Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group

Abstract

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation?

“…In agreement with the FDA workshop, the TTS working group recommended the combination of plasmapheresis, IVIg, and corticosteroids as standard of care to remove circulating DSA and/or reduce DSA production 14,71 . The role of additional therapy, mentioned in the FDA workshop as “different add‐on treatments per center preference,” 14 was recognized by the TTS working group as controversial, but in the context of a high risk of immediate graft loss agreed adjunctive therapy may be warranted—viable options include rituximab (anti‐CD20), complement inhibitors (eg, eculizumab), and splenectomy 71 …”

“…Because the majority of the study's ABMR occurred in the first‐year posttransplant, it is not clear if such an approach is as prognostic when active ABMR occurs late (ie, the average time of onset for de novo DSA is 4‐5 years posttransplant) 38 . Moreover, as outlined earlier, the TTS expert working group did not recommend plasmapheresis, IVIg, and rituximab for late active or chronic active ABMR 71 . As such, more studies are required to determine if such a dynamic composite prognostic biomarker has the same utility in late active or chronic active ABMR.…”

“…Given these limitations, the international community, under the sponsorship of The Transplantation Society (TTS), convened an expert consensus working group in 2019 to develop treatment recommendations for ABMR 71 . In part, the goal was to identify a standard of practice, largely based on expert opinion, so that future clinical trials could be developed relative to a common, agreed‐to standard of care.…”

“…For preformed DSA‐associated late active ABMR, the TTS working group consensus remained plasmapheresis, IVIg, and corticosteroids, although adjunctive therapy with rituximab could be considered 70 . However, once memory‐associated ABMR evolves to a chronic active phenotype, the risk of overimmunosuppression with no proven efficacy of any agent shifted the consensus to that of supportive care while maintaining optimized baseline immunosuppression (ie, tacrolimus trough levels >5.0 ng/mL).…”

“…In this context, the TTS working group recommended the optimization of baseline immunosuppression and treatment of TCMR. Evidence in support of plasmapheresis, IVIg, and rituximab was considered too low to recommend as a standard of care but could be considered as an adjunctive therapy 71 …”