Crush-induced acute kidney failure is the second leading cause of high mortality and disability in natural disaster events like earthquakes and major trauma [
1], which subsequently increases the physical, psychological, and economic burden [
2,
3]. The kidney is the most commonly involved organ in crush syndrome. After decompression, the damaged muscular cells rapidly release nephrotoxic breakdown products such as myoglobin, potassium, and urate into the circulation. Furthermore, it leads to urinary cast formation that causes renal tubule obstruction, proximal tubular necrosis and sequential acute renal failure [
4]. Although fluid resuscitation and blood purification are the earliest employed methods that are beneficial and effective for crush injury casualties, immediate therapeutic intervention on the disaster scene is still a challenging issue because the above-mentioned measures are usually unavailable [
5]. Moreover, patients wait for more than five hours on average before being transferred to a hospital in the aftermath of the disaster [
1]. Severe tissue damage develops around 2–4 h after the compression, which becomes irreversible when the duration exceeds six hours. The increase in compression duration leads to a higher incidence of crush syndrome [
6]. Therefore, sincere efforts to explore an effective and feasible measure for protecting the renal function in the pre-hospital care system should be undertaken. A study by Zhao et al. indicated that pretreatment with ischemia–reperfusion cycles could reduce the degree of myocardial ischemia–reperfusion injury and subsequently devised the concept of IPC [
7]. Sequential literary insights stated that IPC could mitigate the inherent tissue damage in both renal and cerebral ischemic injury models. However, few studies reported the protective effect of remote IPC on renal injury caused by crush syndrome through clamping of femoral vessels. Although it has been suggested that IPC ameliorates acute kidney injury induced by limb ischemia/reperfusion via inhibiting Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) signaling in rats [
8], more specific mechanisms require further exploration in this regard. In this study, we evaluated different IPC strategies and investigated the potential mechanisms on a crush injury rabbit models.