Tubular epithelial cell and podocyte apoptosis with de novo sirolimus based immunosuppression in renal allograft recipients with DGF
R. Munivenkatappa1, A. Haririan2, J.C. Papadimitriou1, C.B. Drachenberg1, M. Dinits-Pensy2 and D.K. Klassen2
University of Maryland School of Medicine, Departments of 1Pathology and 2Medicine, Baltimore, Maryland, USA.
Offprint requests to: Dr. David Klassen, Division of Nephrology, University of Maryland Hospital, 22 South Greene St., Baltimore, Maryland 21201, USA. email: Dklassen@medicine.umaryland.edu
Summary. Sirolimus is associated with prolonged delayed graft function (DGF) following renal transplantation and exacerbation of proteinuria. We assessed renal allograft biopsies from DGF patients treated with de novo sirolimus (n = 10) for renal tubular cell and podocyte apoptosis and expression of activated caspase-3, Bcl-2, and mTOR and compared them to biopsies from DGF patients not receiving sirolimus (n = 15). Both groups received mycophenolate mofetil, prednisone and antibody induction. Apoptosis was assessed using terminal deoxynucleodidyl transferase mediated dUTP nick end labeling (TUNEL) staining. Caspase-3, Bcl-2, and mTOR expression were assessed by immunohistochemistry. Sirolimus treated patients had 334±69 TUNEL positive cells per 5 high power fields compared to 5.5±2.9 TUNEL positive cells in control patients (p<0.001). The number of TUNEL positive cells correlated with tubular architectural disruption. Expression of activated caspase-3, Bcl-2, or activated mTOR did not differ between groups. 60% of biopsies from sirolimus treated patients compared to 7% of biopsies from controls showed diffuse podocyte apoptosis (p = 0.007). There was no podocyte expression of activated mTOR, activated caspase-3, or Bcl-2 in either group. These data suggest that DGF patients treated with sirolimus have increased renal tubular cell apoptosis and podocyte apoptosis. Histol Histopathol 25, 189-196 (2010)
Key words: Sirolimus, Apoptosis, Podocyte, Delayed graft function, Kidney