Ischemic Preconditioning in the Animal Kidney, a Systematic Review and Meta-Analysis

Abstract

Ischemic preconditioning (IPC) is a potent renoprotective strategy which has not yet been translated successfully into clinical practice, in spite of promising results in animal studies. We performed a unique systematic review and meta-analysis of animal studies to identify factors modifying IPC efficacy in renal ischemia/reperfusion injury (IRI), in order to enhance the design of future (clinical) studies. An electronic literature search for animal studies on IPC in renal IRI yielded fifty-eight studies which met our inclusion criteria. We extracted data for serum creatinine, blood urea nitrogen and histological renal damage, as well as study quality indicators. Meta-analysis showed that IPC reduces serum creatinine (SMD 1.54 [95%CI 1.16, 1.93]), blood urea nitrogen (SMD 1.42 [95% CI 0.97, 1.87]) and histological renal damage (SMD 1.12 [95% CI 0.89, 1.35]) after IRI as compared to controls. Factors influencing IPC efficacy were the window of protection (<24 h = early vs. ≥24 h = late) and animal species (rat vs. mouse). No difference in efficacy between local and remote IPC was observed. In conclusion, our findings show that IPC effectively reduces renal damage after IRI, with higher efficacy in the late window of protection. However, there is a large gap in study data concerning the optimal window of protection, and IPC efficacy may differ per animal species. Moreover, current clinical trials on RIPC may not be optimally designed, and our findings identify a need for further standardization of animal experiments.

Remote Ischemic Preconditioning and Renoprotection

“…62 IPC-associated protective effects were reported for all three parameters. Interestingly, renoprotection was not evident in the female subgroup, stressing the need for future studies in female subjects.…”

Low-energy shock wave preconditioning reduces renal ischemic reperfusion injury caused by renal artery occlusion

“…Free radical production is one of the most important mechanisms of tissue ischemia-reperfusion injury 11 , low-energy shock waves pretreatment can reduce the renal oxidative stress caused by high-energy shock wave lithotripsy 19 . From this study, 24 hours after reperfusion, serum iNOS and renal tissue MDA levels in the LESP+IR group were both significantly lower than those of the IR group, indicating that low-energy shock pretreatment can reduce free radicals induced by ischemia and reperfusion in a short time.…”

“…Ischemic preconditioning (IPC) is a potent protective strategy in which a brief occlusion of ischemia and reperfusion results in tolerance to subsequent ischemia-reperfusion injury 8,9 . It has been demonstrated in multiple tissues and organs including the heart, liver, small intestine, and renal tissues [10][11][12][13] . Low-energy shock waves have been used in many fields to reduce the damage induced by tissue ischemia or to improve recovery after ischemia.…”

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“…Several IPC methods have been described, including having the stimulus localized at the target organ or remotely from it, having 1 continuous episode of ischemia or several cycles of brief ischemia and reperfusion, and varying the interval between the IPC stimulus and the index ischemia. [1][2][3] A recent systematic review and meta-analysis 2 concluded that, overall, IPC reduces histologic damage and serum creatinine levels; however, some studies reported that IPC does not result in any protection at all. 4,5 Most IPC investigations in kidneys have used an adult male rat as the animal model and a 40-or 45-minute IPC and IRI period.…”

“…Indeed, a recent meta-analysis showed that most regimens have used localized IPC. 2 Of particular note, a continuous regimen of 15 minutes of IPC before injury has been shown to result in histologic and functional protection. 1 MicroRNAs (miRNAs) are a large family of endogenous, small non-coding RNAs that are thought to regulate the expression of the majority of human protein-coding genes.…”