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Clinical Trial: Heme Arginate in patients planned for Cardiac Surgery (HACS)

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Background/Introduction

Acute kidney injury (AKI) is a significant complication of cardiac surgery and is associated with increased morbidity and mortality [1]. Despite much research, there is no specific therapy available. Although AKI can be multifactorial, ischaemia reperfusion injury (IRI) often plays a key role. Thus, cardiac surgery offers an attractive opportunity for translational AKI research given the predictive haemodynamic challenge to renal perfusion.

Hemeoxygenase-1 (HO-1) is a key inducible anti-inflammatory enzyme that catalyses the breakdown of the pro-oxidant protein heme ubiquitously found at inflamed sites. The drug heme arginate has been in use for over 20 years in the treatment of porphyria but also upregulates HO-1 in peripheral blood mononuclear cells (PBMCs) [2] and ameliorates calf muscle ischaemia [3]. In addition, treatment of mice with heme arginate prior to renal IRI strongly upregulates renal HO-1 expression and protects from AKI [4]. We therefore hypothesise that HA may offer a prophylactic therapy for human renal IRI via the upregulation of HO-1.

Aims/Objectives

The HACS Trial aims to determine whether heme arginate will upregulate HO-1 in PBMCs in patients aged 60 or above who are scheduled for cardiac surgery, and to verify its safety in this patient cohort.

Method

20 participants, who are scheduled for elective cardiac surgery, will be randomised to receive 1 mg/kg or 3 mg/kg heme arginate. The primary end point will be the difference in PBMC HO-1 protein from baseline at 24 hours. Secondary end points include HO-1 gene expression, safety and HO-1 genotype.

Results

Results are expected in July 2015. At the time of abstract submission, 14 of 20 participants have been recruited.

Discussion/Conclusion

Data from the HACS trial will inform a subsequent multicentre randomised controlled trial of heme arginate versus placebo in the prevention of AKI in patients deemed to be at higher risk of developing AKI post cardiac surgery

References

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    Thakar CV, Worley S, Arrigain S, Yared JP, Paganini EP: Influence of renal dysfunction on mortality after cardiac surgery: modifying effect of preoperative renal function. Kidney Int. 2005, 67 (3): 1112-1119.

  2. 2.

    Doberer D, Haschemi A, Andreas M, Zapf TC, Clive B, Jeitler M, et al: Haem arginate infusion stimulates haem oxygenase-1 expression in healthy subjects. Br J Pharmacol. 2010, 161 (8): 1751-1762.

  3. 3.

    Andreas M, Schmid AI, Doberer D, Schewzow K, Weisshaar S, Heinze G, et al: Heme arginate improves reperfusion patterns after ischemia: a randomized, placebo-controlled trial in healthy male subjects. J Cardiovasc Magn Reson. 2012, 14: 55-

  4. 4.

    Ferenbach DA, Nkejabega NC, McKay J, Choudhary AK, Vernon MA, Beesley MF, et al: The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice. Kidney Int. 2011, 79 (9): 966-976.

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Author information

Correspondence to Fiona Duthie.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Duthie, F., Zamvar, V., Thomas, R. et al. Clinical Trial: Heme Arginate in patients planned for Cardiac Surgery (HACS). J Cardiothorac Surg 10, A69 (2015) doi:10.1186/1749-8090-10-S1-A69

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Keywords

  • Cardiac Surgery
  • Acute Kidney Injury
  • Ischaemia Reperfusion Injury
  • Porphyria
  • Muscle Ischaemia