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1
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Paccagnella C, Andreola S, Gambaro A, Gambaro G, Caletti C. Immunosuppressive Therapy-Related Cardiovascular Risk Factors in Renal Transplantation: A Narrative Review. Cardiorenal Med 2025; 15:209-228. [PMID: 39956105 DOI: 10.1159/000542378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 10/24/2024] [Indexed: 02/18/2025] Open
Abstract
BACKGROUND Kidney transplantation is the best treatment for patients with chronic renal failure, capable of improving life expectancy and the risk of death from all causes, which, however, remains higher than in the general population. The leading cause of death in transplant patients is cardiovascular events, burdened by a significant impact brought about by anti-rejection therapy. Experimental and clinical studies to date show that in kidney transplant recipients, traditional cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity, tobacco, etc.) may be exacerbated or worsened by the dysmetabolic effects of immunosuppressive drugs, which may also result in additional risk factors such as proteinuria, anemia, and arterial stiffness. The aim of this review was to provide an in-depth evaluation of the effect of immunosuppressive treatments on cardiovascular risk factors. SUMMARY We have investigated and described the main cardiovascular risk factors related to immunosuppressive drugs. We searched for relevant scientific articles in medicine, transplant, cardiologic, and nephrological journals in major medical science libraries. KEY MESSAGES Immunosuppressive drugs allow graft survival and successful bunking of the transplant; however, they are not without significant side effects and should always be prescribed weighing the risk/benefit ratio and the individual patient's therapeutic needs.
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Affiliation(s)
- Chiara Paccagnella
- Nephrology Postgraduate School, Division of Nephrology and Dialysis, Department of Medicine, University of Verona, Verona, Italy
| | - Stefano Andreola
- Division of Nephrology and Dialysis, Department of Medicine, University of Verona, Verona, Italy
| | - Alessia Gambaro
- Division of Cardiology, Department of Medicine, University of Verona, Verona, Italy
| | - Giovanni Gambaro
- Division of Nephrology and Dialysis, Department of Medicine, University of Verona, Verona, Italy
| | - Chiara Caletti
- Division of Nephrology and Dialysis, Department of Medicine, University of Verona, Verona, Italy
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Tönshoff B, Patry C, Fichtner A, Höcker B, Böhmig GA. New Immunosuppressants in Pediatric Kidney Transplantation: What's in the Pipeline for Kids? Pediatr Transplant 2025; 29:e70008. [PMID: 39711054 DOI: 10.1111/petr.70008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 11/05/2024] [Accepted: 12/08/2024] [Indexed: 12/24/2024]
Abstract
The 1- and 5-year patient and graft survival rates of pediatric kidney transplant recipients have improved considerably in recent years. Regardless of early success, kidney transplantation is challenged by suboptimal long-term allograft and patient survival. Many kidney transplants are lost due to immune (rejection) and nonimmune allograft injuries, and patient survival is limited from cardiovascular disease, infection, and malignancy. Many of these co-morbidities are due to side effects of the currently available immunosuppressive drugs, especially calcineurin inhibitors and glucocorticoids, which are associated with long-term toxicity. Hence, there is an urgent need to develop new, more specific and less toxic immunosuppressive drugs. Unfortunately, there have also been no new drug approvals for adult kidney transplant recipients since belatacept in 2012, leaving the immunosuppressive drug armamentarium unchanged for more than 20 years. As a consequence of the lack of innovation in adult kidney transplant recipients, the pipeline of novel immunosuppressive agents for pediatric solid organ transplant recipients is also limited. The most promising agent in the near future, at least for adolescent patients, appears to be belatacept, despite its many limitations. In this review article, we report on three areas that appear to be the most relevant topics at this time: (i) extended-release tacrolimus, (ii) costimulation blockade with belatacept, and (iii) treatment of antibody-mediated rejection. Improved synergies between the pharmaceutical industry and the transplant community are needed to achieve the ultimate goal of improving long-term outcomes in pediatric kidney transplantation.
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Affiliation(s)
- Burkhard Tönshoff
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Christian Patry
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Britta Höcker
- Department of Pediatrics I, Medical Faculty, University Children's Hospital Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Georg A Böhmig
- Department of Medicine III, Medical University of Vienna, Vienna, Austria
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3
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Bertrand D, Chavarot N, Olagne J, Greze C, Gatault P, Danthu C, Colosio C, Jaureguy M, Duveau A, Bouvier N, Le Meur Y, Golbin L, Thervet E, Thierry A, François A, Laurent C, Lemoine M, Anglicheau D, Guerrot D. Biopsy-Proven T-Cell Mediated Rejection After Belatacept Rescue Conversion: A Multicenter Retrospective Study. Transpl Int 2024; 37:13544. [PMID: 39712083 PMCID: PMC11659955 DOI: 10.3389/ti.2024.13544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/20/2024] [Indexed: 12/24/2024]
Abstract
After kidney transplantation, conversion to belatacept is a promising alternative in patients with poor graft function or intolerance to calcineurin inhibitors. The risk of acute rejection has not been well described under these conditions. Here we present a retrospective multicenter study investigating the occurrence of acute rejection after conversion in 901 patients (2011-2021). The incidence of cellular and humoral rejection was 5.2% and 0.9%, respectively. T-cell mediated rejection (TCMR) occurred after a median of 2.6 months after conversion. Out of 47 patients with TCMR, death-censored graft survival was 70.1%, 55.1% and 50.8% at 1 year, 3 years and 5 years post-rejection, respectively. Eight patients died after rejection, mainly from infectious diseases. We compared these 47 patients with a cohort of kidney transplant recipients who were converted to belatacept between 2011 and 2017 and did not develop rejection (n = 238). In multivariate analysis, shorter time between KT and conversion, and the absence of anti-thymocyte globulin induction after KT were associated with the occurrence of TCMR after belatacept conversion. The occurrence of rejection after conversion to belatacept appeared to be less frequent than with de novo use. Nevertheless, the risk of graft loss could be significant in patients with already low renal function.
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Affiliation(s)
- Dominique Bertrand
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Nathalie Chavarot
- Department of Nephrology and Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Jérôme Olagne
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Strasbourg University Hospital, Strasbourg, France
| | - Clarisse Greze
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
| | - Philippe Gatault
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Tours University Hospital, Tours, France
| | - Clément Danthu
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Limoges University Hospital, Limoges, France
| | - Charlotte Colosio
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Reims University Hospital, Reims, France
| | - Maïté Jaureguy
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Amiens University Hospital, Amiens, France
| | - Agnès Duveau
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Angers University Hospital, Angers, France
| | - Nicolas Bouvier
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Caen University Hospital, Caen, France
| | - Yannick Le Meur
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Brest University Hospital, Brest, France
| | - Léonard Golbin
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rennes University Hospital, Rennes, France
| | - Eric Thervet
- Department of Nephrology and Dialysis, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Antoine Thierry
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Poitiers University Hospital, Poitiers, France
| | - Arnaud François
- Department of Pathology, Rouen University Hospital, Rouen, France
| | - Charlotte Laurent
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Mathilde Lemoine
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Dany Anglicheau
- Department of Nephrology and Kidney Transplantation, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Dominique Guerrot
- Department of Nephrology, Kidney Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
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4
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Luo B, Zhong S, Wang X, Guo P, Hou Y, Di W. Management of blood lipids in post-kidney transplant patients: a systematic review and network meta-analysis. Front Pharmacol 2024; 15:1440875. [PMID: 39439889 PMCID: PMC11493609 DOI: 10.3389/fphar.2024.1440875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
Introduction The primary objective of this systematic review was to provide an overview of the efficacy and safety of various lipid-lowering therapies in patients post-kidney transplant (PKT), given the limited existing literature. Considering the restricted number of available studies, this work aimed to summarize the existing evidence regarding the effectiveness of different lipid-lowering treatments in PKT patients. The effects of various lipid-lowering therapeutic regimens on lipid levels were compared, and their safety was assessed, with the heterogeneity of treatment protocols acknowledged. Material and Methods Randomized controlled trials investigating different treatment regimens (DTRs) for regulating lipid levels in PKT patients were systematically retrieved from PubMed, Cochrane Library, and Embase, from inception to March 2024. Literature quality was assessed employing the Cochrane risk of bias assessment tool. Data analysis and graphical representation were performed employing RevMan5.3 and Stata 20.0. The surface under the cumulative ranking area (SUCRA) compared the effects of DTRs on lipid profiles, incidence of adverse events, and all-cause mortality in PKT patients. Results Fifteen studies were included, comprising 5,768 PKT patients and involving 9 treatment regimens. The results revealed that, for changes in high-density lipoprotein cholesterol (HDL-C), the SUCRA rankings from highest to lowest among PKT patients receiving DTRs were statins + ezetimibe (70%), placebo (61.5%), fibrates (57.2%), statins (44.1%), and fish oil (17.3%). Regarding changes in low-DL-C (LDL-C), the SUCRA rankings from highest to lowest among PKT patients receiving DTRs were statins (68.2%), statins + ezetimibe (67.5%), fish oil (53.4%), fibrates (34.5%), and placebo (26.5%). For the change in total cholesterol (TC) levels, a network meta-analysis (NMA) revealed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for TC change were statins + ezetimibe (97.6%), proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 inhibitors) (74.3%), fish oil (64.3%), statins (61.6%), fibrates (47.2%), placebo (31.6%), calcineurin phosphatase inhibitors (11.9%), and immunosuppressants (11.4%). Regarding the change in triglyceride (TG) levels, a NMA showed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for TG change were fibrates (99.9%), statins (68.9%), PCSK9 inhibitors (66.6%), statins + ezetimibe (55.1%), placebo (49.2%), fish oil (45.0%), immunosuppressants (7.8%), and calcineurin phosphatase inhibitors (7.6%). For the occurrence of kidney transplant failure, a NMA revealed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for reducing the incidence of kidney transplant failure were PCSK9 inhibitors (69.0%), calcineurin phosphatase inhibitors (63.0%), statins (61.5%), placebo (55.1%), steroids (51.8%), immunosuppressants (27.1%), and fibrates (22.5%). Regarding all-cause mortality, a NMA showed that among PKT patients receiving DTRs, the SUCRA rankings from highest to lowest for reducing all-cause mortality were PCSK9 inhibitors (90.5%), statins (55.8%), and placebo (3.7%). Conclusion In reducing lipid levels in PKT patients, combination therapy with statins and ezetimibe demonstrated notable advantages and higher effectiveness. PCSK9 inhibitors exhibited greater advantages in reducing adverse events and mortality rates in PKT patients, with higher safety.
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Affiliation(s)
- Bohan Luo
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
- Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Shan Zhong
- Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Xiaoxiao Wang
- Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Pu Guo
- Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yifu Hou
- Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Wenjia Di
- Organ Transplantation Center, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
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Liu X, Shen J, Yan H, Hu J, Liao G, Liu D, Zhou S, Zhang J, Liao J, Guo Z, Li Y, Yang S, Li S, Chen H, Guo Y, Li M, Fan L, Li L, Luo P, Zhao M, Liu Y. Posttransplant complications: molecular mechanisms and therapeutic interventions. MedComm (Beijing) 2024; 5:e669. [PMID: 39224537 PMCID: PMC11366828 DOI: 10.1002/mco2.669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 07/02/2024] [Accepted: 07/08/2024] [Indexed: 09/04/2024] Open
Abstract
Posttransplantation complications pose a major challenge to the long-term survival and quality of life of organ transplant recipients. These complications encompass immune-mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft-versus-host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients.
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Affiliation(s)
- Xiaoyou Liu
- Department of Organ transplantationThe First Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
| | - Junyi Shen
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Hongyan Yan
- Department of Organ transplantationThe First Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
| | - Jianmin Hu
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Guorong Liao
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Ding Liu
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Song Zhou
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Jie Zhang
- Department of Organ transplantationThe First Affiliated Hospital, Guangzhou Medical UniversityGuangzhouChina
| | - Jun Liao
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Zefeng Guo
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Yuzhu Li
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Siqiang Yang
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Shichao Li
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Hua Chen
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Ying Guo
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Min Li
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Lipei Fan
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Liuyang Li
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Peng Luo
- Department of OncologyZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Ming Zhao
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
| | - Yongguang Liu
- Department of Organ transplantationZhujiang HospitalSouthern Medical UniversityGuangzhouChina
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6
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Kanbay M, Copur S, Topçu AU, Guldan M, Ozbek L, Gaipov A, Ferro C, Cozzolino M, Cherney DZI, Tuttle KR. An update review of post-transplant diabetes mellitus: Concept, risk factors, clinical implications and management. Diabetes Obes Metab 2024; 26:2531-2545. [PMID: 38558257 DOI: 10.1111/dom.15575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/09/2024] [Accepted: 03/09/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVE Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. METHODS Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. RESULTS PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. DISCUSSION The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.
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Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - A Umur Topçu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Mustafa Guldan
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Lasin Ozbek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Abduzhappar Gaipov
- Department of Medicine, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Charles Ferro
- Department of Nephrology, University Hospitals Birmingham and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Katherine R Tuttle
- Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington, USA
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7
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Bredewold OW, van Oeveren-Rietdijk AM, Florijn B, Rotmans JI, de Fijter JW, van Kooten C, van Zonneveld AJ, de Boer HC. Conversion from calcineurin inhibitors to belatacept-based immunosuppressive therapy skews terminal proliferation of non-classical monocytes and lowers lymphocyte counts. Transpl Immunol 2024; 82:101976. [PMID: 38199271 DOI: 10.1016/j.trim.2023.101976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 11/26/2023] [Accepted: 12/31/2023] [Indexed: 01/12/2024]
Abstract
Belatacept, a modified form of CTLA-Ig that blocks CD28-mediated co-stimulation of T cells, is an immune-suppressant that can be used as an alternative to calcineurin inhibitors (CNIs). In kidney transplant recipients, belatacept has been associated with improved renal function and reduced cardiovascular toxicity. Monocytes as well as T-lymphocytes play causal roles in the pathophysiology of atherosclerotic disease. We hypothesized that the beneficial impact of the use of belatacept over CNIs on cardiovascular risk could be partly explained by the impact of belatacept therapy on these circulating leukocytes. Hence, we phenotyped circulating leukocytes in transplanted patients with a stable renal function that were randomized between either continuation of CNI or conversion to belatacept in two international studies in which we participated. In 41 patients, we found that belatacept-treated patients consistently showed lower numbers of B-lymphocytes, T-lymphocytes as well as CD14-negative monocytes (CD14NM), especially in non-diabetic patients. Our observation that this decrease was associated to plasma concentrations of TNFα is consistent with a model where CD14NM-production of TNFα is diminished by belatacept-treatment, due to effects on the antigen-presenting cell compartment.
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Affiliation(s)
- O W Bredewold
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands..
| | - A M van Oeveren-Rietdijk
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - B Florijn
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - J I Rotmans
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - J W de Fijter
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - C van Kooten
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - A J van Zonneveld
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - H C de Boer
- Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands
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8
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Schrezenmeier E, Dörner T, Halleck F, Budde K. Cellular Immunobiology and Molecular Mechanisms in Alloimmunity-Pathways of Immunosuppression. Transplantation 2024; 108:148-160. [PMID: 37309030 DOI: 10.1097/tp.0000000000004646] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.
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Affiliation(s)
- Eva Schrezenmeier
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program Universitätsmedizin Berlin, Berlin, Germany
| | - Thomas Dörner
- Department of Rheumatology and Clinical Immunology - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Deutsches Rheumaforschungszentrum (DRFZ), Berlin, Germany
| | - Fabian Halleck
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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9
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Rostaing L, Jouve T, Terrec F, Malvezzi P, Noble J. Adverse Drug Events after Kidney Transplantation. J Pers Med 2023; 13:1706. [PMID: 38138933 PMCID: PMC10744736 DOI: 10.3390/jpm13121706] [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: 11/12/2023] [Revised: 12/04/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023] Open
Abstract
Introduction: Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor-recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. Area covered: Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies.
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Affiliation(s)
- Lionel Rostaing
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, 38043 Grenoble, France; (T.J.); (F.T.); (P.M.); (J.N.)
- Institute for Advanced Biosciences (IAB), INSERM U 1209, CNRS UMR 5309, Université Grenoble Alpes, 38043 Grenoble, France
- Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
| | - Thomas Jouve
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, 38043 Grenoble, France; (T.J.); (F.T.); (P.M.); (J.N.)
- Institute for Advanced Biosciences (IAB), INSERM U 1209, CNRS UMR 5309, Université Grenoble Alpes, 38043 Grenoble, France
| | - Florian Terrec
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, 38043 Grenoble, France; (T.J.); (F.T.); (P.M.); (J.N.)
| | - Paolo Malvezzi
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, 38043 Grenoble, France; (T.J.); (F.T.); (P.M.); (J.N.)
| | - Johan Noble
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, 38043 Grenoble, France; (T.J.); (F.T.); (P.M.); (J.N.)
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10
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Kitchens WH, Larsen CP, Badell IR. Costimulatory Blockade and Solid Organ Transplantation: The Past, Present, and Future. Kidney Int Rep 2023; 8:2529-2545. [PMID: 38106575 PMCID: PMC10719580 DOI: 10.1016/j.ekir.2023.08.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/01/2023] [Accepted: 08/28/2023] [Indexed: 12/19/2023] Open
Abstract
Belatacept is the first costimulatory blockade agent clinically approved for transplant immunosuppression. Although more than 10 years of study have demonstrated that belatacept offers superior long-term renal allograft and patient survival compared to conventional calcineurin inhibitor (CNI)-based immunosuppression regimens, the clinical adoption of belatacept has continued to lag because of concerns of an early risk of acute cellular rejection (ACR) and various logistical barriers to its administration. In this review, the history of the clinical development of belatacept is examined, along with the findings of the seminal BENEFIT and BENEFIT-EXT trials culminating in the clinical approval of belatacept. Recent efforts to incorporate belatacept into novel CNI-free immunosuppression regimens are reviewed, as well as the experience of the Emory Transplant Center in using a tapered course of low-dose tacrolimus in belatacept-treated renal allograft patients to garner the long-term outcome benefits of belatacept without the short-term increased risks of ACR. Potential avenues to increase the clinical adoption of belatacept in the future are explored, including surmounting the logistical barriers of belatacept administration through subcutaneous administration or more infrequent belatacept dosing. In addition, belatacept conversion strategies and potential expanded clinical indications of belatacept are discussed for pediatric transplant recipients, extrarenal transplant recipients, treatment of antibody-mediated rejection (AMR), and in patients with failed renal allografts. Finally, we discuss the novel immunosuppressive drugs currently in the development pipeline that may aid in the expansion of costimulation blockade utilization.
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Affiliation(s)
- William H. Kitchens
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Christian P. Larsen
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - I. Raul Badell
- Division of Transplantation, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA
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11
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Anwar IJ, Berman DM, DeLaura I, Gao Q, Willman MA, Miller A, Gill A, Gill C, Perrin S, Ricordi C, Ruiz P, Song M, Ladowski JM, Kirk AD, Kenyon NS. The anti-CD40L monoclonal antibody AT-1501 promotes islet and kidney allograft survival and function in nonhuman primates. Sci Transl Med 2023; 15:eadf6376. [PMID: 37647390 PMCID: PMC10990482 DOI: 10.1126/scitranslmed.adf6376] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 07/26/2023] [Indexed: 09/01/2023]
Abstract
Prior studies of anti-CD40 ligand (CD40L)-based immunosuppression demonstrated effective prevention of islet and kidney allograft rejection in nonhuman primate models; however, clinical development was halted because of thromboembolic complications. An anti-CD40L-specific monoclonal antibody, AT-1501 (Tegoprubart), was engineered to minimize risk of thromboembolic complications by reducing binding to Fcγ receptors expressed on platelets while preserving binding to CD40L. AT-1501 was tested in both a cynomolgus macaque model of intrahepatic islet allotransplantation and a rhesus macaque model of kidney allotransplantation. AT-1501 monotherapy led to long-term graft survival in both islet and kidney transplant models, confirming its immunosuppressive potential. Furthermore, AT-1501-based regimens after islet transplant resulted in higher C-peptide, greater appetite leading to weight gain, and reduced occurrence of cytomegalovirus reactivation compared with conventional immunosuppression. These data support AT-1501 as a safe and effective agent to promote both islet and kidney allograft survival and function in nonhuman primate models, warranting further testing in clinical trials.
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Affiliation(s)
- Imran J. Anwar
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA
| | - Dora M. Berman
- Diabetes Research Institute, University of Miami; Miami, FL 33136, USA
- Department of Surgery, University of Miami; Miami, FL 33136, USA
| | - Isabel DeLaura
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA
| | - Qimeng Gao
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA
| | | | - Allison Miller
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA
| | - Alan Gill
- ALS Therapy Development Institute; Cambridge, MA 02472, USA
| | - Cindy Gill
- ALS Therapy Development Institute; Cambridge, MA 02472, USA
| | | | - Camillo Ricordi
- Diabetes Research Institute, University of Miami; Miami, FL 33136, USA
- Department of Surgery, University of Miami; Miami, FL 33136, USA
- Department of Microbiology and Immunology, University of Miami; Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami; Miami, FL 33136, USA
- Department of Medicine, University of Miami; Miami, FL 33136, USA
| | - Philip Ruiz
- Department of Surgery, University of Miami; Miami, FL 33136, USA
| | - Mingqing Song
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA
| | - Joseph M Ladowski
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA
| | - Allan D. Kirk
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine; Durham, NC 27710, USA
| | - Norma S. Kenyon
- Diabetes Research Institute, University of Miami; Miami, FL 33136, USA
- Department of Surgery, University of Miami; Miami, FL 33136, USA
- Department of Microbiology and Immunology, University of Miami; Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami; Miami, FL 33136, USA
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12
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Herr F, Dekeyser M, Le Pavec J, Desterke C, Chiron AS, Bargiel K, Mercier O, Vernochet A, Fadel E, Durrbach A. mTOR Inhibition Impairs the Activation and Function of Belatacept-Resistant CD4 +CD57 + T Cells In Vivo and In Vitro. Pharmaceutics 2023; 15:pharmaceutics15041299. [PMID: 37111784 PMCID: PMC10142381 DOI: 10.3390/pharmaceutics15041299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/28/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Calcineurin inhibitors have improved graft survival in solid-organ transplantation but their use is limited by toxicity, requiring a switch to another immunosuppressor in some cases. Belatacept is one option that has been shown to improve graft and patient survival despite being associated with a higher risk of acute cellular rejection. This risk of acute cellular rejection is correlated with the presence of belatacept-resistant T cells. We performed a transcriptomic analysis of in vitro-activated cells to identify pathways affected by belatacept in belatacept-sensitive cells (CD4+CD57-) but not in belatacept-resistant CD4+CD57+ T cells. mTOR was significantly downregulated in belatacept-sensitive but not belatacept-resistant T cells. The inhibition of mTOR strongly decreases the activation and cytotoxicity of CD4+CD57+ cells. In humans, the use of a combination of mTOR inhibitor and belatacept prevents graft rejection and decreases the expression of activation markers on CD4 and CD8 T cells. mTOR inhibition decreases the functioning of belatacept-resistant CD4+CD57+ T cells in vitro and in vivo. It could potentially be used in association with belatacept to prevent acute cellular rejection in cases of calcineurin intolerance.
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Affiliation(s)
- Florence Herr
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
| | - Manon Dekeyser
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
- Hôpital Henri Mondor, Service de Néphrologie, Assistance Publique-Hôpitaux de Paris, 94010 Creteil, France
| | - Jerome Le Pavec
- Inserm, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Université Paris-Saclay, 92350 Le Plessis Robinson, France
- Centre Hospitalier Marie Lannelongue, 92350 Le Plessis Robinson, France
| | - Christophe Desterke
- Inserm, Modèles de Cellules Souches Malignes et Thérapeutiques, Université Paris-Saclay, 94805 Villejuif, France
| | - Andrada-Silvana Chiron
- Unité des Technologies Chimiques et Biologiques pour la Santé, CNRS, INSERM, UTCBS, Université de Paris, 75006 Paris, France
- Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, 94270 Le Kremlin-Bicetre, France
| | - Karen Bargiel
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
| | - Olaf Mercier
- Inserm, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Université Paris-Saclay, 92350 Le Plessis Robinson, France
- Centre Hospitalier Marie Lannelongue, 92350 Le Plessis Robinson, France
| | - Amelia Vernochet
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
| | - Elie Fadel
- Inserm, Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique, Université Paris-Saclay, 92350 Le Plessis Robinson, France
- Centre Hospitalier Marie Lannelongue, 92350 Le Plessis Robinson, France
| | - Antoine Durrbach
- Institut Gustave Roussy, Inserm, Immunologie Intégrative des Tumeurs et Immunothérapie des Cancers, Université Paris-Saclay, 94805 Villejuif, France
- Hôpital Henri Mondor, Service de Néphrologie, Assistance Publique-Hôpitaux de Paris, 94010 Creteil, France
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13
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Sharif A. Interventions Against Posttransplantation Diabetes: A Scientific Rationale for Treatment Hierarchy Based on Literature Review. Transplantation 2022; 106:2301-2313. [PMID: 35696695 DOI: 10.1097/tp.0000000000004198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Posttransplant diabetes (PTD) is a common medical complication after solid organ transplantation. Because of adverse outcomes associated with its development and detrimental impact on long-term survival, strategies to prevent or manage PTD are critically important but remain underresearched. Treatment hierarchies of antidiabetic therapies in the general population are currently being revolutionized based on cardiovascular outcome trials, providing evidence-based rationale for optimization of medical management. However, opportunities for improving medical management of PTD are challenged by 2 important considerations: (1) translating clinical evidence data from the general population to underresearched solid organ transplant cohorts and (2) targeting treatment based on primary underlying PTD pathophysiology. In this article, the aim is to provide an overview of PTD treatment options from a new angle. Rationalized by a consideration of underlying PTD pathophysiological defects, which are heterogeneous among diverse transplant patient cohorts, a critical appraisal of the published literature and summary of current research in progress will be reviewed. The aim is to update transplant professionals regarding medical management of PTD from a new perspective tailored therapeutic intervention based on individualized characteristics. As the gap in clinical evidence between management of PTD versus type 2 diabetes widens, it is imperative for the transplant community to bridge this gap with targeted clinical trials to ensure we optimize outcomes for solid organ transplant recipients who are at risk or develop PTD. This necessary clinical research should help efforts to improve long-term outcomes for solid transplant patients from both a patient and graft survival perspective.
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Affiliation(s)
- Adnan Sharif
- Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
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14
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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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15
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Galeev SR, Gautier SV. Risks and ways of preventing kidney dysfunction in drug-induced immunosuppression in solid organ recipients. RUSSIAN JOURNAL OF TRANSPLANTOLOGY AND ARTIFICIAL ORGANS 2022. [DOI: 10.15825/1995-1191-2022-4-24-38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immunosuppressive therapy (IMT) is the cornerstone of treatment after transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term graft function. However, the expected effects of IMT must be balanced against the major adverse effects of these drugs and their toxicity. The purpose of this review is to summarize world experience on current immunosuppressive strategies and to assess their effects on renal function.
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Affiliation(s)
- Sh. R. Galeev
- Shumakov National Medical Research Center of Transplantology and Artificial Organs
| | - S. V. Gautier
- Shumakov National Medical Research Center of Transplantology and Artificial Organs; Sechenov University
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16
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Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract 2022; 28:923-1049. [PMID: 35963508 PMCID: PMC10200071 DOI: 10.1016/j.eprac.2022.08.002] [Citation(s) in RCA: 221] [Impact Index Per Article: 73.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers. METHODS The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development. RESULTS This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes. CONCLUSIONS This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus.
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Affiliation(s)
| | | | - S Sethu Reddy
- Central Michigan University, Mount Pleasant, Michigan
| | | | | | | | | | | | - Daniel Einhorn
- Scripps Whittier Diabetes Institute, La Jolla, California
| | | | | | - Rajesh Garg
- Lundquist Institute/Harbor-UCLA Medical Center, Torrance, California
| | | | | | | | | | | | - Darin Olson
- Colorado Mountain Medical, LLC, Avon, Colorado
| | | | | | - Archana R Sadhu
- Houston Methodist; Weill Cornell Medicine; Texas A&M College of Medicine; Houston, Texas
| | | | - Carla Stec
- American Association of Clinical Endocrinology, Jacksonville, Florida
| | | | - Katherine R Tuttle
- University of Washington and Providence Health Care, Seattle and Spokane, Washington
| | | | | | | | - Sandra L Weber
- University of South Carolina School of Medicine-Greenville, Prisma Health System, Greenville, South Carolina
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17
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Iglesias M, Brennan DC, Larsen CP, Raimondi G. Targeting inflammation and immune activation to improve CTLA4-Ig-based modulation of transplant rejection. Front Immunol 2022; 13:926648. [PMID: 36119093 PMCID: PMC9478663 DOI: 10.3389/fimmu.2022.926648] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
For the last few decades, Calcineurin inhibitors (CNI)-based therapy has been the pillar of immunosuppression for prevention of organ transplant rejection. However, despite exerting effective control of acute rejection in the first year post-transplant, prolonged CNI use is associated with significant side effects and is not well suited for long term allograft survival. The implementation of Costimulation Blockade (CoB) therapies, based on the interruption of T cell costimulatory signals as strategy to control allo-responses, has proven potential for better management of transplant recipients compared to CNI-based therapies. The use of the biologic cytotoxic T-lymphocyte associated protein 4 (CTLA4)-Ig is the most successful approach to date in this arena. Following evaluation of the BENEFIT trials, Belatacept, a high-affinity version of CTLA4-Ig, has been FDA approved for use in kidney transplant recipients. Despite its benefits, the use of CTLA4-Ig as a monotherapy has proved to be insufficient to induce long-term allograft acceptance in several settings. Multiple studies have demonstrated that events that induce an acute inflammatory response with the consequent release of proinflammatory cytokines, and an abundance of allograft-reactive memory cells in the recipient, can prevent the induction of or break established immunomodulation induced with CoB regimens. This review highlights advances in our understanding of the factors and mechanisms that limit CoB regimens efficacy. We also discuss recent successes in experimentally designing complementary therapies that favor CTLA4-Ig effect, affording a better control of transplant rejection and supporting their clinical applicability.
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Affiliation(s)
- Marcos Iglesias
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
| | - Daniel C. Brennan
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Christian P. Larsen
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, United States
| | - Giorgio Raimondi
- Vascularized and Composite Allotransplantation (VCA) Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
- *Correspondence: Giorgio Raimondi, ; Marcos Iglesias,
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18
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Aziz F, Jorgenson M, Garg N, Parajuli S, Mohamed M, Raza F, Mandelbrot D, Djamali A, Dhingra R. New Approaches to Cardiovascular Disease and Its Management in Kidney Transplant Recipients. Transplantation 2022; 106:1143-1158. [PMID: 34856598 DOI: 10.1097/tp.0000000000003990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Cardiovascular events, including ischemic heart disease, heart failure, and arrhythmia, are common complications after kidney transplantation and continue to be leading causes of graft loss. Kidney transplant recipients have both traditional and transplant-specific risk factors for cardiovascular disease. In the general population, modification of cardiovascular risk factors is the best strategy to reduce cardiovascular events; however, studies evaluating the impact of risk modification strategies on cardiovascular outcomes among kidney transplant recipients are limited. Furthermore, there is only minimal guidance on appropriate cardiovascular screening and monitoring in this unique patient population. This review focuses on the limited scientific evidence that addresses cardiovascular events in kidney transplant recipients. Additionally, we focus on clinical management of specific cardiovascular entities that are more prevalent among kidney transplant recipients (ie, pulmonary hypertension, valvular diseases, diastolic dysfunction) and the use of newer evolving drug classes for treatment of heart failure within this cohort of patients. We note that there are no consensus documents describing optimal diagnostic, monitoring, or management strategies to reduce cardiovascular events after kidney transplantation; however, we outline quality initiatives and research recommendations for the assessment and management of cardiovascular-specific risk factors that could improve outcomes.
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Affiliation(s)
- Fahad Aziz
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Margaret Jorgenson
- Department of Pharmacology, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Neetika Garg
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Sandesh Parajuli
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Maha Mohamed
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Farhan Raza
- Cardiovascular Division, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Didier Mandelbrot
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Arjang Djamali
- Division of Nephrology, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
- Division of Transplantation, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Ravi Dhingra
- Cardiovascular Division, Department of Medicine, University of Wisconsin-Madison School of Medicine and Public Health, University of Wisconsin Hospital and Clinics, Madison, WI
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19
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Dyslipidemia in Renal Transplant Recipients. TRANSPLANTOLOGY 2022. [DOI: 10.3390/transplantology3020020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Dyslipidemia is a frequent complication after kidney transplantation (KT) and is an important risk factor for cardiovascular disease (CVD). Renal transplant recipients (RTRs) are considered at high, or very high, risk of CVD, which is a leading cause of death in this patient group. Despite many factors of post-transplant dyslipidemia, the immunosuppressive treatment has the biggest influence on a lipid profile. There are no strict dyslipidemia treatment guidelines for RTRs, but the ones proposing an individual approach regarding CVD risk seem most suitable. Proper diet and physical activity are the main general measures to manage dyslipidemia and should be introduced initially in every patient after KT. In the case of an insufficient correction of lipemia, statins are the basis for hypolipidemic treatment. Statins should be introduced with caution to avoid serious side-effects (e.g., myopathy) or drug-drug interactions, especially with immunosuppressants. To lower the incidence of adverse effects, and improve medication adherence, ezetimibe in combination with statins is recommended. Fibrates and bile sequestrants are not recommended due to their side-effects and variable efficacy. However, several new lipid-lowering drugs like Proprotein convertase subtilisin/Kexin type9 (PCSK9) inhibitors may have promising effects in RTRs, but further research assessing efficacy and safety is yet to be carried out.
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20
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Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes. Nat Med 2022; 28:999-1005. [PMID: 35393535 DOI: 10.1038/s41591-022-01758-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 02/24/2022] [Indexed: 12/13/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1-71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8-65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07-5.00) (P = 1.92 × 10-7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.
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21
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Influence of Belatacept- vs. CNI-Based Immunosuppression on Vascular Stiffness and Body Composition. J Clin Med 2022; 11:jcm11051219. [PMID: 35268310 PMCID: PMC8911184 DOI: 10.3390/jcm11051219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/12/2022] [Accepted: 02/19/2022] [Indexed: 12/04/2022] Open
Abstract
Background: Arterial stiffness and phase angle (PhA) have gained importance as a diagnostic and prognostic parameter in the management of cardiovascular disease. There are few studies regarding the differences in arterial stiffness and body composition between renal transplant recipients (RTRs) receiving belatacept (BELA) vs. calcineurin inhibitors (CNI). Therefore, we investigated the differences in arterial stiffness and body composition between RTRs treated with different immunosuppressants, including BELA. Methods: In total, 325 RTRs were enrolled in the study (mean age 52.2 years, M −62.7%). Arterial stiffness was determined with an automated oscillometric device. All body composition parameters were assessed, based on bioelectrical impedance analysis (BIA), and laboratory parameters were obtained from the medical files of the patients. Results: We did not detect any significant difference in terms of arterial stiffness and PhA in RTRs undergoing different immunosuppressive regimens, based on CsA, Tac, or BELA. Age was an essential risk factor for greater arterial stiffness. The PhA was associated with age, BMI, time of dialysis before transplantation, and kidney graft function. Conclusion: No significant differences in arterial stiffness and PhA were observed in RTRs under different immunosuppressive regimens. While our data provide additional evidence for arterial stiffness and PhA in RTRs, more research is needed to fully explore these cardiovascular risk factors and the impact of different immunosuppressive regimens.
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22
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Herr F, Desterke C, Bargiel K, Vernochet A, Vanhove B, Vadanici R, Ye F, Dekeyser M, Durrbach A. The proliferation of belatacept-resistant T cells requires early IFNα pathway activation. Am J Transplant 2022; 22:489-503. [PMID: 34431219 DOI: 10.1111/ajt.16811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 07/20/2021] [Accepted: 08/14/2021] [Indexed: 01/25/2023]
Abstract
Belatacept was developed to replace calcineurin inhibitors in kidney transplantation. Its use is associated with better kidney transplant function, a lower incidence of anti-donor antibodies and higher graft survival. However, it is also associated with a higher risk of cellular rejection. We studied the activation and proliferation mechanisms of belatacept-resistant T lymphocytes (TLs), to identify new pathways for control. We performed a transcriptomic analysis on CD4+ CD57+ PD1- memory TLs, which are responsible for a higher incidence of graft rejection, after allogeneic stimulation with activated dendritic cells (aDCs) in the presence or absence of belatacept. After six hours of contact with aDCs, the (CD4+ CD57+ PD1- ) (CD4+ CD57+ PD1+ ) and (CD4+ CD57- ) lymphocytes had different transcriptional profiles with or without belatacept. In the CD4+ CD57+ PD1- population, the IFNα-dependent activation pathway was positively overrepresented, and IRF7 transcript levels were high. IRF7 was associated with IFNα/β and IL-6 regulation. The inhibition of both these cytokines in a context of belatacept treatment inhibited the proliferation of CD4+ CD57+ PD1- T cells. Our results show that IRF7 is rapidly upregulated in belatacept-resistant CD4+ CD57+ PD1- TLs. The inhibition of type I IFN or IL-6 in association with belatacept treatment reduces the proliferation of belatacept-resistant TLs, paving the way for new treatments for use in organ transplantation.
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Affiliation(s)
- Florence Herr
- INSERM UMR1186, Gustave Roussy Institute, Villejuif, France.,Université Paris-Saclay, Orsay, France
| | | | - Karen Bargiel
- INSERM UMR1186, Gustave Roussy Institute, Villejuif, France.,Université Paris-Saclay, Orsay, France
| | - Amelia Vernochet
- INSERM UMR1186, Gustave Roussy Institute, Villejuif, France.,Université Paris-Saclay, Orsay, France
| | | | | | - Fan Ye
- INSERM UMR1186, Gustave Roussy Institute, Villejuif, France
| | - Manon Dekeyser
- INSERM UMR1186, Gustave Roussy Institute, Villejuif, France.,Université Paris-Saclay, Orsay, France.,Henri Mondor Hospital, APHP, Creteil, France
| | - Antoine Durrbach
- INSERM UMR1186, Gustave Roussy Institute, Villejuif, France.,Université Paris-Saclay, Orsay, France.,Henri Mondor Hospital, APHP, Creteil, France
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23
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Ducloux D, Courivaud C. Prevention of Post-Transplant Diabetes Mellitus: Towards a Personalized Approach. J Pers Med 2022; 12:116. [PMID: 35055431 PMCID: PMC8778007 DOI: 10.3390/jpm12010116] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/06/2022] [Accepted: 01/13/2022] [Indexed: 02/01/2023] Open
Abstract
Post-transplant diabetes is a frequent complication after transplantation. Moreover, patients suffering from post-transplant diabetes have increased cardiovascular morbidity and reduced survival. Pathogenesis mainly involves beta-cell dysfunction in presence of insulin resistance. Both pre- and post-transplant risk factors are well-described, and some of them may be corrected or prevented. However, the frequency of post-transplant diabetes has not decreased in recent years. We realized a critical appraisal of preventive measures to reduce post-transplant diabetes.
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Affiliation(s)
- Didier Ducloux
- CHU Besançon, Department of Nephrology, Dialysis and Renal Transplantation, Federation Hospitalo-Universitaire INCREASE, 25000 Besançon, France;
- UMR RIGHT 1098, INSERM-EFS-UFC, 1 Bd Fleming, 25000 Besançon, France
| | - Cécile Courivaud
- CHU Besançon, Department of Nephrology, Dialysis and Renal Transplantation, Federation Hospitalo-Universitaire INCREASE, 25000 Besançon, France;
- UMR RIGHT 1098, INSERM-EFS-UFC, 1 Bd Fleming, 25000 Besançon, France
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24
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Murphy AJ, Febbraio MA. Immune-based therapies in cardiovascular and metabolic diseases: past, present and future. Nat Rev Immunol 2021; 21:669-679. [PMID: 34285393 DOI: 10.1038/s41577-021-00580-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2021] [Indexed: 02/02/2023]
Abstract
Cardiometabolic disorders were originally thought to be driven primarily by changes in lipid metabolism that cause the accumulation of lipids in organs, thereby impairing their function. Thus, in the setting of cardiovascular disease, statins - a class of lipid-lowering drugs - have remained the frontline therapy. In the past 20 years, seminal discoveries have revealed a central role of both the innate and adaptive immune system in driving cardiometabolic disorders. As such, it is now appreciated that immune-based interventions may have an important role in reducing death and disability from cardiometabolic disorders. However, to date, there have been a limited number of clinical trials exploring this interventional strategy. Nonetheless, elegant preclinical research suggests that immune-targeted therapies can have a major impact in treating cardiometabolic disease. Here, we discuss the history and recent advancements in the use of immunotherapies to treat cardiometabolic disorders.
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Affiliation(s)
- Andrew J Murphy
- Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
| | - Mark A Febbraio
- Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
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25
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Wojciechowski D, Wiseman A. Long-Term Immunosuppression Management: Opportunities and Uncertainties. Clin J Am Soc Nephrol 2021; 16:1264-1271. [PMID: 33853841 PMCID: PMC8455033 DOI: 10.2215/cjn.15040920] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The long-term management of maintenance immunosuppression in kidney transplant recipients remains complex. The vast majority of patients are treated with the calcineurin inhibitor tacrolimus as the primary agent in combination with mycophenolate, with or without corticosteroids. A tacrolimus trough target 5-8 ng/ml seems to be optimal for rejection prophylaxis, but long-term tacrolimus-related side effects and nephrotoxicity support the ongoing evaluation of noncalcineurin inhibitor-based regimens. Current alternatives include belatacept or mammalian target of rapamycin inhibitors. For the former, superior kidney function at 7 years post-transplant compared with cyclosporin generated initial enthusiasm, but utilization has been hampered by high initial rejection rates. Mammalian target of rapamycin inhibitors have yielded mixed results as well, with improved kidney function tempered by higher risk of rejection, proteinuria, and adverse effects leading to higher discontinuation rates. Mammalian target of rapamycin inhibitors may play a role in the secondary prevention of squamous cell skin cancer as conversion from a calcineurin inhibitor to an mammalian target of rapamycin inhibitor resulted in a reduction of new lesion development. Early withdrawal of corticosteroids remains an attractive strategy but also is associated with a higher risk of rejection despite no difference in 5-year patient or graft survival. A major barrier to long-term graft survival is chronic alloimmunity, and regardless of agent used, managing the toxicities of immunosuppression against the risk of chronic antibody-mediated rejection remains a fragile balance.
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Affiliation(s)
- David Wojciechowski
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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26
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El Hennawy HM, Faifi ASA, El Nazer W, Mahedy A, Kamal A, Al Faifi IS, Abdulmalik H, Safar O, Zaitoun MF, Fahmy AE. Calcineurin Inhibitors Nephrotoxicity Prevention Strategies With Stress on Belatacept-Based Rescue Immunotherapy: A Review of the Current Evidence. Transplant Proc 2021; 53:1532-1540. [PMID: 34020797 DOI: 10.1016/j.transproceed.2021.03.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/10/2021] [Indexed: 12/29/2022]
Abstract
BACKGROUND A traditional narrative review was performed to evaluate clinical studies that have examined the clinical implications, risk factors, and prevention of calcineurin inhibitors (CNIs) nephrotoxicity with stress on a belatacept-based rescue regimen. METHODS The Cochrane Library, PubMed/MEDLINE, EBSCO (Academic Search Ultimate), ProQuest (Central), and Excerpta Medical databases and Google scholar were searched using the keywords (CNI AND Nephrotoxicity prevention) OR ("Calcineurin inhibitor" AND Nephrotoxicity) OR (Tacrolimus AND Nephrotoxicity) OR (Ciclosporin AND Nephrotoxicity) OR (cyclosporine AND Nephrotoxicity) OR (Belatacept) OR (CNI Conversion) for the period from 1990 to 2020. Fifty-five related articles and reviews were found. CONCLUSION A better understanding of the mechanisms underlying calcineurin inhibitor nephrotoxicity could help in the individualization of therapy for and prevention of CNI nephrotoxicity. Identification of high-risk patients for CNI nephrotoxicity before renal transplantation enables better use and selection of immunosuppression with reduced adverse effects and, eventually, successful treatment of the kidney recipients. Belatacept conversion is a good and safe option in patients with deteriorating renal function attributed to CNI nephrotoxicity.
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Affiliation(s)
- Hany M El Hennawy
- Transplant Surgery Section, Surgery Department, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia.
| | - Abdullah S Al Faifi
- Transplant Surgery Section, Surgery Department, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia
| | - Weam El Nazer
- Nephrology Department, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia
| | - Ahmed Mahedy
- Nephrology Department, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia
| | - Ahmed Kamal
- Nephrology Department, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia
| | - Ibrahim S Al Faifi
- Department of Family Medicine, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia
| | - Hana Abdulmalik
- Department of Surgery, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
| | - Omar Safar
- Department of Urology, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia
| | - Mohammad F Zaitoun
- Department of Pharmacy, Armed Forces Hospital-Southern Regions, Khamis Mushayt, Saudi Arabia
| | - Ahmed E Fahmy
- Department of Surgery, Division of Transplantation, North Shore University Hospital, Northwell Health, Manhasset, New York
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27
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Current Pharmacological Intervention and Medical Management for Diabetic Kidney Transplant Recipients. Pharmaceutics 2021; 13:pharmaceutics13030413. [PMID: 33808901 PMCID: PMC8003701 DOI: 10.3390/pharmaceutics13030413] [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: 02/28/2021] [Revised: 03/16/2021] [Accepted: 03/16/2021] [Indexed: 01/02/2023] Open
Abstract
Hyperglycemia after kidney transplantation is common in both diabetic and non-diabetic patients. Both pretransplant and post-transplant diabetes mellitus are associated with increased kidney allograft failure and mortality. Glucose management may be challenging for kidney transplant recipients. The pathophysiology and pattern of hyperglycemia in patients following kidney transplantation is different from those with type 2 diabetes mellitus. In patients with pre-existing and post-transplant diabetes mellitus, there is limited data on the management of hyperglycemia after kidney transplantation. The following article discusses the nomenclature and diagnosis of pre- and post-transplant diabetes mellitus, the impact of transplant-related hyperglycemia on patient and kidney allograft outcomes, risk factors and potential pathogenic mechanisms of hyperglycemia after kidney transplantation, glucose management before and after transplantation, and modalities for prevention of post-transplant diabetes mellitus.
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28
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Kumar J, Reccia I, Virdis F, Podda M, Sharma AK, Halawa A. Belatacept in renal transplantation in comparison to tacrolimus and molecular understanding of resistance pattern: Meta-analysis and systematic review. World J Transplant 2021; 11:70-86. [PMID: 33816147 PMCID: PMC8009058 DOI: 10.5500/wjt.v11.i3.70] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/23/2020] [Accepted: 02/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The T-cell costimulation blocking agent belatacept has been identified as a possible substitute for calcineurin inhibitors, however, no consensus has been established against its use over the standard care agent Tacrolimus.
AIM To evaluate the effectiveness of belatacept based maintenance immuno-suppressive regimens in comparison to tacrolimus in renal transplantion.
METHODS We did extensive search of all the available literature comparing the role of belatacept to tacrolimus in renal transplant recipients by searching the PubMed, Embase, Cochrane, Crossref, Scopus, clinical trials registry on October 5, 2020.
RESULTS The literature search identified four randomized controlled trials (n = 173 participants) comparing belatacept with tacrolimus. There was no significant difference in estimated renal function at 12 mo [mean difference 4.12 mL/min/1.73 m2, confidence interval (CI): -2.18 to 10.42, P = 0.20]. Further, belatacept group was associated with significant increase in biopsy proven acute rejection [relative risk (RR) = 3.27, CI: 0.88 to 12.11, P = 0.08] and worse 12 mo allograft survival (RR = 4.51, CI: 1.23 to 16.58, P = 0.02). However, incidence of new onset diabetes mellitus was lower with belatacept at 12 mo (RR = 0.26, CI: 0.07 to 0.99, P = 0.05).
CONCLUSION The evidence reviewed in this meta-analysis suggested that belatacept-based maintenance immunosuppression regimens were associated with an increased risk allograft loss in renal transplant recipients with equivalent renal functioning against standard tacrolimus; however, observed significantly reduced new onset diabetes mellitus after transplantation incidence and lower serum low density lipid profile levels in belatacept group. In addition, the adaptation of belatacept in renal transplantation has been forestalled by increased rates of rejection and resistance owing to development of various effector memory T cells through, parallel differentiation and immunological plasticity.
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Affiliation(s)
- Jayant Kumar
- Department of Cancer and Surgery, Imperial College, London W12 0HS, United Kingdom
| | - Isabella Reccia
- Department of Cancer and Surgery, Imperial College, London W12 0HS, United Kingdom
| | - Francesco Virdis
- Department of Emergency General Surgery, Royal Free Hospital, London NW3 2QG, United Kingdom
| | - Mauro Podda
- Department of Surgery, General, Emergency and Robotic Surgical Unit, San Francesco Hospital, Nuoro 08100, Italy
| | - Ajay Kumar Sharma
- Department of Transplantation, Royal Liverpool University Hospital, Liverpool L7 8XP, United Kingdom
| | - Ahmed Halawa
- Department of Surgery, Sheffield Teaching Hospitals, Sheffield S10 2JF, United Kingdom
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29
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Potential Effects of Immunosuppression on Oxidative Stress and Atherosclerosis in Kidney Transplant Recipients. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6660846. [PMID: 33688391 PMCID: PMC7920738 DOI: 10.1155/2021/6660846] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 02/06/2021] [Accepted: 02/13/2021] [Indexed: 01/16/2023]
Abstract
Chronic kidney disease is a public health problem that, depending on the country, affects approximately 8-13% of the population, involving both males and females of all ages. Renal replacement therapy remains one of the most costly procedures. It is assumed that one of the factors influencing the course of chronic kidney disease might be oxidative stress. It is believed that the main mediators of oxidative stress are reactive oxygen species (ROS). Transiently increased concentrations of ROS play a significant role in maintaining an organism's homeostasis, as they are part of the redox-related signaling, and in the immune defense system, as they are produced in high amounts in inflammation. Systemic oxidative stress can significantly contribute to endothelial dysfunction along with exaggeration of atherosclerosis and development of cardiovascular disease, the leading cause of mortality in patients with kidney disease. Moreover, the progression of chronic kidney disease is strictly associated with the atherosclerotic process. Transplantation is the optimal method for renal replacement therapy. It improves better quality of life and prolongs survival compared with hemodialysis and peritoneal dialysis; however, even a successful transplantation does not correct the abnormalities found in chronic kidney disease. As transplantation reduces the concentration of uremic toxins, which are a factor of inflammation per se, both the procedure itself and the subsequent immunosuppressive treatment may be a factor that increases oxidative stress and hence vascular sclerosis and atherosclerotic cardiovascular disease. In the current work, we review the effect of several risk factors in kidney transplant recipients as well as immunosuppressive therapy on oxidative stress.
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30
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Hecking M, Sharif A, Eller K, Jenssen T. Management of post-transplant diabetes: immunosuppression, early prevention, and novel antidiabetics. Transpl Int 2021; 34:27-48. [PMID: 33135259 PMCID: PMC7839745 DOI: 10.1111/tri.13783] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/20/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus-based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium-glucose-linked transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1-RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1-RAs that have not brought forth major concerns, likely indicating that GLP1-RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.
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Affiliation(s)
- Manfred Hecking
- Department of Internal Medicine IIIClinical Division of Nephrology & DialysisMedical University of ViennaViennaAustria
| | - Adnan Sharif
- Department of Nephrology and TransplantationQueen Elizabeth HospitalBirminghamUK
| | - Kathrin Eller
- Clinical Division of NephrologyMedical University of GrazGrazAustria
| | - Trond Jenssen
- Department of Organ TransplantationOslo University HospitalRikshospitaletOsloNorway
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Chevallier E, Jouve T, Rostaing L, Malvezzi P, Noble J. pre-existing diabetes and PTDM in kidney transplant recipients: how to handle immunosuppression. Expert Rev Clin Pharmacol 2020; 14:55-66. [PMID: 33196346 DOI: 10.1080/17512433.2021.1851596] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Preexisting diabetes (PD) and post-transplant diabetes mellitus (PTDM) are common and severe comorbidities posttransplantation. The immunosuppressive regimens are modifiable risk factors. AREAS COVERED We reviewed Pubmed and Cochrane database and we summarize the mechanisms and impacts of available immunosuppressive treatments on the risk of PD and PTDM. We also assess the possible management of these drugs to improve glycemic parameters while considering risks inherent in transplantation. EXPERT OPINION PD i) increases the risk of sepsis, ii) is an independent risk factor for infection-related mortality, and iii) increases acute rejection risk. Regarding PTDM development i) immunosuppressive strategies without corticosteroids significantly reduce the risk but the price may be a higher incidence of rejection; ii) minimization or rapid withdrawal of steroids are two valuable approaches; iii) the diabetogenic role of calcineurin inhibitors(CNIs) is also well-described and is more important for tacrolimus than for cyclosporine. Reducing tacrolimus-exposure may improve glycemic parameters but also has a higher risk of rejection. PTDM risk is higher in patients that receive sirolimus compared to mycophenolate mofetil. Finally, conversion from CNIs to belatacept may offer the best benefits to PTDM-recipients in terms of glycemic parameters, graft and patient-outcomes.
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Affiliation(s)
- Eloi Chevallier
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Thomas Jouve
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Lionel Rostaing
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France.,Université Grenoble Alpes , Grenoble, France
| | - Paolo Malvezzi
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
| | - Johan Noble
- Service De Néphrologie, Hémodialyse, Aphérèses Et Transplantation Rénale, CHU Grenoble-Alpes , Grenoble, France
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Gouin A, Sberro-Soussan R, Courivaud C, Bertrand D, Del Bello A, Darres A, Ducloux D, Legendre C, Kamar N. Conversion From Belatacept to Another Immunosuppressive Regimen in Maintenance Kidney-Transplantation Patients. Kidney Int Rep 2020; 5:2195-2201. [PMID: 33305112 PMCID: PMC7710888 DOI: 10.1016/j.ekir.2020.09.036] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 08/22/2020] [Accepted: 09/15/2020] [Indexed: 11/29/2022] Open
Abstract
Introduction During the coronavirus disease 2019 (Covid-19) pandemic, several physicians have questioned pursuing belatacept in kidney-transplant patients in order to reduce the risk of nosocomial transmission during the monthly infusion. The effect of the conversion from belatacept to another immunosuppressive regimen is underreported. The aim of the present retrospective study was to assess the effect on kidney function and the clinical outcome of the conversion from belatacept to another regimen. Methods We have identified 44 maintenance kidney transplantation patients from five French kidney transplantation centers who were converted from belatacept to another regimen either because of a complication (n = 28) or another reason (patients’ request or belatacept shortage, n = 13). The follow-up after the conversion from belatacept was 27.5 ± 25.3 months. Results Overall, mean estimated glomerular filtration rate (eGFR) decreased from 44.2 ± 16 ml/min per 1.73 m2 at conversion from belatacept to 35.7 ± 18.4 ml/min per 1.73 m2 at last follow-up (P = 0.0002). eGFR significantly decreased in patients who had been given belatacept at transplantation as well as in those who had been converted to belatacept earlier. The decrease was less significant in patients who had stopped belatacept without having experienced any complications. Finally, eGFR decreased more severely in patients who were converted to calcineurin inhibitors (CNIs), compared to those who received mammalian target of rapamycin inhibitor (mTORi). Few patients also developed diabetes and hypertension. Conclusions Thus, transplantation physicians should avoid stopping belatacept when not clinically required.
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Affiliation(s)
- Anna Gouin
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Rebecca Sberro-Soussan
- Service de néphrologie-Transplantation, Hôpital Necker, AP-HP, Paris et Université Paris Descartes, Paris
| | - Cécile Courivaud
- Service de néphrologie, dialyse et transplantation rénale, FHU INCREASE, CHU de Besançon, Besançon, France
| | - Dominique Bertrand
- Service de néphrologie, dialyse et transplantation rénale, CHU de Rouen, Rouen, France
| | - Arnaud Del Bello
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France
| | - Amandine Darres
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France
| | - Didier Ducloux
- Service de néphrologie, dialyse et transplantation rénale, FHU INCREASE, CHU de Besançon, Besançon, France
| | - Christophe Legendre
- Service de néphrologie-Transplantation, Hôpital Necker, AP-HP, Paris et Université Paris Descartes, Paris
| | - Nassim Kamar
- Department of Nephrology and Organ Transplantation, CHU Rangueil, Toulouse, France.,INSERM U1043, IFR-BMT, CHU Purpan, Toulouse, France.,Université Paul Sabatier, Toulouse, France
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Schmitz R, Fitch ZW, Xu H, Ghali A, Mehta AK, Guasch A, Kirk AD. Kidney transplantation using alemtuzumab, belatacept, and sirolimus: Five-year follow-up. Am J Transplant 2020; 20:3609-3619. [PMID: 32515087 DOI: 10.1111/ajt.16121] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/21/2020] [Accepted: 05/28/2020] [Indexed: 01/25/2023]
Abstract
Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)-based regimen could achieve acceptable long-term outcomes and graft survival could be maintained solely with CoB. Forty patients underwent alemtuzumab induction followed by belatacept and sirolimus maintenance therapy. Patients were offered weaning to belatacept monotherapy after 1 year and followed for 5 years. Five-year patient and graft survival rates were 100% and 95%, respectively. Graft function remained stable with a mean estimated glomerular filtration rates of 67 ± 21 and 71 ± 19 at 36 and 60 months, respectively. There was no clinical rejection in the first year; subclinical rejection was detected by protocol biopsy in 4 patients. Twelve patients were successfully weaned to belatacept monotherapy. Cytomegalovirus and Epstein-Barr virus reactivations were well controlled, but 9 patients experienced transient BK viremia during the first year. Alemtuzumab produced profound lymphopenia followed by gradual T cell and more rapid B cell reconstitution to a repertoire deviated toward naïve cells with increased regulatory T cells. This regimen effectively prevents allograft rejection without using steroids or calcineurin inhibitors, enriches for naïve cells susceptible to control with CoB, and permits control of rejection with belatacept monotherapy in selected patients.
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Affiliation(s)
- Robin Schmitz
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Zachary W Fitch
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - He Xu
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
| | - Ada Ghali
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Aneesh K Mehta
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Antonio Guasch
- Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Allan D Kirk
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
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Abstract
Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.
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35
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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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36
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De Novo Belatacept in a Kidney-After-Heart Transplant Recipient. Transplant Direct 2020; 6:e515. [PMID: 32047843 PMCID: PMC6964935 DOI: 10.1097/txd.0000000000000967] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 11/04/2019] [Accepted: 11/08/2019] [Indexed: 11/26/2022] Open
Abstract
Renal injury almost always accompanies the multisystem organ failure that precedes cardiac transplantation and renal function is further compromised by the nephrotoxicity of calcineurin inhibitors posttransplant. Renal dysfunction in turn causes significant morbidity and mortality. The development of belatacept was motivated by need for an alternative to calcineurin-based immunosuppression, particularly in renal transplantation where the nephrotoxicity of calcineurin inhibitors reduce graft longevity and adverse cardiovascular effects of calcineurin inhibitors increase overall mortality. In 2011, the FDA approved belatacept for use in renal transplantation. Seven-year data from the multicenter randomized phase III BENEFIT trial, which compared belatacept with cyclosporine in renal transplant recipients, show belatacept therapy offers both improved renal function and 43% risk reduction for the combined endpoint of graft loss and death. At present, belatacept use is predominantly confined to renal transplant recipients; however, reports of belatacept use in other transplant settings are emerging. Here, we describe successful long-term use of belatacept in a kidney-after-heart transplant recipient and review use of belatacept in cardiothoracic and other nonrenal transplant settings.
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Late Conversion From Calcineurin Inhibitors to Belatacept in Kidney-Transplant Recipients Has a Significant Beneficial Impact on Glycemic Parameters. Transplant Direct 2019; 6:e517. [PMID: 32047845 PMCID: PMC6964931 DOI: 10.1097/txd.0000000000000964] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 11/03/2019] [Accepted: 11/10/2019] [Indexed: 12/13/2022] Open
Abstract
Background. Calcineurin inhibitors (CNIs) and steroids are strongly associated with new-onset diabetes after transplantation, worsening of pre-existing diabetes, and cardiovascular events. We assessed the benefit of conversion from CNI-based to belatacept-based immunosuppression in diabetic kidney-transplant (KT) recipients on glucose control and cardiovascular risk factors. Methods. In this retrospective, noncontrolled single-study conducted between May 2016 and October 26, 2018, we recruited KT recipients converted from CNIs to belatacept at least 6 months after KT. The primary endpoint was the evolution of hemoglobin A1c (HbA1c) between baseline and after 6 months of treatment. Secondary endpoints included modifications to antidiabetic drugs, other cardiovascular risk factors, and renal function. Results. One hundred and three KT recipients were included. Of these, 26 (25%) had type 2 diabetes. The patients were either receiving oral antidiabetic drugs (n = 21; 75%) or insulin therapy (n = 14; 54%). Overall HbA1c decreased significantly from 6.2 ± 1 to 5.8 ± 1%, P < 0.001. In diabetic patients, HbA1c decreased from 7.2 ± 1 to 6.5 ± 1%, P = 0.001. HbA1c significantly decreased in the subgroup of patients with new-onset diabetes after transplantation and whether diabetes was controlled at inclusion or not (ie, HA1c ≤7% or >7%). Moreover, no diabetic patient increased the number of oral antidiabetic drugs and the dose of basal insulin was not statistically different from baseline to 6 months (16 international unit at baseline and 16 international unit at 6 mo, P = 1). One patient had to start treatment by insulin pump. During follow-up, the renal function, body mass index, and hemoglobin level of all 103 patients remained stable, 2 patients presented acute cellular rejection, and no patient suffered from graft loss. Conclusions. A late switch from CNI to belatacept was a valuable therapeutic option for diabetic kidney recipients and substantially improved glycemic parameters.
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38
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Parsons RF, Larsen CP, Pearson TC, Badell IR. Belatacept and CD28 Costimulation Blockade: Preventing and Reducing Alloantibodies over the Long Term. CURRENT TRANSPLANTATION REPORTS 2019; 6:277-284. [PMID: 32158639 PMCID: PMC7063534 DOI: 10.1007/s40472-019-00260-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of Review Highlight developments in T and B cell biology that are helping elucidate the mechanisms underlying CD28 pathway blockade-mediated inhibition of alloantibodies in transplantation, and discuss recent clinical observations on the impact of belatacept on de novo and established HLA antibodies. Recent Findings The identification of T follicular helper cells as the CD4+ T cell subset required for optimal humoral immunity, along with newly identified roles for CD28 and the B7 molecules on B cell lineage cells has begun to pave the way for improved understanding and discovery of the mechanisms of CD28 costimulation blockade-mediated antibody inhibition. There has been resurgent clinical interest in the ability of belatacept to attenuate alloantibody responses. New reports have continued to document its ability to prevent de novo antibody responses, and more recent studies have surfaced exploring its potential to control nascent or pre-existing HLA antibodies. Summary A growing understanding of the mechanisms of anti-CD28-mediated alloantibody inhibition and continued clinical successes will guide the clinical optimization of belatacept and next generation CD28 blockers to prevent and reduce alloantibodies over the long-term.
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Mardomi A, Mohammadi N, Khosroshahi HT, Abediankenari S. An update on potentials and promises of T cell co-signaling molecules in transplantation. J Cell Physiol 2019; 235:4183-4197. [PMID: 31696513 DOI: 10.1002/jcp.29369] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Accepted: 10/07/2019] [Indexed: 02/06/2023]
Abstract
The promising outcomes of immune-checkpoint based immunotherapies in cancer have provided a proportional perspective ahead of exploiting similar approaches in allotransplantation. Belatacept (CTLA-4-Ig) is an example of costimulation blockers successfully exploited in renal transplantation. Due to the wide range of regulatory molecules characterized in the past decades, some of these molecules might be candidates as immunomodulators in the case of tolerance induction in transplantation. Although there are numerous attempts on the apprehension of the effects of co-signaling molecules on immune response, the necessity for a better understanding is evident. By increasing the knowledge on the biology of co-signaling pathways, some pitfalls are recognized and improved approaches are proposed. The blockage of CD80/CD28 axis is an instance of evolution toward more efficacy. It is now evident that anti-CD28 antibodies are more effective than CD80 blockers in animal models of transplantation. Other co-signaling axes such as PD-1/PD-L1, CD40/CD154, 2B4/CD48, and others discussed in the present review are examples of critical immunomodulatory molecules in allogeneic transplantation. We review here the outcomes of recent experiences with co-signaling molecules in preclinical studies of solid organ transplantation.
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Affiliation(s)
- Alireza Mardomi
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Nabiallah Mohammadi
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | | | - Saeid Abediankenari
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Immunogenetics Research Center, Mazandaran University of Medical Sciences, Sari, Iran
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40
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Schroder PM, Fitch ZW, Schmitz R, Choi AY, Kwun J, Knechtle SJ. The past, present, and future of costimulation blockade in organ transplantation. Curr Opin Organ Transplant 2019; 24:391-401. [PMID: 31157670 PMCID: PMC7088447 DOI: 10.1097/mot.0000000000000656] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation pathways continues to evolve. RECENT FINDINGS Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation. SUMMARY Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation.
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Affiliation(s)
- Paul M. Schroder
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, North Carolina, USA
| | - Zachary W. Fitch
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, North Carolina, USA
| | - Robin Schmitz
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, North Carolina, USA
| | - Ashley Y. Choi
- Department of Surgery, Duke Transplant Center, Duke University Medical Center, Durham, North Carolina, USA
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Abstract
Solid organ transplantation (SOT) is a life-saving procedure and an established treatment for patients with end-stage organ failure. However, transplantation is also accompanied by associated cardiovascular risk factors, of which post-transplant diabetes mellitus (PTDM) is one of the most important. PTDM develops in 10-20% of patients with kidney transplants and in 20-40% of patients who have undergone other SOT. PTDM increases mortality, which is best documented in patients who have received kidney and heart transplants. PTDM results from predisposing factors (similar to type 2 diabetes mellitus) but also as a result of specific post-transplant risk factors. Although PTDM has many characteristics in common with type 2 diabetes mellitus, the prevention and treatment of the two disorders are often different. Over the past 20 years, the lifespan of patients who have undergone SOT has increased, and PTDM becomes more common over the lifespan of these patients. Accordingly, PTDM becomes an important condition not only to be aware of but also to treat. This Review presents the current knowledge on PTDM in patients receiving kidney, heart, liver and lung transplants. This information is not only for transplant health providers but also for endocrinologists and others who will meet these patients in their clinics.
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Affiliation(s)
- Trond Jenssen
- Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Anders Hartmann
- Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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42
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Noble J, Jouve T, Janbon B, Rostaing L, Malvezzi P. Belatacept in kidney transplantation and its limitations. Expert Rev Clin Immunol 2019; 15:359-367. [DOI: 10.1080/1744666x.2019.1574570] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Johan Noble
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
- Université Grenoble Alpes, Grenoble, France
| | - Thomas Jouve
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
- Université Grenoble Alpes, Grenoble, France
| | - Bénédicte Janbon
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
| | - Lionel Rostaing
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
- Université Grenoble Alpes, Grenoble, France
| | - Paolo Malvezzi
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
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43
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Pérez-Sáez MJ, Yu B, Uffing A, Murakami N, Borges TJ, Azzi J, El Haji S, Gabardi S, Riella LV. Conversion from tacrolimus to belatacept improves renal function in kidney transplant patients with chronic vascular lesions in allograft biopsy. Clin Kidney J 2018; 12:586-591. [PMID: 31384452 PMCID: PMC6671390 DOI: 10.1093/ckj/sfy115] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Indexed: 01/05/2023] Open
Abstract
Background Conversion from tacrolimus to belatacept has been shown to be beneficial for an increasing number of kidney transplant (KT) patients. Predicting factors for favorable outcomes are still unknown. We aimed to investigate whether histological vascular lesions at the time of conversion might correlate with greater improvement in renal function post-conversion. Methods The study was conducted on a retrospective cohort of 34 KT patients converted from tacrolimus to belatacept. All patients underwent an allograft biopsy prior to conversion. We analyzed the evolution of the estimated glomerular filtration rate (eGFR) at 3 and 12 months after conversion. Results Median time to conversion was 6 (2–37.2) months post-transplant. About 52.9% of patients had moderate-to-severe chronic vascular lesions (cv2–3). We observed an increase in eGFR in the whole cohort from 35.4 to 41 mL/min/1.73 m2 at 3 months (P = 0.032) and 43.7 at 12 months (P = 0.013). Nine patients experienced acute rejection post-conversion, with one graft loss observed beyond the first year after conversion. Patients with cv2–3 had significant improvement in eGFR at 12 months (+8.6 mL/min/1.73 m2; 31.6 to 40.2 mL/min/1.73 m2; P = 0.047) compared with those without these lesions (+6.8 mL/min/1.73 m2; 40.9 to 47.7 mL/min/1.73 m2; P = 0.148). Conclusions Conversion from tacrolimus to belatacept has a beneficial effect in terms of renal function in KT patients. This benefit might be more significant in patients with cv in the biopsy.
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Affiliation(s)
- María José Pérez-Sáez
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Bryant Yu
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Audrey Uffing
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Naoka Murakami
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Thiago J Borges
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jamil Azzi
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Sandra El Haji
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Steve Gabardi
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Leonardo V Riella
- Renal Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
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Sen A, Callisen H, Libricz S, Patel B. Complications of Solid Organ Transplantation: Cardiovascular, Neurologic, Renal, and Gastrointestinal. Crit Care Clin 2018; 35:169-186. [PMID: 30447778 DOI: 10.1016/j.ccc.2018.08.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Despite improvements in overall graft function and patient survival rates after solid organ transplantation, complications can lead to significant morbidity and mortality. Cardiovascular complications include heart failure, arrhythmias leading to sudden death, hypertension, left ventricular hypertrophy, and allograft vasculopathy in heart transplantation. Neurologic complications include stroke, posterior reversible encephalopathy syndrome, infections, neuromuscular disease, seizure disorders, and neoplastic disease. Acute kidney injury occurs from immunosuppression with calcineurin inhibitors or as a result of graft failure after kidney transplantation. Gastrointestinal complications include infections, malignancy, mucosal ulceration, perforation, biliary tract disease, pancreatitis, and diverticular disease. Immunosuppression can predispose to infections and malignancy.
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Affiliation(s)
- Ayan Sen
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA.
| | - Hannelisa Callisen
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
| | - Stacy Libricz
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
| | - Bhavesh Patel
- Department of Critical Care Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA
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45
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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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46
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Mathews DV, Dong Y, Higginbotham LB, Kim SC, Breeden CP, Stobert EA, Jenkins J, Tso JY, Larsen CP, Adams AB. CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J Clin Invest 2018; 128:4557-4572. [PMID: 30222140 PMCID: PMC6159972 DOI: 10.1172/jci95914] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 07/31/2018] [Indexed: 12/30/2022] Open
Abstract
Interrupting T cell costimulatory signals as a strategy to control undesired immune responses, such as occur in autoimmunity or transplantation, has the potential to alleviate many of the unwanted side effects associated with current immunosuppressive therapies. Belatacept, a high-affinity version of CTLA4-Ig that blocks ligand ligation to CD28, has been approved for use in kidney transplant recipients. Despite the long-term benefits associated with its use, such as improved renal function and lower cardiovascular risk, a subset of patients treated with belatacept experience elevated rates of acute T cell-mediated rejection, tempering enthusiasm for its use. Here we demonstrate that costimulation-independent T cell alloreactivity relies on signaling through CD122, the shared IL-2 and IL-15 receptor β-chain. Combined costimulatory and CD122 blockade improved survival of transplanted tissue in mice and nonhuman primates by controlling proliferation and effector function of CD8+ T cells. The high-affinity IL-2 receptor was dispensable for memory CD8+ T cell responses, whereas signaling through CD122 as a component of the high-affinity IL-15 receptor was critical for costimulation-independent memory CD8+ T cell recall, distinguishing specific roles for IL-2 and IL-15 in T cell activation. These studies outline a novel approach for clinical optimization of costimulatory blockade strategies in transplantation by targeting CD122.
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Affiliation(s)
- David V. Mathews
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
| | - Ying Dong
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
| | | | - Steven C. Kim
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
| | | | | | | | - J. Yun Tso
- JN Biosciences, Mountain View, California, USA
| | - Christian P. Larsen
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
- Yerkes National Primate Center, Atlanta, Georgia, USA
| | - Andrew B. Adams
- Emory Transplant Center, Emory University, Atlanta, Georgia, USA
- Yerkes National Primate Center, Atlanta, Georgia, USA
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47
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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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48
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Badell IR, La Muraglia GM, Liu D, Wagener ME, Ding G, Ford ML. Selective CD28 Blockade Results in Superior Inhibition of Donor-Specific T Follicular Helper Cell and Antibody Responses Relative to CTLA4-Ig. Am J Transplant 2018; 18:89-101. [PMID: 28637095 PMCID: PMC5740006 DOI: 10.1111/ajt.14400] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Revised: 06/02/2017] [Accepted: 06/13/2017] [Indexed: 01/25/2023]
Abstract
Donor-specific antibodies (DSAs) are a barrier to improved long-term outcomes after kidney transplantation. Costimulation blockade with CTLA4-Ig has shown promise as a potential therapeutic strategy to control DSAs. T follicular helper (Tfh) cells, a subset of CD4+ T cells required for optimal antibody production, are reliant on the CD28 costimulatory pathway. We have previously shown that selective CD28 blockade leads to superior allograft survival through improved control of CD8+ T cells relative to CTLA4-Ig, but the impact of CD28-specific blockade on CD4+ Tfh cells is unknown. Thus, we identified and characterized donor-reactive Tfh cells in a murine skin transplant model and then used this model to evaluate the impact of selective CD28 blockade with an anti-CD28 domain antibody (dAb) on the donor-specific Tfh cell-mediated immune response. We observed that the anti-CD28 dAb led to superior inhibition of donor-reactive CXCR5+ PD-1high Tfh cells, CD95+ GL7+ germinal center B cells and DSA formation compared with CTLA4-Ig. Interestingly, donor-reactive Tfh cells differentially upregulated CTLA4 expression, suggesting an important role for CTLA4 in mediating the superior inhibition observed with the anti-CD28 dAb. Therefore, selective CD28 blockade as a novel approach to control Tfh cell responses and prevent DSA after kidney transplantation warrants further study.
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Affiliation(s)
- IR Badell
- Emory Transplant Center, Atlanta, GA, USA,Corresponding Author: I. Raul Badell, MD,
| | | | - D Liu
- Emory Transplant Center, Atlanta, GA, USA
| | - ME Wagener
- Emory Transplant Center, Atlanta, GA, USA
| | - G Ding
- Emory Transplant Center, Atlanta, GA, USA
| | - ML Ford
- Emory Transplant Center, Atlanta, GA, USA
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49
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Melilli E, Manonelles A, Montero N, Grinyo J, Martinez-Castelao A, Bestard O, Cruzado J. Impact of immunosuppressive therapy on arterial stiffness in kidney transplantation: are all treatments the same? Clin Kidney J 2017; 11:413-421. [PMID: 29988241 PMCID: PMC6007381 DOI: 10.1093/ckj/sfx120] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Accepted: 09/06/2017] [Indexed: 02/07/2023] Open
Abstract
Arterial stiffness is a biologic process related to ageing and its relationship with cardiovascular risk is well established. Several methods are currently available for non-invasive measurement of arterial stiffness that provide valuable information to further assess patients’ vascular status in real time. In kidney transplantation recipients, several factors could accelerate the stiffness process, such as the use of calcineurin inhibitors (CNIs), the presence of chronic kidney disease and other classical cardiovascular factors, which would explain, at least in part, the high cardiovascular mortality and morbidity. Despite the importance of arterial stiffness as a biomarker of cardiovascular risk, and unlike other cardiovascular risk factors (e.g. left ventricular hypertrophy), only a few clinical trials or retrospective studies of kidney recipients have evaluated its impact. In this review we describe the clinical impact of arterial stiffness as a prognostic marker of cardiovascular disease and the effects of different immunosuppressive regimens on its progression, focusing on the potential benefits of CNI-sparing protocols and supporting the rationale for individualization of immunosuppression in patients with lower arterial elasticity. Among the immunosuppressive drugs, a belatacept-based regimen seems to offer better vascular protection compared with CNIs, although further studies are needed to confirm the preliminary positive results.
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Affiliation(s)
- Edoardo Melilli
- Department of Nephrology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Cataluny, Spain
- Correspondence and offprint requests to: Edoardo Melilli; E-mail:
| | - Anna Manonelles
- Department of Nephrology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Cataluny, Spain
| | - Nuria Montero
- Department of Nephrology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Cataluny, Spain
| | - Josep Grinyo
- Department of Nephrology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Cataluny, Spain
| | | | - Oriol Bestard
- Department of Nephrology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Cataluny, Spain
| | - Josep Cruzado
- Department of Nephrology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Cataluny, Spain
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50
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Bertrand D, Cheddani L, Etienne I, François A, Hanoy M, Laurent C, Lebourg L, Le Roy F, Lelandais L, Loron MC, Godin M, Guerrot D. Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study. Am J Transplant 2017; 17:2937-2944. [PMID: 28707779 DOI: 10.1111/ajt.14427] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 06/02/2017] [Accepted: 07/06/2017] [Indexed: 02/07/2023]
Abstract
Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context. We report a retrospective case control study comparing a CNI to belatacept switch in 17 patients with vascular damage and low eGFR to a control group of 18 matched patients with CNI continuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2-198 months). There was no difference between the two groups regarding eGFR at inclusion, and 3 months before inclusion. In the "CNI to belatacept switch group," mean eGFR increased significantly from 23.5 ± 6.7 mL/min/1.73m2 on day 0, to 30.4 ± 9.1 mL/min/1.73 m2 on month 6 (p < 0.001) compared to the control group, in which no improvement was observed. These results were still significant on month 12. Two patients experienced biopsy-proven acute rejection. One was effectively treated without belatacept discontinuation. Two patients needed belatacept discontinuation for infection. In conclusion, the remplacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR.
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Affiliation(s)
- D Bertrand
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - L Cheddani
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - I Etienne
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - A François
- Department of Anatomy and Pathology, University Hospital, Rouen, France
| | - M Hanoy
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - C Laurent
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - L Lebourg
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - F Le Roy
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - L Lelandais
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - M C Loron
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - M Godin
- Department of Nephrology and Transplantation Centre, Rouen, France
| | - D Guerrot
- Department of Nephrology and Transplantation Centre, Rouen, France
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