Improving the histologic detection of donor-specific antibody-negative antibody-mediated rejection in kidney transplants.

Emerging treatments for antibody-mediated rejection (ABMR, NEJM391 (2):122-132) have increased the importance of ABMR detection when donor-specific antibody (DSA) is negative. We addressed this issue in the Trifecta-Kidney study (ClinicalTrials.gov #NCT04239703) using 3 centralized tests in 690 kidney transplant biopsies: DSA (One Lambda Inc), blood donor-derived cell-free DNA (dd-cfDNA, Prospera™ test, Natera, Inc), and molecular biopsy assessment (MMDx). We used an "AutoBanff 2022" algorithm to model the impact of alternative DSA interpretations on the histologic diagnosis of DSA-negative ABMR following Banff guidelines, including agreement with dd-cfDNA and molecular ABMR. Lowering MFI cutoffs for DSA positivity did not improve the detection of DSA-negative ABMR. However, simply calling all DSA as positive allowed the Banff 2022 guidelines to identify 46% more ABMR cases with no measurable conventional DSA, and per net reclassification improvement increased agreement between histologic diagnoses and both dd-cfDNA (P = 7.72E-7) and molecular ABMR (P = 7.69E-7). New ABMR cases were as strongly positive for dd-cfDNA and molecular ABMR as those found using the conventional DSA interpretation. A validation set analysis using INTERCOMEX study data (ClinicalTrials.gov NCT#01299168) confirmed these findings and found that the new DSA-negative ABMR cases identified by calling all DSA-positive had the same risk for graft loss as those found with conventional DSA interpretation. Trifecta-Kidney Study ClinicalTrials.gov #NCT04239703.