Papaverine effect on postischemic acute renal failure in rats

The effect of papaverine at the time of starting a post-ischemic acute renal failure in rats has been studied. Papaverine administration increases diuresis and reduces serum urea and creatinine levels. The primary role of hemodynamic disorders as responsible for the diminished glomerular filtration rate is supported by the reduced severity of acute renal failure when this vasodilator agent is administered.     

Renal ammoniagenesis during the recovery phase of postischemic acute renal failure in the dog.

Renal ammoniagenesis has been studied in 6 dogs before and 48 h after a 60-min period of renal ischemia induced by clamping the renal artery and in 6 sham-operated animals. Two days after temporary renal ischemia, the dogs showed a 25% decrease in glomerular filtration rate and renal plasma flow and a similar decrease in sodium reabsorption. Renal production of ammonium was not significantly different under basal conditions or 2 days after ischemia, but more ammonia was released by the urine in the postischemic dogs. Renal uptake of glutamine was similar in control and in postischemic kidneys. It is concluded that during the recovery phase of the ischemia, renal ammoniagenesis is conserved.     

Tissue distribution of Neutrophils in postischemic acute renal failure

Polymorphonuclear neutrophil granulocytes (PMNs) seem to participate in the pathogenesis of renal ischemic reperfusion injury. The kidneys from male Sprague Dawley rats were immersion-fixed after 45 min of renal artery clamping followed by reperfusion for 0, 5, 20, and 120 min, respectively. The tissue distribution of PMNs in the kidneys was studied histochemically using naphthol AS-D chloroacetate esterase as a specific marker for these cells. Neutrophil counts per unit sectional area were obtained for renal cortex, outer and inner medulla. In the cortex separate intraglomerular and peritubular counts, and in the outer medulla separate outer and inner stripe counts were made. After 120 min of reperfusion the total renal PMN counts were 488 ±62 (n = 4) compared with 54 ±4 (n = 4) per cm² in nonischemic controls. Within 120 min of reperfusion PMN counts increased by a factor of 8 in the cortex, of 12 in the outer medulla and of 14 in the inner medulla, compared with controls. The ratio of intraglomerular against peritubular PMN counts was approximately 2 in controls, but 0.5 after a 120-min reperfusion interval. The outer stripe of the outer medulla contained only a small number of PMNs whereas PMN counts of 923 ±197 (n = 4) per cm² were found in the inner stripe after 120 min reperfusion. Interestingly, there was a marked increase in PMNs in the inner stripe during the first 5 min of reperfusion but no extravasation of PMNs was observed. Taken together, these data provide the first evidence that PMNs accumulate particularly within peritubular capillaries in the cortex and within the inner stripe of the outer medulla. This distribution pattern is consistent with the hypothesis that PMN-augmented cell injury occurs in the early phase of postischemic acute renal failure. In addition the steady increase in PMNs during reperfusion may further contribute to impaired renal function.     

Renal cortical intermediary metabolism in the recovery phase of postischemic acute renal failure in the dog.

Renal metabolism has been studied in eight dogs before and 48 hr after a 60-min period of renal ischemia induced by clamping the left renal artery with the simultaneous removal of the right kidney, and in 12 sham-operated animals. The study involved the measurement of renal uptake and production of lactate, glutamine, glutamate, alanine, ammonium, and oxygen, and the measurement of the tissue concentrations of ATP, glutamine, lactate, alpha-ketoglutarate, aspartate, and alanine in the renal cortex. Two days after a temporary renal ischemia, the remaining kidney showed a 22% decrease in glomerular filtration rate (GFR) and a 25% decrease in renal plasma flow. Fractional sodium and potassium excretions were similar to those of control dogs. Renal production or extraction of glutamine, glutamate, alanine, ammonium, and oxygen (all expressed by 100 ml of GFR) was not significantly different in basal conditions or 2 days after ischemia, but lactate extraction was reduced in postischemic kidneys (-101 +/- 29 vs -204 +/- 38 mumol/100 ml GFR in control dogs). The cortical concentrations of glutamine and glutamate were lower in postischemic than in control kidneys. No differences were found in cortical concentration of alpha-ketoglutarate, aspartate, lactate, pyruvate, or ATP, but total nucleotides and inorganic phosphate were decreased in postischemic kidneys. It is concluded that in the recovery phase of the ischemia, a decreased lactate uptake is the main metabolic change, and total ATP production is adapted to the decrease of GFR and sodium reabsorption.     

Tissue distribution of neutrophils in postischemic acute renal failure.

Polymorphonuclear neutrophil granulocytes (PMNs) seem to participate in the pathogenesis of renal ischemic reperfusion injury. The kidneys from male Sprague Dawley rats were immersion-fixed after 45 min of renal artery clamping followed by reperfusion for 0, 5, 20, and 120 min, respectively. The tissue distribution of PMNs in the kidneys was studied histochemically using naphthol AS-D chloroacetate esterase as a specific marker for these cells. Neutrophil counts per unit sectional area were obtained for renal cortex, outer and inner medulla. In the cortex separate intraglomerular and peritubular counts, and in the outer medulla separate outer and inner stripe counts were made. After 120 min of reperfusion the total renal PMN counts were 488 +/- 62 (n = 4) compared with 54 +/- 4 (n = 4) per cm2 in nonischemic controls. Within 120 min of reperfusion PMN counts increased by a factor of 8 in the cortex, of 12 in the outer medulla and of 14 in the inner medulla, compared with controls. The ratio of intraglomerular against peritubular PMN counts was approximately 2 in controls, but 0.5 after a 120-min reperfusion interval. The outer stripe of the outer medulla contained only a small number of PMNs whereas PMN counts of 923 +/- 197 (n = 4) per cm2 were found in the inner stripe after 120 min reperfusion. Interestingly, there was a marked increase in PMNs in the inner stripe during the first 5 min of reperfusion but no extravasation of PMNs was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microdissection studies of the structural alterations induced in rat kidneys by experimental postischemic acute renal failure

A unique opportunity presented itself for a morphologic study of experimental unilateral acute renal failure (ARF) in male rats. The ARF had been induced in the rats by temporary occlusion (1h) of the left renal artery. Twenty-nine rats were divided into subsets as follows: 2-3 h, 24 h, 1 week, 2, 4, 8, and 12 weeks following release of occlusion. Microdissection showed a heterogeneous population of abnormally structured proximal tubules in which the regressive lesions of tubular necrosis were combined with the progressive reaction of repair. The lesions demonstrated are reminiscent of those which have been described in ARF in the human and in experimental animals. Many proximal tubules in the 2- to 3-hour subset presented 1-3 disruptive lesions (DLs) while greater numbers of proximal tubules from the 24-hour group presented 1-5 DLs. Many proximal tubules presented no DLs, but nearly all from the 24-hour subset (97-100%) displayed a squamate appearance which paralleled and was caused by acute tubular necrosis. At 1 week, a dilated pars recta was common, but by this time, the squamate pattern had disappeared. Many casts were present. At 2 weeks, many fewer casts were present in proximal tubules and none were seen at 4, 8 or 12 weeks. The nephrons, particularly the proximal tubules, presented a variety of structural alterations at 2, 4, 8 and 12 weeks. Changes of special interest include (1) the presence of swan-necks; (2) a distinctive squamate appearance of the proximal tubules in the animals killed at 24 h; (3) a spiral, curled appearance caused by differential hyperplasia in animals at 4, 8 and 12 weeks, and (4) a tendency for ischemic lesions to involve all layers of the renal cortex.     

Effect of propranolol on glycerol induced acute renal failure in rats

The effect produced by propranolol, administered for a prolonged period of time and in large doses, on renal function in rats has been studied, as well as the modifications induced by this treatment in an experimental model of acute renal failure, and the effects of a single dose of propranolol given 1 hour before provoking failure. Propranolol, administered chronically, causes sodium and water retention and increases creatinine clearance. Acute renal failure induced by glycerol in rats treated for 7 days with propranolol is less severe than the one produced in untreated animals. In this ARF model, a single dose of propranolol does not seem to have a protective effect.     

6-Gingerol prevents cisplatin-induced acute renal failure in rats

BACKGROUND: Nephrotoxicity is a major complication and a dose limiting factor for cisplatin therapy. Recent evidence suggests that enhanced oxidative stress caused by oxygen-centered free radicals may contribute to the pathogenesis of cisplatin-induced acute renal failure. 6-Gingerol is claimed to be a potent antioxidant. The present study was performed to explore the renoprotective potential of 6-gingerol on cisplatin-induced oxidative stress and renal dysfunction. METHODS: 6-Gingerol in dosages of 12.5, 25, 50 mg/kg was administered 2 days before and 3 days after cisplatin administration. Renal injury was assessed by measuring serum creatinine, blood urea nitrogen, creatinine, urea clearance and serum nitrite levels. Renal oxidative stress was assessed by determining renal malondialdehyde levels, reduced glutathione levels and enzymatic activities of superoxide dismutase and catalase. RESULTS: A single dose of cisplatin resulted in marked renal oxidative and nitrosative stress and significantly deranged renal functions. 6-Gingerol treatment significantly and dose-dependently restored renal functions, reduced lipid peroxidation and enhanced the levels of reduced glutathione and activities of superoxide dismutase and catalase. CONCLUSIONS: The present study demonstrates the renoprotective potential of 6-gingerol against cisplatin-induced oxidative stress and renal dysfunction in rats. Hence, 6-gingerol has a potential to be used as therapeutic adjuvant in cisplatin nephrotoxicity.     

Alleviation of experimental acute renal failure in rats by reduction of renal mass

An acute renal failure (ARF) has been produced by glycerol injection on rats unilaterally nephrectomized 48 h before. Rats with reduced renal mass showed polyuria and significantly lower azotemia than controls with ARF. This data might be explained by increased glomerular plasma flow in the remnant kidney previous to ARF induction.     

Beneficial effect of verapamil in ischemic acute renal failure in the rat

To investigate the possible protective effect of Ca2+ blockers in ischemic acute renal failure (ARF), verapamil, in a dose of 10 micrograms/kg body wt/min was administered for 100 min, starting 15 min before the total occlusion of the left renal artery after right nephrectomy in rats. Mean 24-hr creatinine clearance, blood urea, and serum creatinine levels, 24 hr after declamping, were used as a measure of kidney function. These values which were 135 +/- 1.9 microliter/min, 231 +/- 22 mg%, and 2.25 +/- 0.22 mg%, respectively, in the untreated rats, were found to be significantly different, i.e., 326.3 +/- 33.2 microliter/min, P less than 0.001, 112 +/- 25 mg%, P less than 0.001, and 1.26 +/- 0.28 mg%, P less than 0.01, respectively, in the verapamil-treated animals. Increased 24-hr total urine creatinine, sodium, osmolality, and a lower fractional excretion of sodium were also observed in the verapamil-treated rats with ARF. The combination of propranolol 1 mg/kg body wt/min and verapamil 10 micrograms/kg body wt/min for 100 min had no additive effect on renal function. In another group of ARF rats in which verapamil was started after declamping, no alleviating effect was observed. It is concluded that verapamil, an inhibitor of cellular membrane transport, when given prior to the renal ischemia, offers a partial but significant protection in this model of ischemic ARF.     

The effect of atrial natriuretic peptide on acid-base balance in rats with chronic renal failure

We explored the effects of 12-hour infusion of atrial natriuretic peptide (alpha-rANP:rat, 1-28) on arterial acid-base balance, using 5/6 nephrectomized rats with chronic renal failure. Before the infusion, nephrectomized rats had a higher mean arterial blood pressure, greater urine volume, and lower creatinine clearance than the normal controls, but they did not show a significant difference in arterial hydrogen ion concentration (pH), plasma bicarbonate concentration (HCO3-), partial pressure of carbon dioxide (PCO2), plasma base excess (BE), or plasma ANP concentration. alpha-rANP infusion produced a continuous blood pressure reduction in both nephrectomized and control rats. Urine volume and urinary sodium and potassium excretion tended to increase at 2-hour infusion, but not at 12-hour infusion. In the controls alpha-rANP significantly increased pH from 7.47 to 7.50, and decreased PCO2 by 14%. In contrast, in nephrectomized rats alpha-rANP significantly decreased pH from 7.48 to 7.44, HCO3- by 13%, and BE from -0.07 to -3.22 meq/l. Rats with chronic renal failure had greater reduction in HCO3- than the controls (p less than 0.05). There was no difference in plasma ANP level between the two groups. Thus, it is indicated that the long-term infusion of alpha-rANP reduces pH in rats with chronic renal failure, thereby adversely affecting the acid-base balance.     

Effects of oxygen free radical scavengers on uranium-induced acute renal failure in rats

Study was made to determine whether oxygen free radicals mediate uranium-induced acute renal failure (ARF). Superoxide dismutase (SOD), a superoxide anion scavenger, did not prevent uranium acetate (UA) (5 mg/kg, i.v.)-induced renal injury 48 h after injection. In contrast, dimethylthiourea (DMTU), a hydroxyl radical scavenger, significantly attenuated UA-induced rise in serum creatinine concentration (1.11 ± 0.05 (DMTU) vs. 1.40 ± 0.06 mg/dl (control), p < .05), and tubular necrosis. Dimethyl sulfoxide (DMSO), a hydroxyl radical scavenger, decreased UA-induced tubular damage. UA injection caused no increase in renal cortical malondialdehyde (MDA) content. DMTU and DMSO did not modify intrarenal MDA content. UA administration brought about significant increase in plasma renin activity but not in renal cortical renin content. Treatment with DMTU and DMSO had no effect on plasma renin activity or intrarenal renin content. It follows from these findings that DMTU and DMSO may attenuate UA-induced renal injury. Such a protective effect would not be mediated through modulation of lipid peroxidation or renin activity.     

Renal proton magnetic resonance in experimental acute renal failure in rats

Cortical, medullary and papillary T1 and T2 water proton relaxation times were measured at 37 degrees C, 20 MHz. The measurements were made using kidneys from rats affected by many forms of experimental acute renal failure (ARF), namely acute hemorrhagic hypovolemia, angiotensin II administration, antidiuretic hormone (ADH) administration, glycerol, and other nephrotoxins (gentamicin, cisplatinum, cyclosporine), renal artery occlusion for different periods of time, and ureteral ligation. From the T1 and PW (percent tissue water content) the bound water (FB) and HF (percent water bound/g solid) were calculated according to a fast proton diffusion model. In most experimental models studied, the experiments were repeated following paramagnetic enhancement with GdDTPA administration (70 mmol/kg BW). By profiling the deviations from normal, it was possible to differentiate the ischemic (shortened T1, prolonged T2), obstructive (very high T1 and T2 in both cortex and medulla) and nephrotoxic (prolonged T2) forms of ARF. Significant changes in free/bound water compartments occurred, though their biological significance is unknown. T1 and T2 ratios before and after paramagnetic enhancement correlated well with estimates of glomerular filtration rate. In the first minutes following acute hemorrhagic hypovolemia, the intrarenal water distribution remained unchanged. After GdDTPA significant water proton T1 and T2 changes characterized the immediate posthemorrhagic state similar to the effect of ADH.     

Intravenous renal cell transplantation for rats with acute and chronic renal failure

Acute kidney injury (AKI) and chronic renal failure (CKD) are the most challenging problems in nephrology. Multiple therapies have been attempted but these interventions have minimal effects on the eventual outcomes, and all too often the result is end-stage renal disease (ESRD). The only effective therapy for ESRD is renal transplantation but only a small fraction of patients receive transplants. In this work we introduce a novel approach to transplantation designed to regenerate kidneys afflicted by severe AKI or CKD: intravenous renal cell transplantation (IRCT) with adult rat primary renal cells reprogrammed to express the SAA gene localized and engrafted in kidneys of rat recipients that had severe AKI or CKD. IRCT significantly resolved renal dysfunction and limited kidney damage, inflammation, and fibrosis. Severe CKD was successfully improved by IRCT using kidney cells from donor rats or by renal cell self-donation in a form of autotransplantation. We propose that IRCT with adult primary renal cells reprogrammed to express the SAA gene can be used to effectively treat AKI and CKD.     

Increased severity of the acute renal failure induced by HgCl2 on rats with reduced renal mass

In rats unilaterally nephrectomized 2 days before and sham operated controls, an acute fenal failure (ARF) has been induced by subcutaneous HgCl2 injection. The uninephrectomized animals showed a more severe ARF than the sham operated, 60% of the former and 10% of the controls became anuric 48 hours after ARF induction. The increased diuresis and natriuresis produced by acute saline overload did not improve the severity of the ARF. The marked difference in the evolution of this model of ARF with respect to the glycerol induced ARF, which is ameliorated by reduction of renal mass, emphasizes the different pathogenetic mechanism of these two experimental models.     

Preventive effects of hyperbaric oxygen treatment on glycerol-induced myoglobinuric acute renal failure in rats

Myoglobinuric acute renal failure (ARF) is a uremic syndrome caused by traumatic or non-traumatic skeletal muscle breakdown and intracellular elements that are released into the bloodstream. We hypothesized that hyperbaric oxygen (HBO) therapy could be beneficial in the treatment of myoglobinuric ARF caused by rhabdomyolysis. A total of 32 rats were used in the study. The rats were divided into four groups: control, control+hyperbaric oxygen (control+HBO), ARF, and ARF+hyperbaric oxygen (ARF+HBO). Glycerol (8 ml/kg) was injected into the hind legs of each of the rats in ARF and ARF+HBO groups. 2.5 atmospheric absolute HBO was applied to the rats in the control+HBO and ARF+HBO groups for 90 min on two consecutive days. Plasma urea, creatinine, sodium, potassium, calcium, aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, creatinine kinase and urine creatinine and sodium were examined. Creatinine clearance and fractional sodium excretion could then be calculated. Superoxide dismutase, catalase, glutathione and malondialdehyde (MDA) levels were assessed in renal tissue. Tissue samples were evaluated by Hematoxylin-eosin, PCNA and TUNEL staining histopathologically. MDA levels were found to be significantly decreased whereas SOD and CAT were twofold higher in the ARF+HBO group compared to the ARF group. Renal function tests were ameliorated by HBO therapy. Semiquantitative evaluation of histopathological findings indicated that necrosis and cast formation was decreased by HBO therapy and TUNEL staining showed that apoptosis was inhibited. PCNA staining showed that HBO therapy did not increase regeneration. Ultimately, we conclude that, in accordance with our hypothesis, HBO could be beneficial in the treatment of myoglobinuric ARF.