Preprocurement In Situ Donor Lung Tissue Gene Expression Classifies Primary Graft Dysfunction Risk.
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ABSTRACT:
SUBMITTER: Cantu E
PROVIDER: S-EPMC7528788 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
Publications
Preprocurement <i>In Situ</i> Donor Lung Tissue Gene Expression Classifies Primary Graft Dysfunction Risk.
Cantu Edward E Yan Mengying M Suzuki Yoshikazu Y Buckley Taylor T Galati Vito V Majeti Neha N Bermudez Christian A CA Diamond Joshua M JM Christie Jason D JD Feng Rui R
American journal of respiratory and critical care medicine 20201001 7
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Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study Matched case-control observational study: 10 primary graft dysfunction cases vs 16 Good outcome cases. One replicate per array.
2008-09-15 | E-GEOD-9102 | biostudies-arrayexpress
Project description:Primary graft dysfunction (PGD) continues to be a major cause of early death after lung transplantation. Moreover, there remains a lack of accurate pre-transplant molecular markers for predicting PGD. To identify distinctive gene expression signatures associated with PGD, we profiled human donor lungs using microarray technology prior to the graft implantation. The genomic profiles of 10 donor lung samples from patients who subsequently developed clinically defined severe PGD were compared with 16 case-matched donor lung samples from those who had a favorable outcome without PGD. Matched factors used were: recipient age (± 10 years), recipient gender, recipient lung disease, and type of transplantation (single or bilateral). Keywords: Observational case-control study
2008-09-15 | GSE9102 | GEO
Project description:BackgroundPrimary graft dysfunction is a major cause of early mortality following lung transplantation. The International Society for Heart and Lung Transplantation subdivides it into 4 grades of increasing severity.MethodsA retrospective review of the institutional lung transplant database from March 2018 to September 2021 was performed. Patients were stratified into three groups: primary graft dysfunction grade 0 patients, grade 1 or 2 patients, and grade 3 patients. Recipient, donor, and surgical variables were analyzed by logistic regression analysis to identify risk factors for primary graft dysfunction grade 1 or 2 and grade 3.ResultsPrimary graft dysfunction grade 1 to 3 occurred in 45.0% of the cohort (n=68) of whom 33.3% (n=23) had primary graft dysfunction grade 3. Longer operative time was more common in primary graft dysfunction grade 1 to 3 patients (P<0.001). The 1-year survival of the patients with primary graft dysfunction grade 3 was lower than the others (grade 0-2 vs. 3, 93.7% vs. 65.2%, P=0.0006). Univariate analysis showed that acute respiratory distress syndrome, operative time, and intraoperative veno-arterial extracorporeal membrane oxygenation use were risk factors for primary graft dysfunction grades 1 or 2 and grade 3. Multivariate analysis identified that intraoperative veno-arterial extracorporeal membrane oxygenation use was an independent risk factor of primary graft dysfunction grade 1 or 2. Patients with an operative time of more than 8.18 hours had significantly higher incidence of primary graft dysfunction grade 3, acute kidney injury, and digital ischemia.ConclusionsThe calculated predictors of primary graft dysfunction grade 1 or 2 were similar to those of primary graft dysfunction grade 3.
| S-EPMC9992558 | biostudies-literature
Project description:BackgroundMechanical ventilation immediately after lung transplantation may impact the development of primary graft dysfunction (PGD), particularly in cases of donor-recipient size mismatch as ventilation is typically based on recipient rather than donor size.MethodsWe conducted a retrospective cohort study of adult bilateral lung transplant recipients at our center between January 2010 and January 2017. We defined donor-based lung protective ventilation (dLPV) as 6 to 8 ml/kg of donor ideal body weight and plateau pressure <30 cm H2O. We calculated the donor-recipient predicted total lung capacity (pTLC) ratio and used logistic regression to examine relationships between pTLC ratio, dLPV and PGD grade 3 at 48 to 72 hours. We used Cox proportional hazards modelling to examine the relationship between pTLC ratio, dLPV and 1-year survival.ResultsThe cohort included 373 recipients; 24 (6.4%) developed PGD grade 3 at 48 to 72 hours, and 213 (57.3%) received dLPV. Mean pTLC ratio was 1.04 ± 0.18. dLPV was associated with significantly lower risks of PGD grade 3 (OR = 0.44; 95% CI: 0.29-0.68, p < 0.001) and 1-year mortality (HR = 0.49; 95% CI: 0.29-0.8, p = 0.018). There was a significant association between pTLC ratio and the risk of PGD grade 3, but this was attenuated by the use of dLPV.ConclusionsdLPV is associated with decreased risk of PGD grade 3 at 48 to 72 hours and decreased 1-year mortality. Additionally, dLPV attenuates the association between pTLC and both PGD grade 3 and 1-year mortality. Donor-based ventilation strategies may help to mitigate the risk of PGD and other adverse outcomes associated with size mismatch after lung transplantation.
| S-EPMC8886387 | biostudies-literature
Project description:BackgroundPrevious studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients.MethodsWe performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF.ResultsA total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008).ConclusionPatients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.
| S-EPMC8102314 | biostudies-literature
Project description:Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.
| S-EPMC4721238 | biostudies-literature
Project description:BackgroundObesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown.MethodsWe performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height.2 We used logistic regression to examine the associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD.ResultsA total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD.ConclusionsSubcutaneous, but not visceral, adiposity is associated with an increased risk of PGD after lung transplantation.
| S-EPMC6883162 | biostudies-literature
Project description:Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.
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Project description:BACKGROUND: Hypovolemia is common in lung donors before or after brain death. However, its impact on primary graft function (PGD) remains obscure. METHODS: A clinically relevant two-hit model of PGD was established by integrating hypovolemic shock (HS) and cold ischemia-reperfusion in a mouse model of orthotopic lung transplantation (LTx) from C57BL/6 to Balb/c. At -48 hours, HS was induced to donor by withdrawal of blood from femoral artery and keeping the mean arterial pressure at 15±5 mmHg for 4 h. At -24 hours, donor lungs were retrieved from mice with or without HS and stored at 0ºC until transplantation. CD11b-DTR mice were used as donor and treated with Diphtheria Toxin (DT) to deplete graft-infiltrating macrophages. RESULTS: HS mainly caused macrophage-predominant infiltration around pulmonary artery injury systemic inflammatory response, but little impairment of lung function even if in combination with cold ischemia-reperfusion. Transcriptional profiling showed HS pretreatment increased pulmonary damage and alveolar remodeling but ameliorated inflammatory infiltration when compared to one-hit model of 12 hours cold ischemia-reperfusion injury. The allografts with donor DT-treatment one day ahead of HS showed injury and dysfunction at donation and worsened further at 24 hours reperfusion, whereas the allografts with recipient DT-treatment immediately after transplantation showed similar function and histology to the control treated with saline. CONCLUSION: Donor hypovolemia causes pulmonary artery injury and infiltration but has little impact on allograft function, even in combination with 24 h cold ischemia. Graft-infiltrating macrophages are critical in protecting graft from HS-induced injury and cold ischemia-reperfusion injury.
2022-03-30 | GSE156322 | GEO
Project description:Donor-derived cell-free DNA (dd-cf-DNA) has been shown to be an informative biomarker of rejection after lung transplantation (LT) from deceased donors. However, in living-donor lobar LT, because small grafts from blood relatives are implanted with short ischemic times, the detection of dd-cf-DNA might be challenging. Our study was aimed at examining the role of dd-cf-DNA measurement in the diagnosis of primary graft dysfunction and acute rejection early after living-donor lobar LT. Immediately after LT, marked increase of the plasma dd-cf-DNA levels was noted, with the levels subsequently reaching a plateau with the resolution of primary graft dysfunction. Increased plasma levels of dd-cf-DNA were significantly correlated with decreased oxygenation immediately (p?=?0.022) and at 72?hours (p?=?0.046) after LT. Significantly higher plasma dd-cf-DNA levels were observed in patients with acute rejection (median, 12.0%) than in those with infection (median, 4.2%) (p?=?0.028) or in a stable condition (median, 1.1%) (p?=?0.001). Thus, measurement of the plasma levels of dd-cf-DNA might be useful to monitor the severity of primary graft dysfunction, and plasma dd-cf-DNA could be a potential biomarker for the diagnosis of acute rejection after LT.
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