Pub Date : 2024-03-16DOI: 10.1101/2024.03.14.24304302
Wongi Woo, Hye Sung Kim, Ankit Bharat, Young Kwang Chae
Background: Given the increasing need for lung transplants among older patients with a history of cancer, this study analyzed database registry to assess outcomes for DLT recipients with Pre-TM. Methods: This study evaluated the United Network for Organ Sharing (UNOS) registry for adult DLT performed between 2005 and 2023. Patients with a history of previous or multi-organ transplants, and those with donors who had cancer history, were excluded. Propensity-score matching was used to compare patients with or without Pre-TM. Overall and Post-TM-free survival were analyzed. Results: Among the 23,291 recipients of DLT, 8.0%(1,870) had Pre-TM. Compared to those without Pre-TM, patients with Pre-TM had worse overall (hazard ratio[HR] 1.20, 95% confidence interval[CI] 1.12-1.29, p<0.001) and Post-TM-free survival (HR 1.32, 95% CI 1.24-1.41, p<0.001). However, after adjusting for age, sex, and race through propensity-score matching, the survival difference between the groups became non-significant (HR 1.05, 95% CI 0.97-1.13, p=0.229). While the Pre-TM group still had worse Post-TM-free survival, this difference diminished after excluding cutaneous Post-TM (HR 1.06, 95% CI 0.99-1.15, p=0.116). Additionally, the recurrence rate of Pre-TM after transplant wasn't higher than de novo cancers in patients without Pre-TM. Conclusion: Patients with Pre-TM had similar overall survival rates after DLT as those without Pre-TM. Importantly, there is no increased risk of the primary Pre-TM type recurring post-transplant compared to patients without Pre-TM. These findings highlight the necessity for a more nuanced evaluation of transplant candidacy to prevent premature exclusion of Pre-TM patients from life-saving surgeries.
背景：鉴于有癌症病史的老年患者对肺移植的需求不断增加，本研究对数据库登记进行了分析，以评估肺移植术前DLT受者的预后：鉴于有癌症病史的老年患者对肺移植的需求日益增加，本研究分析了数据库登记情况，以评估肺癌前病变 DLT 受者的预后：本研究评估了器官共享联合网络（UNOS）登记的 2005 年至 2023 年间进行的成人 DLT。有既往器官移植史或多器官移植史的患者以及捐赠者有癌症史的患者被排除在外。采用倾向分数匹配法对有无预TM的患者进行比较。对总生存率和无TM后生存率进行了分析：在23291名DLT受者中，8.0%（1870人）有Pre-TM。与没有前骨髓增生症的患者相比，前骨髓增生症患者的总生存期（危险比[HR] 1.20，95% 置信区间[CI] 1.12-1.29，p<0.001）和无骨髓增生症后生存期（HR 1.32，95% 置信区间[CI] 1.24-1.41，p<0.001）更差。然而，通过倾向分数匹配调整年龄、性别和种族后，组间生存率差异变得不显著（HR 1.05，95% CI 0.97-1.13，p=0.229）。虽然TM前组的无TM后生存率仍然较低，但在排除皮肤型TM后，这一差异有所缩小（HR 1.06，95% CI 0.99-1.15，P=0.116）。此外，前骨髓瘤患者移植后的复发率并不比无前骨髓瘤患者的新发癌症高：结论：Pre-TM患者在DLT后的总生存率与无Pre-TM患者相似。重要的是，与没有前TM的患者相比，原发性前TM类型在移植后复发的风险并没有增加。这些发现突出表明，有必要对移植候选者进行更细致的评估，以防止过早地将Pre-TM患者排除在救命手术之外。
{"title":"Rethinking the Impact of Pretransplant Malignancy (Pre-TM) on Double Lung Transplantation (DLT) Eligibility: An Analysis of 23,291 DLT Recipients","authors":"Wongi Woo, Hye Sung Kim, Ankit Bharat, Young Kwang Chae","doi":"10.1101/2024.03.14.24304302","DOIUrl":"https://doi.org/10.1101/2024.03.14.24304302","url":null,"abstract":"Background: Given the increasing need for lung transplants among older patients with a history of cancer, this study analyzed database registry to assess outcomes for DLT recipients with Pre-TM.\u0000Methods: This study evaluated the United Network for Organ Sharing (UNOS) registry for adult DLT performed between 2005 and 2023. Patients with a history of previous or multi-organ transplants, and those with donors who had cancer history, were excluded. Propensity-score matching was used to compare patients with or without Pre-TM. Overall and Post-TM-free survival were analyzed.\u0000Results: Among the 23,291 recipients of DLT, 8.0%(1,870) had Pre-TM. Compared to those without Pre-TM, patients with Pre-TM had worse overall (hazard ratio[HR] 1.20, 95% confidence interval[CI] 1.12-1.29, p<0.001) and Post-TM-free survival (HR 1.32, 95% CI 1.24-1.41, p<0.001). However, after adjusting for age, sex, and race through propensity-score matching, the survival difference between the groups became non-significant (HR 1.05, 95% CI 0.97-1.13, p=0.229). While the Pre-TM group still had worse Post-TM-free survival, this difference diminished after excluding cutaneous Post-TM (HR 1.06, 95% CI 0.99-1.15, p=0.116). Additionally, the recurrence rate of Pre-TM after transplant wasn't higher than de novo cancers in patients without Pre-TM.\u0000Conclusion: Patients with Pre-TM had similar overall survival rates after DLT as those without Pre-TM. Importantly, there is no increased risk of the primary Pre-TM type recurring post-transplant compared to patients without Pre-TM. These findings highlight the necessity for a more nuanced evaluation of transplant candidacy to prevent premature exclusion of Pre-TM patients from life-saving surgeries.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140154261","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 : 2024-02-27DOI: 10.1101/2024.02.23.24303301
Reid Dale, Matthew Leipzig, Nataliya Bahatyrevich, Katharine Casselman Pines, Quidong Chen, Jeffrey Teuteberg, Joseph Woo, Maria Currie
Background: For heart transplantation, optimal donor-recipient matching is an important factor in the ongoing development of the United Network for Organ Sharing (UNOS) continuous distribution framework. Donor-recipient sex-mismatch has decreased since the 1990s, but this may be related to the risk posed by size mismatching, particularly when donor hearts are undersized. Thus, the impact of sex-mismatching, controlling for other factors including size mismatch, is uncertain. Methods: Adult first-time, isolated heart transplant patients from the UNOS database between October 1, 1987 and December 31, 2022 were analyzed. Cohorts were separated into male and female recipients. Propensity score matching on known preoperative risk factors was performed. Equivalence testing via Two One-Sided Testing (TOST) was performed to assess between-arm equivalence in postoperative outcomes. Survival differences were measured by the between-arm ratio of Restricted Mean Survival Time and binary outcome differences by the Odds Ratio (OR). Results: In the propensity matched cohort, we found significant equivalence between arms in both male (TOST P<0.001) and female (TOST P<0.001) recipients for overall survival at all temporal endpoints, postoperative treatment for rejection within one year, and pre-discharge dialysis. Conclusions: Sex-mismatch in isolated heart transplantation confers no additional risk to postoperative outcomes when controlling for other factors, including size mismatch. Consequently, sex-mismatch should not factor into individual assessments of organ acceptance or be incorporated into any national organ allocation policy. Increasing the acceptance of sex-mismatched donors has the potential to expand the donor pool and increase female donor utilization.
{"title":"Sex-Mismatching in Isolated Heart Transplant Confers No Postoperative Risk","authors":"Reid Dale, Matthew Leipzig, Nataliya Bahatyrevich, Katharine Casselman Pines, Quidong Chen, Jeffrey Teuteberg, Joseph Woo, Maria Currie","doi":"10.1101/2024.02.23.24303301","DOIUrl":"https://doi.org/10.1101/2024.02.23.24303301","url":null,"abstract":"Background: For heart transplantation, optimal donor-recipient matching is an important factor in the ongoing development of the United Network for Organ Sharing (UNOS) continuous distribution framework. Donor-recipient sex-mismatch has decreased since the 1990s, but this may be related to the risk posed by size mismatching, particularly when donor hearts are undersized. Thus, the impact of sex-mismatching, controlling for other factors including size mismatch, is uncertain. Methods: Adult first-time, isolated heart transplant patients from the UNOS database between October 1, 1987 and December 31, 2022 were analyzed. Cohorts were separated into male and female recipients. Propensity score matching on known preoperative risk factors was performed. Equivalence testing via Two One-Sided Testing (TOST) was performed to assess between-arm equivalence in postoperative outcomes. Survival differences were measured by the between-arm ratio of Restricted Mean Survival Time and binary outcome differences by the Odds Ratio (OR). Results: In the propensity matched cohort, we found significant equivalence between arms in both male (TOST P<0.001) and female (TOST P<0.001) recipients for overall survival at all temporal endpoints, postoperative treatment for rejection within one year, and pre-discharge dialysis. Conclusions: Sex-mismatch in isolated heart transplantation confers no additional risk to postoperative outcomes when controlling for other factors, including size mismatch. Consequently, sex-mismatch should not factor into individual assessments of organ acceptance or be incorporated into any national organ allocation policy. Increasing the acceptance of sex-mismatched donors has the potential to expand the donor pool and increase female donor utilization.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140003963","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 : 2024-02-08DOI: 10.1101/2024.02.08.24302515
Bastian Engel, Ahmed Alaswad, Alejandro Campos-Murguia, Martijn Zoodsma, Anne Klingbeil, Kinan Chihab, Emily A. Bosselmann, Sophia Heinrich, Björn Hartleben, Danny D. Jonigk, Murielle Verboom, Michael Hallensleben, Robert Geffers, Heiner Wedemeyer, Cheng-Jian Xu, Elmar Jaeckel, Yang Li, Richard Taubert
Background&Aims The role of antibody-mediated rejection (ABMR) after liver transplantation (LT) remains controversial. Chronic ABMR (cABMR) is often subclinical and potentially missed without surveillance biopsies (svLbx) which are not established in most LT centers. Transcriptome analysis previously characterized molecular changes in T cell-mediated rejection (TCMR) after solid organ transplantation. We aimed to identify molecular cABMR signatures after LT for a more comprehensive understanding of cABMR.
{"title":"Molecular signatures of chronic antibody-mediated rejection in human liver transplants","authors":"Bastian Engel, Ahmed Alaswad, Alejandro Campos-Murguia, Martijn Zoodsma, Anne Klingbeil, Kinan Chihab, Emily A. Bosselmann, Sophia Heinrich, Björn Hartleben, Danny D. Jonigk, Murielle Verboom, Michael Hallensleben, Robert Geffers, Heiner Wedemeyer, Cheng-Jian Xu, Elmar Jaeckel, Yang Li, Richard Taubert","doi":"10.1101/2024.02.08.24302515","DOIUrl":"https://doi.org/10.1101/2024.02.08.24302515","url":null,"abstract":"<strong>Background&Aims</strong> The role of antibody-mediated rejection (ABMR) after liver transplantation (LT) remains controversial. Chronic ABMR (cABMR) is often subclinical and potentially missed without surveillance biopsies (svLbx) which are not established in most LT centers. Transcriptome analysis previously characterized molecular changes in T cell-mediated rejection (TCMR) after solid organ transplantation. We aimed to identify molecular cABMR signatures after LT for a more comprehensive understanding of cABMR.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769895","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 : 2024-02-08DOI: 10.1101/2024.02.06.24302324
Rahul Sai Gangula, Mahesh Eswarappa, Rajashekar Reddy, Gireesh Mathihally Siddaiah, Gurudev Konana, Hamsa Reddy, Pooja Prakash Prabhu, Yousuff Mohammad, Lia Sara Anish
Background Urinary Tract Infections (UTIs) are the second most common cause of graft dysfunction, accounting for significant morbidity, and are associated with poor graft and patient survival. This study aimed to determine the association between post-renal transplant UTI and graft outcomes.
{"title":"Effect of Urinary tract infection on the outcome of the Allograft in patients with Renal transplantation","authors":"Rahul Sai Gangula, Mahesh Eswarappa, Rajashekar Reddy, Gireesh Mathihally Siddaiah, Gurudev Konana, Hamsa Reddy, Pooja Prakash Prabhu, Yousuff Mohammad, Lia Sara Anish","doi":"10.1101/2024.02.06.24302324","DOIUrl":"https://doi.org/10.1101/2024.02.06.24302324","url":null,"abstract":"<strong>Background</strong> Urinary Tract Infections (UTIs) are the second most common cause of graft dysfunction, accounting for significant morbidity, and are associated with poor graft and patient survival. This study aimed to determine the association between post-renal transplant UTI and graft outcomes.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139769897","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 : 2023-12-19DOI: 10.1101/2023.12.18.23300165
Thalia Salinas, Carol Li, Catherine Snopkowski, Vijay K Sharma, Darshana M Dadhania, Karsten Suhre, Thangamani Muthukumar, Manikkam Suthanthiran
Introduction. A kidney allograft biopsy may display acute T cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR), or concurrent TCMR + ABMR (MR). Development of noninvasive biomarkers diagnostic of all three types of acute rejection is a useful addition to the diagnostic armamentarium. Methods. We developed customized RT-qPCR assays and measured urinary cell mRNA copy number in 145 biopsy-matched urine samples from 126 kidney allograft recipients and calculated urinary cell three-gene signature score from log10-transformed values for the 18S-normalized CD3E mRNA, 18S-normalized CXCL10 mRNA and 18S rRNA. We determined whether the signature score in biopsy-matched urine specimens discriminates biopsies without rejection (NR, n=50) from biopsies displaying TCMR (n=47), ABMR (n=28) or MR (n=20). Results. Urinary cell three-gene signature discriminated TCMR, ABMR or MR biopsies from NR biopsies (P <0.0001, One-way ANOVA). Dunnett's multiple comparisons test yielded P<0.0001 for NR vs. TCMR; P <0.001 for NR vs. ABMR; and P <0.0001 for NR vs. MR. By bootstrap resampling, optimism-corrected area under the receiver operating characteristic curve (AUC) was 0.749 (bias-corrected 95% confidence interval [CI], 0.638 to 0.840) for NR vs. TCMR (P<0.0001); 0.780 (95% CI, 0.656 to 0.878) for NR vs. ABMR (P<0.0001); and 0.857 (95% CI, 0.727 to 0.947) for NR vs. MR (P<0.0001). All three rejection biopsy categories were distinguished from NR biopsies with similar accuracy (all AUC comparisons P>0.05). Conclusion. Urinary cell three-gene signature score may serve as a universal diagnostic signature of acute rejection due to TCMR, ABMR or MR in human kidney allografts with similar performance characteristics.
{"title":"Urinary Cell Gene Signature of Acute Rejection in Kidney Allografts","authors":"Thalia Salinas, Carol Li, Catherine Snopkowski, Vijay K Sharma, Darshana M Dadhania, Karsten Suhre, Thangamani Muthukumar, Manikkam Suthanthiran","doi":"10.1101/2023.12.18.23300165","DOIUrl":"https://doi.org/10.1101/2023.12.18.23300165","url":null,"abstract":"Introduction. A kidney allograft biopsy may display acute T cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR), or concurrent TCMR + ABMR (MR). Development of noninvasive biomarkers diagnostic of all three types of acute rejection is a useful addition to the diagnostic armamentarium.\u0000Methods. We developed customized RT-qPCR assays and measured urinary cell mRNA copy number in 145 biopsy-matched urine samples from 126 kidney allograft recipients and calculated urinary cell three-gene signature score from log10-transformed values for the 18S-normalized CD3E mRNA, 18S-normalized CXCL10 mRNA and 18S rRNA. We determined whether the signature score in biopsy-matched urine specimens discriminates biopsies without rejection (NR, n=50) from biopsies displaying TCMR (n=47), ABMR (n=28) or MR (n=20).\u0000Results. Urinary cell three-gene signature discriminated TCMR, ABMR or MR biopsies from NR biopsies (P <0.0001, One-way ANOVA). Dunnett's multiple comparisons test yielded P<0.0001 for NR vs. TCMR; P <0.001 for NR vs. ABMR; and P <0.0001 for NR vs. MR. By bootstrap resampling, optimism-corrected area under the receiver operating characteristic curve (AUC) was 0.749 (bias-corrected 95% confidence interval [CI], 0.638 to 0.840) for NR vs. TCMR (P<0.0001); 0.780 (95% CI, 0.656 to 0.878) for NR vs. ABMR (P<0.0001); and 0.857 (95% CI, 0.727 to 0.947) for NR vs. MR (P<0.0001). All three rejection biopsy categories were distinguished from NR biopsies with similar accuracy (all AUC comparisons P>0.05).\u0000Conclusion. Urinary cell three-gene signature score may serve as a universal diagnostic signature of acute rejection due to TCMR, ABMR or MR in human kidney allografts with similar performance characteristics.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138819044","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 : 2023-12-15DOI: 10.1101/2023.12.14.23299955
Elizabeth Krieger, Rehan Qayyum, Amir Toor
Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after hematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting.
杀伤性免疫球蛋白样受体（KIR）和 KIR 配体（KIRL）的相互作用在造血干细胞移植（HCT）后自然杀伤细胞介导的效应中起着重要作用。先前的研究表明，考虑已知的 KIR-KIRL 相互作用可识别出在成人移植环境中具有最佳 NK 细胞介导异体活性的捐献者。
{"title":"Increased Donor Inhibitory KIR Are Associated with Reduced GVHD and Improved Survival Following HLA Matched Unrelated Donor HCT in Pediatric Acute Leukemia","authors":"Elizabeth Krieger, Rehan Qayyum, Amir Toor","doi":"10.1101/2023.12.14.23299955","DOIUrl":"https://doi.org/10.1101/2023.12.14.23299955","url":null,"abstract":"Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated effects after hematopoietic stem cell transplantation (HCT). Previous work has shown that accounting for known KIR-KIRL interactions may identify donors with optimal NK cell-mediated alloreactivity in the adult transplant setting.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138741389","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 : 2023-12-14DOI: 10.1101/2023.12.13.23299859
Simon Schwab, Andreas Elmer, Daniel Sidler, Lisa Straumann, Ueli Stürzinger, Franz Immer
Median waiting times published by transplant organizations around the world may be biased when death or censoring is disregarded. This leads to too optimistic waiting times, particularly in kidney transplantation, and as a consequence can deceive patients on the waiting list, transplant physicians, and healthcare policy maker. Competing risk multistate models are suited for the analysis of time-to-event data of the organ waiting list. Resulting cumulative incidences are probabilities for transplantation or death by a given time, and are a more accurate description of the events occurring on the waiting list. In accordance with the concept of median survival time in survival analysis in clinical trials, we suggest the median time to transplantation (MTT), the waiting time duration at which the transplant probability is 0.50, as a measure of average waiting time.
{"title":"Selection bias in reporting of median waiting times in organ transplantation","authors":"Simon Schwab, Andreas Elmer, Daniel Sidler, Lisa Straumann, Ueli Stürzinger, Franz Immer","doi":"10.1101/2023.12.13.23299859","DOIUrl":"https://doi.org/10.1101/2023.12.13.23299859","url":null,"abstract":"Median waiting times published by transplant organizations around the world may be biased when death or censoring is disregarded. This leads to too optimistic waiting times, particularly in kidney transplantation, and as a consequence can deceive patients on the waiting list, transplant physicians, and healthcare policy maker. Competing risk multistate models are suited for the analysis of time-to-event data of the organ waiting list. Resulting cumulative incidences are probabilities for transplantation or death by a given time, and are a more accurate description of the events occurring on the waiting list. In accordance with the concept of median survival time in survival analysis in clinical trials, we suggest the median time to transplantation (MTT), the waiting time duration at which the transplant probability is 0.50, as a measure of average waiting time.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138717315","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 : 2023-11-16DOI: 10.1101/2023.11.15.23298543
Armin Ahmadi, Jacquelyn Min-Ung Yu, Jennifer E. Loza, Brian Christopher Howard, Ivonne Palma, Peter Adam Than, Naeem Makarm G Goussous, Junichiro Sageshima, Baback Roshanravan, Richard V. Perez
Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion (EVNP) may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. We assessed the association of tissue metabolic changes with changes in kidney injury biomarkers and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12-hour ex vivo normothermic perfusion (EVNP). The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean (SD) age of the deceased kidney donors was 43 (16) years with an average cold ischemia time of 37 (12) hours. Urine output and creatinine clearance progressively increased and peaked at 6 hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% CI 1.5, 140) urinary neutrophil gelatinase-associated lipocalin (NGAL) at 6 hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branch-chained amino acid (BCAA) metabolism. Tissue BCAA levels negatively correlated with urine output among all kidneys at 6 hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Overall, we showed that 6 hours is needed for kidney functional recovery during ENVP and that BCAA metabolism may be a major determinant of organ function and resilience.
目前的肾脏灌注方案并没有针对肾脏的体外生理和代谢需求进行优化。体外恒温灌注(EVNP)可用于区分高危肾脏，以确定是否适合移植。在12小时体外恒温灌注(EVNP)期间，我们评估了8个被认为不适合移植的已故供体肾脏的组织代谢变化与肾损伤生物标志物和功能参数变化的关系。根据血流量和尿量将肾脏分为表现良好和表现不佳两组。死亡肾供者的平均(SD)年龄为43(16)岁，平均冷缺血时间为37(12)小时。尿量和肌酐清除率逐渐增加，并在灌注后6小时达到峰值。与表现良好的患者相比，表现不佳的患者在6小时时尿中性粒细胞明胶酶相关脂质体(NGAL)含量高出71 ng/ml (95% CI 1.5, 140)，对应于峰值功能差异。器官性能是由支链氨基酸(BCAA)代谢的组织代谢差异来区分的。组织BCAA水平与6小时所有肾脏的尿量呈负相关。组织脂质分析显示，在早期灌注时间点，包括甘油脂和鞘脂在内的膜结构成分的积累突出了表现不佳的动物。总的来说，我们发现ENVP期间肾功能恢复需要6小时，BCAA代谢可能是器官功能和恢复力的主要决定因素。
{"title":"Deceased donor kidney function is determined by branch chained amino acid metabolism during ex vivo normothermic perfusion","authors":"Armin Ahmadi, Jacquelyn Min-Ung Yu, Jennifer E. Loza, Brian Christopher Howard, Ivonne Palma, Peter Adam Than, Naeem Makarm G Goussous, Junichiro Sageshima, Baback Roshanravan, Richard V. Perez","doi":"10.1101/2023.11.15.23298543","DOIUrl":"https://doi.org/10.1101/2023.11.15.23298543","url":null,"abstract":"Current kidney perfusion protocols are not optimized for addressing the ex vivo physiological and metabolic needs of the kidney. Ex vivo normothermic perfusion (EVNP) may be utilized to distinguish high-risk kidneys to determine suitability for transplantation. We assessed the association of tissue metabolic changes with changes in kidney injury biomarkers and functional parameters in eight deceased donor kidneys deemed unsuitable for transplantation during a 12-hour ex vivo normothermic perfusion (EVNP). The kidneys were grouped into good and poor performers based on blood flow and urine output. The mean (SD) age of the deceased kidney donors was 43 (16) years with an average cold ischemia time of 37 (12) hours. Urine output and creatinine clearance progressively increased and peaked at 6 hours post-perfusion among good performers. Poor performers had 71 ng/ml greater (95% CI 1.5, 140) urinary neutrophil gelatinase-associated lipocalin (NGAL) at 6 hours compared to good performers corresponding to peak functional differences. Organ performance was distinguished by tissue metabolic differences in branch-chained amino acid (BCAA) metabolism. Tissue BCAA levels negatively correlated with urine output among all kidneys at 6 hours. Tissue lipid profiling showed poor performers were highlighted by the accumulation of membrane structure components including glycerolipids and sphingolipids at early perfusion time points. Overall, we showed that 6 hours is needed for kidney functional recovery during ENVP and that BCAA metabolism may be a major determinant of organ function and resilience.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544166","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 : 2022-11-18DOI: 10.1101/2022.11.16.22281980
Christian Martin, Kathleen S Mahan, Talia D Wiggen, Adam J Gilbertsen, Marshall I Hertz, Ryan C Hunter, Robert A Quinn
Background Progression of chronic lung disease often leads to the requirement for a lung transplant (LTX). Despite improvements in short-term survival after LTX, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the relationship between the metabolome of bronchoalveolar lavage fluid (BALF) collected longitudinally from subjects post-LTX with underlying chronic lung diseases and its association with CLAD severity. Methods Untargeted LC-MS/MS metabolomics was performed on 960 BALF samples collected over 10 years from LTX recipients with alpha-1-antitrypsin disease (AATD, n = 22), cystic fibrosis (CF, n = 46), chronic obstructive pulmonary disease (COPD, n = 79) or pulmonary fibrosis (PF, n = 47). Datasets were analyzed using machine learning and multivariate statistics for associations with underlying disease and final CLAD severity. Results. BALF metabolomes varied by underlying disease state, with AATD LT recipients being particularly distinctive (PERMANOVA, p = 0.001). We also found significant associations of the metabolome with a subjects final CLAD severity score (PERMANOVA, p = 0.001), especially those with underlying CF. Association with CLAD severity was driven by changes in phosphoethanolamine (PE) and phosphocholine lipids that increased and decreased, respectively, and metabolites from the bacterial pathogen Pseudomonas aeruginosa. P. aeruginosa siderophores, quorum-sensing quinolones, and phenazines were detected in BALF, and 4-hydroxy-2-heptylquinoline (HHQ) was predictive of the final CLAD stage in samples from CF patients (R = 0.34; p ≤ 0.01). Relationships between CLAD stage and P. aeruginosa metabolites were especially marked in those with CF, where 61% of subjects had at least one of these metabolites in their first BALF sample after transplant. These molecules also correlated with the relative abundance of P. aeruginosa from microbiome sequence data. Conclusions: BALF metabolomes after LTX are distinctive based on the underlying disease. Metabolomic data also reflected measures of the final CLAD stage, which was driven by a lipid transition from mostly PC to predominantly PE phospholipids, and metabolites from P. aeruginosa. The association of P. aeruginosa metabolites with CLAD stages in LTX recipients indicates this bacterium and its associated metabolites may be drivers of allograft dysfunction.
背景:慢性肺部疾病的进展常常导致需要肺移植(LTX)。尽管LTX术后短期生存率有所提高，但慢性同种异体肺移植功能障碍(chronic lung allograft dysfunction, CLAD)仍然是长期生存率的一个关键挑战。本研究探讨慢性肺部疾病患者ltx术后纵向收集的支气管肺泡灌洗液(BALF)代谢组及其与慢性肺部疾病严重程度的关系。方法对960份BALF样本进行非靶向LC-MS/MS代谢组学分析，这些样本来自10年来患有α -1抗胰蛋白酶疾病(AATD, n = 22)、囊性纤维化(CF, n = 46)、慢性阻塞性肺疾病(COPD, n = 79)或肺纤维化(PF, n = 47)的LTX患者。使用机器学习和多变量统计分析数据集与潜在疾病和最终CLAD严重程度的关联。BALF代谢组因潜在疾病状态而异，AATD LT受体尤其明显(PERMANOVA, p = 0.001)。我们还发现代谢组与受试者最终的CLAD严重程度评分存在显著相关性(PERMANOVA, p = 0.001)，特别是那些有潜在CF的患者。与CLAD严重程度的关联是由磷酸乙醇胺(PE)和磷脂胆碱脂质的变化(分别升高和降低)以及细菌病原体铜绿假单胞菌的代谢物所推动的。BALF中检测到铜绿假单胞菌铁载体、群体感应喹诺酮类药物和非那嗪类药物，4-羟基-2- heptyl喹啉(HHQ)可预测CF患者样本中最终的CLAD阶段(R = 0.34;P≤0.01)。在CF患者中，CLAD分期与铜绿假单胞菌代谢物之间的关系尤为明显，其中61%的受试者在移植后的第一个BALF样本中至少有一种代谢物。这些分子也与微生物组序列数据中铜绿假单胞菌的相对丰度相关。结论:LTX后的BALF代谢组因潜在疾病而不同。代谢组学数据也反映了最终的覆层阶段，这是由主要由PC磷脂到主要由PE磷脂的脂质转变和铜绿假单胞菌的代谢物驱动的。铜绿假单胞菌代谢物与LTX受者的CLAD分期的关联表明，这种细菌及其相关代谢物可能是同种异体移植物功能障碍的驱动因素。
{"title":"Bronchoalveolar lavage metabolome dynamics reflect underlying disease and chronic lung allograft dysfunction","authors":"Christian Martin, Kathleen S Mahan, Talia D Wiggen, Adam J Gilbertsen, Marshall I Hertz, Ryan C Hunter, Robert A Quinn","doi":"10.1101/2022.11.16.22281980","DOIUrl":"https://doi.org/10.1101/2022.11.16.22281980","url":null,"abstract":"Background Progression of chronic lung disease often leads to the requirement for a lung transplant (LTX). Despite improvements in short-term survival after LTX, chronic lung allograft dysfunction (CLAD) remains a critical challenge for long-term survival. This study investigates the relationship between the metabolome of bronchoalveolar lavage fluid (BALF) collected longitudinally from subjects post-LTX with underlying chronic lung diseases and its association with CLAD severity. Methods Untargeted LC-MS/MS metabolomics was performed on 960 BALF samples collected over 10 years from LTX recipients with alpha-1-antitrypsin disease (AATD, n = 22), cystic fibrosis (CF, n = 46), chronic obstructive pulmonary disease (COPD, n = 79) or pulmonary fibrosis (PF, n = 47). Datasets were analyzed using machine learning and multivariate statistics for associations with underlying disease and final CLAD severity.\u0000Results. BALF metabolomes varied by underlying disease state, with AATD LT recipients being particularly distinctive (PERMANOVA, p = 0.001). We also found significant associations of the metabolome with a subjects final CLAD severity score (PERMANOVA, p = 0.001), especially those with underlying CF. Association with CLAD severity was driven by changes in phosphoethanolamine (PE) and phosphocholine lipids that increased and decreased, respectively, and metabolites from the bacterial pathogen Pseudomonas aeruginosa. P. aeruginosa siderophores, quorum-sensing quinolones, and phenazines were detected in BALF, and 4-hydroxy-2-heptylquinoline (HHQ) was predictive of the final CLAD stage in samples from CF patients (R = 0.34; p ≤ 0.01). Relationships between CLAD stage and P. aeruginosa metabolites were especially marked in those with CF, where 61% of subjects had at least one of these metabolites in their first BALF sample after transplant. These molecules also correlated with the relative abundance of P. aeruginosa from microbiome sequence data. Conclusions: BALF metabolomes after LTX are distinctive based on the underlying disease. Metabolomic data also reflected measures of the final CLAD stage, which was driven by a lipid transition from mostly PC to predominantly PE phospholipids, and metabolites from P. aeruginosa. The association of P. aeruginosa metabolites with CLAD stages in LTX recipients indicates this bacterium and its associated metabolites may be drivers of allograft dysfunction.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"198 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544173","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 : 2022-10-01DOI: 10.1101/2022.09.30.22280568
Ilies Benotmane, Jérôme Olagne, Gabriela Gautier-Vargas, Noëlle Cognard, Francoise Heibel, Laura Braun-Parvez, Nicolas Keller, Jonas Martzloff, Peggy Perrin, Romain Pszczolinski, Bruno Moulin, Samira Fafi-Kremer, Sophie Caillard
Objective: This single-center retrospective study evaluated the use of tixagevimab-cilgavimab as an early treatment for COVID-19 in kidney transplant recipients (KTRs) during the omicron wave. Methods: KTRs were deemed at high risk for moderate-to-severe COVID-19 in presence of at least one comorbidity (age >60 years, diabetes, obesity, or cardiovascular disease) associated with a weak humoral response (<264 BAU/mL). All other KTRs were considered at low risk. The two groups were stratified according to the administration of tixagevimab-cilgavimab and compared in terms of COVID-19-related hospitalization, oxygen need, ICU admission, and mortality. Results: Of the 61 KTRs at high risk, 26 received tixagevimab-cilgavimab. COVID-19-related hospitalizations (3.8% versus 34%, p=0.006) and oxygen need (3.8% versus 23%, p=0.04) were significantly less frequent in patients who received tixagevimab-cilgavimab. In addition, non-significant trends towards a lower number of ICU admissions (3.8% versus 14.3% p=0.17) and deaths (0 versus 3, p=0.13) were observed after administration of tixagevimab-cilgavimab. Ten of the 73 low-risk KTRs received tixagevimab-cilgavimab, and no significant clinical benefit was observed in this subgroup. Conclusion: Early administration of tixagevimab-cilgavimab may be clinically useful in high-risk KTRs with COVID-19; however, no major benefit was observed for low-risk patients.
{"title":"Tixagevimab-cilgavimab as an early treatment for COVID-19 in kidney transplant recipients","authors":"Ilies Benotmane, Jérôme Olagne, Gabriela Gautier-Vargas, Noëlle Cognard, Francoise Heibel, Laura Braun-Parvez, Nicolas Keller, Jonas Martzloff, Peggy Perrin, Romain Pszczolinski, Bruno Moulin, Samira Fafi-Kremer, Sophie Caillard","doi":"10.1101/2022.09.30.22280568","DOIUrl":"https://doi.org/10.1101/2022.09.30.22280568","url":null,"abstract":"Objective: This single-center retrospective study evaluated the use of tixagevimab-cilgavimab as an early treatment for COVID-19 in kidney transplant recipients (KTRs) during the omicron wave. Methods: KTRs were deemed at high risk for moderate-to-severe COVID-19 in presence of at least one comorbidity (age >60 years, diabetes, obesity, or cardiovascular disease) associated with a weak humoral response (<264 BAU/mL). All other KTRs were considered at low risk. The two groups were stratified according to the administration of tixagevimab-cilgavimab and compared in terms of COVID-19-related hospitalization, oxygen need, ICU admission, and mortality.\u0000Results: Of the 61 KTRs at high risk, 26 received tixagevimab-cilgavimab. COVID-19-related hospitalizations (3.8% versus 34%, p=0.006) and oxygen need (3.8% versus 23%, p=0.04) were significantly less frequent in patients who received tixagevimab-cilgavimab. In addition, non-significant trends towards a lower number of ICU admissions (3.8% versus 14.3% p=0.17) and deaths (0 versus 3, p=0.13) were observed after administration of tixagevimab-cilgavimab. Ten of the 73 low-risk KTRs received tixagevimab-cilgavimab, and no significant clinical benefit was observed in this subgroup. Conclusion: Early administration of tixagevimab-cilgavimab may be clinically useful in high-risk KTRs with COVID-19; however, no major benefit was observed for low-risk patients.","PeriodicalId":501561,"journal":{"name":"medRxiv - Transplantation","volume":"44 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138544172","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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