Work in Progress: The Current State of Antibody Mediated Rejection

The AHA Statement titled “Antibody-Mediated Rejection (AMR) in Cardiac Transplantation: Emerging Knowledge in Diagnosis and Management,” provides the latest consensus statement on a rapidly evolving field in heart transplantation. The purpose of this statement is to provide an overview of the field as it currently exists in an effort to improve standardization of the diagnosis and treatment of AMR in cardiac transplant recipients. This comprehensive statement is of practical use to the heart transplant community, but, perhaps more importantly, highlights the paucity of data to support any specific prevention, surveillance, or treatment approaches for AMR. The statement thoughtfully identifies the knowledge gaps that exist with respect to AMR in the heart transplant recipient and underscores those areas that should be the focus of future study.

The diagnosis of AMR has been a moving target since the concept was first formally recognized as a clinical problem in 1990.¹ The most current International Society of Heart and Lung Transplantation (ISHLT) consensus statement regarding the diagnosis of AMR was published in December 2013 and further clarifies the 2011 ISHLT grading scale for pathologic AMR (pAMR).^{2, 3} AMR remains at the present time a pathologic diagnosis, as the diagnostic criteria consists of histologic and immunopathologic findings on endomyocardial biopsy. However, as reflected in Figures 3 and 4 of the AHA statement, graft function, symptoms, and the presence of donor-specific antibody (DSA) should be taken into consideration as modifying factors when treatment thresholds are considered. As the AHA statement describes, the previous lack of a standardized definition of AMR has led to a wide variation in the reported incidence of AMR (3-85%), difficulty in identifying clear risk factors for AMR, and inability to plan and complete controlled treatment trials. The current diagnostic clarification by ISHLT combined with the recent AMR AHA statement underscores the fact that AMR represents a clinical continuum, while at the same time attempting to outline categories of AMR that could serve as the basis for treatment trials in the future.

While this statement provides some clarity to the definition of AMR and current treatment strategies, many important questions remain, including:

1. Are there pre-transplantation strategies that could prevent AMR or decrease its severity?
2. What is the optimal frequency of surveillance for AMR?
3. What should be done about subclinical AMR?
4. What is the best treatment approach for symptomatic AMR?
5. Can early treatment of AMR prevent cardiac allograft vasculopathy (CAV) or decrease its severity?

Prevention of AMR

Populations at highest risk of AMR have been described and are briefly reviewed in the AHA statement. While many studies suggest that sensitized patients (those with preformed HLA antibodies) are at higher risk for developing AMR and poor outcomes post-transplant, there are many modifying factors to take into consideration.^4-7

First, what degree of sensitization places a patient at higher risk of poor outcomes post-transplant? Various studies have evaluated the percent panel reactive antibody (PRA) that predicts patients at higher risk of AMR and/or poor outcomes, with PRA thresholds ranging from 10%-50%.^4-11 While some studies did not find a difference in outcomes based on a threshold PRA of 10%, the threshold chosen to determine whether a patient is at higher risk of poor outcomes, the influence of HLA matching with the donor, and which anti-HLA antibodies are more likely to lead to AMR post transplant are areas that require more research.¹¹ While there are promising data regarding the ability of the pre-transplant C1q assay to predict AMR post-transplant, it is not clear if this methodology can consistently and accurately predict which HLA antigens should be avoided in donors.^{12, 13} Second, which desensitization protocols are most effective at lowering antibody production prior to transplantation? Desensitization protocols typically include some combination of IVIg, rituximab, plasmapheresis, and bortezomib, with some even including anti-thymocyte globulin (ATG), and cyclophosphamide.^14-17 There are published and anecdotal reports of patients remaining highly sensitized despite aggressive desensitization regimens and whether desensitization protocols provide enough benefit to justify their risks and/or costs remains to be seen.¹⁵ Third, what is the best approach in listing sensitized patients for transplantation? Waitlist mortality has been shown to be higher in patients listed with a prospective cross-match and while a virtual cross-match can shorten wait list times, there is significant center-dependent variation in practice.^{4, 18} Some centers do not avoid donor antigens due to concerns about waitlist mortality and rely on aggressive desensitizing protocols pre- and/or post-transplant to decrease antibody burden. Other centers use a virtual crossmatch approach (with or without desensitization) and avoid donors with antigens that could be targeted by preformed recipient antibody.^{5, 6, 15, 19} Long-term follow-up is needed to better understand which approach results in the best overall survival for the sensitized patient. Lastly, what is the role of induction therapy in preventing AMR? ATG may affect some B cells, which should make it more efficacious than IL-2 receptor blockade.²⁰ A small randomized, double blind, multicenter, placebo controlled non-inferiority trial of basiliximab and rabbit ATG showed that basiliximab did not meet non-inferiority criteria when compared to rabbit ATG for acute rejection post-transplant. This study did not, however, evaluate AMR specifically.²¹ The role of monoclonal antibody therapies targeting B-cells and plasma cells for induction is not known. Belimumab and atacicept are attractive candidates but studies are currently limited to rheumatologic disease and mouse models of transplantation.^22-25 The use of alemtuzumab is detailed in this AHA statement. However, alemtuzumab must be compared to other forms of induction in a randomized fashion specifically in highly sensitized patients. Induction with rituximab has been associated with a lower incidence of AMR and chronic graft dysfunction in the setting of ABO incompatible renal transplantation, suggesting that it may be beneficial as an induction agent for highly sensitized patients. However, data on the use of rituximab for induction in heart transplantation are very limited.⁵ More data are needed before any specific induction agent or approach can be recommended in pre-sensitized patients for prevention of AMR. For all of these drugs, further study is required with considerations given not only to efficacy in preventing AMR, but also cost, side effects and associated complications

Surveillance of AMR

Determination of the timing of surveillance for AMR is without an evidence-basis and has been left largely up to individual centers in the AHA statement. While DSA testing is likely best done in conjunction with a biopsy and clinical assessment of the patient, the optimal frequency for assessment of DSA by either the Luminex test or C1q assay is not clearly defined and requires further study. Some patients develop de novo DSA more than a year out from transplant and the prognosis for these patients tends to be particularly poor.^26-28 Whether or not outcomes can be improved by early diagnosis and treatment of de novo DSA is yet to be determined. Clarity is also needed on the indication and timing for a repeat biopsy following treatment for AMR. There are few data on how quickly biopsy findings resolve after treatment. Duration of C4d staining can range from weeks to months, but a low level of staining can persist for much longer periods of time and is of unclear significance.^{2, 3, 29}

Subclinical AMR

One of the more challenging aspects of AMR discussed by the authors is the clinical entity of subclinical AMR (complement activation in the absence of organ dysfunction). Treatment for subclinical AMR is not generally recommended, but there is a wide spectrum of possible outcomes for this group of patients ranging from studies describing poor outcomes in those with untreated subclinical AMR to data suggesting that C4D staining could represent accommodation, opposed to AMR, in some patients.³⁰ These highly disparate possibilities for this unique subgroup of patients, strongly supports the need for further study in this area.

Treatment of AMR

There are no controlled trials of therapy for AMR and evidence to guide the best treatment approach is lacking. The AHA statement nicely summarizes and reviews the most common therapeutic modalities utilized for AMR, which range from therapies extrapolated from the kidney transplant recipient, to treatment approaches used for acute cellular rejection in heart transplant recipients, to descriptive clinical studies specific to AMR in heart transplant patients. Outlining these therapeutic options is useful from a practical and educational perspective, but the lack of formal rigorous clinical trials challenges the ability of the authors to offer evidence-based recommendations for treatment. While there are some commonalities among treatment regimens, the wide variety of AMR treatment protocols described in Appendix 1 of the AHA statement highlight the importance of future prospective, controlled clinical trials for AMR in the heart transplant recipient.

Long-Term Effects of AMR

While the optimal treatment methods of AMR are not clear, it is even a greater challenge to understand how treatment of AMR can affect longer-term consequences such as the incidence and severity of cardiac allograft vasculopathy (CAV). The AHA statement describes data supporting a link between AMR and CAV and it seems logical that treatment of AMR could decrease the incidence of CAV.^{28, 31} However, rigorous evaluation of the most effective treatment approach for AMR must be completed prior to determination of whether such treatment can lower the incidence of CAV and/or prolong graft survival.

Pediatric Considerations

An old adage states that children are not just small adults and it also applies to diagnosis and treatment of AMR. While the pathologic diagnosis is no different than in the adult population, the heterogeneous pediatric population presents its own challenges. The percentage of children undergoing transplantation due to a diagnosis of congenital heart disease is relatively high and, therefore, a significant percentage of children listed for heart transplant will have preformed anti-HLA antibodies. In fact, the most recent ISHLT registry report found that 27% of pediatric heart transplant recipients had a PRA of ≥ 10%.³² This statement describes the ongoing NIH sponsored observational, multi-center, prospective cohort study of alloantibodies in pediatric transplant candidates. This study will help to determine whether a positive retrospective cross-match is associated with pre-formed anti HLA-antibodies and whether this positive cross-match increases morbidity and graft loss. These data will be of great value when trying to determine the best way to manage pre-sensitized pediatric patients both before and after transplantation. In addition, children often have limited vascular access due to their small size and history of multiple catheterizations and surgeries. The resulting damage to blood vessels often makes it difficult to easily provide therapies for AMR, such as plasmapheresis. Many children require conscious sedation or even general anesthesia to secure vascular access, which further increases the risk of treatment of AMR in children with graft dysfunction. In the absence of evidence-based therapies, the risk of sedation in the setting of graft dysfunction and the risk of compromising limited vascular access in children must both be considered prior to recommending AMR therapies that require central venous catheters.

The field of AMR in heart transplantation is ripe with opportunity for scientific endeavors. This statement by the AHA clarifies the contemporary understanding regarding AMR, while at the same time identifying the many questions that remain to be answered. This AHA statement represents the beginning of a standardized approach to the diagnosis and management of AMR. A combination of equipoise and targeted, well-designed, multicenter clinical trials are necessary to develop the body of evidence needed to improve outcomes of AMR in heart transplant recipients.