Tubular epithelial cell and podocyte apoptosis with de novo sirolimus based immunosuppression in renal allograft recipients with DGF

Abstract

Sirolimus is associated with prolongeddelayed graft function (DGF) following renaltransplantation and exacerbation of proteinuria. Weassessed renal allograft biopsies from DGF patientstreated with de novosirolimus (n = 10) for renal tubularcell and podocyte apoptosis and expression of activatedcaspase-3, Bcl-2, and mTOR and compared them tobiopsies from DGF patients not receiving sirolimus (n =15). Both groups received mycophenolate mofetil,prednisone and antibody induction. Apoptosis wasassessed using terminal deoxynucleodidyl transferasemediated dUTP nick end labeling (TUNEL) staining.Caspase-3, Bcl-2, and mTOR expression were assessedby immunohistochemistry. Sirolimus treated patients had334±69 TUNEL positive cells per 5 high power fieldscompared to 5.5±2.9 TUNEL positive cells in controlpatients (p<0.001). The number of TUNEL positive cellscorrelated with tubular architectural disruption.Expression of activated caspase-3, Bcl-2, or activatedmTOR did not differ between groups. 60% of biopsiesfrom sirolimus treated patients compared to 7% ofbiopsies from controls showed diffuse podocyteapoptosis (p = 0.007). There was no podocyte expressionof activated mTOR, activated caspase-3, or Bcl-2 ineither group. These data suggest that DGF patientstreated with sirolimus have increased renal tubular cellapoptosis and podocyte apoptosis.