Durrbach
- Assistance Publique-Hôpitaux de Paris, Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Thomas Robert
- Department of Nephrology, Transplantation and Emergency, Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Paris, France
| | - Florence Canoui-Poitrine
- Assistance Publique-Hôpitaux de Paris, Public Health Department/Clinical Research Unit (URC-Mondor), Groupe Hospitalier Henri-Mondor/Albert Chenevier, Créteil, France.,Département Hospitalo-Universitaire A-TVB, Institut Mondor de Recherche Biomédicale - EA 7376 Clinical Epidemiology and Ageing Unit, Université Paris-Est-Créteil, Créteil, France
| | - Philippe Grimbert
- Assistance Publique-Hôpitaux de Paris, Nephrology and Renal Transplantation Department, Institut Francilien de Recherche en Néphrologie et Transplantation, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, Créteil, France.,Université Paris-Est-Créteil, Département Hospitalo-Universitaire Virus-Immunité-Cancer, Institut Mondor de Recherche Biomédicale, Créteil, France.,Assistance Publique-Hôpitaux de Paris, CIC-BT 504, Créteil, France
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Aziz F, Clark D, Garg N, Mandelbrot D, Djamali A. Hypertension guidelines: How do they apply to kidney transplant recipients. Transplant Rev (Orlando) 2018; 32:225-233. [DOI: 10.1016/j.trre.2018.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/05/2018] [Accepted: 06/17/2018] [Indexed: 12/28/2022]
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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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Jones-Hughes T, Snowsill T, Haasova M, Coelho H, Crathorne L, Cooper C, Mujica-Mota R, Peters J, Varley-Campbell J, Huxley N, Moore J, Allwood M, Lowe J, Hyde C, Hoyle M, Bond M, Anderson R. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model. Health Technol Assess 2018; 20:1-594. [PMID: 27578428 DOI: 10.3310/hta20620] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. LIMITATIONS For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. FUTURE WORK High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. CONCLUSION Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013189. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Marcela Haasova
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Louise Crathorne
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Ruben Mujica-Mota
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jaime Peters
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jo Varley-Campbell
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jason Moore
- Exeter Kidney Unit, Royal Devon and Exeter Foundation Trust Hospital, Exeter, UK
| | - Matt Allwood
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jenny Lowe
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Martin Hoyle
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Mary Bond
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Rob Anderson
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
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Abstract
PURPOSE OF REVIEW The review will focus on the impact and current status of costimulatory blockade in renal transplantation. RECENT FINDINGS The mainstay of immunosuppression in kidney transplantation is calcineurin inhibitors (CNIs) which have reduced acute rejection rates but failed to improve long-term allograft survival. Their cardiometabolic side-effects and nephrotoxicity have shifted the focus of investigation to CNI-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of cytotoxic T-lymphocyte associated protein 4 has emerged as part of a CNI-free regimen. Belatacept has demonstrated superior glomerular filtration rate compared with CNIs, albeit with an increased risk of early and histologically severe rejection. Focus on optimizing the belatacept regimen is underway. ASKP1240, which blocks the cluster of differentiation 40 (CD40)/CD154 costimulatory pathway, has just completed a phase 2 trial with a CNI-free regimen. CFZ533, an anti-CD40, is also poised to be tested in a phase 2 trial in renal transplantation. Nonagonistic CD28 antibodies have re-emerged with two anti-CD28 candidates in preclinical development. SUMMARY A reliable, CNI-free regimen that maintains low acute rejection rates and improves long-term renal allograft survival has become an achievable goal with costimulation blockade. The task of clinicians and researchers is to find the optimal combinations to maintain safety and improve efficacy.
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Samy KP, Butler JR, Li P, Cooper DKC, Ekser B. The Role of Costimulation Blockade in Solid Organ and Islet Xenotransplantation. J Immunol Res 2017; 2017:8415205. [PMID: 29159187 PMCID: PMC5660816 DOI: 10.1155/2017/8415205] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/17/2017] [Indexed: 12/17/2022] Open
Abstract
Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials. However, as these humoral immune barriers to cross-species transplantation are overcome with advanced transgenics, cellular immunity to these novel xenografts remains an outstanding issue. Therefore, understanding and optimizing immunomodulation will be paramount for successful clinical xenotransplantation. Costimulation blockade agents have been introduced in xenotransplantation research in 2000 with anti-CD154mAb. Most recently, prolonged survival has been achieved in solid organ (kidney xenograft survival > 400 days with anti-CD154mAb, heart xenograft survival > 900 days, and liver xenograft survival 29 days with anti-CD40mAb) and islet xenotransplantation (>600 days with anti-CD154mAb) with the use of these potent experimental agents. As the development of novel genetic modifications and costimulation blocking agents converges, we review their impact thus far on preclinical xenotransplantation and the potential for future application.
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Affiliation(s)
- Kannan P. Samy
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - James R. Butler
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Ping Li
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - David K. C. Cooper
- Xenotransplantation Program, Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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Cortes-Cerisuelo M, Laurie SJ, Mathews DV, Winterberg PD, Larsen CP, Adams AB, Ford ML. Increased Pretransplant Frequency of CD28 + CD4 + T EM Predicts Belatacept-Resistant Rejection in Human Renal Transplant Recipients. Am J Transplant 2017; 17:2350-2362. [PMID: 28502091 PMCID: PMC5599135 DOI: 10.1111/ajt.14350] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 12/20/2016] [Accepted: 01/11/2017] [Indexed: 02/07/2023]
Abstract
While most human T cells express the CD28 costimulatory molecule constitutively, it is well known that age, inflammation, and viral infection can drive the generation of CD28null T cells. In vitro studies have demonstrated that CD28null cell effector function is not impacted by the presence of the CD28 costimulation blocker belatacept. As such, a prevailing hypothesis suggests that CD28null cells may precipitate costimulation blockade-resistant rejection. However, CD28+ cells possess more proliferative and multifunctional capacity, factors that may increase their ability to successfully mediate rejection. Here, we performed a retrospective immunophenotypic analysis of adult renal transplant recipients who experienced acute rejection on belatacept treatment as compared to those who did not. Intriguingly, our findings suggest that patients possessing higher frequency of CD28+ CD4+ TEM prior to transplant were more likely to experience acute rejection following treatment with a belatacept-based immunosuppressive regimen. Mechanistically, CD28+ CD4+ TEM contained significantly more IL-2 producers. In contrast, CD28null CD4+ TEM isolated from stable belatacept-treated patients exhibited higher expression of the 2B4 coinhibitory molecule as compared to those isolated from patients who rejected. These data raise the possibility that pretransplant frequencies of CD28+ CD4+ TEM could be used as a biomarker to predict risk of rejection following treatment with belatacept.
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Affiliation(s)
| | | | | | | | | | - A B Adams
- Emory Transplant Center, Atlanta, GA
| | - M L Ford
- Emory Transplant Center, Atlanta, GA
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30
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Abstract
The old-for-old allocation policy used for kidney transplantation (KT) has confirmed the survival benefit compared to remaining listed on dialysis. Shortage of standard donors has stimulated the development of strategies aimed to expand acceptance criteria, particularly of kidneys from elderly donors. We have systematically reviewed the literature on those different strategies. In addition to the review of outcomes of expanded criteria donor or advanced age kidneys, we assessed the value of the Kidney Donor Profile Index policy, preimplantation biopsy, dual KT, machine perfusion and special immunosuppressive protocols. Survival and functional outcomes achieved with expanded criteria donor, high Kidney Donor Profile Index or advanced age kidneys are poorer than those with standard ones. Outcomes using advanced age brain-dead or cardiac-dead donor kidneys are similar. Preimplantation biopsies and related scores have been useful to predict function, but their applicability to transplant or refuse a kidney graft has probably been overestimated. Machine perfusion techniques have decreased delayed graft function and could improve graft survival. Investing 2 kidneys in 1 recipient does not make sense when a single KT would be enough, particularly in elderly recipients. Tailored immunosuppression when transplanting an old kidney may be useful, but no formal trials are available.Old donors constitute an enormous source of useful kidneys, but their retrieval in many countries is infrequent. The assumption of limited but precious functional expectancy for an old kidney and substantial reduction of discard rates should be generalized to mitigate these limitations.
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31
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Kim SC, Wakwe W, Higginbotham LB, Mathews DV, Breeden CP, Stephenson AC, Jenkins J, Strobert E, Price K, Price L, Kuhn R, Wang H, Yamniuk A, Suchard S, Farris AB, Pearson TC, Larsen CP, Ford ML, Suri A, Nadler S, Adams AB. Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection. Am J Transplant 2017; 17:1182-1192. [PMID: 28097811 PMCID: PMC5409881 DOI: 10.1111/ajt.14197] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 12/28/2016] [Accepted: 12/29/2016] [Indexed: 01/25/2023]
Abstract
The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.
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Affiliation(s)
- Steven C Kim
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Walter Wakwe
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Laura B Higginbotham
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - David V Mathews
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Cynthia P Breeden
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Allison C Stephenson
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Joe Jenkins
- Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, GA, USA
| | - Elizabeth Strobert
- Yerkes National Primate Research Center, School of Medicine, Emory University, Atlanta, GA, USA
| | - Karen Price
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Laura Price
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Robert Kuhn
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Haiqing Wang
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Aaron Yamniuk
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Suzanne Suchard
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Alton B Farris
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Thomas C Pearson
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Christian P Larsen
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Mandy L Ford
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
| | - Anish Suri
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Steven Nadler
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ, USA
| | - Andrew B Adams
- Emory Transplant Center, Department of Surgery, School of Medicine, Emory University, Atlanta, GA, USA
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32
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Fishman JA. Infection in Organ Transplantation. Am J Transplant 2017; 17:856-879. [PMID: 28117944 DOI: 10.1111/ajt.14208] [Citation(s) in RCA: 504] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/09/2017] [Indexed: 01/25/2023]
Abstract
The prevention, diagnosis, and management of infectious disease in transplantation are major contributors to improved outcomes in organ transplantation. The risk of serious infections in organ recipients is determined by interactions between the patient's epidemiological exposures and net state of immune suppression. In organ recipients, there is a significant incidence of drug toxicity and a propensity for drug interactions with immunosuppressive agents used to maintain graft function. Thus, every effort must be made to establish specific microbiologic diagnoses to optimize therapy. A timeline can be created to develop a differential diagnosis of infection in transplantation based on common patterns of infectious exposures, immunosuppressive management, and antimicrobial prophylaxis. Application of quantitative molecular microbial assays and advanced antimicrobial therapies have advanced care. Pathogen-specific immunity, genetic polymorphisms in immune responses, and dynamic interactions between the microbiome and the risk of infection are beginning to be explored. The role of infection in the stimulation of alloimmune responses awaits further definition. Major hurdles include the shifting worldwide epidemiology of infections, increasing antimicrobial resistance, suboptimal assays for the microbiologic screening of organ donors, and virus-associated malignancies. Transplant infectious disease remains a key to the clinical and scientific investigation of organ transplantation.
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Affiliation(s)
- J A Fishman
- Transplant Infectious Disease and Immunocompromised Host Program and MGH Transplant Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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33
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Herr F, Brunel M, Roders N, Durrbach A. Co-stimulation Blockade Plus T-Cell Depletion in Transplant Patients: Towards a Steroid- and Calcineurin Inhibitor-Free Future? Drugs 2016; 76:1589-1600. [DOI: 10.1007/s40265-016-0656-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Abstract
Infections and malignancies are the expected complications of immunosuppressive therapy, which non-specifically impairs cellular and humoral immune responses in renal transplant recipients. Infections were usually frequent and severe during the early post-transplant period (first year). Recent diagnostic methods (molecular biology) and availability of new antivirals, antifungal and antibiotic drugs made rapid diagnosis and systematic preventive strategies much easier and this resulted in a significant reduction of infections and infectious death in this population. However, new infectious agents like BK polyomavirus, hepatitis E virus, parvovirus (as well as Chigunkunya, West Nile and others in particular areas) were recently recognized as responsible of aggressive infections in the immunocompromised host. Malignancies are also common after transplantation, due to the intensity and duration of immunosuppression. Skin cancers and lymphoproliferative disorders are the most common and are undoubtedly caused by viral infections, but incidence of non-skin cancers is also increased. After reduction of immunosuppression, treatment is similar to non-transplant patients: Results are usually poor and cancer is now the third cause of death in transplant recipients. Due to their anti-proliferative and anti-tumoral properties, incidence of de novo cancer significantly decreased in patients receiving mTor inhibitors as maintenance immunosuppression; furthermore, in patients already diagnosed with Kaposi sarcoma or recurrent skin cancers, introduction of mTor was associated with stabilisation and/or regression of malignant lesions.
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35
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Wojciechowski D, Vincenti F. Costimulatory Blockade and Use of mTOR Inhibitors: Avoiding Injury Part 2. Adv Chronic Kidney Dis 2016; 23:306-311. [PMID: 27742385 DOI: 10.1053/j.ackd.2016.09.004] [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: 11/11/2022]
Abstract
Kidney transplantation immunosuppression relies on a calcineurin inhibitor backbone. Calcineurin inhibitors have reduced early-acute rejection rates but failed to improve long-term allograft survival. Their nephrotoxicity has shifted the focus of investigation to calcineurin inhibitor-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of CTLA4-Ig, has emerged as part of a calcineurin inhibitor-free regimen. Belatacept has demonstrated superior glomerular filtration rate compared with calcineurin inhibitors albeit with an increased risk of early and histologically severe rejection. Focus on optimizing the belatacept regimen to reduce the acute rejection rate while maintaining superior renal function is underway. Belatacept has also been utilized as part of a calcineurin inhibitor-free conversion strategy in stable renal transplant recipients and has demonstrated superior improvement in glomerular filtration rate with conversion vs calcineurin inhibitor continuation. Additional work is underway to better define the role of belatacept in patients on calcineurin inhibitors with allograft dysfunction not due to rejection.
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Garcia VD, Meinerz G, Keitel E. A safety evaluation of belatacept for the treatment of kidney transplant. Expert Opin Drug Saf 2016; 15:1125-32. [PMID: 27309154 DOI: 10.1080/14740338.2016.1202236] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Improving long-term survival in kidney transplantation is one of the main goals in modern immunosuppressive research. Current standard immunosuppression based in a combination of calcineurin inhibitors (CNI) and antiproliferatives, with or without steroids, has improved short-term graft survival. In the last decade, belatacept has been evaluated as a CNI free option regimen addressing better kidney transplant outcomes. AREAS COVERED This paper reviewed the indications, mechanisms of action, pharmacology and published trials using belatacept in different clinical situations. The main objective was to evaluate the safety of this immunosuppressive drug. EXPERT OPINION Kidney transplant patients receiving belatacept demonstrated improvement in renal function, less chronic allograft nephropathy, a more favorable metabolic profile and lower donor-specific antibody formation compared with cyclosporine. Based on the published data and on our personal experience, we have good expectations on belatacept use in the future. If these characteristics will translate in sustained better renal function, less chronic kidney disease-related complications and lower cardiovascular risk, improving patient and graft survival and quality of life, is still to be assessed with longer term follow-up and a larger number of exposed patients.
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Affiliation(s)
- Valter Duro Garcia
- a Head of Renal and Pancreas Transplant Department , Santa Casa de Misericórdia de Porto Alegre (ISCMPA) , Porto Alegre , Brazil
| | - Gisele Meinerz
- b Post-Graduation Program in Pathology , Universidade Federal de Ciências da Saúde de Porto Alegre (UFSCPA) , Porto Alegre , Brazil.,c Renal and Pancreas Transplant Department , ISCMPA , Porto Alegre , Brazil
| | - Elizete Keitel
- b Post-Graduation Program in Pathology , Universidade Federal de Ciências da Saúde de Porto Alegre (UFSCPA) , Porto Alegre , Brazil.,c Renal and Pancreas Transplant Department , ISCMPA , Porto Alegre , Brazil
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Hardinger KL, Sunderland D, Wiederrich JA. Belatacept for the prophylaxis of organ rejection in kidney transplant patients: an evidence-based review of its place in therapy. Int J Nephrol Renovasc Dis 2016; 9:139-150. [PMID: 27307759 PMCID: PMC4888760 DOI: 10.2147/ijnrd.s88816] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Belatacept is a novel immunosuppressive therapy designed to improve clinical outcomes associated with kidney transplant recipients while minimizing use of calcineurin inhibitors (CNIs). METHODS We searched for clinical trials related to administration of belatacept to kidney transplant patients compared to various immunosuppression regimens, as well as for studies that utilized data from belatacept trials to validate new surrogate measures. The purpose of this review is to consolidate the published evidence of belatacept's effectiveness and safety in renal transplant recipients to better elucidate its place in clinical practice. RESULTS Analysis of the results from the Belatacept Evaluation of Nephroprotection and Effi-cacy as First-Line Immunosuppressive Trial (BENEFIT) study, a de novo trial that compared cyclosporine (CsA)-based therapy to belatacept-based therapy in standard criteria donors, found a significant difference in mean estimated glomerular filtration rate (eGFR) of 13-15 mL/min/1.73 m(2) and 23-27 mL/min/1.73 m(2) at 1 year and 7 years, respectively. The BENEFIT-EXT study was similarly designed with the exception that it included extended criteria donors. Renal function improved significantly for the more intensive belatacept group in all years of the BENEFIT-EXT study; however, it was not significant in the less intensive group until 5 years after transplant. Belatacept regimens resulted in lower blood pressure, cholesterol levels, and incidence of new-onset diabetes after transplant compared to CsA-based regimens. Results from conversion of CNIs to belatacept therapy, dual therapy of belatacept with sirolimus, and belatacept with corticosteroid avoidance therapy are also included in this article. CONCLUSION The evidence reviewed in this article suggests that belatacept is an effective alternative in kidney transplant recipients. Compared to CNI-based therapy, belatacept-based therapy results in superior renal function and similar rates of allograft survival. In terms of safety, belatacept was shown to have lower incidence of hypertension, hyperlipidemia, and diabetes; however, incidence of posttransplantation lymphoproliferative disorder and the cost of belatacept may hinder use of this medication.
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Affiliation(s)
- Karen L Hardinger
- Division of Pharmacy Practice and Administration, School of Pharmacy, University of Missouri–Kansas City, Kansas City, MO, USA
| | - Daniel Sunderland
- Division of Pharmacy Practice and Administration, School of Pharmacy, University of Missouri–Kansas City, Kansas City, MO, USA
| | - Jennifer A Wiederrich
- Division of Pharmacy Practice and Administration, School of Pharmacy, University of Missouri–Kansas City, Kansas City, MO, USA
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An Acute Cellular Rejection With Detrimental Outcome Occurring Under Belatacept-Based Immunosuppressive Therapy. Transplantation 2016; 100:1111-9. [DOI: 10.1097/tp.0000000000001004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients. Transplantation 2016; 100:39-53. [PMID: 26680372 PMCID: PMC4683034 DOI: 10.1097/tp.0000000000000869] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.
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Timofte I, Terrin M, Barr E, Sanchez P, Kim J, Reed R, Britt E, Ravichandran B, Rajagopal K, Griffith B, Pham S, Pierson RN, Iacono A. Belatacept for renal rescue in lung transplant patients. Transpl Int 2016; 29:453-63. [PMID: 26678245 DOI: 10.1111/tri.12731] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 08/19/2015] [Accepted: 12/09/2015] [Indexed: 11/28/2022]
Abstract
Renal failure causes morbidity and mortality after lung transplantation and is aggravated by exposure to nephrotoxic immunosuppressant (IS) drugs. We report an off-label experience using belatacept for lung transplant recipients with severe renal insufficiency to reduce nephrotoxic IS exposure. We analyzed data retrospectively from a consecutive series of lung transplant patients with renal insufficiency in whom belatacept treatment was initiated between June 2012 and June 2014 at the University of Maryland Medical Center. Eight patients received belatacept because of acute or chronic renal insufficiency (median) GFR 24 (IQR 18-26). Glomerular filtration rate (GFR) remained stable in two patients and increased in five. One patient with established renal and respiratory failure received only the induction dose of belatacept and died 4 months later of respiratory and multisystem organ failure. Calcineurin inhibitor or sirolimus exposure was safely withheld or reduced without moderate or severe acute rejection during ongoing belatacept in the other seven patients. FEV1 remained stable over the 6-month study interval. Belatacept use appears to permit safe transient reduction in conventional immunosuppressive therapy and was associated with stable or improved renal function in a small retrospective series of lung transplant recipients with acute or chronic renal insufficiency.
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Affiliation(s)
- Irina Timofte
- Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Michael Terrin
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Erik Barr
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Pablo Sanchez
- Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - June Kim
- Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Robert Reed
- Division of Pulmonary and Critical Care, Department of Medicine, VA Maryland Health Care System, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Edward Britt
- Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Bharath Ravichandran
- Department of Pharmacy, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Keshava Rajagopal
- Center for Advanced Heart Failure, Department of Cardiothoracic and Vascular Surgery, University of Texas-Huston, TX, USA
| | - Bartley Griffith
- Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Si Pham
- Division of Cardiac Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Richard N Pierson
- Division of Cardiac Surgery, Department of Surgery, VA Maryland Health Care System, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Aldo Iacono
- Departments of Medicine and Surgery, R Adams Cowley Shock Trauma Center, University of Maryland School of Medicine, Baltimore, MD, USA
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Del Bello A, Marion O, Milongo D, Rostaing L, Kamar N. Belatacept prophylaxis against organ rejection in adult kidney-transplant recipients. Expert Rev Clin Pharmacol 2015; 9:215-27. [PMID: 26691282 DOI: 10.1586/17512433.2016.1112736] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
End-stage renal disease is a major health problem worldwide, with kidney transplantation being the treatment of choice. Calcineurin inhibitors are still the cornerstone of immunosuppressive therapy. However, they have well-known nephrotoxic affects and increase the risk of cardiovascular disease and cancer. In contrast, belatacept is a biological immunosuppressive agent that inhibits the T-cell co-stimulation. It is approved by the US Food and Drug Administration and the European Medicine Agency for use in adult kidney-transplant recipients to prevent acute rejection. Developmental studies show that belatacept is as efficient as calcineurin inhibitors at preventing acute rejection. In addition, kidney function is better and cardiovascular risk factors are reduced in patients given belatacept. Herein, the authors review the published evidence concerning the efficacy and safety of belatacept and discuss its potential specific indications.
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Affiliation(s)
- Arnaud Del Bello
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France.,b Faculte de Medecine , Université Paul Sabatier , Toulouse , France
| | - Olivier Marion
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France
| | - David Milongo
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France
| | - Lionel Rostaing
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France.,b Faculte de Medecine , Université Paul Sabatier , Toulouse , France.,c INSERM U1043, IFR-BMT, CHU Purpan , Toulouse , France
| | - Nassim Kamar
- a Department of Nephrology and Organ Transplantation , CHU Rangueil , Toulouse , France.,b Faculte de Medecine , Université Paul Sabatier , Toulouse , France.,c INSERM U1043, IFR-BMT, CHU Purpan , Toulouse , France
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Scalea JR, Levi ST, Ally W, Brayman KL. Tacrolimus for the prevention and treatment of rejection of solid organ transplants. Expert Rev Clin Immunol 2015; 12:333-342. [PMID: 26588770 DOI: 10.1586/1744666x.2016.1123093] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Since its introduction to the antirejection armamentarium in 1994, tacrolimus has become the workhorse of transplant professionals for avoidance of solid organ transplant rejection. Not only does tacrolimus have potent immunosuppressive qualities that prevent rejection, but dosing is straight forward and it is generally well tolerated. However, in the long term, conditions such as calcineurin inhibitor nephrotoxicity can become a problem. A discussion of the compound, the pharmacokinetics, history, and current approved uses for tacrolimus is described. Indeed, tacrolimus is the most important drug for preventing transplant rejection. However, the increased appreciation for significant side effects, particularly in the long term, has led to building interest in new agents with different mechanisms of action and different metabolism.
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Affiliation(s)
- Joseph R Scalea
- a Division of Transplantation, Department of Surgery , University of Wisconsin , Madison , VA , USA
| | - Shoshana T Levi
- b School of Medicine , University of Virginia , Charlottesville , VA , USA
| | - Winston Ally
- c Department of Pharmacy Services , University of Virginia Health System , Charlottesville , VA , USA
| | - Kenneth L Brayman
- b School of Medicine , University of Virginia , Charlottesville , VA , USA
- d Division of Transplantation, Department of Surgery , University of Virginia , Charlottesville , VA , USA
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Lee W, Satyananda V, Iwase H, Tanaka T, Miyagawa Y, Long C, Ayares D, Cooper DKC, Hara H. In vitro testing of an anti-CD40 monoclonal antibody, clone 2C10, in primates and pigs. Transpl Immunol 2015; 33:185-91. [PMID: 26458513 PMCID: PMC4648655 DOI: 10.1016/j.trim.2015.09.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/29/2015] [Accepted: 09/30/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND The CD40/CD154 and CD28/B7 pathways are important in allo- and xeno-transplantation. Owing to the thrombotic complications of anti-CD154mAb, anti-CD40mAb has emerged as a promising inhibitor of costimulation. Various clones of anti-CD40mAb have been developed against primate species, e.g., clone 2C10 against rhesus monkeys. We have compared the in vitro efficacy of 2C10 to prevent a T cell response in primates and pigs. METHODS The binding of 2C10 to antigen-presenting cells (PBMCs [B cells]) of humans, rhesus and cynomolgus monkeys, baboons, and pigs was measured by flow cytometry, and was also tested indirectly by a blocking assay. The functional capacity of 2C10 was tested by mixed lymphocyte reaction (MLR) with polyclonal stimulation by phytohemagglutinin (PHA) and also with wild-type pig aortic endothelial cells (pAECs) as stimulators. RESULTS There was a significant reduction in binding of 2C10 to baboon PBMCs compared to rhesus, cynomolgus, and human PBMCs, and minimal binding to pig PBMCs. The blocking assay confirmed that the binding of 2C10 was significantly lower to baboon PBMCs when compared to the other primate species tested. The functional assay with PHA showed significantly reduced inhibition of PBMC proliferation in humans, cynomolgus monkeys, and baboons compared to rhesus monkeys, which was confirmed on MLR with pAECs. CONCLUSIONS Since both the binding and functional activity of 2C10 in the baboon is lower than in rhesus monkeys, in vivo treatment using 2C10 in the baboon might require a higher dose or more frequent administration in comparison to rhesus monkeys. It may also be beneficial to develop species-specific clones of anti-CD40mAb.
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Affiliation(s)
- Whayoung Lee
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Vikas Satyananda
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hayato Iwase
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Takayuki Tanaka
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yuko Miyagawa
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Cassandra Long
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - David K C Cooper
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hidetaka Hara
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
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Understanding alterations in drug handling with aging: a focus on the pharmacokinetics of maintenance immunosuppressants in the elderly. Curr Opin Organ Transplant 2015; 20:424-30. [PMID: 26126198 DOI: 10.1097/mot.0000000000000220] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW This review presents current knowledge of the impact of age on the pharmacokinetics of maintenance immunosuppressants. RECENT FINDINGS Over the past decade, there has been a steady increase in older patients on organ transplant waiting lists. As a result, the average age of transplant recipients has significantly increased. The survival and quality-of-life benefits of transplantation in the elderly population have been demonstrated. Advancing age is associated with changes in immune responses, as well as changes in drug handling. Immunosenescence is a physiological part of aging and is linked to reduced rejection rates, but also higher rates of diabetes, infections and malignancies. Physiologic changes associated with age can have a significant impact on the pharmacokinetics of the maintenance immunosuppressive agents. Taken together, these age-related changes impact older transplant candidates and may have significant implications for managing immunosuppression in the elderly. SUMMARY Despite the lack of formal efficacy, safety and pharmacokinetic studies of individual immunosuppressants in the elderly transplant population, there are enough data available for practitioners to be able to adequately manage their older patients. A proficient understanding of the factors that impact the pharmacokinetics of the immunosuppressants in the elderly is essential to managing these patients successfully.
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Pelletier RP, Rajab AA, Diez A, DiPaola NR, Bumgardner GL, Elkhammas EA, Henry ML. Early immunosuppression treatment correlates with laterde novodonor-specific antibody development after kidney and pancreas transplantation. Clin Transplant 2015; 29:1119-27. [DOI: 10.1111/ctr.12636] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2015] [Indexed: 11/28/2022]
Affiliation(s)
- Ronald P. Pelletier
- Division of Transplantation; Department of Surgery; The Ohio State University; Columbus OH USA
| | - Amer A. Rajab
- Division of Transplantation; Department of Surgery; The Ohio State University; Columbus OH USA
| | - Alejandro Diez
- Division of Nephrology; Department of Internal Medicine; The Ohio State University; Columbus OH USA
| | | | - Ginny L. Bumgardner
- Division of Transplantation; Department of Surgery; The Ohio State University; Columbus OH USA
| | - Elmahdi A. Elkhammas
- Division of Transplantation; Department of Surgery; The Ohio State University; Columbus OH USA
| | - Mitchell L. Henry
- Division of Transplantation; Department of Surgery; The Ohio State University; Columbus OH USA
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Tolerogenic Dendritic Cells on Transplantation: Immunotherapy Based on Second Signal Blockage. J Immunol Res 2015; 2015:856707. [PMID: 26543876 PMCID: PMC4620289 DOI: 10.1155/2015/856707] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/23/2015] [Accepted: 06/29/2015] [Indexed: 12/16/2022] Open
Abstract
Dendritic cells (DCs), the most important professional antigen-presenting cells (APC), play crucial role in both immunity and tolerance. It is well known that DCs are able to mount immune responses against foreign antigens and simultaneously tolerate self-antigens. Since DCs can be modulated depending on the surrounding microenvironment, they can act as a bridge between innate and adaptive immunity. However, the mechanisms that support this dual role are not entirely clear. Recent studies have shown that DCs can be manipulated ex vivo in order to trigger their tolerogenic profile, what can be a tool to be used in clinical trials aiming the treatment of various diseases and the prevention of transplant rejection. In this sense, the blockage of costimulatory molecules on DC, in the attempt of inhibiting the second signal in the immunological synapse, can be considered as one of the main strategies under development. This review brings an update on current therapies using tolerogenic dendritic cells modulated with costimulatory blockers with the aim of reducing transplant rejection. However, although there are current clinical trials using tolerogenic DC to treat allograft rejection, the actual challenge is to modulate these cells in order to maintain a permanent tolerogenic profile.
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Talawila N, Pengel LHM. Does belatacept improve outcomes for kidney transplant recipients? A systematic review. Transpl Int 2015; 28:1251-64. [PMID: 25965549 DOI: 10.1111/tri.12605] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 01/19/2015] [Accepted: 05/07/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND Belatacept was intended to provide better outcomes for kidney transplant (KT) recipients by allowing minimization/withdrawal of calcineurin inhibitors (CNI) and steroids. METHODS We searched for randomized controlled trials (RCTs) in adult KT comparing belatacept with CNIs. Methodological quality was assessed. Meta-analyses were performed to calculate odds ratios (OR) and mean differences (MD). RESULTS Six RCTs were included. Pooled analyses found no differences for acute rejection at any time point. Renal function [Calculated glomerular filtration rate (cGFR)] was better with belatacept at 12 and 24 months (MD = 11.7 and 13.7 ml/min/1.73 m(2) ). New onset diabetes after transplantation was lower with belatacept at 12 months (OR = 0.43). Systolic and diastolic blood pressures were lower at 12 months (MD -7.2 and -3.1 mmHg) as were triglycerides at 12 and 24 months (MD = -32.9 and -41.7 mg/dl). Total and low-density lipoprotein cholesterol were lower with belatacept at 24 months (MD = -19.8 and -10.6 mg/dl). There were no differences for other outcomes. CONCLUSION Limited available data suggest a potential benefit for belatacept by reducing the risk of CNI toxicity, especially renal function, without evidence of increased acute rejection. There were no safety issues apart from a possible risk of post-transplant lymphoproliferative disorder in Epstein-barr virus-seronegative recipients. Further studies are required to confirm this benefit.
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Affiliation(s)
- Nishanthi Talawila
- Centre for Evidence in Transplantation, Clinical Effectiveness Unit, Royal College of Surgeons of England and the London School of Hygiene and Tropical Medicine, University of London, London, UK
| | - Liset H M Pengel
- Centre for Evidence in Transplantation, Clinical Effectiveness Unit, Royal College of Surgeons of England and the London School of Hygiene and Tropical Medicine, University of London, London, UK.,Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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Bamoulid J, Staeck O, Halleck F, Khadzhynov D, Brakemeier S, Dürr M, Budde K. The need for minimization strategies: current problems of immunosuppression. Transpl Int 2015; 28:891-900. [PMID: 25752992 DOI: 10.1111/tri.12553] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Revised: 12/30/2014] [Accepted: 02/27/2015] [Indexed: 12/31/2022]
Abstract
New immunosuppressants and the better use of immunosuppressant combination therapy have led to significant improvements in renal allograft outcomes over the last decades. Yet, despite dramatic reduction in rejection rates and improvement in 1-year graft survival, long-term graft attrition rates remained rather constant. Current immunosuppressant combinations are frequently leading to overimmunosuppression and are increasing cardiovascular risk. Importantly, calcineurin inhibitors are nephrotoxic, contribute to cardiovascular risk and chronic allograft dysfunction. Furthermore, immunosuppressant-associated toxicities aggravate immune-mediated nephron injury and side effects lead to nonadherence, an identified important reason for late acute and chronic antibody-mediated rejections. The frequent development of a chronic humoral response indicates rather insufficient immunosuppression of current combinations than simple under-immunosuppression. While there is no evidence that increasing immunosuppressive doses will improve outcomes or reduce de novo HLA-antibody formation, there is clear evidence that adequate minimization strategies will reduce side effect burden. Because of low rejection risk, but frequent side effects, drug minimization is particularly relevant for the many maintenance patients. In summary, new therapeutic strategies need to be developed from adequately powered clinical trials for reduction of the many side effects of immunosuppressants. Such evidence-based and time-dependent immunosuppressive minimization strategies are needed to achieve better long-term outcomes in the future.
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Affiliation(s)
- Jamal Bamoulid
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Staeck
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Dmytri Khadzhynov
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Susanne Brakemeier
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Dürr
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology, Charité Universitätsmedizin Berlin, Berlin, Germany
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Beneficial effect of belatacept on health-related quality of life and perceived side effects: results from the BENEFIT and BENEFIT-EXT trials. Transplantation 2015; 98:960-8. [PMID: 24831918 DOI: 10.1097/tp.0000000000000159] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Patient-reported outcomes are increasingly incorporated in drug evaluation trials. Whether new immunosuppressive drugs result in an improved health-related quality of life (HRQoL) and a reduced side effect experiences remains unknown. Moreover, the relationship between HRQoL and kidney function has never been investigated in kidney transplant recipients. METHODS Using the BENEFIT and BENEFIT-EXT trials, we investigated the following: (a) evolution of HRQoL, assessed by the Medical Outcomes Short Form Health Survey (SF-36) in the first 3 years (baseline, 12, 24, and 36 months) after kidney transplantation; (b) association among kidney function (chronic kidney disease stage), HRQoL, and patient-reported side effects (Modified Transplant Symptom Occurrence and Symptom Distress Scale-59R; BENEFIT trial only); and (c) impact of belatacept and cyclosporine on side effect experience and HRQoL. RESULTS In the BENEFIT trial, all subjects reported clinically meaningful improvements compared with baseline and returned to general population scores, both for physical composite score (PCS) and mental composite score Short Form (36) Health Survey at 12 to 36 months after transplantation. In the BENEFIT-EXT trial, this was observed for PCS only. Belatacept-treated patients reported better absolute PCSs compared with cyclosporine-treated patients. The differences were small but statistically significant at all times. Belatacept-treated patients tended to experience less side effects compared with cyclosporine-treated patients, except for dry skin. Worsening kidney function was associated with a significant decrease in HRQoL. CONCLUSION Worsening in kidney function was associated with lower HRQoL. Compared with cyclosporine, belatacept was associated with improved HRQoL, suggesting that use of non-nephrotoxic immunosuppressants may affect the patient's side effect experience and improve their HRQoL.
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