Mixed Rejection: More Important Than Thought after Heart Transplantation

Abstract

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. 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 5-year 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. 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). 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. 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 5-year freedom from CAV or NF-MACE. 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.