Pub Date : 2022-08-18DOI: 10.1101/2022.08.17.22278895
Mahil Rao, Meelad Amouzgar, James T. Harden, M. Gay Lapasaran, Amber Trickey, Brian Armstrong, Jonah Odim, Tracia Debnam, Carlos O. Esquivel, Sean C. Bendall, Olivia M. Martinez, Sheri M. Krams
Solid organ transplant remains a life-saving therapy for children with end-stage heart, lung, liver, or kidney disease; however, ∼25% of allograft recipients experience acute rejection within the first 12 months after transplant. Our ability to detect rejection early and to develop less toxic immunosuppressive agents is hampered by an incomplete understanding of the immune changes associated with rejection, particularly in the pediatric population. Here we used high-dimensional single-cell proteomic technologies (CyTOF) to generate the first detailed, multi-lineage analysis of the peripheral blood immune composition of pediatric solid organ transplant recipients. We report that the organ transplanted impacts the immune composition post-transplant. When taking these allograft-specific differences into account, we further observed that differences in the proportion of subsets of CD8 and CD4 T cells were significantly associated with allograft health. Together, these data form the basis for mechanistic studies into the pathobiology of rejection to develop less invasive tools to identify early rejection and new immunosuppressive agents with greater specificity and less toxicity.
{"title":"High-dimensional profiling of pediatric immune responses to solid organ transplantation","authors":"Mahil Rao, Meelad Amouzgar, James T. Harden, M. Gay Lapasaran, Amber Trickey, Brian Armstrong, Jonah Odim, Tracia Debnam, Carlos O. Esquivel, Sean C. Bendall, Olivia M. Martinez, Sheri M. Krams","doi":"10.1101/2022.08.17.22278895","DOIUrl":"https://doi.org/10.1101/2022.08.17.22278895","url":null,"abstract":"Solid organ transplant remains a life-saving therapy for children with end-stage heart, lung, liver, or kidney disease; however, ∼25% of allograft recipients experience acute rejection within the first 12 months after transplant. Our ability to detect rejection early and to develop less toxic immunosuppressive agents is hampered by an incomplete understanding of the immune changes associated with rejection, particularly in the pediatric population. Here we used high-dimensional single-cell proteomic technologies (CyTOF) to generate the first detailed, multi-lineage analysis of the peripheral blood immune composition of pediatric solid organ transplant recipients. We report that the organ transplanted impacts the immune composition post-transplant. When taking these allograft-specific differences into account, we further observed that differences in the proportion of subsets of CD8 and CD4 T cells were significantly associated with allograft health. Together, these data form the basis for mechanistic studies into the pathobiology of rejection to develop less invasive tools to identify early rejection and new immunosuppressive agents with greater specificity and less toxicity.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-07-10DOI: 10.1101/2022.07.07.22276374
Baptiste Lamarthée, Jasper Callemeyn, Yannick Van Herck, Asier Antoranz, Dany Anglicheau, Jan Ulrich Becker, Tim Debyser, Frederik De Smet, Katrien De Vusser, Maëva Eloudzeri, Amelie Franken, Wilfried Gwinner, Priyanka Koshy, Dirk Kuypers, Diether Lambrechts, Pierre Marquet, Marion Rabant, Ben Sprangers, Claire Tinel, Thomas Van Brussel, Amaryllis Van Craenenbroeck, Elisabet Van Loon, Thibaut Vaulet, Francesca Bosisio, Maarten Naesens
Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the interactions of the alloreactive inflammatory infiltrate. We performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies and generated cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxic activity is a central mechanism of NK cell mediated graft injury. Multiplexed immunohistochemistry using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results uncovered the central involvement of innate immune cells in the pathogenesis of allograft rejection and indicate several potential therapeutic targets to improve allograft longevity.
{"title":"Transcriptional and spatial profiling of the kidney allograft unravels a central role for FcyRIII+ innate immune cells in rejection","authors":"Baptiste Lamarthée, Jasper Callemeyn, Yannick Van Herck, Asier Antoranz, Dany Anglicheau, Jan Ulrich Becker, Tim Debyser, Frederik De Smet, Katrien De Vusser, Maëva Eloudzeri, Amelie Franken, Wilfried Gwinner, Priyanka Koshy, Dirk Kuypers, Diether Lambrechts, Pierre Marquet, Marion Rabant, Ben Sprangers, Claire Tinel, Thomas Van Brussel, Amaryllis Van Craenenbroeck, Elisabet Van Loon, Thibaut Vaulet, Francesca Bosisio, Maarten Naesens","doi":"10.1101/2022.07.07.22276374","DOIUrl":"https://doi.org/10.1101/2022.07.07.22276374","url":null,"abstract":"Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and the interactions of the alloreactive inflammatory infiltrate. We performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies and generated cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived <em>FCGR3A+</em> monocytes, <em>FCGR3A+</em> NK cells and the severity of intragraft inflammation. Activated <em>FCGR3A+</em> monocytes overexpressed <em>CD47</em> and <em>LILR</em> genes and increased paracrine signaling pathways promoting T cell infiltration. <em>FCGR3A+</em> NK cells overexpressed <em>FCRL3</em>, suggesting that antibody-dependent cytotoxic activity is a central mechanism of NK cell mediated graft injury. Multiplexed immunohistochemistry using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results uncovered the central involvement of innate immune cells in the pathogenesis of allograft rejection and indicate several potential therapeutic targets to improve allograft longevity.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"198 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544167","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-07-02DOI: 10.1101/2022.06.30.22277104
Saurabh Chhabra, Aniko Szabo, Annelie Clurman, Katelynn McShane, Nicholas Waters, Daniel Eastwood, Lisa Samanas, Teng Fei, Gabriel Armijo, Sameen Abedin, Walter Longo, Parameswaran Hari, Mehdi Hamadani, Nirav N. Shah, Lyndsey Runaas, James H. Jerkins, Marcel van den Brink, Jonathan U. Peled, William R. Drobyski
A common feature in the gastrointestinal (GI) tract during allogeneic hematopoietic stem cell transplantation is the loss of microbial diversity and emergence of opportunistic pathogens that can adversely impact survival. Consequently, preventing transplant-associated dysbiosis is an emerging strategy for optimizing treatment outcomes. In this study, we examined the effect of an extended tocilizumab administration schedule in addition to tacrolimus/methotrexate (Tac/MTX) as graft versus host disease (GVHD) prophylaxis on microbial composition in the GI tract along with overall transplant outcomes. Twenty-nine patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched related or unrelated peripheral blood stem cell grafts. The primary end point of the trial was GVHD-free relapse-free survival (GRFS) at 12 months. The cumulative incidences of grades 2-4 and 3-4 acute GVHD were 10.5% and 7% at day 180, respectively. There was one case of GVHD of the lower GI tract within the first 12 months. Non-relapse mortality and relapse-free survival were 3.4% and 86.2% at one year, respectively. GRFS was 38% at one year which was significantly higher than the pre-specified historical control rate of 20% (p=0.02) and therefore met the primary end point of the trial. Fecal samples from this patient population were sequenced and computationally analyzed centrally along with a demographically matched control cohort that received only Tac/MTX for GVHD prophylaxis. This comparative analysis revealed significantly less loss of α-diversity and reduced emergence of pathogenic organisms such as enterococcus in tocilizumab-treated recipients, demonstrating that loss of microbial diversity and enterococcal domination is attenuated in these patients. (Clinicaltrial.gov Identifier: NCT03699631).
{"title":"Mitigation of gastrointestinal graft versus host disease with tocilizumab prophylaxis is accompanied by preservation of microbial diversity and attenuation of enterococcal domination","authors":"Saurabh Chhabra, Aniko Szabo, Annelie Clurman, Katelynn McShane, Nicholas Waters, Daniel Eastwood, Lisa Samanas, Teng Fei, Gabriel Armijo, Sameen Abedin, Walter Longo, Parameswaran Hari, Mehdi Hamadani, Nirav N. Shah, Lyndsey Runaas, James H. Jerkins, Marcel van den Brink, Jonathan U. Peled, William R. Drobyski","doi":"10.1101/2022.06.30.22277104","DOIUrl":"https://doi.org/10.1101/2022.06.30.22277104","url":null,"abstract":"A common feature in the gastrointestinal (GI) tract during allogeneic hematopoietic stem cell transplantation is the loss of microbial diversity and emergence of opportunistic pathogens that can adversely impact survival. Consequently, preventing transplant-associated dysbiosis is an emerging strategy for optimizing treatment outcomes. In this study, we examined the effect of an extended tocilizumab administration schedule in addition to tacrolimus/methotrexate (Tac/MTX) as graft versus host disease (GVHD) prophylaxis on microbial composition in the GI tract along with overall transplant outcomes. Twenty-nine patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched related or unrelated peripheral blood stem cell grafts. The primary end point of the trial was GVHD-free relapse-free survival (GRFS) at 12 months. The cumulative incidences of grades 2-4 and 3-4 acute GVHD were 10.5% and 7% at day 180, respectively. There was one case of GVHD of the lower GI tract within the first 12 months. Non-relapse mortality and relapse-free survival were 3.4% and 86.2% at one year, respectively. GRFS was 38% at one year which was significantly higher than the pre-specified historical control rate of 20% (p=0.02) and therefore met the primary end point of the trial. Fecal samples from this patient population were sequenced and computationally analyzed centrally along with a demographically matched control cohort that received only Tac/MTX for GVHD prophylaxis. This comparative analysis revealed significantly less loss of α-diversity and reduced emergence of pathogenic organisms such as enterococcus in tocilizumab-treated recipients, demonstrating that loss of microbial diversity and enterococcal domination is attenuated in these patients. (Clinicaltrial.gov Identifier: NCT03699631).","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"290 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-26DOI: 10.1101/2022.06.24.22276144
Caitríona M. McEvoy, Queenie Hu, Kento T. Abe, Kevin Yau, Matthew J. Oliver, Adeera Levin, Anne-Claude Gingras, Michelle A. Hladunewich, Darren A. Yuen
Background Kidney transplant recipients (KTR) have a diminished response to SARS-CoV-2 vaccination in comparison to immunocompetent individuals. Deeper understanding of the antibody response in KTRs following third-dose vaccination would enable identification of those who remain unprotected against Omicron and require additional treatment strategies.
{"title":"Humoral Responses in the Omicron Era following Three-Dose SARS-CoV-2 Vaccine Series in Kidney Transplant Recipients","authors":"Caitríona M. McEvoy, Queenie Hu, Kento T. Abe, Kevin Yau, Matthew J. Oliver, Adeera Levin, Anne-Claude Gingras, Michelle A. Hladunewich, Darren A. Yuen","doi":"10.1101/2022.06.24.22276144","DOIUrl":"https://doi.org/10.1101/2022.06.24.22276144","url":null,"abstract":"<strong>Background</strong> Kidney transplant recipients (KTR) have a diminished response to SARS-CoV-2 vaccination in comparison to immunocompetent individuals. Deeper understanding of the antibody response in KTRs following third-dose vaccination would enable identification of those who remain unprotected against Omicron and require additional treatment strategies.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544113","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-06-02DOI: 10.1101/2022.06.02.22275894
Bilgin Osmanodja, Johannes Stegbauer, Marta Kantauskaite, Lars Christian Rump, Andreas Heinzel, Roman Reindl-Schwaighofer, Rainer Oberbauer, Ilies Benotmane, Sophie Caillard, Christophe Masset, Clarisse Kerleau, Gilles Blancho, Klemens Budde, Fritz Grunow, Michael Mikhailov, Eva Schrezenmeier, Simon Ronicke
Background Repeated vaccination against SARS-CoV-2 increases serological response in kidney transplant recipients (KTR) with high interindividual variability. No decision support tool exists to predict SARS-CoV-2 vaccination response in KTR. Methods We developed, internally and externally validated five different multivariable prediction models of serological response after the third and fourth vaccine dose against SARS-CoV-2 in KTR. Using 27 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), LASSO-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 585 vaccinations were used. External validation was performed in four independent, international validation datasets comprising 191, 184, 254, and 323 vaccinations, respectively. Findings LASSO-regularized LR performed on the whole development dataset yielded a 23- and 11-variable model, respectively. External validation showed AUC-ROC of 0.855, 0.749, 0.828, and 0.787 for the sparser 11-variable model, yielding an overall performance 0.819. Interpretation An 11-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions when choosing between different immunization strategies to improve protection against COVID-19 in KTR.
{"title":"Development and Validation of Multivariable Prediction Models of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Recipients","authors":"Bilgin Osmanodja, Johannes Stegbauer, Marta Kantauskaite, Lars Christian Rump, Andreas Heinzel, Roman Reindl-Schwaighofer, Rainer Oberbauer, Ilies Benotmane, Sophie Caillard, Christophe Masset, Clarisse Kerleau, Gilles Blancho, Klemens Budde, Fritz Grunow, Michael Mikhailov, Eva Schrezenmeier, Simon Ronicke","doi":"10.1101/2022.06.02.22275894","DOIUrl":"https://doi.org/10.1101/2022.06.02.22275894","url":null,"abstract":"Background\u0000Repeated vaccination against SARS-CoV-2 increases serological response in kidney transplant recipients (KTR) with high interindividual variability. No decision support tool exists to predict SARS-CoV-2 vaccination response in KTR. Methods\u0000We developed, internally and externally validated five different multivariable prediction models of serological response after the third and fourth vaccine dose against SARS-CoV-2 in KTR. Using 27 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), LASSO-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 585 vaccinations were used. External validation was performed in four independent, international validation datasets comprising 191, 184, 254, and 323 vaccinations, respectively. Findings\u0000LASSO-regularized LR performed on the whole development dataset yielded a 23- and 11-variable model, respectively. External validation showed AUC-ROC of 0.855, 0.749, 0.828, and 0.787 for the sparser 11-variable model, yielding an overall performance 0.819. Interpretation\u0000An 11-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions when choosing between different immunization strategies to improve protection against COVID-19 in KTR.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"107 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-17DOI: 10.1101/2022.05.17.22274980
Ayman Al Jurdi, Leela Morena, Mariesa Cote, Emily Bethea, Jamil Azzi, Leonardo V. Riella
The neutralizing monoclonal antibody combination of tixagevimab/cilgavimab has been shown to reduce the risk of SARS-CoV-2 infection in unvaccinated individuals during the Alpha (B.1.1.7) and Delta (B.1.617.2) waves. However, data on efficacy and safety of tixagevimab/cilgavimab in vaccinated solid organ transplant recipients during the Omicron wave is limited. To address this, we conducted a retrospective cohort study comparing 222 solid organ transplant recipients who received tixagevimab/cilgavimab for pre-exposure prophylaxis and 222 age-matched vaccinated solid organ transplant recipients who did not receive tixagevimab/cilgavimab. Subjects were followed for a mean of 67 ± 18 days. Kaplan-Meier estimates of the 60-day incidence of breakthrough infection were 1.8% in the tixagevimab/cilgavimab group and 4.7% in the control group (P = 0.045). Adverse events were uncommon, occurring in 4% of our cohort and most were mild. There was no significant change in serum creatinine or liver chemistries in kidney and liver transplant recipients respectively. In conclusion, we found that tixagevimab/cilgavimab use is safe and associated with a lower risk of breakthrough SARS-CoV-2 infection in vaccinated solid organ transplant recipients during the Omicron wave.
{"title":"Tixagevimab/cilgavimab pre-exposure prophylaxis is associated with lower breakthrough infection risk in vaccinated solid organ transplant recipients during the Omicron wave","authors":"Ayman Al Jurdi, Leela Morena, Mariesa Cote, Emily Bethea, Jamil Azzi, Leonardo V. Riella","doi":"10.1101/2022.05.17.22274980","DOIUrl":"https://doi.org/10.1101/2022.05.17.22274980","url":null,"abstract":"The neutralizing monoclonal antibody combination of tixagevimab/cilgavimab has been shown to reduce the risk of SARS-CoV-2 infection in unvaccinated individuals during the Alpha (B.1.1.7) and Delta (B.1.617.2) waves. However, data on efficacy and safety of tixagevimab/cilgavimab in vaccinated solid organ transplant recipients during the Omicron wave is limited. To address this, we conducted a retrospective cohort study comparing 222 solid organ transplant recipients who received tixagevimab/cilgavimab for pre-exposure prophylaxis and 222 age-matched vaccinated solid organ transplant recipients who did not receive tixagevimab/cilgavimab. Subjects were followed for a mean of 67 ± 18 days. Kaplan-Meier estimates of the 60-day incidence of breakthrough infection were 1.8% in the tixagevimab/cilgavimab group and 4.7% in the control group (<em>P</em> = 0.045). Adverse events were uncommon, occurring in 4% of our cohort and most were mild. There was no significant change in serum creatinine or liver chemistries in kidney and liver transplant recipients respectively. In conclusion, we found that tixagevimab/cilgavimab use is safe and associated with a lower risk of breakthrough SARS-CoV-2 infection in vaccinated solid organ transplant recipients during the Omicron wave.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-13DOI: 10.1101/2022.05.12.22275019
Roland Roller, Manuel Mayrdorfer, Wiebke Duettmann, Marcel G. Naik, Danilo Schmidt, Fabian Halleck, Patrik Hummel, Aljoscha Burchardt, Sebastian Möller, Peter Dabrock, Bilgin Osmanodja, Klemens Budde
Patient care after kidney transplantation requires integration of complex information to make informed decisions on risk constellations. Many machine learning models have been developed for detecting patient outcomes in the past years. However, performance metrics alone do not determine practical utility. Often, the actual performance of medical professionals on the given task is not known. We present a newly developed clinical decision support system (CDSS) for detection of patients at risk for rejection and death-censored graft failure. The CDSS is based on clinical routine data including 1516 kidney transplant recipients and more than 100 000 data points. Additionally, we conduct a reader study to compare the performance of the system to estimations of physicians at a nephrology department with and without the CDSS. Internal validation shows AUC-ROC scores of 0.83 for rejection, and 0.95 for graft failure. The reader study shows that although the predictions by physicians converge towards the suggestions made by the CDSS, performance in terms of AUC-ROC does not improve (0.6413 vs. 0.6314 for rejection; 0.8072 vs. 0.7778 for graft failure). Finally, the study shows that the CDSS detects partially different patients at risk compared to physicians without CDSS. This indicates that the combination of both, medical professionals and a CDSS might help detect more patients at risk for graft failure. However, the question of how to integrate such a system efficiently into clinical practice remains open.
肾移植后的患者护理需要整合复杂的信息，以便对风险星座做出明智的决定。在过去的几年里，已经开发了许多机器学习模型来检测患者的结果。然而，性能指标本身并不能决定实际效用。通常，医疗专业人员在给定任务中的实际表现是未知的。我们提出了一个新开发的临床决策支持系统(CDSS)，用于检测有排斥和死亡审查移植失败风险的患者。CDSS基于临床常规数据，包括1516名肾移植受者和超过10万个数据点。此外，我们进行了一项读者研究，将该系统的性能与有CDSS和没有CDSS的肾脏病科医生的评估进行比较。内部验证显示，排斥反应的AUC-ROC评分为0.83，移植失败的AUC-ROC评分为0.95。读者研究表明，尽管医生的预测趋近于CDSS的建议，但AUC-ROC的表现并没有改善(0.6413比0.6314拒绝;0.8072 vs 0.7778移植失败)。最后，研究表明，与没有CDSS的医生相比，CDSS检测到部分不同的风险患者。这表明，医学专业人员和CDSS的结合可能有助于发现更多有移植失败风险的患者。然而，如何将这样一个系统有效地融入临床实践的问题仍然是开放的。
{"title":"Evaluation of a clinical decision support system for detection of patients at risk after kidney transplantation","authors":"Roland Roller, Manuel Mayrdorfer, Wiebke Duettmann, Marcel G. Naik, Danilo Schmidt, Fabian Halleck, Patrik Hummel, Aljoscha Burchardt, Sebastian Möller, Peter Dabrock, Bilgin Osmanodja, Klemens Budde","doi":"10.1101/2022.05.12.22275019","DOIUrl":"https://doi.org/10.1101/2022.05.12.22275019","url":null,"abstract":"Patient care after kidney transplantation requires integration of complex information to make informed decisions on risk constellations. Many machine learning models have been developed for detecting patient outcomes in the past years. However, performance metrics alone do not determine practical utility. Often, the actual performance of medical professionals on the given task is not known. We present a newly developed clinical decision support system (CDSS) for detection of patients at risk for rejection and death-censored graft failure. The CDSS is based on clinical routine data including 1516 kidney transplant recipients and more than 100 000 data points. Additionally, we conduct a reader study to compare the performance of the system to estimations of physicians at a nephrology department with and without the CDSS. Internal validation shows AUC-ROC scores of 0.83 for rejection, and 0.95 for graft failure. The reader study shows that although the predictions by physicians converge towards the suggestions made by the CDSS, performance in terms of AUC-ROC does not improve (0.6413 vs. 0.6314 for rejection; 0.8072 vs. 0.7778 for graft failure). Finally, the study shows that the CDSS detects partially different patients at risk compared to physicians without CDSS. This indicates that the combination of both, medical professionals and a CDSS might help detect more patients at risk for graft failure. However, the question of how to integrate such a system efficiently into clinical practice remains open.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-01DOI: 10.1101/2022.04.29.22274396
Tina Thomson, Maria Prendecki, Sarah Gleeson, Paul Martin, Katrina J Spensley, Rute Cardoso De Aguiar, Bynvant Sandhu, Charlotte Seneschall, Jaslyn Gan, Candice L. Clarke, Shanice Lewis, Graham Pickard, David Thomas, Stephen P. McAdoo, Liz Lightstone, Alison Cox, Peter Kelleher, Michelle Willicombe
Background Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population.
{"title":"Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients","authors":"Tina Thomson, Maria Prendecki, Sarah Gleeson, Paul Martin, Katrina J Spensley, Rute Cardoso De Aguiar, Bynvant Sandhu, Charlotte Seneschall, Jaslyn Gan, Candice L. Clarke, Shanice Lewis, Graham Pickard, David Thomas, Stephen P. McAdoo, Liz Lightstone, Alison Cox, Peter Kelleher, Michelle Willicombe","doi":"10.1101/2022.04.29.22274396","DOIUrl":"https://doi.org/10.1101/2022.04.29.22274396","url":null,"abstract":"<strong>Background</strong> Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3<sup>rd</sup>- (V3) and 4<sup>th</sup>- (V4) doses of heterologous and homologous vaccines in a kidney transplant population.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-28DOI: 10.1101/2022.04.27.22274385
Lathan Liou, Elizabeth Mostofsky, Laura Lehman, Soziema Salia, Suruchi Gupta, Francisco J. Barrera, Murray A. Mittleman
Background Black heart transplant recipients have a higher mortality rate than white recipients 6-12 months after transplant. Whether there are racial disparities in post-transplant stroke incidence and all-cause mortality following post-transplant stroke among cardiac transplant recipients is unknown.
{"title":"Racial Disparities in Post-Transplant Stroke and Mortality Following Stroke in Adult Cardiac Transplant Recipients in the United States","authors":"Lathan Liou, Elizabeth Mostofsky, Laura Lehman, Soziema Salia, Suruchi Gupta, Francisco J. Barrera, Murray A. Mittleman","doi":"10.1101/2022.04.27.22274385","DOIUrl":"https://doi.org/10.1101/2022.04.27.22274385","url":null,"abstract":"<strong>Background</strong> Black heart transplant recipients have a higher mortality rate than white recipients 6-12 months after transplant. Whether there are racial disparities in post-transplant stroke incidence and all-cause mortality following post-transplant stroke among cardiac transplant recipients is unknown.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"83 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-13DOI: 10.1101/2022.04.07.22273527
Ivana Sedej, Maja Štalekar, Magda Tušek Žnidarič, Katja Goričar, Nika Kojc, Polona Kogovšek, Vita Dolžan, Miha Arnol, Metka Lenassi
Extracellular vesicle-bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer-unrelated fundamental and biomarker research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well-characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. Using DNase treatment and immunogold labelling TEM, we show that DNA is bound to the surface of urinary EVs. Although the urinary evDNA and cell-free DNA correlated in several characteristics, the DNA integrity index showed evDNA was less fragmented (P < 0.001). Urinary EVs from patients with rejection and non-rejection allograft injury were significantly larger (mean: P = 0.045, median: P = 0.031) and have bound more DNA as measured by normalized evDNA yield (P = 0.018) and evDNA copy number (P = 0.007), compared to patients with normal histology. Urinary evDNA characteristics associated with the degree of interstitial inflammation, combined glomerulitis and peritubular capillaritis, and inflammation in areas of fibrosis (all P < 0.050). The normalized dd-evDNA copy numbers differed between the antibody- and T cell-mediated rejection (P = 0.036). Our study supports the importance of DNA as urine EV cargo, especially as potential non-invasive kidney allograft injury biomarker.
{"title":"Extracellular vesicle-bound DNA in urine is indicative of kidney allograft injury","authors":"Ivana Sedej, Maja Štalekar, Magda Tušek Žnidarič, Katja Goričar, Nika Kojc, Polona Kogovšek, Vita Dolžan, Miha Arnol, Metka Lenassi","doi":"10.1101/2022.04.07.22273527","DOIUrl":"https://doi.org/10.1101/2022.04.07.22273527","url":null,"abstract":"Extracellular vesicle-bound DNA (evDNA) is an understudied extracellular vesicle (EV) cargo, particularly in cancer-unrelated fundamental and biomarker research. Although evDNA has been detected in urine, little is known about its characteristics, localization, and biomarker potential for kidney pathologies. To address this, we enriched EVs from urine of well-characterized kidney transplant recipients undergoing allograft biopsy, characterized their evDNA and its association to allograft injury. Using DNase treatment and immunogold labelling TEM, we show that DNA is bound to the surface of urinary EVs. Although the urinary evDNA and cell-free DNA correlated in several characteristics, the DNA integrity index showed evDNA was less fragmented (<em>P</em> < 0.001). Urinary EVs from patients with rejection and non-rejection allograft injury were significantly larger (mean: <em>P</em> = 0.045, median: <em>P</em> = 0.031) and have bound more DNA as measured by normalized evDNA yield (<em>P</em> = 0.018) and evDNA copy number (<em>P</em> = 0.007), compared to patients with normal histology. Urinary evDNA characteristics associated with the degree of interstitial inflammation, combined glomerulitis and peritubular capillaritis, and inflammation in areas of fibrosis (all <em>P</em> < 0.050). The normalized dd-evDNA copy numbers differed between the antibody- and T cell-mediated rejection (<em>P</em> = 0.036). Our study supports the importance of DNA as urine EV cargo, especially as potential non-invasive kidney allograft injury biomarker.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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