Management Of Antibody-mediated Rejection Research Articles

Novel Technology Has Made It Possible To Diagnose A New Clinical Phenotype Of Rejection called Early Antibody Mediated Rejection, With Significant Therapeutic Implications For Renal Allograft Survival

Novel technology in transplant, specifically, the Molecular Microscope Diagnostic System, has made it possible to diagnose a new clinical phenotype of rejection called "early antibody-mediated rejection." Here, we present 2 kidney transplant recipients who had normal serum creatinine levels but elevated donor-derived cell-free DNA. Allograft biopsies did not show antibody-mediated rejection, but the Molecular Microscope Diagnostic System reported early antibody -mediated rejection. Once considered as an isolated incident occurring after kidney transplant, antibody-mediated rejection is now recognized to be a progressive condition that waxes and wanes over time and may ultimately lead to chronic allograft damage and allograft loss. Hence, if it can be diagnosed early before causing allograft injury, the early diagnosis can represent a paradigm shift in the management of antibody-mediated rejection in kidney transplant recipients, with better treatment outcomes and prolonged allograft survival.

Management of Antibody Mediated Rejection (AMR) in Heart Transplant Patients: The Real World in a French Single Center Treating All Pathological AMR

<h3>Purpose</h3> There is no consensus for the treatment of antibody mediated rejection (AMR) in heart transplant patients (HTP), only expert recommendation with a grey zone in patients without graft dysfunction. The purpose of the study was to report our AMR management since we perform routine screening of donor-specific antibodies (DSA) with EMB in case of positive DSA and treat AMR irrespective of graft dysfunction, severity of AMR or presence of DSA. <h3>Methods</h3> We retrospectively reviewed HTP between 2011 and 2019 and studied patients with AMR defined only on endomyocardial biopsy (EMB) according to the latest ISHLT criteria. <h3>Results</h3> A total of 15 patients developed AMR (5 patients with pAMR 1 and 10 with pAMR2) (Figure1), followed for a mean of 4.6 years; 3 patients (20%) had a graft dysfunction (EF<40%) and 3 (20%) did not have circulating DSA. All patients received intravenous steroids, plasmapheresis (5 to7 sessions only for DSA+ patients) IVig for 2 days and rituximab. The 7 more recent patients had additional IVig therapy (high-dose regimen) for 6 weeks and 5 patients received bortezomib. At the end of the treatment, 12 patients (60%) had normal EMB, 6 patients (50%) had persistent DSA with MFI>5000, 1 patient had persistent graft dysfunction and 80% were alive (Figure1). <h3>Conclusion</h3> despite a short follow up, our experience is encouraging to treat aggressively all pathological AMR irrespective of graft dysfunction or presence of DSA to prevent graft dysfunction and poor outcomes.

Complement-Based Therapy in the Management of Antibody-Mediated Rejection.

Antibody-mediated rejection (AMR) is one of the leading causes of kidney allograft failure and is usually mediated by anti-human leukocyte antigen donor-specific antibodies (DSAs). Activation of classical pathway of the complement system is responsible for downstream effects of DSA and account for significant manifestations of AMR. Currently, the treatment of AMR is based on strategies to remove preformed antibodies or to prevent their production; however, these strategies are often unsuccessful. It is theoretically possible to inhibit complement activity to prevent the effect of DSA on kidney allograft function. Complement inhibitors such as eculizumab, a complement 5 monoclonal antibody, and complement 1 esterase inhibitors (C1 INHs) have been used in prevention and treatment of AMR with variable success. Eculizumab and C1 INH seem to reduce the incidence of early AMR and allow transplantation in highly sensitized kidney transplant recipients, but data on their long-term effect on kidney allograft function are limited. Several case reports described the successful use of eculizumab in the treatment of AMR, but there are no randomized controlled studies that showed efficacy. Treatment of AMR with C1 INH, in addition to standard of care, did not change short-term outcome but long-term studies are underway.

Therapeutic Apheresis in Prevention and Treatment of Antibody-Mediated Rejection of Renal Allografts

Antibody-mediated rejection represents a significant barrier to favourable long-term outcomes after kidney transplantation and is the most common cause of allograft failure. Therapeutic apheresis techniques associated with other treatments, such as immunosuppressive drugs, are commonly used in the prevention and treatment of antibody-mediated injury in pre- and post-transplant protocols. The rationale is related to the removal of donor-specific antibodies as well as other inflammatory mediators, including cytokines, chemokines, complement degradation molecules, and immunomodulatory effects also which determine an increased susceptibility of cell-mediated and humoral immunity to immunosuppressive agents. In this review article, we discuss current knowledge in the use of therapeutic apheresis in the prevention and management of antibody-mediated rejection, in combination with known and other emerging biological immunosuppressive therapies.

Current challenges and opportunities in the management of antibody-mediated rejection in lung transplantation.

There is increasing recognition of the importance of antibody-mediated rejection (AMR) after lung transplantation. The development of donor-specific antibodies, a key feature of AMR, occurs in approximately 30% of lung transplant recipients and is associated with poor posttransplant outcomes. This review highlights recently developed AMR diagnostic criteria in lung transplantation, potential mechanisms that mediate the development of AMR, and discusses current and emerging treatment strategies for this significant, graft-limiting complication. A major advance is the development of consensus guidelines to precisely define AMR amongst lung transplant. Regimens for the treatment of AMR continue to evolve with varying success reported with regards to antibody clearance and improving clinical outcomes. A multimodality treatment approach is common, typically involving a combination of intravenous immune globulin, plasmapheresis, rituximab, and bortezomib or carfilzomib. Recent studies suggest several new agents including tocilizumab, belimumab, daratumumab, plerixafor, and C1 esterase inhibitor as potentially novel and effective therapies to employ in AMR treatment. Despite advancements in the diagnosis of AMR through well defined consensus guidelines, there is limited evidence to guide treatment. Current data suggests that conventional approaches are of suboptimal efficacy, but emerging therapeutic agents with diverse biological mechanisms offer promise for improved AMR treatment.

Current state of pediatric cardiac transplantation.

Pediatric heart transplantation is standard of care for children with end-stage heart failure. The diverse age range, diagnoses, and practice variations continue to challenge the development of evidence-based practices and new technologies. Outcomes in the most recent era are excellent, especially with the more widespread use of ventricular assist devices (VADs). Waitlist mortality remains high and knowledge of risk factors for death while waiting and following transplantation contributes to decision-making around transplant candidacy and timing of listing. The biggest gap impacting both waitlist and overall survival remains mechanical support options for infants and patients with single ventricle physiology. Though acute rejection has decreased progressively, both diagnosis and management of antibody-mediated rejection has become increasingly challenging and complex, as has the ability to understand the implication of anti-HLA antibodies detected both pre- and post-transplantation-including when and how to intervene. Trends in immunosuppression protocols include more use of induction therapy and steroid avoidance or withdrawal protocols. Common long-term morbidities include renal insufficiency, which can be mitigated with surveillance and renal-sparing strategies, and infections. Functional outcomes are excellent, but significant psychosocial challenges exist in relation to neurodevelopment, non-adherence, and transition from child-centered to adult-centered care. Cardiac allograft vasculopathy (CAV) remains a barrier to long-term survival, though it is more apparent that objective evidence of an impact on the allograft is important with regards to impact on outcomes. Retransplantation is rare in pediatric heart transplant recipients. Pediatric heart transplantation continues to evolve in order to address the challenges of the diverse group of patients that reach end-stage heart failure during childhood.

Defining Priorities for Future Research: Results of the UK Kidney Transplant Priority Setting Partnership.

BackgroundIt has been suggested that the research priorities of those funding and performing research in transplantation may differ from those of end service users such as patients, carers and healthcare professionals involved in day-to-day care. The Kidney Transplant Priority Setting Partnership (PSP) was established with the aim of involving all stakeholders in prioritising future research in the field.MethodsThe PSP methodology is as outlined by the James Lind Alliance. An initial survey collected unanswered research questions from patients, carers and clinicians. Duplicate and out-of-scope topics were excluded and the existing literature searched to identify topics answered by current evidence. An interim prioritisation survey asked patients and professionals to score the importance of the remaining questions to create a ranked long-list. These were considered at a final consensus workshop using a modified nominal group technique to agree a final top ten.ResultsThe initial survey identified 497 questions from 183 respondents, covering all aspects of transplantation from assessment through to long-term follow-up. These were grouped into 90 unanswered “indicative” questions. The interim prioritisation survey received 256 responses (34.8% patients/carers, 10.9% donors and 54.3% professionals), resulting in a ranked list of 25 questions that were considered during the final workshop. Participants agreed a top ten priorities for future research that included optimisation of immunosuppression (improved monitoring, choice of regimen, personalisation), prevention of sensitisation and transplanting the sensitised patient, management of antibody-mediated rejection, long-term risks to live donors, methods of organ preservation, induction of tolerance and bioengineering of organs. There was evidence that patient and carer involvement had a significant impact on shaping the final priorities.ConclusionsThe final list of priorities relates to all stages of the transplant process, including access to transplantation, living donation, organ preservation, post-transplant care and management of the failing transplant. This list of priorities will provide an invaluable resource for researchers and funders to direct future activity.

Current status of the evaluation and management of antibody-mediated rejection in kidney transplantation

Antibody-mediated rejection (AMR) has come to the forefront of clinical and research challenges in clinical transplantation. Despite the major progress made over the past two decades, there remains a large number of unanswered diagnostic, prognostic, and therapeutic questions. Here we review the recent studies that have helped improve our understanding of AMR. Complement binding capacity of the HLA antibodies using modified single antigen bead Luminex assays to detect C1q, C4d, or C3d binding, has been associated with risk of AMR and graft failure. However, this property correlates with the antibody mean fluorescent intensity, and, in many cases, may not add additional insight. The use of molecular methods to examine expression profiles in the kidney biopsy specimens, in peripheral mononuclear cells, or urinary chemokine signature, has improved our understanding of the mechanisms of AMR-induced injury and refined our current diagnostic tools. On the treatment front, monoclonal antiinterleukin 6 receptor antibody, and C1 esterase inhibitor have shown promising results in the pilot studies but further larger trials are needed to evaluate their safety and efficacy. We are making constant progress in the pursuit of a better understanding the AMR process and finding new diagnostic and therapeutic options.

Antibody-mediated rejection in pediatric kidney transplantation: pathophysiology, diagnosis, and management.

Kidney transplant is the preferred treatment of pediatric end-stage renal disease. One of the most challenging aspects of pediatric kidney transplant is the prevention and treatment of antibody-mediated rejection (ABMR), which is one of the main causes of graft dysfunction and early graft loss. Most challenges are similar to those faced in adult kidney transplants; however, factors unique to the pediatric realm include naivety of the immune system and the small number of studies and randomized controlled trials available when considering pharmacological treatment options. Here, we present a case of ABMR in a pediatric patient and a review of the pathophysiology, diagnosis, and management of ABMR. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because (1) there still remain many unidentified potential antigens leading to ABMR, (2) children and adults are at different stages of their immune system development, and, thus, (3) the full pathophysiology of alloimmunity is still not completely understood, and (4) the efficacy and safety of treatment in adults may not be directly translated to children. As we continue to gain a better understanding towards the precise alloimmune mechanism that drives a particular ABMR, we can also improve pharmacotherapeutic choices. With continued research, they will become more precise in treating a particular mechanism versus using a broad scope of immunosuppression such as steroids. However, there is much more to be uncovered, such as identifying more non-human leukocyte antigens and their role in alloimmunity, determining the exact mechanism of adults achieving complete operational tolerance, and understanding the difference between pediatric and adult transplant recipients. Making strides towards a better understanding of these mechanisms will lead to continued efficacy and safety in treatment of pediatric ABMR.

Antibody-mediated rejection in lung transplantation: fable, spin, or fact?

The lung transplant community continues to struggle with the diagnosis and management of antibody-mediated rejection. The four diagnostic tenets of donor-specific antibodies, C4d staining, histopathologic changes, and allograft dysfunction, which were largely derived from the early Banff meetings on renal transplantation, have somewhat arbitrarily been applied to lung transplantation. With the passage of time, it is increasingly apparent that merits of these diagnostic pillars are less robust in lung transplantation. In this article, we summarize some of the controversies and challenges surrounding the diagnosis of antibody-mediated rejection in lung transplantation.

The Management of Antibody-Mediated Rejection in the First Presensitized Recipient of a Full-Face Allotransplant

We report on the management of the first full-face transplantation in a sensitized recipient with a positive preoperative crossmatch and subsequent antibody-mediated rejection (AMR). The recipient is a 45-year-old female who sustained extensive chemical burns, with residual poor function and high levels of circulating anti-HLA antibodies. With a clear immunosuppression plan and salvage options in place, a full-face allotransplant was performed using a crossmatch positive donor. Despite plasmapheresis alongside a standard induction regimen, clinical signs of rejection were noted on postoperative day 5 (POD5). Donor-specific antibody (DSA) titers rose with evidence of C4d deposits on biopsy. By POD19, biopsies showed Banff Grade III rejection. Combination therapy consisting of plasmapheresis, eculizumab, bortezomib and alemtuzumab decreased DSA levels, improved clinical exam, and by 6 months postop she had no histological signs of rejection. This case is the first to demonstrate evidence and management of AMR in face allotransplantation. Our findings lend support to the call for an update to the Banff classification of rejection in vascularized composite tissue allotransplantation (VCA) to include AMR, and for further studies to better classify the histology and mechanism of action of AMR in VCA.

Complement Inhibition with Eculizumab to Prevent Antibody Mediated Rejection (AbMR) in Patients with Donor Specific Anti-HLA Antibody (DSAb) and a Positive Cross Match

Introduction: Patients with DSAb & a positive crossmatch risk early AbMR & graft loss. We evaluated the use of the C5 inhibitor eculizumab to prevent AbMR in patients with DSAb and a positive cross match. Methods: 5 patients with DSAb & positive crossmatch received pretransplant plasmapheresis (PP), & Eculizumab pre and post-transplant. Eculizumab was ceased if/when tissue typing and histology suggested significantly reduced DSAb and/or negative crossmatch & normal histology. Results: At a median of 27mths (range 15 to 31), patient and graft survival are 100% with stable renal function and no proteinuria. Eculizumab has been withdrawn in all patients. Patient # 1 had low level DSAb and this has remained so, while patient #3 showed rapid and near complete loss of DSAb. Patient #4 lost a previous graft to AbMR on day 8, & on this occasion developed severe AbMR (biopsy proven d 4) despite eculizumab. Pharmacokinetic & pharmacodynamic studies confirmed binding to & inhibition of C5. The patient received PP & Eculizumab. PP was weaned & ceased after 2months, with improving but persistent AbMR. The patient was maintained on infusions of IVIG and 3 months after IVIG was ceased, there was acute clinical and histological exacerbation of AbMR. C4d staining was absent throughout. Patient #2 maintained stable graft function, with no AbMR or transplant glomerulopathy despite high DSAb (MFI > 10 000) for > 6 mths; C4d staining was strongly +ve suggesting complement activation proximal to C5. Beyond 6months post transplant, the DSAb level has dropped progressively (from MFI > 10000, to under 3000) with corresponding changes in flow cross matching. Patient #5 maintained stable graft function, with no AbMR or transplant glomerulopathy despite DSAb (MFI > 10 000) persisting for more than a month; C4d staining was +ve suggesting complement activation proximal to C5. DSAb level has dropped progressively with corresponding changes in flow cross matching.Table: [Outcomes of DSAb +ve Patients Receiving Eculizumab]Conclusion: Eculizumab (i) may enable transplantation in some patients with DSAb & a positive crossmatch without post transplant plasma exchange(ii) can prevent AbMR despite binding of DSAb to graft & complement activation (C4d staining, normal histology) (iii) AbMR can occur despite inhibition of C5, suggesting damage mediated by proximal complement factors (C3a, C5a) or direct activation by antibody. Further studies are necessary to determine pathways involved in AbMR, & the role of Eculizumab in prevention and management of AbMR.