Renal Postconditioning...Pause for Thought? Correspondence Regarding “Protection Against Renal Ischemia-Reperfusion Injury by Ischemic Postconditioning”

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We read with great interest the recent article by van Den Akker et al. (1), we share their enthusiasm for ischemic postconditioning (IPoC) and have previously published our work on IPoC in the uremic heart (2). We welcome the work done by the authors in setting up the clinical trial investigating the potential benefit of IPoC in the context of non-heart-beating renal transplantation and await with interest the results of their proof-of-concept trial. However, we feel that several important issues are yet to be addressed in this field. The impact of concomitant use of immunosuppressive medications at the time of IPoC is important to investigate further, as there is evidence that they themselves may be protective (3); in addition, treatment with cyclosporine, a commonly used immunosuppressant, can lead to tissue protection via the same common effector pathway of the IPoC signal (4). Second, the effectiveness of IPoC may be detrimental if the index injury is low (5) or may be ineffective at reducing reperfusion injury if the index ischemia is too great so as to cause irreversible injury. We recently performed a series of experiments to investigate the role of IPoC with different ischemia duration to investigate this further. To investigate this, 56 male Wistar rats underwent a unilateral nephrectomy with contralateral renal ischemia (for 0, 25, 30, or 45 min) followed by either an IPoC procedure (5×10 s ischemia-reperfusion) or a sham procedure. All animals were left to recover for 48 h at which point they were sacrificed and assessed for renal injury. When the results (Fig. 1) were analyzed using a two-way analysis of variance as expected, they demonstrated a highly significant association between the duration of ischemia and the subsequent renal injury as measured by serum creatinine concentration (Ps<0.0001), serum urea (P<0.0001), serum potassium (P<0.0001), serum phosphate (P=0.003), and urine output (P<0.0001). However, surprisingly at all time points of the studies, the addition of IPoC did not lead to protection from injury as measured by serum creatinine concentration (P=0.63), serum urea (P=0.62), serum potassium (P=0.40), serum phosphate (P=0.87), and urine output (P=0.86). Reassuringly, we did not demonstrate any deleterious effect of IPoC even at low degrees of injury.FIGURE 1: Relationship between duration of ischemia on subsequent renal injury as measured by serum creatinine (A), serum urea (B), serum phosphate (C), serum potassium (D), and urine output (E) with and without a postconditoning protocol of five cycles of 10 s ischemia-reperfusion.Although we appreciate that many other researchers have demonstrated positive outcomes after renal IPoC as was well documented by van Den Akker et al., we feel that, as with other forms of ischemic conditioning strategies (ischemic preconditioning and remote ischemic preconditioning), there has been a slight failure of translation when taking the profound tissue protection seen in animal models into human clinical trials. The reasons for this are currently unclear but may include a lack of comorbidities (diabetes, senescence, and displidemia) in the animal models studied, a lack of suitable endpoints and underpowered sample size in the clinical trials, or indeed a publication bias to positive animal studies. As such, we feel if is important to inform your readers that, even in experienced hands, ischemic conditioning strategies may not work all the time in every animal model of tissue injury, which should cause a pause for thought before embarking on future translational work. Kieran McCafferty Conor J. Byrne Muhammad M. Yaqoob Translational Medicine and Therapeutics William Harvey Research Institute Queen Mary University London London, UK