title: Perfusion storage reduces apoptosis in a porcine kidney model of donation after cardiac death.
abstract: BACKGROUND
  Donation after cardiac death (DCD) kidneys suffer a high incidence of delayed graft function attributable to warm ischemia and cold ischemia (CI). Neither the mechanism of injury nor type of cell death has been described. Clinical studies suggest that perfusion storage (PS) of DCD kidneys may reduce injury although the mechanism of protection is unknown. In a porcine model of DCD, we hypothesized that DCD kidneys have increased caspase-1 due to warm ischemia (WI) and increased caspase-3 and apoptosis due to CI.
  
  
  METHODS
  Male Yorkshire pigs subjected to cardiac death were perfused with cold University of Wisconsin solution. The perfused kidneys were removed and stored in cold University of Wisconsin solution for 24 hr. Kidney biopsies were obtained before cardiac death and at 0 and 24 hr of CI.
  
  
  RESULTS
  There was an increase in caspase-1 activity due to WI before cold preservation. CI was associated with a massive increase in apoptosis, caspase-3/7 activity, and caspase-3 protein expression. Next, we hypothesized that PS would protect against apoptosis. We compared DCD kidneys subjected to static versus PS for 24 hr. PS significantly reduced proximal tubular apoptosis and was associated with increased B-cell lymphoma-extra large, and hypoxia-inducible transcription factor-1α.
  
  
  CONCLUSIONS
  These findings suggest that in DCD kidneys, WI preferentially activates caspase-1, whereas CI activates caspase-3 and causes apoptosis. PS may protect DCD kidneys through activation of antiapoptotic pathways involving B-cell lymphoma-extra large and hypoxia-inducible transcription factor-1α.
authors.affiliation: Renal Section Denver Veterans Affairs Medical Center, Denver, CO, USA. Alkesh.jani@ucdenver.edu
authors.forename: Alkesh
authors.initials: A
authors.lastname: Jani
authors.forename: Michael
authors.initials: M
authors.lastname: Zimmerman
authors.forename: Jessica
authors.initials: J
authors.lastname: Martin
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Kultigin
authors.initials: K
authors.lastname: Turkmen
authors.forename: Kameswaran
authors.initials: K
authors.lastname: Ravichandran
authors.forename: Arijana
authors.initials: A
authors.lastname: Pacic
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanović
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D050377:Cold Ischemia / Q000379:methods; D003643:Death; D005978:Glutathione; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007328:Insulin; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology*; D008297:Male; D023421:Models, Animal; D009926:Organ Preservation / Q000379:methods*; D019188:Organ Preservation Solutions; D010477:Perfusion; D011887:Raffinose; D034421:Sus scrofa; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting / Q000379:methods; D052096:Warm Ischemia / Q000379:methods; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D051020:bcl-X Protein; D000493:Allopurinol; D020169:Caspases; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose