What is the role of KL-6 (Krebs von den Lungen-6) in interstitial lung disease (ILD)?

KL-6 in Interstitial Lung Disease

Do not measure serum KL-6 for diagnosing or distinguishing IPF from other ILDs in clinical practice, but recognize that elevated KL-6 levels (>1,000 U/mL) are strongly associated with poor prognosis and mortality in patients with established ILD. 1

Diagnostic Role: Not Recommended

The 2018 ATS/ERS/JRS/ALAT guidelines provide a strong recommendation AGAINST measuring serum KL-6 for the purpose of distinguishing IPF from other ILDs due to high false-positive and false-negative rates (>33% incorrect results), which can lead to inappropriate therapy, delayed treatment, or unnecessary additional testing. 1 This recommendation applies specifically to the diagnostic workup of newly detected ILD when trying to differentiate between ILD subtypes.

The guideline panel dismissed KL-6 measurement as a diagnostic approach despite the fact that more than half of patients would be correctly classified, because the error rate was deemed unacceptably high for clinical decision-making. 1

Prognostic Role: Clinically Valuable

KL-6 has significant prognostic utility once ILD is established:

Mortality Prediction

• KL-6 levels >1,000 U/mL predict poor survival with a hazard ratio of 2.95 (95% CI: 1.71-5.08, p=0.0001) in patients with idiopathic interstitial pneumonias and collagen vascular disease-associated ILD. 1
• In IPF specifically, KL-6 >1,000 U/mL carries a hazard ratio of 12.56 (95% CI: 1.195-131.90, p=0.035) for mortality. 1
• The 95% specificity level for poor outcome is 2,750 U/mL. 2

Disease Activity Monitoring

• Serial KL-6 measurements correlate inversely with pulmonary function decline. Decreasing KL-6 levels under therapy correlate with FVC stabilization (p=0.022), while increasing levels correlate with declining FVC (r=-0.562, p<0.0001) and DLCO (r=-0.405, p=0.013). 3
• KL-6 levels decrease significantly under effective therapy (mean decline of 486-547 U/mL at 6-12 months, p<0.05). 3

Radiological Correlations

• Higher KL-6 levels correlate with advanced radiological features including subpleural thickening (p=0.003), septal thickening (p=0.036), and ground-glass opacities (p=0.018). 4

Special Populations

Connective Tissue Disease-Associated ILD

• In CTD-ILD, KL-6 shows 86.7% sensitivity and 71.4% specificity at ≥400 U/mL threshold for detecting ILD. 4
• In pediatric CTD-ILD, a cut-off of 712.5 U/mL yields 81% sensitivity and 72% specificity. 5
• KL-6 is emerging as a promising marker in systemic sclerosis-ILD, particularly in early-stage or less-extensive disease. 1

Clinical Application Algorithm

For established ILD patients:

1. Measure baseline KL-6 for prognostic stratification
2. If KL-6 >1,000 U/mL: patient is at high risk for progression and mortality—consider more aggressive monitoring and earlier intervention 1, 2
3. If KL-6 >2,750 U/mL: very poor prognosis—discuss transplant evaluation or palliative care planning 2
4. Repeat KL-6 at 6-month intervals during treatment to assess therapeutic response 3
5. Rising KL-6 levels suggest inadequate disease control; stable or declining levels suggest effective therapy 3

Important Caveats

• Most validation studies were conducted in Asian populations; data in Caucasian populations is more limited but shows similar trends. 3, 6
• KL-6 testing is costly and not widely available in all regions. 1
• The biomarker reflects type II pneumocyte injury/regeneration and is elevated in 70-100% of various ILDs, limiting its specificity for distinguishing between ILD subtypes. 6
• The ATS/ERS/JRS/ALAT guidelines acknowledge that while KL-6 has prognostic value, the evidence base for biomarkers in ILD remains limited to small cohorts without independent validation. 1