The Risk Factors And Preliminary Explore Of Mechanism For Acute Kidney Injury Associated With Deep Hypothermic Circulatory Arrest

Objective To analyze the incidence and risk factors for acute kidney injury after total aortic arch replacement under deep hypothermic circulatory arrest.Methods We retrospectively analyzed130patients undergoing total aortic arch replacement under deep hypothermic circulatory arrest between June2012and June2013. According to the occurrence of acute kidney injury defined by consensus RIFLE (Risk, Injury, Failure, Loss of function, End-stage renal disease) criteria, they were divided into2groups, the group of acute kidney injury and the group of non-acute kidney injury. Univariate and multiple logistic regression were used to identify the risk factors for acute kidney inury after total aortic arch replacement under deep hypothermic circulatory arrest.Results Mean age was48.8±10.0years;94(72.3%) were men.67(51.5%) had RIFLE scores of I or F, and17(13.1%) required dialysis. Multiple logistic regression showed that the age of patients (OR=1.055,95%CI=1.003-1.110, P=0.039), the diagnosis of aortic dissection (OR=21.770,95%CI=1.888-251.050, P=0.014) and the total requirements of red blood cells (OR=1.108,95%CI=1.002-1.225,P=0.046) were independent risk factors for acute kidney inury after total aortic arch replacement under deep hypothermic circulatory arrest.Conclusions Independent risk factors for acute kidney inury in patients undergoing total aortic arch replacement under deep hypothermic circulatory arrest were increased age, diagnosis of aortic dissection and total requirements of red blood cells. Objectives1. To confirm whether deep hypothermic circulatory arrest can lead to acute kidney injury.2. To investigate the relationship between endoplasmic reticulum stress and acute kidney injury associated with deep hypothermic circulatory arrest.3. To investigate the relationship between inflammatory response and acute kidney injury associated with deep hypothermic circulatory arrest.4. Preliminary explore of the influence of different hypothermic circulatory arrest temperature on postoperative renal function.MethodsTwenty eight male Sprague-Dawley rats were divided into five groups randomly: group A (deep hypothermic circulatory arrest:15℃-20℃, n=6), group B (moderate hypothermic circulatory arrest:20℃-25℃, n=6), group C (mild hypothermic circulatory arrest:25℃-30℃, n=6), group D (cardiopulmonary bypass, n=6) and group E (sham, n=4). After anesthesia induction, endotracheal intubation and puncture, the three groups of hypothermic circulatory arrest A, B and C, underwent30min of hypothermic circulatory arrest at different temperature. Group D underwent cardiopulmonary bypass, without hypothermic circulatory arrest. Group E was the sham group, we monitored hemodynamics from femoral artery catheter, without other operation. At five different time points, pre-operation (T1), before hypothermic circulatory arrest (T2), heart beating normally (T3), remove from cardiopulmonary bypass (T4) and before execution (T5), we monitored blood gas. In the whole process of the experiment, hemodynamic parameters was real-time monitored. After removing from cardiopulmonary bypass, the rats received mechanical ventilation for1hour, then were executed, the kidney and blood were harvested.The serum creatinine values (classic indicators for renal function) were compared bewteen the five groups. We observed the pathological morphological changes of different groups for renal tubular injury using light microscope, and renal tissue ultrastructure changes (including mitochondria, endoplasmic reticulum and nucleus) using scanning electron microscope. TUNEL method was used to detect apoptosis index of the kidney. ELISA method was used to detect the release of proinflammatory factors, IL-1, IL-6and TNF-a. We used Western Blot method to detect the expression of protein, including endoplasmic reticulum stress related protein CHOP, GRP-78, Caspase-12, NF-κB and the apoptosis related proteins Bax, Bcl-2, caspase-3. The mRNA level of caspase-3, CHOP and GRP-78were detected by RealTime PCR.ResultsThe serum creatinine levels of three hypothermic circulatory arrest group A, B, C, were significantly higher than cardiopulmonary bypass group D and the sham group E (P <0.05), but no difference were detected between the three groups. The release of proinflammatory factors, including IL-1, IL-6and TNF-alafa, in the three hypothermic circulatory arrest groups was significantly higher than that in sham group E (P<0.05). Renal tubular injury of three hypothermic circulatory arrest groups were worse than cardiopulmonary bypass group D and sham group E. The higher temperature was, the more severe renal tubular injury was. Ultrastructures were observed using scanning electron microscopy for mitochondria and endoplasmic reticulum, and the result was consistent with the renal tubular injury. In terms of apoptosis, renal apoptosis cells were rare in all groups. CHOP protein and mRNA were significantly higher in three hypothermic circulatory arrest groups than cardiopulmonary bypass group D and the sham group E (P<0.05). There was no significant difference in other protein and mRNA.Conclusions1. This study confirme that deep hypothermic circulatory arrest can lead to acute kidney injury. It was based on multi-level and multi-angle evidence, including the classic renal function indicator serum creatinine, pathological morphological change (light microscopy, scanning electron microscope), the release of proinflammation factors, and the expression of protein CHOP and its mRNA. 2. Taking the ultrastructure change for endoplasmic reticulum and the expression of maker for endoplasmic reticulum (CHOP and its mRNA) into consideration, we speculate that acute kidney injury associated with deep hypothermic circulatory arrest may be induced by endoplasmic reticulum stress.3. Considering the expression of CHOP and its mRNA, proinflammatory factors, and conclusions of recent studies, we speculate that CHOP may lead to acute kidney injury associated with deep hypothermic circulatory arrest through regulating inflammatory reaction.4. Although we did not find the differences in acute kidney injury induced by different hypothermic circulatory arrest temperatures (group A:15℃-20℃, group B:20℃-25℃, group C:25℃-30℃) in terms of serum creatinine, proinflammatory factorsand CHOP, but the pathological morphology indicate that the higher temperature are, the more severe renal tubular injury is. The clinical practice is complex and changeful, we should carry out more rigorous animal experiments and large-scale prospective clinical trials, to further study the influence of different hypothermic circulatory arrest temperature on postoperative renal function.