Basic Science Aspects
Improved Renal Recovery with Postresuscitation N-Acetylcysteine Treatment in Asphyxiated Newborn Pigs
Lee, Tze-Fun*; Liu, Jiang-Qin*; Li, Ying-Qian*; Nasim, Khalida†; Chaba, Todd†; Bigam, David L.‡; Cheung, Po-Yin*‡
*Departments of Pediatrics, †Laboratory Medicine and Pathology, and ‡Surgery, University of Alberta, Edmonton, Alberta, Canada
Received 14 Jun 2010; first review completed 6 Jul 2010; accepted in final form 27 Sep 2010
Address reprint requests to Po-Yin Cheung, MBBS, PhD, FRCP (Can & Edin), NICU Royal Alexandra Hospital,10240 Kingsway Avenue, Edmonton, Alberta, Canada T5H 3V9. E-mail: firstname.lastname@example.org.
The project received support from the Canadian Institutes of Health Research (MOP 53160 and Investigator Award to P.Y.C.).
Renal injury is one of the severe and common complications that occurs early in neonates with asphyxia, and reactive oxygen species have been implicated to play an important role on its pathogenesis. Improved renal recovery has been shown previously with N-acetyl-l-cysteine (NAC) in various acute kidney injuries. Using a subacute swine model of neonatal hypoxia-reoxygenation (H/R), we examined whether NAC can sustain its beneficial effect on renal recovery for 48 h. Newborn piglets were randomly assigned into a sham-operated group (without H/R, n = 6) and two H/R experimental groups (n = 8 each) with 2 h normocapnic alveolar hypoxia and 1 h 100% oxygen of reoxygenation followed by 21% oxygen for 47 h. Five minutes after reoxygenation, piglets received either normal saline (H/R control) or NAC (150-mg/kg bolus and 20 mg/kg per hour i.v. for 24 h) in a blinded, randomized fashion. All piglets were acidotic and in cardiogenic shock after hypoxia. Treating the piglets with NAC significantly increased both renal blood flow and oxygen delivery throughout the reoxygenation period. N-acetyl-l-cysteine treatment also improved the renal function with the attenuation of elevated urinary N-acetyl-β-d-glucosaminidase activity and plasma creatinine concentration observed in H/R controls (both P < 0.05). The tissue levels of lipid hydroperoxides and caspase 3 in the kidney of NAC-treated animals were significantly lower than those of H/R controls. Conclusively, postresuscitation administration of NAC elicits a prolonged beneficial effect in improving renal functional recovery and reducing oxidative stress in newborn piglets with H/R insults for 48 h.
Renal injury is a severe and common complication that occurs early in neonates with asphyxia. Reperfusion injury has been suggested as the cause of kidney damage during resuscitation of neonatal asphyxia (1). After asphyxia, neonates often show symptoms of acute renal failure on the first or second postnatal day, and the mortality rate associated with renal failure is more than 20% (2, 3). Recently, it has been shown that acute renal failure is associated with the severity of neurological damage and adverse neurological outcome (4). Asphyxiated neonates with renal impairment are more likely to have hypotension, hypovolemia, and imbalance of electrolytes. Furthermore, the renal injury is an important factor that affects the fluid management and medication therapies to these infants (5) because of the compromised capacity of clearance of fluid and drugs.
The pathophysiology of reperfusion-induced renal injury is complex. Although the mechanisms underlying ischemia-reperfusion (I/R)- or hypoxia-reoxygenation (H/R)-induced damage to kidneys are likely to be multifactorial and interdependent, there is growing evidence that reactive oxygen species (ROS) play a significant role in the pathogenesis of renal injury (6, 7). Excess production of NO and ROS such as superoxide anion and hydroxyl radical has been reported during H/R or I/R. Some of these radicals and their metabolites cause cellular damage and apoptotic cell death by oxidizing proteins, inducing lipid peroxidation, and damaging DNA. Reducing renal oxidative stress by dietary or pharmacological agents has shown some success in minimizing renal injury (8).
N-acetyl-l-cysteine (NAC), a precursor of glutathione and a potent thiol-containing antioxidant, has been shown to have certain beneficial effects on various forms of acute kidney injury, such as radiocontrast-induced nephropathy, ischemic renal failure, and ureteral obstruction (9-11). In most of these studies, NAC was given before either ischemia (10) or ureteral obstruction (11), which may not be applicable in clinical situations of asphyxiated neonates. Previously, we have shown that postresuscitation treatment with NAC improved renal function and renal perfusion in severely hypoxic newborn piglets during 4 h of reoxygenation (12). As acute renal failure usually becomes more apparent in neonates after 24 h (2, 3), it is not clear if NAC still has prolonged protective effect on minimizing the deterioration of renal function for more than 24 h. To date, there are at least 25 clinical trials studying the effects of NAC in children at risk for renal impairment (ClinicalTrials.gov), which is in part related to its antioxidant action.
Using a subacute swine model of neonatal H/R, we investigated the prolonged effect of postresuscitation treatment with NAC on renal recovery by examining the renal hemodynamic change as well as the function and H/R injury of the kidney. To provide the possible mechanisms through which NAC elicited its beneficial effects, we also examined renal glutathione, lipid hydroperoxides (LPOs), and activated caspase 3 levels. We hypothesized that postresuscitation NAC treatment would improve the renal perfusion and function in asphyxiated newborn piglets for more than 24 h.
All experiments were conducted in accordance with the national guideline and approval of the Animal Care and Use Committee, University of Alberta. Male newborn Yorkshire-Landrace piglets 1 day of age weighing 1.6 to 2.5 kg (1.93 ± 0.04 kg) were used.
The animal preparation was similar to that described previously (12, 13). Briefly, anesthesia was initially maintained with inhaled isoflurane (2%-3%), which was then switched with fentanyl (0.005-0.05 mg/kg per hour), midazolam (0.1-0.2 mg/kg per hour), and pancuronium (0.05-0.1 mg/kg per hour) once mechanical ventilation was commenced. Heart rate, blood pressure, and percutaneous oxygen saturation were continuously monitored throughout the experimental period. Fractional inspired oxygen concentration (Fio2) was maintained at 0.21 to 0.24 for oxygen saturation between 90% and 97%. Maintenance fluids during experimentation consisted of 5% dextrose at 10 mL/kg per hour and Ringer's lactate solution at 2 mL/kg per hour. The body temperature was maintained at 38.5°C to 39.5°C using an overhead warmer and a heating pad.
Argyle catheters (5F; Sherwood Medical Co., St. Louis, Mo) were inserted via the right femoral artery and vein for continuous measurement of mean arterial pressure (MAP) and fluid/medication administration, respectively. Via a tracheotomy, pressure-controlled assisted ventilation was commenced (model IV-100; Sechrist Industries Inc., Anaheim, Calif) with pressure of 20/4 cmH2O at a rate of 18 to 20 breaths/min. Transit time ultrasound flow probes (6SB and 2SB; Transonic Systems Inc., Ithaca, NY) were placed around the main pulmonary and left renal arteries, respectively.
After postsurgical stabilization, piglets were block randomized into a sham-operated group (without H/R, but was ventilated with Fio2 of 0.21 throughout the experimental period, n = 6) or two H/R experimental groups (n = 8 each) with 2-h hypoxia induced by decreasing the Fio2 of 0.10 to 0.13 using nitrogen and oxygen gas mixture. The Fio2 was adjusted as necessary as tolerated by the piglets to obtain severe hypoxemia (Pao2, 20-40 mmHg) for 2 h. After hypoxia, the piglets were resuscitated with an Fio2 of 1.0 for 1 h, followed by 0.21 for the remainder of the experimental period (47 h). Five minutes after reoxygenation, piglets received either saline (H/R control, bolus of 3 mL/kg + continuous infusion of 2 mL/kg per hour, i.v.) or NAC (150 bolus of mg/kg + 20 mg/kg per hour, i.v.) for 24 h in a blinded, randomized fashion. The dosage of NAC was based on our previous studies (12, 13), and the regimen was modified from the protocol used clinically for radiocontrast-induced nephropathy (9) and acetaminophen poisoning. During the 48 h of observation, the piglet was cared for by two experienced team members (J.Q.L. and T.F.L.) alternately who did not know the randomization. Both peak inspiratory pressure (18-25 cmH2O) and respiratory rate (12-20 breaths/min) of ventilation setting were adjusted to maintain normocapnia. The dosages of fentanyl, midazolam, and pancuronium were adjusted to maintain minimum body movements during the experimental period. Propofol (0.1-0.2 mg/kg per hour) was given as needed to maintain anesthesia. A gastric tube was inserted into the stomach orally and drained if needed. A 20-gauge Insyte angiocatheter (Becton Dickinson Infusion Therapy Systems Inc., Sandy, Utah) was inserted into the bladder transcutaneously to drain the urine. Blood gases were studied every 30 min during hypoxia and 100% oxygen of reoxygenation, every 4 h within the first 24 h and every 6 h within the second 24 h. Plasma and urine samples were collected at specific time points and stored at −80°C for subsequent biochemical analysis. At the end of the experiment, the piglet was killed with pentobarbital (100 mg/kg, i.v.). The right kidney was removed rapidly and flash frozen in liquid nitrogen and stored at −80°C for subsequent analysis.
Hemodynamic recordings and calculations
Hemodynamic parameters (heart rate, MAP, blood flows) were recorded at specific time points: baseline (0 min), every 15 min during hypoxia, and at predetermined time points throughout reoxygenation. Cardiac index (CI), a surrogate estimated by the pulmonary artery flow, and renal artery flow index (RAFI) were corrected for individual piglet mass. Oxygen content was determined by the summation of the oxygen content of hemoglobin and the dissolved content of oxygen in blood: (1.36 × hemoglobin level × oxygen saturation) + (0.003 × PO2). Renal oxygen delivery was the product of flow index and arterial oxygen content, whereas renal vascular resistance index was calculated by (MAP − CVP) / RAFI.
Renal tissues were homogenized with 10 μL/mg of 50 mM phosphate buffer containing 1 mM EDTA (pH 7.0). The tissue levels of oxidized and total glutathione (GSSG and GSH, respectively), LPOs, and activated caspase 3 were measured using commercially available assay kits (nos. 703002, 705002, and 10009135, respectively; Cayman Chemical, Ann Arbor, Mich). Tissue lactate was assayed by enzymatic spectrometric methods. Plasma and urine creatinine concentrations were measured using QuantiChrom creatinine assay kit (DICT-500; Bioassay Systems, Hayward, Calif). Urinary N-acetyl-β-d-glucosaminidase (NAG) activity, a specific marker for renal injury, was measured by colorimetric assay (no. 875406; Roche, Indianapolis, Ind), and results were normalized to urinary creatinine values. The protein content was determined by bicinchoninic acid assay kit (Sigma-Aldrich Canada Ltd., Oakville, Ontario, Canada).
Tissues from the right kidney, preserved in 10% formalin, were embedded in paraffin blocks, sectioned, and stained with hematoxylin and eosin. Two pathologists (K.N. and T.C.), who were blinded to the randomization, independently analyzed the slides for H/R-induced injury using the scoring systems previously described (14).
All results are expressed as mean ± SEM. One-way and two-way analyses of variance were used to study the differences between groups as appropriate. Post hoc testing with Tukey method was performed for pairwise comparisons with the H/R control group as appropriate. A χ2 test was used to compare the occurrence of renal failure in the animals. Correlation between variables was studied by Spearman rank-order correlation. Statistical analyses were performed using SigmaStat (V2.0; Jandel Scientific, San Rafael, Calif). Significance was set at P < 0.05.
There was no statistical difference in body weight among three experimental groups. As shown in Table 1, sham-operated piglets did not show any significant change in arterial pH and hemodynamic variables throughout the experimental period.
Effect of NAC treatments on physiologic and systemic hemodynamic changes
After 2 h of normocapnic alveolar hypoxia, all piglets were acidotic and in cardiogenic shock (Table 1). Although the arterial pH of piglets was lower than the normoxic baseline value at the end of hypoxia (P < 0.05), it recovered quickly and was similar to that of the sham-operated group at 12 h after reoxygenation (Table 1). Heart rate increased significantly by the end of hypoxia in hypoxic piglets. At 1 h of reoxygenation, heart rate of NAC group was significantly higher than that of sham-operated and H/R control groups (Table 1). However, there were no statistical differences among all experimental groups thereafter. There was significant hypotension with decreased CI in both H/R groups after 2 h of hypoxia (vs. sham-operated, P < 0.05) (Table 1). The MAP of both H/R groups increased immediately after hypoxia and then improved gradually throughout the reoxygenation period. However, the recovery rate of H/R controls was relatively slower than that of NAC group (Table 1). The CI of H/R controls rebounded immediately upon reoxygenation but remained lower than the sham-operated group throughout the first 12 h of reoxygenation period (P < 0.05) (Table 1). In contrast, the CI of piglets treated with NAC rebounded back to the baseline value within an hour of reoxygenation and was maintained at the same level throughout the recovery period (Table 1). Overall, the CI of NAC-treated piglets was significantly higher than that of H/R control group during the reoxygenation period (two-way repeated-measures ANOVA).
Effect of NAC treatments on renal hemodynamic changes
As shown in Figure 1A, the RAFI decreased markedly at the end of hypoxia. Upon reoxygenation, the RAFI of H/R controls rose immediately but remained significantly lower than the baseline value throughout the reoxygenation period (Fig. 1A). In contrast, the RAFI of NAC-treated piglets rebounded immediately to the baseline value after reoxygenation and maintained about the same level as the sham-operated group afterward (Fig. 1A). Consequently, the RAFI of NAC-treated group was significantly higher than that of H/R control piglets throughout the reoxygenation period (two-way repeated-measures ANOVA). The mean left RAFI/CI ratios of all experimental groups were 4.1% to 4.4% at baseline. The RAFI/CI ratios did not significantly change throughout the reoxygenation period, and there were no differences among groups (data not shown).
At the end of hypoxia, the renal vascular resistance index of both H/R groups was significantly higher than that of the sham-operated group (Fig. 1B). After resuscitation, the increased renal vascular resistance index normalized with no significant difference among experimental groups at 1 h of reoxygenation and the subsequent experimental period (Fig. 1B).
The changes in renal oxygen delivery during H/R are illustrated in Figure 1C. At 2 h of hypoxia, the renal oxygen delivery of two H/R groups decreased similarly to 15% to 19% of the normoxic baseline. As shown in Figure 1C, the pattern of changes in renal oxygen delivery after reoxygenation corresponded to that observed with RAFI. Overall, the oxygen delivery of H/R control piglets was significantly lower than that both of sham-operated and NAC-treated groups during the reoxygenation period (two-way repeated-measures ANOVA).
Effects of NAC treatment on renal function: urinary NAG activity and plasma creatinine concentration
Figure 2A summarizes the change in urinary NAG activities during reoxygenation period. The urinary NAG activity of the H/R control group was significantly higher than both sham-operated and NAC-treated groups at 24 h after reoxygenation. Although the 48-h urinary NAG activity of H/R controls was lower than the respective activity at 24 h, it remained significantly higher than that of the sham-operated group (Fig. 2A). The urinary NAG activity of NAC-treated piglets was lower than that of H/R controls at 48 h; however, the difference was not statistically significant (Fig. 2A).
At 24 and 48 h after reoxygenation, plasma creatinine concentrations of H/R controls, but not NAC-treated piglets, increased (P < 0.05 vs. baseline) and were significantly higher than the corresponding values of the sham-operated group (Fig. 2B). Using 1.0 mg/dL (2 SDs above the mean of sham-operated piglets) as the cutoff for normal plasma creatinine range, all H/R controls had renal failure defined as elevated plasma creatinine greater than 1.0 mg/dL, whereas only 4 NAC-treated piglets (50%) had renal failure, and four NAC-treated animals had no renal failure (P = 0.08 vs. H/R controls, χ2).
Effects of NAC on various biochemical and oxidative stress markers in renal tissues
The LPO level of the control group was significantly higher than those of sham-operated piglets (Table 2). Treating the piglets with NAC significantly reduced the LPO accumulation in kidney tissues by the end of the experiment (Table 2). Similarly, the level of activated caspase 3 in kidney tissue of the control group was significantly higher than those of sham-operated and NAC-treated groups at the end of the experiment (Table 2). The kidney caspase 3 levels correlated positively with LPO accumulation (r = 0.49, P = 0.02). Furthermore, the overall RAFI was negatively correlated with both LPO and caspase 3 levels (r = −0.53, P = 0.01; and r = −0.47, P = 0.03, respectively).
At 48 h after reoxygenation, the tissue contents of total glutathione, oxidized glutathione, glutathione redox ratio (GSSG:GSH) (data not shown), and lactate in the right kidney were not statistically different among groups (Table 2).
Histological features on the kidney
Although the difference did not achieve any statistical significance, the severity of H/R-induced injury in the kidney of experimental groups tended to be higher than that of sham-operated piglets (H/R renal injury score of 0.0 ± 0.17, 1.0 ± 0.38, and 0.5 ± 0.26 for sham-operated, H/R control, and NAC-treated groups, respectively). Severe histological damages including focal hemorrhagic necrosis and cellular casts were observed in three control piglets after H/R.
Although NAC has been used clinically in treating certain free radical-related diseases for decades, the results remain controversial (15). Therefore, more studies are required to provide further information, particularly in neonates, on using NAC as a potential therapy for H/R insult. In this subacute animal model, we were able to observe the continuous hemodynamic changes over the 48-h reoxygenation period. Our results demonstrate that postresuscitation administration of NAC improved overall hemodynamic recovery and renal function as indicated by RAFI, urinary NAG activity, and plasma creatinine concentration. N-acetyl-l-cysteine may elicit its beneficial effect by minimizing H/R-induced renal injury, which is evident from the levels of LPO accumulation and caspase 3 activity. Given the promising findings, further studies are warranted to confirm the efficacy and safety of the drug in asphyxiated neonates.
It is generally believed that the abnormalities of renal function during and after hypoxia contribute to the progressive deterioration observed in H/R injury. Renal injury may reflect the degree of brain injury, where abnormal renal function including oliguria and neurological examination is associated with poor long-term neurological outcome (4, 16). Furthermore, it is important to maintain the renal function in asphyxiated subjects during reperfusion or reoxygenation to minimize damages and to improve clinical care on fluid balance and drug clearance.
The reduction of renal arterial peak velocity correlates with the severity of perinatal asphyxia (17) and may be a good predictor of acute renal failure (18). Restoring renal blood flow has been observed after NAC treatment in rats with renal failure induced either by contrast media (19) or vena cava occlusion (20). A significant decrease in RAFI was observed in H/R controls upon reoxygenation and remained lower than the normoxic value thereafter. It is possible that hyperoxia-induced vasoconstriction via enhancing superoxide/peroxynitrite generation and decreasing NO availability may play a role in the decreased RAFI (20). The normalization of renal vascular resistance index normalized after reoxygenation in H/R piglets with no differences among experimental groups suggests that the decrease in RAFI in H/R controls may be related to the modestly lowered CI and MAP. The rapid improvement on renal blood flow by NAC may be related to an immediate profound amplification of prostaglandin E2 synthesis as that reported in rats with contrast media-induced renal failure (19). Recently, it has also been shown that NAC can have a direct effect on voltage-gated potassium channels to elicit its vasodilatation (21). Reduction in RAFI has been demonstrated to coincide with the development of renal failure in children with cardiopulmonary bypass surgery, and normalization of RAFI occurs in all patients whose renal function recovered (22). Therefore, the significant improvement of renal perfusion by NAC during the initial phase of reoxygenation may provide better outcome of asphyxiated neonates.
In addition to renal hemodynamic changes, we also evaluated the renal function by measuring the urinary NAG activity. Because this enzyme is too large for glomerular filtration and has an intracellular origin, its urinary excretion has been generally accepted as a sensitive and specific marker of acute renotubular damage (23). The temporal profile of urinary NAG activity also signifies the transient nature as well as the use as an early marker of acute renal injury, consistent with our observation in the H/R control group. Treatment with NAC significantly reduced the increase in urinary NAG activity at 24 h after reoxygenation. Similarly, the plasma creatinine concentration of H/R controls significantly increased from baseline at 24 and 48 h of reoxygenation, whereas plasma creatinine concentrations of NAC-treated piglets did not change during the experimental period. Plasma creatinine concentrations are commonly used for the assessment of renal function despite controversies over its specificity (24, 25). In this study, in the absence of a normative range in newborn piglets, we used 2 SDs above the mean level of plasma creatinine to define renal failure (1.0 mg/dL), which is similar to the clinical levels ranging from 0.9 to 1.5 mg/dL used in many neonatal intensive care units. Nearly a 2-fold increase in plasma creatinine was observed in H/R controls by 48 h after resuscitation. N-acetyl-l-cysteine improved renal function and ameliorated the increase in plasma creatinine concentrations. Taken together, our data demonstrated that the deterioration in renal function occurred after H/R, and treating the animals with NAC improved the recovery.
Reactive oxygen species formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states, and cause DNA strand breaks, all potentially damaging to normal cellular function. Therefore, it is likely that the increase in lipid peroxidation observed in the present study is due to ROS production during H/R. Complementary to our findings, several studies have also demonstrated that I/R in the kidney is associated with lipid peroxidation (10, 26). The suggestion of possible involvement of ROS in oxidative stress-induced renal injury in H/R is further supported by the findings with NAC treatment. Accompanied with the functional improvements, NAC also significantly attenuated the LPO accumulation. Similarly, it has also been shown previously that NAC can reduce ROS generation by its direct scavenging action in reperfused heart (27). Thus, our results indicate that NAC may elicit its renal protective effect either directly by scavenging ROS or indirectly by minimizing lipid peroxidation.
N-acetyl-l-cysteine is a precursor of l-cysteine and reduced glutathione, which are involved in endogenous defensive system against oxidative stress. Thus, the beneficial effect of NAC has been suggested to replenish endogenous glutathione that has been depleted during H/R or I/R (28). Although the renal GSH level of the NAC-treated group was slightly higher than the H/R control values, the difference was not statistically significant. As the tissues were collected 24 h after NAC treatment completed, the endogenous glutathione system may have been restored during the prolonged recovery period. Previously in H/R piglets treated with the same dosage of NAC, we did observe significantly higher GSH level when kidney tissues were obtained during the early phase of recovery (4 h after reoxygenation) (12).
Oxidative stress followed by apoptosis has been considered as a critical step of H/R injury. Recent reports have indicated the involvement of caspases, particularly caspase 3, for the initiation and execution of programmed cell death (29). Similar to previous reports (30, 31), a significant increase in activated caspase 3 levels was observed in the kidney of H/R controls, which was reduced by NAC treatment. Preventing caspase 3-dependent cell apoptosis has been suggested to be the main mechanism through which NAC elicits its protection against cisplatin-induced acute renal failure (32, 33). Although the underlying mechanism remains to be determined, it is possible that NAC may attenuate the apoptotic process and confers the renal protection in addition to its effects on the perfusion and oxidative stress of the neonatal kidney.
The duration of hypoxia in our study is longer than others' reports (30-60 min). Our protocol accounts for the elapsed time between the onset of hypoxia, recognition of fetal distress, assessment, diagnosis, and the final decision to intervene, which on average is close to 130 min in cases of fetal distress (nonbleeding) from the recognition to emergency delivery (personal observation) (34). Furthermore, it will be interesting to compare the beneficial effect of NAC in the setting of 21% reoxygenation, although the use of 100% oxygen in the resuscitation of term neonates is still widely practiced. N-acetyl-l-cysteine is the standard therapy in acetaminophen poisoning (15); to date, there are 20 ongoing clinical trials in free radical-related diseases in children (ClinicalTrials.gov). Our findings further support the potential of NAC as therapy for hypoxic insult in neonates.
As demonstrated by functional parameters and oxidative stress markers, this study demonstrates that NAC can provide prolonged beneficial effects in minimizing H/R-induced injury and assisting the recovery of renal function after H/R in neonates.
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