BACKGROUND: Current monitoring after heart transplantation (HT) employs repeated invasive endomyocardial biopsies (EMB). Although positive EMB confirms rejection, EMB fails to predict impending, subclinical, or EMB-negative rejection events. While non-human leukocyte antigen (non-HLA) antibodies have emerged as important risk factors for antibody-mediated rejection after HT, their use in clinical risk stratification has been limited. A systematic review of the role of non-HLA antibodies in rejection pathologies has the potential to guide efforts to overcome deficiencies of EMB in rejection monitoring.
METHODS: Databases were searched to include studies on non-HLA antibodies in HT recipients. Data collected included the number of patients, type of rejection, non-HLA antigen studied, association of non-HLA antibodies with rejection, and evidence for synergistic interaction between non-HLA antibodies and donor-specific anti-human leukocyte antigen antibody (HLA-DSA) responses.
RESULTS: A total of 56 studies met the inclusion criteria. Strength of evidence for each non-HLA antibody was evaluated based on the number of articles and patients in support versus against their role in mediating rejection. Importantly, despite previous intense focus on the role of anti-major histocompatibility complex class I chain-related gene A (MICA) and anti-angiotensin II type I receptor antibodies (AT1R) in HT rejection, evidence for their involvement was equivocal. Conversely, the strength of evidence for other non-HLA antibodies supports that differing rejection pathologies are driven by differing non-HLA antibodies.
CONCLUSIONS: This systematic review underscores the importance of identifying peri-HT non-HLA antibodies. Current evidence supports the role of non-HLA antibodies in all forms of HT rejection. Further investigations are required to define the mechanisms of action of non-HLA antibodies in HT rejection.

UNASSIGNED: Antibody-mediated rejection (ABMR) is a major cause of late kidney allograft failure, but its economic and humanistic impacts have not been well-characterized in the literature.
UNASSIGNED: We reviewed available literature on economic burden (costs and healthcare resource use) and humanistic burden (health-related quality of life impacts [HRQOL] and utility estimates) in patients diagnosed with kidney transplant rejection; ABMR-specific studies were of particular interest. In total, 21 publications reporting economic and humanistic burden were included in the review; 9 of these reported ABMR-specific outcomes. The reviewed studies consistently showed a greater burden associated with ABMR-related transplant rejection than with non-ABMR transplant rejection.
UNASSIGNED: Evidence suggests greater economic burden and increased HRQOL impairment with ABMR-related kidney transplant rejection relative to non-ABMR, although small sample sizes and missing definitions for ABMR make meaningful comparisons between studies challenging. Because no International Classification of Diseases (ICD)-10 codes currently describe the etiologies of transplant rejection, it is difficult to characterize the burden of distinct types of transplant rejection. The paucity of high-quality data on the burden of ABMR in kidney transplant rejection demonstrates the need for more etiology-centric ICD-10 codes.

The relationship between blood transfusion following kidney transplantation (KT) and the development of de novo donor-specific antibodies (dnDSA) is controversial. This was investigated by conducting a meta-analysis of studies on patients who underwent KT with or without blood transfusion, and by evaluating the effect of post-KT blood transfusion on clinical outcomes of kidney transplant recipients. Relevant studies in the PubMed, EMBASE, and Cochrane Library databases were identified from inception to July 1, 2022. Two reviewers independently extracted data from the selected articles and estimated study quality. A fixed effects or random effects model was used to pool data according to the heterogeneity among studies. Data included in the meta-analysis were derived from 11 studies with a total of 19,543 patients including 6191 with and 13,352 without blood transfusion post-KT. We assessed the pooled associations between blood transfusion and occurrence of dnDSA and clinical outcomes of transplant recipients. Blood transfusion was strongly correlated with the development of dnDSA (relative risk [RR] = 1.40, 95% confidence interval [CI]: 1.17-1.67; P < 0.05). Patients with blood transfusion had a higher risk of developing anti-human leukocyte antigen (HLA) class I dnDSA than non-transfused patients (RR = 1.75, 95% CI: 1.14-2.69; P < 0.05) as well as significantly higher rates of antibody-mediated rejection (AMR) (RR = 1.41, 95% CI: 1.21-2.35; P < 0.05) and graft loss (RR = 1.75, 95% CI: 1.30-2.35; P < 0.05). There were no statistically significant differences between the two groups in the development of anti-HLA antibodies, anti-HLA class II dnDSA, and anti-HLA class I and II dnDSA; delayed graft function; T cell-mediated rejection; acute rejection; borderline rejection; or patient death. Our results suggest that blood transfusion was associated with dnDSA development in KT recipients. The findings of this systematic review also suggest that post-KT blood transfusion recipients have a higher risk of AMR, and graft loss compared with non-transfused patients. Evidence from this meta-analysis indicates that the use of blood transfusion post-KT is associated with a significantly higher risk of immunological sensitization. More and higher quality results from large randomized controlled trials are still needed to inform clinical practice.

Chronic kidney disease (CKD) is a major public-health problem that increases the risk of end-stage kidney disease (ESKD), cardiovascular diseases, and other complications. Kidney transplantation is a renal-replacement therapy that offers better survival compared to dialysis. Antibody-mediated rejection (ABMR) is a significant complication following kidney transplantation: it contributes to both short- and long-term injury. The standard-of-care (SOC) therapy combines plasmapheresis and Intravenous Immunoglobulins (IVIg) with or without steroids, with or without rituximab: however, despite this combined treatment, ABMR remains the main cause of graft loss. IL-6 is a key cytokine: it regulates inflammation, and the development, maturation, and activation of T cells, B cells, and plasma cells. Tocilizumab (TCZ) is the main humanized monoclonal aimed at IL-6R and appears to be a safe and possible strategy to manage ABMR in sensitized recipients. We conducted a literature review to assess the place of the anti-IL-6R monoclonal antibody TCZ within ABMR protocols.
We systematically reviewed the PubMed literature and reviewed six studies that included 117 patients and collected data on the utilization of TCZ to treat ABMR.
Most studies report a significant reduction in levels of Donor Specific Antibodies (DSAs) and reduced inflammation and microvascular lesions (as found in biopsies). Stabilization of the renal function was observed. Adverse events were light to moderate, and mortality was not linked with TCZ treatment. The main side effect noted was infection, but infections did not occur more frequently in patients receiving TCZ as compared to those receiving SOC therapy.
TCZ may be an alternative to SOC for ABMR kidney-transplant patients, either as a first-line treatment or after failure of SOC. Further randomized and controlled studies are needed to support these results.

Complement-binding donor-specific human leukocyte antigen (HLA) antibodies in kidney recipients have been associated with a higher risk of allograft rejection and loss. The objective of this meta-analysis was to investigate the correlation between C1q-binding donor-specific antibodies (DSAs) and clinical outcomes in kidney transplantation (KT) recipients.
We conducted systematic searches in the PubMed, EMBASE, and the Cochrane Library databases to identify all studies since inception to August 2021 that compared clinical outcomes between C1q + DSA and C1q-DSA patients who underwent KT. Data were independently extracted by two reviewers who assessed the risk of bias. Data were summarized with fixed effects or random effects models according to heterogeneity. We assessed clinical outcomes including graft loss, rejection, delayed graft function (DGF), and all-cause patient death.
Twenty-six studies with a total of 1337 patients were included: 485 with C1q-binding DSAs, and 850 without C1q-binding DSAs. Compared with the C1q-DSA group, the C1q + DSA group had significant increases in antibody-mediated rejection (AMR) (relative risk [RR] = 2.09, 95% confidence interval [CI], 1.53-2.86; P < 0.00001), graft loss (RR = 2.40, 95% CI, 1.66-3.47; P < 0.00001), and death (RR = 3.13, 95% CI, 1.06-9.23; P = 0.04). The C1q + DSA and C1q-DSA groups did not show significant differences in T-cell-mediated rejection, acute rejection, acute cellular rejection, mixed rejection, or DGF.
The findings of this systematic review suggest that C1q + DSA KT have a higher risk of AMR, graft loss, and death compared with C1q-DSA patients. Monitoring C1q-binding DSAs allows risk stratification of recipients and guides physician management.

Antibody-mediated rejection (AMR) is a rare and serious complication after lung transplantation, with no characteristic of pathological manifestation, no systematic standard treatment, and the poor efficacy and prognosis. We reported a case of early AMR after lung transplantation and the relevant literature has been reviewed. A male patient presented with symptoms of cold 99 days after transplantation and resolved after symptomatic treatment. He admitted to the hospital 14 days later because of a sudden dyspnea and fever. Anti-bacteria, anti-fungi, anti-virus, and anti-pneumocystis carinii treatment were ineffective, and a dose of 1 000 mg methylprednisolone did not work too. The patient\'s condition deteriorated rapidly and tracheal intubation was done to maintain breathing. Serum panel reactive antibody and donor specific antibody showed postive in humen leukocyte antigen (HLA) II antibody. Pathological examination after transbronchial transplantation lung biopsy showed acute rejection. Clinical AMR was diagnosed combined the donor-specific antibody with the pathological result. The patient was functionally recovered after combined treatment with thymoglobuline, rituximab, plasmapheresis, and immunoglobulin. No chronic lung allograft dysfunction was found after 3 years follow up. We should alert the occurrence of AMR in lung transplantation recipient who admitted to hospital with a sudden dyspnea and fever while showed no effect after common anti-infection and anti-rejection treatment. Transbronchial transplantation lung biopsy and the presence of serum donor-specific antibody are helpful to the diagnosis. The treatment should be preemptive and a comprehensive approach should be adopted.
抗体介导排斥反应(antibody-mediated rejection，AMR)是肺移植术后一种少见而严重的并发症，无特征性病理表现，无系统的标准治疗方案，治疗效果及预后较差。现报告1例肺移植术后早期AMR的病例并进行相关文献复习。本病例为男性患者，于右肺移植术后第99天出现感冒症状，经对症治疗后好转，14 d后突发气促、发热，抗细菌、真菌、病毒及卡氏肺孢子虫治疗无效，予1 000 mg甲基强的松龙治疗无效，患者病情迅速加重，予气管插管使其维持呼吸。血清群体反应性抗体和供体特异性抗体检查示：人白细胞抗原(humen leukocyte antigen，HLA)II类抗体阳性，经纤维支气管镜对移植肺取活体组织行病理检查提示急性排斥反应。结合供体特异性抗体和临床表现诊断为AMR。予兔抗人胸腺细胞免疫球蛋白+利妥昔单抗注射液+血浆置换+免疫球蛋白治疗后患者的呼吸功能恢复正常，随访3年未发生慢性移植肺功能衰竭。肺移植后受者突然出现气促、发热，常规抗感染及抗细胞排斥反应治疗无效时应警惕其发生AMR。经纤维支气管镜移植肺活体组织检查、血清供体特异性抗体检测有助于明确诊断。治疗应抓紧时机，采用综合治疗的方法。.

BACKGROUND: Anti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been recognized as non-HLA antibodies associated with allograft rejection and poor allograft outcomes after kidney transplantation. The aim of this study was to assess the risk anti-AT1R-Abs pose for rejection and graft loss among kidney transplant populations.
METHODS: We systematically searched PubMed, EMBASE, and the Cochrane Library databases for relevant articles published from inception until June 2021 to identify all studies concerning the role AT1R-Abs play in the clinical outcome after kidney transplantation. Two reviewers independently identified studies, abstracted outcome data, and assessed the quality of the studies. The meta-analysis was summarized using the fixed-effects models or random-effects models, according to heterogeneity. The major outcomes included delayed graft function, acute rejection, graft loss, or patient death after transplantation.
RESULTS: Twenty-one eligible studies involving a total of 4,023 kidney transplantation recipients were included in the evaluation to identified. Meta-analysis results showed that the AT1R-Ab positive kidney transplant (KT) group had a greater incidence of antibody-mediated rejection (RR = 1.94, 95%CI: 1.61-2.33, P < 0.00001) and graft loss (RR = 2.37, 95%CI: 1.50-3.75, P = 0.0002) than did the AT1R-Abs negative KT group. There was no significant statistical difference in delayed graft function rate, T-cell mediated rejection, mixed rejection, acute cellular rejection, acute rejection, and patient death rate between AT1R-Ab positive KT and AT1R-Ab negative KT groups.
CONCLUSIONS: Our study shows that the presence of anti-AT1R-Abs was associated with a significantly higher risk of antibody-mediated rejection and graft loss in kidney transplantation. Future studies are still needed to evaluate the importance of routine anti-AT1R monitoring and therapeutic targeting. These results shows that assessment of anti-AT1R-Abs would be helpful in determining immunologic risk and susceptibility to immunologic events for recipients.

Antibody-mediated rejection is a rare complication following liver transplantation and there is a lack of a comprehensive treatment strategy to provide detailed information about the dose and duration of antibody-mediated rejection treatment. This study describes eight adult liver transplantation recipients who developed antibody-mediated rejection between 2002 and 2021 in our center, as well as a review of the literature on the reported cases of antibody-mediated rejection in liver transplantation recipients. Our center\'s medical records were reviewed retrospectively to extract the necessary data on patients\' characteristics, management, and outcomes. Then, a comprehensive search using Embase, PubMed, Web of Science, Cochrane library, and Google Scholar databases was conducted without time limitation until June, 2021. Finally, a stepwise protocol was developed for managing acute, chronic, and recurrent antibody-mediated rejection in liver transplantation patients, based on our own experience, reported cases in the literature, and data from kidney transplantation. By review of the literature, 24 case studies containing 64 patients were identified and their management strategies and outcomes were evaluated. Although, various combinations of corticosteroids, plasma exchange, intravenous immunoglobulin, and biological agents are used in the treatment of acute antibody-mediated rejection in liver transplantation, treatment strategies should be classified according to the type, severity, and the timing of its onset. Given the importance of early treatment, rituximab and/or bortezomib should be started as soon as possible if no improvement in liver enzymes/bilirubin is observed during the initial treatment strategy using corticosteroids, plasma exchange and intravenous immunoglobulin. This article is protected by copyright. All rights reserved.

The weight of human leukocyte antigen (HLA) matching in kidney allocation algorithms, especially in the United States, has been devalued in a stepwise manner, supported by the introduction of modern immunosuppression. The intent was further to reduce the observed ethnic/racial disparity, as data emerged associating HLA matching with decreased access to transplantation for African American patients. In recent years, it has been increasingly recognized that a leading cause of graft loss is chronic antibody-mediated rejection, attributed to the development of de novo antibodies against mismatched donor HLA expressed on the graft. These antibodies are most frequently against donor HLA-DQ molecules. Beyond their impact on graft survival, generation of de novo donor-specific HLA antibodies also leads to increased sensitization, as measured by panel-reactive antibody metrics. Consequently, access to transplantation for patients returning to the waitlist in need of a second transplant is compromised. Herein, we address the implications of reduced HLA matching policies in kidney allocation. We highlight the observed diminished outcome data, the significant financial burden, the long-term health consequences, and, more important, the unintended consequences. We further provide recommendations to examine the impact of donor-recipient HLA class II and specifically HLA-DQα1β1 mismatching, focusing on collection of appropriate data, application of creative simulation approaches, and reconsideration of best practices to reduce inequalities while optimizing patient outcomes.

Antibody-mediated rejection (AMR) is a leading cause of kidney allograft failure, but its incidence, risk factors, and outcomes are not well understood.
We searched Ovid MEDLINE, Cochrane, EMBASE, and Scopus from January 2000 to January 2020 to identify published cohorts of ≥500 incident adult or 75 pediatric kidney transplant recipients followed for ≥1 year post-transplant.
At least two reviewers screened 5061 articles and abstracts; 28 met inclusion criteria. Incidence of acute AMR was 1.1%-21.5%; most studies reported 3%-12% incidence, usually within the first year post-transplant. Few studies reported chronic AMR incidence, from 7.5%-20.1% up to 10 years. Almost all patients with acute or chronic AMR received corticosteroids and intravenous immunoglobulin; most received plasmapheresis, and approximately half with rituximab. Most studies examining death-censored graft failure identified AMR as an independent risk factor. Few reported refractory AMR rates or outcomes, and none examined costs. Most studies were single-center and varied greatly in design.
Cohort studies of kidney transplant recipients demonstrate that AMR is common and associated with increased risk of death-censored graft failure, but studies vary widely regarding populations, definitions, and reported incidence. Gaps remain in our understanding of refractory AMR, its costs, and resulting quality of life.