Pub Date : 2024-09-16DOI: 10.1101/2024.09.16.24313494
Jason Dehn, Brent Logan, Bronwen E. Shaw, Steven Devine, Stefan O. Ciurea, Mary Horowitz, Naya He, Iskra Pusic, Samer A. Srour, Sally Arai, Mark Juckett, Joseph Uberti, LaQuisa Hill, Sumithira Vasu, William J. Hogan, Brandon Hayes-Lattin, Peter Westervelt, Asad Bashey, Nosha Farhadfar, Michael R. Grunwald, Eric Leifer, Heather Symons, Ayman Saad, Jenny Vogel, Connor Erickson, Kelly Buck, Stephanie J. Lee, Joseph Pidala
Importance: Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood. Objective: To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor. Design: This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months. Settings: National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers. Participants: Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkins and non-Hodgkins lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available. Intervention: Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (~25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective. Main Outcome: Cumulative incidence of transplantation by Search Prognosis arm Results: Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113). Conclusions: A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor. Trial Registration: NCT#03904134
{"title":"Access to Allogeneic Cell Transplantation Based on Donor Search Prognosis: An Interventional Trial","authors":"Jason Dehn, Brent Logan, Bronwen E. Shaw, Steven Devine, Stefan O. Ciurea, Mary Horowitz, Naya He, Iskra Pusic, Samer A. Srour, Sally Arai, Mark Juckett, Joseph Uberti, LaQuisa Hill, Sumithira Vasu, William J. Hogan, Brandon Hayes-Lattin, Peter Westervelt, Asad Bashey, Nosha Farhadfar, Michael R. Grunwald, Eric Leifer, Heather Symons, Ayman Saad, Jenny Vogel, Connor Erickson, Kelly Buck, Stephanie J. Lee, Joseph Pidala","doi":"10.1101/2024.09.16.24313494","DOIUrl":"https://doi.org/10.1101/2024.09.16.24313494","url":null,"abstract":"Importance: Patients requiring allogeneic hematopoietic cell transplantation have variable likelihoods of identifying an 8/8 HLA-matched unrelated donor. A Search Prognosis calculator can estimate the likelihood. Objective: To determine if using a search algorithm based on donor search prognosis can result in similar incidence of transplant between patients Very Likely (>90%) vs Very Unlikely (<10%) to have a matched unrelated donor. Design: This interventional trial utilized a Search Prognosis-based biologic assignment algorithm to guide donor selection. Trial enrollment from June 13, 2019-May 13, 2022; analysis of data as of September 7, 2023 with median follow-up post-evaluability of 14.5 months.\u0000Settings: National multi-center Blood and Marrow Transplantation Clinical Trials Network 1702 study of US participating transplant centers.\u0000Participants: Acute myeloid and lymphoid leukemias, myelodysplastic syndrome, Hodgkins and non-Hodgkins lymphomas, severe aplastic anemia, and sickle cell disease patients referred to participating transplant centers were invited to participate. 2225 patients were enrolled and 1751 were declared evaluable for this study. Patients were declared evaluable once it was determined no suitable HLA-matched related donor was available.\u0000Intervention: Patients assigned to the Very Likely arm were to proceed with matched unrelated donor, while Very Unlikely were to utilize alternative donors. A third stratum, Less Likely (~25%) to find a matched unrelated donor, were observed under standard center practices, but were not part of the primary objective.\u0000Main Outcome: Cumulative incidence of transplantation by Search Prognosis arm Results: Evaluable patients included 1751 of which 413 (24%) were from racial/ethnic minorities. Search prognosis was 958 (55%) Very Likely, 517 (30%) Less Likely and 276 (16%) Very Unlikely. 1171 (67%) received HCT, 384 (22%) died without HCT, and 196 (11%) remained alive without HCT. Among the 1,234 patients, the adjusted cumulative incidence (95% CI) of HCT at 6-months was 59.8% (56.7-62.8) in the Very Likely group versus 52.3% (46.1-58.5) in the Very Unlikely (P=0.113).\u0000Conclusions: A prospective Search Prognosis-based algorithm can be effectively implemented in a national multicenter clinical trial. This approach resulted in rapid alternative donor identification and comparable rates of HCT in patients Very Likely and Very Unlikely to find a matched unrelated donor. Trial Registration: NCT#03904134","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268207","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 : 2024-09-15DOI: 10.1101/2024.09.13.24313304
Jerome Dumortier, sarah hamada, emma wischlen, celine mandier, noemie laverdure, olivier boillot, ilias kounis, Vincent Allain, Valerie Hervieux, sophie a Collardeau-Frachon, Valerie Dubois, Cyrille Feray
HLA evolutionary divergence (HED), a continuous metric quantifying the differences between each amino acid of two homologous HLA alleles, reflects the importance of the immunopeptidome presented to T lymphocytes. It has been associated with rejection after liver transplantation. This retrospective cohort study aimed to analyze the potential effect of donor or recipient HED on liver transplant rejection in a new series of patients transplanted during childhood and followed in adulthood. The study included 120 children who had been transplanted between 1991 and 2010 and were followed by routine biopsies and histological evaluations with a median of 14.1 years post-LT. Liver biopsies were performed routinely 1, 5, 10 and 20 years after transplantation and in the event of liver dysfunction. HED was calculated using the physicochemical Grantham distance for donor and recipient class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1) alleles. The influence of HED on rejection was analyzed by means of IPW and target trial emulation using g methods. Based on the IPW score, donor HED class I was correlated with the occurrence of late (>90 days) rejection (HR, 1.19, 95% CI: 1.01-1.40) independently of HLA mismatches, donor age and initial induction. This emulated target trial confirmed that donor HED class I has a causal effect on liver graft rejection and this relationship was observed long-term.
{"title":"Donor HLA class 1 evolutionary divergence and late allograft rejection after liver transplantation in children: an emulated target trial.","authors":"Jerome Dumortier, sarah hamada, emma wischlen, celine mandier, noemie laverdure, olivier boillot, ilias kounis, Vincent Allain, Valerie Hervieux, sophie a Collardeau-Frachon, Valerie Dubois, Cyrille Feray","doi":"10.1101/2024.09.13.24313304","DOIUrl":"https://doi.org/10.1101/2024.09.13.24313304","url":null,"abstract":"HLA evolutionary divergence (HED), a continuous metric quantifying the differences between each amino acid of two homologous HLA alleles, reflects the importance of the immunopeptidome presented to T lymphocytes. It has been associated with rejection after liver transplantation. This retrospective cohort study aimed to analyze the potential effect of donor or recipient HED on liver transplant rejection in a new series of patients transplanted during childhood and followed in adulthood. The study included 120 children who had been transplanted between 1991 and 2010 and were followed by routine biopsies and histological evaluations with a median of 14.1 years post-LT. Liver biopsies were performed routinely 1, 5, 10 and 20 years after transplantation and in the event of liver dysfunction. HED was calculated using the physicochemical Grantham distance for donor and recipient class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1) alleles. The influence of HED on rejection was analyzed by means of IPW and target trial emulation using g methods. Based on the IPW score, donor HED class I was correlated with the occurrence of late (>90 days) rejection (HR, 1.19, 95% CI: 1.01-1.40) independently of HLA mismatches, donor age and initial induction. This emulated target trial confirmed that donor HED class I has a causal effect on liver graft rejection and this relationship was observed long-term.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268262","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 : 2024-09-12DOI: 10.1101/2024.09.11.24313488
Ruoting Li, Sait Tunc, Osman Ozaltin, Matthew J Ellis
Background. Despite the increasing disparity between the number of patients awaiting kidney transplants and the availability of deceased donor kidneys, a significant number of donated kidneys go unused. Early identification of organs at high risk of nonuse can facilitate effective allocation interventions, ensuring these organs are offered to patients who could potentially benefit from them. While several machine learning models have been developed to predict nonuse risk, the complexity of these models compromises their practical implementation. Methods. We propose implementable nonuse risk prediction models that consist of a minimal set of variables, including the Kidney Donor Risk Index (KDRI), along with factors selected by machine learning models or transplantation experts. Our approach takes into account the influence of Organ Procurement Organization (OPO) behavior on kidney disposition. Results. The proposed models demonstrate competitive performance compared to more complex models that involve a large number of variables. Importantly, they maintain simplicity and interpretability. Conclusions. Our results provide accurate risk predictions, offer valuable insights into key factors contributing to kidney nonuse, and underscore significant variations among OPOs in the allocation of hard-to-place kidneys. These findings can inform the design of effective organ allocation interventions, increasing the likelihood of transplantation for hard-to-place kidneys.
{"title":"Improving Deceased Donor Kidney Utilization: Predicting Risk of Nonuse with Interpretable Models","authors":"Ruoting Li, Sait Tunc, Osman Ozaltin, Matthew J Ellis","doi":"10.1101/2024.09.11.24313488","DOIUrl":"https://doi.org/10.1101/2024.09.11.24313488","url":null,"abstract":"Background. Despite the increasing disparity between the number of patients awaiting kidney transplants and the availability of deceased donor kidneys, a significant number of donated kidneys go unused. Early identification of organs at high risk of nonuse can facilitate effective allocation interventions, ensuring these organs are offered to patients who could potentially benefit from them. While several machine learning models have been developed to predict nonuse risk, the complexity of these models compromises their practical implementation. Methods. We propose implementable nonuse risk prediction models that consist of a minimal set of variables, including the Kidney Donor Risk Index (KDRI), along with factors selected by machine learning models or transplantation experts. Our approach takes into account the influence of Organ Procurement Organization (OPO) behavior on kidney disposition. Results. The proposed models demonstrate competitive performance compared to more complex models that involve a large number of variables. Importantly, they maintain simplicity and interpretability. Conclusions. Our results provide accurate risk predictions, offer valuable insights into key factors contributing to kidney nonuse, and underscore significant variations among OPOs in the allocation of hard-to-place kidneys. These findings can inform the design of effective organ allocation interventions, increasing the likelihood of transplantation for hard-to-place kidneys.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142177245","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 : 2024-08-06DOI: 10.1101/2024.08.05.24311510
Leslie L Seijo, Ying Gao, Legna Betancourt, Aida Venado, Steven R Hays, Jasleen Kukreja, Daniel Calabrese, John R Greenland, Jonathan P Singer
Lung transplantation aims to improve health–related quality of life (HRQL) and survival. While lung function improvements are associated with these outcomes, the association between physical functioning and these outcomes is less clear. We investigated the association between changes in patient-reported physical functioning and HRQL, chronic lung allograft dysfunction (CLAD), and survival after lung transplantation. This single–center prospective cohort study analyzed 220 lung transplant recipients who completed the 15–item Lung Transplant Valued Life Activities (LT–VLA) before and repeatedly after transplant. HRQL was assessed using generic, respiratory disease–specific, and utility measures. Associations between 0.3–point changes (the minimally important difference) in LT–VLA as a time–varying predictor on HRQL, CLAD, and mortality were tested using linear regression and Cox proportional hazard models. Models were adjusted for demographics, disease diagnosis, and post–operative lung function as a time–varying covariate. Participants were 45% female and 75% White, with a mean age of 56 (±12) years. Each 0.3–point improvement in LT–VLA was associated with substantially improved HRQL across all measures (adjusted p–values <0.01). Each 0.3–point improvement in LT–VLA was associated with a 13% reduced hazard of CLAD (adjusted HR: 0.87, 95% CI: 0.76–0.99, p=0.03) and a 19% reduced hazard of mortality (adjusted HR: 0.81, 95% CI: 0.67–0.95, p=0.01). Improvements in patient–reported physical functioning after lung transplantation are associated with improved HRQL and reduced risk of CLAD and death, independent of allograft function. The simplicity of the LT–VLA suggests it could be a valuable monitoring or outcome measure in both clinical and research settings.
{"title":"Improvements in Patient-Reported Functioning after Lung Transplant is Associated with Improved Quality of Life and Survival","authors":"Leslie L Seijo, Ying Gao, Legna Betancourt, Aida Venado, Steven R Hays, Jasleen Kukreja, Daniel Calabrese, John R Greenland, Jonathan P Singer","doi":"10.1101/2024.08.05.24311510","DOIUrl":"https://doi.org/10.1101/2024.08.05.24311510","url":null,"abstract":"Lung transplantation aims to improve health–related quality of life (HRQL) and survival. While lung function improvements are associated with these outcomes, the association between physical functioning and these outcomes is less clear. We investigated the association between changes in patient-reported physical functioning and HRQL, chronic lung allograft dysfunction (CLAD), and survival after lung transplantation. This single–center prospective cohort study analyzed 220 lung transplant recipients who completed the 15–item Lung Transplant Valued Life Activities (LT–VLA) before and repeatedly after transplant. HRQL was assessed using generic, respiratory disease–specific, and utility measures. Associations between 0.3–point changes (the minimally important difference) in LT–VLA as a time–varying predictor on HRQL, CLAD, and mortality were tested using linear regression and Cox proportional hazard models. Models were adjusted for demographics, disease diagnosis, and post–operative lung function as a time–varying covariate. Participants were 45% female and 75% White, with a mean age of 56 (±12) years. Each 0.3–point improvement in LT–VLA was associated with substantially improved HRQL across all measures (adjusted p–values <0.01). Each 0.3–point improvement in LT–VLA was associated with a 13% reduced hazard of CLAD (adjusted HR: 0.87, 95% CI: 0.76–0.99, p=0.03) and a 19% reduced hazard of mortality (adjusted HR: 0.81, 95% CI: 0.67–0.95, p=0.01). Improvements in patient–reported physical functioning after lung transplantation are associated with improved HRQL and reduced risk of CLAD and death, independent of allograft function. The simplicity of the LT–VLA suggests it could be a valuable monitoring or outcome measure in both clinical and research settings.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141941220","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 : 2024-07-09DOI: 10.1101/2024.07.08.24310086
Guillermo Costaguta, Andrea Romero, Alejandro Costaguta
Introduction: Organ transplantation is the sole effective treatment for several end-stage organ diseases. However, donor organ availability is critically insufficient. This shortage is driven by several factors, with access to accurate information being a key determinant of an individual's willingness to donate organs. Methods: A cross-sectional study based on anonymous surveys from January to December 2019, categorizing participants into healthcare professionals and non-healthcare individuals. Data included willingness to donate organs, reasons for refusal, age, education level, and understanding of brain death. Statistical significance was set at p<0.05. Results: 408 participants were included, 203 from the healthcare sector and 205 from the non-healthcare sector. Among healthcare professionals, 90% were willing to donate organs, compared to 43% in the non-healthcare group (p<0.001). Non-healthcare respondents refused due to fears of being alive during organ removal (74%), concerns about reduced emergency care (21%), and religious beliefs (5%). Despite these concerns, 88% acknowledged that organ donation saves lives, and 95% recognized the gap between organ supply and demand. No significant differences in education levels were found between donors and non-donors, but healthcare professionals had a significantly better understanding of brain death (p<0.001). All respondents indicated they would accept a donated organ if needed. Conclusion: Healthcare professionals are more inclined to be organ donors than those outside the field. Misunderstandings among non-healthcare individuals contribute to higher refusal rates. Tailored awareness campaigns and educational programs could rectify these misconceptions, potentially improving donation rates and mitigating the organ shortage crisis.
{"title":"Influence of Information Access on Organ Donation: A Questionnaire-Based Cross-Sectional Study","authors":"Guillermo Costaguta, Andrea Romero, Alejandro Costaguta","doi":"10.1101/2024.07.08.24310086","DOIUrl":"https://doi.org/10.1101/2024.07.08.24310086","url":null,"abstract":"Introduction: Organ transplantation is the sole effective treatment for several end-stage organ diseases. However, donor organ availability is critically insufficient. This shortage is driven by several factors, with access to accurate information being a key determinant of an individual's willingness to donate organs.\u0000Methods: A cross-sectional study based on anonymous surveys from January to December 2019, categorizing participants into healthcare professionals and non-healthcare individuals. Data included willingness to donate organs, reasons for refusal, age, education level, and understanding of brain death. Statistical significance was set at p<0.05.\u0000Results: 408 participants were included, 203 from the healthcare sector and 205 from the non-healthcare sector. Among healthcare professionals, 90% were willing to donate organs, compared to 43% in the non-healthcare group (p<0.001). Non-healthcare respondents refused due to fears of being alive during organ removal (74%), concerns about reduced emergency care (21%), and religious beliefs (5%). Despite these concerns, 88% acknowledged that organ donation saves lives, and 95% recognized the gap between organ supply and demand. No significant differences in education levels were found between donors and non-donors, but healthcare professionals had a significantly better understanding of brain death (p<0.001). All respondents indicated they would accept a donated organ if needed.\u0000Conclusion: Healthcare professionals are more inclined to be organ donors than those outside the field. Misunderstandings among non-healthcare individuals contribute to higher refusal rates. Tailored awareness campaigns and educational programs could rectify these misconceptions, potentially improving donation rates and mitigating the organ shortage crisis.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141567177","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 : 2024-06-28DOI: 10.1101/2024.06.27.24309579
Romy du Long, Marie S.N. Florquin, Frederike J. Bemelman, Nike Claessen, Hessel Peters-Sengers, Sandrine Florquin, Jesper Kers
Background Plasma cell rich rejection (PCRR) is an uncommon, ill-defined type of renal allograft rejection in the current literature considered a subtype of T cell-mediated rejection (TCMR). PCRR has poorer clinical outcome and is often refractory to classic immunosuppressive therapy. Our study analyzed clinical course, Banff lesion scores and mRNA expression of PCRR compared to (late) rejection. Methods We retrospectively scored and reclassified the last known biopsy of 263 renal transplant recipients, morphologically classified as rejection according to the 2019 Banff classification. mRNA expression analysis was performed using the Nanostring B-HOT panel on a subset of cases. PCRR was compared to (late) TCMR, ABMR and mixed rejection for renal function follow-up and graft survival. Results mRNA analysis revealed uniquely expressed genes in PCRR including LOX, CPA3, IL4, IL17F, and MMP12. PCRR is enriched for genes related to mast cells, memory B- and T-cells and transcripts involved in NK cells and allograft fibrosis with heterogeneity in gene expression in biopsies with PCRR. PCRR might be a late event compared to late TCMR and ABMR, with a higher degree of total inflammation and fibrosis. Graft survival and renal function was similar to late TCMR and ABMR during a 5-year follow-up period after renal biopsy. Conclusion PCRR represents a distinct late-onset stage of inflammation displaying diverse gene expression patterns, with presence of mainly mast cells, NK cells and transcripts involved in renal allograft fibrosis. Clinical outcomes in patients with PCRR appeared more similar to late TCMR and ABMR.
{"title":"CLINICOPATHOLOGICAL AND MOLECULAR CHARACTERISTICS OF PLASMA CELL RICH REJECTION IN RENAL TRANSPLANT BIOPSIES","authors":"Romy du Long, Marie S.N. Florquin, Frederike J. Bemelman, Nike Claessen, Hessel Peters-Sengers, Sandrine Florquin, Jesper Kers","doi":"10.1101/2024.06.27.24309579","DOIUrl":"https://doi.org/10.1101/2024.06.27.24309579","url":null,"abstract":"Background\u0000Plasma cell rich rejection (PCRR) is an uncommon, ill-defined type of renal allograft rejection in the current literature considered a subtype of T cell-mediated rejection (TCMR). PCRR has poorer clinical outcome and is often refractory to classic immunosuppressive therapy. Our study analyzed clinical course, Banff lesion scores and mRNA expression of PCRR compared to (late) rejection. Methods\u0000We retrospectively scored and reclassified the last known biopsy of 263 renal transplant recipients, morphologically classified as rejection according to the 2019 Banff classification. mRNA expression analysis was performed using the Nanostring B-HOT panel on a subset of cases. PCRR was compared to (late) TCMR, ABMR and mixed rejection for renal function follow-up and graft survival. Results\u0000mRNA analysis revealed uniquely expressed genes in PCRR including LOX, CPA3, IL4, IL17F, and MMP12. PCRR is enriched for genes related to mast cells, memory B- and T-cells and transcripts involved in NK cells and allograft fibrosis with heterogeneity in gene expression in biopsies with PCRR. PCRR might be a late event compared to late TCMR and ABMR, with a higher degree of total inflammation and fibrosis. Graft survival and renal function was similar to late TCMR and ABMR during a 5-year follow-up period after renal biopsy. Conclusion\u0000PCRR represents a distinct late-onset stage of inflammation displaying diverse gene expression patterns, with presence of mainly mast cells, NK cells and transcripts involved in renal allograft fibrosis. Clinical outcomes in patients with PCRR appeared more similar to late TCMR and ABMR.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141509168","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 : 2024-06-26DOI: 10.1101/2024.06.24.24309444
Andrea Fernandez Valledor, Cathrine Marie Moeller, Gal Rubinstein, Salwa Rahman, Daniel Oren, julia baranowska, Changhee Lee, Ruben Anthony Salazar, Carolyn Hennecken, Afsana Rahman, Boaz Elad, Dor Lotan, Ersilia Marie DeFilippis, Adil Yunis, Justin A Fried, Jayant Raikhelkar, Kyung T. Oh, David Bae, Edward Lin, Sun Hi Lee, Matthew Regan, Melana Yuzefpolskaya, Paolo C. Colombo, David Majure, Farhana Latif, Kevin J Clerkin, Gabriel T Sayer, Nir Uriel
Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx) of biopsy specimens in heart transplant (HT) recipients with suspected rejection. Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide inter-observer variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection. Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels. Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific anti-rejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017). Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of anti-rejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.
{"title":"Clinical Utility of the Molecular Microscope Diagnostic System in a Real-World Transplant Cohort: Moving Towards a New Paradigm","authors":"Andrea Fernandez Valledor, Cathrine Marie Moeller, Gal Rubinstein, Salwa Rahman, Daniel Oren, julia baranowska, Changhee Lee, Ruben Anthony Salazar, Carolyn Hennecken, Afsana Rahman, Boaz Elad, Dor Lotan, Ersilia Marie DeFilippis, Adil Yunis, Justin A Fried, Jayant Raikhelkar, Kyung T. Oh, David Bae, Edward Lin, Sun Hi Lee, Matthew Regan, Melana Yuzefpolskaya, Paolo C. Colombo, David Majure, Farhana Latif, Kevin J Clerkin, Gabriel T Sayer, Nir Uriel","doi":"10.1101/2024.06.24.24309444","DOIUrl":"https://doi.org/10.1101/2024.06.24.24309444","url":null,"abstract":"Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx) of biopsy specimens in heart transplant (HT) recipients with suspected rejection. Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide inter-observer variability combined with a relatively common incidence of \"biopsy-negative\" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection. Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels. Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific anti-rejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017). Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of anti-rejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141509169","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 : 2024-05-30DOI: 10.1101/2024.05.29.24308114
Krzysztof Batko, Anna Sączek, Małgorzata Banaszkiewicz, Jolanta Małyszko, Ewa Koc-Żórawska, Marcin Żórawski, Karolina Niezabitowska, Katarzyna Siek, Alina Bętkowska-Prokop, Marcin Krzanowski, Katarzyna Krzanowska
Introduction Limited tools exist for predicting kidney function in long-term kidney transplant recipients (KTRs). Elabela and apelin are APJ receptor agonists that constitute the apelinergic axis, which is a recently discovered system regulating vascular and cardiac tissue, in opposition to renin-angiotensin-aldosterone.
{"title":"Risk Prediction In Long Term Kidney Transplant Recipients – Model Development Using Apelinergic Markers And Machine Learning Tools","authors":"Krzysztof Batko, Anna Sączek, Małgorzata Banaszkiewicz, Jolanta Małyszko, Ewa Koc-Żórawska, Marcin Żórawski, Karolina Niezabitowska, Katarzyna Siek, Alina Bętkowska-Prokop, Marcin Krzanowski, Katarzyna Krzanowska","doi":"10.1101/2024.05.29.24308114","DOIUrl":"https://doi.org/10.1101/2024.05.29.24308114","url":null,"abstract":"<strong>Introduction</strong> Limited tools exist for predicting kidney function in long-term kidney transplant recipients (KTRs). Elabela and apelin are APJ receptor agonists that constitute the apelinergic axis, which is a recently discovered system regulating vascular and cardiac tissue, in opposition to renin-angiotensin-aldosterone.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"6 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141197203","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 : 2024-05-27DOI: 10.1101/2024.05.27.24307975
Maral Baghai Arassi, Manuel Feißt, Kai Krupka, Atif Awan, Elisa Benetti, Ali Duzova, Isabella Guzzo, Jon Jin Kim, Sabine König, Mieczysław Litwin, Jun Oh, Anja Bücher, Lars Pape, Licia Peruzzi, Mohan Shenoy, Sara Testa, Lutz T. Weber, Jakub Zieg, Britta Höcker, Alexander Fichtner, Burkhard Tönshoff, the Cooperative European Pediatric Renal Transplant Initiative Research Network
Background Data on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a uniform tacrolimus-based immunosuppressive regimen are scarce.
{"title":"Age-related differences in rejection rates, infections and tacrolimus exposure in pediatric kidney transplant recipients – a benchmark study of the CERTAIN registry","authors":"Maral Baghai Arassi, Manuel Feißt, Kai Krupka, Atif Awan, Elisa Benetti, Ali Duzova, Isabella Guzzo, Jon Jin Kim, Sabine König, Mieczysław Litwin, Jun Oh, Anja Bücher, Lars Pape, Licia Peruzzi, Mohan Shenoy, Sara Testa, Lutz T. Weber, Jakub Zieg, Britta Höcker, Alexander Fichtner, Burkhard Tönshoff, the Cooperative European Pediatric Renal Transplant Initiative Research Network","doi":"10.1101/2024.05.27.24307975","DOIUrl":"https://doi.org/10.1101/2024.05.27.24307975","url":null,"abstract":"<strong>Background</strong> Data on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a uniform tacrolimus-based immunosuppressive regimen are scarce.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141197108","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 : 2024-03-28DOI: 10.1101/2024.03.27.24304863
Caryn Libbert, Fiona He, Najla El Jurdi, Helen Fagrelius, Mark Juckett, Joseph Maakaron, William Juckett, Nicholas Evanoff, Donald Dengel, Shernan G Holtan
Allogeneic hematopoietic cell transplantation (alloHCT) is a vital therapy for various hematologic diseases, though it demands high physiological resilience. Frailty, a syndrome impacting the body's ability to withstand stress, affects outcomes of alloHCT across all ages. This study examines the relationship between frailty and peri-transplant activity and sleep patterns using Fitbit devices. In this pilot study, adults scheduled for their first myeloablative alloHCT at the University of Minnesota from June 2022 to January 2023 were included if they had a compatible device for the Fitbit app. Participants were monitored for activity and sleep from admission to day +30 post-transplant. Frailty was assessed pre-transplant using Fried Phenotype criteria. Data were analyzed for activity and sleep patterns differences among not frail, pre-frail, and frail groups. Nine patients provided sufficient data for analysis, showing significant variances in activity levels and sleep patterns across frailty categories. Not frail patients exhibited significantly higher daily steps and active minutes than pre-frail and frail patients. Not frail patients also had the highest amount of restorative deep and rapid eye movement sleep. Due to Fitbit methodology and likely frequent interruptions, 28% of the days in the first month post-transplant had a recorded sleep time of 0 minutes. Although our sample size was small, our findings underscore the importance of frailty in influencing activity and sleep patterns among alloHCT recipients.
{"title":"Frailty is associated with low physical activity and poor sleep quality in patients undergoing myeloablative allogeneic hematopoietic cell transplantation: A Fitbit Pilot Study","authors":"Caryn Libbert, Fiona He, Najla El Jurdi, Helen Fagrelius, Mark Juckett, Joseph Maakaron, William Juckett, Nicholas Evanoff, Donald Dengel, Shernan G Holtan","doi":"10.1101/2024.03.27.24304863","DOIUrl":"https://doi.org/10.1101/2024.03.27.24304863","url":null,"abstract":"Allogeneic hematopoietic cell transplantation (alloHCT) is a vital therapy for various hematologic diseases, though it demands high physiological resilience. Frailty, a syndrome impacting the body's ability to withstand stress, affects outcomes of alloHCT across all ages. This study examines the relationship between frailty and peri-transplant activity and sleep patterns using Fitbit devices. In this pilot study, adults scheduled for their first myeloablative alloHCT at the University of Minnesota from June 2022 to January 2023 were included if they had a compatible device for the Fitbit app. Participants were monitored for activity and sleep from admission to day +30 post-transplant. Frailty was assessed pre-transplant using Fried Phenotype criteria. Data were analyzed for activity and sleep patterns differences among not frail, pre-frail, and frail groups. Nine patients provided sufficient data for analysis, showing significant variances in activity levels and sleep patterns across frailty categories. Not frail patients exhibited significantly higher daily steps and active minutes than pre-frail and frail patients. Not frail patients also had the highest amount of restorative deep and rapid eye movement sleep. Due to Fitbit methodology and likely frequent interruptions, 28% of the days in the first month post-transplant had a recorded sleep time of 0 minutes. Although our sample size was small, our findings underscore the importance of frailty in influencing activity and sleep patterns among alloHCT recipients.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140313515","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：