**Related Adverse Events**

[28] Fontan-associated liver disease: Implications for heart transplantation. Journal of Heart

[29] StrategFontan-associated protein-losing enteropathy and heart transplant: A pediatric heart transplant study analysis. Journal of Heart and Lung Transplantation. 2015;

[30] Fiberoptic monitoring of central venous oxygen saturation (Pediasat) in small children undergoing cardiac surgery: Continuous is not continuous. Version3. F1000Research. 2014 Jan 23 [revised 2014 Jun 13];**3**:23. DOI: 10.12688/f1000research.3-23.v3. eCollection 2014

[31] Cyanotic congenital heart disease (CCHD): Focus on hypoxiemia, secondary erythrocy-

[32] Plastic bronchitis in patient with Fontan physiology: Review of the literature and preliminary experience with Fontan conversion and cardiac transplantation. World Journal

[33] Strategies to treat protein-losing enteropathy. Pediatric Cardiac Surgery Annual of the

tosis, and coagulation alterations. Pediatric Anaesthesia. 2015;**25**:981-989

for Pediatric and Congenital Heart Surgery. 2012;**3**(3):364-372

Seminars in Thoracic and Cardiovascular Surgery. 2002;**5**:3-11

and Lung Transplantation. 2016;**35**(1):26-33

**34**(9):1169-1176

156 Heart Transplantation

**Chapter 11**

**Provisional chapter**

**Humoral Rejection in Cardiac Transplantation:**

**Humoral Rejection in Cardiac Transplantation:** 

DOI: 10.5772/intechopen.76143

After a successful heart transplantation, fundamental keys to achieve good results in the long term are to establish immunosuppressive therapy in the postoperative period in an appropriate manner and to ensure continuity of follow-ups. Despite the fact that these stages are maintained perfectly, patients may face one or more rejection episodes. T-cellmediated acute cellular rejection of the cardiac allograft has well-established treatment algorithms, whereas antibody-mediated rejection (AMR) is challenging to diagnose, and its treatment varies between centers. Investigators reported that AMR is among the most important factors to improving long-term outcomes. Improved understanding of the roles of acute and chronic AMR has evolved in recent years following a major progress in the technical ability to detect and quantify recipient antihuman leukocyte antigen (HLA) antibody production. Recently, a study of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. There are some questions regarding the classification of AMR, the diagnostic approaches, and the treatment strategies for managing. In this chapter, we are discuss the effector mechanisms that are used by antibodies to eliminate antigens and clinical experience about AMR and its treatment

**Keywords:** heart transplantation, rejection, humoral, plasmapheresis, rituximab

Orthotopic heart transplantation (OHT) is still the gold standard of treatment among endstage heart failure. Worldwide, about 3500 heart transplantations are performed annually [1]. However, shortage of donors and allograft dysfunction are the most common problems cardiac surgeons have to cope with. Rejection is the most common reason for allograft dysfunction and

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Management of Antibody-Mediated Rejection**

**Management of Antibody-Mediated Rejection**

Umit Kervan, Dogan Emre Sert and Nesrin Turan

Umit Kervan, Dogan Emre Sert and Nesrin Turan

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

with a discussion about the latest articles.

http://dx.doi.org/10.5772/intechopen.76143

**Abstract**

**1. Introduction**

#### **Humoral Rejection in Cardiac Transplantation: Management of Antibody-Mediated Rejection Humoral Rejection in Cardiac Transplantation: Management of Antibody-Mediated Rejection**

DOI: 10.5772/intechopen.76143

Umit Kervan, Dogan Emre Sert and Nesrin Turan Umit Kervan, Dogan Emre Sert and Nesrin Turan

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76143

#### **Abstract**

After a successful heart transplantation, fundamental keys to achieve good results in the long term are to establish immunosuppressive therapy in the postoperative period in an appropriate manner and to ensure continuity of follow-ups. Despite the fact that these stages are maintained perfectly, patients may face one or more rejection episodes. T-cellmediated acute cellular rejection of the cardiac allograft has well-established treatment algorithms, whereas antibody-mediated rejection (AMR) is challenging to diagnose, and its treatment varies between centers. Investigators reported that AMR is among the most important factors to improving long-term outcomes. Improved understanding of the roles of acute and chronic AMR has evolved in recent years following a major progress in the technical ability to detect and quantify recipient antihuman leukocyte antigen (HLA) antibody production. Recently, a study of the immunobiology of B cells and plasma cells that pertains to allograft rejection and tolerance has emerged. There are some questions regarding the classification of AMR, the diagnostic approaches, and the treatment strategies for managing. In this chapter, we are discuss the effector mechanisms that are used by antibodies to eliminate antigens and clinical experience about AMR and its treatment with a discussion about the latest articles.

**Keywords:** heart transplantation, rejection, humoral, plasmapheresis, rituximab

#### **1. Introduction**

Orthotopic heart transplantation (OHT) is still the gold standard of treatment among endstage heart failure. Worldwide, about 3500 heart transplantations are performed annually [1]. However, shortage of donors and allograft dysfunction are the most common problems cardiac surgeons have to cope with. Rejection is the most common reason for allograft dysfunction and

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

is responsible for 25% of postoperative deaths [2]. Episodes of rejection may emerge at any time after transplantation as acute or chronic cellular rejection (CR), humoral rejection (=antibodymediated = vascular rejection (AMR)), or mixed rejection. Despite AMR that is known to be rare, it is potentially lethal due to the capillary vasculopathy caused by neutrophil and macrophage infiltration in endothelial cells [3, 4]. Today, treatment of rejection episodes is directed mostly to cellular response. Each center sets the treatment in the light of their experience. In this chapter, we will discuss the effector mechanisms that are used by antibodies to eliminate antigens and clinical experience about AMR and its treatment with discussing the latest articles.

eliminate the antigen [6]. AMR develops when recipient antibody is directed against donor human leukocyte antigens (HLA) on the endothelial layer of the allograft. Antibodies induce fixation and activation of the complement cascade, resulting in tissue injury. Complement and immunoglobulin are deposited within the allograft microvasculature, which results in an inflammatory process that is characterized by endothelial cell activation, upregulation of cytokines, infiltration of macrophages, increased vascular permeability, and microvascular

Humoral Rejection in Cardiac Transplantation: Management of Antibody-Mediated Rejection

http://dx.doi.org/10.5772/intechopen.76143

161

AMR is mediated by donor-specific antibodies and is histologically defined by linear deposits of immunoglobulin (Ig) and complement in the myocardial capillaries [7]. Herskowitz et al. [8] described AMR for the first time in 1987 as an arteriolar vasculitis with poor outcome. Hammond et al. [9] firstly demonstrated that vascular rejection is associated with deposits of antibodies and complement activation. AMR incidence is reported between 8 and 15% [10–12], and it has been reported concurrent with CR in up to 24% of cases. Approximately 50% of heart transplant recipients who develop rejection >7 years after transplantation have evidence of AMR [12]. AMR was described as an acute phenomenon seen in weeks to months just after OHT. However, in recent years, studies have been reported that it also occurs in the longer term [9, 13, 14]. Rejection can be hyperacute (occurring within minutes after the vascular anastomosis (0–7 days)) in patients who are sensitized to donor HLA antigens and acute (occurring days to weeks after transplantation) because of the development of de novo donor-specific antibody (DSA) and preexisting DSA. Early AMR tends to be associated with a higher prevalence of allograft dysfunction and hemodynamic compromise. Late (occurring 3 months after transplantation) or chronic rejection most likely because of heightened recognition (occurring months to years after transplantation) [15]. Risk factors include young age, female gender, high levels of pretransplant panel-reactive antibodies (PRAs), positive donorspecific crossmatch, cytomegalovirus infection, prior OKT3 use, and artificial heart devices [10, 13]. Olsen et al. [16] stated that 23% of patients had AMR episodes for the second time resulting in graft loss in two-thirds due to the continuous complement activation and production of donor-reactive antibodies that cause graft dysfunction by sensitized memory B cells. As the definition of AMR has evolved and more sensitive diagnostic modalities have become available, there is increasing evidence that AMR is a spectrum of immunologic injury that ranges from subclinical, histological, immunologic, and/or serological findings without graft

thrombosis. This process ultimately manifests as allograft dysfunction [6].

**(AMR))**

**3.1. Diagnosis**

**3. Humoral rejection (=antibody-mediated = vascular rejection** 

dysfunction (i.e., subclinical AMR) to overt AMR with hemodynamic compromise.

The first description of humoral rejection was included in the 1990 International Society of Heart and Lung Transplantation (ISHLT) criteria defined as positive immunofluorescence, vasculitis, or severe edema in the absence of cellular infiltrate [14, 17]. The classification AMR 0 was assigned in the absence of histological or immunopathologic features. Confirmation of
