Page 79 - Read Online

Zor et al. Mini-invasive Surg 2018;2:12 I http://dx.doi.org/10.20517/2574-1225.2017.34 Page 3 of 7

paramount importance in IRI [20,21] . In their study, Xue et al. demonstrated the evidence that IPC mediated
[22]
homing of endothelial progenitor cells played an important role in the protection of IRI. Despite all these
increasing number of published studies evaluating the exact mechanisms of IRI, protective effects of IPC
remains far from complete.

ANIMAL STUDIES AND CLINICAL EVIDENCE OF IPC
Since Murry et al. described IPC in the late 1980s, several studies demonstrating its protective effects on
[1]
kidney have been published. In 2012, Wever et al. published a systematic review and meta-analysis of
[16]
experimental animal studies regarding renal IPC. Serum creatinine, BUN levels and histologic changes
were evaluated. They found that serum creatinine and BUN levels decreased significantly and the histologic
changes were less important in the IPC group. They also performed subgroup analysis to investigate several
predefined factors such as window of protection (early or late), site of preconditioning (remote and local),
species (mouse or rat) and gender. In conclusion they found that IPC had persistent protective effects in all
subgroups except for female experiments (only two studies). This meta-analysis indisputably demonstrates
that renal IPC has protective effects to subsequent IRI, at least for small animals, since 91% of all studies were
performed in rats or mice. On the flip side, there are unfortunately limited numbers of larger animal studies,
with conflicting results. In a porcine model, Hernandez et al. demonstrated that IPC had no protective
[23]
effect. Yoon et al. also demonstrated similar results. In their study on pigs, they found that IPC had no
[24]
effect on serum creatinine. In contrast, levels of renal injury markers were lower in the late phase of IPC
performed pigs, indicating protective effect that was not reflected in serum creatinine. Taken together, later
studies suggest that the positive protective effects of IPC in small animals like rats may not be applicable to
larger animal models. It seems that alternative IPC regimens need to be determined in the future.

In the light of the studies published to date, now we can talk about that IPC induces biphasic protection
against IRI. Early mediators including adenosine, bradykinins, catecholamines, and opioids provide a strong,
but short-lived, “classic” early protection [25,26] . While short-term mediators provide the initial protection, the
activation of transcription factors and de novo protein synthesis provide a late onset, less stronger but more
durable protection against ischemia called “second window of protection” . The concept was previously
[27]
described for cardiac IPC but it is also applicable for renal IPC . In a systematic review, Wever et al.
[16]
[28]
demonstrated that second window (≥ 24 h) of protection was more effective in decreasing serum creatinine
after renal IRI. In their study on dogs, Kosieradzki et al. were not able to demonstrate either early or late
[29]
protective effects of IPC. But the study was performed on dogs and previous studies demonstrated that the
effect of IPC in each animal species varies.

REMOTE ISCHEMIC PRECONDITIONING
In routine clinical practice the role of local IPC is very limited due to the increased risk of damage to the
vascular structures. Additionally, even short-term ischemia may lead further injury in the target tissue. To
avoid from the effects of local IPC the term of remote IPC is introduced, which is a more potentially clinically
practical technique. This term describes the application of IPC stimulus to a remote organ e.g. a limb, which is
relatively resistant to IRI. The underlying mechanisms of remote IPC are not fully demonstrated, but current
concepts suggest that the protective mediators are produced secondary to the stimulus created by remote
IPC. These produced mediators carry the protective effect from the site of remote IPC to the target organ .
[30]
It can be performed noninvasively by simply inflating and deflating a standard blood-pressure cuff placed on
the upper arm or thigh to induce transient ischemia and reperfusion . Most of the studies published to date
[31]
demonstrated its cardiac protective effects, but there are also some studies that have revealed the potential of
protective properties on kidney injury. Wever et al. reported 30% to 60% improvement of renal protection
[16]
and reduction of renal tubule damage with remote IPC. In another study, Ali et al. found that it reduced
[32]
the incidence of renal impairment. In the meta-analysis of Wever et al. , renoprotective effects of brief
[16]