Serum KL-6 level and the development of bronchiolitis obliterans syndrome in lung transplant recipients.
ABSTRACT KL-6 is a glycoprotein expressed by pulmonary epithelial cells, and its serum level has been used as a marker of disease activity in a variety of respiratory illnesses. Previously, we showed that KL-6 was elevated in lung transplant recipients diagnosed with BOS. In this study, we followed serum KL-6 levels and lung functions prospectively in lung transplant recipients who were within the first five-yr post-transplant and had no evidence of BOS at the time of study entry. Mean peak KL-6 levels were 596.16 ± 309.32 U/mL in the nine recipients who developed BOS compared to 352.41 ± 140.68 in 36 recipients who did not (p = 0.05). Six of the nine patients with BOS had an absolute rise in KL-6 above baseline level >200 U/mL compared to two of the 37 who had the same increase in KL-6 but did not develop BOS. Using the 200 U/mL elevation of KL-6 from baseline as a threshold for a positive test would produce a sensitivity of 67%, specificity of 95%, PPV of 75%, and a NPV of 92%. In addition, mean KL-6 levels of patients during acute rejection were not significantly elevated compared to the prerejection mean KL-6 levels (p = 0.71). We conclude that serum KL-6 is a relatively specific marker of BOS in lung transplant recipients.
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ABSTRACT: Lung transplantation is the treatment of choice for patients with end-stage lung disease. However, long-term survival is limited due to the development of chronic rejection in the donor lung of the transplant recipient, called bronchiolitis obliterans syndrome (BOS). BOS is diagnosed after lung transplantation when a decline in lung function occurs, which is not due to rejection, infection or problems of the bronchial anastomosis. The development of BOS is characterized by persistent injury of the airway epithelium that is caused by several factors. This process leads to inflammation and remodeling, which is followed by an aberrant repair response, and finally fibrosis and occlusion of the small airways of the allograft. When BOS is diagnosed, the process is already at an advanced and mostly irreversible stage and treatment options are limited. The current status of diagnosis of BOS clearly indicates the need for biomarkers in serum and DNA that may detect processes leading to BOS before the decline in lung function occurs. These unmet needs are the basis of this thesis. TLRs are critical molecules for activation of the innate immune system by recognition of pathogens, and they can prevent the induction of allograft tolerance. Genetic polymorphisms in Toll-like receptor (TLR)2, TLR4 and TLR9 might contribute to patients’ susceptibility for BOS. These genetic polymorphisms could predispose to increased secretion of pro-inflammatory cytokines, causing injury and inflammation of the airway epithelium. The exact role of different types of cytokines in rejection or tolerance of the allograft is under debate. We showed that the T helper (Th)1 cytokines were similar between patients who developed BOS (BOSpos)and those who did not (BOSneg)patients. However, the Th2 cytokines revealed a different pattern between these two groups. This suggests that Th2 cytokines are involved in the process of chronic rejection, possibly due to the inhibition of transplant tolerance, the absence of inhibition of the Th1 response and the influence on proliferation of regulatory T-cells. In relation to excessive injury and chronic inflammation, the process of fibrogenesis is considered to be of central importance to the development of BOS. Normally, after injury of the airway epithelium an adequate repair mechanism is required to prevent fibrogenesis. BOSpos patients, however, seem to have an impaired repair mechanism and a profibrotic airway milieu. They had a different genotype distribution of matrix metalloproteinase (MMP)7 and lower levels of MMP-7 than BOSneg patients which might contribute to an impaired repair mechanism of the airway epithelium. Besides, there is more degradation and turnover of the extracellular matrix in BOSpos patients than in BOSneg patients as shown by increased levels of MMP-9. Though, the functionality of the genetic polymorphisms in the caveolin-1 (CAV1) gene is not known, it might contribute to fibrogenesis as well through the transforming growth factor beta signaling pathway. In conclusion, genetic polymorphisms in TLRs, MMP7 and CAV1 and biomarkers in serum, such as Th2 cytokines, MMP-7 and MMP-9, are related to the development of BOS after lung transplantation, and may be potential biomarkers for clinical decision making.
- Bronchiolitis Obliterans Syndrome in Lung Transplantation, Edited by Keith C. Meyer, Allan R. Glanville, 01/2013: chapter Role of Autoimmunity in the Pathogenesis of Obliterative Bronchiolitis: pages 183-198; Springer New York Heidelberg Dordrecht London., ISBN: 978-1-4614-7635-1
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ABSTRACT: Bronchiolitis obliterans syndrome (BOS) is a life-threatening complication after lung transplantation that is characterized by progressive fibrosis in the small airways. However, little is known about sensitive markers for detecting BOS. Our study compared the clinical utility of serum KL-6 level, a marker for pulmonary fibrosis, with that of neutrophilia in bronchoalveolar lavage fluid (BALF) for detecting BOS. Levels of serum KL-6 were evaluated in 152 samples from 53 lung transplant recipients (BOS, 15; non-BOS, 38) and in 27 samples from age- and sex-matched healthy individuals. Pulmonary function tests, arterial blood gas analysis, and BALF cell differentials were simultaneously evaluated. Serum KL-6 levels were significantly increased in the BOS group compared with the non-BOS group and the healthy individuals (p < 0.0001). Receiver operating characteristic curve analysis for detecting BOS showed the largest area under the curve for KL-6 compared with lactate dehydrogenase, C-reactive protein, or neutrophils percentage in BALF. Serum KL-6 correlated with the decline in forced expiratory volume in 1 second (FEV(1)) from post-lung transplant baseline (r = 0.43; p = 0.0001). Serum KL-6 levels are increased and correlate with the decline from baseline in FEV(1) in lung transplant recipients. The diagnostic accuracy of serum KL-6 level is better than that of BALF neutrophilia for detecting BOS.The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 08/2011; 30(12):1374-80. DOI:10.1016/j.healun.2011.07.010 · 5.61 Impact Factor