The DARA-MVI Study is a prospective, randomized, controlled, open-label trial designed to evaluate the effect of daratumumab on microvascular inflammation (MVI) in kidney transplant recipients with C4d-negative biopsies. Participants with biopsy-proven MVI will be randomized to receive either daratumumab or observation with standard monitoring. The study will assess changes in histologic MVI score, donor-derived cell-free DNA (dd-cfDNA), donor-specific antibodies (DSA), and graft function over 12 months.

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).

The study also aims to explore correlations between histologic, molecular (dd-cfDNA), and serologic (DSA) indicators of alloimmune activity. This will help determine whether daratumumab can interrupt subclinical alloimmune injury and delay chronic graft deterioration.

If successful, this study could define a novel therapeutic approach for antibody-independent microvascular inflammation and clarify the role of plasma-cell-directed therapies in complex post-transplant immune responses.

Inclusion:

Age ≥ 18, kidney transplant recipients (first or higher, living or deceased donor), biopsy-proven MVI (g ≥ 1 and/or ptc ≥ 1), C4d-negative, DSA-negative (Cohort 1) or DSA-positive (Cohort 2), informed consent.

Exclusion:

C4d-positive biopsy, active TCMR ≥ IA, infection or malignancy, multi-organ transplant, prior anti-CD38 therapy, pregnancy, breastfeeding.

De-identified individual participant data underlying the published results will be made available upon reasonable request from qualified researchers after publication, following institutional and ethical approval. Supporting documents (protocol, statistical analysis plan) may also be shared.

from 01/MAR/2025 for 20 years

Open-label (pathology and laboratory assessments blinded)