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

Abstract

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.