Induction of HO-1; a Therapeutic Approach to Reduce Ischaemia Reperfusion Injury (IRI) Following Deceased Donor Renal Transplantation

Study Overview
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Brief Summary
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This is a blinded, placebo-controlled, randomised controlled trial looking at the effects of Heme arginate (HA) on cadaveric renal transplantation. The investigators know that HA can upregulate HO-1, which has been shown to have a protective effect on animal transplants. The investigators will be giving HA/placebo to participants prior to transplant and repeat again on day 2 post-transplant and compare outcomes.

Detailed Description
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Patients will be recruited from the East of Scotland transplant waiting list and consent when they arrive in the hospital. The investigators will randomise them to drug or placebo and give the infusion prior to induction for their transplant. A blood sample will be taken prior to infusion and a renal biopsy will be taken before the graft is implanted. These will be used as baseline values. Patients will receive standard care from our unit. The investigators will use the routine blood test results (urea and creatinine) to determine the function of the graft. The investigators will take blood samples 24 hours after infusion of drug/placebo and use this to determine the primary outcome. Blood tests will be taken daily and a renal biopsy taken on day 5 to fulfil secondary objectives.

Official Title
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A Randomised Placebo-Controlled Trial to Investigate the Effect of Pre-treatment With Haem Arginate (Normosang) on Heme-Oxygenase 1 (HO-1) Upregulation in Recipients of Deceased Donor Kidneys

Conditions
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Graft Failure, Ischemia-reperfusion Injury

Intervention / Treatment
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* Drug: Heme arginate (Normosang)
* Drug: 0.9% sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: all patients receiving a cadaveric single kidney transplant patients on a standard immunosuppressive regime Exclusion Criteria: patients on different immunosuppressives patients receiving 3rd or subsequent kidney transplant patients are fully anti-coagulated patients unable to take Heme Arginate patients unable to give informed consent patients on combined anti-platelet agents

Ages Eligible for Study
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Minimum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Heme arginate (Normosang)<br>This arm will receive 2 doses of Heme Arginate (trade name Normosang); 1 dose prior to transplant and another on day 2. This is a product derived from human hemin and has been used for over 20 years in clinical practice with few side-effects. | Drug: Heme arginate (Normosang)<br>* 3mg/kg as a single IV infusion prior to transplant over 30 mins and same dose repeated on day 2 post-transplantation. Each drug infusion will be followed by 100ml saline IV to flush the line.<br>* Other names: Hemin;|
| Placebo Comparator: 0.9% saline<br>The saline will be given as an IV infusion in the same manner as the Heme Arginate (active comparator) infusion. | Drug: 0.9% sodium chloride<br>* Solution for infusion, this will be given prior to transplantation and again on day 2; the same as active drug.<br>* Other names: Normal saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Macrophage/monocyte HO-1 protein levels | We will measure the level of HO-1 protein in isolated macrophages/ monocytes in a peripheral blood sample taken at 24 hours after drug infusion | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Macrophage/monocyte HO-1 mRNA levels | We will measure HO-1 mRNA levels in macrophages/monocytes from a peripheral blood sample taken at 24 hours. | 24 hours | 
| HO-1 protein in kidney transplant | We will measure the level of HO-1 protein in kidney tissue from a biopsy sample taken 5 days after drug infusion. This will be compared to baseline | 5 days | 
| Effect on transplanted kidney function | We will record how the kidney functions by determining presence or absence of delayed graft function. | daily for 5 days | 
| Urinary biomarkers as markers of injury | We will collect urine to measure the presence of specific urinary biomarkers and correlate with renal function. | daily for 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Transplantation, Ischemia-reperfusion injury, Heme-oxygenase 1, Heme arginate