Histologic Features of Mixed Rejection in Heart Transplantation: More Than Just Cellular + Antibody-Mediated Rejection?

PurposeMixed rejection (MR) in heart transplantation appears to be the coalescence of cellular rejection (CR) and antibody-mediated rejection (AMR) in a biopsy. We wondered whether there were distinguishing histologic characteristics of MR which might shed light on the interaction of cellular and antibody mediated rejection events.MethodsDiscrete histologic and immunocytochemical data elements have been recorded on each biopsy by the examining pathologist since the inception of the UTAH Cardiac Transplant Program. Biopsy scores have been modified to reflect the 2013 ISHLT scores for CR and pAMR scores for AMR in our program from 1986-2015. Using CR or pAMR scores of >0 as positive, the percent of biopsies with that diagnosis and the specific histologic features were calculated. An extension of logistic regression was used for statistical analysis which adjusted for patient specific features.Results32,467 biopsies from 1283 patients qualified for analysis. The findings are shown in Table 1. (*Scale was 1-5; threshold for positive was >2; generalized finding of mild severity=3) The features of each type of rejection including MR were significantly different from each other. MR showed significant increases in endothelial changes over CR or AMR alone; AMR showed significantly more chronic ischemic damage as detected histologically.ConclusionBiopsies with mixed rejection contain significantly increased capillary changes. These may be the consequence of further cytokine generation and neutrophil accumulation which may lead to greater severity of damage than either CR or AMR alone. If these observations are validated prospectively, it might impact our approach to the monitoring and management of MR in heart transplantation.Tabled 1Type of RejectionCapillary Endothelial Activation*Capillary Macrophage Adherence*Myocyte Necrosis (Y/N)Neutrophils (Y/N)Biopsy Chronic Ischemic Damage*Lymphocytic Infiltrates (Y/N)None33.9%15.1%1.2%0.5%20.2%7.8%CR65.4%44.9%19.1%0.8%20.4%96.0%AMR72.0%55.2%3.9%5.2%33.3%9.9%MR93.5%89.3%38.8%6.8%22.5%92.9%p Value<0.001<0.001<0.001<0.001<0.001<0.001 Open table in a new tab PurposeMixed rejection (MR) in heart transplantation appears to be the coalescence of cellular rejection (CR) and antibody-mediated rejection (AMR) in a biopsy. We wondered whether there were distinguishing histologic characteristics of MR which might shed light on the interaction of cellular and antibody mediated rejection events. Mixed rejection (MR) in heart transplantation appears to be the coalescence of cellular rejection (CR) and antibody-mediated rejection (AMR) in a biopsy. We wondered whether there were distinguishing histologic characteristics of MR which might shed light on the interaction of cellular and antibody mediated rejection events. MethodsDiscrete histologic and immunocytochemical data elements have been recorded on each biopsy by the examining pathologist since the inception of the UTAH Cardiac Transplant Program. Biopsy scores have been modified to reflect the 2013 ISHLT scores for CR and pAMR scores for AMR in our program from 1986-2015. Using CR or pAMR scores of >0 as positive, the percent of biopsies with that diagnosis and the specific histologic features were calculated. An extension of logistic regression was used for statistical analysis which adjusted for patient specific features. Discrete histologic and immunocytochemical data elements have been recorded on each biopsy by the examining pathologist since the inception of the UTAH Cardiac Transplant Program. Biopsy scores have been modified to reflect the 2013 ISHLT scores for CR and pAMR scores for AMR in our program from 1986-2015. Using CR or pAMR scores of >0 as positive, the percent of biopsies with that diagnosis and the specific histologic features were calculated. An extension of logistic regression was used for statistical analysis which adjusted for patient specific features. Results32,467 biopsies from 1283 patients qualified for analysis. The findings are shown in Table 1. (*Scale was 1-5; threshold for positive was >2; generalized finding of mild severity=3) The features of each type of rejection including MR were significantly different from each other. MR showed significant increases in endothelial changes over CR or AMR alone; AMR showed significantly more chronic ischemic damage as detected histologically. 32,467 biopsies from 1283 patients qualified for analysis. The findings are shown in Table 1. (*Scale was 1-5; threshold for positive was >2; generalized finding of mild severity=3) The features of each type of rejection including MR were significantly different from each other. MR showed significant increases in endothelial changes over CR or AMR alone; AMR showed significantly more chronic ischemic damage as detected histologically. ConclusionBiopsies with mixed rejection contain significantly increased capillary changes. These may be the consequence of further cytokine generation and neutrophil accumulation which may lead to greater severity of damage than either CR or AMR alone. If these observations are validated prospectively, it might impact our approach to the monitoring and management of MR in heart transplantation.Tabled 1Type of RejectionCapillary Endothelial Activation*Capillary Macrophage Adherence*Myocyte Necrosis (Y/N)Neutrophils (Y/N)Biopsy Chronic Ischemic Damage*Lymphocytic Infiltrates (Y/N)None33.9%15.1%1.2%0.5%20.2%7.8%CR65.4%44.9%19.1%0.8%20.4%96.0%AMR72.0%55.2%3.9%5.2%33.3%9.9%MR93.5%89.3%38.8%6.8%22.5%92.9%p Value<0.001<0.001<0.001<0.001<0.001<0.001 Open table in a new tab Biopsies with mixed rejection contain significantly increased capillary changes. These may be the consequence of further cytokine generation and neutrophil accumulation which may lead to greater severity of damage than either CR or AMR alone. If these observations are validated prospectively, it might impact our approach to the monitoring and management of MR in heart transplantation.