A Randomized Controlled Study of Daratumumab for Microvascular Inflammation (MVI) in Kidney Transplant Recipients With or Without Donor-Specific Antibodies

Microvascular inflammation (MVI) is a histologic feature associated with antibody-mediated injury and poor long-term graft outcomes in kidney transplantation. However, the optimal management of MVI-particularly in C4d-negative, donor-specific antibody (DSA)-negative cases-remains undefined. Recent data suggest that activation of plasma cells and long-lived memory B cells may contribute to persistent endothelial injury even in the absence of circulating DSA.

Daratumumab, a human monoclonal antibody targeting CD38, has demonstrated potent depletion of plasma cells and immunomodulatory effects in autoimmune diseases and in early reports of antibody-mediated rejection (ABMR) resistant to standard therapy. Building on this evidence, the DARA-MVI study aims to evaluate whether daratumumab can attenuate microvascular inflammation and stabilize graft function in kidney transplant recipients with biopsy-proven MVI but negative C4d staining.

This is a prospective, randomized, open-label, controlled trial enrolling adult kidney transplant recipients who undergo indication or surveillance biopsy revealing MVI (glomerulitis [g] and/or peritubular capillaritis [ptc] ≥ 1). Participants will be randomized in a 1:1 ratio to receive either (1) daratumumab subcutaneous therapy (1800 mg monthly for 3 months) or (2) observation under standard clinical monitoring. A non-randomized reference group of biopsy-negative, DSA-negative, and dd-cfDNA-negative transplant recipients will serve as a comparative baseline for biomarker trajectories.

All participants will undergo structured follow-up for 12 months, including serial assessment of graft function, dd-cfDNA (fraction and copy number), and DSA at baseline and every 3 months. Repeat biopsy at 12 months will evaluate histologic response (change in Banff MVI score: g + ptc).

The primary objective is to determine whether daratumumab reduces microvascular inflammation compared to observation. Secondary objectives include evaluation of changes in donor-derived cell-free DNA, emergence or resolution of DSA, estimated glomerular filtration rate (eGFR), and safety outcomes (adverse events, infection, and cytopenia).