Preclinical Evidence for the Efficacy of Ischemic Postconditioning against Renal Ischemia-Reperfusion Injury, a Systematic Review and Meta-Analysis

Abstract

Background: Renal ischemia-reperfusion injury (IRI) is a major cause of kidney damage after e.g. renal surgery and transplantation. Ischemic postconditioning (IPoC) is a promising treatment strategy for renal IRI, but early clinical trials have not yet replicated the promising results found in animal studies.

Method: We present a systematic review, quality assessment and meta-analysis of the preclinical evidence for renal IPoC, and identify factors which modify its efficacy.

Results: We identified 39 publications studying >250 control animals undergoing renal IRI only and >290 animals undergoing renal IRI and IPoC. Healthy, male rats undergoing warm ischemia were used in the vast majority of studies. Four studies applied remote IPoC, all others used local IPoC. Meta-analysis showed that both local and remote IPoC ameliorated renal damage after IRI for the outcome measures serum creatinine, blood urea nitrogen and renal histology. Subgroup analysis indicated that IPoC efficacy increased with the duration of index ischemia. Measures to reduce bias were insufficiently reported.

Conclusion: High efficacy of IPoC is observed in animal models, but factors pertaining to the internal and external validity of these studies may hamper the translation of IPoC to the clinical setting. The external validity of future animal studies should be increased by including females, comorbid animals, and transplantation models, in order to better inform clinical trial design. The severity of renal damage should be taken into account in the design and analysis of future clinical trials.

Fig 1. Flow chart of study selection.

The number of studies in each phase are shown between brackets.

Fig 2. Risk of bias and study quality assessment.

Top: Reporting of five key study quality indicators was found to be poor in many cases. Bottom: Using SYRCLE's risk of bias tool, the risk of selection, performance, detection, attrition and other biases was assessed. Lack of (adequate) reporting of measures to reduce bias resulted in a high percentage of unclear risk of bias for most items.

Fig 3. Meta-analysis creatinine.

The summary effects show a decrease in serum creatinine after local or remote IPoC. One study investigating the combination of local and remote IPoC showed no effect. Data are presented as NMD and 95% CI. Within subgroup weights from random effects analysis are shown.

Fig 4. Meta-analysis blood urea nitrogen.

The summary effects show a decrease in blood urea nitrogen after local or remote IPoC. One study investigating the combination of local and remote IPoC showed no effect. Data are presented as NMD and 95% CI. Within subgroup weights from random effects analysis are shown.

Fig 5. Meta-analysis renal histology.

The summary effects show a decrease renal damage score after local or remote IPoC, and the combination of the two. Data are presented as MD and 95% CI. Within subgroup weights from random effects analysis are shown.

Fig 6. Publication bias.

Trim and fill analysis for studies on local IPoC indicates funnel plot asymmetry for respectively creatinine (A), BUN (C) and renal histology (E). The 95% confidence interval of Egger’s regression line (dashed lines) does not include the origin of the graph, indicating no small study effects for creatinine (B), BUN (D) and renal histology (F).