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    Review of 'The anti-coagulants ASIS or APC do not protect against renal ischemia/ reperfusion injury'

    The anti-coagulants ASIS or APC do not protect against renal ischemia/ reperfusion injuryCrossref
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    The anti-coagulants ASIS or APC do not protect against renal ischemia/ reperfusion injury

    Renal ischemia/reperfusion (I/R) injury is the main cause of acute renal failure. The severity of injury is determined by endothelial damage as well as inflammatory and apoptotic processes. The anti-coagulants active site inhibited factor VIIa (ASIS) and activated protein C (APC) are besides their anti-coagulant function also known for their cytoprotective properties. In this study the effect of ASIS and APC was assessed on renal I/R injury and this in relation to inflammation and apoptosis. Our results showed no effect of ASIS or APC on renal injury as determined by histopathological scoring as well as by BUN and creatinin levels. Furthermore, no effect on fibrin staining was detected but ASIS did reduce TF activity levels after a 2 hrs reperfusion period. Neither ASIS nor APC administration influenced overall inflammation markers, although some inflammatory effects of ASIS on interleukin (IL)-1β and tumor necrosis factor (TNF)-α were detectable after 2 hrs of reperfusion. Finally, neither APC nor ASIS had an influence on cell signaling pathways or on the number of apoptotic cells within the kidneys. From this study we can conclude that the anti-coagulants ASIS and APC do not have protective effects in renal I/R injury in the experimental setup as used in this study which is in contrast to the protective effects of these anti-coagulants in other models of I/R.

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      renal ischemia/reperfusion,anti-coagulants,inflammation,apoptosis

      Review text

      The paper by Loubele and coworkers is a logical extension of published work on the effect of anticoagulant drugs on ischemia reperfusion injury. In a well characterized ischemia reperfusion model in mice, in which one kidney is clamped and subsequently reperfused while the contralateral kidney is removed, the authors show no effect of the anticoagulants ASIS and APC on ischemia reperfusion injury. Importantly, the dosages applied were previously shown to be effective in different ischemia reperfusion models. The analyses of ischemia reperfusion injury were thorough: kidney function markers, histology, inflammatory and hemostasis markers (protein and/or mRNA) and apoptosis were not appreciably different between vehicle and ASIS or APC treated animals. The study has been well executed and I agree with the main conclusions. I have a few minor comments aimed at further improvement of the manuscript. First, an analysis of kidney injury markers and stainings for inflammatory cells would have made the study complete. Second, the lack of effect of the anticoagulants (in particular of ASIS) on fibrin deposition in the kidney is unexpected given the observations that the drugs result is systemic anticoagulant activity, and the increased in kidney tissue factor after ischemia reperfusion. Are there indications that the fibrin deposition in the kidney originates from intrinsic (rather than TF-mediated) activation of coagulation? Third, the conclusion that the amount of tissue factor decreases after 2 hours of reperfusion seems unjustified. As the authors employ an activation assay, it is no surprise that TF activity in ASIS treated animals is decreased as the TF in the cell homogenate is likely (partially) occupied by ASIS. Forth, the remark in the materials and methods section ‘for ASIS the optimal dose was determined by a dose-finding study’ is unclear. What was the endpoint of such a dose-finding study? Finally, the argument that anticoagulants did have effects in previous studies perhaps because in those studies both kidneys were clamped is unclear. Why would this difference in experimental set-up explain differences between the published and present study?


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