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Zhang D, Wen J, Dong J, Ma R, Li S, Wu J, Wen N, Lei Z, Li H, Yin J, Sun X. Evaluating the efficacy of basiliximab versus no induction in low-immunological-risk kidney transplant recipients: a propensity score matched analysis. Ren Fail 2025; 47:2460729. [PMID: 39978365 PMCID: PMC11843659 DOI: 10.1080/0886022x.2025.2460729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/23/2025] [Accepted: 01/25/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND The optimal use of induction therapy in low-immunological-risk kidney transplant recipients (KTRs) remains uncertain. While Basiliximab (BSX) is widely utilized, its comparative outcomes with no induction therapy require further evaluation. METHOD This single-center retrospective cohort study included 182 low-immunological-risk KTRs who underwent transplantation between January 2022 and March 2023. Patients were assigned to either no induction (n = 41) or BSX induction (n = 141) groups. Propensity score matching (PSM) minimized selection bias and controlled for confounding factors. Primary outcomes included the incidence of first acute rejection (AR) within 12 months, while secondary outcomes encompassed graft function, infection rates, and adverse events. RESULT After 12 months, the cumulative AR incidence was comparable between groups (p = 0.46). The no induction group demonstrated superior renal function, with consistently higher estimated glomerular filtration rates (eGFR) at early postoperative intervals. Additionally, this group exhibited reduced infection-related hospitalizations (respiratory infections: 7.32 vs. 29.1%, p = 0.008) and hematological complications (thrombocytopenia: 0.00% vs. 12.8%, p = 0.014). Mortality and graft loss rates were similar between groups. CONCLUSION In low-immunological-risk KTRs, no induction therapy achieves comparable AR prevention and renal function outcomes to BSX while reducing infection and hematological complications. These findings challenge the necessity of universal induction therapy in this population and support a personalized approach to immunosuppression protocols.
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Affiliation(s)
- Dahao Zhang
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Jiqiu Wen
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Jianhui Dong
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Rong Ma
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Shijian Li
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Jihua Wu
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Ning Wen
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Zhiying Lei
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Haibin Li
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Jun Yin
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
| | - Xuyong Sun
- Institute of Transplantation Medicine, The Second Affiliated Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Organ Transplantation, Guangxi Key Laboratory of Organ Donation and Transplantation, Nanning, China
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Hsu FM, Pickering H, Rubbi L, Thompson M, Reed EF, Pellegrini M, Schaenman JM. DNA methylation predicts infection risk in kidney transplant recipients. Life Sci Alliance 2025; 8:e202403124. [PMID: 40324822 PMCID: PMC12053434 DOI: 10.26508/lsa.202403124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/15/2025] [Accepted: 04/22/2025] [Indexed: 05/07/2025] Open
Abstract
Kidney transplantation (KTx) is the method of choice for treating kidney failure. Identifying biomarkers predictive of transplant (Tx) outcomes is critical to optimize KTx; however, the immunosuppressive therapies required after KTx must also be considered. We applied targeted bisulfite sequencing (TBS-seq) to PBMCs isolated from 90 patients, with samples collected pre- and post-Tx (day 90), to measure DNA methylation changes. Our findings indicate that the PBMC DNA methylome is significantly affected by induction immunosuppression with anti-thymocyte globulin (ATG). We discovered that the risk of infection can be predicted using DNA methylation profiles, but not gene expression profiles. Specifically, 515 CpG loci associated with 275 genes were significantly impacted by ATG induction, even after accounting for age, sex, and cell-type composition. Notably, ATG-associated hyper-methylation down-regulates genes critical for immune response. In conclusion, this clinical omics study reveals that the immunosuppressant ATG profoundly impacts the DNA methylome of KTx recipients and identifies biomarkers that could be used in pre-Tx screening of patients vulnerable to infection, thereby informing immunosuppression strategies post-Tx.
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Affiliation(s)
- Fei-Man Hsu
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
- Institute for Quantitative and Computational Biosciences - The Collaboratory, University of California Los Angeles, Los Angeles, CA, USA
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Liudmilla Rubbi
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
| | - Michael Thompson
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Matteo Pellegrini
- Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
- Institute for Quantitative and Computational Biosciences - The Collaboratory, University of California Los Angeles, Los Angeles, CA, USA
| | - Joanna M Schaenman
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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Briant AR, Morello R, Sérée O, Vigneron N, Wilson S, Besch C, Houssel-Debry P, Pageaux GP, Coilly A, Dumortier J, Altieri M. Is Survival Impacted by One or Several Successive Cancers After Liver Transplantation? A French National Study. Clin Transplant 2025; 39:e70109. [PMID: 39945212 DOI: 10.1111/ctr.70109] [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: 07/25/2024] [Revised: 10/09/2024] [Accepted: 02/02/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND AND AIM De novo cancers after liver transplantation (LT) are major causes of complications and mortality after LT. No report was found in the literature on several successive cancers (SSC). The aim of this study was to see if the survival of one or more cancers was different and to study the survival prognostic factors of patients with one cancer or SSC after LT. METHODS Using data from the French national database, 114 French patients who underwent LT between 1993 and 2012 were followed up until their death or until June 2016. The Cox model performed to analyze potential risk factors (cancer characteristics, immunosuppressive therapy (IT), smoking, and alcohol use). RESULTS After an average follow-up of 9.8 ± 5.1 years, 52 patients developed 1 cancer, 49 had 2 cancers, and 13 had 3 cancers. The reduction in survival time was significantly and independently associated with the metastatic stage (hazard ratio (HR) = 3.98, 95% confidence interval (95% CI) = [1.45-10.93], p < 0.001), ENT (otolaryngology), and respiratory cancer versus genitourinary (HR = 8.28, 95% CI = [3.12-22.02], p < 0.001), and SSC (HR = 2.54, 95% CI = [1.39-4.65], p = 0.014). CONCLUSION The patients with ENT, respiratory cancers have a shorter survival. The stage of cancer and SSC reduces median survival at 10 years. The earliness of the first cancer should be taken as a warning signal of risk of SSC and impaired survival.
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Affiliation(s)
- Anaïs R Briant
- Normandie Univ, UNICAEN, CHU de Caen Normandie, Research and Innovation Department and Methodology Platform, Biostatistics and Clinical Research Units, Caen, France
- OncoNormandie, DSRC, Caen, France
| | - Rémy Morello
- Normandie Univ, UNICAEN, CHU de Caen Normandie, Research and Innovation Department and Methodology Platform, Biostatistics and Clinical Research Units, Caen, France
| | | | - Nicolas Vigneron
- Normandie Univ, UNICAEN, CHU de Caen Normandie, Research and Innovation Department and Methodology Platform, Biostatistics and Clinical Research Units, Caen, France
- Unicancer, Comprehensive Cancer Center F. Baclesse, Calvados General Tumor Registry, Caen, France
- UFR Santé Caen France: U1086 INSERM- "ANTICIPE", Caen, France
| | - Sarah Wilson
- Normandie Univ, UNICAEN, CHU de Caen Normandie, Research and Innovation Department and Methodology Platform, Biostatistics and Clinical Research Units, Caen, France
- UFR Santé Caen France: U1086 INSERM- "ANTICIPE", Caen, France
| | - Camille Besch
- Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, CHRU Hautepierre, Strasbourg, France
| | - Pauline Houssel-Debry
- Hôpital Universitaire de Pontchaillou, Service d'Hépatologie et Transplantation hépatique, Rennes, France
| | | | - Audrey Coilly
- AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM, Unité 1193, Université Paris-Saclay, Villejuif, France
| | - Jérôme Dumortier
- Hospices civils de Lyon, Hôpital Edouard Herriot, Unité de transplantation hépatique, et Université Claude Bernard Lyon 1, Lyon, France
| | - Mario Altieri
- Normandie Univ, UNICAEN, CHU de Caen Normandie, Research and Innovation Department and Methodology Platform, Biostatistics and Clinical Research Units, Caen, France
- UFR Santé Caen France: U1086 INSERM- "ANTICIPE", Caen, France
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Li W, Hua M, Guo J, Jia W. Pneumocystis Jirovecii Pneumonia in Two Immunosuppressed Non-HIV Infected Patients: A Clinical and Therapeutic Analysis. Infect Drug Resist 2025; 18:285-295. [PMID: 39835165 PMCID: PMC11742741 DOI: 10.2147/idr.s495188] [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: 09/26/2024] [Accepted: 01/01/2025] [Indexed: 01/22/2025] Open
Abstract
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection that often occurs secondary to human immunodeficiency virus (HIV) infection. However, for non-HIV immunocompromised patients, such as those undergoing novel immunosuppressive treatments to manage malignancies, organ transplants, or connective tissue diseases, PJP is emerging as an increasing threat. The clinical manifestations of PJP in HIV-infected and non-HIV-infected patients differ significantly. In non-HIV-infected patients, PJP progresses rapidly and is challenging to diagnose, resulting in severe respiratory failure and a poor prognosis. We describe lymphocytopenia in two women who were recently treated with methotrexate, tacrolimus, and corticosteroids for immunosuppressive therapy following adjuvant chemotherapy for breast cancer and kidney transplantation. The initial examination included a high-resolution chest CT indicating atypical pneumonia, and treatment was initiated with trimethoprim - sulfamethoxazole and oxygen support. Subsequently, bronchoscopy and bronchoalveolar lavage with mNGS detected Pneumocystis jirovecii. After 3 weeks of treatment with cotrimoxazole, the two patients recovered significantly and their condition was stable.
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Affiliation(s)
- Weiran Li
- Department of Clinical Medicine, School of Medicine, Qinghai University, Xining, People’s Republic of China
| | - Mao Hua
- Department of Clinical Medicine, School of Medicine, Qinghai University, Xining, People’s Republic of China
| | - Jin Guo
- Department of Clinical Medicine, School of Medicine, Qinghai University, Xining, People’s Republic of China
| | - Wenbo Jia
- Department of Clinical Medicine, School of Medicine, Qinghai University, Xining, People’s Republic of China
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Kang M, Park HK, Kim KS, Choi D. Animal models for transplant immunology: bridging bench to bedside. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:354-376. [PMID: 39233453 PMCID: PMC11732767 DOI: 10.4285/ctr.24.0029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/05/2024] [Accepted: 07/07/2024] [Indexed: 09/06/2024]
Abstract
The progress of transplantation has been propelled forward by animal experiments. Animal models have not only provided opportunities to understand complex immune mechanisms in transplantation but also served as a platform to assess therapeutic interventions. While small animals have been instrumental in uncovering new therapeutic concepts related to immunosuppression and immune tolerance, the progression to human trials has largely been driven by studies in large animals. Recent research has begun to explore the potential of porcine organs to address the shortage of available organs. The consistent progress in transplant immunology research can be attributed to a thorough understanding of animal models. This review provides a comprehensive overview of the available animal models, detailing their modifications, strengths, and weaknesses, as well as their historical applications, to aid researchers in selecting the most suitable model for their specific research needs.
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Affiliation(s)
- Minseok Kang
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Hwon Kyum Park
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Kyeong Sik Kim
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul, Korea
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Li S, Wang Z, Dong Z, Cao Y, Wang H. Cumulative rabbit anti-human thymocyte globulin dose to recipient weight during the peri-operative period is an independent risk factor for early postoperative urinary tract infection after kidney transplantation. Ren Fail 2024; 46:2414841. [PMID: 39412045 PMCID: PMC11485816 DOI: 10.1080/0886022x.2024.2414841] [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: 04/16/2024] [Revised: 08/15/2024] [Accepted: 10/06/2024] [Indexed: 10/19/2024] Open
Abstract
Anti-human thymocyte globulin-Fresenius (ATG-F) is frequently utilized to achieve successful induction for kidney transplantation recipients. This study aimed to examine the association between the ATG-F dose-to-recipient-weight ratio (ADR) and the risk of developing urinary tract infections (UTIs) following kidney transplantation. Data of kidney transplant recipients who underwent ATG-F-induction peri-operatively in a medical center were retrospectively collected, and the incidence of UTIs during the first postoperative year was also recorded. The risk of UTI associated with ADR was analyzed, and receiver operating characteristic curves were drawn to determine the optimal ADR, followed by Cox regression models. In total, 131 recipients were included, with an UTI incidence of 19.08% and a mean interval of 3.08 months. The optimal ADR was 6.34, involving 41 and 90 patients in the low ADR and high ADR groups, respectively. The UTI-free rate in the low ADR group was significantly higher than that in the high ADR group (p = 0.007). Cox regression analysis indicated that a high ADR independently increased the risk of UTI following kidney transplantation (hazard ratio: 5.306, 95% confidence interval: 1.243-22.660, p = 0.024). There was no significant difference in rejection rate between the high ADR and low ADR groups. In conclusion, a high ADR increased the incidence of early postoperative UTI among kidney transplant recipients.
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Affiliation(s)
- Shujuan Li
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ziyu Wang
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhen Dong
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanwei Cao
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongyang Wang
- Department of Kidney Transplantation, The Affiliated Hospital of Qingdao University, Qingdao, China
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Reineke M, Speer C, Bundschuh C, Klein JAF, Loi L, Sommerer C, Zeier M, Schnitzler P, Morath C, Benning L. Impact of induction agents and maintenance immunosuppression on torque teno virus loads and year-one complications after kidney transplantation. Front Immunol 2024; 15:1492611. [PMID: 39606231 PMCID: PMC11599233 DOI: 10.3389/fimmu.2024.1492611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Accepted: 10/28/2024] [Indexed: 11/29/2024] Open
Abstract
Background Torque teno virus load (TTVL) is gaining importance as a surrogate parameter to assess immunocompetence in kidney transplant recipients. Although the dynamics of TTVL have been investigated before, the impact of different induction agents and variations in immunosuppressive maintenance therapies on TTVL remain unknown. Methods In this retrospective study, TTVL was quantified in 537 plasma or serum samples from 134 patients transplanted between 2018 and 2021. TTVL was examined pre-transplantation and 30-, 90-, 180-, and 360-days post-transplant. To assess the influence of induction therapy on TTVL, 67 patients receiving anti-thymocyte globulin (ATG) induction were matched with 67 patients receiving an interleukin-2 receptor antagonist (IL2-RA) induction in terms of age, sex, and donor modality. Results Following transplantation, there was a steep increase in TTVL post-transplant for all patients with peak viral loads at 90 days post-transplant (median TTVL [IQR] 7.97×106, [4.50×105-1.12×108]) followed by subsequently declining viral loads. Compared to patients receiving IL2-RA as induction therapy, patients receiving ATG had significantly higher peak viral loads 3 months post-transplant (median TTVL [IQR] 2.82×107 [3.93×106-1.30×108] vs. median TTVL [IQR] 2.40×106 [5.73×104-2.60×107]; P<0.001). Throughout all post-transplant time points, patients receiving additional rituximab for induction along with higher tacrolimus target levels exhibited the highest TTVL.Patients whose TTVL 3-months post-transplant exceeded the currently proposed cutoff to predict infections within the first year post-transplant [6.2 log10] showed a trend towards a higher risk of being hospitalized with an infection in the following 9 months, albeit without being statistically significant (HR=1.642, P=0.07). Conclusions Higher TTVL reflects the greater immunosuppressive burden in immunological high-risk patients receiving intensive immunosuppression. The choice of induction agent and intensified immunosuppressive maintenance therapy notably affects TTVL at 3 months post-transplant and beyond, necessitating careful consideration when interpreting and applying TTVL cutoffs to monitor immunocompetence post-transplant.
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Affiliation(s)
- Marvin Reineke
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Claudius Speer
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
- Department of Cardiology, Angiology and Pneumology, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Bundschuh
- Medical Faculty Heidelberg, Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany
| | - Julian A. F. Klein
- Medical Faculty Heidelberg, Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany
| | - Lisa Loi
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Claudia Sommerer
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research, German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany
| | - Martin Zeier
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
| | - Paul Schnitzler
- Medical Faculty Heidelberg, Department of Infectious Diseases, Virology, Heidelberg University, Heidelberg, Germany
- German Center for Infection Research, German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany
| | - Christian Morath
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
- German Center for Infection Research, German Center for Infection Research (DZIF), Heidelberg Partner Site, Heidelberg, Germany
| | - Louise Benning
- Department of Nephrology, University Hospital Heidelberg, Heidelberg, Germany
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Zhang J, Pei J, Yu C, Luo J, Hong Y, Hua Y, Wei G. CCR7 and CD48 as Predicted Targets in Acute Rejection Related to M1 Macrophage after Pediatric Kidney Transplantation. J Immunol Res 2024; 2024:6908968. [PMID: 38957433 PMCID: PMC11217580 DOI: 10.1155/2024/6908968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 05/28/2024] [Accepted: 06/12/2024] [Indexed: 07/04/2024] Open
Abstract
Background Kidney transplantation (KT) is the best treatment for end-stage renal disease. Although long and short-term survival rates for the graft have improved significantly with the development of immunosuppressants, acute rejection (AR) remains a major risk factor attacking the graft and patients. The innate immune response plays an important role in rejection. Therefore, our objective is to determine the biomarkers of congenital immunity associated with AR after KT and provide support for future research. Materials and Methods A differential expression genes (DEGs) analysis was performed based on the dataset GSE174020 from the NCBI gene Expression Synthesis Database (GEO) and then combined with the GSE5099 M1 macrophage-related gene identified in the Molecular Signatures Database. We then identified genes in DEGs associated with M1 macrophages defined as DEM1Gs and performed gene ontology (GO) and Kyoto Encyclopedia of Genomes (KEGG) enrichment analysis. Cibersort was used to analyze the immune cell infiltration during AR. At the same time, we used the protein-protein interaction (PPI) network and Cytoscape software to determine the key genes. Dataset, GSE14328 derived from pediatric patients, GSE138043 and GSE9493 derived from adult patients, were used to verify Hub genes. Additional verification was the rat KT model, which was used to perform HE staining, immunohistochemical staining, and Western Blot. Hub genes were searched in the HPA database to confirm their expression. Finally, we construct the interaction network of transcription factor (TF)-Hub genes and miRNA-Hub genes. Results Compared to the normal group, 366 genes were upregulated, and 423 genes were downregulated in the AR group. Then, 106 genes related to M1 macrophages were found among these genes. GO and KEGG enrichment analysis showed that these genes are mainly involved in cytokine binding, antigen binding, NK cell-mediated cytotoxicity, activation of immune receptors and immune response, and activation of the inflammatory NF-κB signaling pathway. Two Hub genes, namely CCR7 and CD48, were identified by PPI and Cytoscape analysis. They have been verified in external validation sets, originated from both pediatric patients and adult patients, and animal experiments. In the HPA database, CCR7 and CD48 are mainly expressed in T cells, B cells, macrophages, and tissues where these immune cells are distributed. In addition to immunoinfiltration, CD4+T, CD8+T, NK cells, NKT cells, and monocytes increased significantly in the AR group, which was highly consistent with the results of Hub gene screening. Finally, we predicted that 19 TFs and 32 miRNAs might interact with the Hub gene. Conclusions Through a comprehensive bioinformatic analysis, our findings may provide predictive and therapeutic targets for AR after KT.
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Affiliation(s)
- Jie Zhang
- Department of Urology Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, China
| | - Jun Pei
- Department of Urology Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, China
| | - Chengjun Yu
- Department of Urology Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, China
| | - Jin Luo
- Department of Urology Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, China
| | - Yifan Hong
- Department of Urology Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, China
| | - Yi Hua
- Department of Urology Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, China
| | - Guanghui Wei
- Department of Urology Children's Hospital of Chongqing Medical UniversityNational Clinical Research Center for Child Health and DisordersMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, China
- Chongqing Key Laboratory of Structural Birth Defect and Reconstruction, Chongqing, China
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Engen RM, Bartosh SM. Long-term outcomes of two-dose alemtuzumab induction in pediatric kidney transplantation. Pediatr Transplant 2024; 28:e14753. [PMID: 38623881 DOI: 10.1111/petr.14753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/15/2024] [Accepted: 03/26/2024] [Indexed: 04/17/2024]
Abstract
BACKGROUND Alemtuzumab is a lymphocyte depleting agent used for induction in kidney transplant, but long-term information on its use in pediatric recipients remains sparse. METHODS We performed a single-center retrospective cohort study of 57 pediatric kidney transplant recipients receiving alemtuzumab 20 mg/m2/dose ×2 doses for induction immunosuppression. All patients underwent surveillance biopsies, and 91.3% underwent steroid withdrawal by day 4 post-transplant. Outcomes of interest included graft survival, development of donor specific antibodies (DSA), incidence of viremia and PTLD, and duration of lymphopenia. RESULTS Median follow-up time was 7.9 years (IQR 5-13.6 years). Median graft survival was 16.5 years (95% CI 11.6-unknown). DSA developed in 36.5% at a median of 944 days (IQR 252-2113 days). Incidences of BK polyomavirus DNAemia (BKPyV-DNAemia), CMV DNAemia, and EBV DNAemia were 38.6%, 22.8%, and 14%, respectively; one patient developed PTLD at 13.3 years post-transplant. Median duration of lymphopenia was 365 days (IQR 168-713 days); 19.3% of patients remained lymphopenic at 3 years post-transplant. There was no association between duration of lymphopenia and graft survival, rejection, DSA detection, or viremia. CONCLUSIONS A two-dose alemtuzumab induction protocol can have excellent outcomes with a steroid-free maintenance immunosuppression regimen. More comprehensive, multicenter, comparative studies of pediatric kidney transplant are needed to improve long-term outcomes.
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Affiliation(s)
- Rachel M Engen
- Department of Pediatrics, University of Wisconsin Madison, Madison, Wisconsin, USA
| | - Sharon M Bartosh
- Department of Pediatrics, University of Wisconsin Madison, Madison, Wisconsin, USA
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Ashoor IF, Engen RM, Puliyanda D, Hayde N, Peterson CG, Zahr RS, Solomon S, Kallash M, Garro R, Jain A, Harshman LA, McEwen ST, Mansuri A, Gregoski MJ, Twombley KE. Antibody-mediated rejection in pediatric kidney transplant recipients: A report from the Pediatric Nephrology Research Consortium. Pediatr Transplant 2024; 28:e14734. [PMID: 38602171 PMCID: PMC11013566 DOI: 10.1111/petr.14734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 01/22/2024] [Accepted: 02/20/2024] [Indexed: 04/12/2024]
Abstract
BACKGROUND Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. There is a paucity of large-scale pediatric-specific data regarding AMR treatment outcomes. METHODS Data were obtained from 14 centers within the Pediatric Nephrology Research Consortium. Kidney transplant recipients aged 1-18 years at transplant with biopsy-proven AMR between 2009 and 2019 and at least 12 months of follow-up were included. The primary outcome was graft failure or an eGFR <20 mL/min/1.73 m2 at 12 months following AMR treatment. AMR treatment choice, histopathology, and DSA class were also examined. RESULTS We reviewed 123 AMR episodes. Median age at diagnosis was 15 years at a median 22 months post-transplant. The primary outcome developed in 27.6%. eGFR <30 m/min/1.73 m2 at AMR diagnosis was associated with a 5.6-fold higher risk of reaching the composite outcome. There were no significant differences in outcome by treatment modality. Histopathology scores and DSA class at time of AMR diagnosis were not significantly associated with the primary outcome. CONCLUSIONS In this large cohort of pediatric kidney transplant recipients with AMR, nearly one-third of patients experienced graft failure or significant graft dysfunction within 12 months of diagnosis. Poor graft function at time of diagnosis was associated with higher odds of graft failure.
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Affiliation(s)
- Isa F Ashoor
- Department of Pediatrics, Harvard Medical School and Boston Children's Hospital, Boston, Massachusetts, USA
| | - Rachel M Engen
- Department of Pediatrics, University of Wisconsin Madison, Madison, Wisconsin, USA
| | - Dechu Puliyanda
- Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Nicole Hayde
- Department of Pediatrics, Children's Hospital at Montefiore, Bronx, New York, USA
| | - Caitlin G Peterson
- Division of Pediatric Nephrology and Hypertension, University of Utah, Salt Lake City, Utah, USA
| | - Rima S Zahr
- Department of Pediatrics, Division of Pediatric Nephrology and Hypertension, University of Tennessee Health Sciences Center, Memphis, Tennessee, USA
| | - Sonia Solomon
- Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Boston Children's Health Physicians, Valhalla, New York, USA
| | - Mahmoud Kallash
- Department of Pediatrics, Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Rouba Garro
- Department of Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Amrish Jain
- Department of Pediatrics, Central Michigan University and Children's Hospital of Michigan, Detroit, Michigan, USA
| | - Lyndsay A Harshman
- Stead Family Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA
| | - Scott T McEwen
- Division of Pediatric Nephrology, University of Minnesota Masonic Children's Hospital, Minneapolis, Minnesota, USA
| | - Asifhusen Mansuri
- Department of Pediatrics, Children's Hospital of Georgia, Augusta University, Augusta, Georgia, USA
| | - Mathew J Gregoski
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Katherine E Twombley
- Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA
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Jha PK, Bansal SB, Sharma R, Sethi SK, Bansal D, Nandwani A, Kher A, Yadav DK, Gadde A, Mahapatra AK, Rana AS, Sodhi P, Jain M, Kher V. Role of Induction in a Haplomatch, Related, Low-Risk, Living-Donor Kidney Transplantation with Triple Drug Immunosuppression: A Single-Center Study. Indian J Nephrol 2024; 34:246-251. [PMID: 39114397 PMCID: PMC11302600 DOI: 10.4103/ijn.ijn_84_23] [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: 03/07/2023] [Accepted: 05/01/2023] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND The role of induction in low-risk, living-donor kidney transplants being treated with tacrolimus, mycophenolate mofetil, and prednisolone is debatable. MATERIALS AND METHODS This was a retrospective study that consisted of patients undergoing living kidney transplantation between February 2010 and June 2021 with a related haplomatch donor, with maintenance immunosuppression of tacrolimus, mycophenolate mofetil, and prednisolone. High-risk transplants, such as second or more transplants, immunologically incompatible transplants, and steroid-free transplants, were excluded. Patients were divided into three groups: no induction, basiliximab induction, and thymoglobulin induction, and the outcomes of all three were compared. RESULTS A total of 350 transplants were performed. There was a significant difference in the recipient sex distribution (P = 0.0373) and the number of preemptive transplants (P = 0.0272) between the groups. Other parameters were comparable. Biopsy-proven acute rejection (BPAR) was significantly less frequent in the thymoglobulin group than in the no-induction (5.3% vs. 17.5%; P = 0.0051) or basiliximab (5.3% vs. 18.8%; P = 0.0054) group. This persisted even after we performed multivariate regression analysis (thymoglobulin vs. no-induction group, P = 0.0146; thymoglobulin vs. basiliximab group, P = 0.0237). There was no difference in BPAR between the basiliximab and no-induction groups. There were no differences in other outcomes between the groups. CONCLUSION In a low-risk haplomatch, related, living-donor kidney transplant on tacrolimus, mycophenolate mofetil, and prednisolone, BPAR was significantly lower with thymoglobulin as opposed to no induction or basiliximab induction with a similar short-term patient and death-censored graft survival and infection rates. Basiliximab did not provide any benefit over no induction.
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Affiliation(s)
- Pranaw K. Jha
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Shyam B. Bansal
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Reetesh Sharma
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Sidharth K. Sethi
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Dinesh Bansal
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Ashish Nandwani
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Ajay Kher
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Dinesh K. Yadav
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Ashwini Gadde
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Amit K. Mahapatra
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Abhyuday S. Rana
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Puneet Sodhi
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Manish Jain
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
| | - Vijay Kher
- Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta – The Medicity, Gurugram, Haryana, India
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12
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Ranawaka R, Dayasiri K, Sandamali E, Gamage M. Management strategies for common viral infections in pediatric renal transplant recipients. World J Transplant 2024; 14:89978. [PMID: 38576764 PMCID: PMC10989477 DOI: 10.5500/wjt.v14.i1.89978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/19/2023] [Accepted: 01/04/2024] [Indexed: 03/15/2024] Open
Abstract
Viral infections have been considered as a major cause of morbidity and mortality after kidney transplantation in pediatric cohort. Children are at high risk of acquiring virus-related complications due to immunological immaturity and the enhanced alloreactivity risk that led to maintenance of high immunosuppressive regimes. Hence, prevention, early detection, and prompt treatment of such infe ctions are of paramount importance. Among all viral infections, herpes viruses (herpes simplex virus, varicella zoster virus, Epstein-Barr virus, cytomegalovirus), hepatitis B and C viruses, BK polyomavirus, and respiratory viruses (respiratory syncytial virus, parainfluenza virus, influenza virus and adenovirus) are common in kidney transplant recipients. These viruses can cause systemic disease or allograft dysfunction affecting the clinical outcome. Recent advances in tech nology and antiviral therapy have improved management strategies in screening, monitoring, adoption of prophylactic or preemptive therapy and precise trea tment in the immunocompromised host, with significant impact on the outcome. This review discusses the etiology, screening and monitoring, diagnosis, pre vention, and treatment of common viral infections in pediatric renal transplant recipients.
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Affiliation(s)
- Randula Ranawaka
- Department of Paediatrics, Faculty of Medicine, University of Colombo and Lady Ridgeway Hospital for Children, Colombo 0094, Sri Lanka
| | - Kavinda Dayasiri
- Department of Paediatrics, Facullty of Medicine, University of Kelaniya, Ragama 0094, Sri Lanka
| | - Erandima Sandamali
- Department of Nursing, Faculty of Allied Health Sciences, University of Ruhuna, Galle 0094, Sri Lanka
| | - Manoji Gamage
- Division of Nutrition, Ministry of Health, Colombo 0094, Sri Lanka
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13
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Liu Y, Zheng J, He Q, Zhang H, Wen P, Wen P, Ge J, Yang Y, Zhang T, Wang R. Impact of varied immunosuppressive agents and posttransplant diabetes mellitus on prognosis among diverse transplant recipients (Experimental studies). Int J Surg 2024; 110:01279778-990000000-01056. [PMID: 38349011 PMCID: PMC11020014 DOI: 10.1097/js9.0000000000001135] [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: 09/04/2023] [Accepted: 01/24/2024] [Indexed: 04/18/2024]
Abstract
The success of solid organ transplantation (SOT) and the use of immunosuppressive agents offer hope to patients with end-stage diseases. However, the impact of posttransplant diabetes mellitus (PTDM) on SOT patients has become increasingly evident. In our study, we utilized the Scientific Registry of Transplant Recipients (SRTR) database to investigate the association between PTDM and patient survival in various types of organ transplantations, including liver, kidney, intestinal, heart, lung, and combined heart-lung transplantations (all P<0.001). Our findings revealed a negative effect of PTDM on the survival of these patients. Furthermore, we examined the effects of both generic and innovator immunosuppressive agents on the development of PTDM and the overall survival of different SOT populations. Interestingly, the results were inconsistent, indicating that the impact of these agents may vary depending on the specific type of transplantation and patient population. Overall, our study provides a comprehensive and systematic assessment of the effects of different immunosuppressive agents on prognosis, as well as the impact of PTDM on the survival of patients undergoing various types of SOT. These findings emphasize the need for further research and highlight the importance of optimizing immunosuppressive regimens and managing PTDM in SOT patients to improve their long-term outcomes.
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Affiliation(s)
- Yuan Liu
- Department of Liver Transplantation, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinxin Zheng
- School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai, China
| | - Qining He
- Department of Liver Transplantation, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haijiao Zhang
- Huadong Hospital Affiliated to Fudan University, Shanghai, China
| | - Peizhen Wen
- Organ Transplantation Institute of Xiamen University, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, China
| | - Peihao Wen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jifu Ge
- Department of Kidney Transplantation, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yang Yang
- School of Public Health, Imperial College London, South Kensington Campus, London SW72AZ, United Kingdom
| | - Tao Zhang
- Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Rangrang Wang
- Huadong Hospital Affiliated to Fudan University, Shanghai, China
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14
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Atamna A, Yahav D, Hirzel C. Prevention of Oncogenic Gammaherpesvirinae (EBV and HHV8) Associated Disease in Solid Organ Transplant Recipients. Transpl Int 2023; 36:11856. [PMID: 38046068 PMCID: PMC10689273 DOI: 10.3389/ti.2023.11856] [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: 07/27/2023] [Accepted: 11/07/2023] [Indexed: 12/05/2023]
Abstract
Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population. Four non-hepatitis viruses have been recognized as oncogenic in SOT recipients-EBV, cause of EBV-associated lymphoproliferative diseases; human herpes virus 8 (HHV8), cause of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease; human papilloma virus, cause of squamous cell skin cancers, and Merkel cell polyomavirus, cause of Merkel cell carcinoma. Two of these viruses (EBV and HHV8) belong to the human herpes virus family. In this review, we will discuss key aspects regarding the clinical presentation, diagnosis, treatment, and prevention of diseases in SOT recipients associated with the two herpesviruses.
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Affiliation(s)
- Alaa Atamna
- Infectious Diseases Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Dafna Yahav
- Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
- Infectious Diseases Unit, Sheba Medical Center, Ramat-Gan, Israel
| | - Cédric Hirzel
- Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland
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15
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Erez DL, Pizzo H, Rodig N, Richardson T, Somers M. Outcomes based on induction regimens in pediatric kidney transplantation: a NAPRTCS and PHIS collaborative study. Pediatr Nephrol 2023; 38:3455-3464. [PMID: 37154962 DOI: 10.1007/s00467-023-05955-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND Induction agent used at the time of kidney transplant is often based upon center practice and recipient characteristics. We evaluated outcomes across induction therapies among children enrolled in the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) transplant registry with data in the Pediatric Health Information System (PHIS). METHODS This is a retrospective study of merged data from NAPRTCS and PHIS. Participants were grouped by induction agent: interleukin-2 receptor blocker (IL-2 RB), anti-thymocyte/anti-lymphocyte globulin (ATG/ALG), and alemtuzumab. Outcomes assessed included 1-, 3-, and 5-year allograft function and survival, rejection, viral infections, malignancy, and death. RESULTS A total of 830 children transplanted between 2010 and 2019. At 1 year post-transplant, the alemtuzumab group had higher median eGFR (86 ml/min/1.73 m2) compared to IL-2 RB and ATG/ALG (79 and 75 ml/min/1.73 m2, respectively; P < 0.001); at 3 and 5 years, there was no difference. Adjusted eGFR over time was similar across all induction agents. Rejection rates were lower among the alemtuzumab group vs. IL-2RB and ATG (13.9% vs. 27.3% and 24.6%, respectively; P = 0.006). Adjusted ATG/ALG and alemtuzumab had higher hazard ratio for time to graft failure compared to IL-2 RB (HR 2.48 and HR 2.11, respectively; P < 0.05). Incidence of malignancy, mortality, and time to first viral infection was similar. CONCLUSION Although rejection and allograft loss rates were distinct, the incidences of viral infection and malignancy were comparable across induction agents. By 3 years post-transplant, there was no difference in eGFR. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Daniella Levy Erez
- Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Schneider Children's Medical Center, Petach Tiqva, Israel.
| | - Helen Pizzo
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
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16
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Eisinger F, Mühlbacher T, Na A, Althaus K, Nadalin S, Birkenfeld AL, Heyne N, Guthoff M. Standardized, risk-adapted induction therapy in kidney transplantation. J Nephrol 2023; 36:2133-2138. [PMID: 37688753 PMCID: PMC10543942 DOI: 10.1007/s40620-023-01746-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 07/28/2023] [Indexed: 09/11/2023]
Abstract
BACKGROUND The choice of induction therapy in kidney transplantation is often non-standardized and centre-specific. Clinicians can choose between depleting and non-depleting antibodies, which differ in their immunosuppressive capacity and the concomitant risk of infection. We herein present a standardized risk-stratified algorithm for induction therapy that might help to balance the risk of rejection and/or serious infection. METHODS Prior to kidney transplantation, patients were stratified into low-risk, intermediate-risk or high-risk according to our protocol based on immunologic risk factors. Depending on their individual immunologic risk, patients received basiliximab (low risk), antithymocyte globulin (intermediate risk) or low-dose alemtuzumab (high risk) for induction therapy. We analysed the results after 3 years of implementation of our risk-stratified induction therapy protocol at our kidney transplant centre. RESULTS Between 01/2017 and 05/2020, 126 patients were stratified in accordance with our protocol (low risk/intermediate risk/high risk: 69 vs. 42 vs. 15 patients). The median follow-up time was 1.9 [1.0-2.5] years. No significant difference was observed in rejection rate and allograft survival (low risk/intermediate risk/high risk: 90.07% vs. 80.81% vs. 100% after 3 years (p > 0.05)) among the groups. The median eGFR at follow-up was (low risk/intermediate risk/high risk) 47 [33-58] vs 58 [46-76] vs 44 [22-55] ml/min/1.73 m2. Although the rate of viral and bacterial infections did not differ significantly, we observed a higher rate of opportunistic fungal infections with alemtuzumab induction. CONCLUSIONS Our strategy offers facilitated and individualized choice of induction therapy in kidney transplantation. We propose further evaluation of our algorithm in prospective trials.
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Affiliation(s)
- Felix Eisinger
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Thomas Mühlbacher
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany
| | - Ario Na
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany
| | - Karina Althaus
- Center for Clinical Transfusion Medicine, University of Tübingen, Tübingen, Germany
| | - Silvio Nadalin
- Department of General-, Visceral- and Transplant Surgery, University of Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Nils Heyne
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Martina Guthoff
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany.
- Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
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Zhang L, Zou H, Lu X, Shi H, Xu T, Gu S, Yu Q, Yin W, Chen S, Zhang Z, Gong N. Porcine anti-human lymphocyte immunoglobulin depletes the lymphocyte population to promote successful kidney transplantation. Front Immunol 2023; 14:1124790. [PMID: 36969156 PMCID: PMC10033525 DOI: 10.3389/fimmu.2023.1124790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/24/2023] [Indexed: 03/11/2023] Open
Abstract
IntroductionPorcine anti-human lymphocyte immunoglobulin (pALG) has been used in kidney transplantation, but its impacts on the lymphocyte cell pool remain unclear.MethodsWe retrospectively analyzed 12 kidney transplant recipients receiving pALG, and additional recipients receiving rabbit anti-human thymocyte immunoglobulin (rATG), basiliximab, or no induction therapy as a comparison group.ResultspALG showed high binding affinity to peripheral blood mononuclear cells (PBMCs) after administration, immediately depleting blood lymphocytes; an effect that was weaker than rATG but stronger than basiliximab. Single-cell sequencing analysis showed that pALG mainly influenced T cells and innate immune cells (mononuclear phagocytes and neutrophils). By analyzing immune cell subsets, we found that pALG moderately depleted CD4+T cells, CD8+T cells, regulatory T cells, and NKT cells and mildly inhibited dendritic cells. Serum inflammatory cytokines (IL-2, IL-6) were only moderately increased compared with rATG, which might be beneficial in terms of reducing the risk of untoward immune activation. During 3 months of follow-up, we found that all recipients and transplanted kidneys survived and showed good organ function recovery; there were no cases of rejection and a low rate of complications.DiscussionIn conclusion, pALG acts mainly by moderately depleting T cells and is thus a good candidate for induction therapy for kidney transplant recipients. The immunological features of pALG should be exploited for the development of individually-optimized induction therapies based on the needs of the transplant and the immune status of the patient, which is appropriate for non-high-risk recipients.
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Affiliation(s)
- Limin Zhang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Haoyong Zou
- Department of Research and Development, Wuhan Institute of Biological Products, Wuhan, China
| | - Xia Lu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Huibo Shi
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Tao Xu
- Department of Intensive Care Unit, Wuhan Fourth Hospital, Wuhan, China
| | - Shiqi Gu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Qinyu Yu
- Department of Research and Development, Wuhan Institute of Biological Products, Wuhan, China
| | - Wenqu Yin
- Department of Research and Development, Wuhan Institute of Biological Products, Wuhan, China
| | - Shi Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Zhi Zhang
- Department of Research and Development, Wuhan Institute of Biological Products, Wuhan, China
- *Correspondence: Nianqiao Gong, ; Zhi Zhang,
| | - Nianqiao Gong
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology; Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
- *Correspondence: Nianqiao Gong, ; Zhi Zhang,
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18
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Rousse J, Royer PJ, Evanno G, Lheriteau E, Ciron C, Salama A, Shneiker F, Duchi R, Perota A, Galli C, Cozzi E, Blancho G, Duvaux O, Brouard S, Soulillou JP, Bach JM, Vanhove B. LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation. Front Immunol 2023; 14:1137629. [PMID: 36875084 PMCID: PMC9978386 DOI: 10.3389/fimmu.2023.1137629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Anti-thymocyte or anti-lymphocyte globulins (ATGs/ALGs) are immunosuppressive drugs used in induction therapies to prevent acute rejection in solid organ transplantation. Because animal-derived, ATGs/ALGs contain highly immunogenic carbohydrate xenoantigens eliciting antibodies that are associated with subclinical inflammatory events, possibly impacting long-term graft survival. Their strong and long-lasting lymphodepleting activity also increases the risk for infections. We investigated here the in vitro and in vivo activity of LIS1, a glyco-humanized ALG (GH-ALG) produced in pigs knocked out for the two major xeno-antigens αGal and Neu5Gc. It differs from other ATGs/ALGs by its mechanism of action excluding antibody-dependent cell-mediated cytotoxicity and being restricted to complement-mediated cytotoxicity, phagocyte-mediated cytotoxicity, apoptosis and antigen masking, resulting in profound inhibition of T-cell alloreactivity in mixed leucocyte reactions. Preclinical evaluation in non-human primates showed that GH-ALG dramatically reduced CD4+ (p=0.0005,***), CD8+ effector T cells (p=0.0002,***) or myeloid cells (p=0.0007,***) but not T-reg (p=0.65, ns) or B cells (p=0.65, ns). Compared with rabbit ATG, GH-ALG induced transient depletion (less than one week) of target T cells in the peripheral blood (<100 lymphocytes/L) but was equivalent in preventing allograft rejection in a skin allograft model. The novel therapeutic modality of GH-ALG might present advantages in induction treatment during organ transplantation by shortening the T-cell depletion period while maintaining adequate immunosuppression and reducing immunogenicity.
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Affiliation(s)
| | | | | | | | - Carine Ciron
- Research and Development, Xenothera, Nantes, France
| | - Apolline Salama
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | | | - Roberto Duchi
- Transplantation Immunology Unit, Padua University Hospital, Padova, Italy
| | - Andrea Perota
- Transplantation Immunology Unit, Padua University Hospital, Padova, Italy
| | - Cesare Galli
- Transplantation Immunology Unit, Padua University Hospital, Padova, Italy
| | - Emmanuele Cozzi
- Avantea, Laboratorio di Tecnologie della Riproduzione, Cremona, Italy
| | - Gilles Blancho
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Odile Duvaux
- Research and Development, Xenothera, Nantes, France
| | - Sophie Brouard
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Jean-Paul Soulillou
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
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Johnson AC, Silva JAF, Kim SC, Larsen CP. Progress in kidney transplantation: The role for systems immunology. Front Med (Lausanne) 2022; 9:1070385. [PMID: 36590970 PMCID: PMC9800623 DOI: 10.3389/fmed.2022.1070385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 11/16/2022] [Indexed: 12/23/2022] Open
Abstract
The development of systems biology represents an immense breakthrough in our ability to perform translational research and deliver personalized and precision medicine. A multidisciplinary approach in combination with use of novel techniques allows for the extraction and analysis of vast quantities of data even from the volume and source limited samples that can be obtained from human subjects. Continued advances in microfluidics, scalability and affordability of sequencing technologies, and development of data analysis tools have made the application of a multi-omics, or systems, approach more accessible for use outside of specialized centers. The study of alloimmune and protective immune responses after solid organ transplant offers innumerable opportunities for a multi-omics approach, however, transplant immunology labs are only just beginning to adopt the systems methodology. In this review, we focus on advances in biological techniques and how they are improving our understanding of the immune system and its interactions, highlighting potential applications in transplant immunology. First, we describe the techniques that are available, with emphasis on major advances that allow for increased scalability. Then, we review initial applications in the field of transplantation with a focus on topics that are nearing clinical integration. Finally, we examine major barriers to adapting these methods and discuss potential future developments.
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Low dose rabbit antithymocyte globulin is non-inferior to higher dose in low-risk pediatric kidney transplant recipients. Pediatr Nephrol 2022; 37:2091-2098. [PMID: 35006359 DOI: 10.1007/s00467-021-05407-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 11/02/2021] [Accepted: 12/01/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Currently, there is no consensus among pediatric kidney transplant centers regarding the use and regimen for immunosuppressive induction therapy. METHODS In this single center, retrospective cohort study, pediatric kidney transplant recipients transplanted between 1 May 2013 and 1 May 2018 with rabbit antithymocyte globulin (rATG) induction were included. We stratified patients based on immunological risk, with high risk defined as those with repeat transplant, preformed donor specific antibody, current panel-reactive antibodies > 20%, 0 antigen match and/or African-American heritage. Outcome of interest was the incidence of biopsy proven acute rejection by 1 year. RESULTS A total of 166 patients met inclusion criteria. Age of patients was 12 years (11 mo-21 y), (median, range), 21.5% received a living donor transplant and 50.6% were female. Low-immunologic-risk patients were divided into 2 groups, those who received the lower cumulative rATG dose of ≤ 3.5 mg/kg (n = 52) versus the higher cumulative dose of > 3.5 mg/kg (n = 47). The median total dose in the lower dose group was 3.1 (IQR 0.3) and 4.4 (IQR 0.8) in the higher dose group, P < 0.001. Rejection rate did not differ significantly between the 2 treatment groups (7/52 vs. 6/47). None in the lower dose group developed BK nephropathy versus 3 in the higher dose group. Graft loss due to BK nephropathy occurred in 1 patient in the higher dose group. Graft loss in the whole cohort at 12 months was a rare event (n = 1) with 99.5% graft survival and 100% patient survival. CONCLUSIONS Reduced rATG dosing (≤ 3.5 mg/kg) when compared to higher dosing (> 3.5 mg/kg) is safe and effective in low-risk pediatric kidney transplant recipients without increasing risk of rejection. A higher resolution version of the Graphical abstract is available as Supplementary information.
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21
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Comparison of early and late Pneumocystis jirovecii Pneumonia in kidney transplant patients: the Korean Organ Transplantation Registry (KOTRY) Study. Sci Rep 2022; 12:10682. [PMID: 35739203 PMCID: PMC9226063 DOI: 10.1038/s41598-022-14580-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 06/09/2022] [Indexed: 11/09/2022] Open
Abstract
Late Pneumocystis jirovecii pneumonia (PJP) is not rare in the era of universal prophylaxis after kidney transplantation. We aimed to determine the nationwide status of PJP prophylaxis in Korea and compare the incidence, risk factors, and outcomes of early and late PJP using data from the Korean Organ Transplantation Registry (KOTRY), a nationwide Korean transplant cohort. We conducted a retrospective analysis using data of 4,839 kidney transplant patients from KOTRY between 2014 and 2018, excluding patients who received multi-organ transplantation or were under 18 years old. Cox regression analysis was performed to determine risk factors for early and late PJP. A total of 50 patients developed PJP. The number of patients who developed PJP was same between onset before 6 months and onsets after 6 months. There were no differences in the rate, duration, or dose of PJP prophylaxis between early and late PJP. Desensitization, higher tacrolimus dose at discharge, and acute rejection were associated with early PJP. In late PJP, old age as well as acute rejection were significant risk factors. In conclusion late PJP is as common and risky as early PJP and requires individualized risk-based prophylaxis, such as prolonged prophylaxis for old patients with a history of rejection.
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Wen Y, Zhao M, Fu S, Gu Z, Chen W, Zhao Q, Shu W, Tao X, Zhang F. Pharmaceutical services based on therapeutic care pathway for kidney transplantation from donors of infants and young children: a single-center experience. Transl Pediatr 2022; 11:834-847. [PMID: 35800269 PMCID: PMC9253932 DOI: 10.21037/tp-21-515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 02/11/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The pharmaceutical services based on therapeutic care pathway for kidney transplantation from infants and young children (age <3 years, weight <15 kg) to pediatric recipients can detect and resolve medication-related problems. In this paper, we report our experience on pharmaceutical services based on therapeutic care pathway to evaluate the therapeutic effects and assess the feasibility of perioperative treatment protocols. METHODS We performed a retrospective study of 12 recipients who received their graft from infants and young children, between September 2011 and December 2013 at our institution. As providers of pharmaceutical services, the clinical pharmacists collected and reviewed the clinical data from all patients, including the clinical characteristics, outcome indices, and follow-up dates. A three-step-protocol of pharmaceutical services including clinician's application, pharmacist consultation, and ongoing direct pharmaceutical care and follow-up was used through the entire length of patient's admission, hospitalization, and discharge. This protocol was developed and refined based on the guidelines for transplant perioperative treatment and experiences of the clinical pharmacists to standardize the workflow, and improve the medical treatment and quality of life of patients. RESULTS There was no acute rejection, graft loss, or death in 10 recipients after transplantation, and another 2 received nephrectomy due to dysfunction. Postoperative follow-up of the patients who received the pharmaceutical services from the clinical pharmacist showed an effectiveness in managing medication-related complications, patient-related factors, and an improvement of the outcomes. CONCLUSIONS The three-step protocol of pharmaceutical services for pharmaceutical care and individual dosing regimen sponsored by pharmacists facilitated access to personalized therapies for children undergoing kidney transplantation in our hospital.
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Affiliation(s)
- Yan Wen
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Mengpei Zhao
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Shangxi Fu
- Department of Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhichun Gu
- Department of Pharmacy, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wansheng Chen
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Qing Zhao
- Department of Pharmacy, Zhabei Central Hospital of Jing'an District, Shanghai, China
| | - Wei Shu
- Department of Pharmacy, Zhabei Central Hospital of Jing'an District, Shanghai, China
| | - Xia Tao
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Feng Zhang
- Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, China
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Gupta A, Bhalla AK, Malik M, Gupta A, Bhargava V, Tiwari V, Gaur L, Gupta P, Jain M, Rana DS. Anti-T-Lymphocyte Immunoglobulin (Grafalon) as an Induction Agent for Renal Transplantation: A Real-World, Retrospective, Single-Center Experience. EXP CLIN TRANSPLANT 2022; 20:480-486. [PMID: 35620891 DOI: 10.6002/ect.2021.0432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Polyclonal antithymocyte globulins are widely used in the induction regimens of solid-organ transplant recipients; however, their doses and outcomes remain to be standardized in Indian patients. We report our clinical experience from the real-world use of Grafalon (an anti-T-lymphocyte globulin; ATG-Fresenius) as an induction agentin renal transplant recipients from India. MATERIALS AND METHODS In this retrospective, single- center, observational study, we analyzed the medical records of 177 consecutive, kidney-only transplant recipients who received induction therapy with Grafalon from September 2016 to March 2018 at our center. Incidences of biopsy-proven acute rejection and graft dysfunction, immunosuppression protocol, Grafalon dosage, 18-month post-transplant graft and patient survival, treatment-related adverse events, and infective complications were reported. RESULTS Mean age of patients was 41.46 years (range, 14-68 years), (85% were males). The average dose of Grafalon was 5.81 ± 1.95 mg/kg (range, 2.41 to 10.07 mg/kg). Graft dysfunction (ie, at least 20% increase in serum creatinine from baseline) was observed in 26 patients (14%): 11 patients (6.2%) had biopsy-proven acute rejections, 11 patients (6.2%) had acute tubular necrosis, and 4 patients (2.2%) had calcineurin inhibitor toxicity. Seven deaths were recorded: 2 each from fungal pneumonia, bacterial pneumonia, and acute coronary syndrome and 1 with urinary tract infection with septicemia. Death-censored graft survival was 100% at 12 months and 98% at 18-month follow-up; overall patient survival was 96%. Infective complications occurred in 40 patients (22.5%), with the most common being urinary tract infection in 32 patients (18%). No malignancies were reported. CONCLUSIONS Use of a potent induction therapy like anti-T-lymphocyte globulin (Grafalon) is often restricted by the risk of side effects and lack of local clinical evidence supporting its role in long-term graft survival. Real-world evidence support the safe and effective use of anti-T-lymphocyte globulin as an induction agent in renal transplant recipients with an individualized dosing approach.
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Affiliation(s)
- Ashwani Gupta
- From the Department of Nephrology, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, India
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Effectiveness of Prophylactic Human Cytomegalovirus Hyperimmunoglobulin in Preventing Cytomegalovirus Infection following Transplantation: A Systematic Review and Meta-Analysis. Life (Basel) 2022; 12:life12030361. [PMID: 35330112 PMCID: PMC8955988 DOI: 10.3390/life12030361] [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: 01/25/2022] [Revised: 02/18/2022] [Accepted: 02/28/2022] [Indexed: 11/29/2022] Open
Abstract
Cytomegalovirus (CMV) is a common infection occurring in patients undergoing solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). CMV-specific hyperimmunoglobulin (CMVIG) has been used for the past four decades and is typically administered either prophylactically or pre-emptively. The present meta-analysis evaluated CMV infection rates in SOT patients who received prophylactic CMVIG. PubMed and the Cochrane Library were searched for studies published up to October 2021. The primary endpoint was CMV infection rate. Thirty-two SOT studies were identified (n = 1521 CMVIG-treated and n = 1196 controls). Prophylactic CMVIG treatment was often associated with a lower risk of CMV infection in transplant recipients. The average CMV infection rate was 35.8% (95% confidence interval [CI]: 33.4−38.2%) in patients treated prophylactically with CMVIG and 41.4% (95% CI: 38.6−44.2%) in the control group not receiving CMVIG (p = 0.003). Similar results were observed in analyses limited to publications evaluating currently available CMVIG products (Cytotect CP and Cytogam; p < 0.001). In combination with the established safety profile for CMVIG, these results suggest that prophylactic CMVIG treatment in patients undergoing solid organ transplantation may be beneficial, particularly in those at high risk of CMV infection or disease.
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The Evolution of Molecular Recognition: From Antibodies to Molecularly Imprinted Polymers (MIPs) as Artificial Counterpart. J Funct Biomater 2022; 13:jfb13010012. [PMID: 35225975 PMCID: PMC8883926 DOI: 10.3390/jfb13010012] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/15/2022] [Accepted: 01/26/2022] [Indexed: 02/07/2023] Open
Abstract
Molecular recognition is a useful property shared by various molecules, such as antibodies, aptamers and molecularly imprinted polymers (MIPs). It allows these molecules to be potentially involved in many applications including biological and pharmaceutical research, diagnostics, theranostics, therapy and drug delivery. Antibodies, naturally produced by plasma cells, have been exploited for this purpose, but they present noticeable drawbacks, above all production cost and time. Therefore, several research studies for similar applications have been carried out about MIPs and the main studies are reported in this review. MIPs, indeed, are more versatile and cost-effective than conventional antibodies, but the lack of toxicity studies and their scarce use for practical applications, make it that further investigations on this kind of molecules need to be conducted.
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Nikolova A, Patel JK. Induction Therapy and Therapeutic Antibodies. Handb Exp Pharmacol 2022; 272:85-116. [PMID: 35474024 DOI: 10.1007/164_2021_570] [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] [Indexed: 06/14/2023]
Abstract
Prevention of allograft rejection is one of the crucial goals in solid organ transplantation to ensure durability of the graft and is chiefly mediated by cellular and humoral pathways targeting cell surface alloantigens. The risk of rejection is highest in the first post-transplant year and wanes with time albeit the risk always exists and varies with the type of organ transplanted. Induction therapies refer to the use of high-intensity immunosuppression in the immediate post-operative period to mitigate the highest risk of rejection. This term encompasses chiefly the use of antibody therapies directed against one of the key pathways in T-cell activation or abrogating effects of circulating alloantibodies. These antibodies carry more potent immunomodulatory effect than maintenance immunosuppressive therapy alone and many of them lead to durable immune cell depletion. A variety of monoclonal and polyclonal antibodies have been utilized for use not only for induction therapy, but also for treatment of allograft rejection when it occurs and as components of desensitization therapy before and after transplantation to modulate circulating alloantibodies.
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Kolonko A, Więcek A. Safety of Antithymocyte Globulin Use in Kidney Graft Recipients During the COVID-19 Pandemic. Ann Transplant 2021; 26:e933001. [PMID: 34697282 PMCID: PMC8556699 DOI: 10.12659/aot.933001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background There are many safety concerns regarding the use of antithymocyte globulin (ATG) in kidney transplant recipients (KTRs) during the ongoing COVID-19 pandemic. Hereby, we present our recent experience with ATG administration both as induction therapy and as an anti-rejection treatment. Material/Methods We retrospectively analyzed all patients transplanted during the first 12 months of the COVID-19 pandemic who were treated with thymoglobulin. The ATG dosing, lymphocyte number and percentage in blood smear, adverse effects (thrombocytopenia and infectious complications), and kidney graft function up to 12 months and patients’ outcomes were analyzed and compared to KTRs who received basiliximab induction. Results During pandemic, a total of 31 patients were treated with ATG and 59 received basiliximab. The median cumulative ATG doses were 275 (175–325) mg in the induction subgroup and 263 (200–275) mg in the anti-rejection treatment subgroup. Mild thrombocytopenia was noted in 7 (22.6%) and 13 (29.5%) patients, respectively. There were more infectious complications among patients treated with ATG as compared with the basiliximab subgroup (32.3 vs 10.2%, P<0.01), but there were similar incidence rates of thrombocytopenia. Kidney graft function up to 12 months after transplant was comparable (1.1 [1.0–1.9] vs 1.1 [1.0–1.4] mg/dl, respectively). Conclusions 1. ATG use in the induction protocol or as the anti-rejection treatment during the COVID-19 pandemic appears to be safe and the risk of adverse events is acceptable. 2. During the COVID-19 pandemic the necessary use of ATG should not be postponed, especially in KTRs with increased immunologic risk.
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Affiliation(s)
- Aureliusz Kolonko
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
| | - Andrzej Więcek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland
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Storti G, Favi E, Albanesi F, Kim BS, Cervelli V. Adipose-Derived Stem/Stromal Cells in Kidney Transplantation: Status Quo and Future Perspectives. Int J Mol Sci 2021; 22:11188. [PMID: 34681848 PMCID: PMC8538841 DOI: 10.3390/ijms222011188] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/11/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Kidney transplantation (KT) is the gold standard treatment of end-stage renal disease. Despite progressive advances in organ preservation, surgical technique, intensive care, and immunosuppression, long-term allograft survival has not significantly improved. Among the many peri-operative complications that can jeopardize transplant outcomes, ischemia-reperfusion injury (IRI) deserves special consideration as it is associated with delayed graft function, acute rejection, and premature transplant loss. Over the years, several strategies have been proposed to mitigate the impact of IRI and favor tolerance, with rather disappointing results. There is mounting evidence that adipose stem/stromal cells (ASCs) possess specific characteristics that could help prevent, reduce, or reverse IRI. Immunomodulating and tolerogenic properties have also been suggested, thus leading to the development of ASC-based prophylactic and therapeutic strategies in pre-clinical and clinical models of renal IRI and allograft rejection. ASCs are copious, easy to harvest, and readily expandable in culture. Furthermore, ASCs can secrete extracellular vesicles (EV) which may act as powerful mediators of tissue repair and tolerance. In the present review, we discuss the current knowledge on the mechanisms of action and therapeutic opportunities offered by ASCs and ASC-derived EVs in the KT setting. Most relevant pre-clinical and clinical studies as well as actual limitations and future perspective are highlighted.
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Affiliation(s)
- Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, Italy; (G.S.); (V.C.)
| | - Evaldo Favi
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy
- Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy;
| | - Francesca Albanesi
- Kidney Transplantation, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20135 Milan, Italy;
| | - Bong-Sung Kim
- Division of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland;
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University, 00133 Rome, Italy; (G.S.); (V.C.)
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Olaso D, Manook M, Moris D, Knechtle S, Kwun J. Optimal Immunosuppression Strategy in the Sensitized Kidney Transplant Recipient. J Clin Med 2021; 10:3656. [PMID: 34441950 PMCID: PMC8396983 DOI: 10.3390/jcm10163656] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/09/2021] [Accepted: 08/15/2021] [Indexed: 01/10/2023] Open
Abstract
Patients with previous sensitization events against anti-human leukocyte antigens (HLA) often have circulating anti-HLA antibodies. Following organ transplantation, sensitized patients have higher rates of antibody-mediated rejection (AMR) compared to those who are non-sensitized. More stringent donor matching is required for these patients, which results in a reduced donor pool and increased time on the waitlist. Current approaches for sensitized patients focus on reducing preformed antibodies that preclude transplantation; however, this type of desensitization does not modulate the primed immune response in sensitized patients. Thus, an optimized maintenance immunosuppressive regimen is necessary for highly sensitized patients, which may be distinct from non-sensitized patients. In this review, we will discuss the currently available therapeutic options for induction, maintenance, and adjuvant immunosuppression for sensitized patients.
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Affiliation(s)
| | | | | | - Stuart Knechtle
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; (D.O.); (M.M.); (D.M.)
| | - Jean Kwun
- Duke Transplant Center, Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; (D.O.); (M.M.); (D.M.)
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Sandal S, Boyarsky BJ, Massie A, Chiang TP, Segev DL, Cantarovich M. Immunosuppression practices during the COVID-19 pandemic: A multinational survey study of transplant programs. Clin Transplant 2021; 35:e14376. [PMID: 34050961 PMCID: PMC8209940 DOI: 10.1111/ctr.14376] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/03/2021] [Accepted: 05/24/2021] [Indexed: 12/17/2022]
Abstract
During the COVID-19 pandemic, there has been wide heterogeneity in the medical management of transplant recipients. We aimed to pragmatically capture immunosuppression practices globally following the early months of the pandemic. From June to September 2020, we surveyed 1267 physicians; 40.5% from 71 countries participated. Management decisions were made on a case-by-case basis by the majority (69.6%) of the programs. Overall, 76.8% performed ≥1 transplantation and many commented on avoiding high-risk transplantations. For induction, 26.5% were less likely to give T-cell depletion and 14.8% were more likely to give non-depleting agents. These practices varied by program-level factors more so than the COVID-19 burden. In patients with mild, moderate and severe COVID-19 symptoms 59.7%, 76.0%, and 79.5% decreased/stopped anti-metabolites, 23.2%, 45.4%, and 68.2% decreased/stopped calcineurin inhibitors, and 25.7%, 43.9%, and 57.7% decreased/stopped mTOR inhibitors, respectively. Also, 2.1%, 30.6%, and 46.0% increased steroids in patients with mild, moderate, and severe COVID-19 symptoms. For prevalent transplant recipients, some programs also reported decreasing/stopping steroids (1.8%), anti-metabolites (10.3%), calcineurin inhibitors (4.1%), and mTOR inhibitors (5.5%). Transplant programs changed immunosuppression practices but also avoided high-risk transplants and increased maintenance steroids. The long-term ramifications of these practices remain to be seen as programs face the aftermath of the pandemic.
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Affiliation(s)
- Shaifali Sandal
- Division of NephrologyMulti‐Organ Transplant ProgramDepartment of MedicineMcGill University Health CentreMontrealQCCanada
- Research Institute of the McGill University Health CentreMontrealQCCanada
| | - Brian J. Boyarsky
- Department of SurgeryJohns Hopkins University School of MedicineBaltimoreMDUSA
- Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreMDUSA
| | - Allan Massie
- Department of SurgeryJohns Hopkins University School of MedicineBaltimoreMDUSA
- Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreMDUSA
| | - Teresa Po‐Yu Chiang
- Department of SurgeryJohns Hopkins University School of MedicineBaltimoreMDUSA
| | - Dorry L. Segev
- Department of SurgeryJohns Hopkins University School of MedicineBaltimoreMDUSA
- Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreMDUSA
| | - Marcelo Cantarovich
- Division of NephrologyMulti‐Organ Transplant ProgramDepartment of MedicineMcGill University Health CentreMontrealQCCanada
- Research Institute of the McGill University Health CentreMontrealQCCanada
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van Alem CMA, Metselaar JM, van Kooten C, Rotmans JI. Recent Advances in Liposomal-Based Anti-Inflammatory Therapy. Pharmaceutics 2021; 13:pharmaceutics13071004. [PMID: 34371695 PMCID: PMC8309101 DOI: 10.3390/pharmaceutics13071004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 01/13/2023] Open
Abstract
Liposomes can be seen as ideal carriers for anti-inflammatory drugs as their ability to (passively) target sites of inflammation and release their content to inflammatory target cells enables them to increase local efficacy with only limited systemic exposure and adverse effects. Nonetheless, few liposomal formulations seem to reach the clinic. The current review provides an overview of the more recent innovations in liposomal treatment of rheumatoid arthritis, psoriasis, vascular inflammation, and transplantation. Cutting edge developments include the liposomal delivery of gene and RNA therapeutics and the use of hybrid systems where several liposomal bilayer features, or several drugs, are combined in a single formulation. The majority of the articles reviewed here focus on preclinical animal studies where proof-of-principle of an improved efficacy-safety ratio is observed when using liposomal formulations. A few clinical studies are included as well, which brings us to a discussion about the challenges of clinical translation of liposomal nanomedicines in the field of inflammatory diseases.
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Affiliation(s)
- Carla M. A. van Alem
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (C.M.A.v.A.); (C.v.K.)
| | - Josbert M. Metselaar
- Institute for Experimental Molecular Imaging, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany;
| | - Cees van Kooten
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (C.M.A.v.A.); (C.v.K.)
| | - Joris I. Rotmans
- Department of Internal Medicine, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (C.M.A.v.A.); (C.v.K.)
- Correspondence: ; Tel.: +31-(0)-7152-62148
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Ritschl PV, Günther J, Hofhansel L, Ernst S, Ebner S, Sattler A, Weiß S, Weissenbacher A, Oberhuber R, Cardini B, Öllinger R, Biebl M, Denecke C, Margreiter C, Resch T, Schneeberger S, Maglione M, Kotsch K, Pratschke J. Perioperative Perfusion of Allografts with Anti-Human T-lymphocyte Globulin Does Not Improve Outcome Post Liver Transplantation-A Randomized Placebo-Controlled Trial. J Clin Med 2021; 10:jcm10132816. [PMID: 34202355 PMCID: PMC8267618 DOI: 10.3390/jcm10132816] [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: 03/28/2021] [Revised: 06/05/2021] [Accepted: 06/17/2021] [Indexed: 11/16/2022] Open
Abstract
Due to the lack of suitable organs transplant surgeons have to accept unfavorable extended criteria donor (ECD) organs. Recently, we demonstrated that the perfusion of kidney organs with anti-human T-lymphocyte globulin (ATLG) prior to transplantation ameliorates ischemia-reperfusion injury (IRI). Here, we report on the results of perioperative ATLG perfusion in a randomized, single-blinded, placebo-controlled, feasibility trial (RCT) involving 30 liver recipients (LTx). Organs were randomly assigned for perfusion with ATLG/Grafalon® (AP) (n = 16) or saline only (control perfusion = CP) (n = 14) prior to implantation. The primary endpoint was defined as graft function reflected by aspartate transaminase (AST) values at day 7 post-transplantation (post-tx). With respect to the primary endpoint, no significant differences in AST levels were shown in the intervention group at day 7 (AP: 53.0 ± 21.3 mg/dL, CP: 59.7 ± 59.2 mg/dL, p = 0.686). Similarly, exploratory analysis of secondary clinical outcomes (e.g., patient survival) and treatment-specific adverse events revealed no differences between the study groups. Among liver transplant recipients, pre-operative organ perfusion with ATLG did not improve short-term outcomes, compared to those who received placebo perfusion. However, ATLG perfusion of liver grafts was proven to be a safe procedure without the occurrence of relevant adverse events.
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Affiliation(s)
- Paul Viktor Ritschl
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
- Clinician Scientist Program, Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Str. 2, 10178 Berlin, Germany
| | - Julia Günther
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Lena Hofhansel
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen, 52074 Aachen, Germany
| | - Stefanie Ernst
- Biostatistics Unit, Clinical Research Unit, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Susanne Ebner
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Arne Sattler
- Department of General, Visceral- and Vascular Surgery, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany;
| | - Sascha Weiß
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Annemarie Weissenbacher
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Rupert Oberhuber
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Benno Cardini
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Matthias Biebl
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Christian Denecke
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Christian Margreiter
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Thomas Resch
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Stefan Schneeberger
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Manuel Maglione
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Katja Kotsch
- Department of General, Visceral- and Vascular Surgery, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany;
- Correspondence: ; Tel.: +49-30-450-552247
| | - Johann Pratschke
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
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The influence of the antithymocyte globulin dose on clinical outcomes of patients undergoing kidney retransplantation. PLoS One 2021; 16:e0251384. [PMID: 33979389 PMCID: PMC8115839 DOI: 10.1371/journal.pone.0251384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 04/26/2021] [Indexed: 01/01/2023] Open
Abstract
Optimizing antithymocyte globulin (rATG) dosage is critical for high immunological risk patients undergoing a repeat kidney transplant. This natural retrospective cohort study compared clinical outcomes of two successive cohorts of consecutive recipients of retransplants receiving 5 x 1 mg/kg (rATG-5, n = 100) or a single 3 mg/kg (rATG-3, n = 110) dose of rATG induction therapy. All patients had negative complement-dependent cytotoxicity crossmatch and no anti-HLA A, B, DR donor-specific antibodies (DSA). The primary endpoint was efficacy failure (first biopsy-proven acute rejection, graft loss, or death) at 12 months. There was no difference in the cumulative incidence of efficacy failure (18.0% vs. 21.8%, HR = 1.22, 95% CI 0.66–2.25), respectively. There were no differences in 3-years freedom from biopsy proven acute rejection, and patient, graft, and death-censored graft survivals. There were no differences in the incidence of surgical complications (25.0% vs. 18.2%; p 0.151), early hospital readmission (27.8% vs. 29.5%; p = 0.877) and CMV infections (49% vs. 40%; p = 0.190). There were also no differences in the incidence (59.6% vs. 58.7%, p = 0.897) and duration of delayed graft function but a stable difference in estimate glomerular filtration rate was observed from month 1 (54.7±28.8 vs. 44.1±25.3 ml/min/1.73 m2, p = 0.005) to month 36 (51.1±27.7 vs. 42.5±24.5, p = 0.019). Mean urinary protein concentration (month 36: 0.38±0.81 vs. 0.70±2.40 g/ml, p = 0.008) and mean chronic glomerular Banff score in for cause biopsies (months 4–36: 0.0±0.0 vs. 0.04±0.26, p = 0.044) were higher in the rATG-3 group. This cohort analysis did not detect differences in the incidence of efficacy failure and in safety outcomes at 12 months among recipients of kidney retransplants without A, B, and DR DSA, receiving induction therapy with a single 3 mg/kg rATG dose or the traditional 5 mg/kg rATG.
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Impact of HLA Mismatching on Early Subclinical Inflammation in Low-Immunological-Risk Kidney Transplant Recipients. J Clin Med 2021; 10:jcm10091934. [PMID: 33947168 PMCID: PMC8125522 DOI: 10.3390/jcm10091934] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/20/2021] [Accepted: 04/27/2021] [Indexed: 01/17/2023] Open
Abstract
The impact of human leukocyte antigen (HLA)-mismatching on the early appearance of subclinical inflammation (SCI) in low-immunological-risk kidney transplant (KT) recipients is undetermined. We aimed to assess whether HLA-mismatching (A-B-C-DR-DQ) is a risk factor for early SCI. As part of a clinical trial (Clinicaltrials.gov, number NCT02284464), a total of 105 low-immunological-risk KT patients underwent a protocol biopsy on the third month post-KT. As a result, 54 presented SCI, showing a greater number of total HLA-mismatches (p = 0.008) and worse allograft function compared with the no inflammation group (48.5 ± 13.6 vs. 60 ± 23.4 mL/min; p = 0.003). Multiple logistic regression showed that the only risk factor associated with SCI was the total HLA-mismatch score (OR 1.32, 95%CI 1.06-1.64, p = 0.013) or class II HLA mismatching (OR 1.51; 95%CI 1.04-2.19, p = 0.032) after adjusting for confounder variables (recipient age, delayed graft function, transfusion prior KT, and tacrolimus levels). The ROC curve illustrated that the HLA mismatching of six antigens was the optimal value in terms of sensitivity and specificity for predicting the SCI. Finally, a significantly higher proportion of SCI was seen in patients with >6 vs. ≤6 HLA-mismatches (62.3 vs. 37.7%; p = 0.008). HLA compatibility is an independent risk factor associated with early SCI. Thus, transplant physicians should perhaps be more aware of HLA mismatching to reduce these early harmful lesions.
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Odler B, Deak AT, Pregartner G, Riedl R, Bozic J, Trummer C, Prenner A, Söllinger L, Krall M, Höflechner L, Hebesberger C, Boxler MS, Berghold A, Schemmer P, Pilz S, Rosenkranz AR. Hypomagnesemia Is a Risk Factor for Infections after Kidney Transplantation: A Retrospective Cohort Analysis. Nutrients 2021; 13:1296. [PMID: 33919913 PMCID: PMC8070921 DOI: 10.3390/nu13041296] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/07/2021] [Accepted: 04/07/2021] [Indexed: 01/16/2023] Open
Abstract
INTRODUCTION Magnesium (Mg2+) deficiency is a common finding in the early phase after kidney transplantation (KT) and has been linked to immune dysfunction and infections. Data on the association of hypomagnesemia and the rate of infections in kidney transplant recipients (KTRs) are sparse. METHODS We conducted a single-center retrospective cohort study of KTRs transplanted between 2005 and 2015. Laboratory data, including serum Mg2+ (median time of the Mg2+ measurement from KT: 29 days), rate of infections including mainly urinary tract infections (UTI), and common transplant-related viral infections (CMV, polyoma, EBV) in the early phase after KT were recorded. The primary outcome was the incidence of infections within one year after KT, while secondary outcomes were hospitalization due to infection, incidence rates of long-term (up to two years) infections, and all-cause mortality. RESULTS We enrolled 376 KTRs of whom 229 patients (60.9%) suffered from Mg2+ deficiency defined as a serum Mg2+ < 0.7 mmol/L. A significantly higher incidence rate of UTIs and viral infections was observed in patients with versus without Mg2+ deficiency during the first year after KT (58.5% vs. 47.6%, p = 0.039 and 69.9% vs. 51.7%, p < 0.001). After adjustment for potential confounders, serum Mg2+ deficiency remained an independent predictor of both UTIs and viral infections (odds ratio (OR): 1.73, 95% CI: 1.04-2.86, p = 0.035 and OR: 2.05, 95% CI: 1.23-3.41, p = 0.006). No group differences according to Mg2+ status in hospitalizations due to infections and infection incidence rates in the 12-24 months post-transplant were observed. In the Cox regression analysis, Mg2+ deficiency was not significantly associated with all-cause mortality (HR: 1.15, 95% CI: 0.70-1.89, p = 0.577). CONCLUSIONS KTRs suffering from Mg2+ deficiency are at increased risk of UTIs and viral infections in the first year after KT. Interventional studies investigating the effect of Mg2+ supplementation on Mg2+ deficiency and viral infections in KTRs are needed.
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Affiliation(s)
- Balazs Odler
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
- Transplant Center Graz, Medical University of Graz, A-8036 Graz, Austria;
| | - Andras T. Deak
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
- Transplant Center Graz, Medical University of Graz, A-8036 Graz, Austria;
| | - Gudrun Pregartner
- Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, A-8036 Graz, Austria; (G.P.); (R.R.); (A.B.)
| | - Regina Riedl
- Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, A-8036 Graz, Austria; (G.P.); (R.R.); (A.B.)
| | - Jasmin Bozic
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
| | - Christian Trummer
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (C.T.); (S.P.)
| | - Anna Prenner
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
- Transplant Center Graz, Medical University of Graz, A-8036 Graz, Austria;
| | - Lukas Söllinger
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
| | - Marcell Krall
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
| | - Lukas Höflechner
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
| | - Carina Hebesberger
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
- Transplant Center Graz, Medical University of Graz, A-8036 Graz, Austria;
| | - Matias S. Boxler
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
| | - Andrea Berghold
- Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, A-8036 Graz, Austria; (G.P.); (R.R.); (A.B.)
| | - Peter Schemmer
- Transplant Center Graz, Medical University of Graz, A-8036 Graz, Austria;
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, A-8036 Graz, Austria
| | - Stefan Pilz
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (C.T.); (S.P.)
| | - Alexander R. Rosenkranz
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria; (B.O.); (A.T.D.); (J.B.); (A.P.); (L.S.); (M.K.); (L.H.); (C.H.); (M.S.B.)
- Transplant Center Graz, Medical University of Graz, A-8036 Graz, Austria;
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Ashoor IF, Beyl RA, Gupta C, Jain A, Kiessling SG, Moudgil A, Patel HP, Sherbotie J, Weaver DJ, Zahr RS, Dharnidharka VR. Low-Dose Antithymocyte Globulin Has No Disadvantages to Standard Higher Dose in Pediatric Kidney Transplant Recipients: Report From the Pediatric Nephrology Research Consortium. Kidney Int Rep 2021; 6:995-1002. [PMID: 33912749 PMCID: PMC8071617 DOI: 10.1016/j.ekir.2021.01.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 12/14/2020] [Accepted: 01/04/2021] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION Rabbit antithymocyte globulin (rATG) dosing strategies for induction in pediatric kidney transplantation vary between centers. It is not known whether a lower rATG induction dose provides safe and effective immunosuppression compared with a "standard" higher dose. METHODS We performed a retrospective multicenter study of all isolated first-time kidney transplant recipients <21 years old who received rATG induction between 1 January 2010 and 31 December 2014 at 9 pediatric centers. An a priori cutoff of a 4.5-mg/kg cumulative rATG dose was used to identify low (≤ 4.5 mg/kg) and standard (> 4.5 mg/kg) exposure groups. Outcomes examined included 12 months posttransplant graft function (estimated glomerular filtration rate [eGFR]); the occurrence of acute rejection, donor-specific antibody (DSA), neutropenia, and viral infection (cytomegalovirus [CMV], Epstein-Barr virus [EBV], and BK virus); and 24-month outcomes of posttransplant lymphoproliferative disorder (PTLD) occurrence and patient and graft survival. RESULTS Two hundred thirty-five patients were included. Baseline features of the low and standard rATG dose groups were similar. By 12 months, the rATG dose group had no significant impact on the occurrence of neutropenia, positive DSA, or viral polymerase chain reaction (PCR). Graft function was similar. Acute rejection rates were similar at 17% (low dose) versus 19% (standard dose) (P = 0.13). By 24 months, graft survival (96.4% vs. 94.6%) and patient survival (100% vs. 99.3%) were similar between the low- and standard-dose groups (P = 0.54 and 0.46), whereas the occurrence of PTLD trended higher in the standard-dose group (0% vs. 2.6%, P = 0.07). CONCLUSION A low rATG induction dose ≤ 4.5 mg/kg provided safe and effective outcomes in this multicenter low immunologic risk pediatric cohort. Prospective studies are warranted to define the optimal rATG induction dose in pediatric kidney transplantation.
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Affiliation(s)
- Isa F. Ashoor
- Division of Nephrology, Department of Pediatrics, LSU Health New Orleans, New Orleans, Louisiana, USA
| | - Robbie A. Beyl
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Charu Gupta
- Children’s National Hospital, Washington, DC, USA
| | - Amrish Jain
- Department of Pediatrics, Wayne State University, Detroit, Michigan, USA
| | | | - Asha Moudgil
- Children’s National Hospital, Washington, DC, USA
| | | | - Joseph Sherbotie
- Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | | | - Rima S. Zahr
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Vikas R. Dharnidharka
- Division of Pediatric Nephrology, Hypertension and Pheresis, Washington University and St. Louis Children’s Hospital, St. Louis, Missouri, USA
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De Novo Carcinoma after Solid Organ Transplantation to Give Insight into Carcinogenesis in General-A Systematic Review and Meta-Analysis. Cancers (Basel) 2021; 13:cancers13051122. [PMID: 33807849 PMCID: PMC7961956 DOI: 10.3390/cancers13051122] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 02/20/2021] [Accepted: 03/02/2021] [Indexed: 11/21/2022] Open
Abstract
Simple Summary Patients receiving a solid organ transplantation, such as a kidney, liver, or lung transplantation, inevitably have to take drugs to suppress the immune system in order to prevent rejection of the transplanted organ. However, these drugs are known to cause malignancies in the long term. This study focuses specifically on newly developed carcinomas in patients who use those drugs after a solid organ transplantation. This systematic review and meta-analysis of published data show a 20-fold risk to develop a carcinoma after solid organ transplantation compared to the general population, with specifically increased risks in patients who receive cyclosporine or azathioprine. By comparing the different pathways involved in immunosuppression and the occurrence of carcinoma development, new insights can be discovered for future research and understanding of carcinoma development in transplantation patients and the general population as well. Abstract Immunosuppressive therapy after solid organ transplantation leads to the development of cancer in many recipients. Analysis of the occurrence of different types of de novo carcinomas in relation to specific immunosuppressive drugs may give insight into their carcinogenic process and carcinogenesis in general. Therefore, a systematic search was performed in Embase and PubMed. Studies describing over five de novo carcinomas in patients using immunosuppressive drugs after solid organ transplantation were included. Incidence per 1000 person-years was calculated with DerSimonian–Laird random effects model and odds ratio for developing carcinomas with the Mantel–Haenszel test. Following review of 5606 papers by title and abstract, a meta-analysis was conducted of 82 studies. The incidence rate of de novo carcinomas was 8.41. Patients receiving cyclosporine developed more de novo carcinomas compared to tacrolimus (OR1.56, 95%CI 1.00–2.44) and mycophenolate (OR1.26, 95%CI 1.03–1.56). Patients receiving azathioprine had higher odds to develop de novo carcinomas compared to mycophenolate (OR3.34, 95%CI 1.29–8.65) and head and neck carcinoma compared to tacrolimus (OR3.78, 95%CI 1.11–12.83). To conclude, patients receiving immunosuppressive drugs after solid organ transplantation have almost a 20-fold increased likelihood of developing carcinomas, with the highest likelihood for patients receiving cyclosporine A and azathioprine. Looking into altered immune pathways affected by immunosuppressive drugs might lead to better understanding of carcinogenesis in general.
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Jarmi T, Khouzam S, Shekhar N, Hosni M, White L, Hodge DO, Mai ML, Wadei HM. The Impact of Different Induction Immunosuppressive Therapy on Long-Term Kidney Transplant Function When Measured by Iothalamate Clearance. J Clin Med Res 2021; 12:787-793. [PMID: 33447312 PMCID: PMC7781286 DOI: 10.14740/jocmr4369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 11/11/2020] [Indexed: 01/06/2023] Open
Abstract
Background Improvement in short-term outcomes after kidney transplant has been achieved by using different induction and maintenance therapeutic approaches. Long-term outcomes have not matched the expectations of the transplant stakeholders. Our study aimed to address the early impact of induction agents on long-term outcome of kidney transplant when measured by iothalamate clearance. Methods All adult kidney transplant recipients between January of 2012 and December of 2016 were reviewed. Six hundred forty-nine patients were divided into three groups based on the induction agent (basiliximab, alemtuzumab, and thymoglobulin). Protocoled 4 months and 48 months kidney allograft function evaluations with iothalamate clearance test were compared among the three groups. Results Patients who received basiliximab were significantly older with no difference among African American and Caucasians. The 48 months assessment showed significant decline in median iothalamate clearance in basiliximab group at 49 mL/min vs. alemtuzumab group 64.8 mL/min and thymoglobulin 60 mL/min with P = 0.007. The basiliximab group developed a significant higher proteinuria measured by spot urine to creatinine ratio at 48 months. Conclusions The use of basiliximab as an induction agent for kidney transplant is associated with significant decline in kidney function 4 years post transplantation when measured by iothalamate clearance.
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Affiliation(s)
- Tambi Jarmi
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Samir Khouzam
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Nitika Shekhar
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Meray Hosni
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Launia White
- Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - David O Hodge
- Department of Health Sciences Research, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Martin L Mai
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
| | - Hani M Wadei
- Department of Transplant, Mayo Clinic Florida, Jacksonville, FL 32224, USA
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Good-Weber M, Roos M, Mueller TF, Rüsi B, Fehr T. Tailored immunosuppression after kidney transplantation - a single center real-life experience. BMC Nephrol 2020; 21:501. [PMID: 33228545 PMCID: PMC7686677 DOI: 10.1186/s12882-020-02137-5] [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: 03/04/2020] [Accepted: 10/29/2020] [Indexed: 11/30/2022] Open
Abstract
Background Kidney allograft survival continuously improved with introduction of novel immunosuppressants. However, also immunologically challenging transplants (blood group incompatibility and sensitized recipients) increase. Between 2006 and 2008, a new tailored immunosuppression scheme for kidney transplantation was implemented at the University Hospital in Zurich, together with an ABO-incompatible transplant program and systematic pre- and posttransplant anti-human leukocyte antigen (HLA) antibody screening by Luminex technology. This study retrospectively evaluated the results of this tailored immunosuppression approach with a particular focus on immunologically higher risk transplants. Methods A total of 204 consecutive kidney transplantations were analyzed, of whom 14 were ABO-incompatible and 35 recipients were donor-specific anti-HLA antibodies (DSA) positive, but complement-dependent cytotoxicity crossmatch (CDC-XM) negative. We analyzed patient and graft survival, acute rejection rates and infectious complications in ABO-compatible versus -incompatible and in DSA positive versus negative patients and compared those with a historical control group. Results Overall patient, death-censored allograft survival and non-death-censored allograft survival at 4 years were 92, 91 and 87%, respectively. We found that (1) there were no differences between ABO-compatible and -incompatible and between DSA positive and DSA negative patients concerning acute rejection rate and graft survival; (2) compared with the historical control group there was a significant decrease of acute rejection rates in sensitized patients who received an induction with thymoglobulin; (3) there was no increased rate of infection among the patients who received induction with thymoglobulin compared to no induction therapy. Conclusions We observed excellent overall mid-term patient and graft survival rates with our tailored immunosuppression approach. Induction with thymoglobulin was efficient and safe in keeping rejection rates low in DSA positive patients with a negative CDC-XM. Supplementary Information The online version contains supplementary material available at 10.1186/s12882-020-02137-5.
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Affiliation(s)
- Miriam Good-Weber
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Malgorzata Roos
- Department of Biostatistics, Epidemiology, Biostatistics and Prevention Institute, University Zurich, Zurich, Switzerland
| | - Thomas F Mueller
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland
| | - Barbara Rüsi
- HLA Typing Laboratory, University Hospital Zurich, Zurich, Switzerland
| | - Thomas Fehr
- Division of Nephrology, University Hospital Zurich, Zurich, Switzerland. .,Department of Internal Medicine, Cantonal Hospital Graubünden, Loestrasse 170, 7000, Chur, Switzerland.
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Boucquemont J, Foucher Y, Masset C, Legendre C, Scemla A, Buron F, Morelon E, Garrigue V, Pernin V, Albano L, Sicard A, Girerd S, Ladrière M, Giral M, Dantal J, for the DIVAT consortium. Induction therapy in kidney transplant recipients: Description of the practices according to the calendar period from the French multicentric DIVAT cohort. PLoS One 2020; 15:e0240929. [PMID: 33091057 PMCID: PMC7580969 DOI: 10.1371/journal.pone.0240929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 10/06/2020] [Indexed: 11/19/2022] Open
Abstract
Background There is extensive literature with comparisons between Anti-Thymocyte Globulin (ATG) and Basiliximab (BSX) as induction therapy in kidney transplant recipients. The purpose of our benchmarking study was to describe the consequences in terms of practices in 6 transplantation centers of a French prospective cohort. Methods We included adult patients who received a first or second kidney graft between 2013 and 2019 (n = 4157). We used logistic regressions to identify characteristics associated with the use of ATG or BSX. Results Use of ATG between the centers ranged from 41% to 75%. We observed different factors associated with the treatment decision. Compared to a first transplant, performing a second graft was the only factor significantly associated with the choice of ATG in all centers. The AUC ranged from 0.67 to 0.91, indicating that the centers seemed to define their own rules. As a result, for patients with the same low immunological risk, the probability of receiving ATG varied from 7% to 36%. We stratified the analyses according to two periods, from 2013 to 2015 and from 2016 to 2019. A similar heterogeneity was observed, and in some cases ATG indications between the centers were inverted. Conclusions The heterogeneity of induction therapy practices did not decrease in France, even if the reated literature is prolific. This illustrates the necessity to improve the literature by using meta-analyses of recent studies stratified by graft and patient profiles.
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Affiliation(s)
- Julie Boucquemont
- INSERM UMR 1246—SPHERE, Nantes University, Tours University, Nantes, France
- * E-mail: (JD); (JB)
| | - Yohann Foucher
- INSERM UMR 1246—SPHERE, Nantes University, Tours University, Nantes, France
- Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Christophe Masset
- Centre Hospitalier Universitaire de Nantes, Nantes, France
- CRTI UMR 1064, Inserm, Université de Nantes; ITUN, CHU Nantes; RTRS « Centaure », Nantes, France
| | - Christophe Legendre
- Kidney Transplant Center, Necker University Hospital, APHP, RTRS « Centaure », Paris Descartes and Sorbonne Paris Cité Universities, Paris, France
| | - Anne Scemla
- Kidney Transplant Center, Necker University Hospital, APHP, RTRS « Centaure », Paris Descartes and Sorbonne Paris Cité Universities, Paris, France
| | - Fanny Buron
- Nephrology, Transplantation and Clinical Immunology Department, RTRS « Centaure », Edouard Herriot University Hospital, Hospices Civils, Lyon, France
| | - Emmanuel Morelon
- Nephrology, Transplantation and Clinical Immunology Department, RTRS « Centaure », Edouard Herriot University Hospital, Hospices Civils, Lyon, France
| | - Valérie Garrigue
- Nephrology, Dialysis and Transplantation Department, Lapeyronie University Hospital, Montpellier, France
| | - Vincent Pernin
- Nephrology, Dialysis and Transplantation Department, Lapeyronie University Hospital, Montpellier, France
| | - Laetitia Albano
- Department of Nephrology and Renal Transplantation, Hospital Pasteur, Nice, France
| | - Antoine Sicard
- Department of Nephrology and Renal Transplantation, Hospital Pasteur, Nice, France
| | - Sophie Girerd
- Renal Transplantation Department, Brabois University Hospital, Nancy, France
| | - Marc Ladrière
- Renal Transplantation Department, Brabois University Hospital, Nancy, France
| | - Magali Giral
- Centre Hospitalier Universitaire de Nantes, Nantes, France
- CRTI UMR 1064, Inserm, Université de Nantes; ITUN, CHU Nantes; RTRS « Centaure », Nantes, France
- Centre d’Investigation Clinique en Biothérapie, Nantes, France
| | - Jacques Dantal
- Centre Hospitalier Universitaire de Nantes, Nantes, France
- CRTI UMR 1064, Inserm, Université de Nantes; ITUN, CHU Nantes; RTRS « Centaure », Nantes, France
- * E-mail: (JD); (JB)
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Reassessing Rabbit Antithymocyte Globulin Induction in Kidney Transplantation (RETHINK): An Analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry. Transplant Direct 2020; 6:e598. [PMID: 32903852 PMCID: PMC7447457 DOI: 10.1097/txd.0000000000001042] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 06/25/2020] [Indexed: 01/29/2023] Open
Abstract
Supplemental Digital Content is available in the text. Background. There is no consensus on rabbit antithymocyte globulin (rATG) dose used for induction immunosuppression in pediatric kidney transplants. We aimed to identify whether a lower rATG dose provides safe and effective immunosuppression compared with a higher dose. Methods. We retrospectively analyzed all first-time kidney transplant recipients (aged <21 y) in the North American Pediatric Renal Trials and Collaborative Studies registry since 1998 on mycophenolate mofetil– and tacrolimus-based immunosuppression with rATG induction. An a priori cutoff of 7.5 mg/kg cumulative rATG dose was used to identify low (<7.5 mg/kg) and high (≥7.5 mg/kg) exposure groups. Primary outcome was time to first-acute rejection episode. Secondary outcomes included graft function, patient survival, hospitalizations due to infections, and time to first-posttransplant lymphoproliferative disorder episode. Results. Four hundred fifty-five patients met inclusion criteria (59% male, 49% whites, 26% blacks, 38% living donor source). Median cumulative rATG dose was 6.8 mg/kg with a median of 5 doses and a median 1.5 mg/kg/dose introduced at a median of postoperative 0 days. Sixty-four percent received <7.5 mg/kg total rATG. There was no difference in age at transplant, gender, race, end-stage renal disease causes, or HLA mismatch among groups. Time to first-acute rejection was similar (P = 0.07). There was no significant difference in graft or patient survival or time to posttransplant lymphoproliferative disorder. Hospitalization for infection rates was similar. Conclusions. These data demonstrate a wide variation in cumulative rATG induction dose. A smaller rATG dose <7.5 mg/kg may provide effective and safe immunosuppression compared with a higher dose.
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Helanterä I, Ibrahim HN, Lempinen M, Finne P. Donor Age, Cold Ischemia Time, and Delayed Graft Function. Clin J Am Soc Nephrol 2020; 15:813-821. [PMID: 32404337 PMCID: PMC7274280 DOI: 10.2215/cjn.13711119] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/05/2020] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Increased donor age is one of the most important risk factors for delayed graft function (DGF), and previous studies suggest that the harmful effect of cold ischemia time is increased in kidneys from older donors. Our aim was to study the association of increased donor age and cold ischemia time with the risk of delayed graft function in a large cohort kidney transplants from the current era. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Scientific Registry of Transplant Recipients was used for this observational, retrospective registry analysis to identify all deceased donor kidney transplantations in the United States between 2010 and September 2018, who were on dialysis pretransplantation (n=90,810). The association of donor age and cold ischemia time with the risk of DGF was analyzed in multivariable models adjusted for recipient characteristics (age, race, sex, diabetes, calculated panel-reactive antibodies, pretransplant dialysis duration) and donor characteristics (cause of death, sex, race, body mass index, creatinine, donation after circulatory death status, history of hypertension, and HLA mismatch). RESULTS Cold ischemia time and donor age were independently associated with the risk of DGF, but the risk of DGF was not statistically significantly lower in donor age categories between 50 and 64 years, compared with donors ≥65 years. The harmful association of cold ischemia time was not higher in kidneys from older donors in any age category, not even among donation after circulatory death donors. When donor risk was assessed with kidney donor profile index, although a statistically significant interaction with cold ischemia time was found, no practically meaningful increase in cold-ischemia susceptibility of kidneys with a high kidney donor profile index was found. CONCLUSIONS We were unable to demonstrate an association between donor age and DGF. The association of longer cold ischemia time with the risk of DGF was not magnified in older or more marginal donors.
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Affiliation(s)
- Ilkka Helanterä
- Abdominal Center, Department of Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Hassan N Ibrahim
- Department of Medicine, Houston Methodist Hospital, Houston, Texas
| | - Marko Lempinen
- Abdominal Center, Department of Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Patrik Finne
- Abdominal Center, Department of Nephrology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Guthoff M, Berger K, Althaus K, Mühlbacher T, Bakchoul T, Steurer W, Nadalin S, Königsrainer A, Heyne N. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrol 2020; 21:178. [PMID: 32404066 PMCID: PMC7218828 DOI: 10.1186/s12882-020-01767-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 03/16/2020] [Indexed: 01/08/2023] Open
Abstract
Background Induction therapy is crucial in kidney transplantation and constitutes an important cornerstone for long-term allograft survival. Alemtuzumab is a depleting CD52-specific antibody with T- and B-cell activity, leading to prolonged lymphocyte depletion for up to 12 months, with profound immunosuppression and an associated risk of serious infections. Current concepts aim to optimize dosing strategies to reduce side effects. Here we present data from an ongoing centre protocol consisting of low-dose alemtuzumab induction and tailored immunosuppression in sensitized patients undergoing kidney transplantation. Methods 10-year results of the protocol were analysed. Low-dose alemtuzumab induction consisted of a single dose of 20 mg intraoperatively, followed by tacrolimus and corticosteroids for initial immunosuppression, with mycophenolate mofetil suspended until a total lymphocyte count (TLC) >5% or 200/μl was reached. Results Between 01/2007 and 04/2017, 46 patients were treated in accordance with the protocol in 48 kidney transplantations. Median PRAmax was 43 [22-76; IQR] %; all patients had negative CDC-crossmatch prior to transplantation. Low-dose alemtuzumab was well tolerated. Median time to TLC recovery was 77 [62-127; IQR] d. Within a median follow-up of 3.3 [1.5-5.6; IQR] years, 12 (25%) patients developed BPAR, 10 of which were antibody-mediated (3 acute, 7 chronic ABMR). Death-censored 5-year allograft survival was 79.2%, with an excellent allograft function at the end of follow-up. There was no increased rate of infections, in particular viral infections. Conclusions Our protocol, comprising low-dose alemtuzumab induction, initial suspension of mycophenolate mofetil and triple maintenance immunosuppression, provides excellent patient and allograft outcome in sensitized renal allograft recipients.
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Affiliation(s)
- Martina Guthoff
- Department of Diabetology, Endocrinology, Nephrology, Section of Nephrology and Hypertension, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 47, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Kilian Berger
- Department of Diabetology, Endocrinology, Nephrology, Section of Nephrology and Hypertension, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany
| | - Karina Althaus
- Center for Clinical Transfusion Medicine, Otfried-Müller-Str. 4/1, 72076, Tübingen, Germany
| | - Thomas Mühlbacher
- Department of Diabetology, Endocrinology, Nephrology, Section of Nephrology and Hypertension, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany.,Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 47, 72076, Tübingen, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Tamam Bakchoul
- Center for Clinical Transfusion Medicine, Otfried-Müller-Str. 4/1, 72076, Tübingen, Germany
| | - Wolfgang Steurer
- Department of General- and Visceral Surgery, Leonberg Hospital, Rutesheimer Str. 50, 71229, Leonberg, Germany
| | - Silvio Nadalin
- Department of General-, Visceral- and Transplant Surgery, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany
| | - Alfred Königsrainer
- Department of General-, Visceral- and Transplant Surgery, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany
| | - Nils Heyne
- Department of Diabetology, Endocrinology, Nephrology, Section of Nephrology and Hypertension, University of Tübingen, Otfried-Müller-Str. 10, 72076, Tübingen, Germany. .,Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at the University of Tübingen, Otfried-Müller-Str. 47, 72076, Tübingen, Germany. .,German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
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Santiago JL, Pérez-Flores I, Sánchez-Pérez L, Moreno de la Higuera MA, Calvo-Romero N, Querol-García J, Culebras E, Urcelay E, Fernández-Pérez C, Sánchez-Fructuoso AI. The Interferon-Gamma +874 A/T Polymorphism Is Not Associated With CMV Infection After Kidney Transplantation. Front Immunol 2020; 10:2994. [PMID: 31998298 PMCID: PMC6961530 DOI: 10.3389/fimmu.2019.02994] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 12/05/2019] [Indexed: 12/15/2022] Open
Abstract
The +874 A/T polymorphism in the interferon gamma (IFNG) gene has been associated with Cytomegalovirus (CMV) infection risk in lung and kidney transplant recipients. To replicate this association, we performed a retrospective observational study of this polymorphism and immunosuppressive therapies considering the prophylactic treatment in 600 consecutive kidney transplanted recipients. We found no association of the aforementioned polymorphism with CMV infection in univariate and multivariate analyses regardless of the prophylactic treatment. In addition, the immunosuppressive treatment with mammalian target of rapamycin inhibitors (imTOR) showed a protective effect in all patients independently of prophylaxis. Moreover, in the adjusted model, we found interactions between prophylaxis with high-risk (Donor+/Recipient-, D+/R-) status (p-interaction = 0.01), with thymoglobulin induction therapy (p-interaction = 0.03) and with thymoglobulin anti-rejection therapy (p-interaction = 0.002). Data also revealed that prophylaxis was not an advantage in the not D+/R- and without thymoglobulin therapy group (HR = 0.98, p = 0.95). The benefit of prophylaxis was observed in all groups with thymoglobulin therapy, but it was maximal in the high-risk CMV infection group with both thymoglobulin induction therapy and thymoglobulin anti-rejection therapy (HR = 0.01, p < 0.001). In conclusion, the IFNG +874 polymorphism is not a predictive marker of CMV infection. The protective effect of imTOR is not improved with prophylaxis. Interestingly, the thymoglobulin therapy associated with prophylaxis is not a risk factor for CMV infection, and prophylaxis is not effective in recipients with no high-risk CMV status and without thymoglobulin therapy.
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Affiliation(s)
- Jose Luis Santiago
- Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Isabel Pérez-Flores
- Nephrology Department Hospital Clínico San Carlos, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Luis Sánchez-Pérez
- Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Maria Angeles Moreno de la Higuera
- Nephrology Department Hospital Clínico San Carlos, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Natividad Calvo-Romero
- Nephrology Department Hospital Clínico San Carlos, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Javier Querol-García
- Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Esther Culebras
- Microbiology Department Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Elena Urcelay
- Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Cristina Fernández-Pérez
- Clinical Research and Methodology Unit, Facultad de Medicina, Hospital Clínico San Carlos Universidad Complutense de Madrid, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
| | - Ana Isabel Sánchez-Fructuoso
- Nephrology Department Hospital Clínico San Carlos, Facultad de Medicina, Universidad Complutense de Madrid, Instituto de Investigación Sanitaria San Carlos (IdISSC), Madrid, Spain
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Bittermann T, Hubbard RA, Lewis JD, Goldberg DS. The use of induction therapy in liver transplantation is highly variable and is associated with posttransplant outcomes. Am J Transplant 2019; 19:3319-3327. [PMID: 31243887 PMCID: PMC6883120 DOI: 10.1111/ajt.15513] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/17/2019] [Accepted: 06/07/2019] [Indexed: 01/25/2023]
Abstract
The use of induction immunosuppression in liver transplantation (LT) remains controversial. This was a retrospective cohort study of adult, first-time liver-alone recipients (N = 69 349) at 114 US centers between 2005 and 2018 using data from the United Network for Organ Sharing. The comparative effectiveness of nondepleting and depleting induction (NDI and DI) was assessed. Overall, 27% of recipients received induction with 65.7% of the variance in the receipt of induction being attributed to transplant center alone. NDI and DI were associated with a lower risk of death/graft failure compared to no induction (adjusted hazard ratio 0.90 [95% confidence interval (CI): 0.86-0.95] and 0.91 [95% CI: 0.85-0.97], respectively; P < .001). In nondialysis recipients at the mean transplant estimated glomerular filtration rate (eGFR), NDI was associated with an adjusted gain in eGFR by 6 months of +3.8 mL/min per 1.73 m2 and DI of +3.33 mL/min per 1.73 m2 compared to no induction (P < .001). Recipients with lower eGFR at LT had greater predicted improvement in eGFR (interaction P < .001). Only NDI was associated with a reduced risk of acute rejection in the first year post-LT (odds ratio 0.87, 95% CI: 0.8-0.94). Significant variability in induction practices exists, with center being a major determinant. The absolute incremental benefits of NDI and DI over no induction were small.
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Affiliation(s)
- Therese Bittermann
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Rebecca A. Hubbard
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - James D. Lewis
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - David S. Goldberg
- Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania,Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Irure J, Sango C, San Segundo D, Fernández-Fresnedo G, Ruiz JC, Benito-Hernández A, Asensio E, López-Hoyos M, Rodrigo E. Late Plasma Cell Depletion After Thymoglobulin Induction in Kidney Transplant Recipients. EXP CLIN TRANSPLANT 2019; 17:732-738. [DOI: 10.6002/ect.2018.0261] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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47
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Platt JL, Cascalho M. Non-canonical B cell functions in transplantation. Hum Immunol 2019; 80:363-377. [PMID: 30980861 PMCID: PMC6544480 DOI: 10.1016/j.humimm.2019.04.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 04/04/2019] [Accepted: 04/09/2019] [Indexed: 12/18/2022]
Abstract
B cells are differentiated to recognize antigen and respond by producing antibodies. These activities, governed by recognition of ancillary signals, defend the individual against microorganisms and the products of microorganisms and constitute the canonical function of B cells. Despite the unique differentiation (e.g. recombination and mutation of immunoglobulin gene segments) toward this canonical function, B cells can provide other, "non-canonical" functions, such as facilitating of lymphoid organogenesis and remodeling and fashioning T cell repertoires and modifying T cell responses. Some non-canonical functions are exerted by antibodies, but most are mediated by other products and/or direct actions of B cells. The diverse set of non-canonical functions makes the B cell as much as any cell a central organizer of innate and adaptive immunity. However, the diverse products and actions also confound efforts to weigh the importance of individual non-canonical B cell functions. Here we shall describe the non-canonical functions of B cells and offer our perspective on how those functions converge in the development and governance of immunity, particularly immunity to transplants, and hurdles to advancing understanding of B cell functions in transplantation.
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Affiliation(s)
- Jeffrey L Platt
- Departments of Surgery and of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States.
| | - Marilia Cascalho
- Departments of Surgery and of Microbiology & Immunology, University of Michigan, Ann Arbor, MI, United States
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48
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Agarwal G, Mannon RB. Post-Transplant Lymphoproliferative Disorder in a Kidney Transplant Recipient. Clin J Am Soc Nephrol 2019; 14:751-753. [PMID: 30803963 PMCID: PMC6500951 DOI: 10.2215/cjn.00180119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Gaurav Agarwal
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Roslyn B Mannon
- Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
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49
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Attias P, Melica G, Boutboul D, De Castro N, Audard V, Stehlé T, Gaube G, Fourati S, Botterel F, Fihman V, Audureau E, Grimbert P, Matignon M. Epidemiology, Risk Factors, and Outcomes of Opportunistic Infections after Kidney Allograft Transplantation in the Era of Modern Immunosuppression: A Monocentric Cohort Study. J Clin Med 2019; 8:jcm8050594. [PMID: 31052269 PMCID: PMC6572426 DOI: 10.3390/jcm8050594] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/16/2019] [Accepted: 04/22/2019] [Indexed: 12/21/2022] Open
Abstract
Epidemiology of opportunistic infections (OI) after kidney allograft transplantation in the modern era of immunosuppression and the use of OI prevention strategies are poorly described. We retrospectively analyzed a single-center cohort on kidney allograft adult recipients transplanted between January 2008 and December 2013. The control group included all kidney recipients transplanted in the same period, but with no OI. We analyzed 538 kidney transplantations (538 patients). The proportion of OI was 15% (80 and 72 patients). OI occurred 12.8 (6.0–31.2) months after transplantation. Viruses were the leading cause (n = 54, (10%)), followed by fungal (n = 15 (3%)), parasitic (n = 6 (1%)), and bacterial (n = 5 (0.9%)) infections. Independent risk factors for OI were extended criteria donor (2.53 (1.48–4.31), p = 0.0007) and BK viremia (6.38 (3.62–11.23), p < 0.0001). High blood lymphocyte count at the time of transplantation was an independent protective factor (0.60 (0.38–0.94), p = 0.026). OI was an independent risk factor for allograft loss (2.53 (1.29–4.95), p = 0.007) but not for patient survival. Post-kidney transplantation OIs were mostly viral and occurred beyond one year after transplantation. Pre-transplantation lymphopenia and extended criteria donor are independent risk factors for OI, unlike induction therapy, hence the need to adjust immunosuppressive regimens to such transplant candidates.
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Affiliation(s)
- Philippe Attias
- AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, 94010 Créteil, France.
| | - Giovanna Melica
- AP-HP (Assistance Publique-Hôpitaux de Paris), Infectious Disease Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, 94010 Créteil, France.
| | - David Boutboul
- AP-HP (Assistance Publique-Hôpitaux de Paris), Clinical Immunology Department, Hôpital Saint Louis, 75010 Paris, France.
- INSERM U967 HIPI, Université Paris Diderot, 75012 Paris, France.
| | - Nathalie De Castro
- AP-HP (Assistance Publique-Hôpitaux de Paris), Infectious Disease Department, Hôpital Saint Louis, 75010 Paris, France.
| | - Vincent Audard
- AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, 94010 Créteil, France.
- Université Paris-Est-Créteil, (UPEC), DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, 94010 Créteil, France.
| | - Thomas Stehlé
- AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, 94010 Créteil, France.
- Université Paris-Est-Créteil, (UPEC), DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, 94010 Créteil, France.
| | - Géraldine Gaube
- AP-HP (Assistance Publique-Hôpitaux de Paris), Infectious Disease Department, Groupe Hospitalier Henri-Mondor/Albert Chenevier, 94010 Créteil, France.
| | - Slim Fourati
- AP-HP (Assistance Publique-Hôpitaux de Paris, Clinical Microbiology Department, Virology, Bacteriology and Infection Control Units, 94010 Créteil, France.
- Université Paris-Est-Créteil (UPEC), DHU (département hospitalo-universitaire) VIC (virologie immunité cancer), IMRB (Institut Mondor de Recherche Biomédicale), INSERM U955, équipe 18, 94010 Créteil, France.
| | - Françoise Botterel
- AP-HP (Assistance Publique-Hôpitaux de Paris, Clinical Microbiology Department, Virology, Bacteriology and Infection Control Units, 94010 Créteil, France.
- Université Paris-Est-Créteil (UPEC), DHU (département hospitalo-universitaire) VIC (virologie immunité cancer), IMRB (Institut Mondor de Recherche Biomédicale), INSERM U955, équipe 18, 94010 Créteil, France.
- EA Dynamyc, Université Paris Est Créteil⁻ Ecole vétérinaire de Maison Alfort, F-94000 Créteil, France.
| | - Vincent Fihman
- AP-HP (Assistance Publique-Hôpitaux de Paris, Clinical Microbiology Department, Virology, Bacteriology and Infection Control Units, 94010 Créteil, France.
- Université Paris-Est-Créteil (UPEC), DHU (département hospitalo-universitaire) VIC (virologie immunité cancer), IMRB (Institut Mondor de Recherche Biomédicale), INSERM U955, équipe 18, 94010 Créteil, France.
- EA Dynamyc, Université Paris Est Créteil⁻ Ecole vétérinaire de Maison Alfort, F-94000 Créteil, France.
| | - Etienne Audureau
- Université Paris-Est-Créteil, UPEC, DHU (Département Hospitalo-Universitaire) A-TVB, IMRB (Institut Mondor de Recherche Biomédicale)- EA 7376 CEpiA (Clinical Epidemiology And Ageing Unit), 94010 Créteil, France.
| | - Philippe Grimbert
- AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, 94010 Créteil, France.
- Université Paris-Est-Créteil, (UPEC), DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, 94010 Créteil, France.
- AP-HP, CIC-BT 504, 94010 Créteil, France.
| | - Marie Matignon
- AP-HP (Assistance Publique-Hôpitaux de Paris), Nephrology and Renal Transplantation Department, Groupe Hospitalier Henri-Mondor/Albert-Chenevier, 94010 Créteil, France.
- Université Paris-Est-Créteil, (UPEC), DHU (Département Hospitalo-Universitaire) VIC (Virus-Immunité-Cancer), IMRB (Institut Mondor de Recherche Biomédicale), Equipe 21, INSERM U 955, 94010 Créteil, France.
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Sandal S, Bae S, McAdams-DeMarco M, Massie AB, Lentine KL, Cantarovich M, Segev DL. Induction immunosuppression agents as risk factors for incident cardiovascular events and mortality after kidney transplantation. Am J Transplant 2019; 19:1150-1159. [PMID: 30372596 PMCID: PMC6433494 DOI: 10.1111/ajt.15148] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 09/30/2018] [Accepted: 10/19/2018] [Indexed: 01/25/2023]
Abstract
Low T cell counts and acute rejection are associated with increased cardiovascular events (CVEs); T cell-depleting agents decrease both. Thus, we aimed to characterize the risk of CVEs by using an induction agent used in kidney transplant recipients. We conducted a secondary data analysis of patients who received a kidney transplant and used Medicare as their primary insurance from 1999 to 2010. Outcomes of interest were incident CVE, all-cause mortality, CVE-related mortality, and a composite outcome of mortality and CVE. Of 47 258 recipients, 29.3% received IL-2 receptor antagonist (IL-2RA), 33.3% received anti-thymocyte globulin (ATG), 7.3% received alemtuzumab, and 30.0% received no induction. Compared with IL-2RA, there was no difference in the risk of CVE in the ATG (adjusted hazard ratio [aHR] 0.98, 95% confidence interval [CI] 0.92-1.05) and alemtuzumab group (aHR 1.01, 95% CI 0.89-1.16), but slightly higher in the no induction group (aHR 1.06, 95% CI 1.00-1.14). Acute rejection did not modify this association in the latter group but did increase CVE by 46% in the alemtuzumab group. There was no difference in the hazard of all-cause or CVE-related mortality. Only in the ATG group, a 7% lower hazard of the composite outcome of mortality and CVE was noted. Induction agents are not associated with incident CVE, although prospective trials are needed to determine a personalized approach to prevention.
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Affiliation(s)
- Shaifali Sandal
- Department of Medicine, Divisions of Nephrology and Multi-Organ Transplant Program, McGill University Health Centre, Montreal, QC
| | - Sunjae Bae
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Mara McAdams-DeMarco
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Allan B. Massie
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Krista L. Lentine
- Center for Abdominal Transplantation, Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Marcelo Cantarovich
- Department of Medicine, Divisions of Nephrology and Multi-Organ Transplant Program, McGill University Health Centre, Montreal, QC
| | - Dorry L. Segev
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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