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Peer-reviewedCC BYRespiratory Research

Exosomal KL-6 surpasses total plasma KL-6 in the diagnosis of Interstitial Lung Disease (ILD)

  • Huimin Huang1
  • Ruogu Lai1
  • Junqi Li2
  • Qian Han1
  • Yunpeng Xiao3
  • Xinru Wei4
  • Jin Li5
  • Ziyi Zhang1
  • Yanting Fang1
  • Yunxin Lai1
  • Ping Zhang4
  • Xiaoxiao Li6
6 more authors
  • Jie Zhang7
  • Shuilian Yu8
  • Fei Yuan9
  • Jia Li1
  • Baoqing Sun1
  • Jin Su3
9 affiliations
  1. 1Department of Clinical Laboratory, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University
  2. 2Medical Research Center, Tianjian Laboratory of Advanced Biomedical Sciences, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou University
  3. 3Guangzhou National Laboratory
  4. 4Feichuang Biomedical Technology (Guangzhou) Co., Ltd
  5. 5Guangzhou Jinyu Medical Laboratory Group Co., Ltd
  6. 6Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University
  7. 7Department of Radiation Medicine, Faculty of Preventive Medicine, Fourth Military Medical University
  8. 8Department of Rheumatology and Immunology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University
  9. 9Department of Rheumatology, Dongguan People’s Hospital
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Abstract

Background Krebs Von den Lungen-6 (KL-6) is an established biomarker for interstitial lung diseases (ILDs), but the utility of exosomal KL-6 versus plasma KL-6 in connective tissue disease-associated ILD (CTD-ILD) remains unclear. Methods We integrated single-cell transcriptomic re-analysis (GSE135893) with a multi-center cohort of 223 subjects, including 167 ILD, 22 CTD without ILD[CTD (Non-ILD)], 34 healthy controls(HCs). Plasma and exosomal KL-6 were measured, and diagnostic performance was evaluated via Receiver operating characteristic(ROC) analysis. Ten progressive ILD patients were monitored longitudinally. Results Single-cell sequencing revealed a significantly stronger correlation between Mucin 1 (MUC1)and exosomal markers (CD63/CD81) in alveolar type II cells from ILD patients compared to HCs, suggesting a potential vesicular association of KL-6. Clinical validation demonstrated that both plasma and exosomal KL-6 levels were significantly elevated in the ILD group. Crucially, for distinguishing CTD-ILD patients with negative plasma KL-6 results [CTD-ILD (plasma KL-6-)] from HCs, exosomal KL-6 [Area under the curve(AUC) = 0.900] outperformed plasma KL-6 (AUC = 0.879). More importantly, in differentiating CTD-ILD (plasma KL-6-) from CTD (Non-ILD), exosomal KL-6 again showed superior diagnostic accuracy (AUC = 0.782, sensitivity = 90.0%, specificity = 77.3%) compared to plasma KL-6 (AUC = 0.705, sensitivity = 65.0%, specificity = 81.8%). Plasma and exosomal KL-6 concentrations were highly correlated (rs = 0.968, p < 0.001). In longitudinal monitoring, both biomarkers increased in patients with radiographic disease progression. Conclusions Exosomal KL-6 is superior to plasma KL-6 for diagnosing CTD-ILD, especially in plasma KL-6-negative patients, and shows potential for monitoring disease progression.

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Cite

BibTeXRIS
BibTeX
@article{huang2026exosomal,
  title = {{Exosomal KL-6 surpasses total plasma KL-6 in the diagnosis of Interstitial Lung Disease (ILD)}},
  author = {Huimin Huang and Ruogu Lai and Junqi Li and Qian Han and Yunpeng Xiao and Xinru Wei and Jin Li and Ziyi Zhang and Yanting Fang and Yunxin Lai and Ping Zhang and Xiaoxiao Li and Jie Zhang and Shuilian Yu and Fei Yuan and Jia Li and Baoqing Sun and Jin Su},
  journal = {Respiratory Research},
  year = {2026},
  month = jul,
  doi = {10.1186/s12931-026-03816-x},
  url = {https://doi.org/10.1186/s12931-026-03816-x},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Exosomal KL-6 surpasses total plasma KL-6 in the diagnosis of Interstitial Lung Disease (ILD)
AU  - Huimin Huang
AU  - Ruogu Lai
AU  - Junqi Li
AU  - Qian Han
AU  - Yunpeng Xiao
AU  - Xinru Wei
AU  - Jin Li
AU  - Ziyi Zhang
AU  - Yanting Fang
AU  - Yunxin Lai
AU  - Ping Zhang
AU  - Xiaoxiao Li
AU  - Jie Zhang
AU  - Shuilian Yu
AU  - Fei Yuan
AU  - Jia Li
AU  - Baoqing Sun
AU  - Jin Su
PY  - 2026
DA  - 2026/07/01
JO  - Respiratory Research
DO  - 10.1186/s12931-026-03816-x
UR  - https://doi.org/10.1186/s12931-026-03816-x
AB  - Background Krebs Von den Lungen-6 (KL-6) is an established biomarker for interstitial lung diseases (ILDs), but the utility of exosomal KL-6 versus plasma KL-6 in connective tissue disease-associated ILD (CTD-ILD) remains unclear. Methods We integrated single-cell transcriptomic re-analysis (GSE135893) with a multi-center cohort of 223 subjects, including 167 ILD, 22 CTD without ILD[CTD (Non-ILD)], 34 healthy controls(HCs). Plasma and exosomal KL-6 were measured, and diagnostic performance was evaluated via Receiver operating characteristic(ROC) analysis. Ten progressive ILD patients were monitored longitudinally. Results Single-cell sequencing revealed a significantly stronger correlation between Mucin 1 (MUC1)and exosomal markers (CD63/CD81) in alveolar type II cells from ILD patients compared to HCs, suggesting a potential vesicular association of KL-6. Clinical validation demonstrated that both plasma and exosomal KL-6 levels were significantly elevated in the ILD group. Crucially, for distinguishing CTD-ILD patients with negative plasma KL-6 results [CTD-ILD (plasma KL-6-)] from HCs, exosomal KL-6 [Area under the curve(AUC) = 0.900] outperformed plasma KL-6 (AUC = 0.879). More importantly, in differentiating CTD-ILD (plasma KL-6-) from CTD (Non-ILD), exosomal KL-6 again showed superior diagnostic accuracy (AUC = 0.782, sensitivity = 90.0%, specificity = 77.3%) compared to plasma KL-6 (AUC = 0.705, sensitivity = 65.0%, specificity = 81.8%). Plasma and exosomal KL-6 concentrations were highly correlated (rs = 0.968, p < 0.001). In longitudinal monitoring, both biomarkers increased in patients with radiographic disease progression. Conclusions Exosomal KL-6 is superior to plasma KL-6 for diagnosing CTD-ILD, especially in plasma KL-6-negative patients, and shows potential for monitoring disease progression.
SN  - 1465-993X
SN  - 1465-9921
ER  -