title: Hypoxia and Complement-and-Coagulation Pathways in the Deceased Organ Donor as the Major Target for Intervention to Improve Renal Allograft Outcome.
abstract: BACKGROUND
  In the last few decades, strategies to improve allograft survival after kidney transplantation have been directed to recipient-dependent mechanisms of renal injury. In contrast, no such efforts have been made to optimize organ quality in the donor. Optimizing deceased donor kidney quality opens new possibilities to improve renal allograft outcome.
  
  
  METHODS
  A total of 554 kidney biopsies were taken from donation after brain death (DBD) and donation after cardiac death (DCD) kidneys before donation, after cold ischemia and after reperfusion. Healthy living donor kidney biopsies served as controls. Transcriptomics was performed by whole genome microarray analyses followed by functional pathway analyses.
  
  
  RESULTS
  Before organ retrieval and before cessation of blood circulation, metabolic pathways related to hypoxia and complement-and-coagulation cascades were the major pathways enhanced in DBD donors. Similar pathways were also enriched in DCD donors after the first warm ischemia time. Shortly after reperfusion of DCD grafts, pathways related to prolonged and worsening deprivation of oxygen were associated with delayed graft function in the recipient.
  
  
  CONCLUSIONS
  In conclusion, this large deceased donor study shows enrichment of hypoxia and complement-and-coagulation pathways already in DBD donors before cessation of blood flow, before organ retrieval. Therefore, future intervention therapies should target hypoxia and complement-and-coagulation cascades in the donor to improve renal allograft outcome in the recipient.
authors.affiliation: 1 Department of Pathology, Academic Medical Center Amsterdam, the Netherlands. 2 Department of Pediatrics, University Medical Center Groningen, University of Groningen, the Netherlands. 3 Department of Nephrology, Leiden University Medical Center, Leiden, the Netherlands. 4 Department of Nephrology, University Medical Center Groningen, Groningen, the Netherlands. 5 Department of Epidemiology, Unit of Genetic Epidemiology and Bioinformatics, University Medical Center Groningen, University of Groningen, the Netherlands. 6 Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands. 7 Department of Surgery, University of Oxford, Oxford, United Kingdom. 8 Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Damman
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Mohamed R
authors.initials: MR
authors.lastname: Daha
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Most
authors.forename: Bahram
authors.initials: B
authors.lastname: Sanjabi
authors.forename: Pieter
authors.initials: P
authors.lastname: van der Vlies
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: Rutger J
authors.initials: RJ
authors.lastname: Ploeg
authors.forename: Christina
authors.initials: C
authors.lastname: Krikke
authors.forename: Henri G D
authors.initials: HG
authors.lastname: Leuvenink
authors.forename: Marc A
authors.initials: MA
authors.lastname: Seelen
mesh_terms: D064591:Allografts; D001777:Blood Coagulation; D015331:Cohort Studies; D050377:Cold Ischemia; D003167:Complement Activation; D051799:Delayed Graft Function / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D000860:Hypoxia / Q000517:prevention & control; D016030:Kidney Transplantation; D008315:Malondialdehyde / Q000652:urine; D015424:Reperfusion; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D008315:Malondialdehyde