Intra-graft Coagulation Events in Clinical Renal Transplantation and Delayed Graft Function
NCT ID: NCT02568696
Last Updated: 2018-03-29
Study Results
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Basic Information
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UNKNOWN
100 participants
OBSERVATIONAL
2015-06-30
2018-12-31
Brief Summary
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Detailed Description
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In clinical kidney transplantation organ retrieval, cold-preservation of the graft as well as restoration of the blood flow to the transplant cause tissue damage (ischemia/reperfusion injury). Clinically these events can manifest themselves as delayed graft function (DGF), which is usually defined as the need for dialysis during first week after transplantation. DGF increases the risk of developing chronic rejection and subsequently loss of the transplant.
Ischaemia/reperfusion injury is biologically characterized by local profound inflammatory response, activation of the coagulation system and endothelial dysfunction in the transplanted organ. After reperfusion activated neutrophils cause tissue damage in the graft by production of reactive oxygen species (ROS) and release of proteolytic enzymes, which lead to plugging of the capillaries by accumulation of thrombocytes and fibrin. Blood flow is further diminished by increased blood viscosity and local vasoconstriction and swelling of the endothelial cells. Disorders of the microcirculation lead to "no-reflow" phenomenon whereby locally tissues remain ischemic, despite of good blood flow in the organ artery and vein.
Coagulation is activated in the renal transplant during reperfusion, when circulating factor VIIa (FVIIa) comes into contact with the tissue factor (TF), which is expressed on the endothelium due to ischaemia. FVII-TF complex activates factor X (FX) and activated FX (FXa) cleaves thrombin (FII) from prothrombin. Thrombin activates thrombocytes, cleaves fibrin from fibrinogen and activates factor XIII( FXIII), which stabilizes fibrin clot. Fibrin has been demonstrated to accumulate in the kidney graft during reperfusion. Fibrin accumulation is aggravated by inhibition of fibrinolysis due to reperfusion.
Furthermore, the investigators conducting this current research project, have previously gained indirect evidence in a small cohort study, that accumulation of fibrin occurs even before reperfusion, during donor care and organ retrieval. Most importantly, specifically this pre-reperfusion fibrin deposition was related to DGF.
Patients and sample size
There were several limitations in investigators previous study concerning intra-graft coagulation events in DGF. It was conducted as a part of a larger trial in renal transplantation and included only 30 patients in two study arms with different immunosuppressant regimens (peri-operative basiliximab and conventional triple therapy). Therefore, a new study, with larger sample size and standardized immunosuppression is warranted.
Therefore, in this current prospective observational study surgical technique, anaesthesia and hemodynamic management, immunosuppressive medications are strictly standardized. Sample size is increased to 100. The investigators prospectively screen all adult patients receiving their first kidney transplant from cadaveric donor. Only patients scheduled to receive local standard triple immunosuppressant therapy with cyclosporine A, mycophenolate mofetil and methylprednisolone are included.
Blood samples and prospective data collection
Blood samples for assessment of intra-graft coagulation events (generation of thrombin and fibrin, activation and inhibition of fibrinolysis) are drawn peri-operatively. Predefined clinical and demographical data are collected preoperatively and prospectively during 3 months after kidney transplantation to assess the influence of these coagulation events on delayed graft function according to Halloran criteria (8) (primary outcome) and acute cell mediated graft rejection (primary outcome).
Conditions
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Study Design
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CASE_ONLY
PROSPECTIVE
Eligibility Criteria
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Inclusion Criteria
* cadaveric transplantation
* conventional standard immunosuppression plan (methylprednisolone, cyclosporin A, mycophenolate mofetil)
Exclusion Criteria
* other than local standard immunosuppression
* panel reactive antibodies (PRA) \>30%
* warfarin therapy
* dual anti-platelet therapy
* use of low molecular weight heparins (LMWH) or fondaparinux during last two weeks before surgery for other indication than hemodialysis
18 Years
ALL
No
Sponsors
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University of Helsinki
OTHER
Helsinki University Central Hospital
OTHER
Responsible Party
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Arie Passov
MD, Resident in Anaesthesiology and Intensive Care Medicine
Principal Investigators
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Eero Pesonen, PhD
Role: STUDY_CHAIR
Helsinki University Central Hospital
Locations
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Helsinki University and Helsinki University Hospital
Helsinki, , Finland
Countries
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References
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Eltzschig HK, Eckle T. Ischemia and reperfusion--from mechanism to translation. Nat Med. 2011 Nov 7;17(11):1391-401. doi: 10.1038/nm.2507.
Nemeth N, Furka I, Miko I. Hemorheological changes in ischemia-reperfusion: an overview on our experimental surgical data. Clin Hemorheol Microcirc. 2014;57(3):215-25. doi: 10.3233/CH-131648.
Sevastos J, Kennedy SE, Davis DR, Sam M, Peake PW, Charlesworth JA, Mackman N, Erlich JH. Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood. 2007 Jan 15;109(2):577-83. doi: 10.1182/blood-2006-03-008870. Epub 2006 Sep 21.
Esmon CT. Targeting factor Xa and thrombin: impact on coagulation and beyond. Thromb Haemost. 2014 Apr 1;111(4):625-33. doi: 10.1160/TH13-09-0730. Epub 2013 Dec 12.
Sorensen-Zender I, Rong S, Susnik N, Lange J, Gueler F, Degen JL, Melk A, Haller H, Schmitt R. Role of fibrinogen in acute ischemic kidney injury. Am J Physiol Renal Physiol. 2013 Sep 1;305(5):F777-85. doi: 10.1152/ajprenal.00418.2012. Epub 2013 Jun 26.
Favreau F, Thuillier R, Cau J, Milin S, Manguy E, Mauco G, Zhu X, Lerman LO, Hauet T. Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model. Am J Transplant. 2010 Jan;10(1):30-9. doi: 10.1111/j.1600-6143.2009.02924.x. Epub 2009 Dec 2.
Turunen AJ, Lindgren L, Salmela KT, Kyllonen LE, Petaja J, Pesonen EJ. Intragraft coagulation events and delayed graft function in clinical renal transplantation. Transplantation. 2008 Mar 15;85(5):693-9. doi: 10.1097/TP.0b013e31816615d8.
Halloran PF, Aprile MA, Farewell V, Ludwin D, Smith EK, Tsai SY, Bear RA, Cole EH, Fenton SS, Cattran DC. Early function as the principal correlate of graft survival. A multivariate analysis of 200 cadaveric renal transplants treated with a protocol incorporating antilymphocyte globulin and cyclosporine. Transplantation. 1988 Aug;46(2):223-8.
Other Identifiers
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Dnro/64/13/03/02/2015
Identifier Type: OTHER
Identifier Source: secondary_id
Dnro/64/13/03/02/2015
Identifier Type: -
Identifier Source: org_study_id
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