Local and Remote Ischemic Postconditioning Are Synergistic in Reducing Renal Damage, an Animal Study

In the current era of meticulous surgical technique and modern immunosuppressive therapy, ischemia reperfusion injury (IRI) is one of the major determinants of early and long-term allograft function after kidney transplantation. In an experimental model of renal IRI, we showed that remote ischemic preconditioning using the hind limb as remote organ is effective in reducing IRI. Others reported that remote ischemic per- and postconditioning also significantly reduce renal IRI in a comparable model. Here, we report the first data on the combined effect of local and remote ischemic postconditioning (LIPostC and RIPostC, respectively) on renal IRI. Male Sprague-Dawley rats weighing approximately 300 grams were randomized into five groups. Five sham-operated animals served as a baseline control (sham). All other animals were uninephrectomized by removal of the left kidney and subjected to 25 minutes of renal ischemia (by clamping the renal artery and vein of the right kidney) and 48 hours of reperfusion. Eight animals underwent renal IRI only (no IPostC). Nine animals underwent three cycles of RIPostC by brief hind limb ischemia, induced by inflating small blood pressure cuffs around both hind limbs for five minutes, followed by five minutes of reperfusion (RIPostC). Nine animals underwent LIPostC, induced by six cycles of eight seconds of ischemia, followed by eight seconds of reperfusion (LIPostC). Seven animals underwent both postconditioning procedures (RIPostC + LIPostC). After 48 hours, blood, urine and renal tissue samples were analyzed to assess renal function and damage. Renal IRI caused a decline in renal function, as reflected by an increase in plasma creatinine, plasma urea and fractional excretion of sodium (FENa). These detrimental effects were only partially reduced by RIPostC or LIPostC alone. However, the combined application of RIPostC + LIPostC significantly reduced the IRI-induced decrease in renal function. Furthermore, a similar additive effect of RIPostC + LIPostC was observed for renal histological damage, as assessed by scoring periodic acid Schiff-stained sections of renal cortex on a 0-5 scale by an investigator blinded for allocation. In contrast with a previous report, RIPostC did not significantly reduce plasma creatinine and urea levels in our model. This may be explained by the use of a shorter sustained ischemic stimulus (25 versus 45 minutes) and hind limb occlusion by blood pressure cuff, rather than clamping of the iliac vessels. Nevertheless, we demonstrate that RIPostC effectively prevents a IRI-induced increase in FENa. More importantly, we show that RIPostC and LIPostC have additive protective effects on IRI of the kidney. Since the application of a local and/or remote ischemic preconditioning stimulus in postmortal organ donors is difficult to implement into clinical practice, we believe that combined local and remote IPostC is a highly interesting alternative approach.