IL-6 Blockade for Antibody-Mediated Transplant Rejection: What Does the Evidence Say?

Two of the most significant challenges in transplantation medicine are human leukocyte antigen sensitization, which limits access to kidney transplantation for patients with end-stage kidney disease owing to the lack of effective desensitization strategies, and chronic active antibody-mediated rejection (cAMR), a major cause of allograft dysfunction and graft loss following transplantation. Despite its substantial clinical significance, there remains a lack of high-quality evidence and well-established therapeutic algorithms for the management of cAMR, while many patients continue to be excluded from kidney transplantation because of immunological barriers. Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a central role in both innate and adaptive immune responses. Beyond its immunological functions, IL-6 has been implicated in the pathogenesis of a wide range of conditions, including atherosclerotic cardiovascular disease, diabetes mellitus, and various neurological disorders. Consequently, targeting the IL-6/IL-6 receptor signaling pathway has emerged as a promising therapeutic strategy in transplantation medicine, particularly for desensitization protocols and the treatment of cAMR. However, the current evidence base is restricted to studies evaluating tocilizumab and clazakizumab, with clinical benefits remaining inconsistent across studies. Limited evidence is available regarding the desensitization effectiveness of tocilizumab monotherapy. In cAMR, the phase III IMAGINE trial found no improvement in kidney function with clazakizumab despite reduced C-reactive protein. Current evidence does not support a routine IL-6 pathway blockade in cAMR, while further studies are required to prove the potential benefits in desensitization. In this narrative review, we comprehensively examine the role of IL-6 in the pathophysiology of kidney transplantation and critically appraise the available clinical evidence regarding IL-6/IL-6R-targeted therapies for the management of human leukocyte antigen sensitization and cAMR.