Antithymocyte Globulin Induction is Associated with Complement Deposition in Pediatric Cardiac Transplant Biopsies

Abstract

Purpose Antithymocyte globulin (ATG) has been increasingly used as a means of induction immunosuppression (I-I) in pediatric cardiac transplantation (PCT). ATG contains polyclonal antibodies directed primarily against human T-lymphocytes and may also contain other antibodies with affinity for endothelial surface antigens and other tissues in the transplanted organ, resulting in complement (C4d) deposition (C4dD). This phenomenon has been demonstrated in endomyocardial biopsies (EMB) of adult cardiac transplants though the effects of C4dD on rejection risk remain unclear. It has been thought that use of basiliximab for induction may avoid the risk of (C4dD) and decrease the risk of rejection. We examined C4dD and incidence of rejection the relationship among children treated with ATG I-I as well as those treated with basiliximab I-I. Methods A retrospective review of charts of patients with PCT performed at our center between June 2012 and April 2018 was performed. Results of C4d immunohistochemistry were available from all EMB of patients (n=56). Results The population was predominantly male (70%) with a median age of 10 years (IQR 2.63 -14.46 years). 28 patients received ATG and 28 patients received basiliximab as induction therapy. Sixty percent (60%) of the ATG patients had C4dD on the 1st biopsy post-transplant and 25% of patients had a persistent C4dD on the next 5 EMB. When C4dD was demonstrated in ATG patients, other markers of significant rejection were rare; only 4% had ACR grade 2 or higher by the revised 2004 ISHLT grading system (historically 3A, 3B and 4 rejection) and/or histologic evidence of AMR. Only 3% of patients receiving basiliximab for induction had C4dD on any EMB in the first year post-transplant. When C4dD was demonstrated in basiliximab patients, other markers of significant rejection were found frequently; 57% had ACR grade 2 or higher by the revised 2004 ISHLT grading system and/or histologic evidence of AMR. Conclusion C4d deposition was more common on EMB up to 1 year post-PCT in patients receiving ATG induction, compared to basiliximab. Despite less C4dD in basiliximab EMBs, these patients had more rejection episodes. The presence of C4dD may thus not be an accurate measure of rejection in PCT patients and should be taken into consideration when reviewing and determining treatment options. Antithymocyte globulin (ATG) has been increasingly used as a means of induction immunosuppression (I-I) in pediatric cardiac transplantation (PCT). ATG contains polyclonal antibodies directed primarily against human T-lymphocytes and may also contain other antibodies with affinity for endothelial surface antigens and other tissues in the transplanted organ, resulting in complement (C4d) deposition (C4dD). This phenomenon has been demonstrated in endomyocardial biopsies (EMB) of adult cardiac transplants though the effects of C4dD on rejection risk remain unclear. It has been thought that use of basiliximab for induction may avoid the risk of (C4dD) and decrease the risk of rejection. We examined C4dD and incidence of rejection the relationship among children treated with ATG I-I as well as those treated with basiliximab I-I. A retrospective review of charts of patients with PCT performed at our center between June 2012 and April 2018 was performed. Results of C4d immunohistochemistry were available from all EMB of patients (n=56). The population was predominantly male (70%) with a median age of 10 years (IQR 2.63 -14.46 years). 28 patients received ATG and 28 patients received basiliximab as induction therapy. Sixty percent (60%) of the ATG patients had C4dD on the 1st biopsy post-transplant and 25% of patients had a persistent C4dD on the next 5 EMB. When C4dD was demonstrated in ATG patients, other markers of significant rejection were rare; only 4% had ACR grade 2 or higher by the revised 2004 ISHLT grading system (historically 3A, 3B and 4 rejection) and/or histologic evidence of AMR. Only 3% of patients receiving basiliximab for induction had C4dD on any EMB in the first year post-transplant. When C4dD was demonstrated in basiliximab patients, other markers of significant rejection were found frequently; 57% had ACR grade 2 or higher by the revised 2004 ISHLT grading system and/or histologic evidence of AMR. C4d deposition was more common on EMB up to 1 year post-PCT in patients receiving ATG induction, compared to basiliximab. Despite less C4dD in basiliximab EMBs, these patients had more rejection episodes. The presence of C4dD may thus not be an accurate measure of rejection in PCT patients and should be taken into consideration when reviewing and determining treatment options.