Beneficial effect of pentoxifylline on cisplatin-induced acute renal failure in rabbits

Pentoxifylline (PTX) has been reported to inhibit TNF-alpha production and prevent several types of acute renal failure. This study was undertaken to determine the effect of PTX on the cisplatin-induced acute renal failure in rabbits. Rabbits received a single injection of cisplatin (5 mg/kg, i.p.) with or without PTX pretreatment (30 mg/kg, i.v.). Alterations in renal function, apoptotic cell death, and TNF-alpha mRNA expression were measured at 24 or 48 h after cisplatin injection. Cisplatin caused an increase in BUN and serum creatinine levels, a reduction in GFR, and an increase in fractional Na+ excretion. Such changes were significantly attenuated by PTX pretreatment (30 mg/kg, i.p.) 30 min before and 24 h after cisplatin injection. Morphological evaluation showed that cisplatin injection induced diffuse proximal tubular necrosis and the effect was reduced by PTX pretreatment. Cisplatin induced apoptotic cell death in renal cortex and the effect was significantly prevented by PTX. Treatment of opossum kidney cells with cisplatin resulted in cell death, which was significantly prevented by PTX. The increase in lipid peroxidation and the decrease in renal blood flow induced by cisplatin were not affected by PTX. The expression of TNF-alpha mRNA was increased after cisplatin injection and the effect was inhibited by PTX pretreatment. These results suggest that cisplatin-induced acute renal failure in rabbits is associated with an induction of TNF-alpha-mediated apoptosis, and that PTX may exert a protective effect against cisplatin nephrotoxicity by inhibiting TNF-alpha production.     

Effect of pentoxifylline on ischemic acute renal failure in rabbits.

Previous studies have demonstrated that levels of tumor necrosis factor-alpha (TNF-alpha) or its mRNA expression are increased in acute renal failure of various types including ischemia/reperfusion injury. This study was undertaken to determine whether pentoxifylline (PTX), an inhibitor of TNF-alpha production, provides a protective effect against ischemic acute renal failure in rabbits. Renal ischemia was induced by clamping bilateral renal arteries for 60 min. Animals were pretreated with PTX (30 mg/kg, i.v.) 10 min before release of clamp. At 24 h of reperfusion of blood after ischemia, changes in renal function, renal blood flow, and the expression of TNF-alpha mRNA were evaluated. Ischemia/reperfusion caused a marked reduction in GFR, which was accompanied by an increase of serum creatinine levels. Such changes were significantly attenuated by PTX pretreatment. PTX ameliorated the impairment of renal tubular function, but it had no effect on the reduction of renal blood flow induced by ischemia/reperfusion. The protective effect of PTX on functional changes was supported by morphological studies. The impairment of glucose and phosphate reabsorption in postischemic kidneys was associated with a depression in the expression of Na+-glucose and Na+-Pi transporters. The expression of TNF-alpha mRNA was increased after reperfusion, which was inhibited by PTX pretreatment. The PTX pretreatment in vitro prevented the release of lactate dehydrogenase induced by an oxidant t-butylhydroperoxide in rabbit renal cortical slices, but it did not produce any effect on the oxidant-induced lipid peroxidation, suggesting that PTX protection is not resulted from its antioxidant action. These results suggest that PTX may exert a protective effect against ischemic acute renal failure by inhibiting the production of TNF-alpha in rabbits.     

Effect of vitamin E and pentoxifylline on glycerol-induced acute renal failure

The pathogenesis of acute renal failure may involve, among other causes, ischemia, vascular congestion, arachidonic acid pathways, and reactive oxygen metabolites. The aim of this study is to evaluate the effects of pentoxifylline and vitamin E on the prevention of experimental acute renal failure induced by glycerol. Eighty-five Sprague-Dawley rats weighing 170-230 g were included in the study. The rats were randomly divided into four groups: group 1 was given 1 ml saline; group 2, glycerol; group 3, glycerol plus vitamin E, and group 4, glycerol plus pentoxifylline. Extent of histological renal tubular necrosis and regeneration in each animal were graded. Blood urea nitrogen, serum creatinine, and creatine kinase concentrations were measured. Mean blood urea nitrogen and serum creatinine concentrations and tubular injury scores were significantly lower in group 1 than in groups 2-4 (p < 0.001), but there were no significant differences among groups 2-4. We conclude that postinsult administration of vitamin E and pentoxifylline does not have a beneficial effect on prevention and severity of acute renal failure and that controlled, multicenter studies involving a large number of patients are needed to clarify this subject.     

Blood viscosity in experimental acute renal failure

We measured blood viscosity in rats 24 h after induction of acute renal failure by glycerol or HgCl2 injections. The blood viscosity values of rats with acute renal failure were significantly higher than those of controls at any shear rates. The mean values of plasma fibrinogen in animals with glycerol - (302.5 +/- 35.2 mg/100 ml) or HgCl2 - (342.1 +/- 15.9 mg/100 ml) induced acute renal failure were significantly elevated compared to control levels (169.6 +/- 16.7 mg/100 ml). We believe that the increased blood viscosity in acute renal failure was primarily due to high concentration of plasma fibrinogen. The elevated blood viscosity may affect capillary microvascular circulation of glomerular capillary beds.     

Role of vascular decongestion in ischemic acute renal failure defined by postinsult administration of pentoxifylline

The patholophysiologic significance of vascular congestion in the mechanism of ischemic acute renal failure following postocclusive reflow was studied with a novel hemorheologic probe, pentoxifylline. Using the autoperfused rat kidney model, inulin clearances (CIN), urine flow rates (UFR), renal electrolyte excretions, and renal hemodynamic parameters (RVR, RBP, RBF) were compared in saline- and pentoxifylline-treated anesthetized rats prior to and following a 45-min occlusive period. Renal functional and hemodynamic parameters were significantly altered in saline controls. In contrast, postischemia treatment with pentoxifylline was associated with significant recovery in CIN and UFR, and stable RVR, RBF, and RBP. Kidneys treated with saline infusion had pronounced vascular congestion, in contrast to those administered pentoxifylline. Coupled with the absence in medullary hyperemia, the present experiments support the role of vascular congestion in ischemic acute renal failure. Pentoxifylline, administered in pharmacologic doses after the insult, provided benefit during the initiation phase of postischemic acute renal failure. These data strengthen the opinion that ischemic insult results in vascular congestion, and that restoration of blood flow will prevent further deterioration in renal function.     

Urinary biochemistry in experimental septic acute renal failure.

BACKGROUND: Several biochemical urine tests and derived indices are reported as useful in the diagnosis of acute renal failure (ARF) and its classification in prerenal (hypoperfusion) or intrarenal (acute tubular) necrosis. However, they have not been adequately studied in sepsis, the most frequent cause of ARF in ICU. METHODS: In 10 female Merino ewes, we implanted flow probes around the pulmonary and renal arteries to measure cardiac output and renal blood flow (RBF) continuously. Cardiovascular variables were monitored and urine samples collected during a 48 h control period and one week later during a 48 h period of hyperdynamic sepsis induced by an infusion of live Escherichia coli. RESULTS: Infusion of live E. coli induced systemic hyperdynamic sepsis with renal vasodilatation and increased RBF. Serum creatinine increased from 73.3 +/- 15.1 to 276.9 +/- 156.3 micromol/l (P < 0.05) and creatinine clearance decreased from 84.6 +/- 21.4 to 27.5 +/- 21.4 ml/min (P < 0.05). Urine sodium concentration (UNa) decreased significantly from 164.5 +/- 50.4 to 14.6 +/- 14.3 mmol/l, fractional excretion of sodium (FeNa) from 1.5 +/- 0.17 to 0.12 +/- 0.11%, fractional excretion of urea nitrogen (FeUn) from 62.7 +/- 9.5 to 11.5 +/- 15.4%, and urine osmolality from 724.8 +/- 277.1 mosmol/l to 329.0 +/- 52.1 mosmol/l. The u/p creatinine ratio did not change. CONCLUSION: Sustained Gram-negative sepsis induced a hyperdynamic state and hyperaemic ARF. Despite increased renal perfusion, UNa, FeNa and FeUn decreased significantly. Our findings suggest that, in sepsis, these urinary biochemical changes are not reliable markers of renal hypoperfusion.     

Renal blood flow in experimental septic acute renal failure

Reduced renal blood flow (RBF) is considered central to the pathogenesis of septic acute renal failure (ARF). However, no controlled experimental studies have continuously assessed RBF during the development of severe septic ARF. We conducted a sequential animal study in seven female Merino sheep. Flow probes were implanted around the pulmonary and left renal arteries. Two weeks later, systemic hemodynamics and RBF were monitored continuously during a 48-h control period and, after a week, during a 48-h period of hyperdynamic sepsis induced by continuous Escherichia coli infusion. Infusion of E. coli induced hyperdynamic sepsis with significantly increased cardiac output (3.8+/-0.4 vs 9.8+/-1.1 l/min; P<0.05), decreased mean arterial pressure (89.2+/-3.2 vs 64.3+/-5.3 mm Hg; P<0.05), and increased total peripheral conductance (42.8+/-3.5 in controls vs 153.7+/-24.7 ml/min/mm Hg in septic animals; P<0.05). Hyperdynamic sepsis was associated with marked renal vasodilatation (renal conductance: 3.0+/-0.7 vs 11.4+/-3.4 ml/min/mm Hg; P<0.05) and a marked increase in RBF (262.3+/-47.7 vs 757.4+/-250.1 ml/min; P<0.05). Serum creatinine increased over 48 h (73+/-18 vs 305+/- micromol/l; P<0.05) whereas creatinine clearance decreased (95.5+/-25.9 vs 20.1+/-19.3 ml/min; P<0.05). After 24 h, urine output decreased from 1.4 to 0.3 ml/kg/h (P<0.05). Infusion of E. coli induced hyperdynamic sepsis and ARF. Septic ARF in this setting was associated with a marked increase in RBF and with renal vasodilatation.     

Effects of a stable prostacyclin analog on experimental ischemic acute renal failure.

The effect of OP-41483, a stable prostacyclin (PGI2) analog, on ischemic acute renal failure (ARF) was investigated in dogs. Administration of OP-41483 for three days after ischemia significantly increased renal cortical blood flow (RCBF) when compared with dogs treated with the saline vehicle. In the OP-41483-treated group, serum creatinine levels remained relatively low during postoperative days 1-3 and mean survival time was prolonged. Injection of a silicone rubber vascular casting compound (Microfil) revealed increased numbers of visible renal cortical glomeruli and microvessels compared to the saline vehicle group. Histologic sections showed only very limited tubular necrosis, whereas sections of kidneys treated with saline showed extensive tubular necrosis. In conclusion, this stable prostacyclin analog provided a significant degree of protection for the kidneys from ischemic injury and may be useful in a clinical setting.     

Theoretical analysis of pathogenetic mechanisms in experimental acute renal failure

A network thermodynamic model of glomerular dynamics has been employed to determine the degree of change in individual glomerular vascular resistances, hydraulic conductivity and proximal tubule pressure that, singly or in concert, could lower GFR to the degree expected in experimental acute renal failure (ARF). In both the rat and dog, the analysis shows that filtration failure is not achieved until preglomerular resistance (RA) is increased at least twofold or postglomerular resistance (RE) is decreased by 74% or more with all other determinants held at control values. Tubular obstruction alone will not provide failed filtration until tubule pressure is increased to 30 to 40 mm Hg in the rat and 44 mm Hg in the dog. A much smaller change in tubular pressure can contribute greatly to the development of filtration failure, however, when occurring in association with major change in individual vascular resistances. Glomerular capillary resistance must be increased to a value more than twice the normal sum of RA and RE (greater than fivefold in the dog), and glomerular capillary hydraulic conductivity lowered to below 5% of control, as isolated changes, before full filtration failure is approached. There is no reason to believe that most forms of ARF relate to only a single abnormality, however, and the effect of concomitant changes in individual resistances, hydraulic conductivity and proximal tubule pressure on glomerular filtration and blood flow is presented in the text and figures. A possible mechanism by which altered blood viscosity at the efferent arteriole may contribute to ARF is discussed and quantified. The degree of change in any determinant required to exert a given effect on filtration is independent of etiology, thus rendering the results of this analysis equally valid for any other pathological event which causes a significantly reduced GFR in the rat or dog.     

Effect of dose on renal diatrizoate concentrations in experimental acute renal failure.

In rats with glycerol-induced acute renal failure (ARF) and controls, renal concentrations of 125I-labelled sodium diatrizoate were measured 5 min after intravenous doses ranging from 14 to 1,800 mg/kg body weight. Renal concentrations of diatrizoate, at all doses, were much higher in controls than in ARF. A linear relationship existed between dose and renal concentration in ARF. In controls, at doses above 225 mg/kg body weight, the fraction of the dose present in the kidneys diminished and renal iodine content approached that observed in ARF. Differences in diatrizoate concentration which existed between cortical and medullary zones in healthy kidneys at low dises were progressively eliminated as dosage increased, consistent with the osmatic fiutryiv rggrvy of diatrizoate. In ARF, the pattern of intrarenal distribution at all doses was similar to that seen in controls at high doses, though concentrations in outer cortex were consistently slightly higher than those in inner cortex. These observations suggest continuing though reduced, filtration of diatrizoate in ARF by glomeruli already subjected to a large solute load.     

Klotho reduces apoptosis in experimental ischaemic acute renal failure.

BACKGROUND: Klotho is associated with the suppression of several ageing phenotypes. Because high klotho gene expression was detected in the kidney and several studies have found altered expression in animal models, we explored the physiological relevance of klotho expression in the kidney under renal ischemia reperfusion injury (IRI). METHODS: Male Wistar rats were subjected to bilateral renal ischemia or sham operation, followed by reperfusion for 6, 12 or 24 h, or 2 to 10 days. Renal expression of klotho was assessed by real-time PCR or Western blotting. Creatinine levels were determined. Immunohistochemical studies and TUNEL staining were performed. An adenovirus harbouring the mouse klotho gene (ad-kl) was intravenously administered to one group of rats before renal IRI. RESULTS: Renal klotho mRNA and protein expressions were significantly reduced in IRI rats the first day after ischemia. Pre-treatment with ad-kl resulted in a robust induction of klotho mRNA and protein in the liver but not in the kidney. Ad-kl gene transfer improved serum creatinine and the histological changes. Apoptosis induced by IRI was attenuated following ad-kl administration. CONCLUSION: The data suggest klotho to be involved in the pathophysiology of IRI. Downregulation of renal klotho exacerbates ischaemic acute renal failure, and klotho gene induction has therapeutic potential in managing ischaemic renal damage.     

Effects of pentoxifylline on the haematologic status in anaemic patients with advanced renal failure.

OBJECTIVE: Erythropoietin (EPO) deficiency is the main cause of renal anaemia. However, inhibition of erythropoiesis by cytokines such as tumour necrosis factor alpha (TNF-a) may play an important role. The aim of this work was to study the effects of pentoxifylline, an agent with anti-TNF-a properties, on the haematologic status in anaemic patients with advanced renal failure. MATERIAL AND METHODS: In a prospective study, 7 anaemic patients with advanced renal disease (creatinine clearance <30 ml/min) were treated with pentoxifylline (400 mg orally daily) for 6 months. The evolution of haemoglobin, haematocrit, creatinine clearance and serum EPO and TNF-a a concentrations were compared with those obtained from an untreated control group. RESULTS: Haemoglobin and haematocrit significantly increased in the pentoxifylline-treated patients (9.9+/-0.5 g/dl and 27.9+/-1.6% at baseline; 10.6+/-0.6 g/dl and 31.3+/-1.9% at the 6th month, respectively, p < 0.01), whereas no variation was seen in the control group. Serum EPO levels remained stable in all patients. However, the serum TNF-a concentration decreased significantly in patients receiving pentoxifylline (basal 623+/-366 pg/ml; 6th month 562+/-358 pg/ml, p < 0.01), but not in the control group. CONCLUSIONS: Our findings suggest that the inhibition of erythropoiesis by cytokines may play a significant role in renal anaemia. The administration of agents with anti-cytokine properties, such as pentoxifylline, can improve the haematologic status in anaemic patients with advanced renal failure.     

胎肾细胞移植治疗急性肾功能衰竭的动物实验研究

进行了胎肾细胞移植治疗二氯化汞造成的动物实验。致死量组：细胞移植组平均存活４．２８天，对照组存活３．０２天；重中毒量组：１２０小时细胞移植组平均ＢＵＮ１０．６ｍｍｏｌ／Ｌ，Ｃｒ２２９μｍｏｌ／Ｌ，放射性核素每分钟闪烁计数３３７８ｒ／ｍｉｎ，对照组：ＢＵＮ３２．７ｍｍｏｌ／Ｌ，Ｃｒ８２９μｍｏｌ／Ｌ，ｃｐｍ值１３７３ｒ／ｍｉｎ；中毒量组；细胞移植组ＢＵＮ７．８ｍｍｏｌ／Ｌ，ｃＲ１６７．５μＭＯＬ／ｌ     

Effects of pentoxifylline in Adriamycin-induced renal disease in rats

Tumor necrosis factor- (TNF-) is a mediator of inflammation in human and animal renal disease. Pentoxiphylline (PTX) is an inhibitor of TNF-. In this study we examined the effects of PTX on TNF-, proteinuria, nitrite production, and apoptosis in an experimental model of Adriamycin (ADR) nephropathy in rats. Rats were divided into four groups: untreated Wistar rats (controls), PTX treatment alone, ADR treatment alone to induce nephropathy, and ADR treatment followed by PTX. ADR treatment followed by PTX treatment prevented the increase in serum TNF- levels and proteinuria in rats with ADR-nephropathy (P<0.05). Urine nitrite levels were significantly increased in the ADR-induced nephropathy group and the increase was prevented in the ADR-induced nephropathy group when they also received PTX. The urine nitrite levels were not different between the PTX-treated group and the untreated control rats. PTX prevented the rise of serum TNF- in ADR nephropathy rats and a decrease in proteinuria, urine nitrite, and apoptosis in the renal tissue. These findings suggest a beneficial anti-inflammatory effect of PTX.     

An experimental model for unilateral ischaemic acute renal failure in dog

We determined the recovery of unilateral ischaemic acute renal failure in both ischaemic and non-ischaemic canine kidneys. Split renal clearance studies were repeated for seven weeks after 90 minutes of left renal artery clamping. Clearance of inulin and para-aminohippuric acid in the ischaemic kidneys dropped significantly for 3 weeks. Significant increase of the fractional excretion of sodium in those kidneys was observed at only 1 week after ischaemia. In the contralateral non-ischaemic kidneys, these indices did not change significantly throughout the experiments. This animal model of acute renal failure would be helpful in testing possible preventive measures and therapy for human acute renal failure.     

Proton magnetic resonance in experimental acute and chronic renal failure in rats

Kidney cortical and medullary "spin-lattice" (T1) and "spin-spin" (T2) relaxation times were measured by spectroscopy in several types of experimental renal failure in rats. The T1 and the measured tissue water content were used to calculate the fraction bound (FB) and hydration fraction (HF) according to a fast proton diffusion model. The present study demonstrated the possibility to differentiate between normal and pathological renal tissue resulting from renal artery clamping (RAC), renal pedicle clamping (RPC) with or without reflow, glycerol-induced acute renal failure with or without previous dehydration, and chronic hypertensive renal failure induced by 5/6 nephrectomy and saline loading, with low (6%) or normal (21%) protein diet. Shortened T1 and prolonged T2 found in both cortex and medulla of the glycerol-induced ARF in dehydrated rats seem to represent a MR ischemic pattern. The prolongation of T1 and T2 and the increase in water content in the other groups seem to relate to different amounts of tubular obstruction and renal congestion. In summary, characteristic MR properties of different types of renal failure may provide etiological and pathogenetic diagnostic possibilities.     

Effect of anticoagulation on renal function and protein excretion in experimental acute ischemic renal failure

Female Sprague-Dawley rats underwent right nephrectomy and 40 min left renal artery occlusion (RAO). After 15 min of reflow, polyethylene glycol 1000 (PEG1000) was infused to induce osmotic diuresis and to enable glomerular filtration rate (GFR) measurements. Urine was collected during a 90 min period, and the concentrations of PEG1000, albumin, IgG, IgM and fibrin(ogen)/degradation products (FIB) were assessed both in plasma and urine by radial immuno diffusion technique Groups of rats were subjected to saline + RAO, warfarin + RAO or sham-operation. GFR as measured by PEG1000 clearance averaged 0.61, 0.036 and 0.094 mL/min/100g BW/kidney in sham-operated, saline + RAO and warfarin + RAO rats, respectively. Urinary excretion of albumin and IgG increased substantially in both ischemic groups. IgM was not detected in any of the urine samples. FIB excretion was lowest in the saline + RAO group, possibly due to retention of FIB-containing obstructions in the tubules. Rats subjected to warfarin + RAO had significantly higher excretion of FIB. This result suggests that warfarin does not prevent the glomerular sieving of macromolecules in the glomerular filter, but reduces tubular obstruction by preventing fibrin formation, which may explain its positive effect on GFR.     

Effects of dietary protein on uranyl-nitrate-induced acute renal failure

The effects of dietary protein both before and after uranyl-nitrate-induced acute renal failure were investigated. Male Sprague-Dawley rats were maintained on high-protein (60%), normal-protein (20%), low-protein (5%) and no-protein diets for 8 days prior to intravenous administration of uranyl nitrate (10 mg/kg). Immediately following uranyl nitrate injection, some rats on normal-protein diets were switched to no-protein, low-protein or high-protein diets, while some of the rats on high-protein diets were switched to low-protein diets. Serum and urine creatinine levels and urine volumes were monitored for 2 weeks following uranyl nitrate treatment. Rats conditioned to no-protein and low-protein diets exhibited significantly lower mortalities than rats maintained on normal-protein diets. Rats maintained on high protein diets exhibited better renal function than rats maintained on lower dietary protein regimes, but these rats had mortality rates similar to rats maintained on normal-protein diets. Shifting the rats on normal-protein diets to low- or no-protein diets immediately after uranyl nitrate administration did not improve their renal function or survival rates. However, shifting the rats on normal-protein diets to high-protein diets immediately following uranyl nitrate injection resulted in significantly higher mortalities (93%) than in rats maintained on either normal or high dietary protein throughout the experimental period. Finally, shifting rats on high dietary protein to low-protein diets immediately following uranyl nitrate administration resulted in both improved renal function and survival compared with rats shifted from normal to restricted dietary protein (5%) immediately following uranyl nitrate injection.(ABSTRACT TRUNCATED AT 250 WORDS)