Serum KL-6 Levels In Patients Research Articles

Change in Serum KL-6 Level during Biologic Treatment for Psoriasis.

We previously analyzed data from blood examination screenings, including serum Krebs von den Lungen (KL) -6 level, before starting biologic treatment for psoriasis in a real-world setting. However, we did not follow change in KL-6 level after the initiation of biologics. Furthermore, there has been no follow-up study of certolizumab pegol, risankizumab, or tildrakizumab. This study evaluated change in serum KL-6 levels in patients during treatment with biologics, including certolizumab pegol, risankizumab, and tildrakizumab. We analyzed data from 111 patients. Change in KL-6 level was regarded as significant if it increased to greater than 500 U/mL at least once and if the maximum level after treatment with biologics was at least 1.5 times that of the baseline level. KL-6 level significantly changed during treatment with TNF inhibitors, IL-17 inhibitors, and IL-23 inhibitors in 9 (20.9%), 2 (6.3%), and 2 (5.6%) patients, respectively. Mean age, mean baseline KL-6 level, and frequency of TNF inhibitor use were higher in patients with a significant change in KL-6 level than those in patients without a significant change. Ten patients had minor interstitial changes on chest CT scans but no clinical signs suggesting interstitial pneumonia. Older patients with psoriasis and high baseline KL-6 levels must be carefully monitored during treatment with biologics, especially TNF inhibitors. Monitoring of KL-6 level and chest CT scans is necessary to exclude the possibility of drug-induced interstitial pneumonia.

KL-6 as a Biomarker of Interstitial Lung Disease Development in Patients with Sjögren Syndrome: A Retrospective Case-Control Study.

ObjectiveKrebs von den Lungen-6 (KL-6) is expressed on regenerating type II pneumocytes and has been recognized as biomarkers in interstitial lung disease (ILD). We aim to identify the role of the serum KL-6 level in patients with newly diagnosed Sjögren syndrome (SS), as well as the correlation between the immunoassays.MethodsPatients with newly diagnosed SS and receiving HRCT for clinical reason during follow-up were included. Baseline KL-6 level was measured via enzyme-linked immunosorbent assay (ELISA) and latex particle-enhanced turbidimetric immunoassay (LETIA).ResultsOf the 39 patients, 21 (53.85%) developed interstitial lung disease (ILD) by the conclusion of the follow-up period. The median time to diagnosis of ILD was 2.24 years (IQR 1.15–4.34) in the ILD group. The median serum KL-6 level, measured using ELISA, was 1232 U/mL (IQR 937–2242) and 764.5 U/mL (IQR 503.25–1035.75) in the ILD group and the non-ILD group, respectively (p = 0.001). The median LETIA for serum KL-6 was 329 U/mL (IQR 235–619) and 245 U/mL (IQR 215.25–291) in the ILD group and the non-ILD group, respectively (p = 0.074).ConclusionSerum KL-6 levels were higher in newly diagnosed SS patients with ILD diagnosis during follow-up. Thus, the serum KL-6 level can serve as a valuable biomarker to identify hidden ILD in patients with newly diagnosed SS patients. However, the immunoassay procedure may influence the efficacy of the prediction and its clinical association.

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome

Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

Elevated serum KL-6 in pediatric asthma exacerbation: a proof of alveolar injury

Background: Asthma is one of the most popular chronic diseases in children. It is defined as a complicated inflammatory disorder in which the patient suffers from chronic and persistent inflammation of the airways. The sialylated glycoprotein Krebs von den Lungen-6 (KL-6), one of the lung epithelium-specific proteins, has been recognized as a significant biomarker which directly associates with interstitial lung disease (ILD) pathogenesis, indicating the extent of damage and regeneration of type II pneumocytes. Objective: the aim of this study is to investigate the degree of alveolar damage in asthmatic children with acute exacerbation as reflected by serum KL-6 levels. Methods: This cross-sectional controlled study included 50 patients with acute asthma exacerbation diagnosed as per the GINA guidelines definition and 50 age- and sex-matched healthy children as controls. Spirometry was done for all participants. Serum KL-6 level was estimated by Enzyme Linked Immunosorbent Assay (ELISA), and total serum IgE level was measured via the electrochemiluminescence technology. Results: The asthma patients included 35 (70%) males and 15 (30%) females with mean age of 10.76 ±1.9 years. Forty-seven patients (94%) had a positive family history of bronchial asthma and 32 (64%) had other atopic manifestations The mean serum KL-6 level in patients was more than double the mean level of the control group (115.79 vs 55.64). No significant relation was observed between KL-6 serum level and age, family history of asthma, seasonal variation, or atopic manifestation among the cases. Serum total IgE levels were significantly higher in cases compared to controls (P<0.05). Conclusion: Serum KL-6 levels in pediatric asthma patients may be a useful diagnostic tool for detecting and monitoring the severity of airway inflammation. The use of serum KL-6 alone may help to differentiate between asthmatic patients in exacerbation and healthy controls.

Krebs von den Lungen-6 associated with chest high-resolution CT score in evaluation severity of patients with interstitial lung disease

AimsThe purpose of this prospective, single-center study was to measure the value of Krebs von den Lungen-6 (KL-6), a kind of transmembrane mucoprotein, in diagnosing interstitial lung disease (ILD) and in assessing the severity of ILD. MethodsWe enrolled 184 patients and 30 healthy controls. Ninety-eight patients were diagnosed with ILD, 47 with pneumonia, 19 with non-small cell lung cancer without ILD (NSCLC/non-ILD) and 20 with other lung diseases. Serum KL-6 levels, CT scores of high-resolution computerised tomography (HRCT) and pulmonary function in ILD patients were assessed. ResultsThe mean value of serum KL-6 in patients with ILD, pneumonia, NSCLC/non-ILD, other lung diseases and healthy controls were 1000.67±882.73U/ml, 234.11±91.02U/ml, 269.95±149.23U/ml, 234.85±83.51U/ml and 189.03±55.50U/ml, respectively. Serum KL-6 levels of patients with ILD were significantly higher than that of other groups (P<0.000). The level of serum KL-6 in patients with pneumonia, NSCLC/non-ILD and other lung diseases was also statistically higher than healthy controls (P<0.05). When the cut-off value was 312U/ml, the sensitivity and specificity of KL-6 for the diagnosis of ILD was 84.7% and 85.3% respectively (AUC: 0.936, 95% CI: 0.906–0.965). The serum KL-6 levels in patients with ILD were significantly positively correlated with the CT scores (r=0.539, P=0.000) and negatively correlated with DLCO (r=−0.513, P=0.000). ConclusionSerum KL-6 might be useful in the diagnosis of ILD, especially in the hard-to-diagnose cases, with high sensitivity and specificity. Furthermore, KL-6 might be a valuable marker for evaluation of ILD severity.

P1.03-025 Serum KL-6 Levels in Patients with Lung Cancer

Serum levels of KL-6 are widely used as an indicator of activity of interstitial lung disease. Although KL-6 was initially developed as a serum marker for malignancies, it is still unknown if KL-6 can be used as a biological marker of lung cancer. This study aimed to determine the properties of serum KL-6 levels in patients with lung cancer. First, serum KL-6 elimination kinetics after resection of lung cancer was investigated in 7 patients. Postoperative time course of serum KL-6 levels was analyzed using non-linear least square analysis with the fitting equation; C(t)=C0exp(-kt)+Cp, where k is the rate constant of elimination. The biological half-life was calculated as loge2/k. Next, serum KL-6, CEA, and CYFRA levels of patients with lung cancer and benign chest disease were retrospectively reviewed. A total of 226 patients with lung cancer and 103 patients with benign chest disease were included in this study. Serum KL-6 levels were measured using the electrochemiluminescence immunoassay method. The cut-off level of KL-6 was 500 U/ml. Rate constant of elimination and biological half-life of KL-6 in initial 7 patients were 0.827±0.275 day-1 and 0.93±0.35 day, respectively. These data implies that lung cancer cells produce KL-6 molecule and release it into the serum. Among 329 patients, serum KL-6 levels were above the cut-off level in 44 patients (19.5%) with lung cancer and 4 patients (3.9%) with benign chest disease. The mean serum KL-6 level in patients with lung cancer was significantly (p=0.0027) higher (375 ± 232 U/ ml) than that in patients with benign chest disease (296 ± 177 U/ml). Serum KL-6 levels in patients with lung cancer were significantly correlated with tumor size (p<0.0001), stage (p<0.0001), and individual TNM descriptors (T; p<0.0001, N; p=0.0047, M; p=0.0003). ROC analysis revealed that AUC of KL-6 was 0.6348 (p=0.0015), and that was inferior to CEA (AUC=0.8127, p<0.0001) and CYFRA (AUC=0.7103, p<0.0001). The sensitivity, specificity, true positive rate, true negative rate, and accuracy of KL-6 were 19.5%, 95.0%, 91.7%, 35.2%, and 43.5%, respectively. Serum KL-6 levels are well correlated with the progressiveness of lung cancer. KL-6 might be useful as a biological marker to monitor the recurrence and the effect of therapy in lung cancer.

Prognostic value of serial serum KL-6 measurements in patients with idiopathic pulmonary fibrosis.

The prognostic significance of serial measurements of serum KL-6 levels in patients with idiopathic pulmonary fibrosis (IPF) is unclear; hence, it was assessed in this study. Medical records of 66 patients with IPF, who were not treated with pirfenidone prior to enrollment, were retrospectively reviewed for information on clinical progress, forced vital capacity (FVC), survival, and serum KL-6 levels. We assessed initial serum levels of KL-6, serial changes in serum KL-6 levels, yearly decline in FVC (ΔFVC), and the rate of decline (%ΔFVC). Patients with increased serum KL-6 levels during follow-up had a significantly steeper decline in ΔFVC than those with no KL-6 increase (-201 vs. -50.7ml/year; p=0.0001). Patients with both initial serum KL-6 ≥1000U/ml and serial increases in serum KL-6 had the steepest decline, while those with both initial serum KL-6 <1000ml and no serial increases in KL-6 had the least decline in ΔFVC and %ΔFVC. Relative to the non-increased KL-6 group, survival in the increased KL-6 group tended to be poorer (p=0.0530). Patients with both initial serum KL-6 values <1000U/ml and no serial increase in KL-6 had more favorable prognoses than those with serial increases in KL-6 or initial serum KL-6 values ≥1000U/ml (p<0.0044). Prognosis was significantly poorer in patients with serial KL-6 changes >51.8U/ml/year than in those with serial KL-6 changes <51.8U/ml/year (p=0.0009). Thus, serial serum KL-6 measurements can be useful for assessing prognosis in patients with IPF.

(99) - Interleukin-1α Induced Interleukin-8 Production in Human Airway Epithelial Cells Pretreated With Azithromycin: A Possible Mechanism for Neutrophilic BOS?

Purpose: The chronic lung allograft dysfunction-CLAD, a life-threatening complication after lung transplantation, consists of an obstructive form (bronchiolitis obliterans syndrome-BOS) and a restrictive form (restrictive allograft syndrome-RAS). KL-6 is a reliable biomarker for disease assessment in lung fibrosis. In our previous study serum KL-6 levels at baseline were found to be increased in lung transplant recipients with BOS compared to those without. Aim of this study was to investigate whether changes over time in serum-KL-6 levels can predict CLAD. Methods: KL-6 in serum was measured by ELISA in 53 lung transplanted patients from 2007 to 2014. The percentage change of serum KL-6 levels from baseline was determined. Serum LDH was used as a comparison biomarker. The accuracy of serum KL-6 in predicting CLAD was evaluated using receiver operating characteristic (ROC) curve and Kaplan-Meier analysis. Results: Survival at 7 years after transplant was 54% (27 patients). Twentyeight patients (56%) developed CLAD in a median time of 75 months (CI 42-108). KL-6 was measured over time in 22 patients with complete follow-up data (9 with CLAD and 13 without CLAD).The average increase of serum KL-6 levels in patients with CLAD was 37% (vs. -2% by patients without CLAD, p= 0,018), whereas changes of serum LDH levels were not found different between these groups over time. The ROC analysis showed that an increase in serum KL-6 level by 22% was the best predictor for the development of CLAD with a sensitivity of 89% and a specificity of 77%. Kaplan-Meier analysis confirmed the predictive value of this cut off for the development of CLAD (Log-Rank p= 0.044). Conclusion: Lung transplant recipients with CLAD show higher baseline serum KL-6 levels than those without CLAD. A significant increase in serum KL-6 levels over time seems to predict the development of CLAD.

Serum KL-6 elevation and possible pulmonary involvement in patients with rheumatoid arthritis treated with biological agents.

Interstitial lung disease (ILD) is associated with rheumatoid arthritis (RA) itself and is also induced by biological and non-biological disease-modifying antirheumatic drugs. The glycoprotein Krebs von den Lungen-6 (KL-6) is reported to be a marker for the activity of ILD. To elucidate the relationship between serum KL-6 levels in patients with RA treated with biological agents and pulmonary involvement on computed tomography of the chest. The subjects were 307 patients with RA treated with infliximab, etanercept, adalimumab, or tocilizumab. Medical records were reviewed to investigate serum KL-6 levels, disease activity, and pulmonary imaging findings. Levels of KL-6 were abnormally elevated in 25 patients (8.1%): 15 patients (11.2%) treated with infliximab, 6 patients (4.4%) treated with etanercept, and 4 patients (22.2%) treated with adalimumab, but in no patients treated with tocilizumab. However, no clinical pulmonary events developed. Computed tomography of the chest showed the start or progression of interstitial fibrotic change in 5 of 25 (20%) patients with abnormal KL-6 values. The changes in disease activity did not differ significantly between patients who showed elevated KL-6 values and those who did not. Serum KL-6 levels were elevated in 8.1% of patients with RA treated with biological agents. Careful observation is necessary for these patients regarding lung fibrosis.

Different MUC1 gene polymorphisms in German and Japanese ethnicities affect serum KL-6 levels

KL-6 is a high-molecular-weight glycoprotein classified as human Mucin-1 (MUC1). KL-6 has been reported to be a sensitive biomarker for interstitial lung diseases (ILDs) in the Japanese population. It is also known that polymorphisms in the MUC1 gene affect serum levels of KL-6. This study was conducted to evaluate serum levels of KL-6 and MUC1 polymorphisms in both German and Japanese populations. Serum levels of KL-6 were measured in 267 patients with ILDs (152 German and 115 Japanese) and 186 healthy subjects (HS) (76 German and 110 Japanese). In addition, rs4072037 single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction. The optimal cutoff values for discriminating patients with ILDs from HS was determined by receiver operating characteristic analysis based on ethnicity and rs4072037 genotypes. The serum KL-6 levels in patients with ILDs were significantly higher compared with HS in both the German and the Japanese cohorts (both p<0.001). The discriminating cutoff value of serum KL-6 in the German cohort was significantly higher than the value in the Japanese cohort. The difference in the serum levels of KL-6 was significantly associated with the rs4072037 genotype distribution. Even in the German cohort, the serum KL6 levels were significantly higher in patients with ILDs than HS. Because of differences in the genotype distribution of rs4072037, the KL-6 cutoff value for the German cohort that discriminated patients with ILDs from HS was significantly higher than the value in the Japanese cohort.

Serum KL-6 Levels in Patients with Lung Cancer

Serum KL-6 Levels in Patients with Lung Cancer

Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease

BackgroundA high incidence of interstitial lung disease (ILD) has been reported in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), particularly in Japanese populations. A previous report from our laboratory demonstrated that KL-6 was a useful serum biomarker to assess the severity of drug-induced pneumonitis. Based on these observations, this study was conducted to evaluate the risk factors of EGFR-TKIs induced ILD and the usefulness of monitoring serum KL-6 levels in patients who developed EGFR-TKIs induced ILD in a large multi-institutional setting.MethodsWe retrospectively reviewed clinical records and radiographies of 341 patients with advanced NSCLCs who were treated with EGFR-TKIs, and analyzed risk factors for the development of EGFR-TKIs induced ILD. Changes of circulating levels of KL-6 were also evaluated in the patients who developed EGFR-TKIs induced ILD.ResultsAmong the 341 patients included in this study, 20 (5.9%) developed EGFR-TKIs induced ILD, and 9 (2.6%) died from ILD. Univariate analyses revealed that only preexisting pulmonary fibrosis was a significant risk factor for the development of EGFR-TKIs induced ILD (p = 0.003). Absolute levels of circulating KL-6 at neither baseline nor the onset of ILD could discriminate between life-threatening and non-life threatening EGFR-TKIs induced ILDs. However, we found that the ratios of serum KL-6 levels just after the onset of EGFR-TKIs induced ILD to those at baseline could quite precisely distinguish survivors from non-survivors (p = 0.006) as well as acute interstitial pneumonia (AIP) pattern from non-AIP pattern (p = 0.005).ConclusionsThe results of this study strongly support the potential of KL-6 as a diagnostic biomarker for life-threatening EGFR-TKIs induced ILD. Monitoring of KL-6 is also useful to evaluate the progression and severity of EGFR-TKIs induced ILD.

Comparison of pulmonary thin section CT findings and serum KL-6 levels in patients with sarcoidosis

This study aimed to compare thin-section CT images from sarcoidosis patients who had either normal or elevated serum KL-6 levels. 101 patients with sarcoidosis who underwent thin-section CT examinations of the chest and serum KL-6 measurements between December 2003 and November 2008 were retrospectively identified. The study group comprised 75 sarcoidosis patients (23 male, 52 female; aged 19-82 years, mean 54.1 years) with normal KL-6 levels (152-499 U ml(-1), mean 305.7 U ml(-1)) and 26 sarcoidosis patients (7 male, 19 female; aged 19-75 years, mean 54.3 years) with elevated KL-6 levels (541-2940 U ml(-1), mean 802.4 U ml(-1)). Two chest radiologists, unaware of KL-6 levels, retrospectively and independently interpreted CT images for parenchymal abnormalities, enlarged lymph nodes and pleural effusion. CT findings in sarcoidosis patients consisted mainly of lymph node enlargement (70/75 with normal KL-6 levels and 21/26 with elevated KL-6 levels), followed by nodules (50 and 25 with normal and elevated levels, respectively) and bronchial wall thickening (25 and 21 with normal and elevated levels, respectively). Ground-glass opacity, nodules, interlobular septal thickening, traction bronchiectasis, architectural distortion and bronchial wall thickening were significantly more frequent in patients with elevated KL-6 levels than those with normal levels (p<0.001, p<0.005, p<0.001, p<0.001, p<0.001 and p<0.001, respectively). By comparison, there was no significant difference in frequency of lymph node enlargement between the two groups. These results suggest that serum KL-6 levels may be a useful marker for indicating the severity of parenchymal sarcoidosis.

Serum KL‐6 levels in lung cancer patients with or without interstitial lung disease

It is not known whether lung cancer patients with interstitial lung disease (ILD) might have higher serum levels of KL-6, a high molecular weight glycoprotein classified as a polymorphic epithelial mucin. In addition, prognosis of these patients with elevated serum KL-6 levels might be poorer than that with normal KL-6 levels, but it has not been well clarified. Serum KL-6 levels in 273 lung cancer patients with or without ILD, and prognostic significance of elevated serum KL-6 levels in these patients were studied using uni- and multivariate analyses. Serum KL-6 levels were elevated (>500 U/ml) in 73.5% of lung cancer patients with ILD and in 33.7% of those without ILD. Serum KL-6 levels in lung cancer patients with ILD were significantly higher than those without ILD. In lung cancer patients with ILD, elevated serum KL-6 has no prognostic significance, but in those without ILD, however, it was one of the unfavorable prognostic factors. Elevated serum KL-6 levels can be observed in lung cancer patients both with and without ILD. Having ILD has strong prognostic impact in patients with lung cancer. In those without ILD, however, elevated KL-6 levels may be related to poor prognosis.

Comparison of pulmonary CT findings and serum KL-6 levels in patients with cryptogenic organizing pneumonia

The aim of this study was to retrospectively compare high-resolution CT findings among cryptogenic organizing pneumonia (COP) patients with normal and elevated serum KL-6 levels. Chest CT scans performed between April 1999 and April 2007 in 20 COP patients with a normal KL-6 level and 17 COP patients with an elevated KL-6 level were evaluated retrospectively by two chest radiologists. The CT findings in the COP patients with either a normal or an elevated KL-6 level mainly consisted of consolidation (n = 17 and n = 13, respectively) followed by ground-glass opacity (n = 11 and n = 13, respectively). Traction bronchiectasis and architectural distortion were significantly more frequent in patients with an elevated KL-6 level than in those with normal levels (n = 7 and n = 1, and n = 13 and n = 3, respectively) (p = 0.0077 and p = 0.00017, respectively). In follow-up CT scans, a relapse within 1 year after initial treatment with steroids, performed in 16 patients with a normal KL-6 level and 16 with an elevated KL-6 level, occurred in 2 (12.5%) patients with a normal KL-6 level and in 6 (37.5%) with an elevated KL-6 level. The frequency of relapse in patients with an elevated KL-6 level was higher than in those with a normal KL-6 level; however, no significant difference between the two groups was observed (p = 0.103). In conclusion, CT findings of traction bronchiectasis and architectural distortion in COP patients are associated with increased serum KL-6 levels, which might be related to a relapse after treatment.

Serum KL-6 Level is Elevated in Chronic Hepatitis C Patients with Combination Therapy of Pegylated Interferon and Ribavirin

The aim of this study was to evaluate whether or not combination therapy of pegylated interferon (IFN) and ribavirin for chronic hepatitis (CH) C patients enhances the serum level of KL-6, a sensitive marker for interstitial pneumonia. CH C patients proven histologically and treated with combination therapy of pegylated IFN-alpha-2b and ribavirin, IFN monotherapy or untreated for 48 weeks were retrospectively selected in chronological order in groups of 25. Serum levels of KL-6 were measured by enzyme-linked immunosorbent assay by use of serum stored at -80 degrees C before and at 12, 24, 36, 48 weeks after the initiation of treatment or follow up. The average serum KL-6 levels in patients treated with combination therapy of pegylated IFN and ribavirin increased by 21% at 12 weeks after the start, 23% at 24 weeks, and 28% at 48 weeks. In patients treated with combination therapy of pegylated IFN and ribavirin, the serum KL-6 level significantly increased during treatment. Patients achieved an elevated serum KL-6 level of more than 450 U/ml with statistical significance when: 1) combination therapy was given (P=0.011), 2) serum KL-6 level pretreatment was high more than 300 U/ml (P=0.014). The present study suggests that onset of interstitial pneumonia should be carefully checked in the combination therapy of pegylated-IFN and ribavirin.

Elevation of Serum Krebs von den Lunge–6 Levels in Patients With Tubulointerstitial Nephritis and Uveitis Syndrome

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. 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. 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 beta(2)-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 beta(2)-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. 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 beta(2)-microglobulin measurements.

Increased levels of KL‐6 and subsequent mortality in patients with interstitial lung diseases

KL-6 is a specific marker in patients with interstitial lung diseases (ILDs); however, the relationship between elevated levels of KL-6 and subsequent mortality is not well defined. To determine if elevated serum levels of KL-6 are associated with increased mortality, and to identify the most suitable cut-off level of KL-6 by which to distinguish between good prognosis and poor prognosis, we evaluated the prognostic significance of serum KL-6 levels in patients with stable-state ILDs. Two hundred and nineteen patients diagnosed with ILDs (152 with idiopathic interstitial pneumonia and 67 with collagen disease-associated pulmonary fibrosis) at Tsukuba University Hospital from April 1999 to October 2005 were entered in this study. Serum KL-6 levels in patients with ILDs were measured with a commercially available enzyme immunoassay kit, and these patients were then followed up. During the follow-up period, 58 of the 219 patients died of respiratory failure. Patients who died during this period had higher levels of KL-6 than did those who did not (P = 0.0004). The receiver operating characteristic curve analysis showed 1000 U mL(-1) as the most suitable cut-off level by which to distinguish between the two groups of patients. The 95% specificity serum KL-6 level with poor outcome was 2750 U mL(-1). In univariate and multivariate analysis, elevated serum KL-6 (>1000 U mL(-1)) in the stable state indicated poor prognosis (P = 0.0005, log-rank test; P = 0.0001, Cox proportional hazard model). Elevated KL-6 level may provide simple, yet valuable information by which to identify patients with ILDs who are at increased risk for subsequent mortality.

Analysis of the Effect of Surgical Lung Biopsy on Serum KL-6 Levels in Patients with Interstitial Pneumonia: Surgical Lung Biopsy Does not Elevate Serum KL-6 Levels

It is well known that the serum level of KL-6 can be an indicator of disease activity in patients with interstitial pneumonia (IP). However, surgical lung biopsy is often required for the diagnosis of IP, although this can result in IP exacerbation. The effect of surgical lung biopsy on the serum level of KL-6 in patients with IP was analyzed. Thirty-two cases of IP were examined in this study. There were no cases showing exacerbation of IP. The serum level of KL-6 demonstrated 1067+/-550 U/ml (mean+/-SD) before lung biopsy, 991+/-471 U/ml a day, 824+/-377 U/ml 4 days and 826+/-384 U/ml 7 days after lung biopsy. The serum KL-6 levels on the 1st, 4th, 7th day after the lung biopsy were significantly lower than that before the lung biopsy (P<0.05, P<0.01 and P<0.01, respectively). The percent decrease of the serum KL-6 levels on the 4th day (the lowest level) was dependent on the urine volume, and the analysis of the urinary levels of KL-6 showed a transient increase in urinary KL-6 excretion, suggesting that the decrease in serum KL-6 levels associated with surgical lung biopsy may be caused by this increase in urinary KL-6 excretion. Surgical lung biopsy of patients with IP has little effect on the increase in serum KL-6 levels. An elevation of serum KL-6 after surgical lung biopsy may indicate exacerbation of IP.

Detection of serum and intrahepatic KL-6 in anti-HCV positive patients with hepatocellular carcinoma.

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 [Formula: see text] U/ml (319U/ml for HCC with LC, 342.8U/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.