The Roles of Oxidative Stress in Acute and Chronic Renal Disease
Date Issued
2010
Date
2010
Author(s)
Hsu, Shih-Ping
Abstract
Oxidative stress, a status of imbalance between the production of reactive oxygen species (ROS) and the antioxidant protection, results in significant damage to cell structures and relates to many human diseases, such as neurological diseases, cardiovascular diseases, cancer and aging. Moreover, it is interesting and worth to clarify the roles of oxidative stress in acute and chronic renal disease.
In acute kidney injury (AKI), oxidative stress is presumed to play certain roles in the pathogenic mechanisms. Iodinated contrast media (CM)-induced nephropathy (CMIN) is a common cause of AKI and a major complication after application of CM. Two main mechanisms have been proposed on the basis of the results from experimental studies in CM-induced renal damage: 1) CM decrease renal perfusion; and, 2) CM directly damage renal tubules, increasing ROS. In recent years, some clinical studies have demonstrated N-acetylcysteine (NAC; an antioxidant) can prevent CMIN. However, evidence from experimental studies is waiting to be demonstrated.
Chronic kidney disease (CKD) is not only threatening the whole world population but also becoming a nation-wide health problem in Taiwan. CVD is the main death cause in patients with CKD, including those undergoing dialysis therapy for end-stage renal disease (ESRD). The high cardiovascular risks in CKD patients are partially related to increased oxidative stress, which links to inflammation and atherosclerosis. Therefore, it is worth to explore if antioxidants could be used to treat or prevent the risks and complications related to the oxidative stress in ESRD patients.
In order to clarify whether the more oxidative stress in AKI, the larger damage to the kidney, we explored the effects of CM on RENA, renal hemodynamics, plasma renin activity (PRA), ROS production and renal injury in rats. Four types of CM including Ioxitalamate (high-osmolar, ionic), Ioxaglate (low-osmolar, ionic), Iohexol (low-osmolar, non-ionic), and Iodixanol (iso-osmolar, non-ionic) were given intravenously (1600 mg I/kg body weight) to urethane-anesthetized female Wistar rats. We measured RENA by electrophysiologic recording techniques, renal blood flow (RBF) with Doppler ultrasound, PRA by radioimmunoassay, and ROS by an in vivo chemiluminescence method. We graded the severity of CM-induced vacuoles in cortical tubular cells stained by hematoxylin and eosin, and apoptosis production in outer medulla by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. Besides, the effects of pretreatment with intravenous β-adrenoceptor antagonist propranolol (10 mg/kg body weight), antioxidant NAC (100 mg/kg body weight) and renal denervation on CM-induced pathophysiologic parameters were determined. We found Ioxitalamate significantly increased RENA and renal vascular resistance (RVR), PRA, renal ROS production within one hour, and formation of vacuoles and TUNEL-apoptosis in renal tubular cells 2 hours later; other CM had less effect on these parameters. On the other hand, propranolol, NAC, or renal denervation partially attenuated the Ioxitalamate-aggravated responses on RENA, PRA, ROS production, and vacuole and TUNEL-apoptosis formation in renal tubular cells.
The above findings demonstrated high-osmolar CM, Ioxitalamate, induced the most oxidative stress and caused the most damage to the kidney. Moreover, Ioxitalamate may induce acute tubular injury via aggravation of RENA, adrenergic signaling, PRA, and ROS production. Pretreatment with β-adrenergic blockers may modulate RENA and less Ioxitalamate-induced acute tubular injury. Pretreatment with NAC can also moderate Ioxitalamate-induced acute tubular injury via not only reducing ROS production as expected but also stabilizing RENA.
In order to realize whether long-term supplement with antioxidants can improve the oxidative stress and related damage in hemodialysis (HD) patients, we first tested NAC in a clinical trial. Besides, we also tried catechins, potent antioxidants extracted from green tea, in HD patients because there was no report yet.
In the trial with NAC, we explored the efficacy of oral NAC supplement in anemia and oxidative stress in HD patients. Of the eligible patients (n = 325) in an outpatient HD unit, 49 received NAC 200 mg orally thrice a day during the first 3 months, while the other 276 patients not receiving NAC were observed. During the 4-month study, 11 patients receiving NAC withdrew but had no severe adverse effects, while 49 patients not receiving NAC had negative confounding events. Thus only the data of the remaining patients, 38 taking NAC and 227 not taking NAC, were analyzed for efficacy. The demographic and laboratory data of both groups were similar at baseline. When the erythropoietin dosage was stable throughout, only the NAC group had a significant increase in hematocrit, accompanied with a decrease in plasma levels of 8-isoprostane and oxidized low-density lipoprotein. Analyzed as in a nested case-control study, NAC supplementation was also found to be one significant predictor of positive outcomes of uremic anemia. In summary, oral NAC supplement may be promising therapy for uremic anemia and oxidative stress in HD patients.
In the trial with catechins, we evaluated the effects of decaffeinated green tea extract (catechins) supplement on HD-induced ROS, atherosclerotic risk factors, and proinflammatory cytokines. We enrolled 6 healthy subjects and 54 HD patients for this study. First, the pharmacokinetics of one oral dose of catechins were compared between the healthy (n = 6) and HD patients (n = 10). Second, in the 10 HD patients, we compared the antioxidant effects of three different doses (0, 455, and 910 mg) of oral catechins to that of oral vitamin C (500 mg) during an HD session. Third, the other 44 HD patients participated in a 7-month interventional study, including 30 patients taking placebo throughout and 14 patients taking catechins (455 mg) daily from the third to the fifth month. Compared to the healthy, the HD patients (n = 10) had later peaks and decay of plasma catechins after one oral dose. In the 10 HD patients, catechins supplement reduced HD-enhanced plasma HOCl activity more effectively than placebo or vitamin C. Between treatments with 455 and 910 mg of catechins, there was no significant difference in reducing plasma HOCl activity. Catechins also significantly reduced pro-inflammatory cytokine expression enhanced by HD. In the 7-month interventional study, in comparison to the 30 HD patients taking placebo, the 14 patients had less predialysis plasma H2O2 and HOCl activities, phosphatidyl choline hydroperoxide, C-reactive protein (CRP), and pro-inflammatory cytokine levels during the 3 months when they took catechins daily. In summary, catechins reduce HD-induced H2O2/HOCl production, atherosclerotic risk factor, and pro-inflammation.
Based on the findings in the above two clinical trials, oral NAC supplement is probably a safe and effective therapy for uremic anemia in those who can tolerate NAC; catechins may reduce HD-induced ROS, atherosclerosis risk, and pro-inflammation. That is, we demonstrated long-term supplementation with antioxidants, like NAC or catechins, may improve the oxidative stress and related damage in HD patients.
In conclusion, the results in the rat experiment and clinical trials clarify: 1) the more oxidative stress in AKI, the larger damage to the kidney; and, 2) long-term supplementation with antioxidants can improve the oxidative stress in HD patients. Further experimental and clinical studies have been conducted on the basis of the above significant findings.
Subjects
oxidative stress
iodinated contrast media
renal efferent nerve activity
N-acetylcysteine
green tea extract (catechins)
hemodialysis
SDGs
Type
thesis
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