A Comparative Analysis of Nephrotoxicity Induced by Voclosporin and Cyclosporine A Using Kidney Microphysiological Systems

Abstract

Calcineurin inhibitor (CNI)-induced nephrotoxicity presents a major obstacle to long-term kidney transplant survival and patient quality of life. While the classic CNI cyclosporin A (CsA) is effective in preventing graft rejection, it can cause substantial renal injury through complex mechanisms involving mitochondrial dysfunction, excessive reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and disrupted cell cycle regulation—processes exacerbated by the hypoxic environment of the kidney cortex where proximal tubule epithelial cells (PTECs) primarily localize. In contrast, the newer agent voclosporin (VOC) achieves immunosuppression with notably reduced nephrotoxic effects, yet the molecular basis for this difference remains unclear. We combined RNA sequencing with a physiologically relevant, three-dimensional kidney microphysiological system (MPS) to compare the transcriptomic and cellular responses of PTECs exposed to CsA and VOC. Our analyses revealed that CsA induces broad perturbations in cell cycle progression and proteostatic pathways, coupled with robust ER stress responses and enrichment of ferroptosis-related genes associated with oxidative damage. In contrast, VOC elicited subtler alterations in similar pathways, suggesting a more measured adaptive response that preserves mitochondrial integrity and maintains ATP and ROS homeostasis. These findings underscore the importance of delineating the distinct cellular and transcriptomic mechanisms induced by CsA and VOC, which will be critical for developing safer immunosuppressive regimens, improving graft longevity, and ultimately enhancing patient outcomes in solid organ transplantation.