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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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      Major concerns:
      Methods: Recent studies suggest that isoflurane mediates protective effects in kidney I/R injury.

      Figure 1: What are the plasma levels of BUN or creatinine in uninjured mice? What happens with BUN and creatinine plasma levels when ASIS was administered at the beginning of the ischemic period?

      Figure 2A: The authors should possible increase the N number to reach significance in the ASIS treated group with regard to the histopathological score.

      Figure 3A. The authors claim that ASIS treatment significant reduced tissue factor activity even in the figure a "significant" difference was not indicated.

      Figure 3B: How was the deposition of fibrin scored? How do the authors explain an increased fibrin score in the ASIS treated group at 2hrs reperfusion?

      Figure 4 and 5: The stats are missing in the figures.

      The authors used human ASIS in their mouse model. It is known that human FVII/FVIIa has a lower affinity to mouse tissue factor compared to mouse FVII/FVIIa. The reduced activity of human ASIS in mice could lead to the negative findings.

      The authors compared their study to an older study by Frank et al. (JTH 2005). Frank et. al. used selective clamping of the renal arteries to induce ischemia. Here the authors clamped the whole pedicle. It is possible that the two different ischemia models have different effects on the kidney due to their severity.

      Minor concerns:
      Introduction: The reference for a protective effect of APC against diabetic nephropathy is missing.


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