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148 Donor Lung Surfactant Protein D Gene Polymorphisms Are Associated with Bronchiolitis Obliterans Syndrome and Mortality after Lung Transplantation
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The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
Progression of Cavitities Progression
Survival following sirolimus, years
D NC D P NC PC P NC D
5 1 6 4 1 4 4 4 1
(alive) (alive) weeks (alive)
D Disappeared; NC: new cavity; P: persistent
Conclusions: Sirolimus impairs local healing in the lung and may result in cavitation.The incidence of cavitating lung lesions is double in the sirolimus group suggesting a possible association. The risk of cavitities is higher when trough levels above 12 ng/ml. Concurrent infection is a potential confounder. Sirolimus cavitities may be associated with significant worsening in lung function and prognosis is worse when cavity persists or progress.
Surgical Interest”, University of Bologna, Bologna, Italy; 2Penn State University, Hershey; 3Lung Transplant Program, University of Toronto, Toronto, Canada; 4Lung Transplant Program, Columbia University, New York. Purpose: Bronchiolitis obliterans is the major factor limiting long-term success of lung transplantation. Gene polymorphisms of surfactant proteins, key players in lung innate immunity, have been associated with various lung diseases. The aim of this study was to investigate the association between donor lung SP-D gene polymorphisms with recipient post transplant bronchiolitis obliterans syndrome and survival. Methods and Materials: Lung-Tx pts (192) were prospectively followed by PFTs, and bronchoscopies with BAL and biopsies. Donor DNA was assayed for SP-D gene polymorphisms of two single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met11Thr) of the N-terminal domain, and in codon 160 (Ala160Thr) of the C-terminal domain, using the pyrosequencing method. Results: BOS was diagnosed in 49 pts. The table shows the SP-D genotype frequency for codon 11 (Met11Thr), and codon 160 (Ala160Thr). Recipients of lung allografts with the Thr/Thr11-encoding genotype had significantly earlier BOS development and reduced survival compared to those with the Met/Met11-encoding genotypes. No significant association was noted for SP-D variants Ala/Thr160.
147 Induction vs. Non-Induction in Heart Transplantation: The Controversy Continues R.P. Morrissey, L. Czer, M. Kittleson, J. Patel, E. Schwarz, G. Jamero, M. Kawano, M. Rafiei, B. Azarbal, A. Trento, J. Kobashigawa. CedarsSinai Heart Institute, Los Angeles, CA. Purpose: No randomized trials have demonstrated benefit of induction therapy in heart transplant recipients. This observational study reviews two large, local programs in the same era in which one program used routine anti-thymocyte globulin (ATG) induction and the other program used routine triple drug therapy without induction (reserved for patients with renal insuffiency to delay calcineurin inhibitor (CNI) initiation). With a case-control design, the impact of ATG induction on heart transplant outcomes was assessed. Methods and Materials: Between 2000 and 2009, 188 patients(pts) underwent routine induction therapy with ATG. A 1:1 control group of pts without induction was matched for age, sex, listing status and reason for transplant. Pts with baseline SCr ⬎2.5 mg/dl were excluded from this study since these pts may have received induction to delay initiation of CNI. Outcomes assessed were 5-year survival, freedom from cardiac allograft vasculopathy (CAV, angiographic stenosis ⬎ 30%), freedom from nonfatal major adverse cardiac events (NF-MACE: myocardial infarction, heart failure, PCI, ICD, stroke, and new peripheral vascular disease), and 1-year freedom from any-treated rejection. Results: There was no difference between groups in 5-year survival (81% vs. 82%, p⫽0.91) 5-year freedom from CAV (84% vs. 87%, p⫽0.57) or 1-year freedom from rejection (93% vs. 91%, p⫽0.43) However, the induction group exhibited a lower freedom from NF-MACE compared to the non-induction group (85% vs. 92%, p⫽0.037). Conclusions: Induction immunosuppression therapy does not appear to have an advantage over non-induction immunosuppression. Specifically, there was no difference in 1-year freedom from any-treated rejection, and pts on induction therapy demonstrated significantly higher incidence of NF-MACE. The cause of increased incidence of NF-MACE in the induction group remains unknown. A randomized trial is still needed to assess any benefit of induction therapy. 148 Donor Lung Surfactant Protein D Gene Polymorphisms Are Associated with Bronchiolitis Obliterans Syndrome and Mortality after Lung Transplantation B. Aramini,1 S. Diangelo,2 D. Lederer,4 J. Wilt,4 L. Shah,4 S. Mattioli,1 S. Keshavjee,3 J. Floros,2 S. Arcasoy,4 J. Sonett,4 F. D’Ovidio.1,4 1PhD Program in “Pneumo-Cardio-Thoracic Sciences of Medical and
Table 1 Met/Met11 Met/Thr11 Thr/Thr11 Ala/Ala160 Ala/Thr160 Thr/Thr160
SP-D genotype frequency 31% 54% 15% 48% 43% 9%
(60) (104) (28) (91) (83) (18)
Conclusions: Donor lung SP-D gene polymorphisms are associated with post transplant clinical outcomes. Lung allografts with the SP-D Thr/Thr11encoding genotype of are associated with earlier BOS development and reduced survival. The observed donor genetic differences, potentially via their effects on innate immunity seem to influence post transplant clinical outcomes. 149 BOS Is Associated with Increased Expression of C4d on Airway Bronchial Epithelial Cells Using Flow Cytometry – Potential Use in Diagnosing AMR G. Hodge,1,2 S. Hodge,1,2 D. Chambers,3 P. Hopkins,3 P.N. Reynolds,1,2 M. Holmes,1,2,4 C.-L. Liew.1,2,4 1Lung Research, Hanson Institute, Adelaide, Australia; 2Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia; 3●●●; 4●●●. Purpose: Antibody-mediated rejection (AMR) is likely to play a role in chronic allograft rejection manifesting as bronchiolitis obliterans syndrome (BOS) and leading to irreversible graft dysfunction following lung transplantation (LTx). Current techniques for assessing AMR in LTx using immunofluorescence techniques to identify subendothelial C4d deposition lack sensitivity, reproducibility and precision and require tissue biopsy, limiting routine clinical use in diagnosis or monitoring. Epithelial cell C4d deposition, as opposed to the classically described endothelial deposition, may be particularly important in the development of BOS (Magro). We hypothesised that a novel technique involving flow cytometric analysis of C4d on epithelial cells obtained by minimally invasive bronchial brushings
The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
Progression of Cavitities Progression
Survival following sirolimus, years
D NC D P NC PC P NC D
5 1 6 4 1 4 4 4 1
(alive) (alive) weeks (alive)
D Disappeared; NC: new cavity; P: persistent
Conclusions: Sirolimus impairs local healing in the lung and may result in cavitation.The incidence of cavitating lung lesions is double in the sirolimus group suggesting a possible association. The risk of cavitities is higher when trough levels above 12 ng/ml. Concurrent infection is a potential confounder. Sirolimus cavitities may be associated with significant worsening in lung function and prognosis is worse when cavity persists or progress.
Surgical Interest”, University of Bologna, Bologna, Italy; 2Penn State University, Hershey; 3Lung Transplant Program, University of Toronto, Toronto, Canada; 4Lung Transplant Program, Columbia University, New York. Purpose: Bronchiolitis obliterans is the major factor limiting long-term success of lung transplantation. Gene polymorphisms of surfactant proteins, key players in lung innate immunity, have been associated with various lung diseases. The aim of this study was to investigate the association between donor lung SP-D gene polymorphisms with recipient post transplant bronchiolitis obliterans syndrome and survival. Methods and Materials: Lung-Tx pts (192) were prospectively followed by PFTs, and bronchoscopies with BAL and biopsies. Donor DNA was assayed for SP-D gene polymorphisms of two single-nucleotide variations altering amino acids in the mature protein in codon 11 (Met11Thr) of the N-terminal domain, and in codon 160 (Ala160Thr) of the C-terminal domain, using the pyrosequencing method. Results: BOS was diagnosed in 49 pts. The table shows the SP-D genotype frequency for codon 11 (Met11Thr), and codon 160 (Ala160Thr). Recipients of lung allografts with the Thr/Thr11-encoding genotype had significantly earlier BOS development and reduced survival compared to those with the Met/Met11-encoding genotypes. No significant association was noted for SP-D variants Ala/Thr160.
147 Induction vs. Non-Induction in Heart Transplantation: The Controversy Continues R.P. Morrissey, L. Czer, M. Kittleson, J. Patel, E. Schwarz, G. Jamero, M. Kawano, M. Rafiei, B. Azarbal, A. Trento, J. Kobashigawa. CedarsSinai Heart Institute, Los Angeles, CA. Purpose: No randomized trials have demonstrated benefit of induction therapy in heart transplant recipients. This observational study reviews two large, local programs in the same era in which one program used routine anti-thymocyte globulin (ATG) induction and the other program used routine triple drug therapy without induction (reserved for patients with renal insuffiency to delay calcineurin inhibitor (CNI) initiation). With a case-control design, the impact of ATG induction on heart transplant outcomes was assessed. Methods and Materials: Between 2000 and 2009, 188 patients(pts) underwent routine induction therapy with ATG. A 1:1 control group of pts without induction was matched for age, sex, listing status and reason for transplant. Pts with baseline SCr ⬎2.5 mg/dl were excluded from this study since these pts may have received induction to delay initiation of CNI. Outcomes assessed were 5-year survival, freedom from cardiac allograft vasculopathy (CAV, angiographic stenosis ⬎ 30%), freedom from nonfatal major adverse cardiac events (NF-MACE: myocardial infarction, heart failure, PCI, ICD, stroke, and new peripheral vascular disease), and 1-year freedom from any-treated rejection. Results: There was no difference between groups in 5-year survival (81% vs. 82%, p⫽0.91) 5-year freedom from CAV (84% vs. 87%, p⫽0.57) or 1-year freedom from rejection (93% vs. 91%, p⫽0.43) However, the induction group exhibited a lower freedom from NF-MACE compared to the non-induction group (85% vs. 92%, p⫽0.037). Conclusions: Induction immunosuppression therapy does not appear to have an advantage over non-induction immunosuppression. Specifically, there was no difference in 1-year freedom from any-treated rejection, and pts on induction therapy demonstrated significantly higher incidence of NF-MACE. The cause of increased incidence of NF-MACE in the induction group remains unknown. A randomized trial is still needed to assess any benefit of induction therapy. 148 Donor Lung Surfactant Protein D Gene Polymorphisms Are Associated with Bronchiolitis Obliterans Syndrome and Mortality after Lung Transplantation B. Aramini,1 S. Diangelo,2 D. Lederer,4 J. Wilt,4 L. Shah,4 S. Mattioli,1 S. Keshavjee,3 J. Floros,2 S. Arcasoy,4 J. Sonett,4 F. D’Ovidio.1,4 1PhD Program in “Pneumo-Cardio-Thoracic Sciences of Medical and
Table 1 Met/Met11 Met/Thr11 Thr/Thr11 Ala/Ala160 Ala/Thr160 Thr/Thr160
SP-D genotype frequency 31% 54% 15% 48% 43% 9%
(60) (104) (28) (91) (83) (18)
Conclusions: Donor lung SP-D gene polymorphisms are associated with post transplant clinical outcomes. Lung allografts with the SP-D Thr/Thr11encoding genotype of are associated with earlier BOS development and reduced survival. The observed donor genetic differences, potentially via their effects on innate immunity seem to influence post transplant clinical outcomes. 149 BOS Is Associated with Increased Expression of C4d on Airway Bronchial Epithelial Cells Using Flow Cytometry – Potential Use in Diagnosing AMR G. Hodge,1,2 S. Hodge,1,2 D. Chambers,3 P. Hopkins,3 P.N. Reynolds,1,2 M. Holmes,1,2,4 C.-L. Liew.1,2,4 1Lung Research, Hanson Institute, Adelaide, Australia; 2Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia; 3●●●; 4●●●. Purpose: Antibody-mediated rejection (AMR) is likely to play a role in chronic allograft rejection manifesting as bronchiolitis obliterans syndrome (BOS) and leading to irreversible graft dysfunction following lung transplantation (LTx). Current techniques for assessing AMR in LTx using immunofluorescence techniques to identify subendothelial C4d deposition lack sensitivity, reproducibility and precision and require tissue biopsy, limiting routine clinical use in diagnosis or monitoring. Epithelial cell C4d deposition, as opposed to the classically described endothelial deposition, may be particularly important in the development of BOS (Magro). We hypothesised that a novel technique involving flow cytometric analysis of C4d on epithelial cells obtained by minimally invasive bronchial brushings