Potential non-invasive predictive biomarkers of Chronic Lung Allograft Dysfunction

Abstract

Lung transplantation (LT) remains the definitive treatment for patients with advanced respiratory diseases. Despite significant advances, LT continues to have the poorest long-term survival outcomes among all solid organ transplants (SOT). The primary factor limiting post-transplant survival is chronic lung allograft dysfunction (CLAD), which is the leading cause of morbidity and mortality beyond the first year post-transplant, with a mortality rate approaching 30% and a major impact on five-year survival. CLAD is currently classified into three main phenotypes: bronchiolitis obliterans syndrome (BOS), restrictive allograft syndrome (RAS), and a mixed phenotype._x000D_ _x000D_ Early detection of CLAD through reliable biomarkers could enhance therapeutic and preventive strategies, improving patient outcomes. Consequently, there has been growing interest in identifying biomarkers capable of detecting graft injury and dysfunction at early stages. Krebs von den Lungen 6 (KL-6), a mucin primarily secreted by injured type II pneumocytes, has emerged as a promising biomarker for diagnosing the RAS phenotype. Additionally, donor-derived cellfree DNA (dd-cfDNA) has shown potential as a sensitive marker of lung graft injury and has been investigated in the context of allograft rejection._x000D_ _x000D_ The main objective of this thesis was to evaluate the diagnostic utility of two biomarkers —KL-6 (Part 1) and dd-cfDNA (Part 2) — for CLAD. Both biomarkers were measured longitudinally in two separate cohorts of lung transplant recipients and analyzed in relation to CLAD development over time. _x000D_ _x000D_ The first study (Part 1) revealed that while KL 6 levels did not differ significantly when comparing all patients with CLAD to those without, stratification by CLAD phenotype uncovered that patients with RAS/mixed phenotypes had significantly higher KL-6 levels over time compared to stable and BOS patients, with differences emerging by 12 months post-transplant. Moreover, analysis of KL-6 levels at six months post-transplant identified a threshold that could predict patients at increased risk of developing RAS-type CLAD._x000D_ _x000D_ In the second study (Part 2), the temporal dynamics of dd-cfDNA levels were analyzed. An increase in dd-cfDNA was observed from six months posttransplant onwards. While no statistically significant association was detected between dd-cfDNA levels and pulmonary function decline, patients with progressively increasing dd-cfDNA over time showed a higher risk of developing CLAD and greater mortality risk. Consistent with previous literature, elevated ddcfDNA levels were also observed in some patients who did not develop CLAD, supporting its potential role as a marker of lung graft injury._x000D_ _x000D_ In conclusion, the studies presented in this thesis advance biomarker-based monitoring in lung transplant recipients and support the potential utility of KL-6 and dd-cfDNA for early diagnosis and risk stratification of CLAD. These findings may facilitate identification of patients at increased risk, enabling improved posttransplant care and outcomes. Further research is warranted to validate these biomarkers in larger cohorts and explore their integration into personalized posttransplant monitoring strategies in clinical practice.

Date of Award	1 Dec 2025
Original language	English
Awarding Institution	Universitat Autònoma de Barcelona (UAB)
Supervisor	Susana Gomez Olles (Director) & Cristina Berastegui Garcia (Director)