In Focus
The impact of antibodies against human neutrophil antigens in kidney transplant rejection
The potential of anti-HNA-3 antibodies to cause graft damage
Kidney transplantation is a life-saving procedure for patients with end-stage renal disease, but the success of the transplant is often challenged by immune-mediated rejection.
While the role of Human Leukocyte Antigen (HLA) antibodies in antibody-mediated rejection (ABMR) is well-established, emerging evidence highlights the significance of non-HLA antibodies, particularly those targeting Human Neutrophil Antigens (HNA), in graft dysfunction and rejection. Among these, anti-HNA-3 antibodies have garnered attention due to their potential to cause severe complications, including acute and chronic rejection, even in the absence of HLA donor-specific antibodies (DSA). This text explores the importance of anti-HNA antibodies in kidney transplantation, drawing on recent research to elucidate their role in rejection mechanisms, clinical outcomes, and potential strategies for management.
The Role of Non-HLA Antibodies in Kidney Transplantation
A range of non-HLA proteins have been documented as potential targets for antibodies in solid organ transplantation. Not all of these proteins are expressed on the surface of leucocytes and, therefore, may remain undetected in standard crossmatch assays used in transplantation. They can be identified in some cases using endothelial cell crossmatch techniques and solid-phase assays. Some of these proteins are expressed on leucocytes and may lead to an unexplained positive crossmatch in patients without detectable HLA-DSA. A notable example is the HNA-3 system, which has been implicated in ABMR. HNA-3 is a bi-allelic system encoded by the SLC44A2 gene (CTL2 protein), with two variants, HNA-3a and HNA-3b, expressed on neutrophils, lymphocytes, platelets, and endothelial cells, including those in the kidney. This expression makes it a potential target for immune-mediated damage in transplant recipients (Figure 1).
Anti-HNA-3 Antibodies and Rejection Mechanisms
Anti-HNA-3 antibodies are primarily formed through alloimmunization, often occurring during pregnancy, blood transfusion, or previous transplantation. These antibodies have been associated with severe complications, including transfusion-related acute lung injury (TRALI) and neonatal alloimmune neutropenia. In TRALI, the interaction of donor-derived anti-HNA-3a IgG antibodies with circulating neutrophils and pulmonary endothelial cells expressing HNA-3a triggers a series of events, including the production of ROS, potentially inducing apoptotic signals that adversely affect endothelial barrier function. This impairment leads to heightened endothelial permeability and interendothelial junction disruption, contributing to severe TRALI symptoms. In renal transplantation, when antibodies bind to specific components of the graft tissue, similar responses also occur. Activation of intracellular signaling pathways and inflammatory mediator release can instigate pathological processes such as localized inflammation, vascular damage, and graft rejection. Therefore, the similarity between the events lies in the ability of antibodies to trigger immune and inflammatory reactions impacting tissue integrity and function. Several studies have documented the clinical relevance of anti-HNA-3 antibodies in kidney transplantation. For instance, Key et al. (2019) reported cases of kidney transplant recipients with preformed anti-HNA-3a antibodies who experienced severe ABMR and graft loss within the first year post-transplant 2. Similarly, Cannon et al. (2023) found that patients with anti-HNA-3 antibodies often required augmented immunosuppression to prevent rejection 1. More recently, Martins et al. (2025) reported that preformed anti-HNA-3 antibodies were associated with an increased risk of recurrent acute rejection compared to a matched cohort of patients without these antibodies 3. These findings underscore the potential of anti-HNA-3 antibodies to cause significant graft damage, even in the absence of HLA-DSA.
Clinical Outcomes and Challenges
The presence of anti-HNA-3 antibodies poses significant challenges in kidney transplantation. Patients with these antibodies often experience complicated post-transplant courses, including early and chronic ABMR. In some cases, anti-HNA-3 antibodies can lead to unexplained positive crossmatches, delaying or preventing transplantation. The high frequency of HNA-3a expression in the population (approximately 95% in Caucasians) means that patients with anti-HNA-3a antibodies face limited donor compatibility, further complicating their transplant process. Moreover, the detection of anti-HNA-3 antibodies is not routinely performed in most transplant centers, leading to underdiagnosis and inadequate management. Current standard methods for detecting these antibodies, such as granulocyte immunofluorescence testing (GIFT) and granulocyte agglutination testing (GAT), are labor-intensive and not widely available. Although commercial assays, such as Luminex®LABScreen MULTI, have shown promise, they are not yet standardized for routine clinical use. This lack of standardized testing or access to reference granulocyte laboratories contributes to the uncertainty surrounding the prevalence and clinical significance of anti-HNA-3 antibodies in transplantation.
Figure 1. CTL2 expression overview (Source)
Strategies for Management
Given the potential for anti-HNA-3 antibodies to cause recurrent acute rejection of kidney transplants, there is a growing need for strategies to mitigate their impact. One approach is to screen high-risk patients, such as multiparous women or those with a history of blood transfusion, for anti-HNA-3 antibodies prior to transplantation. This could help identify patients at risk of ABMR and guide the selection of compatible donors. In cases where HNA-incompatible transplantation is unavoidable, augmented immunosuppression or plasma exchange, may be necessary to prevent graft rejection.
Conclusions
Anti-HNA antibodies, particularly anti-HNA-3, represent an important but underrecognized factor in kidney transplantation. Their ability to cause rejection, even in the absence of HLA-DSA, highlights the need for greater awareness and research into their role in transplantation immunology. As the field moves towards personalized medicine, the development of standardized testing methods and targeted management strategies for anti-HNA-3 antibodies will be crucial to improving transplant outcomes. Further studies are needed to elucidate the prevalence, mechanisms, and clinical impact of these antibodies, paving the way for more effective prevention and treatment of rejection in kidney transplant recipients.
References
- Cannon E, Stevenson K, Little AM, et al. Kidney transplant outcomes in patients with antibodies to human neutrophil antigen 3a. Transpl Immunol. 2023;81:101905.
- Key T, Carter V, Day S, et al. Human neutrophil antibodies associated with early and chronic antibody mediated rejection in kidney transplant recipients. J Renal Transplant Sci. 2019;2:81-84.
- Martins JO, Silva Junior HT, Moritz E, et al. Impact of preformed antibodies against human neutrophil antigen-3 (anti-HNA-3) with episodes of acute rejection in a cohort of 1256 kidney transplanted patients. Clin Transplant. 2025. Accepted for publication.
