Department of Anesthesiology, University of Lubeck, Lubeck, Germany.
Kidney Blood Press Res. 2009;32(2):81-90. doi: 10.1159/000209378. Epub 2009 Mar 24.
BACKGROUND/AIMS: Raised cytokine levels and a hypoperfusion-associated decrease in glomerular filtration rate (GFR) are hallmarks of the genesis of septic acute renal failure (ARF). Therefore, anti-inflammatory as well as renal vasodilating therapeutic strategies may afford renal protection during septic ARF. The present study was designed to determine the effects of administration of urodilatin, pentoxifylline and theophylline to improve renal function in an ex-vivo model of 'septic renal injury'.
Eight series of experiments were performed: no intervention, perfusion with a suspension containing Escherichia coli bacteria (strain 536/21); E. coli + 10 microg/l urodilatin, E. coli + 20 microg/l urodilatin, E. coli + 100 microM theophylline, E. coli + 100 microM pentoxifylline and E. coli + URO 20 microg/l given 90 min after start of perfusion. Renal vascular and glomerular functional parameters as well as TNF-alpha release were analyzed up to 180 min.
Perfusion with E. coli caused an acute deterioration of renal vascular and glomerular function. URO 20 microg/l and PTX decreased renal vascular resistance (RVR) from 83.7 +/- 18.4 to 9.2 +/- 1.1 and 8.6 +/- 2.2 mm Hg/ml/min/g kidney and increased renal perfusion flow rate (PFR) from 8.2 +/- 1.5 to 14.6 +/- 0.8 and 14.1 +/- 2.2 ml/min/g kidney. As a result, GFR improved from 102.1 +/- 15.6 to 442 +/- 48.3 and 525.8 +/- 57 microl/min/g kidney during treatment with URO 20 microg/l and PTX, respectively. Renal TNF-alpha release was significantly reduced by URO 20 microg/l (from 178 +/- 23 to 45.2 +/- 2 and 47 +/- 3 pg/ml) in the E. coli + URO 20 microg/l and by PTX in the E. coli + PTX group if added to the perfusion medium upon start of perfusion. Interestingly, URO 20 microg/l also decreased RVR significantly from 62.2 +/- 6.1 to 35.9 +/- 6.0 mm Hg/ml/min/g kidney, improved PFR from 5.4 +/- 1.0 to 8.7 +/- 1.0 ml/min/g kidney, increased GFR from 160 +/- 43.3 to 280.7 +/- 27.9 microl/min/g kidney, and decreased TNF-alpha release to 122 +/- 18 pg/ml if applied 90 min after induction of septic ARF. In contrast, URO 10 microg/l did not significantly increase urine flow and did not appear to significantly improve renal perfusion. Theophylline showed no beneficial effects at all.
This suggests that urodilatin and pentoxifylline might be useful to protect renal function if given before a septic renal insult. Additionally, treatment with urodilatin is capable of restoring renal function in early Gram-negative sepsis-induced ARF even if given after the septic insult.
背景/目的：细胞因子水平升高和肾小球滤过率（GFR）的低灌注相关下降是引发脓毒性急性肾衰竭（ARF）的特征。因此，抗炎和肾血管扩张治疗策略可能在脓毒性 ARF 期间提供肾脏保护。本研究旨在确定给予尿多利肽、己酮可可碱和茶碱以改善“脓毒性肾损伤”体外模型中肾功能的效果。
进行了 8 组实验：无干预、用含有大肠杆菌（菌株 536/21）的悬浮液灌注；大肠杆菌+10μg/l 尿多利肽，大肠杆菌+20μg/l 尿多利肽，大肠杆菌+100μM 茶碱，大肠杆菌+100μM 己酮可可碱和大肠杆菌+URO 20μg/l，在灌注开始后 90 分钟给予。分析了 180 分钟内的肾血管和肾小球功能参数以及 TNF-α释放。
大肠杆菌灌注导致肾血管和肾小球功能急性恶化。URO 20μg/l 和 PTX 将肾血管阻力（RVR）从 83.7±18.4 降至 9.2±1.1 和 8.6±2.2mmHg/ml/min/g 肾脏，并将肾灌注流量（PFR）从 8.2±1.5 增加至 14.6±0.8 和 14.1±2.2ml/min/g 肾脏。结果，在 URO 20μg/l 和 PTX 治疗期间，GFR 分别从 102.1±15.6 改善至 442±48.3 和 525.8±57μl/min/g 肾脏。URO 20μg/l（从 178±23 降至 45.2±2 和 47±3pg/ml）和 PTX 在大肠杆菌+PTX 组中在灌注开始时添加到灌注介质中时，肾 TNF-α释放显著减少。有趣的是，URO 20μg/l 还显著降低 RVR 从 62.2±6.1 至 35.9±6.0mmHg/ml/min/g 肾脏，改善 PFR 从 5.4±1.0 至 8.7±1.0ml/min/g 肾脏，增加 GFR 从 160±43.3 至 280.7±27.9μl/min/g 肾脏，并降低 TNF-α释放至 122±18pg/ml，如果在脓毒性 ARF 诱导后 90 分钟应用。相比之下，URO 10μg/l 并没有显著增加尿量，似乎也没有显著改善肾灌注。茶碱根本没有显示出有益的效果。
这表明尿多利肽和己酮可可碱可能在脓毒症肾损伤前给予时有助于保护肾功能。此外，在革兰氏阴性菌引起的脓毒症诱导的 ARF 早期，即使在脓毒症损伤后给予，尿多利肽治疗也能够恢复肾功能。
