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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.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.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.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.

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.

Purpose The molecular pathogenesis of chronic lung allograft dysfunction (CLAD) is poorly understood. We hypothesized that microarray analysis of TBBs and mucosal biopsies from the third bronchial bifurcation (3BMBs) would provide insight into biological pathways through gene ontology (GO) analysis. Methods We performed gene expression microarray analysis of 498 TBBs and 324 3BMBs from 10 international centers, comparing CLAD+ and CLAD- cases. CLAD was defined per 2019 ISHLT guidelines. Bayes-moderated t-tests were used to identify CLAD-associated genes. We performed GO biological process analysis with CLAD-associated genes with false discovery rate Results In TBBs CLAD-associated GO terms described lung development regulation, injury response, epithelial proliferation, epithelial-mesenchymal transition, and angiogenesis (Fig. 1A). In 3BMBs the GO terms included endocytosis and intracellular trafficking, cell-cell/cell-substrate adhesion, collagen/matrix metabolism, but unlike TBBs included immunity (Fig. 1B). Time correction did not affect transcript associations with CLAD in TBBs but diminished them in 3BMBs. Excluding biopsies with coexistent rejection or infection removed associations in TBBs but strengthened them in 3BMBs even after correcting for time post-transplant. Conclusion In our biopsy set the molecular CLAD phenotype resembles a parenchymal response to wounding that overlaps other pathologies. CLAD-associated molecular changes were independent of time in TBBs but not 3BMBs, suggesting that CLAD is primarily a time dependent airway process involving injury and either adaptive or innate immunity. Unlike TBBs, molecular changes in 3BMBs were identifiable despite coexistent rejection or infection, suggesting this biopsy format may better capture CLAD information.

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.

Przedstawiono przypadek 66-letniej chorej z guzkami pluc o średnicy do 1 cm obserwowanymi od 2 lat. Chora byla dializowana od wielu lat z powodu przewleklej niewydolności nerek, jednakze bez cech niewydolności oddechowej, z prawidlowymi stezeniami wapnia w surowicy. Drogą otwartej biopsji pluca pobrano kilka pojedynczych guzkow, a wynik histopatologiczny oceniono jako przerzutowe zwapnienia plucne (metastatic pulmonary calcification – MPC). Na podstawie przeglądu piśmiennictwa opisano kliniczne, morfologiczne i patofizjologiczne cechy MPC wraz z ich diagnostyką, z odniesieniem do prezentowanego przypadku. Slowa kluczowe: niewydolnośc nerek, guz pluca, zwapnienia przerzutowe. Abstract