Use of serum KL-6 level for detecting patients with restrictive allograft syndrome after lung transplantation

Autoři: Cristina Berastegui aff001;  Susana Gómez-Ollés aff001;  Alberto Mendoza-Valderrey aff001;  Thais Pereira-Veiga aff001;  Mario Culebras aff001;  Victor Monforte aff001;  Berta Saez aff001;  Manuel López-Meseguer aff001;  Helena Sintes-Permanyer aff001;  Victoria Ruiz de Miguel aff001;  Carlos Bravo aff001;  Judit Sacanell aff003;  María-Antonia Ramon aff001;  Laura Romero aff004;  María Deu aff004;  Antonio Román aff001
Působiště autorů: Servei de Pneumologia, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain aff001;  Ciber Enfermedades Respiratorias (Ciberes) aff002;  Servei de Medicina Intensiva, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain aff003;  Servei de Cirurgia Toràcica, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain aff004
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226488


KL-6 is an antigen produced mainly by damaged type II pneumocytes that is involved in interstitial lung disease. Chronic lung allograft dysfunction (CLAD) after lung transplantation (LT) is a major concern for LT clinicians, especially in patients with restrictive allograft syndrome (RAS). We investigated KL-6 levels in serum and bronchoalveolar lavage fluid (BALF) as a potential biomarker of the RAS phenotype. Levels of KL-6 in serum and BALF were measured in 73 bilateral LT recipients, and patients were categorized into 4 groups: stable (ST), infection (LTI), bronchiolitis obliterans syndrome (BOS), and RAS. We also studied a healthy cohort to determine reference values for serum KL-6. The highest levels of KL-6 were found in the serum of patients with RAS (918 [487.8–1638] U/mL). No differences were found for levels of KL-6 in BALF. Using a cut-off value of 465 U/mL serum KL-6 levels was able to differentiate RAS patients from BOS patients with a sensitivity of 100% and a specificity of 75%. Furthermore, higher serum KL-6 levels were associated with a decline in Forced Vital Capacity (FVC) at 6 months after sample collection. Therefore, KL-6 in serum may well be a potential biomarker for differentiating between the BOS and RAS phenotypes of CLAD in LT recipients.

Klíčová slova:

Biomarkers – Bronchiolitis – Cystic fibrosis – Chronic obstructive pulmonary disease – Interstitial lung diseases – Lung transplantation – Opacity – Spirometry


1. Chambers DC, Yusen RD, Cherikh WS, Goldfarb SB, Kucheryavaya AY, Khusch K, et al. The Registry of the International Society for Heart and Lung Transplantation: Thirty-fourth Adult Lung And Heart-Lung Transplantation Report-2017; Focus Theme: Allograft ischemic time. J Heart Lung Transplant 2017;36: 1047–1059. doi: 10.1016/j.healun.2017.07.016 28784324

2. Verleden GM, Glanville AR, Lease ED, Fisher AJ, Calabrese F, Corris PA, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT.J Heart Lung Transplant. 2019;38(5):493–503. doi: 10.1016/j.healun.2019.03.009 30962148

3. Sato M, Waddell TK, Wagnetz U, Roberts HC, Hwang DM, Haroon A, et al. Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction. J Heart Lung Transplant 2011;30: 735–742. doi: 10.1016/j.healun.2011.01.712 21419659

4. Glanville AR, Verleden GM, Todd JL, Benden C, Calabrese F, Gottlieb J, et al. Chronic lung allograft dysfunction: Definition and update of restrictive allograft syndrome-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019;38(5):483–492. doi: 10.1016/j.healun.2019.03.008 31027539

5. Berastegui C, Gómez-Ollés S, Sánchez-Vidaurre S, Culebras M, Monforte V, López-Meseguer M, et al. BALF cytokines in different phenotypes of chronic lung allograft dysfunction in lung transplant patients. Clin Transplant 2016.

6. Ofek E, Sato M, Saito T, Wagnetz U, Roberts HC, Chaparro C, et al. Restrictive allograft syndrome post lung transplantation is characterized by pleuroparenchymal fibroelastosis. Mod Pathol 2013;26: 350–356. doi: 10.1038/modpathol.2012.171 23018877

7. Kohno N. Serum marker KL-6/MUC1 for the diagnosis and management of interstitial pneumonitis. J Med Invest 1999;46: 151–158. 10687309

8. Ohshimo S, Yokoyama A, Hattori N, Ishikawa N, Hirasawa Y, Kohno N. KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts. Biochem Biophys Res Commun 2005;338: 1845–1852. doi: 10.1016/j.bbrc.2005.10.144 16289035

9. Nisticò P, Bissell MJ, Radisky DC. Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol. 2012;4(2).

10. Ishikawa N, Hattori N, Yokoyama A, Kohno N. Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases. Respir Investig 2012;50: 3–13. doi: 10.1016/j.resinv.2012.02.001 22554854

11. Hirasawa Y, Kohno N, Yokoyama A, Inoue Y, Abe M, Hiwada K. KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. Am J Respir Cell Mol Biol 1997;17: 501–507. doi: 10.1165/ajrcmb.17.4.2253 9376125

12. Yokoyama A, Kondo K, Nakajima M, Matsushima T, Takahashi T, Nishimura M, et al. Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis. Respirology 2006;11: 164–168. doi: 10.1111/j.1440-1843.2006.00834.x 16548901

13. Totani Y, Demura Y, Ameshima S, Ishizaki T, Miyamori I. The usefulness of serum KL-6 levels for the diagnosis of disease activity in idiopathic interstitial pneumonia. Nihon Kokyuki Gakkai Zasshi 2000;38: 437–441. 10979280

14. Oyama T, Kohno N, Oyama H, Okuda Y, Namba S, Takasugi K. Serum KL-6: a useful marker for early detection of methotrexate-induced interstitial pneumonia. Mod Rheumatol 2002;12: 366–367. doi: 10.3109/s101650200067 24384010

15. Kohno N, Awaya Y, Oyama T, Yamakido M, Akiyama M, Inoue Y, et al. KL-6, a mucin-like glycoprotein, in bronchoalveolar lavage fluid from patients with interstitial lung disease. Am Rev Respir Dis 1993;148: 637–642. doi: 10.1164/ajrccm/148.3.637 8368634

16. Walter JN, Fan LL, Bag R, Zhang H, Doan M, Mallory GB, et al. Serum KL-6 as a marker for bronchiolitis obliterans syndrome after lung transplantation. Transplantation 2006;82: 709–711. doi: 10.1097/ 16969297

17. Ohshimo S, Bonella F, Sommerwerck U, Teschler H, Kamler M, Jakob HG, et al. Comparison of serum KL-6 versus bronchoalveolar lavage neutrophilia for the diagnosis of bronchiolitis obliterans in lung transplantation. J Heart Lung Transplant 2011;30: 1374–1380. doi: 10.1016/j.healun.2011.07.010 21871820

18. Haberman B, Doan ML, Smith EO, Schecter MG, Mallory GB, Elidemir O. Serum KL-6 level and the development of bronchiolitis obliterans syndrome in lung transplant recipients. Pediatr Transplant 2010;14: 903–908. doi: 10.1111/j.1399-3046.2010.01373.x 20667031

19. Bessa V, Bonella F, Ohshimo S, Weinreich G, Kleibrink B, Costabel U, et al. Changes in serum KL-6 levels are associated with the development of chronic lung allograft dysfunction in lung transplant recipients. Transpl Immunol 2019;52:40–44. doi: 10.1016/j.trim.2018.10.006 30391371

20. Meyer KC, Raghu G, Verleden GM, Corris PA, Aurora P, Wilson KC, et al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J 2014;44: 1479–1503. doi: 10.1183/09031936.00107514 25359357

21. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. J Heart Lung Transplant 2014;33: 127–133. doi: 10.1016/j.healun.2013.10.022 24374027

22. Sato M, Hwang DM, Waddell TK, Singer LG, Keshavjee S. Progression pattern of restrictive allograft syndrome after lung transplantation. J Heart Lung Transplant 2013;32: 23–30. doi: 10.1016/j.healun.2012.09.026 23260703

23. Lin WC, Chen CW, Huang YW, Chao L, Chao J, Lin YS, et al. Kallistatin protects against sepsis-related acute lung injury via inhibiting inflammation and apoptosis. Sci Rep. 2015;5:12463. doi: 10.1038/srep12463 26198099

24. Horimasu Y, Hattori N, Ishikawa N, Kawase S, Tanaka S, Yoshioka K, et al. Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels. Respir Med 2012;106: 1756–1764. doi: 10.1016/j.rmed.2012.09.001 22995277

25. Verleden SE, Vos R, Vanaudenaerde BM, Verleden GM. Chronic lung allograft dysfunction phenotypes and treatment. J Thorac Dis 2017;9: 2650–2659. doi: 10.21037/jtd.2017.07.81 28932572

26. Estenne M, Maurer JR, Boehler A, Egan JJ, Frost A, Hertz M, et al. Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria. J Heart Lung Transplant 2002;21: 297–310. doi: 10.1016/s1053-2498(02)00398-4 11897517

27. Nathani N, Perkins GD, Tunnicliffe W, Murphy N, Manji M, Thickett DR. Kerbs von Lungren 6 antigen is a marker of alveolar inflammation but not of infection in patients with acute respiratory distress syndrome. Crit Care 2008;12: R12. doi: 10.1186/cc6785 18269741

28. Inoue Y, Barker E, Daniloff E, Kohno N, Hiwada K, Newman LS. Pulmonary epithelial cell injury and alveolar-capillary permeability in berylliosis. Am J Respir Crit Care Med 1997;156: 109–115. doi: 10.1164/ajrccm.156.1.9612043 9230733

Článek vyšel v časopise


2020 Číslo 1