Microvascular inflammation in kidney allografts: New directions for patient management.

Abstract

Microvascular inflammation (MVI) is a key histological feature of immune-mediated injury at the capillary interface of renal allografts, characterized by immune cell infiltration into glomerular and peritubular capillaries. While traditionally associated with antibody-mediated rejection (AMR), many MVI cases lack detectable donor-specific antibodies (DSA), suggesting the involvement of antibody-independent immune mechanisms or alternative triggers, such as viral infections or ischemia-reperfusion injury. The Banff 2022 scheme introduced a subcategory, "MVI, DSA-negative, C4d-negative", within an overarching AMR/MVI category. This subcategory -similar to AMR- was shown to carry a significant risk of graft failure. Its recognition marks a major advancement, offering a robust framework for investigating the pathophysiology of MVI, which may involve a wide array of overlapping triggers. Emerging evidence from transcriptome analyses highlights natural killer (NK) cells as possible effectors, regardless of DSA status. Therapies targeting NK cells, particularly the anti-CD38 antibody felzartamab, have shown promising reductions in MVI and molecular injury. Notably, the U.S. Food and Drug Administration has approved an MVI-based primary endpoint for a phase 3 trial evaluating this approach, representing a critical step toward the development of new therapeutics. Recognizing MVI as a multifaceted histological phenotype -driven by diverse triggers- may signal a paradigm shift in transplant medicine.