Description of the condition
Ischaemia reperfusion injury is defined as damage to an organ that occurs after a critical period of ischaemia, followed by restoration of blood supply. This can happen spontaneously, such as in stroke or myocardial infarction, or during transplantation and other types of surgery. Cells become deprived of oxygen in the ischaemic phase, and as a result, metabolism switches from aerobic to anaerobic glycolysis, leading to cell swelling, acidosis, ATP depletion, intracellular sodium (Na+) and calcium ion (Ca2+) overload and inhibition of the mitochondrial respiration chain. This leads to cell death in minutes to hours, depending on the cell type. Restoration of blood flow after ischaemia is therefore essential for cell survival. However, reperfusion of ischaemic tissue invokes paradoxical effects that are detrimental, rather than beneficial, to cells. This particularly holds true for sudden restoration of oxygen (which leads to oxidative stress), pH (which can induce cell death), and evoked inflammatory response. Inflammatory response induces adhesion of cytokine-releasing leukocytes, which attracts neutrophils, macrophages, lymphocytes and dendritic cells to the site. This may cause further release of reactive oxygen species and microvascular dysfunction (Bonventre 1988; Piper 1998; Yellon 2007).
Ischaemia reperfusion injury can lead to organ dysfunction or failure and is a significant clinical problem in transplantation, shock and major surgery. The high metabolism and vascular anatomy of the kidney is particularly sensitive to ischaemia reperfusion injury. The critical ischaemic period is organ-dependent: 15 to 20 minutes of ischaemia has been shown to cause irreversible damage to the kidney (Jaeschke 2002; Safian 2001; Schrier 2004).
Description of the intervention
Ischaemic preconditioning is a short and harmless period of deprivation of blood supply to particular organs or tissue, followed by a period of reperfusion (Chen 2009; Hausenloy 2009; Yin 1998). Preconditioning stimulus is applied before onset of ischaemia reperfusion injury to a target organ. In 1986 it was shown that ischaemic preconditioning on the heart can reduce ischaemia reperfusion injury, (local ischaemic preconditioning) (Murry 1986), and has since been reproduced in many other target organs. Later on, studies have shown that ischaemic preconditioning of remote organs and tissues at a distance can protect the target organ from ischaemia reperfusion injury as well (remote ischaemic preconditioning) (Przyklenk 1993). Use of the limbs as remote tissue offers many advantages, since skeletal muscle is less susceptible to ischaemia reperfusion injury than visceral tissues.
A typical schedule of four, five minute periods of ischaemic preconditioning, separated by five minutes of reperfusion, applied directly before the ischaemia reperfusion injury period of the target organ, is used in most clinical studies. Numerous variations to this schedule have been studied in animals and the efficacy of the ischaemic preconditioning has been shown to vary, depending on the preconditioned tissue volume, length of ischaemic preconditioning, reperfusion and time between ischaemic preconditioning and ischaemia reperfusion injury. The optimal schedule is still unclear and is probably different for different target organs and species (Alreja 2012; Cochrane 1999; Wever 2012).
How the intervention might work
Several endogenous molecules have been implicated in local and remote ischaemic preconditioning signalling, most of which are known to have cytoprotective effects. Downstream, the ultimate protective step in ischaemic preconditioning signalling appears to be inhibition of mitochondrial permeability transition pore opening, which prevents cell death. Remote and local ischaemic preconditioning appear to be similar in terms of invoking mitochondrial permeability transition pore inhibition, and many signalling molecules seem to be similar to those implicated in local ischaemic preconditioning signalling. However, remote ischaemic preconditioning requires transduction of the protective signal from the remote organ or tissue to the target organ.
The protective effects of ischaemic preconditioning are found both directly after application of the stimulus (early window of protection; EWOP), and in the days or weeks following (second window of protection). In animal models, both windows of protection have been shown to reduce renal ischaemia reperfusion injury (Wever 2012). Although there are similarities in the mechanisms underlying early and second windows of protection, the second window of protection has been found to require de novo protein synthesis of distal mediators such as iNOS and COX-2. However, remote ischaemic preconditioning signalling has been most extensively studied in the early window of protection, where three major pathways have been indicated in this process (Figure 1): the humoral route, the neurogenic pathway and alteration of immune cells. Signalling via the humoral route (upper route in Figure 1) requires release of signalling molecules such as adenosine or endorphins from the remote organ into the bloodstream, which are then carried to the target organ to exert their protective effects via their respective receptors.
The nervous system also appears to play a role in some models of remote ischaemic preconditioning: denervation or ganglion blockade inhibit the protective effect of remote ischaemic preconditioning (middle route). Activation of the neurogenic pathway by peptides released from the remote organ may cause systemic factor release (combined humoral-neurogenic route), lead to local factor release or activation of central reflexes. Both the humoral and the neurogenic pathways are thought to induce various kinase cascades and eventually prevent opening of the mitochondrial permeability transition pore in the target organ cells, thereby reducing cell death. Thirdly, remote ischaemic preconditioning has been shown to modulate gene and receptor expression on immune cells, which therefore pose a third signalling pathway that presumably reduces damage by altering the inflammatory response (lower route) (Tapuria 2008).
Why it is important to do this review
Despite that the efficacy of ischaemic preconditioning has been acknowledged since described by Murry 1986, the technique was introduced into clinical trials only relatively recently; however, results to date have not been consistently positive (Ali 2007; Choi 2011; Walsh 2008; Walsh 2010; Zimmerman 2011). Although experimental data show promise, the mechanism underlying ischaemic preconditioning signalling remains unclear and the optimal preconditioning protocol remains unknown (Wever 2012).
The kidney is very sensitive to ischaemia reperfusion injury, and therefore, is an organ system that can benefit from ischaemic preconditioning. Furthermore, kidney function and damage are very well documented and can be tested using robust endpoints. The kidney is therefore an ideal target organ to investigate the protective effects of ischaemic preconditioning on renal ischaemia reperfusion injury.