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OBM Transplantation

(ISSN 2577-5820)

OBM Transplantation (ISSN 2577-5820) is an international peer-reviewed Open Access journal published quarterly online by LIDSEN Publishing Inc., which covers all evidence-based scientific studies related to transplantation, including: transplantation procedures and the maintenance of transplanted tissues or organs; assimilation of grafted tissue and the reconstitution of removed organs or parts of organs; transplantation of heart, lung, kidney, liver, pancreatic islets and bone marrow, etc. Areas related to clinical and experimental transplantation are also of interest.

OBM Transplantation is committed to rapid review and publication, and we aim at serving the international transplant community with high accessibility as well as relevant and high quality content.

The journal publishes all types of articles in English. There is no restriction on the length of the papers. We encourage authors to be concise but present their results in as much detail as necessary, as reviewers are expected to emphasize scientific rigor and reproducibility.

 
 

Publication Speed (median values for papers published in 2024): Submission to First Decision: 6.7 weeks; Submission to Acceptance: 14.4 weeks; Acceptance to Publication: 4 days (1-2 days of FREE language polishing included)

 
 
Current Issue: 2025  Archive: 2024 2023 2022 2021 2020 2019 2018 2017
Open Access Review

Antibody-Mediated Rejection in Kidney Transplantation: Immunopathogenesis, Innate–Adaptive Crosstalk, and Therapeutic Advances

Livia Maria Surdi , Maribel Dagher , Tamara Merhej , John Choi , Jamil R. Azzi *

  1. Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

* Correspondence: Jamil R. Azzi

Academic Editor: Rending Wang

Special Issue: Antibody Mediated Rejection in Kidney Transplantation

Received: April 17, 2025 | Accepted: August 27, 2025 | Published: September 10, 2025

OBM Transplantation 2025, Volume 9, Issue 3, doi:10.21926/obm.transplant.2503258

Recommended citation: Surdi LM, Dagher M, Merhej T, Choi J, Azzi JR. Antibody-Mediated Rejection in Kidney Transplantation: Immunopathogenesis, Innate–Adaptive Crosstalk, and Therapeutic Advances. OBM Transplantation 2025; 9(3): 258; doi:10.21926/obm.transplant.2503258.

© 2025 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Antibody-mediated rejection (ABMR) remains a major barrier to long-term graft survival in kidney transplantation. Defined by the presence of donor-specific antibodies (DSAs) and characteristic histological changes, such as C4d deposition in peritubular capillaries, ABMR can present acutely, chronically, or subclinically, often manifesting as graft dysfunction. Recent advances in genomic profiling and diagnostic assays have improved our understanding of its pathophysiology, yet therapeutic strategies remain limited. Early detection through routine monitoring and timely intervention, particularly in subclinical ABMR, may improve outcomes. In this review, we provide an in-depth analysis of ABMR in kidney transplantation, with a particular emphasis on recent insights into its immunopathogenesis—emphasizing the dynamic crosstalk between innate and adaptive immunity and its implications for allograft injury. We also discuss how this evolving understanding is reshaping current diagnostic approaches and informing the development of innovative therapeutic strategies. Key findings from recent literature underscore the need for a more integrated approach that bridges mechanistic insight with clinical application, aiming to improve diagnostic precision and long-term graft outcomes.

Graphical abstract

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Keywords

Antibody-mediated rejection; kidney transplantation; donor-specific antibodies; graft dysfunction

1. Introduction

Kidney transplantation remains the most effective treatment for patients with end-stage renal disease (ESRD), significantly improving survival rates, quality of life, and reduced treatment costs compared with hemodialysis [1]. The introduction of new potent and precise multimodal immunotherapy in recent decades has significantly reduced acute rejection rates and considerably improved 1-year graft survival following renal transplantation. Improvements in graft half-life for both living and deceased donor transplants have also been shown [2]. While graft survival within the first year exceeds 90%, more than 50% of kidney allografts are lost by the 10th year post-transplant [3]. No significant improvement has been noted when it comes to long-term kidney allograft outcomes [4]. Apart from recurrence of the original disease in the graft, antibody-mediated rejection (ABMR) has been the major cause of kidney transplant failure and is considered as one of the major obstacles to long-term outcomes [5]. Patients with ABMR, specifically those with subclinical ABMR, have a 3.5-fold increased risk of graft loss, highlighting its severe impact on outcomes [6].

The clinical presentation of ABMR in kidney transplantation includes a decline in renal function, frequently detected through routine monitoring. Diagnosis is based on a combination of serological, histological and immunopathological criteria defined by the Banff classification. these criteria include, but are not limited to the detection of donor-specific antibodies (DSAs) against HLA or other alloantigens, and histopathological findings on kidney biopsy that show evidence of microvascular inflammation such as glomerulitis (g) and peritubular capillaritis (ptc) [7]. Immunohistochemical staining for C4d in peritubular capillaries indicating complement activation, is also a supportive marker of ABMR. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines highlight the importance of these criteria for diagnosis [8].

Formerly, ABMR following renal transplantation was a devastating occurrence that predictably led to allograft loss. It has been the focus of active research in the field and has led to an increased understanding of the molecular and histologic changes that underlie this humoral type of rejection as well as potential therapeutic interventions. However, there are still several unknown pathways, which help explain the limited effectiveness of some of the currently available therapies used to treat ABMR. This review focuses on ABMR as a central cause of long-term graft failure and explores two main aspects: the immunopathogenic mechanisms underlying ABMR, with special attention to the crosstalk between innate and adaptive immunity, and the current and emerging therapeutic strategies. By connecting fundamental immunology with clinical translation, we aim to provide a comprehensive yet focused synthesis of the latest evidence.

2. Pathophysiology of ABMR

From an immunological perspective, both innate and adaptive immune responses contribute to allograft rejection [9]. While the adaptive immune system has historically been considered the main driver of ABMR pathogenesis, emerging evidence highlights a crucial role for the innate immune system. The innate immune system first recognizes donor antigens, presenting specific epitopes to the adaptive immune system. This process triggers a humoral response, leading to the production of donor-specific antibodies (DSAs), which primarily target donor human leukocyte antigen (HLA) molecules.

DSAs are classified into pre-existing and de novo DSAs. Pre-existing DSAs arise from previous sensitizing events, such as pregnancy, blood transfusion, or prior transplantation and are usually identified during pre-transplant screening with single antigen bead assay (SAB). In contrast, de novo DSAs can emerge at any time post-transplant after the recognition of the alloantigens, such as allo-HLA molecules, by the host immune cells. The development of de novo DSAs is often related to insufficient immunosuppressive therapy or patient non-adherence [10,11]. The likelihood of developing de novo DSAs during the post-transplant phase cannot be accurately estimated or predicted. However, several studies have attempted to identify predictive factors associated with an increased risk of de novo DSAs developing in kidney transplant recipients. Known risk factors include the presence of pre-transplant HLA-specific antibodies, previous transplants, graft inflammation [12], high HLA mismatches, especially at the HLA-DQ locus, inadequate immunosuppression and nonadherence to treatment [13].

Additionally, recent evidence has highlighted a correlation between de novo DSA formation, the Mean Fluorescence Intensity (MFI) of anti-HLA antibodies, and donor-derived cell-free DNA (dd-cfDNA) levels. MFI is commonly used in Luminex assays to estimate the strength of anti-HLA antibodies, while dd-cfDNA is a biomarker of graft injury, reflecting donor-derived DNA fragments released into the recipient’s circulation. This evidence suggests that dd-cfDNA monitoring, especially when combined with DSA testing, could provide a valuable minimally invasive approach for assessing the risk of de novo DSA formation and subsequent graft injury [14]. However, it's important to note that while dd-cfDNA shows promise in predicting early detection of de novo DSA, more research is needed to fully establish its predictive value and optimal use in clinical practice.

Whether the DSAs are pre-existing or de novo, their interaction with alloantigens triggers an immune response that culminates in graft injury and rejection.

2.1 The Role of HLA in Mediating Allograft Rejection

HLA is located on the short arm of chromosome 6 (position 6p21) and is inherited from both parents. It is considered one of the most polymorphic regions of the human genome and this high degree of polymorphism explains the significant variability among individuals [15]. As mentioned above, subtle structural differences between HLA alleles trigger immune responses, underscoring the important role of HLA in the immunopathogenesis of rejection [16].

The HLA gene comprises two principal regions, each encoding a distinct HLA class. Specifically, Class I HLA is expressed on the surface of all nucleated cells, including endothelial cells within the transplanted kidney. It is defined by the loci HLA-A, HLA-B, and HLA-C. The major role of Class I HLA molecules is to present segments of endogenous and other cytoplasmic proteins after they are processed by the proteasome. These peptide-Class I HLA complexes are surveyed by cytotoxic cells, such as CD8+ T cells or natural killer cells (NK cells) [17]. While self-peptides presented by HLA induce inhibitory signals, non-self peptides, such as viral peptides, lead to lymphocyte activation and cytotoxic responses. In contrast, Class II HLA, characterized by the loci HLA-DR, -DQ and -DP, is primarily found on the surface of professional antigen-presenting cells (APCs), including dendritic cells, macrophages and B cells.

One of the major roles of APCs is to recognize and phagocytose exogenous antigens. Within the intracellular environment, these antigens are internalized into endosomal and lysosomal vesicles, which are characterized by a highly acidic environment. This, together with the action of proteolytic enzymes, ensures the degradation of antigens into small peptides. Subsequently, these peptide fragments are loaded onto class II HLA molecules and transported to the cell surface, where the peptide-HLA complex is recognized by CD4+ T lymphocytes in the lymph nodes, initiating and amplifying the adaptive immune response [18].

In kidney transplant recipients, the presence of DSAs together with a pro-inflammatory milieu rich in cytokines (such as IFN-gamma, IFN-γ), may cause upregulation of HLA Class II molecules on donor endothelial cells via the JAK-STAT signaling pathway [19]. This upregulation increases the likelihood of de novo DSA formation, thereby escalating the immune response and promoting a positive feedback loop that contributes to both acute and chronic ABMR [20] (Figure 1).

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Figure 1 Schematic representation of the vicious cycle initiated by DSAs in antibody-mediated rejection. DSAs bind to donor HLA (Class I and II) antigens, triggering complement activation and promoting an inflammatory response. This inflammatory response leads to the recruitment of inflammatory cells, which contribute to endothelial injury. Concurrently, inflammatory cytokines such as IFN-γ induce the up-regulation of HLA Class II expression on endothelial cells, enhancing further DSA binding and perpetuating the cycle. Moreover, the complement activation can cause a direct injury to the endothelial cells.

A primary predictor of allograft rejection in clinical practice is the degree of HLA mismatch between donor and recipient. A higher number of mismatches correlates with a greater risk of de novo DSA production and allograft failure [21]. Beyond HLA mismatch, individual variability in HLA expression also influences the risk of rejection. For instance, certain HLA-DQ alleles, such as HLA-DQ5, are associated with higher expression levels on endothelial cells and a greater risk of microvascular injury. In contrast, alleles like HLA-DQ7 and HLA-DQ8 exhibit lower expression levels and do not appear to increase this risk [22].

Considering this inter-individual and inter-locus variability, the risk of rejection may not solely depend on the presence of an allele mismatch but also on the level of allele expression on graft endothelial cells [22]. Since undetected mismatches or variations in allele expression can contribute to antibody formation and immune activation, pre-transplant compatibility assessments are essential. For instance, living donor transplants increase the likelihood of graft survival by allowing a better screening and selection of potential donors with fewer HLA mismatches, particularly when the donor is a close relative.

2.2 The Role of Non-HLA Antigens in Kidney Transplantation

While HLA molecules remain the principal alloantigens involved in the pathogenesis of kidney allograft rejections, growing evidence highlights the contribution of non-HLA antigens in graft dysfunction and rejection [23,24]. Senev et al. collected the data from a cohort of 935 kidney transplant patients who underwent kidney biopsy. They showed that more than half of the patients met the Banff histological criteria for ABMR, without the presence of circulating HLA-DSA [25]. In a subsequent study from the same group, a more extensive cohort of HLA-DSA negative ABMR cases was tested for the presence in the serum of non-HLA antibodies, including anti-AT1R and anti-MICA. The authors demonstrated a significantly higher prevalence of these antibodies in patients with histological ABMR compared to matched controls without rejection, supporting their potential pathogenic role. These findings suggest that non-HLA DSAs may contribute to the pathogenesis of ABMR in the absence of classical HLA-DSA [23].

The most significant non-HLA antigens are the Minor Histocompatibility Antigens (mHAs). These are polymorphic proteins expressed in the allograft and presented by the recipient’s antigen presenting cells (APC) to naïve T cells, thereby eliciting adaptive immune responses. Even in the presence of HLA compatibility, this interaction may lead to chronic rejection [26,27]. The genetic basis for mHAs is a non-synonymous single nucleotide polymorphism (nsSNPs) which results in mutations in the amino acid sequence of the corresponding protein, leading to variations among individuals. For instance, proteins encoded by the Y chromosome (HY antigens) have been extensively studied as a culprit of rejection in male-to-female transplant [28].

Another critical non-HLA antigen is the MHC class I chain-related protein A (MICA) expressed on endothelial cells. Different studies, including data from a French multicenter cohort study, have shown a correlation between the detection of anti-MICA antibodies and worse graft outcomes. These antibodies are associated with a higher incidence of ABMR and reduced graft survival, even in recipients with no HLA-mismatches at the time of transplantation [29,30]. Importantly, MICA and its homolog MHC class I chain-related protein B (MICB) can interact with the NKG2D receptor expressed on natural killer (NK) cells, potentially triggering NK cell-mediated cytotoxicity against the allograft, further contributing to allograft rejection [31,32].

Furthermore, anti‐endothelial cell antibodies (AECA), first identified in 1980, have been associated with an increased risk of rejection [33,34]. Among these antigens, some examples include antibodies against angiotensin II type 1 receptor (AT1R) and endothelin receptor A (ETAR), both expressed on the surface of endothelial cells. However, not every transplant recipient with positive AT1R and ETAR antibodies experiences allograft dysfunction, suggesting that their pathogenic potential may depend on additional factors, including the degree of ischemia-reperfusion injury [35], the immunologic milieu [36], genetic polymorphisms [37] or antibody titer [38,39]. Therefore, detection of these antibodies may help identify patients at risk of ABMR even in the absence of HLA-DSA, although routine clinical implementation is still lacking.

In summary, despite growing evidence supporting the pathogenic role of non-HLA antibodies, their use in clinical practice remains limited and not routinely incorporated into transplant immunological screening. The findings from Senev et al. and others reinforce the need to reconsider current diagnostic criteria and explore the integration of non-HLA antibody screening, especially in patients with histological evidence of ABMR but no detectable HLA-DSA [23,25]. However, the absence of standardized testing protocols and consensus thresholds for positivity still represents a major barrier to routine clinical implementation. Prospective multicenter studies will be critical to define the true clinical utility of these biomarkers.

2.2.1 HLA and Non-HLA: Pre-Transplant Screening

HLA and non-HLA antibody screening play a critical role in transplant immunology, influencing both pre-transplant compatibility assessments and early risk stratification.

Pre-transplant HLA screening is typically performed through three main approaches: HLA typing, Luminex-based single antigen bead (SAB) assays, and physical or virtual crossmatch.

HLA Typing identifies the recipient's HLA alleles and compares them to the donor's HLA alleles to estimate the risk of mismatch [40].

However, crossmatching is a mandatory pre-transplant test, which determines whether a recipient has pre-existing antibodies against donor HLA or non-HLA molecules. Traditionally, this is done through physical crossmatch, which involves mixing recipient serum with live donor lymphocytes to detect complement-dependent cytotoxicity or flow cytometry-based crossmatch [41], but its main limitation is the need for viable donor cells and the time required to obtain results [42].

To improve sensitivity and specificity, Luminex-based SAB assays have been introduced. These assays detect and quantify DSAs with high resolution by exposing recipient serum to fluorescent beads coated with individual HLA antigens [43]. This approach allows for a more precise characterization of alloimmune risk.

Nevertheless, virtual crossmatch (vXM) has become an essential tool in transplantation, as it allows the evaluation of immunological compatibility between a recipient and a potential donor [44]. This is done by analyzing the recipient’s pre-transplant HLA antibody profile using data from SAB assays and donor HLA typing. vXM enables early risk stratification and helps predict the likelihood of antibody-mediated rejection before transplantation [44]. Unlike traditional physical crossmatch, which requires actual donor cells, vXM facilitates more rapid and efficient organ allocation while minimizing unexpected immunologic incompatibilities and reducing rejection rates [40].

Detection of non-HLA antibody in kidney transplantation can also be performed using both cell-based and solid-phase assays. Early cell-based crossmatch assays use primary endothelial cells, such as Human Umbilical Vein Endothelial Cells (HUVEC) or donor-derived endothelial cells, to screen for antibodies against targets such as AT1R and MICA [45]. In parallel, solid-phase methods, such as ELISAs and Luminex-based assays, provide rapid, high-throughput detection using native antigen preparations. These methods are especially useful for identifying antibodies like anti-AT1R and anti-ETAR [46,47]. Recent advances also include protein microarrays and genome-wide analyses to uncover novel antigenic targets linked to graft outcomes [48,49].

Despite these advancements, limitations remain, particularly in the detection of non-HLA antibodies that may contribute to graft dysfunction. Moreover, the lack of standardized thresholds remains challenges for clinical implementation.

2.2.2 The Role of ABO Antibodies in Kidney Transplantation

Historically considered a major barrier to transplantation, ABO-incompatible (ABOi) kidney transplants have become a viable option over the past few decades, particularly in Asia and Europe, thanks to advances in immunosuppressive protocols and desensitization strategies [50]. ABO incompatibility is caused by the presence of preformed antibodies against A and B antigens, primarily IgM and IgG, which can cause hyperacute rejection through complement activation and rapid graft destruction [51]. These antibodies are produced by B lymphocytes in response to blood group antigens, which are expressed not only on red blood cells but also on endothelial and distal tubular cells of the transplanted kidney [52]. In this context, rejection occurs via complement-mediated cytotoxicity, leading to endothelial damage, thrombosis and rapid allograft necrosis. These mechanisms are similar to those observed with donor-specific anti-HLA antibodies. The main desensitization strategies include plasmapheresis, intravenous immunoglobulins (IVIG), and anti-CD20 monoclonal antibodies, such as rituximab.

A recent study by a Swiss group examined the impact of pre-transplant DSA on the risk of developing ABMR in living donor kidney transplants, comparing ABOi and ABO-compatible (ABOc) recipients [53]. They observed a higher incidence of ABMR in ABOi transplants compared to ABOc transplants; however, this did not significantly affect graft or overall survival, which remained similar between the two groups. Additionally, the presence of pre-transplant DSA was associated with significantly worse long-term outcomes in both ABOi and ABOc living donor kidney transplants. This may suggest that the risk associated with pre-transplant DSA could be comparable, regardless of ABO compatibility [53].

However, ABOi transplantation seems to be associated with an increased risk of infections and thrombotic complications, particularly in the early post-transplant period [51]. The development of novel therapeutic approaches, such as complement inhibitors, could further improve the safety and efficacy of this type of transplant [54,55].

2.3 Alloantigen Recognition and Immune Activation: The Driving Forces of Transplant Immunity

In the absence of prior sensitization to donor antigens, the recognition of non-self-epitopes is initially mediated by the innate immune system, exerting its function through antigen-presenting cells (APCs), including dendritic cells (DCs), macrophages and B cells.

In fact, three different pathways of alloantigen recognition have been identified as contributing to graft rejection. The first pathway known as “direct”, involves donor’s APCs, specifically DCs, which migrate from the graft to the recipient’s lymph nodes. There, they present donor-derived antigens to naïve T cells, notably donor’s HLA. This pathway is predominant in the early post-transplant phase, since donor APCs are short-lived and decline over time [56]. The second pathway, known as “indirect”, relies on recipient-derived APCs, which capture and process donor alloantigens from the graft. These phagocytic APCs degrade the alloantigens into smaller peptides and present them on their own HLA Class II molecules. The alloantigen-HLA complex is then recognized by the recipient’s CD4+ T cells, eliciting an adaptive immune response that become more prominent in the last phase of rejection and is strongly associated with chronic graft injury [57]. Finally, the third pathway also called “semi-direct”, consists of an interaction between recipient and donors APCs which leads to an exchange of part of the donor APCs membrane, including the intact peptide-HLA complex, to the recipients’ APCs. Consequently, recipient APCs can simultaneously present both self- and donor-derived HLA to naïve T cells [58].

In all three pathways, the DCs expressing CC-chemokine receptor 7 (CCR7) migrate to the T-cell zone of lymph nodes. This migration is facilitated by a chemokine concentration gradient consisting of C-C motif 19 and 21 (CCL19 and CCL21), secreted by high endothelial venules (HEVs) and fibroblastic reticular cells [59].

The migration of DCs into the T zone of the lymph node with subsequent alloantigen presentation of HLA II complex to TCR of naïve CD4+ T cells represent the first stimulatory signal for T cell activation. Additional costimulatory signals will follow; the second signal for activation is the interaction of CD80/CD86 expressed on DCs and CD28 on naïve T cells. Finally, a third signal consists of cytokine-driven proliferation and survival, primarily mediated by IL-2 secretion from naïve T cells and CD25 upregulation, culminating in full T-cell activation.

A critical step in ABMR is the differentiation of CD4 T cells into T follicular helper cell (Tfh), a specialized subset of T cells. This differentiation is promoted by a pro-inflammatory environment, mainly consisting in high concentration of IL-6 produced by DCs [60,61] (Figure 2).

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Figure 2 Activation of naïve CD4⁺ T cells and their differentiation into T follicular helper (Tfh) cells. (A) Dendritic cells (DCs) migrate into the lymph node following CCL19/CCL21 gradients through high endothelial venules (HEVs), reaching the T cell zone. There, DCs interact with naïve CD4⁺ T cells, providing three signals: antigen presentation via HLA-II/TCR (signal 1), co-stimulation through CD80/CD86–CD28 (signal 2), and cytokines such as IL-2 (signal 3). (B) Upon activation, T cells are further stimulated by IL-6 and IL-21, which promote Bcl-6 expression and drive commitment to the Tfh lineage. Differentiated Tfh cells upregulate CXCR5, ICOS, and CD40L, enabling migration to the B cell follicles where they interact with B lymphocytes to support germinal center responses.

Tfh are characterized by the expression of CXC-chemokine receptor 5 (CXCR5), B-cell lymphoma 6 (bcl-6) and Inducible T-Cell Co-Stimulator (ICOS), all of which are essential for their survival, differentiation, and germinal center formation [62,63]. Particularly, ICOS is a co-stimulatory molecule belonging to the CD28/B7 family, essential for Tfh cell survival and proliferation; Bcl-6 is a repressor transcriptional factor crucial for the differentiation in Tfh cell and for the germinal center formation [60,64].

Finally, Tfh guided by the CCL13 gradient, which is a CXCR5 ligand, migrate from the T-cell zone to the B-cell follicles, where they interact with B cells [65,66]. This interaction is reinforced by different co-stimulatory signals, such as ICOS-ICOSL and CD40-CD40L interactions, as well as IL-21 signaling.

These exchanges contribute to the formation of germinal centers within the secondary follicles of lymph nodes, where B cells undergo the “germinal center reaction”. This reaction generates memory B cells and plasma cells, but it also enables somatic hypermutation and affinity maturation, ensuring high specificity for donor HLA antigens [67,68]. Long-lived plasma cells migrate to the bone marrow and continuously produce DSAs, while memory B cells persist in secondary lymphoid organs, providing a rapid source of antibody production upon antigen re-exposure [69].

Circulating DSAs bind to donor HLA on graft endothelial cells, activating the classical complement cascade and leading to C4d deposition as well as formation of the membrane attack complex (MAC) formed by C5b-C9 proteins [70]. The MAC causes direct endothelial and parenchymal injury through pore formation, increased membrane permeability and subsequent inflammation [12]. This injury further promotes the release of pro-inflammatory cytokines and the upregulation of adhesion molecules, including ICAM-1, VCAM-1 and E-selectin [71]. These molecules facilitate leukocyte adhesion and infiltration into the graft, thereby amplifying inflammation and driving progressive ischemia and fibrosis [72,73].

Beyond complement activation, DSAs can also cause graft injury through another toxic pathway known as antibody-dependent cell-mediated cytotoxicity (ADCC). In this pathway, the Fc portion of DSAs engages Fcγ receptors on immune effector cells, including NK cells and cytotoxic T cells, triggering endothelial damage even in the absence of C4d deposition [74].

Clinically, ABMR can manifest as either C4d-positive or C4d-negative rejection. While C4d-negative ABMR has been considered less severe, evidence suggests that it is still associated with poor graft outcomes. Orandi et al. [75] compared graft survival in C4d-negative versus C4d-positive ABMR, reporting 1- and 2-year survival rates of 93.4% and 90.2% in the C4d-negative group, versus 86.8% and 82.6% in the C4d-positive group. These findings underscore that both complement- and non-complement-mediated mechanisms substantially contribute to graft injury, highlighting the importance of recognizing and managing all forms of ABMR.

2.4 The Innate Immune System: A Key Player in ABMR

The adaptive immune system is the principal effector in the pathophysiology of ABMR; however, emerging evidence highlights that the innate immune system is actively involved in the rejection process. NK cells, macrophages, the complement system and other innate immune components interact with DSAs to initiate and exacerbate inflammation and cytotoxic cascades that worsen graft injury. Innate immune cells are further recruited into the graft by the increased concentration of C3a and C5a, complement fragments [76]. As described previously, the complement system is a central component of innate immunity that is activated during ABMR, and the classical pathway is activated primarily through the binding of DSAs. In fact, the classical pathway of complement cascade is initiated by the interaction between DSAs and C1q, triggering the activation of the C1r and C1s proteins. The formation of the C3 convertase (C4b2a) and subsequently C5 convertase culminates in the assembly of the membrane attack complex (MAC, C5b-C9), which directly damages endothelial cells and increases vascular permeability [77]. A comprehensive review of the complement cascade and its role in ABMR has been summarized in multiple articles [78,79]. A hallmark of ABMR is C4d deposition, a fragment of C4, in peritubular capillaries detected in the kidney biopsy [80].

Macrophages and monocytes are a critical component of the innate immune response in ABMR. They amplify graft injury by promoting inflammation, tissue damage, and fibrosis [81]. Monocytes originate in the bone marrow from common myeloid progenitors, circulate in the blood and migrate to peripheral tissues in response to inflammation, where they differentiate into resident macrophages. Notably, two main tissue-resident macrophages (TRMs) exist within tissues. The first type, mentioned previously, originates from circulating monocytes, while the second type emerges from the yolk sac progenitors established during embryogenesis, capable of self-renewal and persistence. As a result, the transplanted organ contains both types of cells [82].

After transplantation, both donor TRMs and recipient-derived macrophages coexist within the graft [83]. The role of donor TRMs in transplant outcomes is not yet clear, but different groups are exploring their role in graft rejection. For instance, a recent study by Kopecky et al demonstrated in a murine heart transplant model that donor monocyte-derived CCR2+ macrophages promote inflammation and drive allograft rejection. In contrast, the selective depletion of donor CCR2- macrophages originating from the yolk sac decreases allograft survival. This study also included single-cell analysis, highlighting significant heterogeneity among recipient monocytes, macrophages and dendritic cells [83]. These findings suggest that macrophages may either promote or suppress rejection depending on their phenotype.

In addition to donor macrophages, recipient macrophages expressing Fcγ receptors can interact with the Fc region of DSAs. This interaction stimulates the release of pro-inflammatory cytokines that contribute to the tissue damage within the graft [84].

Distinct macrophage subsets exert distinct roles during various stages of ABMR: pro-inflammatory macrophages (M1) predominate in early stages and release cytokines such as IL-6 and TNF-α. In contrast, M2 macrophages (M2) may play a role in chronic ABMR, promoting fibrosis via TGF-β and IL-10 [85]. The diverse roles of macrophages highlight the need to understand their dynamics in the pathophysiology of transplant rejection.

NK cells are another crucial innate immune population involved in ABMR. Originating from the common lymphoid progenitor in the bone marrow and are released into the lymphatic system. These cells play a remarkable role in the pathogenesis of ABMR [86]. Their involvement is primarily through the interaction between the CD16 (FcγRIII) on their surface and the Fc portion of DSAs bound to donor endothelial cells. This interaction activates NK cells, leading to a subsequent release of granzyme and perforin, causing direct damage to endothelial cells. This process is known as antibody-dependent cellular cytotoxicity (ADCC) [87]. NK cells also produce large amounts of interferon-gamma (IFN-γ), further activating macrophages and endothelial cells. This process intensifies the inflammatory response and exacerbates tissue damage within the graft.

In addition, numerous studies have emphasized the involvement of NK cells and macrophages in the pathophysiology of kidney rejection, demonstrated the increased infiltration in peritubular capillaries in both C4d-positive and C4d-negative ABMR lesions [88]. Notably, in C4d-negative ABMR, where complement activation is absent, NK cell-mediated cytotoxicity still represents a major mechanism of endothelial damage [89]. All this evidence should encourage researchers to focus more on the role of NK cells in the pathophysiology of rejection, with the aim of using these cells as a therapeutic target [90].

2.5 Role of Ischemia-Reperfusion Injury (IRI) and DAMP Expression

Ischemia-reperfusion injury (IRI) significantly contributes to delayed graft function (DGF), acute rejection, and chronic graft dysfunction [91]. Following the donor’s death, particularly in cases of cardiac arrest (donation after cardiac death - DCD), hemodynamic instability reduces renal perfusion, triggering complement activation and innate immune responses. This injury is exacerbated during kidney retrieval, as clamping the renal artery induces significant ischemia. Following retrieval, the organ undergoes a storage period known as “cold ischemia”, during which it is usually preserved on ice. While this method extends the organ’s viability, it can also cause additional damage, increasing DGF rates [92].

Various endogenous molecules, released or exposed by stressed or dying cells during IRI, have been implicated in the pathophysiology of kidney rejection [93]. These molecules, known as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), are recognized by pattern recognition receptors (PRRs) like TLRs, expressed on innate immune cells [94,95]. The interaction between DAMPs and PRRs trigger pro-inflammatory responses and endothelial activation [96]. In recent years, several DAMPs have been identified as key drivers of immune activation leading to graft rejection [93]. Well-characterized DAMPs include heat-Shock protein (HSP), high-mobility group box 1 (HMGB-1) and ATP [56,97]. Injured cells can also release mitochondrial components such as mitochondrial DNA and N-formyl peptides, which mimic bacterial signals and activate immune responses [98,99]. Additionally, during IRI, components of the extracellular matrix – such as hyaluronate and heparan sulfate – can break down into smaller fragments, acting as potent extracellular DAMPs, further promoting activation of the innate immune system [97].

In recent decades, the rising demand for kidney transplantation, coupled with a limited supply of available organs, has prompted clinicians to explore strategies for increasing the donor pool [100]. This includes broadening donor criteria to include extended criteria donors (ECD) and DCD donors [101]. However, these donor categories, particularly DCD donors who experience more severe ischemia, are associated with increased risk of DGF and subsequent rejection [102,103].

Although preventing cold ischemia-induced damage is important to reduce the likelihood of rejection, further attention should be directed to reperfusion damage [93,97]. Indeed, once recipient vasculature is connected to graft renal artery, reperfusion typically induces pro-inflammatory genes upregulation [103]. These pathways are mediated by an enhanced expression of transcription factors such as Nuclear Factor Kappa B (NF-κB) and Toll-like receptors (TLRs) [104]. In addition, multiple mechanisms including apoptosis, necroptosis, autophagy, microvascular dysfunction, and transcriptional reprogramming can cause additional damage to the kidney [105,106]. This results in the activation of both the innate and adaptive immune systems characterized by inflammatory cell infiltration and heightened immune activation [92].

The introduction of kidney machine perfusion techniques, which allow organ perfusion prior to implantation, has contributed to reducing the risk of DGF and subsequent immune activation [107]. A recent meta-analysis comparing different perfusion techniques highlighted a significant reduction in DGF rates when hypothermic machine perfusion (HMP) was used instead of static cold storage (SCS) [108]. Nevertheless, no significant differences were observed between HMP and oxygenated HMP (HMP + O2). Regarding rejection rates, no substantial differences were observed between SCS and HMP; however, HMP + O2 appears to be associated with a reduction in acute rejection episodes, as confirmed by histological analysis kidney biopsies [108].

In conclusion, the interplay between DAMPs, PRRs, and innate immune cells represents a pivotal mechanism driving IRI-induced injury.

2.6 Immunoregulation in Kidney Transplantation: A Matter of Tolerance

The immunoregulatory system is a key component of immunity that maintains a balance between immune activation and suppression, ultimately promoting immunotolerance. In ABMR, this serves as a crucial mechanism to foster tolerance and mitigate harmful stimuli. The main protagonists of the immunoregulatory response are regulatory macrophages (Mregs) and regulatory T cells (Tregs). Together, they work to minimize tissue damage and regulate the immune response, with the ultimate goal of preserving graft function and enhancing long-term graft survival [109].

2.6.1 Regulatory T Cells (Tregs)

Tregs are a specialized subset of CD4+ T cells that play a crucial role in maintaining immunotolerance in transplantation. The concept of immunotolerance was introduced in 1970, when Gershon and Kondo demonstrated that exposing immune cells to a non-self-antigen could induce immune tolerance [110]. This mechanism was not initially attributed to a specific subpopulation; however, it introduced the concept of immune tolerance. In 1995, Sakaguchi et al. first identified CD4+ CD25+ cells and demonstrated that depleting CD25 (the α-chain of IL-2 receptor) and transferring them into mice could spontaneously induce autoimmune diseases [111]. Less than a decade later, in 2003, two independent research groups described forkhead box P3 (FOXP3) expression in CD4+ CD25+ T cells and elucidated its role in immunoregulation [112,113]. FOXP3 was found to be a critical transcription factor for Treg function, along with another transcription factor, Helios, which is essential for maintaining their immunoregulatory activity [114].

Tregs modulate immune responses through various mechanisms, including the secretion of immunoregulatory cytokines such as IL-10, IL-35 and TGF-β, direct cell-to-cell interactions, and the up-regulation of inhibitory receptors like cytotoxic T-lymphocyte associated antigen-4 (CTLA-4). The interaction between CTLA-4 and CD80/CD86 on APCs stimulate the production of indoleamine-2,3-dioxygenase (IDO), which inhibits T cell activation and proliferation, thereby reducing effector T cell activity and limiting B cell responses [115]. Additionally, activated Tregs release cytolytic enzymes, such as perforin and granzymes A and B, which target effector T cells, inducing cytotoxicity and apoptosis [116].

Finally, Tregs can suppress T follicular helper (Tfh) cells, thereby limiting their ability to activate B cells. However, upon TCR activation, Tregs up-regulate CXCR5, enabling their migration to the border between T and B cell zones, as well as into germinal centers (GCs), guided by the high concentration of CXCL13. Simultaneously, they downregulate CCR7, which typically retains cells in the T-cell zone. In this region, they can interact directly with and inhibit B cells [117] (Figure 3).

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Figure 3 (A-B) The role of Tregs in immune regulation within the lymph node. (A) Representation of the lymph node microenvironment. The left side shows the T cell zone, where naïve T cells interact with dendritic cells (DCs), and Tregs are present. The right side shows the immune regulation, where Tregs inhibit naïve T cell activation via CTLA-4/CD86 interaction, the production of indoleamine 2,3-dioxygenase (IDO), and the secretion of immunosuppressive factors such as IL-10 and TGF-β. (B) Interactions of Tregs in the T-B border. The left side highlights Tregs’ cytotoxic effect on naïve T cells through granzyme B release, inducing apoptosis. The right side shows Tregs migrating to the B cell zone, driven by CXCL13, and inhibiting B cell differentiation into plasma cells through regulatory cytokines (IL-10, TGF-β) and CTLA-4/CD86 signaling.

While CD4+ Tregs are the most extensively studied regulatory T-cell population, recent years have seen growing scientific interest in the role of the CD8+ Treg subset in autoimmune diseases and kidney transplant tolerance. This population has been well-characterized in mice since the early 2000s. CD8+ Tregs are distinguished by high expression of CD122 (also known as IL-2 receptor β chain, IL-2Rβ) and inhibitory Ly49 receptor (Ly49A, Ly49 C/I, Ly49F, Ly49G). The human equivalent of Ly49 is the killer cell immunoglobulin-like receptor (KIR) gene.

Unlike CD4+ Tregs, CD8+ Tregs express FOXP3 only under inducible conditions but exhibit constitutive expression of Helios. Over the past two decades, numerous studies have highlighted the critical role of Helios in maintaining the immune homeostasis. A defect in this transcription factor can disrupt tolerance, leading to the development of autoimmune diseases [114].

Similar to CD4+ Tregs, CD8+ Tregs exert their functions through by secreting cytotoxic molecules such as perforin, which targets and kills alloreactive CD4+ T cells and Tfh cells [118].

In recent years, a subset of CD8+ Tregs has been identified that specifically recognizes a particular type of MHC class Ib molecule, Qa-1 in mice and HLA-E in humans, expressed on CD4+ effector T cells. Research by Hye-Jung Kim and colleagues has demonstrated the crucial role of this interaction in maintaining immunotolerance. In fact, blocking the interaction between these two cell populations resulted in the development of a severe systemic lupus erythematosus–like autoimmune disease, highlighting its essential role in immune regulation [119].

Another important discovery, observed in a murine heart transplant model, emphasizes the interaction between Qa-1-restricted CD8+ Tregs and CD4+ Tfh cells. This interaction is linked to the suppression of the Tfh cell activity, which in turn suppresses B cell function and the production of DSAs, ultimately reducing the risk of ABMR [120].

These findings have motivated researchers to explore therapeutic strategies aimed at enhancing Treg function in solid organ transplantation, reducing the incidence of ABMR and improving allograft survival.

Emerging technologies, such as cell therapies currently applied in onco-hematology, are increasingly being explored for potential applications in different medical fields, including autoimmune diseases and transplantation. Recent studies have reported promising results on the use of CD19-targeting CAR-T cells in autoimmune diseases, such as systemic lupus erythematosus (SLE), demonstrating their ability to deplete pathogenic B cells and reduce autoantibody production [121]. Given the critical role of B cells and donor-specific antibodies in ABMR, CD19 CAR-T cell therapy could similarly modulate the alloimmune response, potentially mitigating ABMR and improving graft survival. Moreover, the development of alternative and more effective therapeutic strategies could enable a reduction in conventional immunosuppressive treatments, minimizing their associated adverse effects.

2.6.2 Regulatory Macrophages

A specialized subset of cells contributing to the immune regulation are the regulatory macrophages (Mregs). These cells exert their functions by the secretion of cytokines such as interleukin-10 (IL-10) and TGF-β which play a crucial role in promoting immune tolerance and facilitating tissue repair [109,122]. An interesting feature emerges when Mregs are activated by IFN-γ: in this context, they release TGF-β, which inhibits T-cell proliferation and promotes the expansion of Tregs. In addition, Mregs can induce the expression of T-cell immunoreceptors with Ig and ITIM domains (TIGIT) on CD4+ T cells. These TIGIT+ CD4+ T cells can suppress effector T cells and inhibit dendritic cell maturation, thereby enhancing immune regulation [123].

Over the past few decades, Mregs have been subject to various clinical trials investigating their role in immune tolerance induction in kidney transplantation. In the Transplant Acceptance-Inducing Cell trial I (TAIC I) trial [124], Hutchinson et al. investigated the use of donor-derived TAICs, a type of immunoregulatory macrophage, in kidney transplant recipients. Although the trial primarily focused on tapering immunosuppressive therapy and acute cellular rejection, it provided insight into the ability of regulatory macrophages to modulate alloimmune responses. While these results highlight the potential of Mregs in immune regulation, their specific role in preventing ABMR remains unclear. Further research is needed to determine whether Mreg-based therapies can reduce the incidence or the severity of ABMR.

3. Clinical Presentation and Diagnosis of ABMR

The clinical presentation of ABMR is associated with a deterioration in kidney function, often evidenced by a rise in serum creatinine levels. This can occur acutely or chronically. Symptoms may be nonspecific, including malaise, fever, or graft tenderness, but many cases are asymptomatic and detected through routine monitoring [8].

An early detection of kidney allograft dysfunction, and a timely diagnosis of ABMR is crucial, as ABMR can result in irreversible damage to the allograft if not properly managed with full functional recovery [4]. Kidney transplant recipients should be monitored with signs of ABMR with a frequency that balances early detection and clinical pragmatism. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend frequent monitoring in the early post-transplant period, with visits 2-3 times per week during the first month, every 1-3 weeks during months 2-3, every 4-8 weeks during months 4-12, and every 2-4 months after the first year [125]. This schedule allows for the early detection of graft dysfunction and the presence of de novo DSAs, which are critical for detecting ABMR. For high-risk patients, with preexisting DSAs or those who develop de novo DSAs, protocol biopsies are recommended within the first-year post-transplant to detect subclinical ABMR [126].

The gold standard for diagnosis of kidney allograft rejection or lack thereof is based on kidney pathology acquired through allograft biopsies and relies on the Banff classification to segregate the findings [127].

The Banff classification is a standardized framework that classifies and rates kidney transplant rejection depending on histological features. It was created in 1991 and has since been updated numerous times to improve its precision and clinical applicability [128], with the last Banff meeting taking place in 2022 [80].

This classification divides antibody-mediated rejection into acute antibody-mediated rejection (aABMR), chronic active antibody-mediated rejection (caABMR), and chronic (inactive) antibody-mediated rejection (cABMR). Nevertheless, patients often manifest multiple types of rejection concomitantly. Several acute and chronic histological findings are taken into consideration in this classification to confirm rejection.

In acute rejection, modifications of this form of rejection include i for interstitial inflammation, t for tubulitis, v for arteritis, g for glomerulitis, PTC for peritubular capillary inflammation and c4d representing complement 4d product [7,127]; whereas, chronic rejection variations are ct for tubular atrophy, ci for interstitial fibrosis, cv for arteriolopathy, cg for chronic glomerulopathy (or transplant glomerulopathy), and peritubular capillary basement membrane thickening [127].

Light microscopy is generally used to diagnose the majority of these changes, however, c4d, which is a histologic indicator of complement activation, can be diagnosed through either immunofluorescence or immunohistochemistry, making it a unique histological component [127]. Also, electron microscopy helps in depicting peritubular capillary basement membrane thickening [128,129].

For each variation, a grade ranging from 0 to 3 is given, and the degree of rejection is established on the gravity of one or a combination of the findings above [127].

There are three criteria that should be met to diagnose aABMR (Figure 4) [127,130]. caABMR is a pathological process resulting from continuous antibody-mediated damage, which causes chronic harm to endothelial cells and remodeling of the allograft matrix [131]. In addition to the same diagnostic criteria of aABMR, in caABMR, there is also chronic changes of cg, peritubular capillary basement membrane thickening, or chronic thickening of the arteriolar intima cv. In chronic (inactive) caABMR, we find these similar chronic changes without the presence of active inflammation. During the 2022 Banff meeting, two supplemental ABMR subtypes were added to the profiles cited in the table, which are: probable ABMR marked by circulating DSA and individual microvascular inflammation (MVI) lesions that do not meet the histological threshold for MVI (g + ptc < 2) and which doesn’t require treatment unless in certain situations such as high-risk crossmatch positive transplants which aren’t correlated yet with significant MVI superior to the threshold, or if there is a rapid deterioration of kidney function among patients with de novo HLA-DSA [7]; and MVI which exceeds the histological threshold but is deficient of circulating DSA and shows negative C4d staining in the peritubular capillaries. Also, during this meeting new diagnostic techniques relying on computerized reporting algorithms were presented [80]. These systems insert “raw” histological and other data into a software program which then generates classifications based on Banff guidelines or alternative algorithms. Among these presentations, the “Software-assisted sign out” (SAS) designed at Pittsburgh, the Banff automation system from the Paris Transplant Institute [132], and machine-learning classifiers designed to analyze kidney graft scores in conjunction with clinical data [133].

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Figure 4 Diagnostic criteria for active ABMR (all 3 criteria must be met) [127,130].

4. Treatment

Management strategies for both clinical and subclinical forms of ABMR differ across transplant centers and often involve a combination of treatments such as high-dose steroids, plasmapheresis, and intravenous immunoglobulin (IVIG). However, the use of additional therapies varies widely. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines, as cited by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative, suggest plasmapheresis, IVIG and Rituximab as therapeutic options, but only with a weak recommendation (2C), reflecting the low level of evidence and reliance on expert consensus rather than high-quality randomized data [125]. A 2018 systematic review highlighted that, despite limited evidence, plasmapheresis and IVIG have become standard treatments for ABMR. Rituximab has been deemed ineffective, and the roles of bortezomib and complement inhibitors remain uncertain [134].

Additionally, the timing and presence of chronic changes in ABMR play a critical role in determining the course of treatment (Table 1). Notably, plasmapheresis, while occasionally utilized, does not directly address the root cause of ABMR and should be used judiciously [135].

Table 1 Therapeutic options in acute and late ABMR based on the 2019 consensus [135].

In addition to the standard therapeutic options, other, less used, alternatives exist. We cite the ones below.

4.1 Complement Inhibitors

The activation of the classical complement pathway plays a critical role in the downstream effects of DSA and is a key contributor to the manifestations of ABMR [136]. Complement inhibitors, such as Eculizumab, a monoclonal antibody targeting complement protein C5 activation, and complement 1 esterase inhibitors (C1 INHs), have been employed for the treatment of ABMR with varying levels of success. This molecule can cause a variety of side effects, including infection with encapsulated bacteria (ie. Streptococcus pneumonia, Neisseria meningitidis, Haemophilus influenza etc.) [54]. Therefore, vaccination against these pathogens and/or prophylactic antibiotics are required before treatment initiation. Eculizumab showed success when treating grave or refractory cases of ABMR in HLA- or ABO-incompatible kidney transplants [137,138,139,140]. However, it is not routinely used in the treatment of ABMR.

4.2 Proteasome Inhibitors

An example of proteasome inhibitors originally used to treat multiple myeloma is Bortezomib. This molecule has also been utilized in the management of ABMR, particularly due to its ability to target protein synthesis rate which is characteristic of plasma cells and leading to their apoptosis [141]. Since its use in 2008, several case reports and retrospective studies have demonstrated Bortezomib’s efficacy in treating ABMR, especially in conjunction with other treatment options [17,142,143,144,145]. However, the BORTEJECT trial which is the sole study assessing Bortezomib's potential to prevent GFR decline in late DSA-positive ABMR among kidney transplant recipients, revealed no significant improvement in the eGFR slope, two-year graft survival, urinary protein levels, DSA concentrations, or rejection phenotypes compared to placebo. Additionally, Bortezomib was linked to notable gastrointestinal and hematologic toxicities [146].

4.3 Splenectomy

This surgical procedure is considered a rescue intervention when cases are refractory to plasmapheresis and/or IVIG. In fact, a case series of four patients with severe refractory ABMR showed improvement of urine output and a decrease of creatinine 48 hours following laparoscopic splenectomy [147]. However, this technique is not yet routinely recommended for the treatment of ABMR [135].

5. Novel Emerging Therapies

5.1 Carfilzomib

Carfilzomib is a second-generation irreversible proteasome inhibitor with a comparable mode of action to Bortezomib. This molecule was tested on six animal kidney transplant recipients along with Belatacept as a desensitizing agent. These two agents demonstrated a notably extended survival of the graft and decreased ABMR scores on kidney biopsy at 1 month. However, a progressive rebound of DSA and ABMR were then noticed in four of five animals with long-term graft survival [148]. Carfilzomib has only been used in the management of ABMR in patients with lung and heart transplants and showed promising outcomes [149,150]. No data exists yet for its use in treating ABMR in human kidney transplant recipients. Nevertheless, clinical trials in organ transplantation (CTOT-42) are ongoing to study the efficacy of Carfilzomib in the management of chronic active ABMR. Finally, some of the reported adverse events included fatigue, diarrhea, mild peripheral neuropathy, cytopenias such as thrombocytopenia and neutropenia, as well as both viral and bacterial infections. In some cases, septic shock led to fatal outcomes [151].

5.2 Interleukin-6 Antagonist Treatments

Interleukin-6 (IL-6) is an inflammatory cytokine with an established role in B-cell and T-cell stimulation, multiplication and function. Moreover, IL-6 has been identified as a critical component in key signaling pathways linked to rejection in transplant patients [152]. Many molecules have been developed that target either IL-6 or its receptor; from these molecules, we mention the ones below.

5.2.1 Tocilizumab

Tocilizumab is the pioneering recombinant humanized monoclonal antibody designed to target the interleukin-6 receptor (IL-6R). It is FDA-approved for the management of rheumatoid arthritis and juvenile idiopathic arthritis [151]. In kidney transplant, Tocilizumab has been used, alongside IVIG, as a desensitizing agent in a phase I/II trial and showed efficacy and safety in decreasing DSA levels and prohibiting the development of ABMR [153]. Not many published studies evaluating the use of Tocilizumab in acute ABMR exist; however, Pottebaum et al. examined using both Tocilizumab and standard therapy for acute ABMR in seven kidney transplant patients. The authors noticed either a stabilization or improvement in kidney function, along with a reduction of DSA concentrations by ≥50% observed in four patients. However, when Tocilizumab was administered for less than six months, many patients had recurrent rejection [154]. On the other hand, in chronic active ABMR, Tocilizumab has been broadly studied in multiple studies with encouraging outcomes [155,156]. In the most recent study published in 2021 by Noble et al., the authors conducted a retrospective study in 40 kidney transplant patients receiving Tocilizumab monthly for the management of chronic active ABMR. After 12 months of follow-up, there was no evidence of clinical or histological deterioration, except in patients who presented with more advanced clinical severity at the start of treatment [157]. In contrast, conflicting results were published by Kumar et al. regarding Tocilizumab’s safety and efficacy in 10 kidney transplant recipients with chronic active ABMR. Tocilizumab was given with a median of five doses. At a median 12-month follow-up, no improvements were observed in renal function, the trajectory of eGFR decline, or histological findings on protocol biopsies. In addition, one patient passed away due to a complicated hip infection [158].

5.2.2 Clazakizumab

Clazakizumab is a genetically engineered humanized monoclonal IgG1 antibody with high affinity for IL-6 [159]. Its use remains under careful investigation and has also been explored in conditions such as rheumatoid and psoriatic arthritis.

In a phase 2 single-center open-label study, Clazakizumab was given monthly to 10 kidney transplant recipients with refractory active ABMR for 12 months. The treatment demonstrated a trend toward stabilizing eGFR, lowering DSA titers, and reducing graft inflammation [160]. These findings have led to the initiation of a large phase 3 placebo-controlled clinical trial (IMAGINE), currently recruiting participants from North America, Europe, Asia, and Australia.

Additionally, Doberer et al. conducted a pilot randomized controlled trial to assess the safety and efficacy of Clazakizumab in late ABMR. In part A of the study, 20 kidney transplant recipients with positive DSA at least one year post-transplant were randomized to receive Clazakizumab or a placebo weekly for 12 weeks. Clazakizumab demonstrated a slower decline in eGFR and significantly reduced DSA titers compared to the placebo group. In part B, where all patients received Clazakizumab for an additional 40 weeks, the eGFR decline rate improved further. However, 25% of participants experienced serious adverse events, including diverticulitis, pleural effusions, and acute kidney injury [161].

Finally, Sitluximab and Sirukumab are additional interleukin-6 inhibitors that haven’t yet been evaluated in kidney transplantation [162,163].

5.2.3 Daratumumab

Daratumumab is a human immunoglobulin G1K monoclonal antibody. It is the first human-specific therapy in its class to target CD38-expressing plasma cells. This FDA-approved antibody is used for the treatment of newly diagnosed or relapsed/refractory multiple myeloma [151]. Its immunomodulatory effects are mediated through several Fc-dependent immune effector mechanisms, including antibody-dependent cellular phagocytosis, antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and direct cellular apoptosis [164].

Notably, Daratumumab can interfere with cross-matching and red blood cell (RBC) antibody screening by binding to CD38 on RBCs, leading to a positive indirect Coombs test. Another key consideration is the potential for resistance during therapy, often attributed to complement-inhibitory proteins, such as CD55 and CD59, or the development of antidrug antibodies [165].

Kwun et al. investigated the use of Daratumumab as a desensitizing agent in a sensitized nonhuman primate model and in two clinical cases of combined heart–kidney transplantation for managing ABMR. The study demonstrated a significant reduction in DSA titers in both the animal model and clinical cases when Daratumumab was used for desensitization and ABMR management. However, in the nonhuman primate model, this reduction in DSA titers was not sustained, as all recipients experienced a rapid rebound of antibodies [166]. Additionally, numerous recent case reports have showed hopeful outcomes of Daratumumab in managing ABMR. One example is a case report published by Spica et al. in which Daratumumab was administered as a rescue therapy, after standard therapy failed, to a patient with ABO-incompatible kidney transplant and refractory ABMR. The blood group antibody concentration was reduced and sustained at low levels, facilitating the recovery of graft function [167]. To date, more than 304 clinical trials are being conducted to evaluate Daratumumab’s efficacy in numerous pathological conditions, one of which is its use as a desensitizing agent in kidney transplant [151].

Finally, Isatuximab is another example of a CD-38 inhibitor, approved for the management of multiple myeloma, but has not been tested yet in kidney transplant recipients [168].

5.2.4 Belimumab

Belimumab is a humanized IgG1 monoclonal antibody targeting B lymphocyte stimulator (BLyS). BLyS, also referred to as B-cell activating factor (BAFF), is a tumor necrosis factor (TNF) family cytokine that supports B-cell maturation, survival, and activation. Excessive BLyS expression is linked to autoimmunity. In kidney transplant recipients, elevated serum BLyS levels have been correlated with the development of de novo donor-specific antibodies (DSA) and an increased risk of antibody-mediated rejection (ABMR) [169,170]. Belimumab is FDA approved for the treatment of systemic lupus erythematosus and has been used in the management of lupus nephritis with proven efficacy [171]. Despite its use in lupus nephritis, Belimumab has not been widely investigated in the management of active ABMR. A case report described the use of Belimumab in a combined kidney–pancreas transplant recipient experiencing mixed rejection of the kidney allograft. Despite conventional treatments with TPE, Rituximab, and IVIG, persistent DSA and inflammation were observed. Belimumab administration resulted in a reduction of class II DSA levels and an improvement in graft function [172]. On the contrary, in a phase 2 randomized controlled trial, Belimumab was evaluated for the prevention of ABMR [173]. In this trial, 28 kidney transplant recipients were divided into 2 groups receiving either Belimumab or placebo, in addition to the conventional immunosuppressive drugs Basilixmab, mycophenolate, prednisone and tacrolimus. In conclusion, when combined to the standard therapy, Belimumab is effective and did not pose a higher risk of infection compared to the placebo.

5.2.5 Imlifidase

Imlifidase is an innovative recombinant cysteine protease produced by Streptococcus pyogenes that fragments human IgG antibodies at the lower hinge region of their heavy chains. This breaking disrupts complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, impairs B-cell receptor function, and reduces natural killer (NK) cell activity [174]. This molecule was initially studied and continues to be investigated in ongoing research as a component of desensitization protocols [175]. Imlifidase shows promise as an innovative treatment option for managing ABMR. However, its use may be constrained by the risk of antibody rebound, including anti-imlifidase antibodies, DSAs, and total IgG levels. While our understanding of these risks remains limited, they may be mitigated by administering anti-CD20 antibodies and/or IVIg. Additionally, several significant drug interactions must be considered. Since imlifidase cleaves IgG antibodies, co-administered antibody-based therapies could be affected. To preserve the efficacy of concurrent treatments, it is recommended to separate the administration of IVIG by 12 hours, Rituximab, Basiliximab, rabbit antithymocyte globulin, and Alemtuzumab by 4 days, and Belatacept by 1 week [174].

In summary, while targeting IL-6 seems like a promising novel therapeutic option, recent studies have shown limited efficacy and disappointing results, particularly for Clazakizumab. While these molecules remain in clinical development, they will not be in routine practice for the management of ABMR in the foreseeable future. It is finally important to note that, given Tocilizumab’s proven nephroprotective effects in auto-immune kidney disease such as patients with ANCA vasculitis and glomerulonephritis with or without underlying rheumatoid arthritis and Tofacitinib’s high immunosuppressive efficacy, these anti-IL-6 therapies could be considered an alternative for the highly nephrotoxic calcineurin inhibitors [176].

5.3 Novel CD-20 Therapies

Rituximab, among the anti-CD20 antibody therapies, is a widely recognized treatment in solid organ transplantation and is frequently incorporated into contemporary strategies for managing ABMR in kidney transplant recipients. Currently, several studies have been published evaluating the effectiveness of other anti-CD20 monoclonal antibodies in treating antibody-mediated diseases. One example is Ofatumumab, a substitute anti-CD20 therapy approved for managing relapsing multiple sclerosis. In a published case report, this drug was given to a sensitized combined heart-kidney transplant patient along with TPE, IVIG and Tocilizumab as a desensitizing protocol. The patient did not exhibit rejection one year after the transplant with adequate kidney and heart allograft performance [177]. Additionally, Obinutuzumab, a glyco-engineered type II anti-CD20 monoclonal antibody, has demonstrated enhanced B-cell depletion compared to Rituximab, a type I anti-CD20 antibody. In the phase 1 THEORY trial, Obinutuzumab showed potential for B-cell depletion in desensitization protocols for highly sensitized kidney transplant candidates. However, its impact on reducing anti-HLA antibodies has been unreliable [178]. Finally, Inebilizumab is a therapeutic agent targeting CD19 expressed on B cells, leading to their depletion. An attempt to study this molecule in highly sensitized patients awaiting first or second kidney transplants failed due to insufficient participant recruitment in the study [179].

5.4 Adjustment of Immunosuppressive Regimens in ABMR

The addition of therapies targeting antibody-mediated rejection (AMR), such as plasmapheresis, intravenous immunoglobulin, anti-CD20 antibodies, or proteasome inhibitors, to standard immunosuppression increases the cumulative risk of infection and malignancy, particularly in the context of already potent maintenance regimens [85,180,181,182]. This risk is especially pronounced in patients with prior exposure to lymphocyte-depleting agents or those with comorbidities. Therefore, individualized adjustment of immunosuppressive protocols is necessary to balance the efficacy of AMR treatment with the minimization of adverse effects [182,183]. One of the adopted approaches is the minimization, withdrawal, or substitution of calcineurin inhibitors (CNIs), all while considering the increased risk of acute rejection [184,185]. Practically, protocol modifications in response to AMR may include switching from azathioprine to mycophenolate mofetil (MMF), from MMF to Sirolimus, or from Cyclosporine to Tacrolimus, as well as increasing the dose of MMF or corticosteroids [180,182]. In patients with infection, malignancy, or post-transplant lymphoproliferative disorder, immunosuppression is often reduced or modified, with mammalian target of rapamycin (mTOR) inhibitors-based regimens considered in certain malignancy scenarios and CNI minimization or withdrawal in the setting of viral-driven lymphoproliferative disease [182,183,186].

Finally, while several fundamental features that define antibody-mediated rejection are shared between the Banff and KDIGO frameworks, important differences remain in their diagnostic and therapeutic emphasis. This is highlighted in Table 2.

Table 2 Summary Table comparing KDIGO and Banff Guidelines on ABMR.

6. Limitations

Our review provides a comprehensive overview of the current understanding of ABMR in kidney transplantation, yet several limitations must be acknowledged. First, while the pathophysiology of ABMR is increasingly understood, many mechanistic insights remain based on preclinical models or limited patient cohorts, which may not capture the full heterogeneity of clinical presentations. Additionally, diagnostic criteria continue to evolve, and while the Banff classification provides a structured framework, its reliance on histopathology and DSA detection may result in diagnostic ambiguity, especially in borderline or mixed rejection phenotypes. Also, treatment recommendations, both standard and emerging, are largely informed by small-scale studies or expert consensus, with a relative scarcity of large randomized controlled trials (RCTs) directly comparing therapeutic strategies. Finally, the rapidly evolving landscape of novel immunomodulatory therapies introduces both promise and uncertainty, as long-term safety and efficacy data remain limited. These factors underscore the need for ongoing research, collaborative registries, and more robust clinical trials to refine the management of ABMR and improve transplant outcomes.

7. Conclusion

ABMR in clinical practice is a complex process with a wide gray zone area. The histologic criteria, primarily guided by the Banff classification, have played an invaluable role in standardizing the diagnosis of ABMR. Evidence underscores the significant role of DSA in both acute and chronic ABMR. However, histologic assessment of biopsy samples has low specificity and high interobserver variability, moreover, not all DSA detected by current assays cause injury to the allograft and ABMR can often come with undetectable DSAs. Likewise, C4d has significant limitations as a marker of ABMR. It also remains unclear which combination therapy is the most effective all while considering drug toxicity. While much progress has been made in advancing our understanding, research attempts are ongoing to resolve the ambiguous events and to define risk stratification strategies for ABMR phenotypes to guide prevention and therapy. Modern tools to improve diagnosis, especially when facing increasingly complex phenotypes must be available moving forward. Reliable biomarkers for diagnosis and prognosis as well as prediction models have shown promising findings however, there remains significant potential for further optimization and improvement.

Author Contributions

LMS and MD contributed equally to writing the review and would like to share first co-authorship. LMS, MD and TM wrote the manuscript under the supervision of JA and JC.

Funding

The authors received no financial support for the research, authorship and publication of this article.

Competing Interests

The author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest.

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