Combination Strategies with Daratumumab to Mitigate Rebound in Kidney Transplant ABMR: A Real-World Study

Background: A randomized trial has shown that daratumumab monotherapy can reduce donor-specific antibodies (DSA) and slow graft function decline in antibody-mediated rejection (ABMR). However, rebound of immune injury after treatment discontinuation remains a major unresolved challenge. We aimed to evaluate whether combination strategies centered on daratumumab could mitigate rebound and improve clinical outcomes in a real-world setting.
Methods: We conducted a single-center real-world study including 12 kidney transplant recipients diagnosed with active or chronic active ABMR. At baseline, 66.7% had g ≥2, 91.7% had ptc ≥2, 33.3% had cg ≥2, and 9.1% were C4d-positive. Patients received daratumumab-based therapy, either as monotherapy (n=2) or in combination with standard-of-care (SOC) and adjunctive agents, including anti-CD20 antibodies (n=5), complement C5 inhibitors (n=1), IL-6 receptor inhibitors (n=2), and BAFF/APRIL inhibitors (n=2). Clinical and immunological parameters, including eGFR, proteinuria, donor-derived cell-free DNA (cfDNA), DSA levels, lymphocyte subsets, and histopathology, were longitudinally assessed.
Results: With a median follow-up of 11 months, renal function remained stable, with a 1-year eGFR change of 4.69 [4.30, 9.06] ml/min/1.73 m². A reduction of >50% in DSA was observed in 100% of patients, and cfDNA normalized in all cases. Importantly, combination strategies with anti-CD20 antibodies, BAFF/APRIL inhibitors or IL-6 receptor inhibitors appeared to mitigate post-treatment rebound of immune activity. Adverse events were manageable, including upper respiratory infections (n=6), urinary tract infections (n=2), leukopenia (n=3), and infusion-related reactions (n=8).
Conclusions: Daratumumab-based regimens effectively reduce DSA and stabilize graft function in kidney transplant ABMR. Combination strategies targeting multiple immune pathways may help prevent rebound injury following CD38-directed therapy, with an acceptable safety profile. These findings provide a potential strategy to overcome a key limitation of daratumumab monotherapy.