Repeated remote ischemic preconditioning and isoflurane anesthesia in an experimental model of renal ischemia-reperfusion injury

Ischemia reperfusion injury (IRI) is tissue damage caused by the restoration of blood flow after a period of deprived circulation of that tissue [1]. The deficit of oxygen and nutrients during the ischemic phase creates a condition in which the return of blood flow induces oxidative stress, inflammation and results in apoptosis of the cell [2]. This may lead to tissue damage and loss of organ function [3]. The kidney is an organ especially vulnerable to IRI, due to its high-energy demand and delicate microcirculation. IRI of the kidney is a significant clinical problem in shock, renal transplantation and major cardiac or vascular surgery [4]. A promising method to diminish IRI was first described in 1986 by Murry [5], he discovered that short harmless periods of ischemia can protect the heart against a prolonged ischemic period; this phenomenon is called ischemic preconditioning (IPC). It was later described that the interruption of blood flow to an organ different than the target organ could also have a protective effect on IRI. This phenomenon is known as remote ischemic preconditioning (RIPC) [6]. Although the exact mechanism of RIPC is unknown, prevention of apoptosis by closure of the mitochondrial permeability transition pores (mPTP), seems to play a pivotal role [3]. A limb is often used as the remote organ for the application of the RIPC stimulus as the blood flow can safely and easily be obstructed by insufflation of a blood pressure cuff around an arm or leg. Experimental studies have shown that RIPC does not only protect against IRI in the heart, but also in other organs, including the kidney [7].

Not only a distant ischemic impulse can cause renal protection from IRI, some anesthetics also protect the kidney against IRI. In myocardial and renal animal studies, [8] anesthetics have shown to reduce IRI in a similar signaling cascade as RIPC, known as anesthetic preconditioning (APC). Volatile anesthetics have extensively been tested for their APC effectiveness in cardiac studies: isoflurane, sevoflurane, desflurane [9, 10], halothane [11] and ether derived anesthetics [12] have proven clinical and preclinical cardioprotective effects. Experiments with intravenous anesthetics, propofol, barbitarates and ketamine [13–15] show no protective effect and have been demonstrated to inhibit mKATP channels which is an indication these anesthetics might diminish the protective effect of APC or RIPC [16]. The effects of multiple periods of anesthetics on IRI are unknown.

In general, animal studies show that RIPC is effective in reducing renal IRI [17]; however, human studies show disappointing results, with a small or non-significant protective effect [18, 19]. Cumulating evidence exists that in cardiac IRI models, repeating the RIPC stimulus over a period of multiple days, repeated RIPC (RepRIPC), could be more effective as compared to single dose RIPC [13, 20, 21]. It is unclear if this holds true for renal IRI. In this study we test whether the null-hypothesis could be rejected that single dose and repeated RIPC are equally effective in an experimental model of renal IRI.