Treatment Of Acute Antibody-mediated Rejection Research Articles

Successful treatment of acute antibody-mediated rejection of liver allograft with imlifidase: A case report

Although the incidence of acute antibody mediated rejection in liver transplantation is low, the consequences of acute antibody mediated rejection can be devastating, often leading to severe fibrotic changes and early graft loss. Conventional treatment modalities for management of moderate-to-severe acute antibody mediated rejection in liver transplant continue to rely on of corticosteroids, plasmapheresis, and intravenous immunoglobulin. However, management of refractory, severe antibody mediated rejection remains without a clear gold-standard approach. This case report describes successful first use of Imlifidase, an Ig-G degrading enzyme, for management of acute refractory antibody mediated rejection following orthotopic liver transplant. This 41-year-old woman developed acute antibody meditated rejection and donor specific antibodies within two weeks of undergoing an A2 to O liver transplant. Following unsuccessful treatment with conventional modalities, treatment with Imlifidase resulted in normalization of liver function, resolution of antibody mediated rejection on surveillance biopsy, and disappearance of donor specific antibodies. Imlifidase could represent a promising treatment for refractory antibody mediated rejection in liver transplantation and warrants further study.

Acute Antibody-mediated Rejection Coexisting With T Cell-mediated Rejection in Pediatric ABO-incompatible Transplantation.

Background.The management and outcome of ABO-incompatible (ABO-I) liver transplantation (LT) has been improving over the past few decades. Recently, the introduction of a pathological evaluation of acute antibody-mediated rejection (AMR) for liver allograft has provided a new recognition of allograft rejection in LT.Methods.One hundred and one pediatric ABO-I LTs performed in our institute were retrospectively analyzed. We assessed the clinical manifestations, diagnosis, and treatment of acute AMR, focusing on the recipient age and pathological findings.Results.Twelve cases (11.9%) of acute AMR related to ABO-I were observed. Nine cases developed mixed T cell–mediated rejection (TCMR)/AMR. These consisted of 6 patients in the younger age group for whom the preconditioning treatment was not indicated and 4 patients in the older age group to whom rituximab was administered as planned. Two patients in the older age group to whom preoperative rituximab was not administered as planned developed isolated AMR. Acute AMR in the older group required plasma exchange for treatment, regardless of the coexistence of TCMR. In contrast, those in the younger group were successfully treated by intravenous methylprednisolone pulse and intravenous immunoglobulin without plasma exchange, accounting for mild immune reaction.Conclusions.Acute ABO-I AMR can develop simultaneously with TCMR, even in young patients with a compromised humoral immune response following ABO-I LT. Establishing the accurate diagnosis of AMR with a pathological examination, including component 4d staining, is crucial for optimizing treatment.

Costs of Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients

Antibody-mediated rejection (AMR) remains challenging in kidney transplant recipients. It may negatively impact the graft survival, and its treatment is associated to relatively high expenses. The aim of our study was to assess the costs of treatment of acute AMR in the Polish settings. A total of 11 kidney transplant recipients with acute AMR diagnosed between September 2016 and August 2019 and treated in our center were included. Direct costs of inpatient and outpatient care in the first year after AMR diagnosis from the perspective of a transplant center were retrospectively calculated. The costs of treatment of acute AMR were considerably high, with a mean 1-month cost of treatment 12,718 PLN (∼€2925; ∼3307 US dollars). That means that costs of management of kidney transplant recipients with acute AMR are almost 2-fold higher than hemodialysis. Intravenous immunoglobulin was responsible for the majority (55%) of costs. Treatment of acute AMR increases the costs of post-kidney transplant care in involved patients. Therefore, efforts should be made to minimize the risk for acute AMR. Despite its potential clinical benefits, management of acute AMR is even more expensive than dialysis. Therefore, further cost-effectiveness analyses are needed to justify the spending and to establish the best treatment regimens.

Treatment of Acute Antibody-Mediated Rejection in Children Post-Kidney Transplantation: A Single Center’s Experience

Introduction Acute antibody-mediated rejection (aAMR) can negatively impact renal allografts outcomes. To date, there has not been a consistent therapeutic approach to manage aAMR. The aim of the study is to evaluate the tolerance and efficacy of an institutional protocol of methylprednisolone, intravenous gamma globulin (IVIG), rituximab, and bortezomib used to treat aAMR in pediatric renal transplant recipients (pRTRs). Methods A retrospective chart review was performed on 10 pediatric renal transplant recipients (pRTRs) who were diagnosed with aAMR on a renal biopsy performed between January 2014 and November 2015. Results Over the study period, 9.5% of pRTRs had aAMR. Sixty percent of whom had concurrent acute cellular rejection (ACR). Renal allografts survival was 100% during the the first post-aAMR. At the time of diagnosis of aAMR, estimated glomerular filtration rate (eGFR) had decreased by 42% (mean at baseline eGFR=67.2±19.5 mL/min/1.73 m2 vs mean at aAMR eGFR=38.9±14.2 mL/min/1.73 m2; p=0.002). At 1-year post rejection, eGFR had increased by 26% as compared eGFR at the time of rejection (mean eGFR=49.0±13.2 mL/min/1.73 m2; p=0.006). Immuno-dominant donor-specific anti-HLA antibody titers (iDSAs) class I and class II decreased by 69% and 15% at 6-month follow-up visit. No serious opportunistic infections nor malignancy were reported in our subjects. Conclusion Our study suggests that our protocol improved kidney function with 100% graft survival at 1-year post aAMR episode. The percentage decline in iDSAs class I titers was more significant than class II. Furthermore, our treatment protocol was well-tolerated with no life threatening complications.

Infectious complications and graft outcome following treatment of acute antibody-mediated rejection after kidney transplantation: A nationwide cohort study.

Acute antibody-mediated rejection (AMR) remains a challenge after kidney transplantation (KT). As there is no clear-cut treatment recommendation, accurate information on current therapeutic strategies in real-life practice is needed. KT recipients from the multicenter Swiss Transplant Cohort Study treated for acute AMR during the first post-transplant year were included retrospectively. We aimed at describing the anti-rejection protocols used routinely, as well as patient and graft outcomes, with focus on infectious complications. Overall, 65/1669 (3.9%) KT recipients were treated for 75 episodes of acute AMR. In addition to corticosteroid boluses, most common therapies included plasmapheresis (56.0%), intravenous immunoglobulins (IVIg) (38.7%), rituximab (25.3%), and antithymocyte globulin (22.7%). At least one infectious complication occurred within 6 months from AMR treatment in 63.6% of patients. Plasmapheresis increased the risk of overall (hazard ratio [HR]: 2.89; P-value = 0.002) and opportunistic infection (HR: 5.32; P-value = 0.033). IVIg exerted a protective effect for bacterial infection (HR: 0.29; P-value = 0.053). The recovery of renal function was complete at 3 months after AMR treatment in 67% of episodes. One-year death-censored graft survival was 90.9%. Four patients (6.2%) died during the first year (two due to severe infection). In this nationwide cohort we found significant heterogeneity in therapeutic approaches for acute AMR. Infectious complications were common, particularly among KT recipients receiving plasmapheresis.

Rigetto anticorpo-mediato nel trapianto di rene: fisiopatologia, clinica e terapia

Introduction. Over the past two decades, our thinking has changed from considering rejection as primarily a T-cell mediated process to the realization that insufficient control of the humoral arm of a recipient’s immune system is the factor primarily responsible for the allograft dysfunction and loss. Acute Antibody Mediated Rejection (ABMR) in kidney transplantation is a severe complication that frequently occurs after transplantation and is due either to pre-transplant Donor Specific Antibodies (DSAs) or to de novo DSAs. New techniques to detect DSAs in the recipient serum and advances in the assessment of graft pathology have allowed us to recognize this entity in recent years.
 Methods. The treatment of ABMR is a multistep process consisting in the desensitization of the patients with preformed antibodies to prevent acute ABMR: in case of acute ABMR, the antibodies are removed from the serum and anti-B cells immunosuppressants are used.
 Results and Discussion. Along with our knowledge on acute ABMR, a distinct entity has been recognized: the chronic AMBR. Chronic ABMR is a frequent cause of late graft dysfunction and is characterized by a typical histopathologic feature. The treatment is often difficult and new drugs are now tested to control the disease.

Plasma volume treated with double filtration plasmapheresis and outcomes of acute antibody-mediated rejection in kidney transplant recipients: A retrospective cohort study.

A retrospective cohort study was conducted to evaluate the association between the plasma volume treated by double filtration plasmapheresis and allograft outcomes for the treatment of acute antibody-mediated rejection in kidney transplant recipients. Patients were divided into two groups: group 1, plasma volume treated between 1 and <1.3 total plasma volume and group 2, plasma volume treated ≥1.3 total plasma volume. Primary outcome was ≥50% reduction of serum creatinine rising from baseline value at 1 month. A total of 32 courses (146 sessions) of double filtration plasmapheresis were performed; 17 and 15 courses in group 1 and group 2, respectively. Primary outcome occurred in 41% of group 1 and 40% of group 2 (adjusted risk ratio 1.15 [95%CI, 0.48-2.76]). Graft loss at 1 year did not differ between the two groups (adjusted hazard ratio 0.65 [95%CI, 0.23-1.87]). Infection tendency seemed to be higher in group 2 (40% vs 18%, P = .243).

Eculizumab and Intravenous Immunoglobulins for the Treatment of Acute Antibody-Mediated Rejection after Lung and Liver Transplantation

Eculizumab and Intravenous Immunoglobulins for the Treatment of Acute Antibody-Mediated Rejection after Lung and Liver Transplantation

Prognostic Value of the Persistence of C1q-Binding Anti-HLA Antibodies in Acute Antibody-Mediated Rejection in Kidney Transplantation.

The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown. We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment. Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect. The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.

Treatment of Acute Antibody-Mediated Rejection.

Acute antibody-mediated rejection (AMR) remains an important challenge in the field of kidney transplantation despite the advances in immunosuppressive strategies, and has been recognized as an important cause of allograft dysfunction and graft loss. The treatments of acute AMR are not standardized and poor evidence is currently available on the effectiveness of therapy regimens with combinations of drugs. Standard treatment for acute AMR is based on 3 cornerstones: removal of donor-specific antibodies (DSAs) from the bloodstream, reduction of DSAs synthesis, and inhibition of the interaction between DSAs and human leukocyte antigen antigens on donor's cells. In this paper, we discuss the mechanism of action of the principal drugs currently in use, the main published studies on this topic, and the future insights related to the treatment of acute AMR.

Bortezomib for refractory acute antibody-mediated rejection in kidney transplant recipients: A single-centre case series.

Acute antibody-mediated rejection (ABMR) after kidney transplantation (KT) is associated with poor allograft survival. Current therapies for ABMR are able to deplete B-lymphocytes but do not target plasma cells. Bortezomib is a proteasome inhibitor that can eliminate plasma cells and has demonstrated utility in the treatment of ABMR. A retrospective study was carried out from 2010 to 2014, including all patients with ABMR refractory to conventional treatment who received bortezomib. Bortezomib (1.3 mg/m(2) ) was administered intravenously on days 1, 4, 8, and 11. Renal function, graft survival, follow-up biopsies, and donor-specific antibodies (DSA) were recorded. We identified seven patients. Of these, high immunological risk was found in 6 of 7, preformed DSA were found in 5 of 7, flow cytometry crossmatch was positive in 4 of 7, and desensitization before KTx was provided in 6 of 7 patients. ABMR was diagnosed at a median of 90 days (8-167) post-KT. After bortezomib therapy, renal function improved or stabilized in 5 of 7 patients and progressively deteriorated in 2 of 7, leading to haemodialysis after 7 and 11 months, respectively. Follow-up kidney biopsies showed persistence of ABMR in 2 of 7, chronic active ABMR 3 of 7 and inactive chronic lesions in 2 of 7. DSA titres significantly decreased after treatment (P = 0.028). All patients experienced mild adverse events. After a follow-up of 22 ± 18 months, three grafts were lost (42%) and four remained functioning. Bortezomib could be useful as an adjuvant therapy for ABMR refractory to conventional treatment with acceptable mid-term outcomes in these severe cases. More research is needed to develop strategies to better preserve graft function after refractory ABMR.

Correlations of lymphocyte subset infiltrates with donor-specific antibodies and acute antibody-mediated rejection in endomyocardial biopsies.

Acute antibody-mediated rejection (AMR) is a major complication after heart transplantation, posing a significant risk for allograft failure, cardiac allograft vasculopathy, and poor survival. While the inflammatory milieu of cellular rejection and Quilty lesions is well known, the immunologic components of AMR are not well understood. Our aim was to better define the immunophenotype of infiltrating lymphocytes in biopsies with AMR, specifically in relation to donor-specific antibodies to human leukocyte antigen (HLA) class I, II, or both. We performed a retrospective analysis of cardiac transplant patients with concurrent endomyocardial biopsies (EMB), donor-specific antibody (DSA) measurements, and immunofluorescence for C4d at our institution (2005-2011). DSA was evaluated against HLA class I and class II specificities pre- and posttransplant using flow cytometry and/or Luminex bead assays. Acute cellular rejection (ACR) and pathologic AMR (pAMR) were based on the International Society for Heart and Lung Transplantation 2005/2013 reports. Immunohistochemical analysis for CD3, CD4, CD8, and CD79a was performed using standard immunohistochemical protocols on one formalin-fixed, paraffin-embedded EMB from each patient. The number of lymphocytes expressing each protein was enumerated microscopically at 400×. Ratios of T:B cells and CD4:CD8 T cells were then calculated for each EMB. Seventy-nine cardiac transplant patients who had pre- and posttransplant DSA measurements were analyzed. Of these 79 patients, 37 had DSA against HLA class I, HLA class II, or both. Of patients with DSA, the average CD4:CD8 ratio in the EMB was 0.80, while those with only ACR had a CD4:CD8 ratio of 1.49. Interestingly, the T:B cell ratio in patients with and without DSA was 5.7 and 5.5, respectively. Cardiac transplant patients with DSA against HLA have more CD8 cytotoxic T cells than CD4 helper T cells in the EMB lymphocytic infiltrate compared with patients without DSA against HLA. The inflammatory infiltrate T:B cell ratio was similar in patients both with and without DSA. The relative increase of cytotoxic T cells in EMB while the patient has DSA suggests a possible pathogenic role of these cells and may aid in the diagnosis and treatment of AMR.

Use of Bortezomib as Anti-Humoral Therapy in Kidney Transplantation

This study aimed to investigate the effect of bortezomib in the desensitization and treatment of acute antibody mediated rejection (AAMR) in kidney transplantation. Nine patients who received bortezomib therapy for desensitization (DSZ group, n = 3) or treatment of AAMR (AAMR group, n = 6) were included in this study. In the DSZ group, 2 patients required DSZ owing to positive cross match and 1 owing to ABO mismatch with high baseline anti-ABO antibody titer (1:1,024). Bortezomib was used at 1, 3, 8, and 11 days from the start of the treatment. In the AAMR group, 3 patients showed full recovery of allograft function after bortezomib use and decrease in donor specific anti-HLA antibody (HLA-DSA). However, 3 patients did not respond to bortezomib and experienced allograft failure. In the DSZ group, negative conversion of T-CDC (complement-dependent cytotoxicity) was achieved, and HLA-DSA was decreased to lower than a weak level (median fluorescence intensity [MFI] < 5,000) in 2 patients. In the case of ABO mismatch kidney transplantation, the anti-A/B antibody titer decreased to below the target (≤ 1:16) after bortezomib therapy. Therefore, bortezomib could be an alternative therapeutic option for desensitization and treatment of AAMR that is unresponsive to conventional therapies.

Acute Antibody-Mediated Rejection in Kidney Transplantation: Clinical and Therapeutic Aspects

Acute Antibody Mediated Rejection (ABMR) in kidney transplantation is a severe complication that frequently occurs after transplantation and is due either to pre-transplant Donor-Specific Antibodies (DSAs) or to de novo DSAs. New techniques to detect DSAs in the recipient serum and advances in the assessment of graft pathology have allowed us to recognize this entity in recent years. The treatment of ABMR is a multistep process consisting of the desensitization of the patients with preformed antibodies to prevent acute ABMR: in cases of acute ABMR, the antibodies are removed from the serum and anti-B cells immunosuppressants are used.

Clinical Management of Kidney Allograft Dysfunction

Allograft dysfunction is a common problem after kidney transplant. Allograft rejection is an important entity, and timely diagnosis and appropriate treatment are essential for caring transplant recipients. Hyperacute rejection is mediated by the preformed donor specific antibody, while accelerated acute rejection represents an anamnestic response by memory B and T cells. They occur early after transplant. Acute cellular rejection is relatively common and usually responds to pulse corticosteroids or antithymocyte globulin (ATG). The complexity of antibody-mediated rejection (AMR) as well as its detrimental effect has been increasingly recognized. The treatment of acute AMR requires a combination of several modalities, such as plasmapheresis or immunoadsorption, IVIG, corticosteroids, rituximab and ATG. After treatment of rejection episode, the maintenance immunosuppressive drugs should be adjusted to prevent further acute rejection and/or evolution into chronic active rejection. Chronic rejection is not reversible and it has been recognized as the most important cause of chronic graft dysfunction and failure.

Eculizumab Treatment of Acute Antibody-Mediated Rejection in Renal Transplantation: Case Reports

The occurrence of acute antibody-mediated rejection (AMR), especially in more severe cases, continues to be associated with a poor prognosis for implant survival. Here, we have reported the results of treatment of two patients who developed AMR associated with thrombotic microangiopathy immediately after transplantation. We used a single dose of eculizumab at an early stage jointly with conventional modalities of steroid boluses, plasmapheresis, intravenous immunoglobulin, and rituximab. In both cases, the clinical course was favorable. Eculizumab, a monoclonal antibody with a high affinity for complement protein C5, prevents generation of the final membrane attack complex, blocking this cascade. To date, there are a few reports of the usefulness of eculizumab in AMR. Eculizumab can help to stop endothelial damage, especially in severe cases that show a risk of progression to cortical necrosis, by providing a therapeutic window until the other modalities begin to control the immune response. In our experience, the use of eculizumab can be beneficial in the treatment of AMR.

The Treatment of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients—A Systematic Review

Antibody-mediated rejection (AMR) is a recognized cause of allograft loss in kidney transplant recipients. A range of therapies targeting removal of circulating donor-specific antibodies (DSAs), blocking their effect or reducing production have been reported. We conducted a systematic review to determine the efficacy of treatments for acute AMR in renal allografts. Electronic databases, reference lists, and conference proceedings were searched for controlled trials. Nonrandomized publications were reviewed for the purpose of discussion. We identified 10,388 citations, including five randomized and seven nonrandomized controlled trials. The randomized studies were small (median, 13 patients/arm; range, 5-23), of which, four examined plasmapheresis (one suggested benefit) and one for immunoadsorption (also suggesting benefit). Marked heterogeneity was evident, including the definition and severity of AMR and the treatment regimen. The end point of graft survival was common to all studies. Small, nonrandomized controlled studies suggested benefit from rituximab or bortezomib. The effects of dose and regimen on the clinical response to any of the current treatments were not apparent from the available data. Data describing the efficacy of treatments for AMR in renal allografts are of low or very low quality. Larger randomized controlled trials and dose-response studies are required.

Summary of FDA Antibody-Mediated Rejection Workshop

The Food and Drug Administration (FDA) held an open public workshop in June 2010 to discuss the current state of science related to antibody-mediated rejection (AMR) in kidney transplantation. Desensitization, acute AMR and chronic AMR (CAMR) were considered in the context of clinical trial design. Participants discussed experiences with HLA antibody detection and quantitation and the utility of monitoring donor-specific antibodies (DSAs) to inform the management of patients with AMR. The role for animal models was discussed. Diagnostic and prognostic features of histology were presented, followed by discussion of sensitivity and specificity of various criteria. The published literature on treatment of acute AMR was summarized, which consisted of case series and limited data from controlled clinical trials. Considerations for future clinical trials were presented, including endpoints and statistical evaluations of outcome. Although many issues need further consideration, the meeting enabled an important exchange of ideas between experts in the field.

Treatment of Acute Antibody-Mediated Rejection: A Single-Center Experience

Introduction Acute antibody-mediated rejection (AMR) leads to graft loss. The combination of plasmapheresis (PP), intravenous immunoglobulin (IVIG), and rituximab (RTX) has been reported to be effective therapy. Patients and methods Between October 2005 and September 2009, 8 (4.7%) kidney transplant recipients developed AMR, diagnosed by severe acute rejection and extensive C4d staining in peritubular capillaries. Results All patients were treated with two to six sessions of PP with IVIG added after the last PP. In two patients, RTX was prescribed after PP and IVIG. Baseline immunosuppression was based on steroids, mycophenolate mofetil or azathioprine, and tacrolimus or cyclosporine or everolimus. The presence of subsequent significant decrease in anti-HLA class I antibodies was demonstrated in a highly sensitized patient before and after transplantation with PP treatment. An increase was observed before the diagnosis of AMR. After a mean follow-up of 10 months (range = 1–23), patient and graft survivals were 100% and 50%, respectively. Three patients lost their transplants to AMR refractory to treatment and one patient, due to interstitial fibrosis and tubular atrophy at 23 months after AMR. Finally, four patients recovered renal function, showing a mean serum creatinine of 2.2 ± 0.45 mg/dL. Conclusions Early diagnosis and treatment with PP, IVIG, and RTX may resolve AMR. PP before and after transplantation in high-risk patients may result in anti-HLA class I and class II antibody removal from plasma and prevention of AMR.

Treatment of Simultaneous Acute Antibody-Mediated Rejection and Acute Cellular Rejection With Alemtuzumab in Kidney Transplantation: A Case Report

This is a case report of a living related donor kidney transplantation using basiliximab induction and maintenance immunosuppression with cyclosporine, mycophenolate sodium, and steroid. On the second posttransplant day, the patient developed acute antibody-mediated rejection, which was treated with plasmapheresis and intravenous immunoglobulin (IVIG). Five days later, the graft had still not responded to the treatment. Another biopsy revealed additional acute cellular rejection (Banff IIA). As alemtuzumab can rapidly deplete T and B lymphocytes, monocytes, and natural killer cells, the patient was treated with alemtuzumab (30 mg subcutaneously) together with methylprednisolone (500 mg) and two more plasmaphereses. The kidney graft responded within 48 hours, producing more than 4 L of urine per day. The total lymphocyte decreased from 530/μL to 50/μL remaining in the 50 to 220/μL range. The patient received valgancyclovir and cotrimoxazole as infection prophylaxis. The kidney graft responded well to the rescue treatment and the patient was discharged with a serum creatinine of 1.1 mg/mL and has been uneventfully followed in the outpatient clinic for 8 months. Today, with the potent, effective, and selective immunosuppressive regimens, the rate and severity of acute cellular rejection in kidney transplantation has decreased in most centers. However, the rate of acute antibody-mediated rejection has increased to levels greater than those of acute cellular rejection in many centers. Acute antibody-mediated rejection is more difficult and expensive to treat successfully. The treatment of acute antibody-mediated rejection included plasmapheresis and IVIG. Herein we have reported a case of kidney transplantation simultaneously developing acute antibody-mediated and acute cellular rejection; the patient was successfully treated with alemtuzumab.