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.

Figure 1. Flow chart of study selection.

The number of studies in each phase is indicated between brackets.

Figure 2. Quality assessment score, averaged per item.

Many studies scored poorly on key characteristics of scientific practice, and measures to avoid bias, such as characteristics of the subject population, randomization, blinding and exclusion criteria.

Figure 3. Effect of IPC on serum creatinine after renal IRI.

Left side favours control (renal IRI only), right side favours IPC. An overall beneficial effect of IPC on serum creatinine was observed (1.54 [1.16, 1.93]). Data presented as SMD and 95% CI.

Figure 4. Effect of IPC on BUN after renal IRI.

Left side favours control (renal IRI only), right side favours IPC. An overall beneficial effect of IPC on BUN was observed (1.42 [0.97, 1.87]). Data presented as SMD and 95% CI.

Figure 5. Effect of IPC on renal histology after renal IRI.

Left side favours control (renal IRI only), right side favours IPC. An overall beneficial effect of IPC on renal histology was observed (1.22 [0.89, 1.35]). Data presented as SMD and 95% CI.