- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02568696
Intra-graft Coagulation Events in Clinical Renal Transplantation and Delayed Graft Function (KTX)
Activation of Coagulation Pathways in Clinical Renal Allotransplantation and Delayed Graft Function and Acute Rejection of the Graft
Study Overview
Status
Detailed Description
Background
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).
Study Type
Enrollment (Actual)
Contacts and Locations
Study Locations
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Helsinki, Finland, 00029
- Helsinki University and Helsinki University Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Sampling Method
Study Population
Description
Inclusion Criteria:
- adult person (over 18 years old)
- cadaveric transplantation
- conventional standard immunosuppression plan (methylprednisolone, cyclosporin A, mycophenolate mofetil)
Exclusion Criteria:
- previous kidney transplant
- 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
Study Plan
How is the study designed?
Design Details
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Trans-renal difference/ratio of plasma concentrations of coagulation measurements
Time Frame: Two minutes after reperfusion of the kidney transplant
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Trans-transplant difference/ratio is determined in order to correlate intra-graft coagulation events to the incidences of other primary outcomes.
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Two minutes after reperfusion of the kidney transplant
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Delayed Graft Function
Time Frame: During 1 week after kidney transplantation
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Delayed graft function is assessed by Halloran criteria: oliguria < 1000ml/24h for more than 2 days after transplantation or plasma creatinine >500 micromol/l during the first week after transplantation or more than one dialysis during the first week after transplantation (Halloran et al, Transplantation 1988;46:223-8.)
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During 1 week after kidney transplantation
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Acute cell mediated graft rejection
Time Frame: During 3 months after kidney transplantation
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During 3 months after kidney transplantation
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Plasma creatinine value (micromol/L)
Time Frame: At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
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At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
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Plasma urea value (mmol/L)
Time Frame: At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
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At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
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Estimated glomerular filtration rate (ml/min/1.73 m2)
Time Frame: At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
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Estimated glomerular filtration rate is calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
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At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
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Urine output (ml/24h)
Time Frame: Pre-operative urine output (ml/24h) and daily urine output (ml/24h) during the first week after transplantation
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Urine output (ml/24h) before the surgery and during the first week after transplantation will be recorded
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Pre-operative urine output (ml/24h) and daily urine output (ml/24h) during the first week after transplantation
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Renal artery and renal vein blood flow (ml/min)
Time Frame: Immediately after blood sample retrieval during reperfusion
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Renal artery and renal vein blood flow (ml/min) are measured intra-operatively immediately after blood sample retrieval using a specific probe
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Immediately after blood sample retrieval during reperfusion
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Fluid balance during surgery and post-anesthesia care unit stay (ml)
Time Frame: From the start of the kidney transplantation surgery until the discharge from post-anesthesia care unit (up to 24 hours from the start of the surgery)
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All fluids infused from the start of the kidney transplantation surgery until discharge from the post-anaesthesia care unit (until discharge to the ward) are recorded.
All fluids losses (blood loss, urine output) during this period are recorded.
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From the start of the kidney transplantation surgery until the discharge from post-anesthesia care unit (up to 24 hours from the start of the surgery)
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Transfusion
Time Frame: From the start of the kidney transplantation surgery until the discharge from post-anesthesia care unit (up to 24 hours from the start of the surgery)
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All blood products used during this time frame are recorded and reported
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From the start of the kidney transplantation surgery until the discharge from post-anesthesia care unit (up to 24 hours from the start of the surgery)
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Prothrombin fragment 1+2 (F1+2)
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess thrombin generation.
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Fibrinopeptide A
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess fibrin generation.
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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D-dimers
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess fibrin degradation
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Tissue type plasminogen activator
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess activation of fibrinolysis.
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Plasminogen activator inhibitor
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess inhibition of fibrinolysis.
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Syndecan-1
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess degradation of endothelial glycocalyx
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Myeloperoxidase and/or lactoferrin
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess activation of neutrophiles
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Interleukin 6, interleukin 8, interleukin 10
Time Frame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Preoperative value and the trans-transplant difference and/or ratio is determined in order to assess activation/inhibition of inflammation
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Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
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Number of hemodialyses and their indication after surgery
Time Frame: From the start of the surgery until 3 months after surgery
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All dialysis sessions will be recorded during first post-operative week.
Indication for dialysis (oliguria, hyperkalemia, hypervolemia, acidosis) will be recorded during first post-operative week.
At 1 and 3 months after surgery only number of dialyses/week will be recorded
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From the start of the surgery until 3 months after surgery
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Collaborators and Investigators
Collaborators
Investigators
- Study Chair: Eero Pesonen, PhD, Helsinki University Central Hospital
Publications and helpful links
General Publications
- 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.
- 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.
- 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.
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- Dnro/64/13/03/02/2015 (Other Identifier: Ethics Committee, Department of Surgery, Hospital District of Helsinki and Uusimaa)
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