Organ Transplantation

Editorial introductions No abstract available

Editorial: Circulating antibodies in heart transplantation No abstract available

Impact of pretransplant antibodies on outcomes after heart transplantation Purpose of review Since the discovery of human leukocyte antigen (HLA) in the 1950s, there has been great interest in the role of antibodies in posttransplant rejection. The development of the lymphocyte toxicity test by Terasaki et al. in the 1960s was the first step toward understanding the role of antibodies in posttransplant rejection. Recent findings Subsequently, various organs have been transplanted and improving posttransplant outcomes have become a focus of research. In particular, methods to measure antibodies that affect posttransplant outcomes, including anti-HLA antibodies, and methods to desensitize patients from specific antibodies have been explored. One recent method for measuring antibodies is called the solid-phase assay, which uses purified HLA fixed to microbeads. This assay does not use donor lymphocytes and allows clinicians to test the reactivity of patient serum against a panel of antibodies. It has also enabled the identification of specific anti-HLA antibodies using a single HLA. Summary In addition to advances in methods to measure and analyze anti-HLA antibodies, the clinical impact of non-HLA antibodies has also received much attention recently.

Crossing low-level donor-specific antibodies in heart transplantation Purpose of review Donor-specific antibodies (DSA) detected by solid-phase single-antigen bead (SAB) immunoassays have been associated with antibody-mediated rejection (AMR), cardiac allograft vasculopathy (CAV) and decreased survival after heart transplantation. The clinical relevance of low-level DSA is equivocal. This review examines the techniques used to define low-level DSA, the limitations of these techniques and recent clinical experience crossing low-level DSA. Recent findings Solid-phase multiplex bead immunoassays were introduced to solid-organ transplantation over 15 years ago. These technologies have a much greater sensitivity and specificity than older cell-based immunoassays. It was hoped that this increased resolution would lead to better outcomes by avoiding donors with antigens that transplant candidates produced antibodies against. Although some transplant patients with DSA show increased risk of AMR and decreased survival, a subset of patients with DSA at the time of transplant have outcomes comparable with patients with no DSA. Recent studies have demonstrated that DSA delineated according to titration studies and C1q assays better define low-level DSA that are well tolerated to cross. Early experience with crossing low-level DSA shows promise in kidney and heart transplantation. Summary Preliminary findings from heart and kidney transplant patients show acceptable outcomes after crossing low-level DSA. The policy of crossing low-level DSA increases the donor pool for sensitized heart transplant candidates.

Desensitization for sensitized patients awaiting heart transplant Purpose of review This review summarizes contemporary desensitization strategies for patients awaiting cardiac transplantation in an era when specific management is still somewhat controversial. Recent findings The number of sensitized patients awaiting heart transplantation is rising. Clinical assessment of antibody levels is mostly focused on human leukocyte antigen (HLA) antibodies. Sensitization to HLA antigens increases the risk of antibody medicated rejection and cardiac allograft vasculopathy after transplant, thus translates to reduced access to compatible donors and increased wait time to transplant. Desensitization therapy is commonly considered in listed patients with cPRA more than 50%, to either decrease the amount of circulating anti-HLA antibodies, reduce the antibody production, or a combination of both. Despite promising results on specific therapies (e.g., plasmapheresis, intravenous immunoglobulin, rituximab, bortezomib), there is a significant gap in knowledge on desensitization therapies in heart transplantation. Most data are from small observational studies and extrapolated from nonheart solid organ transplants. Summary Management of the sensitized patient awaiting heart transplant is individualized. Desensitization can facilitate negative cross-match and successful transplantation, but is associated with significant cost and potential adverse effects. The long-term outcomes of desensitization therapy remain to be determined, further emphasizing the importance of personalizing the treatment approach to each patient.

Does the Canadian allocation system for highly sensitized patients work? Purpose of review The number of sensitized heart transplant candidates is rising. Highly sensitized patients are disadvantaged because they encounter longer waiting times to heart transplant. Strategies to reduce their waiting times include waitlist prioritization and desensitization therapies. The purpose of this review is to describe the listing category for highly sensitized patients in the Canadian allocation system, examine the advantages and limitations of this strategy and provide an approach to the management of the highly sensitized patient awaiting heart transplant. Recent findings Analysis of data from the United Network of Organ Sharing shows that the incidence of death or removal from the waitlist in patients listed for heart transplant increases as the calculated panel reactive antibody (cPRA) increases and is independent of medical urgency. In the Canadian allocation system, patients with cPRA more than 80% have a similar incidence of death on the waitlist as less sensitized patients, suggesting they survive to be transplanted. Furthermore, prioritizing and transplanting highly sensitized patients has been associated with acceptable post-transplant outcomes. Summary The Canadian allocation system prioritizes highly sensitized patients to increase equity and access to transplantation while maintaining good post-transplant outcomes. Not all highly sensitized patients can wait for an organ, even if prioritized. A pragmatic individualized approach would consider the medical stability of the patient, the likelihood of transplant with a negative crossmatch and then determine whether waitlist prioritization or desensitization is the more appropriate strategy.

The clinical impact of donor-specific antibodies on antibody-mediated rejection and long-term prognosis after heart transplantation Purpose of review Outcomes after cardiac transplantation have improved over past decades, but long-term graft survival remains limited in part because of uncertainty regarding clinical implications of donor-specific antibodies (DSAs). The purpose of this review is to consolidate recent advances in knowledge on the topic of DSA and their potential to impact long-term prognosis after heart transplantation. Recent findings The presence of persistent DSA increases the risk of poor outcome after heart transplantation, including development of antibody-mediated rejection (AMR), graft failure, cardiac allograft vasculopathy, and mortality. Importantly, different DSA vary in clinical significance. DSA capable of activating the complement cascade portend a higher risk of developing AMR. human leukocyte antigen class I and class II antigens are expressed differently within the heart, and so, clinical manifestations of class I and class II DSA vary accordingly. Further, compared with class I, class II DSA carry an increased risk of graft loss and mortality. When comparing preexisting DSA with formation of de-novo DSA, de-novo DSA are associated with worse outcome. Summary DSAs are generally associated worse long-term prognosis after heart transplantation but vary in their clinical significance. Recognition of specific risk profiles is essential for guiding posttransplant antibody management.

The meaning of donor-specific antibodies after heart transplant Purpose of review Antibody-mediated rejection (AMR) is a major contributor of impaired long-term survival after heart transplantation (HTx). The presence of circulating donor-specific antihuman leukocyte antigen (HLA) antibodies (DSAs) is considered as a mandatory criterion for AMR after HTx. DSA are known prognostic biomarkers of outcome, for example, recipients with de-novo DSA have a three-fold increased risk of mortality. Recent findings Although the awareness of the impact and prognosis of DSA on the survival has been increased in the HTx community over the last decade, the management of DSA pre and posttransplant varies among centers and is mainly based on the experience of transplant physicians. Thus, firm consensus strategies for each HTx recipient should be established by a center advisory board of experts in the field of HLA genetics, transplantation immunology, and HTx to evaluate the immunological risk preoperatively and also continuously during the posttransplant course. Consequently, the recent advances of invasive and noninvasive diagnostic tools should be applied, according to the risk, laboratory findings, and clinical events of the recipient. Such individual strategy will result in tailored therapeutic options. Summary Novel standards for the management of DSA in HTx recipients on the basis of an interdisciplinary approach of experts will improve diagnostics for personalized medicine.

The impact of asymptomatic antibody-mediated rejection on outcome after heart transplantation Purpose of review Defining criteria for antibody-mediated rejection (AMR) in heart transplantation were standardized a few years ago, but very little is known about asymptomatic cardiac AMR. We will start the review with a background summarizing the timeline of cardiac AMR. Then we will cover past and current knowledge about asymptomatic cardiac AMR and its impact on outcome after transplantation, with added insight from experience with other solid-organ transplants. Recent findings The incidence of asymptomatic cardiac AMR had likely been under-estimated because biopsy surveillance for it in the absence of clinical manifestation was not the norm. Recent data indicate that it may be more common especially when counting concomitant acute cellular rejection (mixed rejection). Also a higher risk of cardiac allograft vasculopathy (CAV) and cardiovascular mortality have been linked to it. The primary implication of these findings is whether therapeutic intervention is warranted, but the appropriate target patient population likely to benefit from treatment is yet to be determined. Summary Asymptomatic cardiac AMR is not uncommon and it negatively impacts outcome after heart transplantation.

Does the antibody mediated rejection grading scale have prognostic prediction? Yes, but the picture is still blurry Purpose of review Antibody-mediated rejection (ABMR) is a condition difficult to diagnose and treat, which may significantly impair the outcome of heart transplant recipients. In clinical practice, diagnosis is based on immunopathology grading of endomyocardial biopsies (EMB). Despite its value, the current diagnostic system has several pitfalls that have been addressed in recent literature. Recent findings Pathology grading of ABMR (pAMR) has a relevant prognostic factor. However, it does not capture several nuances, such as chronic vs. acute ABMR, mixed rejection or microvascular inflammation. Molecular biology-based assays are shedding new light on the mechanisms of ABMR, which could improve the precision of ABMR diagnosis. Summary These new findings have the potential to rearrange EMB grading system and to guide more precisely decision-making, but studies validating the therapeutic management based on molecular-pathology coupling are still missing.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com