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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). Aprotinin (Trasyslol), an anti-fibrinolytic, is also suggested to inhibit thrombin-PAR1-induced endothelial hyperpermeability. 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. The jugular vein and femoral artery were cannulated and connected to the CPB circuit, consisting of a roller pump and membrane oxygenator. A secondary dose of 33.000 KIU/kg aprotinin was given 60 minutes after initiation of CPB. Cremaster and renal microcirculatory perfusion were assessed using intravital microscopy and contrast echography before CPB and 10 and 60 minutes 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 minutes 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/sec, 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.
Treatment with aprotinin preserved cremaster microcirculatory perfusion following CPB, but did not prevent renal perfusion disturbances nor renal injury following CPB despite preservation of renal endothelial integrity and reduction of renal edema formation. Future studies should focus on identifying therapeutic strategies to improve renal perfusion and function following CPB.
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