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Kidney Week

Abstract: FR-PO733

Cyclosporine Distinctly Damages Proximal Tubules, Tacrolimus the Filtration Barrier in Calcineurin Inhibitor Nephrotoxicity

Session Information

  • Transplantation: Basic
    November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 2101 Transplantation: Basic

Authors

  • Demirci, Hasan, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Popovic, Suncica, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Yilmaz, Duygu Elif, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Mutig, Kerim, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
  • Bachmann, Sebastian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Background

Calcineurin inhibitors (CNI) are the backbone for immunosuppression after solid organ transplantation. Although succesful in preventing kidney transplant rejection, their nephrotoxic side affects 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). We asked whether CsA and Tac exert distinct damage patterns during onset stages CNI nephropathy. We combined mulitomics analysis with histopatholgy from rat kidney exposed to continuous CNI delivery.

Methods

CsA and Tac were administired chronically in wild type Wistar rats using osmotic minipumps (total n=112) over 4 weeks. Physiological parameters were controlled. Animals were prepared for high-end morphological analysis, elective immunostaining, and multiomics analysis. Large scale electron microscopy, confocal stimulated emission-depletion (STED) and 3D-structured illumination microscopy were used for pathology. Standart biochemistry, RNAseq, proteomic, and phosphoproteomic technology was performed to identify molecular alterations.

Results

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 CsA, showing prominent deteriorations in pore endothelium and podocytes along with impaired VEGF/VEGFR2 signalling and podocyte-specific gene expression. By contrast, proximal tubule epithelia were more severely affected by CsA than by Tac, revealing lysosomal dysfuction and enhanced apoptosis and necrosis along with impaired proteostais and oxidative stress.

Conclusion

We conclude that pathogenic alterations in renal microenvironments are specific for either treatment. Should this translate to the clinical setting, CNI choice should reflect individual risk factor for renal vasculature and tubular epithelia. As a step in this direction, we share products identified from multiomics for differential pathonomonic biomarkers.

Funding

  • Government Support – Non-U.S.