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45 Antibody-Mediated Rejection in Heart Transplantation: Clinical Follow-Up
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The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
Methods and Materials: Between January 2007 and August 2010, 95 patients with ELISA-PRA⬎10% and with HLA-specific antibodies determined by Luminex bead array (L-IGG) underwent heart transplantation (HTx). 33(34%) HTx recipients exhibited pre-Tx DSA. Four patients with DSA⬎8000 MFI assessed by L-IGG were considered virtual crossmatch (VCXM) positive and all were CXM positive, 3 were CDC-AHG T cell⫹ and 1 was B cell CXM⫹. All other HTx patients had DSA level⬍8000 MFI. Immunosuppression (IS) consisted of tacrolimus and MMF and 88(93%) had also induction therapy with alemtuzumab. Frequency of acute severe rejection (ACR) and presence of diffuse C4d in tissue was evaluated in DSA and non-DSA cohorts with one year follow-up. Results: VCXM negative defined as DSA⬍8000 MFI correlated 100% with the negative CDC-CXM performed with pre-Tx sera within 24 hr of HTx. Peri-operative plasmapheresis and IVIG was used in CXM⫹ patients. Post-op ECMO use: 3% in DSA group vs. 10% in non-DSA group (p⫽0.4). Freedom from diffuse C4d staining in first year was 92% in non-DSA group vs. 68% in DSA group (pⴝ0.02). Of the CXM positive HTx recipients one patient post-Tx had persistent high level of DSA and developed diffuse C4d in tissue. Freedom from ACR was 78% in non-DSA group vs. 81% in DSA group (p⫽0.7). Overall, graft survival was similar or better in DSA group (30 days, 1 year, 3 years 97%, 97%, 97%; vs. non-DSA group, 94%, 85%, 74%; (pⴝ0.04). Conclusions: Although, HTx patients with DSA exhibited increased C4d in heart biopsies, the frequency of ACR was similar and overall survival was not worse at 3 years in DSA vs. non-DSA cohort. Under induction therapy with tacrolimus and MMF maintenance IS, sensitized HTx patients can be safely transplanted with pre-and post-transplant evaluation of DSA levels. Further studies are needed to evaluate the long term outcomes in these high risk HTx candidates. 44 Timing of the Development of Donor Specific Antibody after Heart Transplantation Impacts Long-Term Outcome M. Kittleson,1 J. Patel,1 M. Kawano,1 Z. Goldstein,1 M. Rafiei,1 N. Reinsmoen,1 E. Reed,2 A. Hage,1 E. Schwarz,1 F. Esmailian,1 J. Kobashigawa.1 1Cedars-Sinai Heart Institute, Los Angeles, CA; 2 University of California, Los Angeles, Los Angeles, CA. Purpose: The development of donor specific antibodies (DSA) after heart transplant (HT) negatively impacts long term outcomes. Whether early development of DSA (⬍ 1 year post transplant) is worse than late development of DSA (⬎ 1 year post transplant) is not clear. The purpose of the current study was to compare the characteristics and outcomes of HT recipients with early vs late development of DSA. Methods and Materials: We evaluated 69 HT pts transplanted between 2003-09 who had available HLA antibody screens by Luminex bead assay. Any DSA regardless of titers was reported as positive. Controls matched 2:1 to the early and late DSA groups for age, gender, and era were used to compare outcomes. Outcomes assessed: subsequent 3-year survival, freedom from cardiac allograft vasculopathy (CAV), and freedom from nonfatal major adverse cardiac events (NF-MACE, defined as myocardial infarction, heart failure, stenting, defibrillator, stroke, and new peripheral vascular disease). Results: Of the 69 pts with available antibody data, 20 had early DSA (mean 5⫾5 mos post-transplant) and 12 had late DSA (mean 31⫾12 mos post-transplant). Compared with their controls, early DSA pts had lower subsequent 3-year survival (65% vs 90%., p⫽0.018) and lower subsequent 3-year freedom from CAV (85% vs. 97%, p⫽0.044). In contrast, the late DSA group had similar subsequent 3-year survival (83% vs. 88%, p⫽0.69) and freedom from CAV (83% vs. 96%, p⫽0.19) compared with controls. There was no significant difference in freedom from NF-MACE between either DSA group and their respective controls. Early and late DSA groups were not compared due to small sample size. Conclusions: Heart transplant recipients who develop early DSA within 1 year after heart transplant have significantly higher risk of subsequent 3-year mortality. In this study, late development of DSA did not impact outcomes, but longer-term follow-up of this group is necessary to confirm these findings. These results indicate that early vs late development of DSA may require different treatment approaches.
45 Antibody-Mediated Rejection in Heart Transplantation: Clinical Follow-Up S.E. Fedson,1 M.K. Mizra,2 Y. Chi,2 A.N. Husain.2 1Medicine, Univ of Chicago, Chicago, IL; 2Pathology, University of Chicago, Chicago, IL. Purpose: C4d is widely accepted as a marker for antibody-mediated rejection in cardiac allografts. The aim of this prospective study was to determine the significance of C4d immunoreactivity in endomyocardial biopsies by correlating with cardiac dysfunction, cardiac allograft vasculopathy (CAV) and mortality. Methods and Materials: 1771 biopsies from 200 heart transplant patients were stained prospectively by IHC for C4d deposition on paraffin-embedded tissue using anti-human C4d polyclonal antibody. Strong diffuse endothelial staining was considered positive. Cardiac dysfunction at the time of positive biopsy was evaluated by echocardiography and intracardiac filling pressures. Patients were followed for 1-6 years. Results: Positive staining of C4d was present in 43 biopsies (2.4%) from 25 patients (12.5%). The mean follow up was 3.7 years. The average time from transplant to the first episode of C4d positivity was 370 days (range 8 to 986d). 9 patients had clinically significant cardiac dysfunction at the time of positive biopsy. Of the 26 patients with strong CD4 positivity, 14 patients (7%) died, 8 of whom (50%) had cardiac dysfunction at the time of positive biopsy (p⫽0.03). In those pts who died, mean time to C4d positivity was 447 days compared with 251 days in those pts still living. (p⫽ns) The mean time between first episode of C4d positivity and death was 513 days (ranging from 3 to 1872 days). The mean PRA was 24.6% in all pts, and 19.8% in pts still alive and 27.8% in pts who have died (p⫽ns). Autopsy was performed on 6 patients; CAV was noted in all 6 patients (100%). Conclusions: C4d positivity correlated with poorer outcomes. 14 out of 25 patients who showed C4d positivity died (56%) (Institutional 3-year post-transplant survival is 78%). The outcome is even worse when C4d positivity is associated with cardiac dysfunction (100% mortality). C4d staining late after transplantation is also associated with poorer outcomes. 46 Temporal Trends in the Prevalence of Primary Graft Dysfunction after Lung Transplantation in the Lung Transplant Outcomes Group (LTOG) Cohort H.Y. Robbins,1 S.M. Arcasoy,1 S. Bhorade,2 M.M. Crespo,3 S.M. Kawut,4 V.N. Lama,5 J.B. Orens,6 S.M. Palmer,7 P.D. Shah,8 R. Shah,4 J.R. Sonett,1 L.B. Ware,8 A. Weinacker,9 K.M. Wille,10 J.D. Christie,4 D.J. Lederer.1 1Columbia University, New York, NY; 2University of Chicago, Chicago, IL; 3University of Pittsburgh, Pittsburgh, PA; 4 University of Pennsylvania, Philadelphia, PA; 5University of Michigan, Ann Arbor, MI; 6Johns Hopkins, Baltimore, MD; 7Duke University, Durham, NC; 8Vanderbilt University, Nashville, TN; 9Stanford University, Palo Alto, CA; 10University of Alabama at Birmingham, Birmhingham, AL. Purpose: The lung allocation system (LAS) in the US has led to the transplantation of more ill lung transplant candidates. We hypothesized that transplant recipients would have a higher risk of primary graft dysfunction (PGD) under this system compared to earlier years. Methods and Materials: We performed a retrospective cohort study within LTOG, a multi-center study which examines risk factors for PGD. We included 730 participants transplanted between March 30, 2002 and August 5, 2009. Odds ratios (OR) for PGD grade 3 compared to PGD grades 0 and 1 were estimated using logistic regression. Results: The prevalence of PGD grade 3 increased over time (p ⬍ 0.01). The increase remained significant after adjustment for procedure, diagnosis, and cardiopulmonary bypass time (CPB). Adjustment for pulmonary artery systolic pressure, ischemic time, donor PaO2 and age, and recipient age and gender did not alter these results. Higher LAS score was independently associated with an increase in PGD grade 3 (OR 1.13 per each 5 unit increase in LAS, 95% CI 1.03-1.23, p ⫽ 0.01, n⫽449) after adjustment for procedure, diagnosis, and CPB.
The Journal of Heart and Lung Transplantation, Vol 30, No 4S, April 2011
Methods and Materials: Between January 2007 and August 2010, 95 patients with ELISA-PRA⬎10% and with HLA-specific antibodies determined by Luminex bead array (L-IGG) underwent heart transplantation (HTx). 33(34%) HTx recipients exhibited pre-Tx DSA. Four patients with DSA⬎8000 MFI assessed by L-IGG were considered virtual crossmatch (VCXM) positive and all were CXM positive, 3 were CDC-AHG T cell⫹ and 1 was B cell CXM⫹. All other HTx patients had DSA level⬍8000 MFI. Immunosuppression (IS) consisted of tacrolimus and MMF and 88(93%) had also induction therapy with alemtuzumab. Frequency of acute severe rejection (ACR) and presence of diffuse C4d in tissue was evaluated in DSA and non-DSA cohorts with one year follow-up. Results: VCXM negative defined as DSA⬍8000 MFI correlated 100% with the negative CDC-CXM performed with pre-Tx sera within 24 hr of HTx. Peri-operative plasmapheresis and IVIG was used in CXM⫹ patients. Post-op ECMO use: 3% in DSA group vs. 10% in non-DSA group (p⫽0.4). Freedom from diffuse C4d staining in first year was 92% in non-DSA group vs. 68% in DSA group (pⴝ0.02). Of the CXM positive HTx recipients one patient post-Tx had persistent high level of DSA and developed diffuse C4d in tissue. Freedom from ACR was 78% in non-DSA group vs. 81% in DSA group (p⫽0.7). Overall, graft survival was similar or better in DSA group (30 days, 1 year, 3 years 97%, 97%, 97%; vs. non-DSA group, 94%, 85%, 74%; (pⴝ0.04). Conclusions: Although, HTx patients with DSA exhibited increased C4d in heart biopsies, the frequency of ACR was similar and overall survival was not worse at 3 years in DSA vs. non-DSA cohort. Under induction therapy with tacrolimus and MMF maintenance IS, sensitized HTx patients can be safely transplanted with pre-and post-transplant evaluation of DSA levels. Further studies are needed to evaluate the long term outcomes in these high risk HTx candidates. 44 Timing of the Development of Donor Specific Antibody after Heart Transplantation Impacts Long-Term Outcome M. Kittleson,1 J. Patel,1 M. Kawano,1 Z. Goldstein,1 M. Rafiei,1 N. Reinsmoen,1 E. Reed,2 A. Hage,1 E. Schwarz,1 F. Esmailian,1 J. Kobashigawa.1 1Cedars-Sinai Heart Institute, Los Angeles, CA; 2 University of California, Los Angeles, Los Angeles, CA. Purpose: The development of donor specific antibodies (DSA) after heart transplant (HT) negatively impacts long term outcomes. Whether early development of DSA (⬍ 1 year post transplant) is worse than late development of DSA (⬎ 1 year post transplant) is not clear. The purpose of the current study was to compare the characteristics and outcomes of HT recipients with early vs late development of DSA. Methods and Materials: We evaluated 69 HT pts transplanted between 2003-09 who had available HLA antibody screens by Luminex bead assay. Any DSA regardless of titers was reported as positive. Controls matched 2:1 to the early and late DSA groups for age, gender, and era were used to compare outcomes. Outcomes assessed: subsequent 3-year survival, freedom from cardiac allograft vasculopathy (CAV), and freedom from nonfatal major adverse cardiac events (NF-MACE, defined as myocardial infarction, heart failure, stenting, defibrillator, stroke, and new peripheral vascular disease). Results: Of the 69 pts with available antibody data, 20 had early DSA (mean 5⫾5 mos post-transplant) and 12 had late DSA (mean 31⫾12 mos post-transplant). Compared with their controls, early DSA pts had lower subsequent 3-year survival (65% vs 90%., p⫽0.018) and lower subsequent 3-year freedom from CAV (85% vs. 97%, p⫽0.044). In contrast, the late DSA group had similar subsequent 3-year survival (83% vs. 88%, p⫽0.69) and freedom from CAV (83% vs. 96%, p⫽0.19) compared with controls. There was no significant difference in freedom from NF-MACE between either DSA group and their respective controls. Early and late DSA groups were not compared due to small sample size. Conclusions: Heart transplant recipients who develop early DSA within 1 year after heart transplant have significantly higher risk of subsequent 3-year mortality. In this study, late development of DSA did not impact outcomes, but longer-term follow-up of this group is necessary to confirm these findings. These results indicate that early vs late development of DSA may require different treatment approaches.
45 Antibody-Mediated Rejection in Heart Transplantation: Clinical Follow-Up S.E. Fedson,1 M.K. Mizra,2 Y. Chi,2 A.N. Husain.2 1Medicine, Univ of Chicago, Chicago, IL; 2Pathology, University of Chicago, Chicago, IL. Purpose: C4d is widely accepted as a marker for antibody-mediated rejection in cardiac allografts. The aim of this prospective study was to determine the significance of C4d immunoreactivity in endomyocardial biopsies by correlating with cardiac dysfunction, cardiac allograft vasculopathy (CAV) and mortality. Methods and Materials: 1771 biopsies from 200 heart transplant patients were stained prospectively by IHC for C4d deposition on paraffin-embedded tissue using anti-human C4d polyclonal antibody. Strong diffuse endothelial staining was considered positive. Cardiac dysfunction at the time of positive biopsy was evaluated by echocardiography and intracardiac filling pressures. Patients were followed for 1-6 years. Results: Positive staining of C4d was present in 43 biopsies (2.4%) from 25 patients (12.5%). The mean follow up was 3.7 years. The average time from transplant to the first episode of C4d positivity was 370 days (range 8 to 986d). 9 patients had clinically significant cardiac dysfunction at the time of positive biopsy. Of the 26 patients with strong CD4 positivity, 14 patients (7%) died, 8 of whom (50%) had cardiac dysfunction at the time of positive biopsy (p⫽0.03). In those pts who died, mean time to C4d positivity was 447 days compared with 251 days in those pts still living. (p⫽ns) The mean time between first episode of C4d positivity and death was 513 days (ranging from 3 to 1872 days). The mean PRA was 24.6% in all pts, and 19.8% in pts still alive and 27.8% in pts who have died (p⫽ns). Autopsy was performed on 6 patients; CAV was noted in all 6 patients (100%). Conclusions: C4d positivity correlated with poorer outcomes. 14 out of 25 patients who showed C4d positivity died (56%) (Institutional 3-year post-transplant survival is 78%). The outcome is even worse when C4d positivity is associated with cardiac dysfunction (100% mortality). C4d staining late after transplantation is also associated with poorer outcomes. 46 Temporal Trends in the Prevalence of Primary Graft Dysfunction after Lung Transplantation in the Lung Transplant Outcomes Group (LTOG) Cohort H.Y. Robbins,1 S.M. Arcasoy,1 S. Bhorade,2 M.M. Crespo,3 S.M. Kawut,4 V.N. Lama,5 J.B. Orens,6 S.M. Palmer,7 P.D. Shah,8 R. Shah,4 J.R. Sonett,1 L.B. Ware,8 A. Weinacker,9 K.M. Wille,10 J.D. Christie,4 D.J. Lederer.1 1Columbia University, New York, NY; 2University of Chicago, Chicago, IL; 3University of Pittsburgh, Pittsburgh, PA; 4 University of Pennsylvania, Philadelphia, PA; 5University of Michigan, Ann Arbor, MI; 6Johns Hopkins, Baltimore, MD; 7Duke University, Durham, NC; 8Vanderbilt University, Nashville, TN; 9Stanford University, Palo Alto, CA; 10University of Alabama at Birmingham, Birmhingham, AL. Purpose: The lung allocation system (LAS) in the US has led to the transplantation of more ill lung transplant candidates. We hypothesized that transplant recipients would have a higher risk of primary graft dysfunction (PGD) under this system compared to earlier years. Methods and Materials: We performed a retrospective cohort study within LTOG, a multi-center study which examines risk factors for PGD. We included 730 participants transplanted between March 30, 2002 and August 5, 2009. Odds ratios (OR) for PGD grade 3 compared to PGD grades 0 and 1 were estimated using logistic regression. Results: The prevalence of PGD grade 3 increased over time (p ⬍ 0.01). The increase remained significant after adjustment for procedure, diagnosis, and cardiopulmonary bypass time (CPB). Adjustment for pulmonary artery systolic pressure, ischemic time, donor PaO2 and age, and recipient age and gender did not alter these results. Higher LAS score was independently associated with an increase in PGD grade 3 (OR 1.13 per each 5 unit increase in LAS, 95% CI 1.03-1.23, p ⫽ 0.01, n⫽449) after adjustment for procedure, diagnosis, and CPB.