Calcineurin inhibitor nephrotoxicity revisited: perspectives emerging from differential impact on renal compartments

Calcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although successful in preventing kidney transplant rejection, their nephrotoxic side effects notoriously contribute to allograft injury despite attempts to optimize their application, often with additional medications. The etiology of chronic renal parenchymal changes is complex irrespective of chosen therapy with either cyclosporine A (CsA) or currently favoured tacrolimus (Tac). The pathogenetic detail of their respective toxicities has not been fully understood. To test whether CsA and Tac cause adverse renal responses differentially, we employed a chronic rat model with continous drug application. Histopathology of the renal compartments was combined with multiomics analysis. Both drugs caused significant albeit differential damage in vasculature and nephron. The glomerular filtration barrier was more affected by Tac than by CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signaling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfunction and enhanced apoptosis along with impaired proteostasis and oxidative stress. We conclude that pathogenetic alterations in renal microenvironments are specific for either treatment. We have identified related biomarkers to adequately address chronic CNI nephropathy in transplant recipients. ### Competing Interest Statement The authors have declared no competing interest.