Urodilatin and Pentoxifylline Prevent the Early Onset of <i>Escherichia coli</i>-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 μM theophylline, E. coli + 100 μM 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.

Phosphodiesterase‐4 inhibition as a therapeutic approach to treat capillary leakage in systemic inflammation

“…It can be postulated that the significant decrease of HCO 3 − in LPS‐treated rats compared to PD‐4‐I may be a sign of acute kidney injury (AKI) with acute loss of tubule cell function and impaired reabsorption of filtered HCO 3 − . In this respect experimental and clinical studies suggested potential protective renal effects of PDI by endothelium‐dependent vascular relaxation (Groesdonk et al 2009). Although this was not specifically addressed in our study we suggest that PD‐4‐I application may prevent prerenal AKI by improvement of fluid balance in septic shock in our model.…”

Effect of pentoxifylline on preventing acute kidney injury after cardiac surgery by measuring urinary neutrophil gelatinase - associated lipocalin

“…It can also affect the microcirculatory blood flow and contribute to the attenuation of interstitial inflammation, down regulation of monocyte chemo-attractant protein-1 gene expression, reduction in the expression of mitogenic and profibrogenic genes, and suppression of the proliferation of interstitial fibroblast and glomerulomesangial cells [8]. However, the preclinical data with regard to PTX and AKI seems controversial [9,10]. The effect of PTX in reducing renal injury by measuring sCr and α-1-microglobulin was investigated and ameasuring sCr and beneficial role of PTX on the prevention of kidney injury was observed [11].…”

An Isolated Perfused Rat Kidney Model for the Evaluation of the Effect of Glucose on Renal Tubular Epithelial Morphology

“…The in vitro isolated perfused rat kidney model has been extensively utilized for investigating renal drug handling and the effects of drugs and various substances on renal vasculature , glomerular function , renal cellular metabolism , and gluconeogenesis . However, the model has not been tested for the investigation into etiologic factors causing changes in renal histology.…”