Urodilatin and Pentoxifylline Prevent the Early Onset of Escherichia coli-Induced Acute Renal Failure in a Model of Isolated Perfused Rat Kidney

Abstract

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’. Methods: Eight series of experiments were performed: no intervention, perfusion with a suspension containing Escherichia coli bacteria (strain 536/21); E. coli + 10 μg/l urodilatin, E. coli + 20 μg/l urodilatin, E. coli + 100 μ M theophylline, E. coli + 100 μ M pentoxifylline and E. coli + URO 20 μg/l given 90 min after start of perfusion. Renal vascular and glomerular functional parameters as well as TNF-α release were analyzed up to 180 min. Results: Perfusion with E. coli caused an acute deterioration of renal vascular and glomerular function. URO 20 μg/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 μl/min/g kidney during treatment with URO 20 μg/l and PTX, respectively. Renal TNF-α release was significantly reduced by URO 20 μg/l (from 178 ± 23 to 45.2 ± 2 and 47 ± 3 pg/ml) in the E. coli + URO 20 μg/l and by PTX in the E. coli + PTX group if added to the perfusion medium upon start of perfusion. Interestingly, URO 20 μg/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 μl/min/g kidney, and decreased TNF-α release to 122 ± 18 pg/ml if applied 90 min after induction of septic ARF. In contrast, URO 10 μg/l did not significantly increase urine flow and did not appear to significantly improve renal perfusion. Theophylline showed no beneficial effects at all. Conclusion: 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.