title: Activated protein C reduces graft neutrophil activation in clinical renal transplantation.
abstract: We studied the role of endogenous activated protein C (APC), the major physiological anti-coagulant with concomitant anti-inflammatory properties, on ischemia/reperfusion (I/R) in 45 patients participating in a larger trial comparing three immunosuppressive protocols in cadaveric renal transplantation: perioperative anti-thymocyte globulin (ATG, Fresenius AG, Bad Homburg, Germany), perioperative basiliximab and conventional triple therapy. Blood samples for assessing plasma APC, protein C, and lactoferrin concentrations, neutrophil CD11b and L-selectin expressions and blood leukocyte differential counts were obtained preoperatively and before reperfusion from central venous cannula, complemented with simultaneous samples from iliac artery and graft vein for calculation of transrenal differences (Delta) of study parameters at 1 and 5 min after reperfusion. Unlike basiliximab or conventional therapy groups, ATG infusion induced a substantial increase in plasma APC concentration (119 [88-144]% before infusion vs. 232 [85-1246]% after infusion, p<0.001), resulting in renal graft sequestration of APC at 1 min after reperfusion (Delta=-72 [-567 to 12]%, p<0.001). Graft APC consumption was associated with transrenal reduction of neutrophil activation markers (L-selectin r=0.7, p=0.01; lactoferrin r=-0.6, p=0.02; CD11b r=-0.8, p=0.001), and with both warm (r=0.6, p=0.01) and cold ischemia time (r=0.6, p=0.02) and donor age (r=0.6, p=0.01). These findings suggest that APC has an anti-inflammatory role in I/R injury in clinical renal transplantation.
authors.affiliation: Helsinki University Hospital, Helsinki, Finland.
authors.forename: Arto J
authors.initials: AJ
authors.lastname: Turunen
authors.forename: José A
authors.initials: JA
authors.lastname: Fernández
authors.forename: Leena
authors.initials: L
authors.lastname: Lindgren
authors.forename: Kaija T
authors.initials: KT
authors.lastname: Salmela
authors.forename: Lauri E
authors.initials: LE
authors.lastname: Kyllönen
authors.forename: Heikki
authors.initials: H
authors.lastname: Mäkisalo
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.forename: Sanna M
authors.initials: SM
authors.lastname: Siitonen
authors.forename: Jari
authors.initials: J
authors.lastname: Petäjä
authors.forename: Eero J
authors.initials: EJ
authors.lastname: Pesonen
mesh_terms: D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000925:Anticoagulants / Q000378:metabolism; D000961:Antilymphocyte Serum / Q000737:chemistry; D000077552:Basiliximab; D039481:CD11b Antigen / Q000097:blood; D006801:Humans; D016030:Kidney Transplantation / Q000379:methods* / Q000473:pathology; D019041:L-Selectin / Q000097:blood; D007781:Lactoferrin / Q000097:blood; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism; D009926:Organ Preservation / Q000379:methods*; D010586:Phagocytes / Q000166:cytology / Q000378:metabolism; D011486:Protein C / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015424:Reperfusion; D015427:Reperfusion Injury; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000925:Anticoagulants; D000961:Antilymphocyte Serum; D039481:CD11b Antigen; D011486:Protein C; D011993:Recombinant Fusion Proteins; D019041:L-Selectin; D000077552:Basiliximab; D007781:Lactoferrin