PGD Is Associated With Persistent Differential Gene Expression After Lung Transplantation

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The Journal of Heart and Lung Transplantation, Vol 34, No 4S, April 2015

4( 46) Cardiac Retransplantation: How Far Have We Come? K. Pandya , K. Lyons, A. Nsair, A. Baas, M. Cadeiras, D. Cruz, L. Reardon, M. Deng, A. Ardehali, E. Depasquale.  Advanced Heart Failure and Cardiac Transplantation, University of California, Los Angeles, Los Angeles, CA. Purpose: Redo heart transplantation (rHT) poses an ethical issue given the scarcity of donors. We sought to investigate long-term outcomes in a large national registry. Methods: 49608 HT & 1630 rHT pts were identified from a national registry (1987-2014) & stratified by era (1: 1987-2001 & 2: 2002-2014). Exclusions included: rHT> 1 & follow-up (FU) loss. Survival was censored at 12y & multivariate Cox proportional hazard regression models were adjusted for age, sex, DM, race, ischemic time, dialysis, etiology, life support, wait time & HLA mismatch. Results: Mean age among rHT was 38.7 + 19.7 years. Amongst rHT pts, transplant vasculopathy (50%) was most common indication while dilated (41%) and ischemic cardiomyopathy (40%) were most prevalent for first-time transplant. Mean follow up time was 4.8 + 5.03 years. During follow up, 50% HT & 54% rHT (p< 0.001) died. Crude survival is shown (Figure). Crude 1 month, 1-, 5- & 10-y post-HT survival was: rHT (89,76,57,39%) vs HT (94,86, 70 & 51%) Unadjusted HR for all-cause mortality (rHT vs HT) was 1.45 (CI 1.35-1.56). Multivariate Cox proportional hazards regression analysis yielded a hazard ratio of 1.39 (CI 1.28 to 1.51). Comparing HT, era 2 vs. era 1: [era 2 [0.69 (0.67-0.72)]. Comparing rHT, era 2 vs. era 1: [0.55 (0.48-0.64)]. After adjustment: HT [era 2 vs 1 [0.66 (0.550.79)] and rHT: era 2 vs era1: [0.44 (0.24-0.80). Conclusion: Short and long-term outcomes in rHT have improved in the more recent era and are approaching that of first-time HT. Offering redo heart transplantation to selected patients is warranted. 

Methods: The United Network for Organ Sharing database was queried for adult (> 18 years) patients undergoing LTx between 2006 and 2012. The population was randomly divided in a 4:1 fashion into derivation and validation cohorts. A multivariable logistic regression model comprised of recipient and donor factors as well as transplant-specific considerations was constructed within the derivation cohort. Points were then assigned to independent predictors (p< 0.05) based on relative odds ratios. A linear equation relating score to predicted mortality was formulated. Risk-groups were established based on score ranges and their ability to predict 1-year mortality was substantiated in the validation cohort. Results: During the study period, 9185 patients underwent LTx and the 1-year mortality was 18.0% (n= 1654). There was a similar distribution of variables between the derivation (n= 1849) and validation cohorts (n= 7336). Of the 13 covariates included in the final model, 9 were ultimately allotted point values (Table). The model had good predictive strength (AUC= 0.65) in the derivation cohort and demonstrated a strong correlation between the observed and predicted risk of 1-year mortality in the validation cohort(r= 0.84). The low (score 0-8), intermediate (score 9-16) and high (score > 16) risk groups experienced an 8.3%, 13.9% and 25.5% risk of mortality (p< 0.001). Conclusion: This is the first known risk model predicting 1-year mortality based on recipient, donor and transplanted-related factors following LTx. This scoring system could influence recipient optimization, alter donor selection and affect postoperative management.

Variable Age 50-59 60-64 > 64 Previous thoracic transplant Preoperative Karnofsky Performance Score 50-70 < 50 Preoperative GFR 45-60 < 45 Albumin < 4 ICU prior to transplant ECMO prior to transplant Donor diabetes Donor CMV+ Total

Points

4 6 7 5 5 7 4 6 4 6 7 5 4 70

4( 49) PGD Is Associated With Persistent Differential Gene Expression After Lung Transplantation J.M. Diamond ,1 E. Cantu,1 D.J. Lederer,2 J. Tobias,1 S. Arcasoy,2 K.M. Olthoff,1 B. Chang,1 R. Feng,1 K. Meyer,3 J. Emond,2 A. Shaked,1 J.D. Christie.1  1University of Pennsylvania, Philadelphia, PA; 2Columbia University, New York, NY; 3University of Wisconsin, Madison, WI.

4( 47) WITHDRAWN 4( 48) A Novel Risk Score to Predict 1-Year Mortality Following Lung Transplant in the Current Era J.C. Grimm ,1 V. Valero 3rd,1 J. Magruder,1 A. Kilic,1 L.L. Silhan,2 P.D. Shah,2 C.A. Merlo,2 A.S. Shah.1  1Surgery, The Johns Hopkins Medical Institution, Baltimore, MD; 2Medicine, The Johns Hopkins Medical Institution, Baltimore, MD. Purpose: We sought to construct a novel scoring system based on recipient- and donor specific characteristics in order to preoperatively stratify LTx patients based on their risk of 1-year mortality.

Purpose: Primary Graft Dysfunction (PGD) is the main cause of early morbidity and mortality after lung transplant. The response to the lung injury of PGD during the first year may have important implications in the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression of mRNA transcripts in subjects with PGD. Methods: Subjects were enrolled in the Clinical Trials in Organ Transplantation-03 (CTOT-03) study at three transplant centers between 2008 and 2010 (NCT00531921). PGD was defined as any grade 3 PGD. Blood was collected from study subjects in PAXgene Blood RNA tubes within 1 hour after reperfusion and again at 3 days, 7 days, 3 months, 6 months, and 12 months after transplant. RNA expression was measured using a Panomics-based panel of 100 hypothesis-driven genes. We first evaluated persistent differences in gene expression amongst genes that were associated with PGD within 1 hour after transplant. We then used mixed models to assess longitudinal differences in gene expression during the first year after transplant in patients with and without PGD. Results: 100 patients were included for this study. 7 genes had persistently decreased expression (> 1.5 fold, FDR< 0.05) at least 7 days after transplant. All of these genes were expressed selectively by T cells and NK cells. 4 genes predominantly associated with innate immunity, were persistently elevated (> 1.5

Abstracts S171 fold, FDR< 0.05) at least 7 days after transplant.11 gene products were differentially expressed in PGD vs. non-PGD subjects. Three gene products, PTX3, IL18R1, and NLRC4, all associated with innate immune and inflammatory responses, were increased throughout the first year after transplant (Table 1). Conclusion: The differences in gene expression associated with PGD persist for several weeks after transplant. Persistent alteration in gene expression amongst genes responsible for innate immune regulation and T-cell function may provide a pathologic link between PGD and long-term allograft dysfunction. 

585 LRTx recipients. Uni- and multivariate Cox regression assessed the effect of recipient, operative, donor, and hospital characteristics on survival. Propensity score matching accounted for baseline differences, and Kaplan-Meier analysis evaluated post-transplant survival in un-matched and matched groups. Results: Before matching, LRTx patients had a greater frequency of ECMO support, mechanical ventilation, and renal insufficiency, and were less likely to receive double LTx (table 1). Given these worse comorbidities, one would expect the inferior survival found in LRTx recipients (figure 1a). Propensitymatching was able to balance covariates between LTx and LRTx groups (table 1). Even after accounting for preoperative characteristics, there remained a significant association between LRTx and death in our matched survival analysis (figure 1b). Multivariable Cox regression confirmed this finding, with LRTx having a hazard ratio of 1.26 for death (95% confidence interval 1.09-1.45). Other risk factors for death are shown in table 1. Conclusion: Even after accounting for recipient, operative, donor, and hospital characteristics, LRTx recipients had worse survival compared with LTx recipients. The independent association between LRTx and death warrants consideration for including LRTx status into the LAS.

4( 50) Pregnancies After Lung Transplantation: A Retrospective Multicenter French Study About 39 Pregnancies C. Bry ,1 D. Hubert,2 M. Reynaud-Gaubert,3 C. Dromer,4 H. Mal,5 D. Grenet,6 V. Boussaud,7 J. Claustre,8 J. Le Pavec,9 M. Murris-Espin,10 I. Danner-Boucher.1  1Service de Pneumologie, Institut du Thorax, CHU de Nantes, Nantes, France; 2Service de Pneumologie, Hopital Cochin, Paris, France; 3Centre de Ressource et de Compétences de la Mucoviscidose Adulte ; Équipe de Transplantation Pulmona, CHU Nord, Marseille, France; 4Service de Pneumologie, CHU Bordeaux, Bordeaux, France; 5Service de Pneumologie, Hopital Bichat -Claude Bernard, Paris, France; 6Pneumology, Hopital FOCH, Suresnes, France; 7Service de Pneumologie, Hopital Europeen Georges-Pompidou, Paris, France; 8Clinique Universitaire de Pneumologie, Pôle Thorax et Vaisseaux, CHU de Grenoble, Grenoble, France; 9Service de Chirurgie Thoracique et Vasculaire, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; 10CRCM Adulte-Service de Pneumologie-Allergologie, CHU de Toulouse, Toulouse, France. Purpose: Pregnancy after lung transplantation remains rare. This French study deals with maternal and newborn outcomes and change in lung function after a pregnancy. Methods: We retrospectively included 39 pregnancies in 35 lung transplant recipients over more than 20 years. Data about patients, course of pregnancies and newborns were collected from nine of the eleven French transplantation centers. Results: Mean age at time of pregnancy was 28±5years. Cystic fibrosis affected 71% of our patients. Mean time between transplantation and pregnancy was 63±44 months. Twenty six births occurred (67%) with a mean term of 36±5 weeks gestation and a mean birth weight of 2409±921 g. Prematurity was observed in 11 cases (43%). Forced expiratory volume in one second was measured at 83,9% pred. before pregnancy and at 77,3% pred. 12 months later (p= 0.04). Ten patients developed chronic lung allograft dysfunction, 22.5±14.6 months after delivery. Up to now, nine patients died with a mean time after transplantation of 8.2±7 years and a mean time after pregnancy of 4.6±6.5 years. Conclusion: Pregnancy in lung transplant recipients is possible. Maternal and newborn complications are more frequent than in general population. Survival in this cohort appears to be similar to global survival observed in lung transplant recipients. Planned pregnancy and multidisciplinary follow-up are crucial. 4( 51) Lung Retransplantation in the Lung Allocation Score Era J.M. Schaffer ,1 P. Chiu,1 B.A. Reitz,1 G. Dhillon,2 J. Woo,1 R. Ha.1   1Cardiothoracic Surgery, Stanford University, School of Medicine, Stanford, CA; 2Pulmonary and Critical Care, Stanford University, School of Medicine, Stanford, CA. Purpose: Lung retransplantation (LRTx) has been employed with increasing frequency in the lung allocation score (LAS) era, despite the worse prognosis of LRTx recipients. Methods: A review of adult lung transplant (LTx) recipients since the LAS implementation (5/2005-12/2012) identified 11,294 first-time LTx recipients and

Demographics, comorbidities, operative, and hospital characteristics before and after matching

Firsttime, all Redo, all (n= 11,294) (n= 585) Age, y

Standard- First-time, Redo, ized Dif- matched matched ference (n= 524) (n= 524)

54.6±13.0 47.4±15.6 -0.502

49.0

48.2

Standardized Hazard DifferRatio for ence death -0.055

1.011 (1.0081.015)

Male gender 6660 (59.0) 334 (57.1) -0.038

309 (59.0) 306 (58.4) -0.012

1.09 (1.011.17)

AfricanAmerican race

958 (8.5)

29 (5.5)

0.024

0.86 (0.750.98)

Private insurance

6308 (56.0) 305 (52.6) -0.069

267 (51.3) 271 (52.1) 0.017

0.89 (0.830.95)

25.2±4.7

23.1±2.7

23.0±4.8

1.001 (0.9931.010)

0 (0.0)

524 (100)

BMI,

kg/m2

Previous lung 0 (0.0) transplant

34 (5.8)

22.8±4.8

-0.104

-0.501

585 (100)

32 (6.1)

-0.005

1.26 (1.091.45)

Diagnosis of 4134 (36.6) 156 (26.7) -0.215 idiopathic pulmonary fibrosis

159 (30.3) 148 (28.2) -0.046

1.00 (used as baseline diagnosis)

Diagnosis 3174 (28.1) 120 (20.5) -0.178 of chronic obstructive pulmonary disease

114 (21.8) 112 (21.4) -0.009

0.91 (0.840.99)

NYHA IV symptoms

1401 (12.4) 168 (27.7) 0.412

129 (24.6) 142 (27.1) 0.057

1.35 (1.241.47)

6-minute walk, ft

777±438

657±504

688±463

0.99975 (0.999670.99982)

Ventilator

546 (4.8)

146 (25.0) 0.589

108 (20.6) 121 (23.1) 0.060

1.21 (1.041.40)

ECMO

145 (1.3)

29 (5.0)

0.212

18 (3.4)

26 (5.0)

0.076

1.72 (1.312.26)

Creatinine clearance, ml/min

102±32

81±34

-0.659

82±26

83±34

0.032

1.16 (1.031.31)

-0.254

656±496

-0.065

High 4362 (38.6) 183 (31.3) -0.154 performing institution

167 (31.9) 167 (31.9)

0.79 (0.740.84)

Moderate- or 8126 (72.0) 447 (76.4) 0.102 high-volume institution

383 (73.1) 402 (76.7) 0.084

0.76 (0.710.82)

Double lung 7440 (65.9) 305 (52.1) -0.282 transplant

278 (53.1) 279 (53.2) 0.004

0.82 (0.760.88)

Race match, 7744 (68.6) 383 (65.5) -0.066 n (%)

290 (55.3) 277 (52.9) -0.050

0.88 (0.820.94)

Complete HLA2208 (22.3) 105 (20.4) -0.047 mismatch (all 6 alleles)

110 (24.3) 89 (19.3) -0.123

1.11 (1.031.20)

Panel985 (9.4) reactive antibody ≥  20%

53 (11.0) 62 (13.0) 0.060

1.18 (1.051.33)

75 (14.1) 0.145