Epithelial cell death markers in bronchoalveolar lavage correlate with chronic lung allograft dysfunction subtypes and survival in lung transplant recipients—a single‐center retrospective cohort study

Levy, Liran; Tigert, A.; Huszti, Ella; Saito, Tomohito; Mitsakakis, Nicholas; Moshkelgosha, Sajad; Joe, Betty; Boonstra, K.; Tikkanen, Jussi; Keshavjee, S.; Juvet, S.; Martinu, T.

doi:10.1111/tri.13444

Cited by 21 publications

(17 citation statements)

References 40 publications

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“…A larger sample size of patients within our selected date range could not be gathered due to limits in the availability of concurrent plasma and BAL samples. Nevertheless, our sample size is consistent with other reported biomarker experiments in LTx (48)(49)(50). Third, we did not test for all the different MASPs, which would have provided additional specificity for the proteases that facilitate lectin pathway activation.…”

Section: L I N I C a L M E D I C I N Esupporting

confidence: 64%

Local complement activation is associated with primary graft dysfunction after lung transplantation

Kulkarni

Ramphal

et al. 2020

JCI Insight

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Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 hours after LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA. RESULTS. In both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared with those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared with subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma. CONCLUSION. Complement activation fragments are detected in the BAL within 24 hours after LTx. Components of all 3 pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD.

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Section: L I N I C a L M E D I C I N Esupporting

confidence: 64%

Local complement activation is associated with primary graft dysfunction after lung transplantation

Kulkarni

Ramphal

et al. 2020

JCI Insight

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“…Finally, to accurately phenotype patients with CLAD in the future, incorporating specific biomarkers would add additional objectivity to the process. 20…”

Section: Figurementioning

confidence: 99%

Risk assessment of chronic lung allograft dysfunction phenotypes: Validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation classification system

Levy

Huszti

Renaud-Picard

et al. 2020

The Journal of Heart and Lung Transplantation

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BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a heterogeneous condition. Characterization of CLAD phenotypes is essential to enhance the understanding of pathogenesis and guide new therapies. The study objective was to validate the new International Society for Heart and Lung Transplantation (ISHLT) CLAD classification system and further explore patients who do not fall into the defined CLAD sub-categories. METHODS: We performed a single-center, retrospective cohort study of adult, first, bilateral lung transplants performed from 2010 to 2015. Patients with CLAD were classified on the basis of the 2019 ISHLT consensus document. CLAD phenotypes and other potential predictors of survival after CLAD onset were assessed using Kaplan−Meier and Cox proportional hazards models. RESULTS: Among the 174 subjects with CLAD, 104 (59.8%) had bronchiolitis obliterans syndrome (BOS), 16 (9.2%) restrictive allograft syndrome (RAS), 9 (5.2%) mixed, and 19 (10.9%) undefined phenotype. A total of 26 patients (14.9%) did not match any of these 4 categories and remained unclassified. Allograft survival post-CLAD onset was longer for patients with BOS (median, 500 days) than patients with RAS (median, 372 days) or mixed (median, 328 days). The 45 patients (26.8%) with undefined/unclassified phenotype were combined and recategorized on the basis of the presence or absence of characteristic RAS-like opacities on chest imaging; those with RAS-like opacities had significantly worse allograft survival than patients with BOS (hazard ratio, 2.14; 95% confidence interval, 1.17−3.93; p = 0.014) and similar survival to RAS or mixed phenotype.

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“…K18 has been proposed as a biomarker for a range of liver conditions including acute liver failure and chronic liver diseases such as viral hepatitis, non-alcoholic fatty liver disease and liver cancer (Ku et al 2016). While an advantage of K18 as a biomarker is that it is an early marker of apoptosis/necrosis; a disadvantage is that it is also a biomarker for dysfunction in tissues other than the liver including the lung (Fu et al 2019;Levy et al 2019;Molnar et al 2019;Tajima et al 2019) (Yang et al 2019). Thus, a panel of 3 or 7 biomarkers may be advantageous over a single biomarker.…”

Section: Discussionmentioning

confidence: 99%

Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans

Llewellyn

Vaidya

Wang

et al. 2021

Toxicological Sciences

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Early diagnosis of drug-induced liver injury (DILI) continues to be a major hurdle during drug development and post marketing. The objective of this study was to evaluate the diagnostic performance of promising biomarkers of liver injury—glutamate dehydrogenase (GLDH), cytokeratin-18 (K18), caspase-cleaved K18 (ccK18), osteopontin (OPN), macrophage colony-stimulating factor (MCSF), MCSF receptor (MCSFR), and microRNA-122 (miR-122) in comparison to the traditional biomarker alanine aminotransferase (ALT). Biomarkers were evaluated individually and as a multivariate model in a cohort of acetaminophen overdose (n = 175) subjects and were further tested in cohorts of healthy adults (n = 135), patients with liver damage from various causes (n = 104), and patients with damage to the muscle (n = 74), kidney (n = 40), gastrointestinal tract (n = 37) and pancreas (n = 34). In the acetaminophen cohort, a multivariate model with GLDH, K18 and miR-122 was able to detect DILI more accurately than individual biomarkers alone. Furthermore, the three-biomarker model could accurately predict patients with liver injury compared to healthy volunteers or patients with damage to muscle, pancreas, gastrointestinal tract and kidney. Expression of K18, GLDH ad miR-122 was evaluated using a database of transcriptomic profiles across multiple tissues/organs in humans and rats. K18 mRNA (Krt18) and MiR-122 were highly expressed in liver whereas GLDH mRNA (Glud1) was widely expressed. We performed a comprehensive, comparative performance assessment of seven promising biomarkers and demonstrated that a three-biomarker multivariate model can accurately detect liver injury.

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Epithelial cell death markers in bronchoalveolar lavage correlate with chronic lung allograft dysfunction subtypes and survival in lung transplant recipients—a single‐center retrospective cohort study

Cited by 21 publications

References 40 publications

Local complement activation is associated with primary graft dysfunction after lung transplantation

Local complement activation is associated with primary graft dysfunction after lung transplantation

Risk assessment of chronic lung allograft dysfunction phenotypes: Validation and proposed refinement of the 2019 International Society for Heart and Lung Transplantation classification system

Evaluating the Sensitivity and Specificity of Promising Circulating Biomarkers to Diagnose Liver Injury in Humans

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