Antibody-mediated Rejection In Heart Transplantation Research Articles

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Microvascular Inflammation: An Incremental Path to Refining the Diagnosis of Antibody-mediated Rejection in Heart Transplantation

Antibody-mediated rejection in heart transplantation

The role of antibody-mediated rejection in predicting survival among heart recipients has been studied in clinical transplantology for over 20 years. This condition is a significant risk factor for heart failure and graft vasculopathy. Antibody-mediated rejection results from activation of the humoral immune system and production of donorspecific antibodies that cause myocardial injury through the complement system. The presence of donor-specific antibodies is associated with lower allograft survival. Treatment of antibody-mediated rejection should take into account the rejection category and the presence or absence of graft dysfunction. The main principle of treatment is to suppress humoral immunity at different levels. World clinical practice has made significant inroads into the study of this issue. However, further research is required to identify and develop optimal treatment regimens for patients with humoral rejection in cardiac transplantation.

Eculizumab for antibody-mediated rejection in heart transplantation: A case-control study.

Complement inhibition offers a novel treatment approach for antibody-mediated rejection (AMR). We examined patients with hemodynamic compromise AMR 2010-2020, comparing eight patients supplemented with eculizumab to 10 patients without; administration was at the treating physician's discretion. There were no significant differences between groups though eculizumab patients had a non-significantly higher inotrope score (208.8mcg/kg/min vs. 2.6mcg/kg/min; P=.22), more extracorporeal membrane oxygenation (ECMO) (62.5%vs. 20%; P=.066), and worse 1-year survival (37.5%vs. 60%; P=.63). The role of eculizumab is uncertain in AMR; multicenter collaborative studies are essential to better define its role.

心臓臓器移植におけるAMR治療の実態とrituximab（遺伝子組換え）使用に関する全国使用実態調査の結果

心臓臓器移植におけるAMR治療の実態とrituximab（遺伝子組換え）使用に関する全国使用実態調査の結果

Antibody-mediated rejection in heart transplantation: new developments and old uncertainties.

Antibody-mediated rejection (AMR) currently represents one of the main problems for clinical management of heart transplant because of its diagnostic complexity and poor evidences supporting treatments. Disorder-based diagnosis is a cornerstone in defining AMR. The limitations of the current classification have been partially overcome by novel studies improving the description of the immune-pathological graft abnormalities, and by new molecular approaches allowing a better understanding of the mechanisms behind AMR and of its relationship with cellular rejection and chronic vasculopathy. In-depth characterization of donor-specific antibodies showed to provide additional prognostic information and guide for treatment. Clinical relevance of AMR is bound to appropriate detection of graft dysfunction. In addition to traditional longitudinal evaluation by echocardiogram, cardiac magnetic resonance and detection of cell-free DNA may represent novel sensitive markers for graft injury that could prompt treatment before dysfunction becomes clinically manifest. Despite improvements in the diagnostic process, therapeutic strategies made little progress in addition to the consolidation of practices supported by limited evidences. Novel complement inhibitors appear promising in changing this scenario. Nevertheless, collaborative multicenter studies are needed to develop standardized approaches tailored to the highly variable clinical and laboratory features of AMR.

Antibody-mediated rejection in heart transplantation: a case presentation

Antibody-mediated rejection in heart transplantation: a case presentation

Anti-HLA antibodies and antibody-mediated rejection in heart transplantation

Anti-HLA antibodies and antibody-mediated rejection in heart transplantation

Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations

Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation. The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR. Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity. MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.

Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association.

Antibody-mediated rejection (AMR) of the cardiac allograft is a poorly defined and challenging diagnosis for transplant recipients and their clinicians. Although even its very existence in heart transplantation was debated until relatively recently, improved immunopathologic and serological techniques to detect myocardial capillary complement deposition and circulating anti-HLA (human leukocyte antigen) antibodies have led to the detection of a spectrum of newly uncovered immunologic changes that characterize AMR. The earliest standardized clinical and pathological criteria for the diagnosis of AMR in heart transplantation became available in 2004, the result of a task force assembled by the International Society for Heart and Lung Transplantation (ISHLT). In 2006, the criteria were refined by the ISHLT Immunopathology Task Force (Table 1). These revisions provide 4 categories of diagnostic criteria: clinical, histopathologic, immunopathologic, and serological assessment.1 Despite these published criteria, currently >50% of heart transplant centers make the diagnosis of AMR based on cardiac dysfunction and the lack of cellular infiltrates on the heart biopsy (preconference survey included in the ISHLT consensus article).2 More recently, the ISHLT Consensus Conference on AMR has redefined the pathological diagnosis of AMR.3 The 2013 ISHLT “Working Formulation for the Standardization of Nomenclature in the Pathologic Diagnosis of Antibody-Mediated Rejection in Heart Transplantation” was published in December 2013. This document provided an update to the 2010 consensus conference.4 It is anticipated that this update to the definition of AMR will reduce variations in the diagnosis of AMR, providing a platform for the development of standardized therapies. The goal of the present scientific statement is to provide the heart transplant professional with an overview of the current status of the diagnosis and treatment of AMR in the cardiac allograft based on recent consensus conferences and the published literature. We include recommendations to facilitate evolving standardization and strategies …

(250) - Mixed Cellular and Antibody-Mediated Rejection in Heart Transplantation: A Distinct Entity or Simply the Sum of Two?

(250) - Mixed Cellular and Antibody-Mediated Rejection in Heart Transplantation: A Distinct Entity or Simply the Sum of Two?

Antibody-mediated Rejection in Heart Transplantation

Heart transplantation is an excellent long-term treatment that confers functionality and longevity in select patients with end-stage heart failure. Yet, allograft rejection continues to pose a significant threat, especially in high-risk recipients and soon after transplantation. Of the two prevailing pathologic types of acute rejection in cardiac allografts, antibody-mediated rejection (AMR) had been variably defined and poorly understood for the past three decades when compared to cellular rejection. As a result, progress in understanding its pathologic and clinical behavior and the ability to find effective therapies had been hindered. Recent years have seen a renewed interest in cardiac AMR with efforts from pathologists, immunologists, and clinicians leading to a standardized diagnostic nomenclature.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

A Survey of Current Practice for Antibody-Mediated Rejection in Heart Transplantation

No evidence based management guidelines exist for antibody mediated rejection (AMR) in heart transplantation. The International Society for Heart and Lung Transplantation (ISHLT) recently introduced standardized pathologic based diagnostic criteria for AMR (pAMR 0-3). We evaluated international practice for the management of AMR focusing on pAMR grade, donor specific antibody (DSA) and allograft function. On-line survey data were analyzed from 184 ISHLT members (physicians-78%, surgeons-20%). The majority were from adult-transplant (84%), medium-large volume centres (transplants/year: 10-25, 61%; 25-50, 19%) across North America (60%) and Europe (26%). Irrespective of pAMR grade and DSA, 83-90% treated a drop in ejection fraction (EF≤45% or >25% decrease). In the presence of stable EF, an increasing number elected treatment for progressively severe pAMR grade (p<0.001) and for accompanying DSA (p<0.05, pAMR 1-3). Intravenous steroid was the most commonly used therapy followed by intravenous immunoglobulin (IVIG) or plasmapheresis, rituximab and thymoglobulin. Plasmapheresis and rituximab were favored for positive versus negative DSA (p<0.05). Using a threshold of ≥70% consensus among respondents, treatment for AMR may be considered for a drop in EF, asymptomatic pAMR 3 or asymptomatic pAMR 2 with DSA. Combination steroid, IVIG and plasmapheresis are suggested as initial therapies.

Type and Extent of HLA Mismatch and Antibody-Mediated Rejection in Heart Transplantation

Purpose Advances in ex-vivo organ perfusion may soon allow for extension of the time between organ procurement and heart transplant. However, presently the necessity for short allograft ischemic time in heart transplantation makes human leukocyte antigen (HLA) matching between donors and recipients impractical. Our aim was to investigate whether HLA mismatch is correlated with antibody mediated rejection (AMR) in heart transplantation. Methods and Materials The records of patients transplanted at the UTAH Cardiac Transplant Program between 1992 and 2011 were reviewed. HLA-mismatch at major antigen class I loci HLA-A and HLA-B, and class II loci HLA-DR and HLA-DQ, were analyzed using the Cox proportional hazards regression model. AMR was defined with the occurrence of ≥ 3 AMR episodes. Results Four hundred and fifty one patients met our inclusion criteria, 77% were male and the age was 45±19 years. HLA-DR and DQ have significant association with the incidence of AMR within the first year and at any time ( table ). There was no significant difference in the incidence of antibody mediated rejection (AMR) in patients with HLA class I mismatch. Conclusions HLA-DR and HLA-DQ mismatch appear to be associated with increased incidence of AMR after heart transplant. Prospective HLA class II antigens matching may result in reduced incidence of AMR and better outcome in heart transplantation. [ Figure 1 ]

Antibody-Mediated Rejection in Heart Transplantation: Does Induction and the Type Matter?

Antibody-Mediated Rejection in Heart Transplantation: Does Induction and the Type Matter?

A longitudinal study of the course of asymptomatic antibody-mediated rejection in heart transplantation

Growing evidence suggests worse cardiac allograft vasculopathy and mortality in patients with asymptomatic antibody-mediated rejection (AMR). Debate continues about whether therapeutic intervention is warranted to avoid adverse outcomes. In this study we examine the course of individual episodes of untreated asymptomatic AMR on follow-up endomyocardial biopsy (EMB). The U.T.A.H. Cardiac Transplant Program database was queried for transplant recipients between 1985 and 2009 who survived beyond 1 year and had at least 1 episode of lone AMR with a follow-up EMB. All EMBs were screened for AMR by immunofluorescence and graded for severity. Data were analyzed based on time from transplant (early, ≤12 months; late, >12 months). Nine hundred fifty-eight patients with a total of 15,448 biopsies qualified for the study. Average age at transplant was 46.7 years; 13% of the patients were female. Within the first year post-transplant, asymptomatic AMR was diagnosed in 13.6% of biopsies compared with 5.2% beyond 1 year. AMR resolved in 65% (early) vs 75% (late) on follow-up EMB. More severe AMR was less likely to improve regardless of time from transplant. Furthermore, after an episode of AMR had resolved, the recurrence rate at 3, 6 and 12 months was 44%, 50.1% and 56.2%, respectively. The incidence of AMR is higher in the first year post-transplant and the likelihood of resolution is less on follow-up EMB, especially when more severe. A small but significant number of cases became worse or did not change. These new findings may be helpful in planning future studies that test whether therapeutic interventions on asymptomatic AMR favorably impact outcomes.

The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: Evolution and current status (2005–2011)

From the Department of Pathology, Stanford University, Stanford, California; Universita of Padua Medical School, Padua, Italy; Royal Brompton and Harefield NHS Trust, London, United Kingdom; Hopital Europeen Georges Pompidou, Paris, France; David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California; Intermountain Medical Center, Salt Lake City, Utah; Queen Elizabeth Hospital, Birmingham, United Kingdom; University of Utah, Salt Lake City, Utah; Cleveland Clinic, Cleveland, Ohio; Papworth Hospital, Papworth, United Kingdom; Brigham & Women’s Hospital, Boston, Massachusetts; Cedars Sinai Heart Institute, Los Angeles, California; University of Maryland School of Medicine, Baltimore, Maryland.

HLA and MICA: Targets of Antibody-Mediated Rejection in Heart Transplantation

The goal of this study was to determine whether antidonor antibodies directed against human leukocyte antigen (HLA) or endothelial cells (ECs) expressed antigens, including major histocompatibility complex class I chain-related antigens A (MICA) are associated with the diagnosis of antibody-mediated rejection (AMR) in heart transplant recipients. We studied posttransplant antidonor HLA antibodies in 168 heart allograft recipients transplanted from October 2001 to December 2005. Among them, there were 37 AMR+ patients and 131 age- and sex- matched AMR- controls. Sera were collected at the time of protocol biopsies and tested for the presence of HLA antibodies. Seventy-two of the 168 patients were genotyped for donor and recipient MICA alleles and were tested for the presence of anti-MICA antibodies. Thirty-one patients who never developed antibodies to HLA or MICA were further tested for anti-EC antibodies. Of 37 AMR+ patients, 22 (60%) developed donor-specific antibodies (DSA) to HLA compared with 6 of 131(4%) AMR- patients (P<0.0001). Of the remaining 15 AMR+ patients, 5 had anti-HLA antibodies that were not donor specific and 10 did not show any HLA antibodies. In the subgroup of 72 patients, all 19 AMR+ patients had clearly demonstrable antibodies reactive with donor HLA, MICA or with nondonor-derived ECs, with 30% of them showed antibodies directed to non-HLA antigens. The incidence of transplant coronary artery disease was significantly higher in patients who had DSA to HLA and MICA compared with patients without DSA.

519 Does Immune System Activation from Cellular Rejection Trigger Antibody-Mediated Rejection in Heart Transplantation?

519 Does Immune System Activation from Cellular Rejection Trigger Antibody-Mediated Rejection in Heart Transplantation?

45 Antibody-Mediated Rejection in Heart Transplantation: Clinical Follow-Up

45 Antibody-Mediated Rejection in Heart Transplantation: Clinical Follow-Up