Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics
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Clinical Proteomics Open Access
RESEARCH
Subclinical effects of remote ischaemic conditioning in human kidney transplants revealed by quantitative proteomics Adam M. Thorne1,2†, Honglei Huang1,2†, Darragh P. O‘Brien2, Marco Eijken3,4, Nicoline Valentina Krogstrup3,5 , Rikke Norregaard4, Bjarne Møller6, Rutger J. Ploeg1*, Bente Jespersen3,4* and Benedikt M. Kessler2*
Abstract Background: Remote ischaemic conditioning (RIC) is currently being explored as a non-invasive method to attenuate ischaemia/reperfusion injuries in organs. A randomised clinical study (CONTEXT) evaluated the effects of RIC compared to non-RIC controls in human kidney transplants. Methods: RIC was induced prior to kidney reperfusion by episodes of obstruction to arterial flow in the leg opposite the transplant using a tourniquet (4 × 5 min). Although RIC did not lead to clinical improvement of transplant outcomes, we explored whether RIC induced molecular changes through precision analysis of CONTEXT recipient plasma and kidney tissue samples by high-resolution tandem mass spectrometry (MS/MS). Results: We observed an accumulation of muscle derived proteins and altered amino acid metabolism in kidney tissue proteomes, likely provoked by RIC, which was not reflected in plasma. In addition, MS/MS analysis demonstrated transient upregulation of several acute phase response proteins (SAA1, SAA2, CRP) in plasma, 1 and 5 days post-transplant in RIC and non-RIC conditions with a variable effect on the magnitude of acute inflammation. Conclusions: Together, our results indicate sub-clinical systemic and organ-localised effects of RIC. Keywords: CONTEXT clinical trial, Remote ischaemic conditioning, Acute phase proteins, ELISA, Proteomics, Mass spectrometry, Kidney transplantation Introduction Remote ischaemic conditioning (RIC) has been propagated as a therapeutic strategy to protect organs against ischaemia/reperfusion injury (IRI). Within the setting of kidney transplantation, organ ischaemia is inevitable, and *Correspondence: [email protected]; [email protected]; [email protected] † Adam M. Thorne and Honglei Huang contributed equally to this work 1 Nuffield Department of Surgical Sciences and Oxford Biomedical Research Centre, University of Oxford, Oxford, UK 2 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK 3 Department of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark Full list of author information is available at the end of the article
the resultant IRI can initiate a multitude of changes in the recipient, ranging from depletion of oxygen and nutritional supplies to mechanical tissue disruption, oedema and infiltration of immune cells [1]. IRI-inflicted tissue damage is complex, involving a variety of mechanisms that are not yet fully understood. Key to this is the production of reactive oxygen species (ROS) by anaerobic metabolism in response to hypoxic stress, a drop in cellular pH, and a rapid depletion of ATP. This constitutes a highly damaging
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