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Effects of Induction on the Risk of Post-Transplant De Novo DSA
Abstracts
S387
974
975
Immunoadsorption for Acute Symptomatic Antibody-Mediated Rejection after Heart Transplantation A. Schaefer,1 G. B€ ohmig,2 A. Zuckermann,1 G. Fischer,3 G. Laufer,1 A. Kaider,4 and A. Aliabadi-Zuckermann.1 1Department of Surgery, Division of Cardiac Surgery, Medical University of Vienna, Vienna, Austria; 2Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Medical University of Vienna, Vienna, Austria; 3Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria; and the 4Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
Combination of Cell-Free DNA with Gene-Expression Profiling in the Diagnosis of Acute Rejection E. Depasquale,1 S. Hall,2 M. Crespo-Leiro,3 A. Kao,4 J. Teuteberg,5 D. Hiller,6 and J. Yee.6 1Department of Medicine-Cardiology, University of California, Los Angeles, Los Angeles, CA; 2Baylor Scott&White Research Institute, Dallas, TX; 3Hospital Universitario A Coru~na, La Coruna, Spain; 4 Saint Luke's Mid America Heart Institute, Kansas, MO; 5Stanford University, Stanford, CA; and the 6CareDx, Inc., Brisbane, CA.
Purpose: Antibody-mediated rejection (AMR) after heart transplantation (HTX) is associated with adverse outcomes. A standardized therapeutic regimen has not yet been defined. Immunoadsorption (IA) has shown promising results in AMR after kidney transplantation. We present our results with IA for acute symptomatic AMR after HTX. Methods: This retrospective single-center study included all consecutive patients with proven and treated symptomatic AMR between 2006 and 2016. Survival from AMR, incidence of cardiac allograft vasculopathy (CAV) as well as donor specific anti-HLA-antibody (DSA) cumulative mean fluorescence intensity (MFI) assessed by LUMINEX single antigen bead assay are described. Results: 22 patients were designated to undergo extracorporeal antibody removal for symptomatic AMR and received IA (n=18, 81,8 %) or plasmapheresis (PP; n=1, 4,5 %). One patient was switched to IA after one initial PP. In two patients IA/PP was not initiated due to unfavorable prognosis. Concomitant therapy was methylprednisolone (100 %), IVIg (9 %) and rituximab (4,5 %). AMR occurred after a median of 5.65 months (IQR 0.4321.4) from HTX. Overall survival after a median follow up of 4.85 years from AMR diagnosis was 63.6 %. Mortality 30 days, 1 year and 5 years after AMR onset was 27.3 %, 31.8 % and 31.8 %. 4 patients (18.2 %) developed severe CAV (ISHLT grade ≥ 2) after a median time of 30.5 months after AMR onset. 21 patients had positive DSA at the time of AMR diagnosis (HLA I only: 13.6 %, HLA II only: 50 %, HLA I+II: 31.8%). Conclusion: Despite high early mortality, long-term outcome of patients surviving the acute phase is encouraging, however we observed an increased burden of CAV. Due to the oftentimes fulminant clinical course, rapid diagnosis and therapy, facilitated by close interdisciplinary cooperation of intensivists, cardiac surgeons and nephrologists is crucial. Next steps include a detailed characterization of DSAs over the treatment period as well as endomyocardial biopsy specimens of patients with AMR.
Purpose: Gene expression profiling testing (GEP; AlloMap) and donorderived cell free DNA (dd-cfDNA; AlloSure) each provide non-invasive means to detect possible heart allograft rejection, including acute cellular rejection (ACR). This report describes the performance of these two molecular diagnostic methods when used together. Methods: A retrospective cohort of 26 heart transplant patients with endomyocardial biopsy-based diagnosis of grade 0 ACR were demographically matched to 27 patients with grade ≥ 2R ACR. The dd-cfDNA (%, AlloSure) and GEP (AlloMap, score 0-39) results were correlated with the biopsy-based diagnosis of ACR. Results: Patients with ACR had significantly higher dd-cfDNA (0.48 vs. 0.07; P < 0.001) and GEP scores (28 vs. 25 P = 0.027). Logistic regression demonstrated that dd-cfDNA and GEP were independently associated with ACR (Figure 1). When dd-cfDNA > 0.2% and GEP scores > 34, we calculated a 26% sensitivity and 92% specificity, and an NPV of 98% and a PPV of 6%. When GEP < 34 and dd-cfDNA < 0.2, the NPV was 99.5%, for ACR. Patients with ACR had a median age of 49 years, 85% were male, 85% were white, and the median time post-transplant was 29 days. Patients with no ACR had a median age of 54 years, 81% were male, 96% were white, and the median time post-transplant was 22 days. Conclusion: In surveillance of heart allograft recipients for rejection, consideration of dd-cfDNA levels together with GEP scores may improve patient management decisions.
976 Effects of Induction on the Risk of Post-Transplant De Novo DSA R.T. Cole,1 J. Minto,2 M. Flattery,3 A. Parikh,4 T. Dong,1 R. Roy,1 L. Bogar,5 A. Morris,1 J. Vega,6 D. Gupta,1 K. Bhatt,1 A. Smith,1 S. Laskar,7 A. Lala,4 K. Shah,3 and P. Shah.8 1Cardiology, Emory Univ Sch of Med, Atlanta, GA; 2George Washington University School of Medicine, Washington DC, GA; 3Virginia Commonwealth University, Richmond, VA; 4Mount Sinai Hospital, New York, NY; 5Department of Cardiac Surgery, Inova Heart and Vascular Institute, Falls Church, VA; 6 Cardiothoracic Surgery, Emory Univ Sch of Med, Atlanta, GA; 7 Cardiology, Emory University School of Medicine, Atlanbta, GA; and the 8 Inova Heart and Vascular Institute, Falls Church, VA.
S388
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Purpose: Nearly 30% of heart transplant recipients develop de novo donor-specific antibodies post-transplant, leading to an increased risk of antibody mediated rejection, graft failure, and death. Given poor response rates to therapies targeting dnDSA once present, therapies preventing dnDSA altogether could impact transplant outcomes. It remains unclear if the use of induction therapy at the time of transplant mitigates the risk of dnDSA development. The present study attempts to address this question in a multicenter, retrospective analysis. Methods: Multicenter, retrospective analysis of 319 heart transplant recipients from 4 participating centers in the U.S. The primary endpoint was the development of dnDSA. Results: In the overall cohort, 206 of 319 (65%) patients received induction therapy at the time of transplant, with 200 (62%) receiving basiliximab and 6 (3%) receiving thymoglobulin. Overall 93 of 319 (29%) patients developed dnDSA post-transplant. The use of induction therapy reduced the risk of dnDSA (Kaplan Meier log rank p = 0.009, Figure 1). When assessing induction type, basiliximab reduced the risk of dnDSA compared to no induction, whereas thyroglobulin did not (Figure 2). However, in a multivariable Cox Regression model incorporating the use of an LVAD as BTT, the use of any induction was no longer statistically significant. Conclusion: Although induction therapy, particularly with basiliximab, reduces the risk of dnDSA post-heart transplant in univariate analysis, this effect is no longer significant in a model incorporating LVAD as BTT.
Results: Patients with mixed rejection compared to ACR and AMR alone had a significantly reduced subsequent 5-year survival (46.2% vs 69.8% and 80.0% respectfully%, p=0.010). Causes of death in the mixed rejection group (n=7) included rejection (3), multi-organ failure (1), trauma (1) and unknown causes (2). There was no significant difference in subsequent 5year freedom from CAV or NF-MACE. Conclusion: Patients with first-year mixed rejection have a significant mortality risk at 5-years. More aggressive immune therapy to treat both cellular and humoral activation pathways may be needed in this group. Larger patient numbers with mixed rejection are needed to confirm these findings.
Endpoints Subsequent 5-Year Survival Subsequent 5-Year Freedom from NF-MACE Subsequent 5-Year Freedom from CAV
Mixed Rejection (n=13)
ACR Alone (n=43)
AMR Alone (n=40)
Log-Rank P-Value
46.2% 53.8%
69.8% 62.8%
80.0% 62.5%
0.010 0.663
76.9%
72.1%
80.0%
0.499
978 Peri-Operative Serum Amiodarone Levels are Not Predictive of Graft Dysfunction in Orthotopic Heart Transplantation J.E. Sanchez, M. Farr, S. Restaino, D. Jennings, V. Topkara, A.R. Garan, P. Kurlansky, P. Colombo, H. Takayama, Y. Naka and K. Takeda. Columbia University College of Physicians & Surgeons, New York, NY.
977 Mixed Rejection: More Important Than Thought after Heart Transplantation E. Kransdorf, M. Kittleson, J. Patel, R. Cole, S. Dimbil, R. Levine, M. Olymbios, T. Kao, L. Czer, B. Azarbal, J. Chung and J.A. Kobashigawa. Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA. Purpose: Mixed rejection is defined as the simultaneous presence of antibody-mediated rejection (AMR) and acute cellular rejection (ACR). Mild forms of AMR and ACR are often found together, but moderate to severe (≥2R) ACR and AMR (≥1) is far less prevalent. We sought to assess whether patients with moderate to severe ACR and AMR together have a greater mortality and/or incidence of cardiac allograft vasculopathy (CAV). Methods: Between 1999 and 2012, we identified 13 heart transplant patients who developed first-year simultaneous ACR (≥2R) and AMR (≥1). Control groups including patients with either ACR (n=43) or AMR (n=40) alone. Endpoints included subsequent 5-year survival, subsequent 5-year freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, and stroke), and subsequent freedom from cardiac allograft vasculopathy as defined by ≥ 30% stenosis by angiography.
Purpose: Primary graft dysfunction (PGD) in orthotopic heart transplant (OHT) carries a large morbidity and mortality. We have previously reported a dose-dependent association with pre-transplant amiodarone usage and PGD in patients with OHT. We conducted a prospective study to elucidate if preoperative serum amiodarone level could predict PGD. Methods: Since 2017, we began to monitor serum amiodarone and amiodarone metabolite levels in the peri-operative period prior transplantation. Degree of PGD was determined for each patient post-operatively using the ISHLT Diagnostic Criteria and Classification of PGD. The data was prospectively collected in 54 patients. The risk of PGD was calculated with linear regression. Results: The median age for the cohort was 54.5 (IQR 45-65) and 77.8% were male. Baseline height and BMI were 172.7cm (IQR 167- 178) and 27.5 kg/m2 (24.6- 30.8), respectively. Forty-one patients (75.9%) were bridged to transplant. Median cardiopulmonary bypass and ischemic times were 132 (IQR 118- 154) and 163 min (IQR 120- 208), respectively. Median intraoperative inotrope score was 6.9 (3.7-12.6). Twenty-six patients (48.2%) were taking amiodarone prior to OHT with a median dose of 200 mg daily, and the median total serum amiodarone level was 1.7mg/mL (1.2-2.1). Two patients (3.7%) experienced mild PGD. One (1.9%) and eleven (20.4%) patients experienced moderate and severe PGD, respectively. The risk of developing PGD was not correlated with amiodarone level (r= 0.31, 95% CI= -1.2-1.9, p=0.68). The risk of developing severe PGD was also not correlated with amiodarone level (r= -0.05, 95% CI=-1.4-1.4, p=0.94). Conclusion: No predictive association could be made between the onetime preoperative amiodarone serum level and the risk of developing PGD.
S387
974
975
Immunoadsorption for Acute Symptomatic Antibody-Mediated Rejection after Heart Transplantation A. Schaefer,1 G. B€ ohmig,2 A. Zuckermann,1 G. Fischer,3 G. Laufer,1 A. Kaider,4 and A. Aliabadi-Zuckermann.1 1Department of Surgery, Division of Cardiac Surgery, Medical University of Vienna, Vienna, Austria; 2Department of Medicine III, Division of Nephrology and Dialysis, Medical University of Vienna, Medical University of Vienna, Vienna, Austria; 3Department for Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria; and the 4Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
Combination of Cell-Free DNA with Gene-Expression Profiling in the Diagnosis of Acute Rejection E. Depasquale,1 S. Hall,2 M. Crespo-Leiro,3 A. Kao,4 J. Teuteberg,5 D. Hiller,6 and J. Yee.6 1Department of Medicine-Cardiology, University of California, Los Angeles, Los Angeles, CA; 2Baylor Scott&White Research Institute, Dallas, TX; 3Hospital Universitario A Coru~na, La Coruna, Spain; 4 Saint Luke's Mid America Heart Institute, Kansas, MO; 5Stanford University, Stanford, CA; and the 6CareDx, Inc., Brisbane, CA.
Purpose: Antibody-mediated rejection (AMR) after heart transplantation (HTX) is associated with adverse outcomes. A standardized therapeutic regimen has not yet been defined. Immunoadsorption (IA) has shown promising results in AMR after kidney transplantation. We present our results with IA for acute symptomatic AMR after HTX. Methods: This retrospective single-center study included all consecutive patients with proven and treated symptomatic AMR between 2006 and 2016. Survival from AMR, incidence of cardiac allograft vasculopathy (CAV) as well as donor specific anti-HLA-antibody (DSA) cumulative mean fluorescence intensity (MFI) assessed by LUMINEX single antigen bead assay are described. Results: 22 patients were designated to undergo extracorporeal antibody removal for symptomatic AMR and received IA (n=18, 81,8 %) or plasmapheresis (PP; n=1, 4,5 %). One patient was switched to IA after one initial PP. In two patients IA/PP was not initiated due to unfavorable prognosis. Concomitant therapy was methylprednisolone (100 %), IVIg (9 %) and rituximab (4,5 %). AMR occurred after a median of 5.65 months (IQR 0.4321.4) from HTX. Overall survival after a median follow up of 4.85 years from AMR diagnosis was 63.6 %. Mortality 30 days, 1 year and 5 years after AMR onset was 27.3 %, 31.8 % and 31.8 %. 4 patients (18.2 %) developed severe CAV (ISHLT grade ≥ 2) after a median time of 30.5 months after AMR onset. 21 patients had positive DSA at the time of AMR diagnosis (HLA I only: 13.6 %, HLA II only: 50 %, HLA I+II: 31.8%). Conclusion: Despite high early mortality, long-term outcome of patients surviving the acute phase is encouraging, however we observed an increased burden of CAV. Due to the oftentimes fulminant clinical course, rapid diagnosis and therapy, facilitated by close interdisciplinary cooperation of intensivists, cardiac surgeons and nephrologists is crucial. Next steps include a detailed characterization of DSAs over the treatment period as well as endomyocardial biopsy specimens of patients with AMR.
Purpose: Gene expression profiling testing (GEP; AlloMap) and donorderived cell free DNA (dd-cfDNA; AlloSure) each provide non-invasive means to detect possible heart allograft rejection, including acute cellular rejection (ACR). This report describes the performance of these two molecular diagnostic methods when used together. Methods: A retrospective cohort of 26 heart transplant patients with endomyocardial biopsy-based diagnosis of grade 0 ACR were demographically matched to 27 patients with grade ≥ 2R ACR. The dd-cfDNA (%, AlloSure) and GEP (AlloMap, score 0-39) results were correlated with the biopsy-based diagnosis of ACR. Results: Patients with ACR had significantly higher dd-cfDNA (0.48 vs. 0.07; P < 0.001) and GEP scores (28 vs. 25 P = 0.027). Logistic regression demonstrated that dd-cfDNA and GEP were independently associated with ACR (Figure 1). When dd-cfDNA > 0.2% and GEP scores > 34, we calculated a 26% sensitivity and 92% specificity, and an NPV of 98% and a PPV of 6%. When GEP < 34 and dd-cfDNA < 0.2, the NPV was 99.5%, for ACR. Patients with ACR had a median age of 49 years, 85% were male, 85% were white, and the median time post-transplant was 29 days. Patients with no ACR had a median age of 54 years, 81% were male, 96% were white, and the median time post-transplant was 22 days. Conclusion: In surveillance of heart allograft recipients for rejection, consideration of dd-cfDNA levels together with GEP scores may improve patient management decisions.
976 Effects of Induction on the Risk of Post-Transplant De Novo DSA R.T. Cole,1 J. Minto,2 M. Flattery,3 A. Parikh,4 T. Dong,1 R. Roy,1 L. Bogar,5 A. Morris,1 J. Vega,6 D. Gupta,1 K. Bhatt,1 A. Smith,1 S. Laskar,7 A. Lala,4 K. Shah,3 and P. Shah.8 1Cardiology, Emory Univ Sch of Med, Atlanta, GA; 2George Washington University School of Medicine, Washington DC, GA; 3Virginia Commonwealth University, Richmond, VA; 4Mount Sinai Hospital, New York, NY; 5Department of Cardiac Surgery, Inova Heart and Vascular Institute, Falls Church, VA; 6 Cardiothoracic Surgery, Emory Univ Sch of Med, Atlanta, GA; 7 Cardiology, Emory University School of Medicine, Atlanbta, GA; and the 8 Inova Heart and Vascular Institute, Falls Church, VA.
S388
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
Purpose: Nearly 30% of heart transplant recipients develop de novo donor-specific antibodies post-transplant, leading to an increased risk of antibody mediated rejection, graft failure, and death. Given poor response rates to therapies targeting dnDSA once present, therapies preventing dnDSA altogether could impact transplant outcomes. It remains unclear if the use of induction therapy at the time of transplant mitigates the risk of dnDSA development. The present study attempts to address this question in a multicenter, retrospective analysis. Methods: Multicenter, retrospective analysis of 319 heart transplant recipients from 4 participating centers in the U.S. The primary endpoint was the development of dnDSA. Results: In the overall cohort, 206 of 319 (65%) patients received induction therapy at the time of transplant, with 200 (62%) receiving basiliximab and 6 (3%) receiving thymoglobulin. Overall 93 of 319 (29%) patients developed dnDSA post-transplant. The use of induction therapy reduced the risk of dnDSA (Kaplan Meier log rank p = 0.009, Figure 1). When assessing induction type, basiliximab reduced the risk of dnDSA compared to no induction, whereas thyroglobulin did not (Figure 2). However, in a multivariable Cox Regression model incorporating the use of an LVAD as BTT, the use of any induction was no longer statistically significant. Conclusion: Although induction therapy, particularly with basiliximab, reduces the risk of dnDSA post-heart transplant in univariate analysis, this effect is no longer significant in a model incorporating LVAD as BTT.
Results: Patients with mixed rejection compared to ACR and AMR alone had a significantly reduced subsequent 5-year survival (46.2% vs 69.8% and 80.0% respectfully%, p=0.010). Causes of death in the mixed rejection group (n=7) included rejection (3), multi-organ failure (1), trauma (1) and unknown causes (2). There was no significant difference in subsequent 5year freedom from CAV or NF-MACE. Conclusion: Patients with first-year mixed rejection have a significant mortality risk at 5-years. More aggressive immune therapy to treat both cellular and humoral activation pathways may be needed in this group. Larger patient numbers with mixed rejection are needed to confirm these findings.
Endpoints Subsequent 5-Year Survival Subsequent 5-Year Freedom from NF-MACE Subsequent 5-Year Freedom from CAV
Mixed Rejection (n=13)
ACR Alone (n=43)
AMR Alone (n=40)
Log-Rank P-Value
46.2% 53.8%
69.8% 62.8%
80.0% 62.5%
0.010 0.663
76.9%
72.1%
80.0%
0.499
978 Peri-Operative Serum Amiodarone Levels are Not Predictive of Graft Dysfunction in Orthotopic Heart Transplantation J.E. Sanchez, M. Farr, S. Restaino, D. Jennings, V. Topkara, A.R. Garan, P. Kurlansky, P. Colombo, H. Takayama, Y. Naka and K. Takeda. Columbia University College of Physicians & Surgeons, New York, NY.
977 Mixed Rejection: More Important Than Thought after Heart Transplantation E. Kransdorf, M. Kittleson, J. Patel, R. Cole, S. Dimbil, R. Levine, M. Olymbios, T. Kao, L. Czer, B. Azarbal, J. Chung and J.A. Kobashigawa. Smidt Heart Institute at Cedars-Sinai, Los Angeles, CA. Purpose: Mixed rejection is defined as the simultaneous presence of antibody-mediated rejection (AMR) and acute cellular rejection (ACR). Mild forms of AMR and ACR are often found together, but moderate to severe (≥2R) ACR and AMR (≥1) is far less prevalent. We sought to assess whether patients with moderate to severe ACR and AMR together have a greater mortality and/or incidence of cardiac allograft vasculopathy (CAV). Methods: Between 1999 and 2012, we identified 13 heart transplant patients who developed first-year simultaneous ACR (≥2R) and AMR (≥1). Control groups including patients with either ACR (n=43) or AMR (n=40) alone. Endpoints included subsequent 5-year survival, subsequent 5-year freedom from non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, and stroke), and subsequent freedom from cardiac allograft vasculopathy as defined by ≥ 30% stenosis by angiography.
Purpose: Primary graft dysfunction (PGD) in orthotopic heart transplant (OHT) carries a large morbidity and mortality. We have previously reported a dose-dependent association with pre-transplant amiodarone usage and PGD in patients with OHT. We conducted a prospective study to elucidate if preoperative serum amiodarone level could predict PGD. Methods: Since 2017, we began to monitor serum amiodarone and amiodarone metabolite levels in the peri-operative period prior transplantation. Degree of PGD was determined for each patient post-operatively using the ISHLT Diagnostic Criteria and Classification of PGD. The data was prospectively collected in 54 patients. The risk of PGD was calculated with linear regression. Results: The median age for the cohort was 54.5 (IQR 45-65) and 77.8% were male. Baseline height and BMI were 172.7cm (IQR 167- 178) and 27.5 kg/m2 (24.6- 30.8), respectively. Forty-one patients (75.9%) were bridged to transplant. Median cardiopulmonary bypass and ischemic times were 132 (IQR 118- 154) and 163 min (IQR 120- 208), respectively. Median intraoperative inotrope score was 6.9 (3.7-12.6). Twenty-six patients (48.2%) were taking amiodarone prior to OHT with a median dose of 200 mg daily, and the median total serum amiodarone level was 1.7mg/mL (1.2-2.1). Two patients (3.7%) experienced mild PGD. One (1.9%) and eleven (20.4%) patients experienced moderate and severe PGD, respectively. The risk of developing PGD was not correlated with amiodarone level (r= 0.31, 95% CI= -1.2-1.9, p=0.68). The risk of developing severe PGD was also not correlated with amiodarone level (r= -0.05, 95% CI=-1.4-1.4, p=0.94). Conclusion: No predictive association could be made between the onetime preoperative amiodarone serum level and the risk of developing PGD.