Kidney Allograft Microvascular Inflammation Reveals Distinct Phenotypes and Outcomes: A Multinational Cohort Study

Background: Microvascular inflammation (MVI) is a key predictor of adverse kidney allograft outcomes, prompting the Banff 2022 Classification to introduce two MVI categories: MVI, DSA-negative and C4d-negative (MVI+DSA-C4d-) and probable antibody-mediated rejection (probable AMR). To date, the clinical significance of these phenotypes remains unclear. Methods: We included 6,099 kidney transplant recipients from 20 transplant centers, who underwent an allograft biopsy between 2004 and 2023. Multimodal data was integrated to classify biopsies according to the Banff 2019 and 2022 Classification. We assessed diagnostic reclassifications and their association with graft outcome, transplant glomerulopathy, and AMR episodes. Results: Among the 14,081 transplant biopsies, MVI+DSA-C4d- and probable AMR were diagnosed in 456 (3.2%) and 265 (1.9%) biopsies, respectively. A total of 721 biopsies were reclassified, with mainly non-rejection biopsies (n=599) being reclassified as MVI+DSA-C4d- (n=361) and probable AMR (n=238). Patients reclassified as MVI+DSA-C4d- showed worse graft survival compared to non-rejection cases (HR=2.3, 95% CI: 1.6-3.3; P<0.001), but better than patients with active AMR (HR=3.0, 95% CI: 2.5-3.7; P<0.001). Those reclassified as probable AMR had a graft survival similar to non-rejection cases (HR=1.5, 95% CI: 0.9-2.5; P=0.122). We observed a similar increased risk for developing transplant glomerulopathy and an AMR episode for both MVI+DSA-C4d- and probable AMR, compared to non-rejection (P<0.001). Conclusion: We demonstrated that MVI+DSA-C4d- and probable AMR are distinct clinical phenotypes, and reclassification of these cases refined patient risk stratification for allograft outcome. Our findings support the introduction of these phenotypes, as their clinical recognition will aid in standardizing therapeutic approaches, improving allograft outcomes.