Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation

Abstract

Antibody-mediated rejection (AMR) is caused by antibodies that recognize donor human leukocyte antigen (HLA) or other targets. As knowledge of AMR pathophysiology has increased, a combination of factors is necessary to confirm the diagnosis and phenotype. However, frequent modifications to the AMR definition have made it difficult to compare data and evaluate associations between AMR and graft outcome. The present paper was developed following a Broad Scientific Advice request from the European Society for Organ Transplantation (ESOT) to the European Medicines Agency (EMA), which explored whether updating guidelines on clinical trial endpoints would encourage innovations in kidney transplantation research. ESOT considers that an AMR diagnosis must be based on a combination of histopathological factors and presence of donor-specific HLA antibodies in the recipient. Evidence for associations between individual features of AMR and impaired graft outcome is noted for microvascular inflammation scores ≥2 and glomerular basement membrane splitting of >10% of the entire tuft in the most severely affected glomerulus. Together, these should form the basis for AMR-related endpoints in clinical trials of kidney transplantation, although modifications and restrictions to the Banff diagnostic definition of AMR are proposed for this purpose. The EMA provided recommendations based on this Broad Scientific Advice request in December 2020; further discussion, and consensus on the restricted definition of the AMR endpoint, is required.

Antibody‐mediated rejection in pediatric kidney transplant recipients: A report from the Pediatric Nephrology Research Consortium

“…The primary outcome was compared across individual and combined AMR treatments, across HLA‐DSA class (Class I, Class II, and combined Class I and II), and across AMR histology subsets as determined by Banff derived composite scores (microvascular injury, acute inflammation, chronic inflammation, and interstitial fibrosis/ tubular atrophy scores) 9,10 . Secondary outcomes included infectious events following AMR treatment and eGFR trajectories following AMR diagnosis.…”

The Clinical Utility of Post-Transplant Monitoring of Donor-Specific Antibodies in Stable Renal Transplant Recipients: A Consensus Report With Guideline Statements for Clinical Practice

“…In light of emerging data one may conclude that (early) acute ABMR with dnDSA (but without transplant glomerulopathy) could be more responsive to maintenance treatment optimization as well as PP and IVIG and eventually novel treatment regimens than patients with caABMR or cABMR, albeit all the treatment options have a low amount of supporting evidence. Active research in this area is ongoing and ABMR definition is becoming more precise [ 174 ]. Thus, there could potentially be benefit in finding and treating patients with early (subclinical) forms of ABMR before they present late with irreversible chronic lesions and clinical dysfunction.…”

The Banff 2022 Kidney Meeting Report: Re-Appraisal of Microvascular Inflammation and the Role of Biopsy-Based Transcript Diagnostics

“…2 Despite this, the Banff 2022 meeting held discussions on room for improvement in the "Banff Process" (Table 1). [3][4][5][6] The Banff Mission has been reformulated and stretch goals identified (Fig. 1, Table 2).…”

“…Introduction of changes before thorough modeling of the consequences of the changes (in at least some cases leading to the elimination of a clinically useful category 3 ) Absence of mechanisms for end-user feedback; frequent changes and poor dissemination of the changes as barriers to consistent implementation of the Classification in routine diagnostic practice Increasingly complicated rules lead to difficulties in communication between pathologists and the patient-facing clinical team, with potential implications for patient management 4,5 Variable definitions of antibody-mediated rejection (AMR) used for enrollment and as end points in observational studies and clinical trials, making systematic review challenging 6 Lack of global applicability of some techniques in the Banff definitions (electron microscopy, biopsy-based transcript diagnostics) Use of strict thresholds between categories of disease, dichotomizing an underlying continuous process definition cases with eg, a v lesion, or acute TMA, or subthreshold MVI. For this reason, we have removed the term "inactive" (reverting to Banff 2017 13,14 ).…”

“…39 Investigations after Banff 2001 documented that apart from patients with preformed HLA-DSA and positive crossmatch, C4d-positive cases with ATI are rare (1%-2%), and not associated with increased risk of graft loss. 6 In ABO-incompatible transplants, C4d positivity has no diagnostic significance. Based on this and other observations, some members of the Banff community highlighted that C4d staining indicates fixation of complement fragments to the endothelium, but not necessarily damage/rejection.…”