Acute kidney injury is a severe complication following cardiopulmonary bypass (CPB) and is associated with capillary leakage and microcirculatory perfusion disturbances. CPB-induced thrombin release results in capillary hyperpermeability via activation of protease-activated receptor 1 (PAR1). We investigated whether aprotinin, which is thought to prevent thrombin from activating PAR1, preserves renal endothelial structure, reduces renal edema and preserves renal perfusion and reduces renal injury following CPB. Rats were subjected to CPB after treatment with 33.000 KIU/kg aprotinin (n = 15) or PBS (n = 15) as control. A secondary dose of 33.000 KIU/kg aprotinin was given 60 min after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 min after weaning from CPB. Renal edema was determined by wet/dry weight ratio and renal endothelial structure by electron microscopy. Renal PAR1 gene and protein expression and markers of renal injury were determined. CPB reduced cremaster microcirculatory perfusion by 2.5-fold (15 (10–16) to 6 (2–10) perfused microvessels, p < 0.0001) and renal perfusion by 1.6-fold (202 (67–599) to 129 (31–292) au/sec, p = 0.03) in control animals. Both did not restore 60 min post-CPB. This was paralleled by increased plasma creatinine (p < 0.01), neutrophil gelatinase-associated lipocalin (NGAL; p = 0.003) and kidney injury molecule-1 (KIM-1; p < 0.01). Aprotinin treatment preserved cremaster microcirculatory perfusion following CPB (12 (7–15) vs. 6 (2–10) perfused microvessels, p = 0.002), but not renal perfusion (96 (35–313) vs. 129 (31–292) au/s, p > 0.9) compared to untreated rats. Aprotinin treatment reduced endothelial gap formation (0.5 ± 0.5 vs. 3.1 ± 1.4 gaps, p < 0.0001), kidney wet/dry weight ratio (4.6 ± 0.2 vs. 4.4 ± 0.2, p = 0.046), and fluid requirements (3.9 ± 3.3 vs. 7.5 ± 3.0 ml, p = 0.006) compared to untreated rats. In addition, aprotinin treatment reduced tubulointerstitial neutrophil influx by 1.7-fold compared to untreated rats (30.7 ± 22.1 vs. 53.2 ± 17.2 neutrophil influx/section, p = 0.009). No differences were observed in renal PAR1 expression and plasma creatinine, NGAL or KIM-1 between groups. Aprotinin did not improve renal perfusion nor reduce renal injury during the first hour following experimental CPB despite preservation of renal endothelial integrity and reduction of renal edema.

中文翻译：

---

实验性体外循环后，通过抑肽酶保护肾内皮完整性和减少肾水肿并不能保护肾灌注和功能

急性肾损伤是体外循环 (CPB) 后的严重并发症，与毛细血管渗漏和微循环灌注障碍有关。CPB 诱导的凝血酶释放通过激活蛋白酶激活受体 1 (PAR1) 导致毛细血管通透性过高。我们研究了被认为可防止凝血酶激活 PAR1 的抑肽酶是否能保护肾内皮结构、减少肾水肿和保护肾灌注并减少 CPB 后的肾损伤。大鼠在用 33.000 KIU/​​kg 抑肽酶 (n = 15) 或 PBS (n = 15) 作为对照处理后进行 CPB。在 CPB 开始后 60 分钟给予二次剂量 33.000 KIU/​​kg 抑肽酶。在 CPB 前和断奶后 10 和 60 分钟，使用活体显微镜检查和对比超声检查评估 Cremaster 和肾脏微循环灌注。通过湿/干重量比和电子显微镜检查肾内皮结构确定肾水肿。测定肾PAR1基因和蛋白表达以及肾损伤标志物。CPB 使提睾管微循环灌注降低 2.5 倍（15 (10-16) 至 6 (2-10) 个灌注微血管，p < 0.0001）和肾灌注降低 1.6 倍 (202 (67-599) 至 129 (31-292) ) au/sec, p = 0.03) 在对照动物中。两者都没有在 CPB 后 60 分钟恢复。这与增加的血浆肌酐（p < 0.01）、中性粒细胞明胶酶相关脂质运载蛋白（NGAL；p = 0.003）和肾损伤分子-1（KIM-1；p < 0.01）平行。抑肽酶治疗在 CPB 后保留了提睾微循环灌注（12 (7-15) 对 6 (2-10) 灌注微血管，p = 0.002），但不能保持肾灌注（96 (35-313) 对 129 (31-292)） au/s, p > 0.9) 与未治疗的大鼠相比。抑肽酶治疗减少了内皮间隙形成（0.5 ± 0.5 与 3.1 ± 1.4 间隙，p < 0.0001）、肾脏湿/干重量比（4.6 ± 0.2 与 4.4 ± 0.2，p = 0.046）和液体需求（3.9 ± 3.3）与未治疗的大鼠相比，7.5 ± 3.0 ml，p = 0.006)。此外，与未治疗的大鼠相比，抑肽酶治疗使肾小管间质中性粒细胞流入减少了 1.7 倍（30.7 ± 22.1 与 53.2 ± 17.2 中性粒细胞流入/切片，p = 0.009）。组间肾脏 PAR1 表达和血浆肌酐、NGAL 或 KIM-1 没有观察到差异。