Nephrotoxic Side Effects of the Calcineurin Inhibitors Cyclosporin A and Tacrolimus Affect Glomeruli and Tubulointerstitium Differentially in Chronic Experimental Settings
- Transplantation: Basic
November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
- 2001 Transplantation: Basic
- 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
- Ellison, David H., Division of Nephrology & Hypertension, Oregon Health & Science University, Portland, Oregon, United States
- Mutig, Kerim, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
- Bachmann, Sebastian, Charite Universitatsmedizin Berlin, Berlin, Berlin, Germany
Chronic calcineurin inhibitor (CNI) nephrotoxicity is a major drawback in current immunosuppressive regimens. Pathology includes vascular/glomerular and tubulointerstitial alterations. Although still commonly in use, cyclosporine A (CsA) is increasingly replaced by tacrolimus (Tac) for a more favorable clinical outcome. Data on their differential pathogenetic effects in the kidney are still scarce.We hypothesized that the major renal compartments are differentially affected by the two drugs. Histological, ultrastructural and gene expressional changes were registered to achieve mechanistic perspectives in controlling CNI nephrotoxicity.
CsA and Tac were administered chronically in wt rats and mice with a megalin-related endocytosis defect. Clinical parameters were controlled. Animals were prepared for high-end morphological analysis, elective immunostaining, and high-throughput technology.
In rats, CsA and Tac produced distinct alterations in glomeruli and tubulointerstitium. Both drugs caused a-SMA-positive fibrotic foci with sclerotic glomeruli and damaged tubules to similar extent. With CsA, glomerular damage was milder than with Tac. Proximal tubules showed increases in dysmorphic lysosomes along with high apoptosis rate and diminished albumin uptake. Megalin-dependent endocytosis was causally involved in the changes. Lysosomal exocytosis was stimulated at the apical cell pole. KIM1 signal was moderate. With Tac, these changes were far less pronounced, but focal tubular necrosis along with KIM-1 signal was enhanced. High throughput analysis showed differential changes between CsA and Tac with almost no overlap between the respective spectra. CsA caused upregulation of components of the unfolded protein response and apoptosis, whereas Tac showed a disproportionately sharp induction of the RAS and vascular structural deterioration.
In sum, CNI nephrotoxicity presented with fundamentally different effects caused by CsA vs. Tac. While CsA mostly affected proximal tubular integrity, Tac was primarily acting on vascular components. Results may serve to better adjust immunosuppressive treatment combinations in transplant patients.