Impact of Immunosuppressive Drug Concentrations on Microvascular Inflammation, Negative Donor-Specific Antibodies, and C4d-Negative Status in Kidney Transplant Recipients.

INTRODUCTION: This study investigated the impact of immunosuppressive drug concentrations on microvascular inflammation (MVI) in kidney transplant recipients with negative donor-specific antibodies (DSA) against human leukocyte antigen (HLA) and negative C4d deposition in peritubular capillaries.

METHODS: We analyzed data from 268 living kidney transplant recipients at the Department of Urology, University of Osaka, Japan. Patients received immunosuppressive therapy comprising extended-release tacrolimus, mycophenolate mofetil (MMF), and/or everolimus, with or without steroids. Graft biopsies were routinely performed at 3, 12, 36 and 60 months post-surgery.

RESULTS: No significant differences were observed between the MVI+DSA-C4d- and MVI-DSAC4d groups regarding graft survival rates (95.5% vs. 96.6%, p = 0.772) or patient survival rates (95.7% vs. 95.9%, p = 0.735). Lower tacrolimus and everolimus concentrations were significantly associated with an increased risk of MVI+DSA-C4d- (tacrolimus: OR, 0.169; 95% CI, 0.055-0.515; p = 0.002; everolimus: OR, 0.386; 95% CI, 0.171-0.874; p = 0.022). In contrast, MPA concentration was not significantly associated with MVI+DSA-C4d- (OR, 0.994; 95% CI, 0.554-1.780; p = 0.984). Steroid discontinuation did not significantly impact the risk of MVI+DSA-C4d- (OR, 1.980; 95% CI, 0.318-12.000; p = 0.470).

CONCLUSION: Lower trough levels of tacrolimus and everolimus correlated with a higher incidence of antibody-independent MVI, supporting the need for tailored immunosuppressive regimens in kidney transplantation.