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Title: HOT study : the development, management and results from phase IIB, randomised controlled trial of heme arginate in recipients of deceased donor renal transplants
Author: Thomas, Rachel Alexandra Barclay
ISNI:       0000 0004 6421 2897
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2016
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Aims There are few proven therapies that can protect against the inevitable ischaemia reperfusion injury (IRI) that occurs during renal transplantation. IRI increases the likelihood of delayed graft function (DGF), which negatively impacts on the long-term survival of a transplanted kidney. One enzyme of interest, heme oxygenase-1 (HO-1), degrades heme and protects against the oxidative stress that occurs secondary to IRI. Clinical renal recipients with higher HO-1 levels have improved graft function post transplant. Heme arginate (HA), a form of hemin, which has been used to treat porphyria for over 30 years, has repeatedly been shown to induce HO-1 in in vivo and in vitro macrophages. It is one of the few HO-1 inducers approved for clinical use and healthy volunteer studies confirmed that HA could also safely induce HO-1 in humans. Prior to the formal start of the MD, the University of Edinburgh successfully applied to NHS Blood and Transplant for funding to investigate whether giving HA to recipients of deceased donor renal grafts prior to transplant could upregulate HO-1 and whether this had any effect on the function and health of the grafts. This MD aims to explain the background behind the proposed study, the process of study approval, planning and trial logistics and protocol. This thesis then describes the methods of sample analysis, the results and future directions for the HOT (Heme Oxygenase-1 in renal Transplantation) study. Methods The HOT study planning and approval process took eight months and the first participant was randomised in January 2012. The study was sponsored by ACCORD, a joint company from University of Edinburgh and NHS Lothian, and recruited patients from the Edinburgh Royal Infirmary Transplant Unit. The protocol was followed to ensure that 40 recipients were randomised blind to either active (two doses 3mg kg-1 HA: pre-operatively, day 2) or placebo (NaCl: same schedule). To ensure that the primary outcome was fulfilled, recipient blood was taken daily for peripheral blood mononuclear cells (PBMC) extraction. After further blinding steps, the PBMCs were analysed for HO-1 protein and mRNA. The secondary outcome measures involved collecting urine for analysis of urinary biomarkers (KIM-1 and NGAL), taking renal graft biopsies pre-op and day 5 for renal HO-1 analysis and collecting renal function data. DGF was calculated daily. To ensure that all adverse event data was captured, the recipients were closely reviewed for 7 days and their renal function was monitored for 90 days. Results The final participant was recruited in May 2013 within the predicted timescale and to budget. This participant completed follow-up in August 2013. Of the 40 participants, three received the infusion but did not receive a transplant and therefore could not give primary outcome data. The remaining 37 did and this was analysed. Adverse events were equivalent between groups and there were no adverse reactions to HA. HA upregulated PBMC HO-1 protein at 24 hours compared to placebo: HA 11.1ng/ml (1.0- 37.0) vs. placebo 0.14ng/ml (-0.7- 0.3)(p= < 0.0001). PBMC HO-1 mRNA was also increased: HA 2.73 fold (1.8- 3.2) vs. placebo 1.41 fold (1.2- 2.2) (p=0.02). HA increased HO-1 protein immunopositivity in day 5 renal tissue compared with placebo: HA 0.21 (-24- 0.7) vs. placebo -0.03 (-76- 0.15) (p=0.02) and the percentage of HO-1 positive renal macrophages also increased: HA 50.8 cells per HPF (40.0- 59.8) vs. placebo 22.3 (0- 34.8) (p=0.012). Renal HO-1 mRNA was also increased in HA group: 2.02 (0.20- 4.03) fold increase compared to 1.68 (0.75- 10.39) fold in the placebo group but it was not significant (p= 0.451). Urinary biomarkers were reduced after HA but not significantly so. Histological injury and DGF rates were similar between the groups. Conclusion HA is safe and effective in renal transplant recipients as reported in this phase II, randomised, placebo controlled, blinded, single-centre study. The primary outcome was achieved and demonstrated for the first time that HA induces HO-1 in peripheral and renal macrophages in kidney transplant recipients. There was also evidence that HA increased HO-1 expression in renal tissue. There was no evidence that HA improved renal function or reduced injury as seen in animal models but it is recognised that the sample size was small and the study was not powered to these endpoints. Larger studies are planned to determine the impact of HO-1 upregulation on clinical outcomes and evaluate the benefit to patients at risk of IRI. The plans for HOT2 are expanded in this thesis.
Supervisor: Marson, Lorna Sponsor: National Health Service (NHS)
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: ischaemia reperfusion injury ; IRI ; renal transplantation ; heme arginate ; heme oxygenase-1 ; HOT study