目标腹腔灌注压治疗腹腔高压诱发缺血再灌注肾损伤的实验研究

Intra-abdominal hypertension（IAH）has tight association with higher incidence rate and mortality in clinic, and data shows that acute kidney injury（AKI）is the most frequent complication of IAH. IAH may induce and aggravate AKI through the ischemic reperfusion injury mechanism. Our preliminary test suggested that the targeted abdominal perfusion pressure (APP）treatment had some protective effects for AKI induced by IAH. However, it is unclear about the specific mechanisms of action. Therefore, we raise the hypothesis that the targeted APP treatment may prevent or abate the occurrence of AKI induced by IAH through lessening the ischemic reperfusion injury of kidney in an appropriate stage. To verify this hypothesis, we plan to establish a porcine model of ischemic reperfusion injury using a CO2 pneumoperitoneum. Small domestic porcines（n=56）will be randomly divided into two groups as IAP=30mmHg continuing time: IAP=6h group(n=28) and IAP=12h group(n=28), and the two groups were further divided into five subgroups as follows: targeted mean arterial pressure treatment group (n=6), targeted APP treatment group (n=6), targeted glomerular filtration gradient treatment group (n=6), control group (n=6) and sham operation group (n=4), the indexes reflecting renal function, renal cortex bloodstream, systemic and intrarenal inflammatory reactions, oxidative stress of nephridial tissue, renal histomorphologies and the signal transduction molecules related with apoptosis will be detected to evaluate the protective role of targeted APP treatment for AKI induced by the ischemic reperfusion injury at different time-points, the concrete mechanism of action of targeted APP will also be explored. This study findings will provide new clinical ideas for the earlier protection and treatment of AKI induced by IAH.

腹腔高压(IAH)具有较高的发病率与病死率，急性肾损伤(AKI)是其最常见的并发症，IAH主要通过缺血再灌注损伤诱发和加重AKI。我们前期的预试验结果提示，目标腹腔灌注压(APP)治疗对IAH诱发的AKI具有一定保护作用。因此，我们提出假说：目标APP治疗在一定时间内可通过减轻肾脏缺血再灌注损伤发挥对IAH诱导AKI的保护作用。为了验证该假说，我们采用CO2气腹法建立小家猪IAH诱发缺血再灌注肾损伤模型，并随机将2个不同时间点小家猪分成5组：目标平均动脉压治疗组、目标APP治疗组、目标肾小球滤过梯度治疗组、对照组和假手术组；利用肾功能学、肾皮质血流、神经体液激素、全身及肾内炎症反应、肾组织形态学、分子病理学等指标，评价目标APP治疗在不同时间内对IAH诱发缺血再灌注肾损伤是否具有保护作用并探索其作用机制，为临床寻找IAH诱发AKI的预防与治疗方法奠定理论基础。

为了验证目标APP治疗在一定时间内可通过减轻肾脏缺血再灌注损伤发挥对IAH诱导AKI的保护作用假说，本课题采用CO2气腹法建立小家猪IAH诱发缺血再灌注肾损伤模型，并随机将2个不同时间点小家猪分成5组：目标平均动脉压治疗组、目标APP治疗组、目标肾小球滤过梯度治疗组、对照组和假手术组；利用肾功能学、肾皮质血流、神经体液激素、全身及肾内炎症反应、肾组织形态学、分子病理学等指标，评价目标APP治疗在不同时间内对IAH诱发缺血再灌注肾损伤是否具有保护作用并探索其作用机制，为临床寻找IAH诱发AKI的预防与治疗方法奠定理论基础。结果发现：⑴随着IAP的升高，实验组和对照组动物的肾皮质血流均明显下降（P<0.05）。实验组动物在IAP=30 mmHg维持15 min时静脉泵入去甲基肾上腺素以维持APP于正常基线水平为治疗目标后，肾皮质血流明显改善，并且在IAP=25 mmHg维持1 h、2 h、4 h、6 h、8 h及减压2h的各时间点，实验组的肾皮质血流均显著高于对照组的对应值（P<0.05）。因此，维持APP于正常基线水平可以改善IAH状态下的肾皮质血流。⑵实验组与对照组在IAP=25 mmHg维持6 h和8 h时血清Cr与血KIM-1、NGAL水平均较基线水平显著升高（P<0.05），提示两组动物均出现了急性肾损伤。IAH 本身可以诱发全身性炎性介质反应，导致血清中TNF-α、IL-1、IL-6 的升高，如在创伤、感染等原发疾病基础上继发IAH，则造成全身炎性介质反应对机体的第二次打击，患者极易发生MODS。但本研究显示相关炎症指标无明显变化，可能未形成明显的炎症反应。本研究中实验组和对照组动物在IAP=25 mmHg维持2 h、4 h、6 h和8 h减压2h时的相关肾脏损伤标记物，APP组较其他各组均明显下降（P＜0.05），由于其为反映AKI的早期生物标志物，APP实验组肾损伤程度较对照组轻，提示目标性APP维持能有效降低肾损伤标记物水平，从而发挥肾脏保护作用。另外，实验组与对照组动物的肾组织病理学检查均未见明显肾小管坏死，提示IAH诱导的肾功能改变早于肾病理学变化。