Preconditioning against renal ischaemia reperfusion injury: the failure to translate to the clinic
- 34 Downloads
Acute kidney injury (AKI) as a result of ischaemia–reperfusion represents a major healthcare burden worldwide. Mortality rates from AKI in hospitalized patients are extremely high and have changed little despite decades of research and medical advances. In 1986, Murry et al. demonstrated for the first time the phenomenon of ischaemic preconditioning to protect against ischaemia–reperfusion injury (IRI). This seminal finding paved the way for a broad body of research, which attempted to understand and ultimately harness this phenomenon for human application. The ability of preconditioning to limit renal IRI has now been demonstrated in multiple different animal models. However, more than 30 years later, a safe and consistent method of protecting human organs, including the kidneys, against IRI is still not available. This review highlights agents which, despite strong preclinical data, have recently failed to reduce AKI in human trials. The multiple reasons which may have contributed to the failure to translate some of the promising findings to clinical therapies are discussed. Agents which hold promise in the clinic because of their recent efficacy in preclinical large animal models are also reviewed.
KeywordsIschaemia Reperfusion Preconditioning Zinc Animal models Translation
Hypoxia inducible factor
Acute kidney injury
Manuscript writing/editing: all authors.
This work was in part supported by the Austin Health Medical Research Foundation and by The University of Melbourne.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
For this type of study formal consent is not required.
- 13.Bolli R, Becker L, Gross G, Mentzer R Jr, Balshaw D, Lathrop DA, Ischemia NWGotToTfPtHf (2004) Myocardial protection at a crossroads: the need for translation into clinical therapy. Circ Res 95:125–134. https://doi.org/10.1161/01.RES.0000137171.97172.d7 CrossRefGoogle Scholar
- 17.Cragg L, Hebbel RP, Miller W, Solovey A, Selby S, Enright H (1998) The iron chelator L1 potentiates oxidative DNA damage in iron-loaded liver cells. Blood 92:632–638Google Scholar
- 20.Duke GJ (1999) Renal protective agents: a review. Crit Care Resusc 1:265–275Google Scholar
- 32.Investigators ACT (2011) Acetylcysteine for prevention of renal outcomes in patients undergoing coronary and peripheral vascular angiography: main results from the randomized acetylcysteine for contrast-induced nephropathy trial (ACT). Circulation 124:1250–1259. https://doi.org/10.1161/CIRCULATIONAHA.111.038943 CrossRefGoogle Scholar
- 34.Jones SP et al (2015) The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res 116:572–586. https://doi.org/10.1161/CIRCRESAHA.116.305462 CrossRefGoogle Scholar
- 38.Karajala V, Mansour W, Kellum JA (2009) Diuretics in acute kidney injury. Minerva Anestesiol 75:251–257Google Scholar
- 43.Lefer D et al (2014) Sodium nitrite fails to limit myocardial infarct size: results from the CAESAR Cardioprotection Consortium (LB645). FASEB J 28:LB645Google Scholar
- 65.Thapalia BA, Zhou Z, Lin X (2014) Autophagy, a process within reperfusion injury: an update. Int J Clin Exp Pathol 7:8322–8341Google Scholar