Monitoring of Serum KL-6 Antigen in a Patient with Radiation Pneumonia

doi:10.1378/chest.101.3.858

Chest

Volume 101, Issue 3, March 1992, Pages 858-860

https://doi.org/10.1378/chest.101.3.858 Get rights and content

Serum marker KL-6 antigen has been reported to be a valuable indicator of the disease activity of interstitial pneumonia.¹ It is not clear how sensitive the serum KL-6 antigen level is in reflecting histologic changes in lung tissues. We report here the results of serial measurements of serum KL-6 antigen in a 76-year-old male patient with radiation pneumonia. Serum KL-6 antigen levels were more sensitive than lactate dehydrogenase and procollagen type III N-terminal pep tide. The level of serum KL-6 antigen appears to reflect the histologic changes of the lung more sensitively than does C-reactive protein.

Section snippets

CASE REPORT

A 76-year-old man began to complain of cough with sputum and general fatigue two months before admission to our hospital. He had first visited a local hospital, where a chest x-ray film revealed a nodular shadow with pleural indentation in the left lung field (Fig 1, A).

On the patient's admission to our hospital, breath sounds were normal, and lymph nodes were not palpable. Histologic examination of the percutaneous lung biopsy specimen revealed the large cell type of lung cancer. The main

DISCUSSION

Radiation pneumonia is one of the factors that restrict the use of radiotherapy against lung cancer. There are only a few methods for diagnosing and assessing the disease activity of radiation pneumonia—chest radiography, ⁶⁷Ga citrate scintigraphy,² spirography, and evaluation of serum markers, such as LDH³ and P3P.⁴

DeRemee³ first reported the use of LDH as an indicator of the presence and disease activity of interstitial pneumonia. The peptide released during the conversion of type III

REFERENCES (6)

KohnoN et al.
New serum indicator of interstitial pneumonitis activity: sialylated carbohydrate antigen KL-6
Chest
(1989)
van der SchootJB et al.
Gallium-67 scintigraphy in lung diseases
Thorax
(1972)
DeRemeeRA.
Serum lactic dehydrogenase activity and diffuse interstitial pneumonitis
JAMA
(1968)

There are more references available in the full text version of this article.

Cited by (72)

MUC1/KL-6 expression confers an aggressive phenotype upon myeloma cells
2018, Biochemical and Biophysical Research Communications
Citation Excerpt :
We describe here the establishment of a myeloma cell line, EMM1, derived from a refractory myeloma patient with secondary plasma cell leukemia and elevated serum KL-6 levels (KL-6+). KL-6, which is a marker of interstitial pneumonitis, is detected in lung cancers, pancreatic cancers, breast cancers, and hematological malignancies [7–11]. We show here that the level of MUC1 is markedly elevated in EMM1 cells compared with those of other myeloma cell lines, and the growth of EMM1 cells is highly dependent on MUC1 expression.
The sialic glycoprotein, MUC1, is known to be involved in the pathogenesis of various types of cancers. KL-6 is one of the surface antigens of MUC1 and also a marker of interstitial pneumonitis. A fraction of patients with myeloma (3.9%) have elevated serum KL-6 levels without any evidence of interstitial pneumonitis and their myeloma cells have high MUC1 expression. We established a myeloma cell line designated EMM1 from a patient with multiple myeloma accompanied with elevated serum KL-6. EMM1 cells expressed high levels of MUC1 compared with other myeloma cell lines. Knockdown of MUC1 in EMM1 cells induced cell cycle arrest during S phase and apoptosis, suggesting that the MUC1 expression is involved in accelerated growth of EMM1 cells. RNA-seq analysis suggests that MUC1 expression activates k-ras and TNFα-induced NFκB pathways in EMM1 cells. We injected EMM1 cells subcutaneously into Rag2^−/−Jak3^−/− Balb/c mice to establish a mouse xenograft model. These mice had aggressive tumor growth that was accompanied by high serum KL-6 levels. In addition, MUC1 knockdown in EMM1 cells led to inhibited tumor growth. These findings demonstrate that MUC1 serves as a potential target for developing drugs for treatment of patients with KL-6⁺ myeloma, and EMM1 cells and EMM1-engrafted mice are useful tools for the development of such novel agents.
Utility of KL-6/MUC1 in the clinical management of interstitial lung diseases
2012, Respiratory Investigation
Citation Excerpt :
A clinical cut-off value of 500 U/mL has been established for distinguishing patients with ILDs from healthy subjects and patients with lung diseases other than ILDs [37]. KL-6/MUC1 serum levels higher than the cut-off value have been observed in more than 70% of patients with ILDs, including IIPs, CVD-IP, HP, RP, D-ILDs, ARDS, pulmonary sarcoidosis, and pulmonary alveolar proteinosis (PAP, Table 2) [15,38–50]. Interestingly, less than 10% of patients with alveolar pneumonia tested positive for KL-6/MUC1.
Interstitial lung diseases (ILDs) are a diverse group of pulmonary disorders characterized by various patterns of inflammation and fibrosis in the interstitium of the lung. Because injury and/or regeneration of type II pneumocytes are prominent histological features of ILDs, substances derived from type II pneumocytes have been the focus of research investigating potential biomarkers for ILD. One important biomarker for ILD is the high-molecular-weight glycoprotein, Krebs von den Lungen-6 (KL-6). KL-6 is now classified as a human MUC1 mucin protein, and regenerating type II pneumocytes are the primary cellular source of KL-6/MUC1 in the affected lungs of patients with ILD. KL-6/MUC1 is detectable in the serum of patients with ILD, and extensive investigations performed primarily in Japan have revealed that serum KL-6/MUC1 is elevated in 70–100% of patients with various ILDs, including idiopathic interstitial pneumonias, collagen vascular disease-associated interstitial pneumonia, hypersensitivity pneumonia, radiation pneumonitis, drug-induced ILDs, acute respiratory distress syndrome, pulmonary sarcoidosis, and pulmonary alveolar proteinosis. The results from these various studies have supported the utility of KL-6/MUC1 as a serum biomarker for detecting these various ILDs. Moreover, KL-6/MUC1 serum levels have been demonstrated to be useful for evaluating disease activity and predicting the clinical outcomes of various ILD types. Based on these observations, we believe that KL-6/MUC1 is currently one of the best and most reliable serum biomarkers available for ILD management.
Serum biomarkers in idiopathic pulmonary fibrosis
2010, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Upon epithelial breakdown, KL-6 is thought to leak into the circulation, where it can be measured by a commercially available ELISA kit. KL-6 has been studied extensively in mainly Japanese patients, where serum levels were found to be increased in various interstitial lung diseases such as radiation pneumonitis [22–24], CTD-associated lung disease [25–27] and drug induced pneumonitis [28]. Interestingly, KL-6 may have a role in fibrosis itself, as it was shown to induce proliferation of lung fibroblasts in vitro [29].
Within the group of Idiopathic Interstitial Pneumonias (IIPs), above all Idiopathic Pulmonary Fibrosis (IPF) poses a considerable diagnostic and therapeutic problem. Although genetic profiling indicates that IPF, Non Specific Interstitial Pneumonia (NSIP), and chronic hypersensitivity pneumonitis (HP) are distinctly different diseases, in every day practice these diseases can be difficult to tell apart. Furthermore, treatment of these diseases is notoriously difficult. Serum biomarkers reflect our understanding of the underlying pathogenesis and potentially fulfill a role in establishing a diagnosis, prognosis and therapy. While no single biomarker is currently able to accurately predict the presence or absence of an IIP, a composite of several markers holds promise for the future. Several biomarkers, such as KL-6, surfactant proteins and circulating fibrocytes, appear to contribute to our insight into disease progression and prognosis. It is however uncertain whether these markers give us additional information to common diagnostic tests and their value has as yet to be validated for every day practice. Fortunately, the potential of biomarkers is increasingly recognized and biomarker data are prospectively gathered in current placebo-controlled therapeutic trials.
Comparative evaluation of serum markers in pulmonary sarcoidosis
2010, Chest
Although several serum markers have shown their ability to reflect lymphocytic alveolitis and disease progression in pulmonary sarcoidosis, to our knowledge no prior study has made comparative evaluations of these markers.
Forty-three patients with pulmonary sarcoidosis were enrolled. BAL fluid (BALF) cells were analyzed, and serum levels of serum amyloid A (SAA), soluble interleukin 2 receptor (sIL-2R), lysozyme, angiotensin-converting enzyme (ACE), and the mucin-like, high-molecular-weight glycoprotein KL-6 were measured at disease presentation. Clinical data, including chest radiographs, were collected at presentation and during follow-ups. Univariate and multivariate analyses were used to identify markers best predictive of increased parenchymal infiltration.
Significantly higher serum levels of sIL-2R, lysozyme, and KL-6 were found in patients with parenchymal infiltration compared with those without parenchymal infiltration. The numbers of total cells and lymphocytes in BALF were significantly higher in patients with parenchymal infiltration. Serum levels of sIL-2R, lysozyme, and KL-6 were significantly correlated with the numbers of total cells, lymphocytes, and CD4⁺ T lymphocytes in BALF. At the cutoff levels determined by receiver operating characteristic curves, sIL-2R, lysozyme, KL-6 serum levels, and the number of BAL lymphocytes showed significant correlations with increased parenchymal infiltrations by univariate analysis. However, multivariate analysis revealed that only KL-6 was a predictor of increased parenchymal infiltration.
Our results suggest that initial serum sIL-2R, lysozyme, and KL-6 levels may reflect lymphocytic alveolitis in pulmonary sarcoidosis. Furthermore, initial serum KL-6 tends to associate with increased parenchymal infiltration in pulmonary sarcoidosis.
Elevation of Serum Krebs von den Lunge-6 Levels in Patients With Tubulointerstitial Nephritis and Uveitis Syndrome
2006, American Journal of Kidney Diseases
Citation Excerpt :
Thus, it is possible that serum KL-6 level is influenced by inflammation of renal lesions in patients with TINU syndrome. Measurement of serum KL-6 is used widely as a diagnostic examination to monitor the activity of various lung diseases.13-18 In the present study, no patient with TINU syndrome had a pulmonary disorder, suggesting that KL-6 in serum could be derived from tissues other than the respiratory organs.
Background: Tubulointerstitial nephritis and uveitis (TINU) syndrome is characterized by a combination of idiopathic acute tubulointerstitial nephritis and uveitis. Krebs von den Lunge-6 (KL-6) is a human glycoprotein secreted by type II alveolar cells in the lung, and its serum levels increase in patients with pneumonia of various causes, as well as ocular sarcoidosis. The aim of the present study is to quantify serum KL-6 levels in patients with TINU syndrome, which has no pulmonary and sarcoid lesions, and elucidate the usefulness of KL-6 for the diagnosis and follow-up of this syndrome. Methods: Serum and urinary samples were obtained from 17 patients with TINU syndrome and 36 age-matched patients with uveitis from other causes. Sarcoidosis was eliminated because serum KL-6 levels increased during their lung lesion. Serum KL-6 level was determined by using a human KL-6 electrochemiluminescence immunoassay. Formalin-fixed paraffin-embedded renal tissue sections were incubated with anti–KL-6 monoclonal antibody, then examined immunohistochemically. Results: Mean serum KL-6 levels for patients with TINU syndrome and those with uveitis from other causes were 363.35 ± 51.06 and 213.19 ± 10.28 U/mL, respectively (P < 0.001). Urinary β₂-microglobulin levels of patients with TINU syndrome and uveitis from other causes were 4.06 ± 1.31 and 0.16 ± 0.20 mg/L, respectively (P < 0.001). All patients with TINU syndrome showed a simultaneous decrease in serum KL-6 and urinary β₂-microglobulin levels after the beginning of treatment. Strong immunoreactivity for KL-6 was observed in renal distal tubules in biopsy tissue of patients with TINU syndrome. Conclusion: We show a significant increase in serum KL-6 levels in patients with TINU syndrome, whereas levels were normal in patients with other causes of uveitis without nephritis. Renal distal tubules stained strongly with anti–KL-6 antibody, suggesting that high KL-6 levels may reflect the renal lesion of TINU syndrome. Serum KL-6 may be a potential laboratory parameter for the diagnosis and follow-up of patients with TINU syndrome that could complement urinary β₂-microglobulin measurements.
Detection of serum and intrahepatic KL-6 in anti-HCV positive patients with hepatocellular carcinoma
2004, Hepatology Research
We investigated the clinical significance of serum and intrahepatic KL-6/MUC1 (KL-6) in patients with hepatitis C virus (HCV) antibody-positive hepatocellular carcinoma (HCC). The subjects included 76 patients diagnosed with anti-HCV positive HCC, 69 with, and 51 without, liver cirrhosis (LC). Frozen serum samples were obtained from each subject to determine the serum KL-6 levels using an enzyme-linked immunosorbent assay. Expression of KL-6 antigen in the liver was also investigated using immunoperoxidase staining. The mean serum KL-6 level in patients with HCC was 329.6±213.0 U/ ml (319 U/ ml for HCC with LC, 342.8 U/ ml for HCC without LC). Serum KL-6 levels in patients with HCC with LC and HCC without LC did not differ. Serum KL-6 levels were elevated with increases in the size of spaces occupied by tumors in the liver. Among patients with HCC, there was no correlation between serum KL-6 levels and alpha-fetoprotein (AFP) levels and protein induced by vitamin K absence or antagonist-II (PIVKA-II) levels. However, some patients with low levels of AFP and PIVKA-II possessed high levels of KL-6. Furthermore, serum KL-6 levels decreased after therapy for HCC nodules. Immunohistochemical staining showed KL-6 antigen was detected within the cell membrane and in the cytoplasm of cancer cells. KL-6 antigen was localized on the membrane and the endoplasmic reticulum of cancer cells in the cancerous foci by electron microscopy. Our results suggest that serum KL-6 levels represent a serological marker of HCC development, because KL-6 expression was localized to the cancer cells in HCC nodules.

View all citing articles on Scopus

: Reprint requests: Dr. Kohno, 2nd Department of Internal Medicine, Ehime University School of Medicine, Onsen-gun, Ehime 791–02, Japan

: The Radiation Effects Research Foundation was established in April 1975 as a private, nonprofit Japanese foundation, supported equally by the Government of Japan, through the Ministry of Health and Welfare, and the Government of the United States, through the National Academy of Sciences under contract with the US Department of Energy.

View full text

Chest

Monitoring of Serum KL-6 Antigen in a Patient with Radiation Pneumonia

Section snippets

CASE REPORT

DISCUSSION

New serum indicator of interstitial pneumonitis activity: sialylated carbohydrate antigen KL-6

Chest

Gallium-67 scintigraphy in lung diseases

Thorax

Serum lactic dehydrogenase activity and diffuse interstitial pneumonitis

JAMA