title: Late graft dysfunction after prolonged cold ischemia of the donor kidney: inhibition by cyclosporine.
abstract: BACKGROUND
  The present study was devised to elucidate the influence of prolonged cold ischemia on the development of chronic transplant dysfunction (CTD) in kidney isografts (Brown Norway-->Brown Norway; BN-->BN) and in kidney allografts (BN-->Wistar Agouti/ Rij [WAG]) under temporary cyclosporine (CsA) therapy.
  
  
  METHODS
  To induce ischemic injury, BN donor kidneys were preserved for 24 hr in 4 degrees C University of Wisconsin solution before transplantation. Renal function (proteinuria), histomorphology according to the BANFF criteria for CTD, and infiltrating cells were assessed. Grafts were examined both early at days 2, 3, 6, and 10, and late at week 26 (allografts) or at week 52 (isografts).
  
  
  RESULTS
  Nonischemic isografts preserved a normal function and morphology. Ischemic isografts developed a progressive proteinuria over time and demonstrated significantly more glomerulopathy with macrophage (Me) infiltration and intimal hyperplasia than nonischemic controls at week 52. During the initial 10 days, there was an increased infiltration of MHC class II+ cells, predominantly CD4+ cells and Mphi, coinciding with up-regulated intercellular adhesion molecule-1 expression. CsA treatment in ischemic isografts inhibited infiltration of MHC II+ cells in the early stage, which was accompanied by significantly less renal damage at week 52 compared with untreated controls (proteinuria: 59+/-8 vs. 134+/-19 mg/24 hr; BANFF score: 2.8+/-0.4 vs. 4.3+/-1.0). Under CsA therapy, 24-hr cold ischemia of the allograft affected neither the onset or progress of proteinuria, nor the histomorphology (BANFF score: 7.8+/-2.4 vs. 7.3+/-1.9). In both ischemic and nonischemic allografts, intercellular adhesion molecule-1 expression and mononuclear cell infiltration (CD4, CD8, Mphi was abundantly present during the first 10 days and function deteriorated rapidly.
  
  
  CONCLUSIONS
  Prolonged cold ischemia plays a role in the induction of CTD, but its deleterious effect can be successfully inhibited by CsA. Therefore, the alloantigeneic stimulus is the overriding component in the multifactorial pathogenesis of CTD.
authors.affiliation: Department of Surgery, Erasmus University, Rotterdam, The Netherlands. kouwenhoven@heel.fgg.eur.nl
authors.forename: E A
authors.initials: EA
authors.lastname: Kouwenhoven
authors.forename: R W
authors.initials: RW
authors.lastname: de Bruin
authors.forename: U W
authors.initials: UW
authors.lastname: Heemann
authors.forename: R L
authors.initials: RL
authors.lastname: Marquet
authors.forename: J N
authors.initials: JN
authors.lastname: Ijzermans
mesh_terms: D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D015925:Cryopreservation; D016572:Cyclosporine / Q000627:therapeutic use*; D005978:Glutathione; D006084:Graft Rejection / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007328:Insulin; D007511:Ischemia / Q000209:etiology*; D007668:Kidney / Q000098:blood supply* / Q000503:physiopathology; D016030:Kidney Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D009926:Organ Preservation / Q000009:adverse effects*; D019188:Organ Preservation Solutions; D011887:Raffinose; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D007166:Immunosuppressive Agents; D007328:Insulin; D019188:Organ Preservation Solutions; C055206:University of Wisconsin-lactobionate solution; D000493:Allopurinol; D016572:Cyclosporine; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose