Apoptosis-Related Molecular Signatures in Calcineurin Inhibitor Nephrotoxicity After Kidney Transplantation

Calcineurin inhibitors (CNIs) such as tacrolimus remain essential for preventing réjection in kidney transplantation; however, their chronic use frequently causes nephrotoxicity and limits long-term graft survival. The molecular mechanisms underlying CNI-induced tubular injury remain incompletely understood and currently require invasive biopsy for confirmation.

Renal biopsies from 21 kidney transplant recipients under tacrolimus therapy were analyzed, including 10 patients with confirmed CNI toxicity (CNIT) and 11 controls without histological or clinical evidence of toxicity. Expression profiling of 96 apoptosis-related genes was performed using RT² Profiler PCR arrays, followed by validation of key targets (BAX, NOL3, XIAP) through quantitative RT-PCR and immunohistochemistry.

Patients with CNIT showed significant overexpression of BAX, NOL3, and XIAP (P = .002, .001, and .022, respectively), indicating activation of the extrinsic apoptotic pathway. Immunohistochemical analysis confirmed BAX protein accumulation in tubular epithelial cells but not in the glomerular region, consistent with localized tubular injury. Control samples displayed only basal gene expression and no BAX staining.

Dysregulation of the extrinsic apoptotic pathway-characterized by BAX upregulation and compensatory increases in antiapoptotic mediators NOL3 and XIAP-underlies the molecular pathology of CNIT. This consistent expression pattern provides mechanistic insight into CNI-induced nephrotoxicity and may support the development of molecular approaches for CNIT detection and monitoring, reducing reliance on invasive biopsy.