Clinical Trial of New Hypothermic Oxygenated Perfusion System Versus Static Cold Storage

Study Overview
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Brief Summary
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With the present study the investigators will evaluate the benefit of end-ischemic HOPE on ECD grafts (livers and kidneys) as compared to SCS. Organs will be perfused through a recently developed machine perfusion (MP) device, from the beginning of back-table procedures till implantation, without increasing CIT. The aim of the study will be demonstrating the ability of HOPE to improve graft function and post-operative outcomes of ECD kidney and liver recipients.

Detailed Description
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Extended criteria donors (ECD) are widely utilized due to organ shortage, but this may increase the risk of graft dysfunction and of poorer outcomes. Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, which allows to redirect anaerobic metabolism to aerobic metabolism under hypothermic conditions and to protect grafts from oxidative species-related damage; these mechanisms may potentially improve graft function and survival. Methods This is an open-label, randomized multicenter clinical trial with the aim of comparing HOPE vs. static cold storage (SCS) in ECD kidney and liver transplantation. In the study protocol - approved by ethics committee - 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to HOPE will be perfused by machine perfusion with cold Belzer solution (4°-10°C) and with continuous oxygenation (partial pressure of oxygen = 500-600 mmHg). In the control group, livers and kidneys undergoing SCS will be steeped in Celsior or University of Wisconsin Belzer solutions and stored in ice. Using the same perfusion machine for both liver and kidney grafts, organs will be perfused from the start of the back-table procedure until implantation, without increasing cold ischemia time (CIT). For each group the investigators will evaluate clinical outcomes, graft function tests and histologic findings, as well as perfusate and the number of allocated organs.

Official Title
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Expanded Criteria Donors in Liver and Kidney Transplantation: Protocol of a Randomised Single Center Clinical Trial of Hypothermic Oxygenated Perfusion Versus Static Cold Storage

Conditions
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Liver Diseases, Kidney Diseases

Intervention / Treatment
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* Device: Kidney-Hypothermic oxygenated
* Device: Liver-Hypothermic oxygenated


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For kidneys: donor age ≥ 60 years or 50-59 years with two or more of the sequent risk factors: death due to cerebrovascular accident, history of hypertension, donor serum creatinine > 1.5 mg/dL, cold ischemia time (CIT) > 20 h; For livers: donors with hemodynamic deterioration, donor age > 65 years, donor body mass index > 30 kg/m2, serum bilirubin > 3 mg/dl, AST or ALT above three times the upper reference threshold, sodium > 165 mmol/l, intensive care unit (ICU) stay > 7 days, steatosis > 40%, CIT > 12 h. Exclusion Criteria: Donor age ≤18 years; Donors after circulatory death (DCD) will be excluded, because Italian law requires 20 minutes of no touch period before death declaration, causing prolonged warm ischemia and subsequent mandatory perfusion of the organ. Split-liver recipients, liver transplantation (LT) for acute liver failure, pre-emptive renal transplant, dual kidney transplantation, and patients with intra-operative surgical complications before the organ implantation.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Kidney-Hypothermic oxygenated<br>Belzer machine perfusion solution at 4°C-10°C in sterile conditions and continuous oxygenation (partial pressure of oxygen=500-600 mmHg) will be used for perfusion 2000 ml for kidneys. | Device: Kidney-Hypothermic oxygenated<br>* Kidney perfusion will be performed through the renal artery at 25-30 mmHg pressure. Flow, pressure and temperature will be monitored and registered on a Universal Serial Bus (USB) memory system during organ perfusion. Gas analysis of the effluent perfusate will be accomplished at the start of perfusion (T0) then every 30 minutes. Two perfusate samples will be collected at the beginning and at the end of perfusion to rule out bacterial or fungal contamination. HOPE will start by flushing the organ at low flow values (20 ml/min) with new oxygenated perfusion fluid during back-table preparation. Organ will be treated with continuous HOPE until transplant. Organ perfusion will be continuously monitored. Minimal perfusion time will be 2 hours for kidneys.<br>|
| No Intervention: Kidney-Static Cold Storage<br>Kidneys undergoing SCS will be stored in sterile organ bags with Celsior or University of Wisconsin solution and cooled in ice. | |
| Experimental: Liver-Hypothermic oxygenated<br>Belzer machine perfusion solution at 4°C-10°C in sterile conditions and continuous oxygenation (partial pressure of oxygen=500-600 mmHg) will be used for perfusion 3000 ml for livers. | Device: Liver-Hypothermic oxygenated<br>* Liver perfusion will be performed through the portal vein at a 5 mmHg pressure. Flow, pressure and temperature will be monitored and registered on a Universal Serial Bus (USB) memory system during organ perfusion. Gas analysis of the effluent perfusate will be accomplished at the start of perfusion (T0) then every 30 minutes. Two perfusate samples will be collected at the beginning and at the end of perfusion to rule out bacterial or fungal contamination. HOPE will start by flushing the organ at low flow values (30 ml/min) with new oxygenated perfusion fluid during back-table preparation. Organ will be treated with continuous HOPE until transplant. Organ perfusion will be continuously monitored. Minimal perfusion time will be 1 hour for livers.<br>|
| No Intervention: Liver-Static Cold Storage<br>Livers undergoing SCS will be stored in sterile organ bags with Celsior or University of Wisconsin solution and cooled in ice. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver Transplant - Early allograft dysfunction (EAD) | Present/Non present | 0-30 days after procedure | 
| Kidney Transplant- Delayed graft function (DGF) | Present/Non present | 0-30 days after procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver and Kidney surgical complications | Present/Non present | 0-6 months after procedure | 
| Liver and Kidney graft function at 6 and 12 months | Functioning/non functioning | 0-12 months after procedure | 
| Patient survival at 6 and 12 months | Alive/Death | 0-12 months after procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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donors and donation, Extended criteria donor, Organ perfusion and preservation, Liver transplantation, Kidney transplantation, Preservation injury, Ischemia reperfusion injury