Tubular epithelial cell and podocyte apoptosis with de novo sirolimus based immunosuppression in renal allograft recipients with DGF.
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.
Munivenkatappa
R
R
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Haririan
A
A
Papadimitriou
J C
JC
Drachenberg
C B
CB
Dinits-Pensy
M
M
Klassen
D K
DK
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D053148:Caspase 3 / Q000032:analysis; D051799:Delayed Graft Function / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D020287:In Situ Nick-End Labeling; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D016030:Kidney Transplantation / Q000009:adverse effects*; D007684:Kidney Tubules / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D050199:Podocytes / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D011241:Prednisone / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D009173:Mycophenolic Acid; D011241:Prednisone; D020123:Sirolimus