Long-term air pollution exposure and the risk of primary graft dysfunction after lung transplantation.

BACKGROUND: Primary graft dysfunction (PGD) contributes substantially to both short and long-term mortality after lung transplantation but the mechanisms that lead to PGD are not well understood. Exposure to ambient air pollutants is associated with adverse events during waitlisting for lung transplantation, and chronic lung allograft dysfunction but its association with PGD has not been studied. We hypothesized that long-term exposure of the lung donor and recipient to high levels of ambient air pollutants would increase the risk of PGD in lung transplant recipients. METHODS: Using data from 1428 lung transplant recipients and their donors enrolled in the Lung Transplant Outcomes Group (LTOG) observational cohort study, we evaluated the association between the development of PGD and zip-code based estimates of long-term exposure to six major air pollutants (ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide, PM2.5 and PM10) in both the lung donor and the lung recipient. Exposure estimates used daily EPA air pollutant monitoring data and were based on the geographic centroid of the each subject's residential zip code. Associations were tested in both univariable and multivariable models controlling for known PGD risk factors. RESULTS: We did not find strong associations between air pollutant exposures in either the donor or the recipient and PGD. CONCLUSIONS: Exposure to ambient air pollutants, at the levels observed in this study, may not be sufficiently harmful to prime the donor lung or the recipient to develop PGD particularly when considering the robust associations with other established PGD risk factors.

Alterations in Circulating Measures of Th2 Immune Responses Pre-Lung Transplant Associates with Reduced Primary Graft Dysfunction.

Primary graft dysfunction (PGD) is a complication of lung transplantation that continues to cause significant morbidity. The Th2 immune response has been shown to counteract tissue-damaging inflammation. We hypothesized that Th2 cytokines/chemokines in blood would be associated with protection from PGD. Utilizing pre-transplant sera from the multicenter Clinical Trials in Organ Transplantation (CTOT-20) study, we evaluated Th2 cytokines/chemokines in 211 patients. Increased concentrations of Th2 cytokines were associated with freedom from PGD, namely IL-4 (Odds Ratio (OR) 0.66 (95% CI 0.45-0.99), p=0.043), IL-9 (OR 0.68 (95% CI 0.49-0.94), p=0.019), IL-13 (OR 0.73 (95% CI 0.55-0.96), p=0.023), and IL-6 (OR 0.74 (95% CI 0.56-0.98), p=0.036). Multivariable regression performed for each cytokine including clinically relevant covariables confirmed these associations and additionally demonstrated association with IL-5 (OR 0.57 (95% CI 0.36-0.89), p=0.014) and IL-10 (OR 0.55 (95% CI 0.32-0.96), p=0.035). Higher levels of Th2 immune response prior to lung translant appear to have a protective effect against PGD, which parallels the Th2 role in resolving inflammation and tissue injury. Pre-transplant cytokine assessments could be utilized for recipient risk stratification.

Impact of Pre-Transplant Left Ventricular Diastolic Pressure on Primary Graft Dysfunction after Lung Transplantation: A Narrative Review.

Lung transplantation (LT) constitutes the last therapeutic option for selected patients with end-stage respiratory disease. Primary graft dysfunction (PGD) is a form of severe lung injury, occurring in the first 72 h following LT and constitutes the most common cause of early death after LT. The presence of pulmonary hypertension (PH) has been reported to favor PGD development, with a negative impact on patients' outcomes while complicating medical management. Although several studies have suggested a potential association between pre-LT left ventricular diastolic dysfunction (LVDD) and PGD occurrence, the underlying mechanisms of such an association remain elusive. Importantly, the heterogeneity of the study protocols and the various inclusion criteria used to define the diastolic dysfunction in those patients prevents solid conclusions from being drawn. In this review, we aim at summarizing PGD mechanisms, risk factors, and diagnostic criteria, with a further focus on the interplay between LVDD and PGD development. Finally, we explore the predictive value of several diastolic dysfunction diagnostic parameters to predict PGD occurrence and severity.

Portal vein arterialization in 25 liver transplant recipients: A Latin American single-center experience.

BACKGROUND: Portal vein arterialization (PVA) has been used in liver transplantation (LT) to maximize oxygen delivery when arterial circulation is compromised or has been used as an alternative reperfusion technique for complex portal vein thrombosis (PVT). The effect of PVA on portal perfusion and primary graft dysfunction (PGD) has not been assessed. AIM: To examine the outcomes of patients who required PVA in correlation with their LT procedure. METHODS: All patients receiving PVA and LT at the Fundacion Santa Fe de Bogota between 2011 and 2022 were analyzed. To account for the time-sensitive effects of graft perfusion, patients were classified into two groups: prereperfusion (pre-PVA), if the arterioportal anastomosis was performed before graft revascularization, and postreperfusion (post-PVA), if PVA was performed afterward. The pre-PVA rationale contemplated poor portal hemodynamics, severe vascular steal, or PVT. Post-PVA was considered if graft hypoperfusion became evident. Conservative interventions were attempted before PVA. RESULTS: A total of 25 cases were identified: 15 before and 10 after graft reperfusion. Pre-PVA patients were more affected by diabetes, decompensated cirrhosis, impaired portal vein (PV) hemodynamics, and PVT. PGD was less common after pre-PVA (20.0% vs 60.0%) (P = 0.041). Those who developed PGD had a smaller increase in PV velocity (25.00 cm/s vs 73.42 cm/s) (P = 0.036) and flow (1.31 L/min vs 3.34 L/min) (P = 0.136) after arterialization. Nine patients required PVA closure (median time: 62 d). Pre-PVA and non-PGD cases had better survival rates than their counterparts (56.09 months vs 22.77 months and 54.15 months vs 31.91 months, respectively). CONCLUSION: This is the largest report presenting PVA in LT. Results suggest that pre-PVA provides better graft perfusion than post-PVA. Graft hyperperfusion could play a protective role against PGD.

Lung transplantation following controlled hypothermic storage with a portable lung preservation device: first multicenter European experience.

Introduction: Compared with traditional static ice storage, controlled hypothermic storage (CHS) at 4-10°C may attenuate cold-induced lung injury between procurement and implantation. In this study, we describe the first European lung transplant (LTx) experience with a portable CHS device. Methods: A prospective observational study was conducted of all consecutively performed LTx following CHS (11 November 2022 and 31 January 2024) at two European high-volume centers. The LUNGguard device was used for CHS. The preservation details, total ischemic time, and early postoperative outcomes are described. The data are presented as median (range: minimum-maximum) values. Results: A total of 36 patients underwent LTx (i.e., 33 bilateral, 2 single LTx, and 1 lobar). The median age was 61 (15-68) years; 58% of the patients were male; 28% of the transplantations had high-urgency status; and 22% were indicated as donation after circulatory death. In 47% of the patients, extracorporeal membrane oxygenation (ECMO) was used for perioperative support. The indications for using the CHS device were overnight bridging (n = 26), remote procurement (n = 4), rescue allocation (n = 2), logistics (n = 2), feasibility (n = 1), and extended-criteria donor (n = 1). The CHS temperature was 6.5°C (3.7°C-9.3°C). The preservation times were 11 h 18 (2 h 42-17 h 9) and 13 h 40 (4 h 5-19 h 36) for the first and second implanted lungs, respectively, whereas the total ischemic times were 13 h 38 (4 h 51-19 h 44) and 15 h 41 (5 h 54-22 h 48), respectively. The primary graft dysfunction grade 3 (PGD3) incidence rates were 33.3% within 72 h and 2.8% at 72 h. Intensive care unit stay was 8 (4-62) days, and the hospital stay was 28 (13-87) days. At the last follow-up [139 (7-446) days], three patients were still hospitalized. One patient died on postoperative day 7 due to ECMO failure. In-hospital Clavien-Dindo complications of 3b were observed in six (17%) patients, and 4a in seven (19%). Conclusion: CHS seems safe and feasible despite the high-risk recipient and donor profiles, as well as extended preservation times. PGD3 at 72 h was observed in 2.8% of the patients. This technology could postpone LTx to daytime working hours. Larger cohorts and longer-term outcomes are required to confirm these observations.

Perioperative fluid balance and early acute kidney injury after lung transplantation.

BACKGROUND: Postoperative acute kidney injury (AKI) after lung transplantation (LTx) is an important factor affecting the short-term outcomes. The focus item of transplantation centers is how to improve the incidence of AKI through optimal management during the perioperative period. OBJECTIVE: The purpose of the study is to investigate the influence of perioperative volume in the development of early AKI following LTx. METHOD: The study involved patients who had undergone LTx between October 2018 to December 2021 at China-Japan Friendship Hospital in Beijing. The patients were monitored for AKI occurring within 72 hours after LTx, as well as the renal outcomes within 30 days. The perioperative volumes were compared and analyzed to determine the impact on various clinical outcomes. RESULTS: 248 patients were enrolled in the study ultimately, with almost half of them (49.6 %) experiencing AKI. 48.8 % of AKI patients received continuous renal replacement therapy (CRRT), with 57.7 % recovered by the end of the 30-day follow-up period. A J-shaped relationship was demonstrated between perioperative volume and AKI incidence. Moreover, maintaining a positive fluid balance would increase the 30-day mortality and lead to poor renal outcomes. CONCLUSION: Perioperative volume is an independent risk factor of early AKI after LTx. Positive fluid balance increases the risk of AKI, 30-day mortality, and adverse renal prognosis. The LTx recipients may benefit from a relatively restrict fluid strategy during and after the lung transplantation.

Necropsy findings in heart transplant recipients with or without primary graft dysfunction.

BACKGROUND: Primary graft dysfunction (PGD) is the leading cause of death in the first year after heart transplant (HT), but pathophysiology and histology are not completely understood. This study describes and compares morphological findings of hearts of patients with and without PGD. METHODS: We included adult patients submitted to HT in a single center who died within the first 14 days after HT and were submitted to necropsy. Clinical and histological data were recorded retrospectively. All heart slides were reviewed by a blinded pathologist. We categorized patients in two groups (PGD and non-PGD) and compared findings between them. RESULTS: Among 322 HTs, 26 patients were included. Median age was 51.5 years, 57.7% were male, 46.1% had non-ischemic cardiomyopathy, 30.8% Chagas cardiomyopathy and 23% ischemic cardiomyopathy. Eleven patients presented PGD, while 15 patients did not. PGD was severe in 72.7% of cases and moderate in 27.3%. PGD group had longer ischemic time (p=0.08), higher incidence of mechanical circulatory support (p=0.004), lower post-transplant biventricular ejection fraction (p=0.005). However, necropsy findings were similar between groups. Necrosis was detected in 80.7% of all cases (p=0.907 comparing groups), taking ≥ 10% of myocardial area in 46.1% of them, and 4 types of necrosis were found either in patients with and without PGD. CONCLUSION: Cardiac pathological findings were similar in HT patients with or without PGD who died within 14 days after the transplant and necrosis was frequent in both groups, raising the hypothesis necrosis is not the cause of cardiac dysfunction in PGD.

Driving pressure association with mortality in post-lung transplant patients: A prospective observational study.

OBJECTIVE: To investigate the association between driving pressure (ΔP) and 90-day mortality in patients following lung transplantation (LTx) in patients who developed primary graft dysfunction (PGD). METHODS: This prospective, observational study involved consecutive patients who, following LTx, were admitted to our intensive care unit (ICU) from January 2022 to January 2023. Patients were separated into two groups according to ΔP at time of admission (i.e., low, ≤15 cmH2O or high, >15 cmH2O). Postoperative outcomes were compared between groups. RESULTS: In total, 104 patients were involved in the study, and of these, 69 were included in the low ΔP group and 35 in the high ΔP group. Kaplan-Meier analysis of 90-day mortality showed a statistically significant difference between groups with survival better in the low ΔP group compared with the high ΔP group. According to Cox proportional regression model, the variables independently associated with 90-day mortality were ΔP and pneumonia. Significantly more patients in the high ΔP group than the low ΔP group had PGD grade 3 (PGD3), pneumonia, required tracheostomy, and had prolonged postoperative extracorporeal membrane oxygenation (ECMO) time, postoperative ventilator time, and ICU stay. CONCLUSIONS: Driving pressure appears to have the ability to predict PGD3 and 90-day mortality of patients following LTx. Further studies are required to confirm our results.

Primary graft dysfunction in heart transplantation: the challenge to survival.

Primary graft dysfunction (PGD) is a life-threatening clinical condition with a high mortality rate, presenting as left, right, or biventricular dysfunction within the initial 24 h following heart transplantation, in the absence of a discernible secondary cause. Given its intricate nature, definitive definition and diagnosis of PGD continues to pose a challenge. The pathophysiology of PGD encompasses numerous underlying mechanisms, some of which remain to be elucidated, including factors like myocardial damage, the release of proinflammatory mediators, and the occurrence of ischemia-reperfusion injury. The dynamic characteristics of both donors and recipients, coupled with the inclination towards marginal lists containing more risk factors, together contribute to the increased incidence of PGD. The augmentation of therapeutic strategies involving mechanical circulatory support accelerates myocardial recovery, thereby significantly contributing to survival. Nonetheless, a universally accepted treatment algorithm for the swift management of this clinical condition, which necessitates immediate intervention upon diagnosis, remains absent. This paper aims to review the existing literature and shed light on how diagnosis, pathophysiology, risk factors, treatment, and perioperative management affect the outcome of PGD.

Intraoperative hypotension during liver transplantation and postoperative outcomes: Retrospective cohort study.

STUDY OBJECTIVES: Evaluation of the association between intraoperative hypotension (IOH) and important postoperative outcomes after liver transplant such as incidence and severity of acute kidney injury (AKI), MACE and early allograft dysfunction (EAD). DESIGN: Retrospective, single institution study. SETTINGS: Operating room. PATIENTS: 1576 patients who underwent liver transplant in our institution between January 2005 and February 2022. MEASUREMENTS: IOH was measured as the time, area under the threshold (AUT), or time-weighted average (TWA) of mean arterial pressure (MAP) less than certain thresholds (55,60 and 65 mmHg). Associations between IOH exposures and AKI severity were assessed via proportional odds models. The odds ratio from the proportional odds model estimated the relative odds of having higher stage of AKI for higher exposure to IOH. Associations between exposures and MACE and EAD were assessed through logistic regression models. Potential confounding variables including patient baseline and surgical characteristics were adjusted for all models. MAIN RESULTS: The primary analysis included 1576 surgeries that met the inclusion and exclusion criteria. Of those, 1160 patients (74%) experienced AKI after liver transplant surgery, with 780 (49%), 248(16%), and 132 (8.4%) experiencing mild, moderate, and severe injury, respectively. No significant association between hypotension exposure and postoperative AKI (yes or no) nor severity of AKI was observed. The odds ratios (95% CI) of having more severe AKI were 1.02 (0.997, 1.04) for a 50-mmHg·min increase in AUT of MAP <55 mmHg (P = 0.092); 1.03 (0.98, 1.07) for a 15-min increase in time spent under MAP <55 mmHg (P = 0.27); and 1.24 (0.98, 1.57) for a 1 mmHg increase in TWA of MAP <55 mmHg (P = 0.068). The associations between IOH and the incidence of MACE or EAD were not significant. CONCLUSION: Our results did not show the association between IOH and investigated outcomes.

Proteomic Analysis of Primary Graft Dysfunction in Porcine Lung Transplantation Reveals Alveolar-Capillary Barrier Changes Underlying the High Particle Flow Rate in Exhaled Breath.

Primary graft dysfunction (PGD) remains a challenge for lung transplantation (LTx) recipients as a leading cause of poor early outcomes. New methods are needed for more detailed monitoring and understanding of the pathophysiology of PGD. The measurement of particle flow rate (PFR) in exhaled breath is a novel tool to monitor and understand the disease at the proteomic level. In total, 22 recipient pigs underwent orthotopic left LTx and were evaluated for PGD on postoperative day 3. Exhaled breath particles (EBPs) were evaluated by mass spectrometry and the proteome was compared to tissue biopsies and bronchoalveolar lavage fluid (BALF). Findings were confirmed in EBPs from 11 human transplant recipients. Recipients with PGD had significantly higher PFR [686.4 (449.7-8,824.0) particles per minute (ppm)] compared to recipients without PGD [116.6 (79.7-307.4) ppm, p = 0.0005]. Porcine and human EBP proteins recapitulated proteins found in the BAL, demonstrating its utility instead of more invasive techniques. Furthermore, adherens and tight junction proteins were underexpressed in PGD tissue. Histological and proteomic analysis found significant changes to the alveolar-capillary barrier explaining the high PFR in PGD. Exhaled breath measurement is proposed as a rapid and non-invasive bedside measurement of PGD.

Transient receptor potential vanilloid 4 channel inhibition attenuates lung ischemia-reperfusion injury in a porcine lung transplant model.

OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a nonselective cation channel important in many physiological and pathophysiological processes, including pulmonary disease. Using a murine model, we previously demonstrated that TRPV4 mediates lung ischemia-reperfusion injury, the major cause of primary graft dysfunction after transplant. The current study tests the hypothesis that treatment with a TRPV4 inhibitor will attenuate lung ischemia-reperfusion injury in a clinically relevant porcine lung transplant model. METHODS: A porcine left-lung transplant model was used. Animals were randomized to 2 treatment groups (n = 5/group): vehicle or GSK2193874 (selective TRPV4 inhibitor). Donor lungs underwent 30 minutes of warm ischemia and 24 hours of cold preservation before left lung allotransplantation and 4 hours of reperfusion. Vehicle or GSK2193874 (1 mg/kg) was administered to the recipient as a systemic infusion after recipient lung explant. Lung function, injury, and inflammatory biomarkers were compared. RESULTS: After transplant, left lung oxygenation was significantly improved in the TRPV4 inhibitor group after 3 and 4 hours of reperfusion. Lung histology scores and edema were significantly improved, and neutrophil infiltration was significantly reduced in the TRPV4 inhibitor group. TRPV4 inhibitor-treated recipients had significantly reduced expression of interleukin-8, high mobility group box 1, P-selectin, and tight junction proteins (occludin, claudin-5, and zonula occludens-1) in bronchoalveolar lavage fluid as well as reduced angiopoietin-2 in plasma, all indicative of preservation of endothelial barrier function. CONCLUSIONS: Treatment of lung transplant recipients with TRPV4 inhibitor significantly improves lung function and attenuates ischemia-reperfusion injury. Thus, selective TRPV4 inhibition may be a promising therapeutic strategy to prevent primary graft dysfunction after transplant.

Impact of recipient and donor pretransplantation body mass index on early postosperative complications after lung transplantation.

BACKGROUND: Prior studies have assessed the impact of the pretransplantation recipient body mass index (BMI) on patient outcomes after lung transplantation (LT), but they have not specifically addressed early postoperative complications. Moreover, the impact of donor BMI on these complications has not been evaluated. The first aim of this study was to assess complications during hospitalization in the ICU after LT according to donor and recipient pretransplantation BMI. METHODS: All the recipients who underwent LT at Bichat Claude Bernard Hospital, Paris, between January 2016 and August 2022 were included in this observational retrospective monocentric study. Postoperative complications were analyzed according to recipient and donor BMIs. Univariate and multivariate analyses were also performed. The 90-day and one-year survival rates were studied. P < 0.05 was considered to indicate statistical significance. The Paris-North Hospitals Institutional Review Board approved the study. RESULTS: A total of 304 recipients were analyzed. Being underweight was observed in 41 (13%) recipients, a normal weight in 130 (43%) recipients, and being overweight/obese in 133 (44%) recipients. ECMO support during surgery was significantly more common in the overweight/obese group (p = 0.021), as were respiratory complications (primary graft dysfunction (PGD) (p = 0.006), grade 3 PDG (p = 0.018), neuroblocking agent administration (p = 0.008), prone positioning (p = 0.007)), and KDIGO 3 acute kidney injury (p = 0.036). However, pretransplantation overweight/obese status was not an independent risk factor for 90-day mortality. An overweight or obese donor was associated with a decreased PaO2/FiO2 ratio before organ donation (p < 0.001), without affecting morbidity or mortality after LT. CONCLUSION: Pretransplantation overweight/obesity in recipients is strongly associated with respiratory and renal complications during hospitalization in the ICU after LT.

Implications of High Sensitivity Troponin Levels After Lung Transplantation.

Trends in high-sensitivity cardiac troponin I (hs-cTnI) after lung transplant (LT) and its clinical value are not well stablished. This study aimed to determine kinetics of hs-cTnI after LT, factors impacting hs-cTnI and clinical outcomes. LT recipients from 2015 to 2017 at Toronto General Hospital were included. Hs-cTnI levels were collected at 0-24 h, 24-48 h and 48-72 h after LT. The primary outcome was invasive mechanical ventilation (IMV) >3 days. 206 patients received a LT (median age 58, 35.4% women; 79.6% double LT). All patients but one fulfilled the criteria for postoperative myocardial infarction (median peak hs-cTnI = 4,820 ng/mL). Peak hs-cTnI correlated with right ventricular dysfunction, >1 red blood cell transfusions, bilateral LT, use of EVLP, kidney function at admission and time on CPB or VA-ECMO. IMV>3 days occurred in 91 (44.2%) patients, and peak hs-cTnI was higher in these patients (3,823 vs. 6,429 ng/mL, p < 0.001 after adjustment). Peak hs-cTnI was higher among patients with had atrial arrhythmias or died during admission. No patients underwent revascularization. In summary, peak hs-TnI is determined by recipient comorbidities and perioperative factors, and not by coronary artery disease. Hs-cTnI captures patients at higher risk for prolonged IMV, atrial arrhythmias and in-hospital death.

Impact of controlled hypothermic preservation on outcomes following heart transplantation.

BACKGROUND: Severe primary graft dysfunction (PGD) is a major cause of early mortality after heart transplant, but the impact of donor organ preservation conditions on severity of PGD and survival has not been well characterized. METHODS: Data from US adult heart-transplant recipients in the Global Utilization and Registry Database for Improved Heart Preservation-Heart Registry (NCT04141605) were analyzed to quantify PGD severity, mortality, and associated risk factors. The independent contributions of organ preservation method (traditional ice storage vs controlled hypothermic preservation) and ischemic time were analyzed using propensity matching and logistic regression. RESULTS: Among 1,061 US adult heart transplants performed between October 2015 and December 2022, controlled hypothermic preservation was associated with a significant reduction in the incidence of severe PGD compared to ice (6.6% [37/559] vs 10.4% [47/452], p = 0.039). Following propensity matching, severe PGD was reduced by 50% (6.0% [17/281] vs 12.1% [34/281], respectively; p = 0.018). The Kaplan-Meier terminal probability of 1-year mortality was 4.2% for recipients without PGD, 7.2% for mild or moderate PGD, and 32.1%, for severe PGD (p < 0.001). The probability of severe PGD increased for both cohorts with longer ischemic time, but donor hearts stored on ice were more likely to develop severe PGD at all ischemic times compared to controlled hypothermic preservation. CONCLUSIONS: Severe PGD is the deadliest complication of heart transplantation and is associated with a 7.8-fold increase in probability of 1-year mortality. Controlled hypothermic preservation significantly attenuates the risk of severe PGD and is a simple yet highly effective tool for mitigating post-transplant morbidity.

Nanoparticle targeting of neutrophil glycolysis prevents lung ischemia-reperfusion injury.

Neutrophils exacerbate pulmonary ischemia-reperfusion injury (IRI) resulting in poor short and long-term outcomes for lung transplant recipients. Glycolysis powers neutrophil activation, but it remains unclear if neutrophil-specific targeting of this pathway will inhibit IRI. Lipid nanoparticles containing the glycolysis flux inhibitor 2-deoxyglucose (2-DG) were conjugated to neutrophil-specific Ly6G antibodies (NP-Ly6G[2-DG]). Intravenously administered NP-Ly6G(2-DG) to mice exhibited high specificity for circulating neutrophils. NP-Ly6G(2-DG)-treated neutrophils were unable to adapt to hypoglycemic conditions of the lung airspace environment as evident by the loss of demand-induced glycolysis, reductions in glycogen and ATP content, and an increased vulnerability to apoptosis. NP-Ly6G(2-DG) treatment inhibited pulmonary IRI following hilar occlusion and orthotopic lung transplantation. IRI protection was associated with less airspace neutrophil extracellular trap generation, reduced intragraft neutrophilia, and enhanced alveolar macrophage efferocytotic clearance of neutrophils. Collectively, our data show that pharmacologically targeting glycolysis in neutrophils inhibits their activation and survival leading to reduced pulmonary IRI.

Impact of the New Definition of Pulmonary Hypertension on the Prevalence of Primary Graft Dysfunction in Lung Transplant Recipients.

BACKGROUND & AIM: Pulmonary hypertension (PH) secondary to lung disease (Group-3 PH) is the second leading cause of PH. The role of PH as a risk factor for primary graft dysfunction (PGD) following lung transplant (LT) is controversial. OBJECTIVE: To assess the impact that the new definition of PH had on the prevalence of PH in patients with advanced lung disease-candidate for LT, and its association with the occurrence of PGD. METHOD: A retrospective study was performed in all patients undergoing cardiac catheterisation referred for consideration as candidates to LT in a centre between 1 January 2017 and 31 December 2022. The baseline and haemodynamic characteristics of patients were analysed, along with the occurrence of PGD and post-transplant course in those who ultimately underwent transplantation. RESULTS: A total of 396 patients were included. Based on the new 2022 European Society of Cardiology/European Respiratory Society definitions, as many as 70.7% of patients met PH criteria. Since the introduction of the 2022 definition, a significant reduction was observed in the frequency of severe Group-3 PH (41.1% vs 10.3%; p<0.001), with respect to the 2015 definition. As many as 236 patients underwent transplantation. None of the variables associated with PH was identified as a risk factor for PGD. CONCLUSION: The new classification did not have any impact on the prevalence of PGD after transplantation. These results exclude that any significant differences exist in the baseline characteristics or post-transplant course of patients with Group-3 PH vs unclassified PH.

Identification of Neutrophil Extracellular Trap-Related Gene Expression Signatures in Ischemia Reperfusion Injury During Lung Transplantation: A Transcriptome Analysis and Clinical Validation.

Purpose: Ischemia reperfusion injury (IRI) unavoidably occurs during lung transplantation, further contributing to primary graft dysfunction (PGD). Neutrophils are the end effectors of IRI and activated neutrophils release neutrophil extracellular traps (NETs) to further amplify damage. Nevertheless, potential contributions of NETs in IRI remain incompletely understood. This study aimed to explore NET-related gene biomarkers in IRI during lung transplantation. Methods: Differential expression analysis was applied to identify differentially expressed genes (DEGs) for IRI during lung transplantation based on matrix data (GSE145989, 127003) downloaded from GEO database. The CIBERSORT and weighted gene co-expression network analysis (WGCNA) algorithms were utilized to identify key modules associated with neutrophil infiltration. Moreover, the least absolute shrinkage and selection operator regression and random forest were applied to identify potential NET-associated hub genes. Subsequently, the screened hub genes underwent further validation of an external dataset (GSE18995) and nomogram model. Based on clinical peripheral blood samples, immunofluorescence staining and dsDNA quantification were used to assess NET formation, and ELISA was applied to validate the expression of hub genes. Results: Thirty-eight genes resulted from the intersection between 586 DEGs and 75 brown module genes, primarily enriched in leukocyte migration and NETs formation. Subsequently, four candidate hub genes (FCAR, MMP9, PADI4, and S100A12) were screened out via machine learning algorithms. Validation using an external dataset and nomogram model achieved better predictive value. Substantial NETs formation was demonstrated in IRI, with more pronounced NETs observed in patients with PGD ≥ 2. PADI4, S100A12, and MMP9 were all confirmed to be up-regulated after reperfusion through ELISA, with higher levels of S100A12 in PGD ≥ 2 patients compared with non-PGD patients. Conclusion: We identified three potential NET-related biomarkers for IRI that provide new insights into early detection and potential therapeutic targets of IRI and PGD after lung transplantation.

Plasma concentrations of histidine-rich glycoprotein in primary graft dysfunction after lung transplantation.

OBJECTIVES: Histidine-rich glycoprotein has been reported as an anti-inflammatory glycoprotein that inhibits acute lung injury in mice with sepsis and as a prognostic biomarker in patients with sepsis. We investigated the relationship between plasma concentrations of histidine-rich glycoprotein and the risk of occurrence of primary graft dysfunction. METHODS: According to the primary graft dysfunction grade at post-transplant 72 h, patients who underwent lung transplantation were divided into three groups: non-primary graft dysfunction group (grade 0-1), moderate primary graft dysfunction group (grade 2), and severe primary graft dysfunction group (grade 3). The plasma concentrations of histidine-rich glycoprotein measured daily during the first post-transplant 7 days were compared among the three groups. Appropriate cutoff values of the concentrations were set for survival analyses after lung transplantation. RESULTS: A total of 68 patients were included. The plasma histidine-rich glycoprotein concentration at post-transplant 72 h was significantly lower in the severe primary graft dysfunction group (n = 7) than in the other two groups [non-primary graft dysfunction group (n = 43), P = 0.042; moderate primary graft dysfunction group (n = 18), P = 0.040]. Patients with plasma histidine-rich glycoprotein concentration ≥34.4 µg/ml at post-transplant 72 h had significantly better chronic lung allograft dysfunction-free survival (P = 0.012) and overall survival (P = 0.037) than those with the concentration <34.4 µg/ml. CONCLUSIONS: Plasma histidine-rich glycoprotein concentrations at post-transplant 72 h might be associated with the risk of development of primary graft dysfunction.