title: Tubular epithelial cell and podocyte apoptosis with de novo sirolimus based immunosuppression in renal allograft recipients with DGF.
abstract: 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.
authors.affiliation: Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: R
authors.initials: R
authors.lastname: Munivenkatappa
authors.forename: A
authors.initials: A
authors.lastname: Haririan
authors.forename: J C
authors.initials: JC
authors.lastname: Papadimitriou
authors.forename: C B
authors.initials: CB
authors.lastname: Drachenberg
authors.forename: M
authors.initials: M
authors.lastname: Dinits-Pensy
authors.forename: D K
authors.initials: DK
authors.lastname: Klassen
mesh_terms: 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
chemical_list: 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