Activation of Coagulation Pathways in Clinical Renal Allotransplantation and Delayed Graft Function and Acute Rejection of the Graft
试验速览
- 阶段
- 不适用
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Trans-renal difference/ratio of plasma concentrations of coagulation measurements
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •adult person (over 18 years old)
- •cadaveric transplantation
- •conventional standard immunosuppression plan (methylprednisolone, cyclosporin A, mycophenolate mofetil)
排除标准
- •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
结局指标
主要结局
Trans-renal difference/ratio of plasma concentrations of coagulation measurements
时间窗: Two minutes after reperfusion of the kidney transplant
Trans-transplant difference/ratio is determined in order to correlate intra-graft coagulation events to the incidences of other primary outcomes.
Delayed Graft Function
时间窗: During 1 week after kidney transplantation
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.)
Acute cell mediated graft rejection
时间窗: During 3 months after kidney transplantation
次要结局
- Plasma urea value (mmol/L)(At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation)
- Estimated glomerular filtration rate (ml/min/1.73 m2)(At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation)
- Plasma creatinine value (micromol/L)(At admission to the hospital, during the first week after transplantation and at 1 and 3 months after renal transplantation)
- Urine output (ml/24h)(Pre-operative urine output (ml/24h) and daily urine output (ml/24h) during the first week after transplantation)
- Renal artery and renal vein blood flow (ml/min)(Immediately after blood sample retrieval during reperfusion)
- Fluid balance during surgery and post-anesthesia care unit stay (ml)(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))
- Transfusion(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))
- Prothrombin fragment 1+2 (F1+2)(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- Fibrinopeptide A(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- D-dimers(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- Tissue type plasminogen activator(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- Plasminogen activator inhibitor(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- Interleukin 6, interleukin 8, interleukin 10(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- Syndecan-1(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- Myeloperoxidase and/or lactoferrin(Blood samples are taken at two timepoints: 1) immediately before the start of the surgery; 2) 2 minutes after reperfusion of the kidney transplant)
- Number of hemodialyses and their indication after surgery(From the start of the surgery until 3 months after surgery)
研究者
Arie Passov
MD, Resident in Anaesthesiology and Intensive Care Medicine
Helsinki University Central Hospital