This document discusses KL-6, a biomarker for interstitial lung diseases. KL-6 is a mucin-like glycoprotein expressed on type II alveolar epithelial cells and bronchiolar epithelial cells. When these cells are proliferating, stimulated, or injured, KL-6 is released into the bloodstream. Multiple studies have found elevated KL-6 serum concentrations in interstitial lung diseases associated with pulmonary fibrosis. KL-6 is a good marker of alveolar epithelial cell injury and correlates with fibrosis seen on CT scans. KL-6 levels can help differentiate between types of lung diseases and indicate prognosis, with levels over 1000 U/mL suggesting progressive disease and poor survival in patients with interstitial lung

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Biomarker: KL-6
Krebs von den Lungen-6

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65% of all patients with interstitial lung diseases (ILD) are ILDs of
unknown aethiology
Diagnosis is difficult
2 From: The European Lung White Book, ERS, 2013
There are more than 300 different
conditions included among the total
number of ILDs
Diagnosis is typically comprised of:
• Physical examination -
Cardiopulmonary exercise test
• Pulmonary function tests - Six-
minute walk test
• X-rays
• CT scans
If no diagnosis is evident :
• Bronchoalveolar lavage (BALf)
• Biopsy

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Diagnosis of Idiopathic Interstitial Pneumonia (IIP)
Diagnosis of Idiopathic Interstitial Pneumonia (IIP)
HRTC is used to separate patients with typical features for UIP/IPF from those with
less specific features associated to other IIP
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 165 2002

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Searching for biomarkers in pulmonary fibrosis
Prognosis
4 Source: Prasse & Müller-Quernheim, Respiratology (2009) 14,788-795
Biomarker with prognostic value
- to predict who will suffer from IPF in future
- to quantify the severity of pulmonary fibrosis (activity of fibrotic
disease process)
- to help for staging organ damage
- to alert to the acceleration of disease progression
- to guide therapeutic intervention (in fibrotic diseases, efficient
treatment strategies are currently largely absent)
Optimal biomarker:
- Non invasive (blood sampling)
- Reliable on standard measurement techniques
- Not sensible to confounding factors (smoking, infections,..)

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Searching for biomarkers in pulmonary fibrosis
Mechanisms contributing to increase serum concentration
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Biomarkers for fibrotic lung disease and their cellular sources.
AEC II, alveolar epithelial cell type II; AM, alveolar
macrophage; ECM, extracellular matrix; KL-6, Krebs von den
Lungen 6 Antigen; MCP-1, monocyte chemotactic protein-1;
SP-A, surfactant protein A; SP-D, surfactant protein D.
Source: Prasse & Müller-Quernheim, Respiratology (2009) 14,788-795
1. Elevated pulmonary production
due to diffuse hyperplasia of alveolar epithelial
cells (AEC, called also pneumocytes)
2. Increase in spillover to the systemic circulation
due to leakage of the alveolo-capillary
membrane
Biomarkers of interest:
• Derived from AEC
o SP-A, SP-D, KL-6
• Produced by alveolar macrophages
o CCL18
• Pro-inflammatory chemokines induce during
immune response (to recruit cells of the immune
system)
o IL-8
o MCP-1(CCL2)

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• KL-6 is a mucin-like, high-molecular weight glycoprotein expressed on the surface membrane of
type II alveolar epithelial cells (AEC II) and broncheolar epithelial cells. (Kohno et al. 1989)
• When these cells are proliferating, stimulated or injured, KL-6 is released. (Kohno et al. 1989)
• Multiple studies indicate that KL-6 serum concentrations are elevated in various ILD associated with
pulmonary fibrosis, on average >1000U/mL (Kobayashi et al, 1995; Kohno et al, 1997)
• Bonella et al. found a stronger correlation for KL-6 than SP-D with HRCT fibrosis scores (Bonella et
al. 2011)
• KL-6 is a good marker of AEC injury (Kohno et al. 1989)
What is KL-6?
Krebs van den Lungen 6 Antigen (KL-6)
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KL-6 (Krebs von den Lungen-6 Antigen)
A good marker for ILD
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Different rates at which KL-6 tests positive in different lung diseases (Kohno et al, 1999).
Abbreviations: HV, health volunteer; CD, collagen disease; PN, ordinary pneumonia; PE, pulmonary emphysema; BE, bronchiectasis;
TB, pulmonary tuberculosis; IPF, idiopathic pulmonary fibrosis; HP, hypersensitivity pneumonia; IPCD, interstitial pneumonia with
collagen disease.

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KL-6 (Krebs von den Lungen-6 Antigen)
Clinical cut-offs
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Serum KL-6 level of higher than 500 U/mL is a marker of the presence of IP, and a level of higher
than 1,000 U/mL is a marker of active IP associated with Connective Tissue Diseases
Source: S Doishita et al, 2011. Intern Med 50: 2889-2892

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• In patients with ILD and connective tissue disease,
o KL-6 serum is relatively stable in individual patients
o Patients with progressive disease have higher KL-6 levels than patients with stable
disease. Elevated KL-6 indicates poor prognosis with a univariate HR of 2,5 (p=0.0001)
o The cut-off value of 1000 U/mL is the most suitable to predict survival (Satoh et al,
2006). The risk of mortality is 12,6-fold higher (Yokoyama et al, 2006) – sensitivity 90%,
specificity of 71% and accuracy of 78% for the prediction of mortality.
o Close correlation between KL-6 levels and the clinical course (Yanaba et al, 2003)
• The median KL-6 serum concentrations in healthy volunteers is 306 U/mL. None of the healthy
volunteers had a KL-6 concentration >500 U/mL. The highest increase in serum KL-6 was described
in patients with acute insterstitial pneumonia or idiopathic ARDS with mean values above 2000
U/mL.
KL-6 (Krebs von den Lungen-6 Antigen)
Suggested clinical utility
9 Ref. Reviews :
Huang et al, BioSciences Trends, 2013
Prasse and Muller-Quernheim, Respiratology, 2009

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Individual cartridge concept: 1 patient = 1 test
Fully automated
Good stability
Reduced waste ideal for low demands
Can be added randomly in between other
routine IA tests
Lumipulse® G KL-6 Immunoreaction Cartridges
A simplified and reliable way for measuring this novel biomarker
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www.fujirebio-europe.com/KL-6
More information is available at:
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