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Abstract: PO2048

Calcineurin Inhibitor Nephrotoxicity as Viewed by Comparative Analysis of the Effects of Cyclosporine A vs. Tacrolimus on Epithelial Pathology in Rodent Models

Session Information

Category: Transplantation

  • 1901 Transplantation: Basic

Authors

  • Popovic, Suncica, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Demirci, Hasan, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Hu, Junda, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Yilmaz, Duygu Elif, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Dittmayer, Carsten, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Ellison, David H., Oregon Health & Science University Oregon Clinical & Translational Research Institute, Portland, Oregon, United States
  • Mutig, Kerim, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Bachmann, Sebastian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

Calcineurin inhibitors (CNI) are widely in use for immunosuppression in transplant recipients. Although essentially beneficial, their nephrotoxicity may cause or aggravate renal disease. We have challenged the hypothesis that the safety of the commonly applied CNI, cyclosporine A (CsA), and tacrolimus (Tac), differs regarding tubulointerstitial pathology. Mechanisms of proteostasis, autophagy and lysosomal dysfunction are addressed.

Methods

We have compared the effects of CsA and Tac in rat and mouse models. A focus was set on epithelial alterations. Adult Wistar rats received CsA (25 mg/kg/d), Tac (2 to 6 mg/kg/d), or vehicle via subcutaneously implanted minipumps. A megalin-deficient mouse model was tested for the role of endocytosis. After 4 wk kidneys were prepared for histopathology or biochemical analysis.

Results

In rats, CsA and Tac produced similar alterations in the tubulointerstitium (Fig. 1). Preferentially the initial proximal tubule (S1, and S2 segments) was affected, displaying dysmorphic lysosomes with peripheral LAMP1 signal, autophagic and mitophagic vacuoles. Dedifferentiation was focally strong, with loss of brush border, basement membrane thickening, and interstitial collagen accumulation. Alterations in unfolded protein response (UPR) and autophagy parameters included significant increases in p-eIF2a, pPERK, CHOP, BiP, and LC3B, and ATG5 products and enhanced epithelial TUNEL signal. Endocytosis was substantially impaired. Cultured NRK cells indicated sensitivity to chemical chaperones ameliorating proteostasis and revealed similar apoptosis rates upon CsA and Tac.

Conclusion

These results suggest that alterations in tubular epithelial proteostasis upon long term CsA- or Tac-induced nephrotoxicity are similar. Addressing restitution of epithelial proteostasis may have renoprotective potential for both drugs.