Vascular and glomerular vs. proximal tubular components in calcineurin inhibitor‐related nephrotoxicity

Abstract

Calcineurin inhibitors (CNI) are widely in use for immunosuppression in transplant recipients, but their nephrotoxicity may cause or aggravate renal disease. CNI pathology includes vascular and tubulointerstitial alterations. We have compared the effects of cyclosporine A (CsA) and tacrolimus (Tac) upon chronic administration in a rat model. We have tested whether Tac caused less damage than CsA. To this end, functional as well as glomerular and tubulointerstitial parameters were compared. Adult Wistar rats received CsA (25 mg/kg/d), Tac (2 mg/kg/d), or vehicle via subcutaneously implanted minipumps. After four weeks, rats were sacrificed and organs removed for protein analysis or perfusion‐fixed and kidneys analyzed for histopathology. NRK cells were treated with graded concentrations of CNI for 24h. For evaluation, confocal immunohistochemistry, EM nanotomy, EM immunostaining, Western blot, and clinical chemistry methods were applied. In rats, CsA and Tac produced distinct alterations in the tubulointerstitium. With CsA, dysmorphic lysosomes with peripheral LAMP1 signal, autophagic and mitophagic vacuoles caused epithelial decay of the initial proximal tubule, while glomerular changes were less pronounced. With Tac, glomerulosclerosis and damage encroachment to proximal tubule were more prominent. Both drugs induced fibrotic upregulation of alpha‐smooth muscle actin in the interstitium. Alterations in unfolded protein response (UPR) parameters included rises in p‐eIF2α, p‐PERK, p‐IRE1, sXBP1, CHOP in CsA‐, but not in Tac‐treated rats. Epithelial TUNEL signal was stronger in the CsA than in the Tac groups. Results were verified in NRK cells using graded caspase‐3 and lysosome formation criteria. Data revealed distinct nephrotoxicity patterns in the two examined immunosuppressive medications. While CsA seems to be primarily tubulotoxic, a stronger glomerular component was detected with Tac. Results may serve to better adjust treatment combinations in transplant patients.