Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease

doi:10.1016/S1053-2498(02)00472-2

The Journal of Heart and Lung Transplantation

Volume 22, Issue 1, January 2003, Pages 58-69

https://doi.org/10.1016/S1053-2498(02)00472-2 Get rights and content

Abstract

Background

Acute cellular rejection is the mechanism of most immune-related injury in cardiac transplant recipients. However, antibody-mediated humoral rejection (HR) has also been implicated as an important clinical entity following orthotopic heart transplantation. Humoral rejection has been reported to play a role in graft dysfunction in the early post-transplant period, and to be a risk factor for the development of transplant coronary artery disease. Some involved in transplantation pathology doubt the existence of clinically significant humoral rejection in cardiac allografts. Those who recognize its existence disagree on its possible role in graft dysfunction or graft coronary artery disease. In this study, we report clinical features of patients with the pathologic diagnosis of HR at our institution since July 1997, when we began systematic surveillance for humoral rejection.

Methods

We reviewed medical records of patients with the pathologic diagnosis of HR without concurrent cellular rejection between July 1997 and January 2001. Diagnosis was based on routine histology (“swollen cells” distending capillaries, interstitial edema and hemorrhage) and immunofluorescence (capillary deposition of immunoglobulin and complement with HLA-DR positivity), or immunoperoxidase staining of paraffin-embedded tissue (numerous CD68-positive macrophages and fewer swollen endothelial cells distending capillaries).

Results

A total of 44 patients (4 to 74 years old) showed evidence of HR without concurrent cellular rejection at autopsy or on one or more biopsies. Although females comprised only 26% of our transplant population, 23 patients (52%) with HR were female. A positive peri-operative flow cytometry T-cell crossmatch was observed in 32% of HR patients compared with 12% of controls (p = 0.02). Hemodynamic compromise consisting of shock, hypotension, decreased cardiac output/index and/or a rise in capillary wedge or pulmonary artery pressure was observed in 47% of patients at the time of diagnosis of HR. Six patients (5 females) died (14% mortality) with evidence of HR at or just before autopsy, 6 days to 16 months after transplantation. The incidence of transplant coronary artery disease was 10% greater at 1 year, and 36% greater at 5 years, in patients with HR when compared with non-HR patients.

Conclusion

Humoral rejection was associated with acute hemodynamic compromise in 47% of patients, and was the direct cause of death in 6 patients (13%). Humoral rejection is a clinicopathologic entity with a high incidence in women and is associated with acute hemodynamic compromise, accelerated transplant coronary artery disease and death.

Section snippets

Patients and tissues studied

The pathologic diagnosis of humoral rejection (HR) was made in a total of 116 endomyocardial biopsy (EMB) specimens from 56 patients between July 1997 and January 2001. During this period, approximately 600 cardiac transplant patients were being followed with surveillance biopsies and coronary angiography at our institution. Of these patients with HR, 44 (77 biopsies) were diagnosed with HR without concurrent acute cellular rejection (ISHLT Grade 0). Individual EMB specimens were obtained from

Patient demographics

A total of 44 patients (4 to 74 years old) showed evidence of HR without concurrent acute cellular rejection. In addition to the findings on H&E-stained histologic sections, the diagnosis was made by immunofluorescence (n = 7) and/or immunohistochemical criteria (n = 37), as indicated. Up to January 2001, a total of 1,090 patients have received orthotopic heart transplantation (OHT) at our institution. Although only 78 (26%) of the 298 patients without HR transplanted since July 1997 were

Discussion

The results of our study confirm the original observations of Hammond and associates9 and further delineate the features and sequelae of HR in cardiac transplant recipients. We have document an increased incidence of HR in women, patients with a history of re-transplantation and those with a positive peri-operative T-cell flow cytometry crossmatch. In addition, patients who develop HR are at an increased risk for early development of TCAD and have a relatively high rejection-associated

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Cost-Effectiveness of Cardiovascular Magnetic Resonance for Rejection Surveillance After Cardiac Transplantation in the Australian Health Care System
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Heart transplantation is an effective treatment for end-stage congestive heart failure, however, achieving the right balance of immunosuppression to maintain graft function while minimising adverse effects is challenging. Serial endomyocardial biopsies (EMBs) are currently the standard for rejection surveillance, despite being invasive. Replacing EMB-based surveillance with cardiac magnetic resonance (CMR)-based surveillance for acute cardiac allograft rejection has shown feasibility. This study aimed to assess the cost-effectiveness of CMR-based surveillance in the first year after heart transplantation.
A prospective clinical trial was conducted with 40 orthotopic heart transplant (OHT) recipients. Participants were randomly allocated into two surveillance groups: EMB-based, and CMR-based. The trial included economic evaluations, comparing the frequency and cost of surveillance modalities in relation to quality-adjusted life years (QALYs) within the first year post-transplantation. Sensitivity analysis encompassed modelled data from observed EMB and CMR arms, integrating two hypothetical models of expedited CMR-based surveillance.
In the CMR cohort, 238 CMR scans and 15 EMBs were conducted, versus (vs) 235 EMBs in the EMB group. CMR surveillance yielded comparable rejection rates (CMR 74 vs EMB 94 events, p=0.10) and did not increase hospitalisation risk (CMR 32 vs EMB 46 events, p=0.031). It significantly reduced the necessity for invasive EMBs by 94%, lowered costs by an average of AUD$32,878.61, and enhanced cumulative QALY by 0.588 compared with EMB. Sensitivity analysis showed that increased surveillance with expedited CMR Models 1 and 2 were more cost-effective than EMB (all p<0.01), with CMR Model 1 achieving the greatest cost savings (AUD$34,091.12±AUD$23,271.86 less) and utility increase (+0.62±1.49 QALYs, p=0.011), signifying an optimal cost–utility ratio. Model 2 showed comparable utility to the base CMR model (p=0.900) while offering the benefit of heightened surveillance frequency during periods of elevated rejection risk.
CMR-based rejection surveillance in orthotopic heart transplant recipients provides a cost-effective alternative to EMB-based surveillance. Furthermore, it reduces the need for invasive procedures, without increased risk of rejection or hospitalisation for patients, and can be incorporated economically for expedited surveillance. These findings have important implications for improving patient care and optimising resource allocation in post-transplant management.
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Subclinical antibody-mediated rejection (AMR) is represented by histopathological and/or immunopathological manifestations in the absence of significant cardiac allograft dysfunction. Treatment remains uncertain as there is a lack of data on asymptomatic heart transplant (HT) recipients (HTR) with a positive cardiac biopsy. We sought to determine the impact of untreated subclinical biopsy-proven AMR, regardless of circulating donor-specific antigen (DSA) expression, when diagnosed on surveillance biopsies in the first year after HT. This retrospective case control study evaluated 260 HTR between May 2004 and February 2021. These comprised 231 controls and 29 patients with untreated subclinical AMR. The mortality event rate was higher in controls (2.63 events per 100 person-years) compared to the scAMR Group (1.71 events per 100 person-years), a difference that did not reach statistical significance (hazard ratio 0.66, CI: 0.18–2.36). The combined event rate of cardiac allograft vasculopathy (CAV), graft dysfunction, or mortality was higher in the subclinical AMR group (5.60 events per 100 person-years) than in controls (3.89 events per 100 person-years) but did not reach statistical significance (hazard ratio 1.63, CI: 0.07–40.09). Our results suggest that subclinical AMR diagnosed in the first year after HT on surveillance biopsy is not associated with decreased survival. This may sway the management of subclinical AMR towards a more conservative approach in transplant-capable institutions that currently prioritize treatment, though prospective, randomized studies of such a management strategy are required.
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The early postoperative management strategies after heart transplantation include optimizing the function of the denervated heart, correcting the causes of hemodynamic instability, and initiating and maintaining immunosuppressive therapy, allograft rejection surveillance, and prophylaxis against infections caused by immunosuppression. The course of postoperative support is influenced by the quality of allograft myocardial protection prior to implantation and reperfusion, donor-recipient heart size matching, surgical technique of orthotopic heart transplantation, and patient factors (eg, preoperative condition, immunologic compatibility, postoperative vasomotor tone, severity and reversibility of pulmonary vascular hypertension, pulmonary function, mediastinal blood loss, and end-organ perfusion). This review provides an overview of the early postoperative care of recipients and includes a brief description of the surgical techniques for orthotopic heart transplantation.
Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse Model
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Cardiac allograft vasculopathy (CAV) limits the long-term success of heart transplants. Generation of donor-specific antibodies (DSAs) is associated with increased incidence of CAV clinically, but mechanisms underlying development of this pathology remain poorly understood. Major histocompatibility complex–mismatched A/J cardiac allografts in B6.CCR5^−/− recipients have been reported to undergo acute rejection with little T-cell infiltration, but intense deposition of C4d in large vessels and capillaries of the graft accompanied by high titers of DSA. This model was modified to investigate mechanisms of antibody-mediated CAV by transplanting A/J hearts to B6.CCR5^−/− CD8^−/− mice that were treated with low doses of anti-CD4 monoclonal antibody to decrease T-cell–mediated graft injury and promote antibody-mediated injury. Although the mild inhibition of CD4 T cells extended allograft survival, the grafts developed CAV with intense C4d deposition and macrophage infiltration by 14 days after transplantation. Development of CAV correlated with recipient DSA titers. Transcriptomic analysis of microdissected allograft arteries identified the Notch ligand Dll4 as the most elevated transcript in CAV, associated with high versus low titers of DSA. More importantly, these analyses revealed a differential expression of transcripts in the CAV lesions compared with the matched apical tissue that lacks large arteries. In conclusion, these findings report a novel model of antibody-mediated CAV with the potential to facilitate further understanding of the molecular mechanisms promoting development of CAV.
Post-transplantation outcomes of sensitized patients receiving durable mechanical circulatory support
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Sensitization, defined as the presence of circulating antibodies, presents challenges, particularly in patients undergoing heart transplantation (HTx) bridged with durable mechanical circulatory support (MCS). We aimed to investigate the post-transplantation outcomes of sensitized MCS patients.
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Sensitized MCS patients (Group A) showed comparable rates of PGD, 1-year survival, and 1-year freedom from AMR with Groups C and D. However, Group A showed significantly higher rates of 1-year freedom from AMR (95.3% vs 85.7%, p = 0.02) and an earlier decline in panel-reactive antibody (PRA) levels (p < 0.01) than sensitized non–MCS patients (Group B). Desensitization therapy effectively reduced the levels of PRA in both Groups A and B. When Group A was further divided according to the presence of preformed donor-specific antibodies (DSA), patients with preformed DSA showed significantly lower rates of 1-year freedom from AMR than those without (84.2% vs 98.5%, p = 0.01).
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View full text

Cardiac rejectionHumoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease

Abstract

Background

Methods

Results

Conclusion

Section snippets

Patients and tissues studied

Patient demographics

Discussion

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