Yariv Siman-Tov

Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury

BACKGROUND Ischemia/reperfusion triggers acute kidney injury (AKI), mainly via aggravating hypoxia, oxidative stress, inflammation and renin-angiotensin system (RAS) activation. We investigated the role of angiotensin-converting enzyme (ACE) inhibition on the progression of AKI in a rat model of ischemia/reperfusion. METHODS Ninety-nine Sprague-Dawley rats were subjected to 1 h ischemia/reperfusion and/or left unilateral nephrectomy, with concurrent intraperitoneal implantation of Alzet pump. Via this pump, they were continuously infused with captopril 0.5 mg/kg/day, captopril 2 mg/kg/day or saline. The rats were sacrificed following 24, 48 or 168 h. Blood samples, 24-h urine collections and kidneys were allocated, to evaluate renal function, angiotensin-II, nitric oxide (NO), apoptosis, hypoxia, oxidative stress and inflammation. RESULTS Serum creatinine and cystatin-C significantly increased in ischemic rats, coinciding with histopathologic intrarenal damage, decreased NO, augmented angiotensin-II, interleukin (IL)-6, IL-10, transforming growth factor-beta. At the acute reperfusion stage, captopril prevented excessive angiotensin-II synthesis, ameliorated renal dysfunction, inhibited intrarenal inflammation and improved histopathologic findings. Most of the renoprotective effects of captopril were limited predominantly to acute reperfusion stage. Concurrently, captopril significantly decreased NO availability, exacerbated intrarenal hypoxia and augmented oxidative stress. CONCLUSIONS At the acute stage of renal ischemia/reperfusion-induced AKI, ACE inhibition substantially contributed to the amelioration of acute injury by improving renal function, inhibiting systemic and intrarenal angiotensin-II, attenuating intrarenal inflammation and preserving renal tissue structure. Later on, at the post-reperfusion stage, most of the beneficial effects of captopril administration on the recuperating post-ischemic kidney were no longer evident. Concurrently, ACE inhibition exacerbated intrarenal hypoxia and accelerated oxidative stress, indicating that renal adaptation to some consequences of ischemia does require bioavailability of RAS components.

Optimization of endotracheal tube cuff filling by continuous upper airway carbon dioxide monitoring.

Inappropriate cuff filling is responsible for various complications related to the use of an endotracheal tube (ETT). In this study, we evaluated an objective, noninvasive method for continuous assessment of leak around the ETT cuff by monitoring carbon dioxide pressure (Pco2) in the upper airway. Pco2 levels were measured by capnography simultaneously between the ETT cuff and the vocal cords, at the oropharynx, and in the nares of the nose. Cuff filling was regulated by an electronic controller to achieve the minimal pressure needed to prevent CO2 leak. Feasibility of the method was assessed in a human simulator and in a porcine model. Clinical function was evaluated in 60 patients undergoing surgery, comparing the method to the standard anesthesiologist evaluation. Linear correlations were observed between the ETT cuff pressure and Pco2 level in the human simulator (R2 = 0.954, P < 0.0001) and in the porcine model (R2 > 0.98, P < 0.0001). Iodine leak around the ETT cuff, in the porcine model, occurred only when Pco2 levels were >2 mm Hg. In the surgery patients, the mean ETT cuff pressure determined clinically by the anesthesiologist was significantly higher than the optimal cuff pressure assessed by Pco2 (25.2 ± 3.6 versus 18.2 ± 7.8 mm Hg, respectively; P < 0.001). According to these findings, optimal ETT cuff filling pressure can be identified by monitoring Pco2 at the nares or the oropharynx.

Application of normobaric hyperoxia therapy for amelioration of haemorrhagic shock-induced acute renal failure*

BACKGROUND Hypoxia resultant from haemorrhagic shock is the primary cause of kidney damage. Application of normobaric hyperoxia therapy (NHT) is an acceptable treatment for acute haemorrhagic shock. We investigated the effect of NHT on amelioration of haemorrhagic shock-induced rat renal failure. METHODS Twenty-four Sprague-Dawley rats were subjected to gradual blood withdrawal/reperfusion, followed by 12-h, 24-h or 48-h NHT. Verification/monitoring of intrarenal hypoxia was performed using Hypoxyprobe-TM-1. Subsequently, cystatin C, urea and creatinine were assessed in serum by a Hitachi autoanalyser, and NO, 3-nitro-tyrosine, STAT-8-isoprostane and NF-kB in renal medullae and cortices by specific ELISAs. RESULTS In rats subjected to haemorrhagic shock, 12- to 48-h NHT significantly reduced intrarenal Hypoxyprobe-TM-1 stained areas and attenuated augmentation of urea, creatinine and cystatin C. Haemorrhagic shock resulted in a 10-fold drop of intrarenal NO availability. 12-h and 24-h, but not 48-h, NHT significantly increased cortical/medullar NO synthesis, the latter, however, not approaching the pre-shock values. Significant shock-induced accumulation of STAT-8-isoprostane and 3-nitro-tyrosine was further exacerbated by NHT. Haemorrhagic shock activated NF-kB in ischaemic tissues, which was not attenuated by NHT. CONCLUSIONS (1) 12- to 48-h NHT decreased intrarenal hypoxia signs and ameliorated deterioration of renal functions in a rat model of haemorrhagic shock-induced renal failure. (2) 12- to 24 h NHT improved bioavailability of NO in cortices/medullae of kidneys recuperating from haemorrhagic shock. (3) If any anti-inflammatory activities were stimulated by NHT, they would not be mediated via the NF-kB pathway. (4) Despite NHT-associated elevation of reactive oxygen species (ROS), early oxygen supply proved mandatory for effective recuperation of ischaemic kidney from detrimental consequences of haemorrhagic shock.

Differential Effects of N-Acetylcysteine, Theophylline or Bicarbonate on Contrast-Induced Rat Renal Vasoconstriction

Background: Vasoconstriction and reactive oxygen species (ROS) accumulation following contrast media (CM) injection are the key factors triggering CM-induced nephropathy. We compared the effects of N-acetylcysteine (NAC), theophylline or sodium bicarbonate on intrarenal vasoconstriction and ROS generation in a rat model of CM-induced nephropathy. Methods: Following a 3-day dehydration, Sprague-Dawley rats received CM (Telebrix) or sham ‘CM’ injection of 0.9% saline. Part of them received NAC, theophylline or bicarbonate prior to CM. Medullar renal blood flow was estimated by laser Doppler. The animals were sacrificed 1, 15 or 30 min after the respective treatments, their kidneys allocated and intrarenal STAT-8 isoprostane, PGE2 and NO assessed. Results: Vasoconstriction was significantly attenuated by NAC. Theophylline only mildly attenuated the perfusion drop at 15 min, and was ineffective following 30 min. Unlike theophylline or bicarbonate, NAC significantly augmented intrarenal PGE2. NAC, theophylline but not bicarbonate, gradually increased intrarenal NO. In all experimental variables, CM-induced ROS accumulation, represented by STAT-8 isoprostane estimation, progressed undisturbed. Conclusions: (1) CM-induced intrarenal vasoconstriction was efficiently prohibited by NAC but not bicarbonate or theophylline; (2) the vasodilatory effect of NAC was mediated via increased PGE2 synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected by any pharmacologic manipulations.

Hyperglycaemia, inflammation, RAS activation: three culprits to blame for acute kidney injury emerging in healthy rats during general anaesthesia.

Aim:  Major surgery under general anaesthesia might evoke acute kidney injury (AKI), sometimes culminating in end stage renal disease. We investigated the roles of hyperglycaemia, inflammation and renin‐angiotensin system (RAS) activation in induction of AKI following anaesthesia by different anaesthetic drugs and/or regimens.

Does dehydration affect thickness of the pyloric muscle? An experimental study

Congenital hypertrophic pyloric stenosis (CHPS) is a common condition in infancy associated with smooth muscle hypertrophy and resulting in pyloric outlet obstruction. The final diagnosis of CHPS is based on precise ultrasonographic measurements of length and width of the pyloric muscle. Based on our clinical and sonographic experience, we observed that smaller measurements of the pyloric muscle were obtained in dehydrated infants than in children examined after proper fluid restoration. The clinical importance of these observations was evident because false-negative results could be obtained. An experimental animal work followed, proving our clinical observation to be true. A significant difference of about 30% to 50% was found between measurements of the muscle thickness of the gastric and pyloric muscles in a state of water deprivation, as compared with a state of full hydration (p < 0.05). Based on our preliminary results, we suggest that children with suspected CHPS should be well hydrated before the ultrasound (US) examination is performed, to avoid false-negative results and a consequent delay in treatment.

Oral N-acetylcysteine has a deleterious effect in acute iron intoxication in rats.

Acute iron intoxication is associated with depletion of reduced glutathione in hepatocytes and changes in the glutathione system enzymes. We hypothesized that treatment with N-acetylcysteine (NAC), a glutathione reducing agent and an antioxidant, would reduce mortality in acute iron intoxication. We used a rat model to test this hypothesis. Male rats were assigned to 4 groups. Group 1 received 400 mg/kg elemental iron by oral gavage, group 2 received the same dose of iron followed by NAC, group 3 received NAC only, whereas group 4 received distilled water. Iron and liver transaminases in the blood, and glutathione system enzymes in the liver and erythrocytes were measured. Mortality in group 2 was significantly higher after 2, 6, and 24 hours compared with group 1 (P < .001). No deaths were observed in groups 3 and 4. Serum iron levels were significantly higher in group 2 rats compared to group 1 rats (P < .001). Hepatic and erythrocyte glutathione system enzymes were significantly lower among rats in group 2 compared to rats in group 1. The administration of NAC probably increased the absorption of iron through the gastrointestinal tract, causing higher serum iron levels with significant hepatic damage. These results indicate that in a rat model of acute iron intoxication, orally administered NAC may increase mortality.

Hepcidin in acute iron toxicity

BACKGROUND Hepcidin regulates extracellular iron concentration by inhibiting iron release from macrophages and preventing iron absorption in the intestine. Our objective was to evaluate the expression of hepcidin in the liver in acute iron poisoning in a rat model. METHODS Male Wistar rats were assigned to group 1, who received 750 mg/kg elemental iron (LD(50)) by gavage, and group 2 (control), who received distilled water. Iron concentrations and liver transaminases were measured in the serum. Hepcidin messenger RNA levels were measured in the liver. RESULTS Mean serum iron levels, aspartate aminotransferase, alanine aminotransferase, and uric acid were significantly higher in group 1 compared to group 2 (P < .0001, P = .01, P < .0001, and P = 0.0001, respectively). Hepcidin messenger RNA levels in the liver were significantly higher in the study group (P = .005). CONCLUSIONS In acute iron intoxication, hepcidin expression in the liver significantly increased. Further studies are needed to determine whether hepcidin levels correlate with the severity of the intoxication.

Rosiglitazone treatment attenuates renal tissue inflammation generated by urinary tract obstruction

Aim:  Peroxisome proliferator‐activated receptor (PPAR)‐γ activation by rosiglitazone decreases manifestation of intrarenal inflammatory hallmarks. Inflammation significantly aggravates renal injury following urinary tract obstruction. The effect of rosiglitazone on renal inflammation following unilateral ureteral obstruction was investigated.

Hyperglycaemia emerging during general anaesthesia induces rat acute kidney injury via impaired microcirculation, augmented apoptosis and inhibited cell proliferation

Aim:  Major surgery under general anaesthesia frequently triggers acute kidney injury by yet unknown mechanisms. We investigated the role of anaesthesia‐triggered systemic hyperglycaemia in impairment of renal functioning, renal tissue injury, intra‐renal Angiotensin‐II synthesis and endogenous insulin production in anaesthetized rats.