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bioRxiv · 10.1101/2023.04.05.535688

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

Demirci, H.·Popovic, S.·Dittmayer, C.·Yilmaz, D. E.·El-Shimy, I. A.·Mülleder, M.·Hinze, C.·Mutig, K.·Bachmann, S.
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Abstract

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. Complex renal parenchymal damage occurs for cyclosporine A (CsA) as well as for the currently favoured tacrolimus (Tac). To test for distinct CsA and Tac damaging patterns, we combined multiomics analysis with histopathology from rat kidneys exposed to continuous CNI delivery. Damage forms varied strikingly. 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. Should this translate to the clinical setting, CNI choice should reflect individual risk factors for renal vasculature and tubular epithelia. As a step in this direction, we share products identified from multiomics for differential pathognomonic biomarkers. Translational StatementCalcineurin inhibitors (CNI) are first-choice immunosuppressive agents. Their nephrotoxic side effects may often limit their use. Tacrolimus is currently preferred to cyclosporine although its superiority remains unclear. Within the nephron, damage to the filtration barrier is greater for tacrolimus, whereas cyclosporine side effects locate more to the proximal tubular epithelium when compared in our rodent model. We identify the distinctive location and nature of damage by both drugs and unravel involved mechanisms. By detecting differential protein signatures we make available pathognomonic biomarkers for renal allograft health under CNI treatment.

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Demirci, H., Popovic, S., Dittmayer, C., Yilmaz, D. E., El-Shimy, I. A., Mülleder, M., Hinze, C., Mutig, K., Bachmann, S.. 2023-04-06. Calcineurin inhibitor nephrotoxicity revisited: perspectives emerging from differential impact on renal compartments. https://doi.org/10.1101/2023.04.05.535688

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