Clinical trial NCT02568696: Intra-graft Coagulation Events in Clinical Renal Transplantation and Delayed Graft Function
Official title: Activation of Coagulation Pathways in Clinical Renal Allotransplantation and Delayed Graft Function and Acute Rejection of the Graft
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: End Stage Renal Disease
Reperfusion Injury
Delayed Graft Function
Kidney Transplantation
Keywords: kidney transplantation
renal transplantation
fibrinolysis
cell mediated rejection
coagulation
delayed graft function
Halloran criteria
graft rejection
thrombin generation
fibrin generation
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
Collaborators: name: University of Helsinki
First posted: 2015-10-06
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: In Finland all adult kidney transplantation surgeries are performed at investigators institution. Study population consists of all adult patients fulfilling inclusion criteria admitted to the hospital for cadaveric renal transplantation.

Brief summary: The purpose of this study is to investigate local activation of the coagulation system in the kidney graft during organ preservation and during early reperfusion in adult kidney transplantation. Generation of thrombin and fibrin as well as activation and inhibition of fibrinolysis will be investigated. Influence of these events on delayed graft function (DGF) and acute cell-mediated rejection will be evaluated.

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).

Eligibility criteria: 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

Primary outcomes:
measure: Trans-renal difference/ratio of plasma concentrations of coagulation measurements
timeFrame: Two minutes after reperfusion of the kidney transplant
measure: Delayed Graft Function
timeFrame: During 1 week after kidney transplantation
measure: Acute cell mediated graft rejection
timeFrame: During 3 months after kidney transplantation
Secondary outcomes:
measure: Plasma creatinine value (micromol/L)
timeFrame: At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
measure: Plasma urea value (mmol/L)
timeFrame: At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
measure: Estimated glomerular filtration rate (ml/min/1.73 m2)
timeFrame: At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation
measure: Urine output (ml/24h)
timeFrame: Pre-operative urine output (ml/24h) and daily urine output (ml/24h) during the first week after transplantation
measure: Renal artery and renal vein blood flow (ml/min)
timeFrame: Immediately after blood sample retrieval during reperfusion
measure: Fluid balance during surgery and post-anesthesia care unit stay (ml)
timeFrame: 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)
measure: Transfusion
timeFrame: 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)
measure: Prothrombin fragment 1+2 (F1+2)
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: Fibrinopeptide A
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: D-dimers
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: Tissue type plasminogen activator
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: Plasminogen activator inhibitor
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: Syndecan-1
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: Myeloperoxidase and/or lactoferrin
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: Interleukin 6, interleukin 8, interleukin 10
timeFrame: Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant
measure: Number of hemodialyses and their indication after surgery
timeFrame: From the start of the surgery until 3 months after surgery
Other outcomes:
Locations:
city: Helsinki
country: Finland
facility: Helsinki University and Helsinki University Hospital
Study officials:
affiliation: Helsinki University Central Hospital
name: Eero Pesonen, PhD
role: STUDY_CHAIR
References:
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.