Cyclosporine A- versus tacrolimus-specific lesions in calcineurin inhibitor nephrotoxicity

BACKGROUND: Calcineurin inhibitors (CNI) such as cyclosporine A (CsA) and tacrolimus (Tac) have revolutionized solid organ transplantation. CNI-associated nephrotoxicity (CNIT) remains a concern. Addressing differences between CsA and Tac in human kidney biopsies systematically, we studied whether specific histopathological features for either drug can be identified. METHODS: Thirty-nine adult kidney and 6 liver transplant recipients with a median of 92.5 months under CNI-based immunosuppression after transplantation were included in a retrospective cohort study. Inclusion criteria were biopsy-proven CNIT defined by severe arteriolar hyalinosis (ah score of 2-3) and absence of other causes of vascular damage. Seventeen biopsies were from patients receiving CsA and 28 from those receiving Tac. Routine histology, electron microscopy, immunohistology and morphometry were used for systematic comparison of selected parameters. RESULTS: Overall CNIT was diagnosed by tubulo-interstitial and arteriolar pathology occurring to similar extent in both, CsA and Tac groups. Analysis at higher resolution, however, revealed differential effects between CsA and Tac. Changes within the glomerular filtration barrier, tendency for glomerular scarring, and interstitial microvascular deteriorations were more prominent in Tac compared to CsA. By contrast, the proximal tubule epithelia were more severely affected by CsA than by Tac, revealing impaired autophagic-lysosomal flux, extensive luminal shedding, affected proteostasis and enhanced KIM-1 expression. CONCLUSIONS: We conclude that the histological lesions in renal microenvironments, identified at high resolution, are specific for either CsA or Tac. Our findings in human kidney biopsies thus consolidate an earlier experimental study in rats (PMID: 38 884 453). Results provide a solid base to optimize the diagnosis and treatment of CNIT.