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

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          Abstract

          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, PGE<sub>2</sub> 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 PGE<sub>2</sub>. 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 PGE<sub>2</sub> synthesis, and (3) ROS accumulation was a primary renal response to CM-induced injury, not affected by any pharmacologic manipulations.

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          Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention.

          In patients undergoing percutaneous coronary intervention (PCI) in the modern era, the incidence and prognostic implications of acute renal failure (ARF) are unknown. With a retrospective analysis of the Mayo Clinic PCI registry, we determined the incidence of, risk factors for, and prognostic implications of ARF (defined as an increase in serum creatinine [Cr] >0.5 mg/dL from baseline) after PCI. Of 7586 patients, 254 (3.3%) experienced ARF. Among patients with baseline Cr 2.0, all had a significant risk of ARF. In multivariate analysis, ARF was associated with baseline serum Cr, acute myocardial infarction, shock, and volume of contrast medium administered. Twenty-two percent of patients with ARF died during the index hospitalization compared with only 1.4% of patients without ARF (P 2.0 are at high risk for ARF. ARF was highly correlated with death during the index hospitalization and after dismissal.
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            Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial.

            Contrast-induced nephropathy remains a common complication of radiographic procedures. Pretreatment with sodium bicarbonate is more protective than sodium chloride in animal models of acute ischemic renal failure. Acute renal failure from both ischemia and contrast are postulated to occur from free-radical injury. However, no studies in humans or animals have evaluated the efficacy of sodium bicarbonate for prophylaxis against contrast-induced nephropathy. To examine the efficacy of sodium bicarbonate compared with sodium chloride for preventive hydration before and after radiographic contrast. A prospective, single-center, randomized trial conducted from September 16, 2002, to June 17, 2003, of 119 patients with stable serum creatinine levels of at least 1.1 mg/dL (> or =97.2 micromol/L) who were randomized to receive a 154-mEq/L infusion of either sodium chloride (n = 59) or sodium bicarbonate (n = 60) before and after iopamidol administration (370 mg iodine/mL). Serum creatinine levels were measured at baseline and 1 and 2 days after contrast. Patients received 154 mEq/L of either sodium chloride or sodium bicarbonate, as a bolus of 3 mL/kg per hour for 1 hour before iopamidol contrast, followed by an infusion of 1 mL/kg per hour for 6 hours after the procedure. Contrast-induced nephropathy, defined as an increase of 25% or more in serum creatinine within 2 days of contrast. There were no significant group differences in age, sex, incidence of diabetes mellitus, ethnicity, or contrast volume. Baseline serum creatinine was slightly higher but not statistically different in patients receiving sodium bicarbonate treatment (mean [SD], 1.71 [0.42] mg/dL [151.2 [37.1] micromol/L] for sodium chloride and 1.89 [0.69] mg/dL [167.1 [61.0] micromol/L] for sodium bicarbonate; P =.09). The primary end point of contrast-induced nephropathy occurred in 8 patients (13.6%) infused with sodium chloride but in only 1 (1.7%) of those receiving sodium bicarbonate (mean difference, 11.9%; 95% confidence interval [CI], 2.6%-21.2%; P =.02). A follow-up registry of 191 consecutive patients receiving prophylactic sodium bicarbonate and meeting the same inclusion criteria as the study resulted in 3 cases of contrast-induced nephropathy (1.6%; 95% CI, 0%-3.4%). Hydration with sodium bicarbonate before contrast exposure is more effective than hydration with sodium chloride for prophylaxis of contrast-induced renal failure.
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              N-acetylcysteine and contrast-induced nephropathy in primary angioplasty.

              Patients with acute myocardial infarction undergoing primary angioplasty are at high risk for contrast-medium-induced nephropathy because of hemodynamic instability, the need for a high volume of contrast medium, and the lack of effective prophylaxis. We investigated the antioxidant N-acetylcysteine for the prevention of contrast-medium-induced nephropathy in patients undergoing primary angioplasty. We randomly assigned 354 consecutive patients undergoing primary angioplasty to one of three groups: 116 patients were assigned to a standard dose of N-acetylcysteine (a 600-mg intravenous bolus before primary angioplasty and 600 mg orally twice daily for the 48 hours after angioplasty), 119 patients to a double dose of N-acetylcysteine (a 1200-mg intravenous bolus and 1200 mg orally twice daily for the 48 hours after intervention), and 119 patients to placebo. The serum creatinine concentration increased 25 percent or more from baseline after primary angioplasty in 39 of the control patients (33 percent), 17 of the patients receiving standard-dose N-acetylcysteine (15 percent), and 10 patients receiving high-dose N-acetylcysteine (8 percent, P<0.001). Overall in-hospital mortality was higher in patients with contrast-medium-induced nephropathy than in those without such nephropathy (26 percent vs. 1 percent, P<0.001). Thirteen patients (11 percent) in the control group died, as did five (4 percent) in the standard-dose N-acetylcysteine group and three (3 percent) in the high-dose N-acetylcysteine group (P=0.02). The rate for the composite end point of death, acute renal failure requiring temporary renal-replacement therapy, or the need for mechanical ventilation was 21 (18 percent), 8 (7 percent), and 6 (5 percent) in the three groups, respectively (P=0.002). Intravenous and oral N-acetylcysteine may prevent contrast-medium-induced nephropathy with a dose-dependent effect in patients treated with primary angioplasty and may improve hospital outcome. (ClinicalTrials.gov number, NCT00237614[ClinicalTrials.gov]). Copyright 2006 Massachusetts Medical Society.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2009
                February 2009
                08 September 2008
                : 29
                : 3
                : 181-191
                Affiliations
                aResearch & Development Department and bDepartment of Nephrology, Assaf Harofeh Medical Center, Zerifin, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
                Article
                154471 Am J Nephrol 2009;29:181–191
                10.1159/000154471
                18781062
                f4ca05a3-a4ae-458e-8eed-a0d6a9931734
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 05 May 2008
                : 16 July 2008
                Page count
                Figures: 5, References: 37, Pages: 11
                Categories
                Original Report: Laboratory Investigation

                Cardiovascular Medicine,Nephrology
                NO,<italic>N-</italic>Acetylcysteine,PGE2 ,Vasoconstriction,Theophylline,Bicarbonate,Oxidative stress,Contrast media,Kidney

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