Summary of 2017 FDA Public Workshop

Abstract

Despite major advances in understanding the pathophysiology of antibody-mediated rejection (AMR); prevention, diagnosis and treatment remain unmet medical needs. It appears that early T cell-mediated rejection, de novo donor-specific antibody (dnDSA) formation and AMR result from patient or physician initiated suboptimal immunosuppression, and represent landmarks in an ongoing process rather than separate events. On April 12 and 13, 2017, the Food and Drug Administration sponsored a public workshop on AMR in kidney transplantation to discuss new advances, importance of immunosuppressive medication nonadherence in dnDSA formation, associations between AMR, cellular rejection, changes in glomerular filtration rate, and challenges of clinical trial design for the prevention and treatment of AMR. Key messages from the workshop are included in this summary. Distinction between type 1 (due to preexisting DSA) and type 2 (due to dnDSA) phenotypes of AMR needs to be considered in patient management and clinical trial design. Standardization and more widespread adoption of routine posttransplant DSA monitoring may permit timely diagnosis and understanding of the natural course of type 2 and chronic AMR. Clinical trial design, especially as related to type 2 and chronic AMR, has specific challenges, including the high prevalence of nonadherence in the population at risk, indolent nature of the process until the appearance of graft dysfunction, and the absence of accepted surrogate endpoints. Other challenges include sample size and study duration, which could be mitigated by enrichment strategies.

Do anti-IL-6R blockers have a beneficial effect in the treatment of antibody-mediated rejection resistant to standard therapy after kidney transplantation?

“…Current treatments to delay the course of chronic AMR (cAMR) remain disappointing. Steroids pulses, intravenous immunoglobulins and plasmapheresis, with or without B cell‐depleting agents, are considered to be the standard of care (SOC) for AMR 3 . However, long‐term efficacy is still elusive 3 …”

Therapies for Chronic Allograft Rejection

“…Although plasma exchange can reduce levels of plasma antibodies and graft injury, it is a transient effect (Ionescu and Urschel, 2019). Plasma exchange may require a combination of treatments that inhibit the formation of dnDSA, particularly class II dnDSA, by newly matured plasma cells and long-lived plasma cells (Velidedeoglu et al, 2018;Ionescu and Urschel, 2019).…”

“…These findings may suggest that not all DSAs cause tissue damage. Moreover, problems such as bead saturation, shared epitope, and prozone effect can lead to MFI values that differ from DSA levels, although antibody titration methods can more accurately measure antibody strength (Velidedeoglu et al, 2018;Schinstock et al, 2020).…”

Therapeutic apheresis in kidney transplantation: An updated review

“…Hence, the ability to successfully deliver incompatible transplants and optimize long-term results is contingent on the ability to successfully approach and manage an AMR. AMR is also of significant burden in non-sensitized individuals, as de novo DSA (dnDSA) can emerge early or late following KT[106].…”