Defining a natural killer cell-enriched molecular rejection-like state in lung transplant transbronchial biopsies.

In lung transplantation, antibody-mediated rejection (AMR) diagnosed using the International Society for Heart and Lung Transplantation criteria is uncommon compared with other organs, and previous studies failed to find molecular AMR (ABMR) in lung biopsies. However, understanding of ABMR has changed with the recognition that ABMR in kidney transplants is often donor-specific antibody (DSA)-negative and associated with natural killer (NK) cell transcripts. We therefore searched for a similar molecular ABMR-like state in transbronchial biopsies using gene expression microarray results from the INTERLUNG study (#NCT02812290). After optimizing rejection-selective transcript sets in a training set (N = 488), the resulting algorithms separated an NK cell-enriched molecular rejection-like state (NKRL) from T cell-mediated rejection (TCMR)/Mixed in a test set (N = 488). Applying this approach to all 896 transbronchial biopsies distinguished 3 groups: no rejection, TCMR/Mixed, and NKRL. Like TCMR/Mixed, NKRL had increased expression of all-rejection transcripts, but NKRL had increased expression of NK cell transcripts, whereas TCMR/Mixed had increased effector T cell and activated macrophage transcripts. NKRL was usually DSA-negative and not recognized as AMR clinically. TCMR/Mixed was associated with chronic lung allograft dysfunction, reduced one-second forced expiratory volume at the time of biopsy, and short-term graft failure, but NKRL was not. Thus, some lung transplants manifest a molecular state similar to DSA-negative ABMR in kidney and heart transplants, but its clinical significance must be established.

Analysis of Donor to Recipient Pathogen Transmission in Relation to Cold Ischemic Time and Other Selected Aspects of Lung Transplantation-Single Center Experience.

BACKGROUND: Infections are one of the leading causes of death in the early postoperative period after lung transplantation (LuTx). METHODS: We analyzed 59 transplantations and culture results of the donor bronchial aspirates (DBA), graft endobronchial swabs (GES), and recipient cultures (RC) before and after the procedure (RBA). We correlated the results with a cold ischemic time (CIT), recipient intubation time, and length of stay in the hospital and intensive care unit (ICU), among others. RESULTS: CIT of the first and second lungs were 403 and 541 min, respectively. Forty-two and eighty-three percent of cultures were positive in DBA and GES, respectively. Furthermore, positive results were obtained in 79.7% of RC and in 33.9% of RBA. Longer donor hospitalization was correlated with Gram-negative bacteria isolation in DBA. Longer CIT was associated with Gram-positive bacteria other than Staphylococcus aureus in GES and it resulted in longer recipient stay in the ICU. Furthermore, longer CIT resulted in the development of the new pathogens in RBA. CONCLUSION: Results of GES brought more clinically relevant information than DBA. Donor hospitalization was associated with the occurrence of Gram-negative bacteria. Positive cultures of DBA, GES, and RBA were not associated with recipient death.

Right Heart Echocardiography Parameters and Other Predictors to Evaluate Mechanical Cardiac Support Necessity During Lung Transplantation.

BACKGROUND: Lung transplantation (LuTx) is a challenge when right heart function fails. Mechanical circulatory support (MCS) is then necessary. METHODS: We aimed to investigate whether preoperative transthoracic echocardiography (TTE) can predict MCS use and help to exclude the sickest patients. Between 2011 and 2018, 52 patients at our institution received LuTx and qualified for this study: 35 bilateral, 16 single, 1 lobar [1] and 1 retransplantation procedure. Of these, 22 were operated using MCS and 30 without MCS. The patients were aged between 18 and 65 years, and 23 were women. The indications were lung fibrosis for 18 patients, chronic obstructive lung disease for 16, cystic fibrosis for 15, primary pulmonary hypertension for 2 and bronchiectasis for 1. TTE was performed up to 30 days before treatment and 1 to 7 days after. RESULTS: Patients undergoing MCS versus patients not undergoing MCS: preoperative right ventricular systolic pressure 56.5 (30) vs 37.8 (11.5) mm Hg (P = .03); tricuspid regurgitation pressure gradient 48.7 (27) vs 30.2 (10.8) mm Hg (P = .015); tricuspid annular plane systolic excursion 17.8 (4.3) vs 19.9 (2.8) mm Hg (P = .04); pulmonary artery diameter 27.5 (5.2) vs 23.9 (4.1) mm (P = .004); age 41.9 (14.1) vs 54.3 (11.8) years (P = .001). Patients who were Dead versus patients who were alive pulmonary valve acceleration time of 82.8 (24.1) vs 104.9 (27.2) ms (hazard ratio [HR] = 0.959, 95% confidence interval [CI] = 0.923-0.996 per ms, P = .02) and pulmonary artery diameter of 28.9 (5.8) vs 24.4 (4.1) mm HR = 1.225, 95% CI = 1.028-1.460 per 1 mm, P = .016 were predictors of death. CONCLUSIONS: Preoperative TTE parameters: right ventricular systolic pressure, tricuspid regurgitation pressure gradient, tricuspid annular plane systolic excursion, and pulmonary artery diameter predicted MCS use during LuTx. Certain values of valve acceleration time and pulmonary artery diameter could help discern LuTx qualification.

The molecular features of chronic lung allograft dysfunction in lung transplant airway mucosa.

BACKGROUND: Many lung transplants fail due to chronic lung allograft dysfunction (CLAD). We recently showed that transbronchial biopsies (TBBs) from CLAD patients manifest severe parenchymal injury and dedifferentiation, distinct from time-dependent changes. The present study explored time-selective and CLAD-selective transcripts in mucosal biopsies from the third bronchial bifurcation (3BMBs), compared to those in TBBs. METHODS: We used genome-wide microarray measurements in 324 3BMBs to identify CLAD-selective changes as well as time-dependent changes and develop a CLAD classifier. CLAD-selective transcripts were identified with linear models for microarray data (limma) and were used to build an ensemble of 12 classifiers to predict CLAD. Hazard models and random forests were then used to predict the risk of graft loss using the CLAD classifier, transcript sets associated with rejection, injury, and time. RESULTS: T cell-mediated rejection and donor-specific antibody were increased in CLAD 3BMBs but most had no rejection. Like TBBs, 3BMBs showed a time-dependent increase in transcripts expressed in inflammatory cells that was not associated with CLAD or survival. Also like TBBs, the CLAD-selective transcripts in 3BMBs reflected severe parenchymal injury and dedifferentiation, not inflammation or rejection. While 3BMBs and TBBs did not overlap in their top 20 CLAD-selective transcripts, many CLAD-selective transcripts were significantly increased in both for example LOXL1, an enzyme controlling matrix remodeling. In Cox models for one-year survival, the 3BMB CLAD-selective transcripts and CLAD classifier predicted graft loss and correlated with CLAD stage. Many 3BMB CLAD-selective transcripts were also increased by injury in kidney transplants and correlated with decreased kidney survival, including LOXL1. CONCLUSIONS: Mucosal and transbronchial biopsies from CLAD patients reveal a diffuse molecular injury and dedifferentiation state that impacts prognosis and correlates with the physiologic disturbances. CLAD state in lung transplants shares features with failing kidney transplants, indicating elements shared by the injury responses of distressed organs.

Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants.

Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased-dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.

Central, peripheral ECMO or CPB? Comparsion between circulatory support methods used during lung transplantation.

BACKGROUND: Chronic obstructive pulmonary disease, cystic fibrosis and usual interstitial pneumonia are three most common indications for lung transplantation (LuTx) in Poland. As a result of irreversible destruction of pulmonary parenchyma and extended respiratory insufficiency that appear afterwards, it is crucial to estimate the reserve of gas exchange in each lung before and during surgery. Altering conditions of gas exchange require adaptation in circulatory system as well. In some of the cases the use of extracorporeal life support appears to be necessary to undergo the transplantation successfully. Cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) used during operation allow to replace the function of heart and lung, but they are also related to complications in the form of acute kidney failure, bleeding, heart arrhythmias or thromboembolic complications. METHODS: We reviewed 77 LuTx from 2009 to 2020 performed at the Department of Thoracic Surgery and Transplantation. 40/77 (51%) patients required intraoperative extracorporeal assistance: 8 required CBP and 32 required ECMO. In the ECMO group 14/32 (44%) patients had peripheral cannulation and 18/32 (56%) had central one. We have calculated the survival rates and reviewed postoperative complications after lung transplantations. Cumulative Kaplan-Meier survival curves were calculated. Differences between the groups were evaluated by the Chi- square analysis for discontinuous variables and t-test for continuous variables. RESULTS: The use of intraoperative central extracorporeal membrane oxygenator was associated with increased survival rates comparing to patients without external support (30-days, 1-year, 3-years, 5-years rates: 78%, 66%, 66%, 66% vs 83%, 65%, 59%, 44% respectively). Furthermore, survival was enhanced comparing to peripheral ECMO or cardiopulmonary bypass as well (50%, 41%, 41%, 33%; 75%, 50%, 50%, 38% respectively). Acute kidney injury and thromboembolic complications occurred statistically more often in case of patients that underwent lung transplantation with support devices (p = 0.005, p = 0.02 respectively). Frequency of other complications was comparable among groups. CONCLUSIONS: The use of central extracorporeal membrane oxygenation should be favorized over peripheral cannulation or cardiopulmonary bypass. CPB should be no longer used during LuTx. Trial registration Not applicable.

Molecular T-cell‒mediated rejection in transbronchial and mucosal lung transplant biopsies is associated with future risk of graft loss.

BACKGROUND: We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies, identifying T-cell‒mediated rejection (TCMR) on the basis of the expression of rejection-associated transcripts, but the relationship of rejection to graft loss is unknown. This study aimed to develop molecular assessments for TBBs and mucosal biopsies and to establish the impact of molecular TCMR on graft survival. METHODS: We used microarrays and machine learning to assign TCMR scores to an expanded cohort of 457 TBBs (367 high surfactant plus 90 low surfactant) and 314 mucosal biopsies. We tested the score agreement between TBB-TBB, mucosal-mucosal, and TBB-mucosal biopsy pairs in the same patient. We also assessed the association of molecular TCMR scores with graft loss (death or retransplantation) and compared it with the prognostic associations for histology and donor-specific antibodies. RESULTS: The molecular TCMR scores assigned in all the TBBs performed similarly to those in high-surfactant TBBs, indicating that variation in alveolation in TBBs does not prevent the detection of TCMR. Mucosal biopsy pieces showed less piece-to-piece variation than TBBs. TCMR scores in TBBs agreed with those in mucosal biopsies. In both TBBs and mucosal biopsies, molecular TCMR was associated with graft loss, whereas histologic rejection and donor-specific antibodies were not. CONCLUSIONS: Molecular TCMR can be detected in TBBs regardless of surfactant and in mucosal biopsies, which show less variability in the sampled tissue than TBBs. On the basis of these findings, molecular TCMR appears to be an important predictor of the risk of future graft failure. TRIAL REGISTRATION: ClinicalTrials.gov NCT02812290.

Surgeon's viewpoint on lung transplantation in cystic fibrosis patients - preliminary report.

INTRODUCTION: The surgeon's viewpoint on a patient with cystic fibrosis differs from that of a pediatrician or internist. The problems a cystic fibrosis specialist encounters are different from those faced by the surgeon who takes over the patient in a very advanced, often terminal stage of the disease. Hence, the main problem for the surgeon is the decision concerning the surgery (lung transplantation, pneumonectomy, lobectomy). It is, therefore, important to lay down fundamental and appropriate rules concerning the indications and contraindications for lung transplantation, especially in patients with cystic fibrosis. AIM: The aim of this study was to analyze the methods of qualifying and preparing patients for surgery, as well as carrying out the procedure of transplantation and postoperative short and long-term care. MATERIAL AND METHODS: The investigation was carried out on 16 patients with cystic fibrosis. Three were operated on and 10 were on the waiting list for transplantation. Two patients on the waiting list died, one patient was disqualified from transplantation. During qualification for lung transplantation, strict indications, contraindications and other factors (such as blood type, patient's height, coexisting complications) were taken under consideration. RESULTS: All the 3 patients after lung transplantation are alive and under our constant surveillance. Ten patients await transplantation, though four of them are suspended due to hepatitis C infection. Two patients on the waiting list died: one from respiratory insufficiency and the other in the course of bridge to-transplant veno-venous extracorporeal membrane oxygenation due to hepatic failure. One patient has been disqualified because of cachexia. CONCLUSIONS: Since lung transplantation is the final treatment of the end-stage pulmonary insufficiency in cystic fibrosis patients, the number of such procedures in cystic fibrosis is still too low in Poland. The fast development of these procedures is highly needed. It is necessary to develop better cooperation between different disciplines and specialists, especially between pediatricians and surgeons. The correct choice of the suitable moment for lung transplantation is crucial for the success of the procedure.

[Primary pulmonary mucosa-associated lymphoid tissue lymphoma: a case report]. / Chloniak typu MALT o lokalizacji plucnej - opis przypadku.

Primary pulmonary lymphoma accounts only 0,5% of all primary lung neoplasms. Mucosa-associated lymphoid tissue (MALT) lymphoma is a low grade B-cell extranodal lymphoma. It is a quite infrequent entity, however it constitutes from 72% to 90% of all pulmonary lung lymphomas. Long-term stimulation of bronchus-associated lymphoid tissue by antigens, smoking, inflammatory disorders or autoimmune diseases are thought to be leading to the development of MALT lymphoma. We present the case of primary pulmonary mucosa-associated lymphoid tissue lymphoma. A 76-year-old man with a history of heavy smoking (22.5 pack years) was admitted to the hospital for a further diagnostics of an abnormal finding in the right lung visualized on the chest X-ray. The diagnostic process, including imagining studies did not reveal the etiology of a lesion in the right lung. The patient was qualified for surgical diagnostics. The histological finding confirmed extranodal marginal low-grade B-cell lymphoma of mucosa -associated lymphoid tissue.

Single lung transplantation in a patient with retrospective positive cross-match.

Lung transplantation is a method useful in such non-malignant end-stage parenchymal and vascular diseases as: chronic obstructive pulmonary disease (COPD), idiopathic interstitial pulmonary fibrosis, cystic fibrosis, or primary pulmonary hypertension. The main aim of this procedure is to extend the patient's lifespan and quality of life. However, the availability of the operation is limited by organ access. In this paper we present the case of a 58-year-old female in the fourth stage of COPD, who was classified to have a single lung transplantation. Because of some technical problems it was decided to transplant a left donor lung in the right recipient lung locus. Positive cross match was demonstrated retrospectively, and we applied five courses of plasmapheresis. Human immunoglobulin and rituximab treatment were performed to decrease the impact of lymphocytotoxic antibodies. The patient survived 498 days after transplantation, 271 in the hospital.

Cardiovascular risk in patients undergoing maintenance hemodialysis with Helixone® membrane: a multicenter randomized study.

INTRODUCTION: The high prevalence and incidence of atherosclerotic vascular complications, such as cardiovascular disease, remain the major cause of morbidity and mortality in patients undergoing dialysis. OBJECTIVES: The aim of the study was to evaluate cardiovascular risk factors in patients dialyzed with a high­flux polysulfone membrane (Helixone®) compared with those dialyzed with a low­flux polysulfone membrane. PATIENTS AND METHODS: This was a crossover randomized study including 90 hemodialysis patients. Group 1 was treated first with high­flux and then with low­flux membranes, while group 2, first with low­flux and then with high­flux membranes for 13 months. Clinical, biochemical, and echocardiographic data were evaluated at baseline and every 3 months during the study. RESULTS: After 6 months of high­flux dialysis, we observed a significant decrease in ß2­microglobulin, lipoprotein(a), C­reactive protein, and parathormone levels and an increase in serum albumin levels. Initially, both groups showed left ventricular hypertrophy. After 6 months of high­flux dialysis, we observed a tendency for an increase in the cardiac index and cardiac output and a decrease in isovolumic relaxation time. CONCLUSIONS: Our study showed that the use of high­flux dialysis with the Helixone® membrane, in comparison with low­flux dialysis with polysulfone membranes, improves middle-molecular clearance. In addition, we showed that a reduction in chronic inflammation during high­flux dialysis may decrease cardiovascular risk. However, further research with longer follow­up is needed to verify our echocardiographic findings.

The clinicopathological determinants of native arteriovenous fistula failure in patients on maintenance hemodialysis.

BACKGROUND: Progressive narrowing of the venous part of dialysis fistulae is caused by hemodynamic and inflammatory factors. OBJECTIVES: The pathogenic and clinical determinants of deterioration of the functioning of arteriovenous fistulae in chronically hemodialyzed patients were evaluated. MATERIAL AND METHODS: The hemodynamic parameters and the activity of inflammatory growth factors in the vessel wall of newly implanted fistulae were assessed and correlated with the clinical course of 34 hemodialyzed patients. Measurements taken at the time of implanting the fistulae included blood flow in the venous part of the anastomosis and its widest diameter by ultrasound Power Doppler, a histopathologic examination of fistula wall samples and measurements of mRNA expression for growth factors PDGFß1 and TGFß in the fistula wall. The results were correlated with clinical data from 36 months' observation: duration of fistula maturation, adequacy of dialysis treatment (eKt/V), the patient's survival, morbidity linked with vascular access problems and general cardiovascular morbidity. RESULTS: The mean duration of fistula maturation was 44.9 days (N = 43, SD = 38.6), whereas the average duration of fistula usage as dialysis access was 795.9 ± 480.6 days. Fistula blood flow at the time of implantation, averaged 1782.2 ± 1735.3 ml/min. The mean number of hospitalization days due to vascular access morbidity was 9.9 ± 15.6 days and it correlated positively with the fistula blood flow (R = 0.596, P = 0.004). There was a negative correlation between the expression of PDGFß1 mRNA and fistula blood flow (R = -0.673, P = 0.011), as well as between TGFß expression and patient survival (R = -0.722, P = 0.002). CONCLUSIONS: Inflammatory activity of the vessel wall growth factors PDGFß1 and TGFß implies impairment of fistula function and the patient's cardiovascular morbidity.