Prediction of lung-transplant rejection by hepatocyte growth factor

doi:10.1016/S0140-6736(04)16148-5

The Lancet

Volume 363, Issue 9420, 8 May 2004, Pages 1503-1508

https://doi.org/10.1016/S0140-6736(04)16148-5 Get rights and content

Summary

Background

Graft rejection is a major complication of lung transplantation. No serological marker of rejection is in common use. Hepatocyte growth factor (HGF) is highly expressed in the lung and produced after acute lung injury; serum concentrations increase in inflammatory lung diseases. We investigated whether HGF could be an accurate marker for prediction of lung-graft rejection.

Methods

Serum concentrations of HGF were measured by ELISA in 109 patients who had undergone lung transplantation (65 for chronic obstructive pulmonary disease; 23 for cystic fibrosis; 21 for idiopathic lung fibrosis), comparing those who had no subsequent events and those with episodes of infection or rejection, as well as in 12 healthy controls.

Findings

The mean baseline serum HGF concentration was 645 ng/L (SD 259) in controls and 1358 ng/L (603) in the patients before transplantation. After transplantation the mean concentration in patients with no events was 1147 ng/L (510) compared with 1559 ng/L (323) in patients with infection (p=0·001 vs controls; change from pretransplant value not significant). Patients with rejection had significantly higher concentrations than all other groups (3972 ng/L [1463], p<0·0001). Logistic regression identified HGF as a predictor for lung graft rejection (p=0·012). After steroid treatment, HGF concentrations returned almost to the preoperative values within 3 days.

Interpretation

HGF might be a marker for graft rejection in lung transplantation. A potential link between viral infection, mainly cytomegalovirus, and HGF, however, remains to be investigated.

Introduction

There has been much progress in lung transplantation since its inception.1, 2, 3, 4 At present, chronic obstructive pulmonary diseases (COPD), including emphysema and α1-antitrypsin deficiency syndrome, are the most common indications for lung transplantation, followed by cystic fibrosis, idiopathic pulmonary fibrosis, and primary pulmonary hypertension.3, 4, 5 The most important causes of morbidity and mortality in lung transplantation are primary graft failure, infection, and acute and chronic rejection.⁴ Surveillance protocols involving transbronchial lung biopsies have shown that most transplant recipients have at least one episode of acute rejection; the frequency is greatest during the first 100 days after transplantation. 4, 6, 7

Clinical criteria alone are imprecise for diagnosis of rejection. Examination of a tissue sample obtained by transbronchial biopsy can diagnose graft rejection, but the procedure is invasive and cannot be done repeatedly.⁷ Morbidity and mortality are increased if early rejection is missed, so markers of rejection are being sought. An ideal marker would be obtainable non-invasively; measurable repeatedly, easily, and quickly; sensitive and specific; and inexpensive. A serological marker would best fit these criteria and could complement clinical features⁷ for more accurate and rapid recognition of graft rejection. Serum adhesion molecules and bronchoalveolar lavage markers have proved to be disappointing markers,8, 9, 10 and none has become a standard test.

Hepatocyte growth factor (HGF) was first detected in the plasma of partially hepatectomised rats¹¹ and later purified from human plasma and lung fibroblasts.12, 13 In addition to its role in regeneration of injured lung,¹⁴ HGF acts in other organs. Studies in animals ssuggest that it is a sensitive measure of kidney-graft rejection.15, 16 Whether HGF can identify lung-graft rejection is unknown. We have investigated this issue.

Section snippets

Patients

We included in this study, which was approved by the institutional ethics committee, 109 patients undergoing lung transplantation who gave informed consent to participate (table 1). 12 healthy volunteers served as controls. Serum samples were collected and coded before and after lung transplantation, daily for the first week, then every 2 days from week 2 to week 5, then weekly to 24 weeks after transplantation. One serum sample was obtained from each control. Episodes of rejection and

Results

The mean serum HGF concentration was 645 ng/L (SD 259) in controls. Before transplantation the mean concentration was 1457 ng/L (703) in patients with COPD, 1401 ng/L (572) in those with cystic fibrosis, and 1217 ng/L (533) in those with idiopathic lung fibrosis (no significant difference); the overall mean in all patients was 1358 ng/L (603). To elucidate how serum concentrations of HGF change after lung transplantation, we plotted the concentrations over time in all patients who had no events

Discussion

Many studies have focused on the roles of cytokines and growth factors in development of inflammatory responses,¹⁸ graft dysfunction,¹⁹ and graft rejection²⁰ after lung transplantation. There is some evidence that serum concentrations of certain interleukins are increased during early haemodynamic failure after lung transplantation.¹⁸ Transforming growth factor β might be important in chronic lung graft rejection with bronchiolitis obliterans, because concentrations of its mRNA are increased in

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Cited by (33)

Lung Transplant Pathology: An Overview on Current Entities and Procedures
2020, Surgical Pathology Clinics
Pretransplant serum human chitinase-like glycoprotein YKL-40 concentrations independently predict bronchiolitis obliterans development in lung transplant recipients
2014, Journal of Thoracic and Cardiovascular Surgery
Citation Excerpt :
The pathogenesis of BOS is not clearly understood; however, the existing evidence on the role of small airway inflammation and acute rejection in BOS strongly suggests that the cellular and humoral storm directed to the allograft is crucial in the pathogenesis of BOS.6 Toward this end, we and others have shown that several growth factors and cytokines are involved in BOS pathogenesis.8,15-17 Our study shows that YKL-40 is elevated in BOS patients and its levels well correlate with BOS severity.
Bronchiolitis obliterans syndrome (BOS) is the main long-term complication limiting survival after lung transplantation. There exists no cure for BOS and its mechanisms are not well understood. Early identification of BOS could therefore contribute to improvement of therapeutic and preventive measures. The human chitinase-like glycoprotein YKL-40 is involved in regulation of inflammatory tissue response and remodeling and is associated with pulmonary fibrosis. However, its role in BOS is unknown.
A total of 57 recipients with irreversible fibrotic BOS and matched 85 recipients without BOS were retrospectively analyzed. Pretransplant serum samples were available at the time of the study. Serum and bronchoalveolar lavage samples were obtained at BOS diagnosis or at a comparable time point in patients without BOS. Additionally, serum samples were obtained 3 months later after BOS diagnosis or after the first sample in patients without BOS. YKL-40 concentrations were analyzed by enzyme-linked immunosorbent assay.
Pretransplant serum YKL-40 concentrations were higher in recipients who developed BOS and were useful in identifying patients at high risk for BOS development (odds ratio, 1.3; 95% confidence interval, 1.01-1.9; P = .02). At BOS diagnosis, posttransplant YKL-40 concentrations were significantly elevated in the serum and bronchoalveolar lavage of patients with BOS compared with those without BOS at a comparable posttransplant time point. Of note, there was no significant association between serum YKL-40 concentrations and the frequency of acute rejection episodes.
Elevated pretransplant serum YKL-40 concentration is associated with BOS development and could be an independent biomarker in early prediction and monitoring of BOS.
Biomarkers of pulmonary rejection
2013, Transplantation Proceedings
Immunologic complications after lung transplantation (LT) include acute cellular rejection (ACR), antibody-mediated rejection (AMR), and most forms of chronic allograft dysfunction (CAD). ACR is an inflammatory process in which the reaction is mediated by the T-cell population. Most episodes of ACR fully recover with treatment, but repeated bouts are considered to be a risk factor for CAD. Biomarker cytokines interleukin (IL)-10, IL-15, IL-6, CCL5, CCR2 and IFNγ may play significant roles in this complication. Formerly bronchiolitis obliterans syndrome (BOS) or chronic rejection or most forms of CAD were considered to be immunologic complications not amenable therapeutic measures. CAD, the main limitation for long-term survival in LT, is characterized histologically by airway epithelial cell apoptosis and luminal fibrosis in the respiratory bronchioles causing airflow obstruction and, in some cases, lung parenchymal affectations causing restrictive lung disease. Several biomarkers have been studied in CAD, IL-6, IL-8, IL-17, IL-23, IL-13, IFN γ, and TGF β cytokines, pH, bile acid, and tripsine of gastroesophageal reflux and toll-like receptors of innate immunity. Herein we have reviewed the literature of biomarkers involved in lung rejection.
Acute Allograft Rejection: Cellular and Humoral Processes
2011, Clinics in Chest Medicine
Citation Excerpt :
Even more attractive are studies of noninvasive means of diagnosing acute rejection without bronchoscopy. Although no effective serum biomarkers are currently in use in clinical lung transplant, many have been studied, and some, such as the hepatocyte growth factor, have been shown to correlate with acute rejection in small single-center studies.30 In 2002, the Cylex Immune Cell Function Assay (ImmuKnow; Cylex, Incorporated, Columbia, MA, USA) was approved by the US Food and Drug Administration to measure global immune function in solid organ transplant recipients.
Endothelin-1 is a useful biomarker for early detection of bronchiolitis obliterans in lung transplant recipients
2010, Journal of Thoracic and Cardiovascular Surgery
Citation Excerpt :
The TBB specimens were also histologically screened for CMV, pneumocystis carinii, toxoplasmosis, and bacterial or invasive fungal infection. Colonization was considered present if the BAL microbiology was positive without histologic or clinical evidence of infection.16 The immunosuppression protocol has been previously described.16
Bronchiolitis obliterans (BO) is a severe complication limiting long-term survival after lung transplantation. To date, no cure exists for BO, and the mechanisms leading to BO are not well understood. Endothelin-1 (ET-1) is a potent mitogenic and profibrotic peptide produced by pulmonary vascular endothelial cells that play a role in the pathophysiology of lung allograft dysfunction. Whether ET-1 could predict BO syndrome (BOS) development is unknown.
Transbronchial biopsy specimens and serum and bronchoalveolar lavage were obtained from 30 lung transplantation patients with and 30 without BOS at 3 points. The serum and bronchoalveolar lavage ET-1 concentrations were measured by enzyme-linked immunosorbent assay, and the ET-1 mRNA expression in the transbronchial biopsy specimens was examined using real-time polymerase chain reaction.
The pretransplant ET-1 serum concentrations were greater in the patients with BOS (P = .02); and ET-1 mRNA was significantly upregulated in the lung grafts of those with versus those without BOS at 3 and 12 months after transplant (P = .01). At 3 and 12 months after transplantation, the ET-1 concentrations were significantly elevated in the serum (P < .01 and P < .0001, respectively) and bronchoalveolar lavage (P < .01 and P = .02, respectively) of patients with compared with those without BOS. On logistic regression analysis, the pretransplant and 3-month post-transplant serum ET-1 level predicted for BOS (odds ratio, 1.01; 95% confidence interval, 1.004–1.025; P < .007; odds ratio, 2.9; 95% confidence interval, 1.01–8.52; P < .001). The serum ET-1 level at 12 months was diagnostic for BOS (odds ratio, 3.9; 95% confidence interval, 1.42–10.80; P = .008).
Elevated serum ET-1 concentrations were predictive of BOS, and the assessment of circulating ET-1 might be beneficial in diagnosing and monitoring BO.
Intermediate and Late Complications of Lung Transplantation
2010, Medical Management of the Thoracic Surgery Patient

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ArticlesPrediction of lung-transplant rejection by hepatocyte growth factor

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

J Heart Lung Transplant

J Thorax Cardiovasc Surg

Biochem Biophys Res Commun

J Biol Chem

Transplant Proc

Chest

J Heart Lung Transplant

J Heart Lung Transplant

Am J Transplant

Biochem Biophys Res Commun

Unilateral lung transplantation for pulmonary fibrosis

N Engl J Med

for the Toronto Lung Transplant Group. Results of single-lung transplantation for bilateral pulmonary fibrosis

N Engl J Med

Results of bilateral lung transplantation

Lung transplantation

N Engl J Med

Articles
Prediction of lung-transplant rejection by hepatocyte growth factor