Sequential CD38 Monoclonal Antibody Induction Followed by Azathioprine Maintenance versus Continuous CD38 Therapy for Chronic Active Antibody-Mediated Rejection: A NK Cell-Targeted Comparative Study

Background: Chronic active antibody-mediated rejection (cAABMR) remains the leading cause of late kidney allograft failure, with limited effective therapeutic options. CD38 monoclonal antibodies have shown promise in depleting natural killer (NK) cells and alleviating microvascular inflammation, but long-term efficacy is compromised by disease recurrence after drug withdrawal. Azathioprine (AZA) exhibits unique NK cell-suppressive properties, providing a potential maintenance strategy.
Methods: We conducted a retrospective comparative study of 8 kidney transplant recipients with biopsy-proven cAABMR. Five patients received CD38 monoclonal antibody induction followed by AZA maintenance (CD38+AZA group), while 3 patients received continuous CD38 therapy (CD38 group). The primary endpoints were estimated glomerular filtration rate (eGFR) slope changes and NK cell dynamics across three treatment phases.
Results: During the induction phase, both groups showed improved renal function, with mean eGFR slopes of -0.509 ml/min/1.73m²/month (CD38+AZA) and 1.504 ml/min/1.73m²/month (CD38 group). In the maintenance phase, the CD38+AZA group maintained stable renal function (mean eGFR slope: 0.152 ml/min/1.73m²/month), whereas the CD38 group exhibited a gradual decline (mean eGFR slope: -0.311 ml/min/1.73m²/month). NK cell counts remained persistently suppressed in the CD38+AZA group (mean: 26.5 cells/µL) during AZA maintenance, compared to rebound in the CD38 group (mean: 42.8 cells/µL). At last follow-up, 4/5 patients in the CD38+AZA group had stable or improved eGFR, versus 1/3 in the CD38 group.
Conclusions: CD38 monoclonal antibody induction followed by AZA maintenance achieves sustained NK cell suppression and stable long-term renal function in cAABMR patients, offering a cost-effective alternative to continuous CD38 therapy.