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.     

Beneficial effect of thyroxin on recovery from toxic acute renal failure

To determine the effect of thyroxin (T4) on the recovery from toxic acute renal failure, rats were injected, subcutaneously, with K-dichromate (15 mg/kg) and at the peak of the renal injury, each animal was given either T4 (4 micrograms/100 g body weight, i.p.) or normal saline (NS). The T4-treated rats had significantly better CIn (669 +/- 35 microliter/min/100 g body weight), improved FENa (0.49 +/- 0.05%) and increased UOsm (835 +/- 50 mOsm/kg) as compared to animals given only NS (CIn 422 +/- 27; FENa 1.02 +/- 0.12; and UOsm 613 +/- 23). A similar dose of T4 given to non-injured control rats had no effect on renal function. The beneficial effect of T4 on dichromate injected rats was sustained and lead to more prompt recovery of glomerular function. To eliminate any hemodynamic effects of T4, an isolated perfused kidney preparation was utilized, and kidneys from dichromate injected rats treated with T4 had significantly better CIn, urine flow and FENa compared to rats given NS. Cellular morphology was better preserved in T4-treated animals. These data indicate that treatment with T4 results in enhanced recovery from an acute toxic renal insult and that this beneficial effect is unlikely to be related to nonspecific systemic effects of the hormone.     

Beneficial effect of thyroxin in the treatment of ischemic acute renal failure

To evaluate the effect of thyroxin (T₄) on recovery from ischemic acute renal failure, rats were treated with T₄ (10 or 20 g/100 g body wt.) or normal saline (NS) either immediately prior to, immediately after or 24 h after 45 min of renal ischemia. Animals given T₄ prior to ischemia had no significant increase in Inulin clearance (C_in) (377±40 l/min per 100 g body wt.) as compared with saline-treated ischemic controls (306±54). In contrast, animals treated immediately after ischemia with either dose of T₄ demonstrated significantly better kidney function (C_in 515±59 l/min per 100 g body wt., U_osm 842±88 mosmol/kg, FE_Na 0.52%±0.12% and C_in 543±71, U_osm 939±103, FE_Na 0.48±0.12, for 10 and 20 g/100 g body wt., respectively). Moreover, the improvement in renal function was sustained and C_in was significantly better at day 3 (748±70) and day 7 (990±75) compared with saline controls (560±30 and 732±45, respectively). Animals which received T₄ 24 h after ischemia showed significantly higher C_in when compared with ischemic controls. To assess the impact of T₄ on recovery of renal ATP,³¹P-NMR was used. T₄-treated rats demonstrated 90%±5% recovery of renal ATP by 120 min of reflow, whereas NS animals had only 64%±1%. In addition, cellular morphology was better preserved in T₄ animals. These data indicate that animals treated postischemically with T₄ showed accelerated and sustained recovery from acute renal failure. This beneficial effect appears to be related to cellular mechanisms which are essential for the restoration of sublethally injured cells.     

Determinants of intrarenal oxygenation: factors in acute renal failure.

Oxygen tension within the renal parenchyma is influenced by two factors: metabolic demand and oxygen supply. There are three regions within the kidney in which there is an anatomical basis for limited oxygen availability. The first is the inner stripe where oxygen diffusion between arterial and venous vasa recta reduces PO2. The other two are the outer stripe and medullary rays which are fed by O2-poor blood from venous vasa recta. The balance between oxygen demand and supply is most critical in the inner stripe where the PO2 is most influenced by transport activity. In contrast, altering transport activities in the outer stripe will not change the prevalence of hypoxic S3 injury but will alter its type (i.e., cell fragmentation related to high GFR and increased workload versus cell edema related to low GFR and minimal workload). The effect of transport activity on medullary ray PO2 has not been well defined. Using sensitive oxygen microelectrodes, cortical PO2 (52 +/- 2 mm Hg) in the rat was found to be higher than medullary PO2 (21 +/- 2 mm Hg, p less than 0.001). How are these observations reflected in current models of acute renal failure? The ischemia-reflow model affects proximal tubules with a predilection for S3 (located within the outer stripe of medulla) after short-term ischemia. With hyperfiltration (induced by glycine or renal hypertrophy) and the pursuant increase in transport related O2 demand, hypoxic mTAL inner stripe injury becomes prominent. Renal parenchymal hypertrophy exaggerates injury in the contrast nephropathy model, in which mTAL inner stripe injury is a predominant feature and medullary PO2 is very low.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effect of retinoic acid on the outcome of experimental acute renal failure.

BACKGROUND: Retinoic acid (RA) exerts beneficial effects on vascular remodelling and experimental nephritis, and plays a role in kidney development. Pathological changes caused by acute renal failure (ARF) result in high mortality. We determined whether RA ameliorates ARF-induced pathology caused by potassium dichromate (PD). METHODS: Adult Wistar female rats (210-250 g) were randomly allocated to four groups: (i) an ARF group that received PD [15 mg/kg body weight (bw), single dose subcutaneously]; (ii) a group that received PD plus RA (1 mg/kg bw) beginning at 5 days before PD and that continued for 14 additional days; (iii) a group that received PD plus thyroxine (T(4); 8 micro g/100 g bw) with RA; and (iv) a group that received only the vehicle for PD (saline solution). We evaluated functional, biochemical and morphological characteristics of the kidneys. RESULTS: PD-induced alterations in serum creatinine, creatinine clearance (C(cr)) and fractional excretion of sodium (FeNa) were less severe when rats received RA. PD increased lipoperoxidation and this alteration was partially blocked by RA. Animals undergoing ARF showed severe histological injury (brush border loss, acidophilia, oedema, pyknosis, karyorhexis, cell detachment and disruption of the basement membrane). These alterations were less severe in RA-treated rats, indicating a protective effect on functional and morphological alterations. Alterations in urinary sediment were reduced by RA. The simultaneous administration of T(4) with RA did not produce additional protection. CONCLUSION: RA exerted beneficial effects on the duration and severity of renal damage induced by PD in a model of renal failure resembling ARF in humans. The protective effect of RA may be mediated by diminished lipoperoxidative damage.     

Beneficial effect of the ANF analog A68828 on recovery from ischemic acute renal failure.

We have recently reported that administration of the ANF analog A68828 improves renal function in an acute model of postischemic acute renal failure. The current investigation examined the question whether a short-term infusion of A68828 can attenuate the long-term decrement in renal function following an ischemic event. Acute renal failure was induced in male Sprague-Dawley rats (200-250 g) by complete occlusion of both renal arteries for 30 min. During the initial 60 min following ischemia, vehicle (0.1% BSA in saline), A68828 (10 micrograms/kg/min); dopamine (10 micrograms/kg/min); A68828 (10 micrograms/kg/min) plus dopamine (10 micrograms/kg/min); or ANF[1-28] (0.5 microgram/kg/min) were infused intravenously. In vehicle-treated animals, a very large increase in plasma creatinine was observed, with peak levels at 2 days postischemia (5.5 +/- 1.2 mg/dL). A68828 alone, A68828 with dopamine, or ANF[1-28] infusion attenuated the rise in plasma creatinine levels by approximately 50% on each day of the study; dopamine alone was no different from vehicle-treated controls. Gross histological examination of kidneys on the fourth day postischemia revealed that significantly less damage occurred only in the group treated with A68828 alone. These results indicate that infusion of a reduced-size analog of ANF for a brief period in the postischemic kidney improves renal function and lessens tissue damage as evaluated several days after the ischemic event. Furthermore, dopamine infusion provides no discernable beneficial effect.     

Beneficial effect of dibutyryl cyclic AMP (DBcAMP) on ischemic acute renal failure in the rat.

To determine the effect of dibutyryl cyclic AMP (DBcAMP) on ischemic acute renal failure (IARF), that disorder was induced in male Wistar rats. After the animals were anesthetized with sodium pentobarbital (50 mg/kg, i.p.), the right kidney was removed and the left renal pedicle was clamped for 60 min. DBcAMP (5 mg/kg, i.p.) was given each 30 min before and after the renal pedicle clamping in half the dose each. Twenty-four hours after surgery, the levels of serum creatinine, BUN, serum potassium, and FENa% were significantly less elevated; and the total urine volume was significantly less decreased for 24 h in the group of IARF given DBcAMP than in the group of IARF alone. The elevation in Ca2+ content of the renal cortex was also significantly lower in the group of IARF given DBcAMP than in the group of IARF alone. These data indicate that DBcAMP can produce a beneficial effect on experimentally induced IARF. Since the intracellular accumulation of Ca2+ has been reported to be a potentially harmful factor in the development of IARF, it is suggested that the effect of DBcAMP on IARF can be in part due to an inhibition of the intracellular accumulation of Ca2+ in the kidney.     

Beneficial effect of verapamil added to chronic ACE inhibitor treatment on renal function in hypertensive elderly patients

This study analysed the effect of low doses ofverapamil added to chronic treatment withangiotensin-converting enzyme (ACE) inhibitors onblood pressure and serum creatinine levels in eightelderly hypertensive patients who had a steadyincrease of serum creatinine while on ACE inhibitors.The study was performed in eight elderly hypertensivesubjects, five men and three women (mean age 70 ±2 years; systolic blood pressure 173 ± 4 mmHg; diastolic blood pressure 99 ± 1 mm Hg) andserum creatinine of 1.60 ± 0.27 mg/dl beforetreatment. During an average of 25 weeks, ACEinhibitors significantly reduced both systolic anddiastolic blood pressures, but serum creatinine levelswere increased over basal levels (0,68 ± 0,20 mg/dl, p < 0.05). During an average of 10 weeks,the addition of verapamil did not decrease bloodpressure further, but serum creatinine levels werereduced to baseline. Our study suggests that theaddition of verapamil to ACE inhibitors can reverseACE-induced increase in creatinine levels in elderlyhypertensive patients in whom this side effect isobserved. This revised version was published online in August 2006 with corrections to the Cover Date.     

Effects of verapamil in the prevention of warm ischaemia induced acute renal failure in dogs

Acute renal failure in the immediate postoperative period remains a significant complication of renal transplantation. A major factor in the pathogenesis may be warm ischaemia (WI). Recent evidence implicates a calcium mediated mechanism as a final common pathway in certain models of acute renal failure. This study was undertaken to evaluate the effects of Verapamil, a calcium antagonist, in the prevention of warm ischaemia-induced acute renal failure following renal autotransplantation in the dog. Twenty-one mongrel dogs were randomly allocated to three groups. Group 1 (control, 8 dogs) received 20 ml normal saline before a standardized 60 min warm ischaemic insult to the left kidney. Group 2 (6 dogs) received Verapamil (0.3 mg/kg) by intravenous injection and Group 3 (7 dogs) received Verapamil (0.3 mg/kg) by intra-arterial injection into the left renal artery prior to the same ischaemic insult. The left kidney was heterotopically grafted to the right iliac fossa in the warm ischaemic period. Contralateral nephrectomy was performed. The dogs were followed up to 7 days after operation by serial creatinine estimation. Histological examination of some autografts was performed. Of the eight controls, six showed marked renal impairment (serum creatinine greater than 800, or death in renal failure). Three of the six dogs given intravenous Verapamil showed marked renal impairment. None of the seven dogs receiving intra-arterial Verapamil showed marked renal impairment (P = 0.013, chi 2 test). The mean rate of serum creatinine rise for each group was analysed by multivariate analyses of variance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beneficial effects of atrial natriuretic factor on cisplatin-induced acute renal failure in the rat

The organometal cisplatin has potent antitumor properties. However, its use is sometimes complicated by significant nephrotoxicity. This is characterized by tubular necrosis and impairment of the glomerular filtration rate (GFR). On the other hand, it has been demonstrated that atrial natriuretic factor (ANF) increases GFR in normal euvolemic rats. In the present study, we have therefore tested if this new potent natriuretic compound could restore some of the renal parameters affected by cisplatin. To investigate this issue, acute renal failure was induced in 9 rats by intraperitoneal injection of cisplatin 10 mg/kg body weight (b.w.). Renal function was studied 72 h later using the 3H-inulin clearance method and was compared with the renal function of 5 normal euvolemic rats. The cisplatin-treated rats showed high blood urea nitrogen levels, a 74% reduction of whole kidney GFR (0.308 +/- 0.047 vs. 1.17 +/- 0.08 ml/min/100 g b.w.) and a significant increase in the fractional excretion of urine, sodium and potassium. After 2 control clearances, synthetic ANF was administered intravenously as a prime (12 micrograms/kg b.w.) and then as a constant infusion (1 microgram/kg/min) to 6 cisplatin-treated rats. This promptly doubled the GFR (0.603 +/- 0.113 ml/min/100 g b.w.) and induced a significant increase in the excretion rate of urine, sodium and potassium. These results demonstrate that the administration of ANF has a beneficial effect on the experimental model of acute renal failure induced by cisplatin.     

Atrial natriuretic peptide and verapamil can prevent gentamicin induced acute renal failure in the rat

Summary: Calcium channel blockers are able to improve renal function in acute renal failure (ARF) and natriuretic peptides can also exert beneficial effects. At present it is unknown whether administration of atrial natriuretic peptide (ANP) and a calcium channel blocker given before a toxic lesion can prevent gentamicin induced ARF. the mechanisms of action of natriuretic peptides and calcium channel blockers are different and, as yet, it has not been clarified if combined administration can augment the effects on renal function. After a basal period we investigated the effects of verapamil (VER, 0.66 mg/kg), ANP, (30 μg/kg) and a combination of both (identical doses as described individually). the drugs were given intravenously for a period of 40 min (infusion period) before gentamicin (15 mg/kg, i.v.) was administered for induction of ARF. Basal values for glomerular filtration rate (GFR, mL/min) were around 1.8 with no differences between the groups. At the end of the infusion period (before application of gentamicin) GFR was significantly elevated with VER + ANP (3.13 ± 0.51), ANP (2.70 ± 0.59) and VER (2.34 ± 0.47) compared to controls (saline, 1.7 ± 0.48). After application of gentamicin GFR significantly dropped in the control group (0.77 ± 0.21, 0.75 ± 0.19, respectively), indicating development of ARF. In contrast with VER + ANP, ANP and VER GFR could be maintained for 30 min (2.47 ± 0.39, 2.28 ± 0.33, 2.22 ± 0.43, respectively) and 130 min (2.11 ± 0.32, 1.86 ± 0.29, 2.11 ± 0.28, respectively) after gentamicin. Moreover ANP and VER revealed natriuretic activity and, due to their vasorelaxing potency, also influenced arterial blood pressure. We conclude that both VER and ANP are able to prevent early gentamicin induced ARF when given before the toxic lesion. Both drugs induce hyperfiltration while infused, in particular when administered in combination.     

Beneficial effects of verapamil in diabetic cardiomyopathy

It has been suggested that the occurrence of an intracellular Ca2+ overload may result in the development of diabetic cardiomyopathy, which is associated with depletion of high-energy phosphate stores and a derangement of ultrastructure and cardiac dysfunction. Accordingly, the effects of verapamil, a Ca2+ antagonist, on cardiac function, ultrastructure, and high-energy phosphate stores in the myocardium were evaluated in rats made diabetic by an intravenous injection of streptozocin (65 mg/kg). Four weeks after the induction of diabetes, the animals were treated with three doses (2, 4, or 8 mg.kg-1.day-1) of verapamil for 4 wk until they were used for the measurement of different parameters. Untreated diabetic animals had slower heart rates, depressed rate of contraction and rate of relaxation, lower peak left ventricular systolic pressure, and elevated left ventricular diastolic pressure. All of these changes were significantly improved in diabetic rats receiving verapamil treatment. The beneficial effects of verapamil were more evident with higher doses (8 mg.kg-1.day-1) than with the lower doses (2 mg.kg-1.day-1). The diabetic animals also showed alterations in myocardial high-energy phosphate stores and exhibited evidence of ultrastructural damage; these abnormalities were improved by verapamil treatment without affecting their hyperglycemic status. Our results demonstrate that verapamil is capable of preventing diabetes-induced myocardial changes and support the involvement of Ca2+ in the cardiac pathology during diabetes.     

The effect of verapamil in reducing the severity of acute tubular necrosis in canine renal autotransplants

Calcium channel blockade has been shown to prevent warm renal ischemic damage. The ability of verapamil to decrease the severity of acute tubular necrosis (ATN) after 24-hr cold storage and autotransplantation was studied in a randomized paired study of 12 dogs. Experimental animals pretreated with intraarterial verapamil and flushing of the harvested kidney with cold intracellular solution containing verapamil demonstrated significantly (P less than .05) greater renal function preservation over their matched controls. A subsequent nonpaired study of 6 dogs treated only with flushing of the harvested kidney with perfusate containing verapamil demonstrated no significant preservation advantage over controls. We conclude that verapamil, administered prior to the ischemic event, can enhance the protective effect of hypothermia and decrease the severity of ATN in ischemically injured kidneys.     

Recombinant human erythropoietin reduces rhabdomyolysis-induced acute renal failure in rats

BackgroundRhabdomyolysis is one of the causes of acute renal failure. Erythropoietin (EPO) has been found to interact with its receptor (EPO-R) expressed in a large variety of non-haematopoietic tissues to induce a range of pleiotropic cytoprotective actions. In this study, we used recombinant human erythropoietin (rhEPO) to study the effects on the glycerol-induced rhabdomyolysis with acute renal failure in rats.MethodsTwenty-four rats were divided into three groups as glycerol group, glycerol + EPO group and normal saline + EPO group. Rhabdomyolysis was induced by intramuscular injection of 10 ml kg^?1 50% glycerol in rats. Ten minutes later, the rats received an intravenous injection of rhEPO (300 U kg^?1). Biochemical substances, including haemoglobin, blood urea nitrogen (BUN), creatinine (Cre), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and creatine phosphokinase (CPK), were measured at 0, 1, 3, 6, 9, 12, 18, 24 and 48 h. Rats were sacrificed 48 h later after glycerol administration and the kidneys were removed immediately for pathology and immunohistochemistry (IHC).ResultsIntramuscular injection of glycerol significantly increased blood BUN, Cre, GOT, GPT and CPK levels and induced severe histopathologic damage in the kidneys. Nuclear factor-κB (NF-κB) and inducible nitric oxide synthase (iNOS) were increased and E-cadherin was decreased after glycerol administration, as detected by IHC in the kidneys. Post-treatment with rhEPO decreased blood BUN, Cre, GOT, GPT and CPK levels, decreased markers of kidney injury and suppressed the release of NF-κB and iNOS after rhabdomyolysis.ConclusionTreatment with rhEPO suppressed the activities of NF-κB and iNOS, decreased BUN, Cre, GOT, GPT and CPK levels, and decreased the markers of kidney injury after rhabdomyolysis. These actions ameliorated rhabdomyolysis-induced acute renal failure in rats.     

Protective effect of carbon monoxide-releasing compounds in ischemia-induced acute renal failure

Heme oxygenase (HO) induction has been demonstrated to be beneficial in limiting the extent of cellular damage after ischemia-induced acute renal failure (ARF). Because increased HO activity is associated with the production of carbon monoxide (CO) as well as the potent antioxidant bilirubin, it is unclear which of the two is of greater importance in the protective effects of HO induction. The purpose of this study was to determine the protective role of CO alone in ischemia-induced ARF. Bilateral clamping of the renal pedicle for 40 min was associated with a ninefold increase in the levels of plasma creatinine 24 h after reperfusion as compared with normal plasma creatinine levels; however, administration of CO donor compounds tricarbonyldichlororuthenium(II) dimer, ([Ru(CO)(3)Cl(2)](2), 10 mg/kg) or tricarbonylchloro(glycinato)ruthenium(II) ([Ru(CO)(3)Cl(glycinate)], (CORM-3) 1 h before the onset of ischemia significantly decreased the levels of plasma creatinine 24 h after reperfusion as compared with vehicle-treated mice. Surprising, treatment with the CO donors was associated with an increase in HO activity 24 h after ischemia. For determining whether the protective effects of the CO donors were due to CO or HO-1 induction, experiments were performed in which HO was inhibited before administration of the CO donors. Pretreatment with the HO inhibitor had no effect on the level of plasma creatinine 24 h after reperfusion after treatment with the CO donor compounds. These results suggest that CO itself may be protective and limit renal damage in ischemia induced ARF.     

Somatosensory evoked potentials in acute renal failure: effect of parathyroidectomy

Effects of acute renal failure (ARF) on somatosensory evoked potentials (SEP) were studied in rats. Cervical and cortical SEPs were measured both before and after bilateral ureteral ligation. A significant augmentation of amplitudes and an increase in latencies of the cortical SEP were observed in ARF. The peripheral nerve conduction velocities were unchanged. Serum parathyroid hormone (PTH) levels in uremic rats were significantly elevated after the bilateral ureteral ligation. In previously parathyroidectomized rats, the bilateral ureteral ligation had no effects on amplitudes of SEP or serum PTH levels.