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1.  N-Acetylcysteine for the Prevention of Contrast-induced Nephropathy 
OBJECTIVE
Contrast-induced nephropathy is a common cause of acute renal failure in hospitalized patients. Although patients are often given N-acetylcysteine to prevent renal injury from contrast agents, there are no clear guidelines supporting its use. We conducted a systematic review to determine whether administering N-acetylcysteine around the time of contrast administration reduces the risk of contrast-induced nephropathy.
DESIGN
We searched MEDLINE, EMBASE, the Cochrane Collaboration Database, bibliographies of retrieved articles, and abstracts of conference proceedings, and consulted with experts to identify relevant studies. Randomized controlled trials of N-acetylcysteine in hospitalized patients receiving contrast were included. Studies were excluded if they did not report change in creatinine or incidence of contrast-induced nephropathy at 48 hours.
MEASUREMENTS AND MAIN RESULTS
Nine randomized controlled trials satisfied all inclusion criteria and were included in the analysis. The difference in mean change in creatinine between the N-acetylcysteine-treated group and controls was −0.27 mg/dl (95% confidence interval [CI], −0.43 to −0.11). The relative risk of developing contrast-induced nephropathy was 0.43 (95% CI, 0.24 to 0.75) in subjects randomized to N-acetylcysteine. Significant heterogeneity existed among studies, suggesting differences in patient populations or study methodology not identified by sensitivity analyses. The incidence of dialysis was rare (0.2%).
CONCLUSIONS
Our findings suggest that N-acetylcysteine helps prevent declining renal function and contrast-induced nephropathy. While N-acetylcysteine is inexpensive and nontoxic, undeviating insistence for dosing at least 12 hours in advance of contrast exposure may delay diagnostic and therapeutic procedures. Future studies are needed to address the longer-term clinical outcomes and cost-effectiveness of this agent.
doi:10.1111/j.1525-1497.2005.30323.x
PMCID: PMC1490056  PMID: 15836554
N-acetylcysteine; contrast-induced nephropathy; acute renal failure; kidney disease
2.  Intravenous N-Acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of Randomized, Controlled Trials 
PLoS ONE  2013;8(1):e55124.
Background
Contrast-induced nephropathy (CIN) is one of the common causes of acute renal insufficiency after contrast procedures. Whether intravenous N-acetylcysteine (NAC) is beneficial for the prevention of contrast-induced nephropathy is uncertain. In this meta-analysis of randomized controlled trials, we aimed to assess the efficacy of intravenous NAC for preventing CIN after administration of intravenous contrast media.
Study Design
Relevant studies published up to September 2012 that investigated the efficacy of intravenous N-acetylcysteine for preventing CIN were collected from MEDLINE, OVID, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and the conference proceedings from major cardiology and nephrology meetings. The primary outcome was CIN. Secondary outcomes included renal failure requiring dialysis, mortality, and length of hospitalization. Data were combined using random-effects models with the performance of standard tests to assess for heterogeneity and publication bias. Meta-regression analyses were also performed.
Results
Ten trials involving 1916 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-induced nephropathy was 0.68 (95% CI, 0.46 to 1.02), a nonsignificant trend towards benefit in patients treated with intravenous NAC. There was evidence of significant heterogeneity in NAC effect across studies (Q = 17.42, P = 0.04; I2 = 48%). Meta-regression revealed no significant relation between the relative risk of CIN and identified differences in participant or study characteristics.
Conclusion
This meta-analysis showed that research on intravenous N-acetylcysteine and the incidence of CIN is too inconsistent at present to warrant a conclusion on efficacy. A large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for intravenous NAC in CIN prevention.
doi:10.1371/journal.pone.0055124
PMCID: PMC3559541  PMID: 23383076
3.  Acetylcysteine for prevention of contrast-induced nephropathy after intravascular angiography: A systematic review and meta-analysis 
BMC Medicine  2004;2:38.
Background
Contrast-induced nephropathy is an important cause of acute renal failure. We assess the efficacy of acetylcysteine for prevention of contrast-induced nephropathy among patients undergoing intravascular angiography.
Methods
We conducted a systematic review and meta-analysis of randomized controlled trials comparing prophylactic acetylcysteine plus hydration versus hydration alone in patients undergoing intravascular angiography. Studies were identified by searching MEDLINE, EMBASE, and CENTRAL databases. Our main outcome measures were the risk of contrast-induced nephropathy and the difference in serum creatinine between acetylcysteine and control groups at 48 h.
Results
Fourteen studies involving 1261 patients were identified and included for analysis, and findings were heterogeneous across studies. Acetylcysteine was associated with a significantly reduced incidence of contrast-induced nephropathy in five studies, and no difference in the other nine (with a trend toward a higher incidence in six of the latter studies). The pooled odds ratio for contrast-induced nephropathy with acetylcysteine relative to control was 0.54 (95% CI, 0.32–0.91, p = 0.02) and the pooled estimate of difference in 48-h serum creatinine for acetylcysteine relative to control was -7.2 μmol/L (95% CI -19.7 to 5.3, p = 0.26). These pooled values need to be interpreted cautiously because of the heterogeneity across studies, and due to evidence of publication bias. Meta-regression suggested that the heterogeneity might be partially explained by whether the angiography was performed electively or as emergency.
Conclusion
These findings indicate that published studies of acetylcysteine for prevention of contrast-induced nephropathy yield inconsistent results. The efficacy of acetylcysteine will remain uncertain unless a large well-designed multi-center trial is performed.
doi:10.1186/1741-7015-2-38
PMCID: PMC526263  PMID: 15500690
4.  Acute kidney injury 
Clinical Evidence  2011;2011:2001.
Introduction
Acute renal failure is characterised by abrupt and sustained decline in glomerular filtration rate, which leads to accumulation of urea and other chemicals in the blood. The term acute kidney injury has been introduced to encompass a wide spectrum of acute alterations in kidney function from mild to severe. Acute kidney injury is classified according to the RIFLE criteria, in which a change from baseline serum creatinine or urine output determines the level of renal dysfunction.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent acute kidney injury in people at high risk? What are the effects of treatments for critically ill people with acute kidney injury? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 82 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: albumin supplementation plus loop diuretics (intravenous), aminoglycosides, aminophylline, amphotericin B, calcium channel blockers, contrast media, dialysis membranes, dopamine, early versus late dialysis, extended daily dialysis, fenoldopam, loop diuretics, mannitol, N-acetylcysteine, natriuretic peptides, renal replacement therapy, sodium bicarbonate-based fluids, sodium chloride-based fluids, and theophylline.
Key Points
Acute renal failure (also called acute kidney injury) is characterised by abrupt and sustained decline in GFR, which leads to accumulation of urea and other chemicals in the blood. It can be classified according to a change from baseline serum creatinine or urine output, with "Risk" being defined by either a 50% increase in serum creatinine, or a urine output of <0.5 mL/kg/hour for at least 6 hours; and "Failure" being defined by a three-fold increase in serum creatinine, or a urine output of <0.3 mL/kg/hour for 24 hours.
In people at high risk of developing acute renal failure, intravenous sodium chloride (0.9%) reduces incidences of acute renal failure compared with unrestricted oral fluids or 0.45% intravenous sodium chloride solution. N-acetylcysteine plus intravenous fluids may reduce contrast nephropathy compared with intravenous fluids alone in people undergoing contrast nephrography, although data about prevention of renal failure are inconclusive. Sodium bicarbonate may be as effective as sodium chloride but the evidence is conflicting so we cannot draw conclusions. Low-osmolality contrast medium is less nephrotoxic compared with high-osmolality media, and iso-osmolar contrast media has similar nephrotoxicity to low-osmolar contrast media. We found insufficient evidence on the effects of prophylactic renal replacement therapy. Single-dose aminoglycosides seem as beneficial as multiple doses for treating infections, but are less nephrotoxic. Lipid formulations of amphotericin B may cause less nephrotoxicity than standard formulations, although the evidence for this is somewhat sparse. Mannitol, theophylline, aminophylline, fenoldopam, and calcium channel blockers do not seem useful treatments for people at high risk of acute renal failure.
We don't know whether continuous renal replacement therapy is any more effective than intermittent renal replacement therapy. High-dose continuous renal replacement therapy was ineffective in treatment of people critically ill with acute kidney injury, and is also associated with an increased risk of hypophosphataemia, hypokalaemia, and hypotension. Synthetic dialysis membranes may be associated with improved survival compared with cellulose-based membranes for treating people with acute renal failure; however, evidence is inconclusive and of variable quality. Loop diuretics plus fluids seem to increase the risk of developing acute renal failure compared with fluids alone, both in high-risk and critically ill people, and do not seem to improve renal function or mortality compared with placebo in people with acute renal failure, but may increase the risks of ototoxicity and volume depletion.We found no evidence that examined whether intravenous albumin supplementation improved the effects of loop diuretics, or whether continuous infusion was any more effective than bolus injection in the treatment of people critically ill with acute renal failure.
Neither natriuretic peptides nor dopamine seem beneficial in either high-risk or critically ill people, and both are associated with significant adverse effects.
We don't know whether early versus late renal replacement therapy or extended daily dialysis improve outcomes in people critically ill with acute kidney injury.
PMCID: PMC3217737  PMID: 21443811
5.  Rationale, design, and baseline characteristics of the Acetylcystein for Contrast-Induced nephropaThy (ACT) Trial: a pragmatic randomized controlled trial to evaluate the efficacy of acetylcysteine for the prevention of contrast-induced nephropathy 
Trials  2009;10:38.
Background
Aceltylcysteine has been evaluated in several small trials as a means of reducing the risk of contrast-induced nephropathy (CIN), however systematic reviews of these studies do not provide conclusive answers. Therefore, a large randomized controlled trial (RCT) is needed to provide a reliable answer as to whether acetylcysteine is effective in decreasing the risk of CIN in high-risk patients undergoing angiographic procedures.
Methods
ACT is a RCT of acetylcysteine versus placebo in 2,300 patients at-risk for CIN undergoing an intravascular angiographic procedure. The randomization list will be concealed. Participants, health care staff, investigators and outcome assessors will be blinded to whether patients receive acetylcysteine or placebo. All analysis will follow the intention-to-treat principle. The study drugs (acetylcysteine 1200 mg or placebo) will be administered orally twice daily for two doses before and two doses after the procedure. The primary outcome is the occurrence of CIN, defined as a 25% elevation of serum creatinine above baseline between 48 and 96 hours after angiography.
Discussion
The first patient entered the trial on September, 2008. Up to April 7, 2009, 810 patients had been included in 35 centers. The mean age was 69 (Standard deviation: 10), 18% had a baseline serum creatinine >1.5 mg/dL, 57% were diabetics and 13% had a history of heart failure. The ongoing ACT Trial is the largest multicentre RCT that will determine whether acetylcysteine is effective in decreasing the risk of CIN in patients at risk undergoing angiography.
Trial registration
Clinicaltrials.gov NCT00736866
doi:10.1186/1745-6215-10-38
PMCID: PMC2706243  PMID: 19497091
6.  Acute renal failure 
Clinical Evidence  2008;2008:2001.
Introduction
Acute renal failure is characterised by abrupt and sustained decline in glomerular filtration rate, which leads to accumulation of urea and other chemicals in the blood. The term acute kidney injury has been recently introduced to encompass a wide spectrum of acute alterations in kidney function from very mild to severe. Acute renal failure/acute kidney injury is classified according to the RIFLE criteria where a change from baseline serum creatinine or urine output determines the level of renal dysfunction.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions to prevent acute renal failure in people at high risk? What are the effects of treatments for critically ill people with acute renal failure? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 77 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: albumin supplementation plus loop diuretics (intravenous), aminoglycosides, aminophylline, amphotericin B, calcium channel blockers, contrast media, dialysis membranes, dopamine, fenoldopam, loop diuretics, mannitol, N-acetylcysteine, natriuretic peptides, renal replacement therapy, sodium bicarbonate-based fluids, sodium chloride-based fluids, and theophylline.
Key Points
Acute renal failure is characterised by abrupt and sustained decline in GFR, which leads to accumulation of urea and other chemicals in the blood. It can be classified according to a change from baseline serum creatinine or urine output, with "Risk" being defined by either a 50% increase in serum creatinine, or a urine output of less than 0.5 mL/kg/hour for at least 6 hours; and "Failure" being defined by a threefold increase in serum creatinine, or a urine output of less than 0.3 mL/kg/hour for 24 hours.
In people at high risk of developing acute renal failure, intravenous sodium chloride (0.9%) reduces incidences of acute renal failure compared with unrestricted oral fluids or 0.45% iv sodium chloride solution. N-acetylcysteine plus intravenous fluids may reduce contrast nephropathy compared with intravenous fluids alone in people undergoing contrast nephrography, although data about prevention of renal failure are inconclusive. Low-osmolality contrast medium is less nephrotoxic compared with high-osmolality media, and iso-osmolar contrast media may be less nephrotoxic compared with low-osmolar contrast media. We found insufficient evidence on the effects of prophylactic renal replacement therapy. Single-dose aminoglycosides seem as beneficial as multiple doses for treating infections, but are less nephrotoxic. Lipid formulations of amphotericin B may cause less nephrotoxicity than standard formulations, although the evidence for this is somewhat sparse. Mannitol, theophylline, aminophylline, fenoldopam, and calcium channel blockers do not seem useful treatments for people at high risk of acute renal failure.
In critically ill people, high-dose continuous renal replacement therapy may reduce mortality compared with low-dose, although we don't know whether continuous therapy is any more effective than intermittent renal replacement therapy. Synthetic dialysis membranes may be associated with improved survival compared with cellulose-based membranes for treating people with acute renal failure; however, evidence is inconclusive and of variable quality. Loop diuretics plus fluids seems to increase the risk of developing acute renal failure compared with fluids alone, both in high-risk and critically ill people, and do not seem to improve renal function or mortality compared with placebo in people with acute renal failure, but may increase the risks of ototoxicity and volume depletion.We found no evidence that examined whether intravenous albumin supplementation improved the effects of loop diuretics, or whether continuous infusion was any more effective than bolus injection in the treatment of people critically ill with acute renal failure.
Neither natriuretic peptides nor dopamine seem beneficial in either high-risk or critically ill people, and both are associated with significant side effects.
PMCID: PMC2907962  PMID: 19445797
7.  N-acetylcysteine does not prevent contrast nephropathy in patients with renal impairment undergoing emergency CT: a randomized study 
BMC Nephrology  2013;14:119.
Background
Patients admitted to the emergency room with renal impairment and undergoing a contrast computed tomography (CT) are at high risk of developing contrast nephropathy as emergency precludes sufficient hydration prior to contrast use. The value of an ultra-high dose of intravenous N-acetylcysteine in this setting is unknown.
Methods
From 2008 to 2010, we randomized 120 consecutive patients admitted to the emergency room with an estimated clearance lower than 60 ml/min/1.73 m2 by MDRD (mean GFR 42 ml/min/1.73 m2) to either placebo or 6000 mg N-acetylcysteine iv one hour before contrast CT in addition to iv saline. Serum cystatin C and creatinine were measured one hour prior to and at day 2, 4 and 10 after contrast injection. Nephrotoxicity was defined either as 25% or 44 μmol/l increase in serum creatinine or cystatin C levels compared to baseline values.
Results
Contrast nephrotoxicity occurred in 22% of patients who received placebo (13/58) and 27% of patients who received N-acetylcysteine (14/52, p = 0.66). Ultra-high dose intravenous N-acetylcysteine did not alter creatinine or cystatin C levels. No secondary effects were noted within the 2 groups during follow-up.
Conclusions
An ultra-high dose of intravenous N-acetylcysteine is ineffective at preventing nephrotoxicity in patients with renal impairment undergoing emergency contrast CT.
Trial registration
The study was registered as Clinical trial (NCT01467154).
doi:10.1186/1471-2369-14-119
PMCID: PMC3682900  PMID: 23731573
Computerized Tomography; Contrast media; Emergency medicine; N-acetylcysteine; Nephrotoxicity
8.  N-acetylcysteine does not prevent contrast-induced nephropathy after cardiac catheterization in patients with diabetes mellitus and chronic kidney disease: a randomized clinical trial 
Trials  2009;10:45.
Background
Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) constitute to be a high-risk population for the development of contrast-induced nephropathy (CIN), in which the incidence of CIN is estimated to be as high as 50%. We performed this trial to assess the efficacy of N-acetylcysteine (NAC) in the prevention of this complication.
Methods
In a prospective, double-blind, placebo controlled, randomized clinical trial, we studied 90 patients undergoing elective diagnostic coronary angiography with DM and CKD (serum creatinine ≥ 1.5 mg/dL for men and ≥ 1.4 mg/dL for women). The patients were randomly assigned to receive either oral NAC (600 mg BID, starting 24 h before the procedure) or placebo, in adjunct to hydration. Serum creatinine was measured prior to and 48 h after coronary angiography. The primary end-point was the occurrence of CIN, defined as an increase in serum creatinine ≥ 0.5 mg/dL (44.2 μmol/L) or ≥ 25% above baseline at 48 h after exposure to contrast medium.
Results
Complete data on the outcomes were available on 87 patients, 45 of whom had received NAC. There were no significant differences between the NAC and placebo groups in baseline characteristics, amount of hydration, or type and volume of contrast used, except in gender (male/female, 20/25 and 34/11, respectively; P = 0.005) and the use of statins (62.2% and 37.8%, respectively; P = 0.034). CIN occurred in 5 out of 45 (11.1%) patients in the NAC group and 6 out of 42 (14.3%) patients in the placebo group (P = 0.656).
Conclusion
There was no detectable benefit for the prophylactic administration of oral NAC over an aggressive hydration protocol in patients with DM and CKD.
Trial registration
NCT00808795
doi:10.1186/1745-6215-10-45
PMCID: PMC2714294  PMID: 19563648
9.  Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial 
PLoS Medicine  2014;11(2):e1001601.
Martin Gallagher and colleagues examine the long-term outcomes of renal replacement therapy (RRT) dosing in patients with acute kidney injury randomized to normal vs. augmented RRT.
Please see later in the article for the Editors' Summary
Background
The incidence of acute kidney injury (AKI) is increasing globally and it is much more common than end-stage kidney disease. AKI is associated with high mortality and cost of hospitalisation. Studies of treatments to reduce this high mortality have used differing renal replacement therapy (RRT) modalities and have not shown improvement in the short term. The reported long-term outcomes of AKI are variable and the effect of differing RRT modalities upon them is not clear. We used the prolonged follow-up of a large clinical trial to prospectively examine the long-term outcomes and effect of RRT dosing in patients with AKI.
Methods and Findings
We extended the follow-up of participants in the Randomised Evaluation of Normal vs. Augmented Levels of RRT (RENAL) study from 90 days to 4 years after randomization. Primary and secondary outcomes were mortality and requirement for maintenance dialysis, respectively, assessed in 1,464 (97%) patients at a median of 43.9 months (interquartile range [IQR] 30.0–48.6 months) post randomization. A total of 468/743 (63%) and 444/721 (62%) patients died in the lower and higher intensity groups, respectively (risk ratio [RR] 1.04, 95% CI 0.96–1.12, p = 0.49). Amongst survivors to day 90, 21 of 411 (5.1%) and 23 of 399 (5.8%) in the respective groups were treated with maintenance dialysis (RR 1.12, 95% CI 0.63–2.00, p = 0.69). The prevalence of albuminuria among survivors was 40% and 44%, respectively (p = 0.48). Quality of life was not different between the two treatment groups. The generalizability of these findings to other populations with AKI requires further exploration.
Conclusions
Patients with AKI requiring RRT in intensive care have high long-term mortality but few require maintenance dialysis. Long-term survivors have a heavy burden of proteinuria. Increased intensity of RRT does not reduce mortality or subsequent treatment with dialysis.
Trial registration
www.ClinicalTrials.gov NCT00221013
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. Chronic kidney disease (caused, for example, by diabetes) gradually destroys the kidneys' filtration units (the nephrons), eventually leading to life-threatening end-stage kidney disease. However, the kidneys can also stop working suddenly because of injury, infection, or poisoning. Acute kidney injury (AKI) is much more common than end-stage kidney disease and its incidence is increasing worldwide. In the US, for example, the number of hospitalizations that included an AKI diagnosis rose from 4,000 in 1996 to 23,000 in 2008. Moreover, nearly half of patients with AKI will die shortly after the condition develops. Symptoms of AKI include changes in urination, swollen feet and ankles, and tiredness. Treatments for AKI aim to prevent fluid and waste build up in the body and treat the underlying cause (e.g., severe infection or dehydration) while allowing the kidneys time to recover. In some patients, it is sufficient to limit the fluid intake and to reduce waste build-up by eating a diet that is low in protein, salt, and potassium. Other patients need renal replacement therapy (RRT), life-supporting treatments such as hemodialysis and hemofiltration, two processes that clean the blood by filtering it outside the body.
Why Was This Study Done?
The long-term outcomes of AKI (specifically, death and chronic kidney disease) and the effects of different RRT modalities on these outcomes are unclear. A recent controlled trial that randomly assigned patients with AKI who were managed in intensive care units (ICUs) to receive two different intensities of continuous hemodiafiltration (a combination of hemodialysis and hemofiltration) found no difference in all-cause mortality (death) at 90 days. Here, the researchers extend the follow-up of this trial (the Randomized Evaluation of Normal vs. Augmented Levels of renal replacement therapy [RENAL] study) to investigate longer-term mortality, the variables that predict mortality, treatment with long-term dialysis (an indicator of chronic kidney disease), and functional outcomes in patients with AKI treated with different intensities of continuous RRT.
What Did the Researchers Do and Find?
For the Prolonged Outcomes Study of RENAL (POST-RENAL), the researchers extended the follow-up of the RENAL participants up to 4 years. Over an average follow-up of 43.9 months, 63% of patients in the lower intensity treatment group died compared to 62% of patients in the higher intensity group. Overall, a third of patients who survived to 90 days died during the extended follow-up. Among the survivors to day 90, 5.1% and 5.8% of patients in the lower and higher intensity groups, respectively, were treated with maintenance dialysis during the extended follow-up. Among survivors who consented to analysis, 40% and 44% of patients in the lower and higher intensity groups, respectively, had albuminuria (protein in the urine, an indicator of kidney damage). Patients in both groups had a similar quality life (determined through telephone interviews). Finally, increasing age, APACHE III score (a scoring system that predicts the survival of patients in ICU), and serum creatinine level (an indicator of kidney function) at randomization were all predictors of long-term mortality.
What Do These Findings Mean?
These findings indicate that patients with AKI in ICUs who require RRT have a high long-term mortality. They show that few survivors require maintenance dialysis for chronic kidney disease but that there is a substantial rate of albuminuria among survivors despite relative preservation of kidney function. The findings also suggest that the intensity of RRT has no significant effect on mortality or the need for dialysis. Because these findings were obtained in a randomized controlled trial, they may not be generalizable to other patient populations. Moreover, although data on mortality and maintenance dialysis were available for all the trial participants, clinical and biochemical outcomes were only available for some participants and may not be representative of all the participants. Despite these study limitations, these findings suggest that survivors of AKI may be at a high risk of death or of developing chronic kidney disease. Survivors of AKI are, therefore, at high risk of further illness and long-term albuminuria reduction strategies may offer a therapeutic intervention for this group of patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001601.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about the kidneys and about all aspects of kidney disease and its treatment; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The Mayo Clinic provides information for patients about acute kidney injury
Wikipedia has a page on acute kidney injury (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers, including a link to a video about acute kidney injury
World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations (IFKF), aims to raise awareness about kidneys and kidney disease; its website provides information about acute kidney injury
The MedlinePlus Encyclopedia has a pages about acute kidney failure and about renal dialysis
The UK National Institute for Health and Care Excellence (NICE) recently published new guidelines on the treatment of acute kidney injury; a clinical practice guideline for acute kidney injury produced by KDIGO (a not-for-profit organization that aims to improve the care and outcomes of kidney disease patients worldwide through the development and implementation of global clinical practice guidelines) is available; the Acute Kidney Injury app provides a fast and simple way to explore guidelines on the diagnosis, prevention, and management of AKI
doi:10.1371/journal.pmed.1001601
PMCID: PMC3921111  PMID: 24523666
10.  Effect of intravenous N-acetylcysteine infusion on haemostatic parameters in healthy subjects 
Gut  2005;54(4):515-521.
Background and aim: N-acetylcysteine is used to treat paracetamol overdose but depresses the activity of plasma coagulation factors II, VII, and X, which are often used to assess liver injury. The aim of this study was to investigate the effect of N-acetylcysteine on haemostasis in normal volunteers.
Methods: Haemostatic parameters in 10 healthy subjects were analysed before and following intravenous infusion of therapeutic doses of N-acetylcysteine, as well as in vitro.
Results: N-acetylcysteine induced significant decreases in plasma levels of vitamin K dependent haemostatic proteins in vivo, being maximal at one hour following the start of infusion, with maximal decreases from 1.00 to 0.73 (0.67–0.79) (mean (95% confidence interval)), 0.66 (0.58–0.73), 0.81 (0.73–0.90), 0.64 (0.57–0.70), 0.74 (0.65–0.82), and 0.61 (0.54–0.67) for factor II, VII, IX, and X activities, protein C activity, and free protein S reactivity, respectively. These data suggest that N-acetylcysteine induces protein modifications affecting activity. Five subjects developed an adverse reaction to infusion of N-acetylcysteine and these were associated with a rapid increase in levels of factor VIII and its carrier protein von Willebrand factor (vWf) from 1.0 to 1.85 (1.08–2.62) and 1.77 (0.83–2.71), respectively, which suggests that the allergic reaction induced release of vWf from endothelial cells. N-acetylcysteine did not affect factor VIII or vWf in subjects without adverse reactions, and nor did it affect factor V or antithrombin in any of the subjects.
Conclusion: Therapeutic doses of N-acetylcysteine cause abnormal haemostatic activity, and this should be taken into account when using haemostatic function tests as an indicator of hepatic injury.
doi:10.1136/gut.2004.043505
PMCID: PMC1774452  PMID: 15753537
von Willebrand factor; coagulation factors; antithrombin; protein C; protein S
11.  Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. 
BMJ : British Medical Journal  1991;303(6809):1026-1029.
OBJECTIVE--To see whether intravenous acetylcysteine would improve outcome in patients with fulminant hepatic failure after paracetamol overdose. DESIGN--A prospective randomised controlled study. SETTING--The Institute of Liver Studies, King's College Hospital, London. PATIENTS--50 consecutive patients (21 male) aged 16-60 with fulminant hepatic failure after paracetamol overdose who had not previously received acetylcysteine. INTERVENTIONS--Conventional intensive liver care plus either acetylcysteine (25 patients) in the same dose regimen as used early after a paracetamol overdose, except that the infusion was continued until recovery from encephalopathy or death, or an equivalent volume of 5% dextrose (25 patients). MAIN OUTCOME MEASURES--Survival; incidence of cerebral oedema, renal failure, and hypotension requiring inotropic support; liver function as assessed by prolongation of the prothrombin time; and degree of encephalopathy. RESULTS--The rate of survival was significantly higher in the acetylcysteine treated group than in the controls (48% (12/25 patients) v 20% (5/25); p = 0.037, 95% confidence interval for difference in proportions surviving 3% to 53%). Acetylcysteine treated patients had a lower incidence of cerebral oedema (40% (10/25) v 68% (17/25); p = 0.047, 95% confidence interval for difference in incidence 2% to 54%), and fewer developed hypotension requiring inotropic support (48% (12/25) v 80% (20/25); p = 0.018, 95% confidence interval 7% to 57%). Rates of deterioration and recovery of liver function, however, were similar in the two groups. No adverse reactions to acetylcysteine were seen. CONCLUSIONS--Acetylcysteine is safe and effective in fulminant hepatic failure after paracetamol overdose.
PMCID: PMC1671790  PMID: 1954453
12.  Is hypoalbuminemia a prognostic risk factor for contrast-induced nephropathy in peritoneal dialysis patients? 
Objective
Residual renal function (RRF) is an important predictor of outcome in peritoneal dialysis (PD) patients. Hypoalbuminemia was found to be an independent risk factor for the development of acute kidney injury. We investigated the possibility of an association between serum albumin levels and the development of iodine contrast media-induced nephropathy (CIN) in PD patients.
Methods
A total of 103 PD patients who underwent invasive angiographies with exposure to iodine contrast media (ICM) were reviewed retrospectively. All patients received 0.9% saline intravenously at a rate of 75 mL per hour for 12 hours prior, during, and 12 hours after exposure to ICM. Acetylcysteine was given orally at a dose of 600 mg twice daily, on the day before and on the day of exposure to ICM. The nonionic, low-osmolar contrast agent iopromide was used at a mean dose of 75.0±15.2 mL. The changes in RRF from baseline to 1 week and 4 weeks after exposure to ICM were recorded. Outcomes of patients with serum albumin levels <3.8 g/dL and those with serum albumin levels ≥3.8 g/dL were compared. A reduction >30% in RRF at 7 days after exposure to ICM was considered CIN.
Results
CIN developed in 27.2% (28/103) of patients. Of the 103 patients, 59.2% (61) had serum albumin levels <3.8 g/dL. Of those, 37.7% (23/61) developed CIN, compared with 11.9% (5/42) of those with serum albumin levels ≥3.8 g/dL (P=0.004). After adjustment for all tested variables in a logistic regression with a stepwise selection model, serum albumin level at exposure to ICM was found to be the most powerful predictor of the development of CIN (odds ratio =4.5; confidence interval =1.5–13.0; P=0.006).
Conclusion
PD patients with serum albumin levels <3.8 g/dL should be monitored carefully when exposed to ICM. Serum albumin level may be considered a potential therapeutic target in the prevention of CIN and preservation of RRF in PD patients.
doi:10.2147/TCRM.S70665
PMCID: PMC4199564  PMID: 25328394
peritoneal dialysis; renal function; iodine radio-contrast media; iodine contrast media-induced nephropathy
13.  Efficacy of N-acetylcysteine in preventing renal injury after heart surgery: a systematic review of randomized trials 
European Heart Journal  2009;30(15):1910-1917.
Aims
The aim of this study was to assess whether perioperative N-acetylcysteine (NAC), an antioxidant, prevents acute renal injury (ARI) after cardiac surgery.
Methods and results
We performed a systematic review of randomized controlled trials (RCTs) of NAC in adult cardiac surgery patients. The RCTs were identified by searching MEDLINE (1960–2008), clinicaltrials.gov website, and hand-searching references of relevant publications. Primary outcome was ARI (absolute increase >0.5 mg/dL or relative increase >25%, in serum creatinine from baseline within 5 days after surgery). Random effects model was used to perform a meta-analysis. Forest plots and I2 test were used to assess heterogeneity among studies. Ten RCTs (n = 1163 patients) were included. Mean age was 70 ± 7.4 years, 71% were male, and 66% underwent coronary artery bypass surgery. N-Acetylcysteine did not reduce ARI incidence [35% NAC vs. 37% placebo; relative risk (RR) 0.91, 95% CI 0.79–1.06, P = 0.24]. Overall, 3.3% of patients required haemodialysis (NAC vs. placebo; RR = 1.13, 95% CI 0.59–2.17) and 3% died (RR = 1.10, 95% CI 0.56–2.16). There was a trend towards reduced ARI incidence among patients with baseline chronic kidney disease assigned to intravenous NAC (RR = 0.80, 95% CI 0.64–1.01, P = 0.06).
Conclusion
This meta-analysis of RCTs showed that prophylactic perioperative NAC in cardiac surgery does not reduce ARI, haemodialysis, or death.
doi:10.1093/eurheartj/ehp053
PMCID: PMC2719697  PMID: 19282300
Cardiac surgery; Kidney; Antioxidants; Meta-analysis; Mortality
14.  Patient selection and preparation strategies for the use of contrast material in patients with chronic kidney disease 
World Journal of Radiology  2012;4(6):253-257.
The prevalence of chronic kidney disease and peripheral arterial disease is increasing. Thus, it is increasingly problematic to image these patients as the number of patients needing a vascular examination is increasing accordingly. In high-risk patients with impaired kidney function, intravascular administration of iodinated contrast media can result in contrast-induced acute kidney injury and Gadolinium can induce nephrogenic systemic fibrosis (NSF). It is important to identify these high-risk patients by means of se-creatinine/e glomerular filtration rate. The indication for contrast examination should counterbalance the increased risk. One or more alternative examination methods without contrast media, such as CO2 angiography, Ultrasound/Doppler examination or magnetic resonance angiography without contrast should be considered, but at the same time, allow for a meaningful outcome of the examination. If contrast is deemed essential, the patient should be well hydrated, the amount of contrast should be restricted, the examination should be focused, metformin and diuretics stopped, and renal function monitored. Sodium bicarbonate and N-acetylcysteine are popular but their efficiency is not evidence-based. There is no evidence that dialysis protects patients with impaired renal function from contrast-induced nephropathy or NSF.
doi:10.4329/wjr.v4.i6.253
PMCID: PMC3391670  PMID: 22778877
Arterial disease; Peripheral; Radiology; Interventional; Diabetes complications; Nephropathies; Diabetic; Renal insufficiency; Chronic; Kidney failure
15.  Interventions for preventing neuropathy caused by cisplatin and related compounds 
Background
Cisplatin and several related antineoplastic agents used to treat many types of solid tumors are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought.
Objectives
To examine the efficacy of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related agents.
Search methods
We searched the Cochrane Neuromuscular Disease Group Specialized Register (25 August 2010), the Cochrane Central Register of Controlled Trials (Issue 3, 2010 in The Cochrane Library), MEDLINE (January 1966 to August 2010), EMBASE (January 1980 to August 2010), LILACS (January 1982 to August 2010), CINAHL (January 1982 to August 2010) for randomized trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related agents among human patients.
Selection criteria
Quasi-randomized or randomized controlled trials whose participants received cisplatin (or related compounds) chemotherapy with or without a potential chemoprotectant (acetylcysteine, amifostine, ACTH, BNP7787, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, or vitamin E) and were evaluated zero to six months after completing chemotherapy using quantitative sensory testing (primary) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary).
Data collection and analysis
We identified 16 randomized trials involving five possible chemoprotective agents in the initial 2006 review. Each study was reviewed by two authors who extracted the data and reached consensus. The 2010 update identified 11 additional randomized trials consisting of nine possible chemoprotective agents, including three treatments (acetylcysteine, calcium and magnesium, and oxcarbazepine) not among those described in the 2006 review. The included trials in the updated review involved eight unrelated treatments and included many disparate measures of neuropathy, resulting in insufficient data for any one measure to combine the results in most instances.
Main results
One of four eligible amifostine trials (541 total participants in all four trials) used quantitative sensory testing and demonstrated a favorable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Of the six eligible glutathione trials (354 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing reported disparate results; meta-analyses of three trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. The single eligible trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), calcium and magnesium (33 participants), and oxcarbazepine (32 participants) and the two eligible trials involving vitamin E (57 participants) did not perform quantitative sensory testing. In all, data from 1,537 participants were included.
Authors' conclusions
At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxycarbazepine, or Vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients.
doi:10.1002/14651858.CD005228.pub3
PMCID: PMC3715044  PMID: 21328275
Antineoplastic Agents [*adverse effects]; Cisplatin [*adverse effects analogs & derivatives]; Neuroprotective Agents [*therapeutic use]; Peptide Fragments [therapeutic use]; Peripheral Nervous System Diseases [chemically induced; *prevention & control]; Humans
16.  Bench-to-bedside review: Preventive measures for contrast-induced nephropathy in critically ill patients 
Critical Care  2005;9(4):361-370.
An increasing number of diagnostic imaging procedures requires the use of intravenous radiographic contrast agents, which has led to a parallel increase in the incidence of contrast-induced nephropathy. Risk factors for development of contrast-induced nephropathy include pre-existing renal dysfunction (especially diabetic nephropathy and multiple myeloma-associated nephropathy), dehydration, congestive heart failure and use of concurrent nephrotoxic medication (including aminoglycosides and amphotericin B). Because contrast-induced nephropathy accounts for a significant increase in hospital-acquired renal failure, several strategies to prevent contrast-induced nephropathy are currently advocated, including use of alternative imaging techniques (for which contrast media are not needed), use of (the lowest possible amount of) iso-osmolar or low-osmolar contrast agents (instead of high-osmolar contrast agents), hyperhydration and forced diuresis. Administration of N-acetylcysteine, theophylline, or fenoldopam, sodium bicarbonate infusion, and periprocedural haemofiltration/haemodialysis have been investigated as preventive measures in recent years. This review addresses the literature on these newer strategies. Since only one (nonrandomized) study has been performed in intensive care unit patients, at present it is difficult to draw firm conclusions about preventive measures for contrast-induced nephropathy in the critically ill. Further studies are needed to determine the true role of these preventive measures in this group of patients who are at risk for contrast-induced nephropathy. Based on the available evidence, we advise administration of N-acetylcysteine, preferentially orally, or theophylline intravenously, next to hydration with bicarbonate solutions.
doi:10.1186/cc3028
PMCID: PMC1269423  PMID: 16137385
contrast-induced nephropathy; fenoldopam; haemodialysis; haemofiltration; intensive care medicine; N-acetylcysteine; sodium bicarbonate; theophylline
17.  Do Intravenous N-Acetylcysteine and Sodium Bicarbonate Prevent High Osmolal Contrast-Induced Acute Kidney Injury? A Randomized Controlled Trial 
PLoS ONE  2014;9(9):e107602.
Background
N-acetylcysteine (NAC) or sodium bicarbonate (NaHCO3), singly or combined, inconsistently prevent patients exposed to radiographic contrast media from developing contrast-induced acute kidney injury (CI-AKI).
Objective
We asked whether intravenous isotonic saline and either NaHCO3 in 5% dextrose or else a high dose of NAC in 5% dextrose prevent CI-AKI in outpatients exposed to high-osmolal iodinated contrast medium more than does saline alone.
Methods
This completed prospective, parallel, superiority, open-label, controlled, computer-randomized, single-center, Brazilian trial (NCT01612013) hydrated 500 adult outpatients (214 at high risk of developing CI-AKI) exposed to ioxitalamate during elective coronary angiography and ventriculography. From 1 hour before through 6 hours after exposure, 126 patients (group 1) received a high dose of NAC and saline, 125 (group 2) received NaHCO3 and saline, 124 (group 3) received both treatments, and 125 (group 4) received only saline.
Results
Groups were similar with respect to age, gender, weight, pre-existing renal dysfunction, hypertension, medication, and baseline serum creatinine and serum cystatin C, but diabetes mellitus was significantly less prevalent in group 1. CI-AKI incidence 72 hours after exposure to contrast medium was 51.4% (257/500), measured as serum creatinine > (baseline+0.3 mg/dL) and/or serum cystatin C > (1.1· baseline), and 7.6% (38/500), measured as both serum creatinine and serum cystatin C > (baseline+0.3 mg/dL) or > (1.25 · baseline). CI-AKI incidence measured less sensitively was similar among groups. Measured more sensitively, incidence in group 1 was significantly (p<0.05) lower than in groups 2 and 3 but not group 4; adjustment for confounding by infused volume equalized incidence in groups 1 and 3.
Conclusion:
We found no evidence that intravenous isotonic saline and either NaHCO3 or else a high dose of NAC prevent CI-AKI in outpatients exposed to high osmolal iodinated contrast medium more than does saline alone.
Trial Registration
ClinicalTrials.gov NCT01612013.
doi:10.1371/journal.pone.0107602
PMCID: PMC4177831  PMID: 25254489
18.  Efficacy of Short-Term High-Dose Statin Pretreatment in Prevention of Contrast-Induced Acute Kidney Injury: Updated Study-Level Meta-Analysis of 13 Randomized Controlled Trials 
PLoS ONE  2014;9(11):e111397.
Background
There have been conflicting results across the trials that evaluated prophylactic efficacy of short-term high-dose statin pre-treatment for prevention of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG). The aim of the study was to perform an up-to-date meta-analysis regarding the efficacy of high-dose statin pre-treatment in preventing CIAKI.
Methods and Results
Randomized-controlled trials comparing high-dose statin versus low-dose statin or placebo pre-treatment for prevention of CIAKI in patients undergoing CAG were included. The primary endpoint was the incidence of CIAKI within 2–5days after CAG. The relative risk (RR) with 95% CI was the effect measure. This analysis included 13 RCTs with 5,825 total patients; about half of them (n = 2,889) were pre-treated with high-dose statin (at least 40 mg of atorvastatin) before CAG, and the remainders (n = 2,936) pretreated with low-dose statin or placebo. In random-effects model, high-dose statin pre-treatment significantly reduced the incidence of CIAKI (RR 0.45, 95% CI 0.35–0.57, p<0.001, I2 = 8.2%, NNT 16), compared with low-dose statin or placebo. The benefit of high-dose statin was consistent in both comparisons with low-dose statin (RR 0.47, 95% CI 0.34–0.65, p<0.001, I2 = 28.4%, NNT 19) or placebo (RR 0.34, 95% CI 0.21–0.58, p<0.001, I2 = 0.0%, NNT 16). In addition, high-dose statin showed significant reduction of CIAKI across various subgroups of chronic kidney disease, acute coronary syndrome, and old age (≥60years), regardless of osmolality of contrast or administration of N-acetylcystein.
Conclusions
High-dose statin pre-treatment significantly reduced overall incidence of CIAKI in patients undergoing CAG, and emerges as an effective prophylactic measure to prevent CIAKI.
doi:10.1371/journal.pone.0111397
PMCID: PMC4219719  PMID: 25369120
19.  Acute Kidney Injury: Quoi de Neuf? 
The Ochsner Journal  2014;14(3):359-368.
Background
Acute kidney injury (AKI) is frequently encountered in the nephrology practice. Serum creatinine, with its many shortcomings, is still the main biomarker used to detect AKI.
Methods
This review focuses on recent advances in definition, diagnosis, risk factors, and molecular mechanisms of AKI. In addition, specific AKI syndromes such as contrast-induced AKI, hepatorenal syndrome, and acute decompensated heart failure are discussed. The connection between AKI and subsequent chronic kidney disease and recent developments in renal replacement therapy are also covered.
Results
Novel biomarkers such as cystatin C and neutrophil gelatinase–associated lipocalin (NGAL) are being investigated to replace serum creatinine in the detection of AKI. Recent studies suggest that intravenous (IV) fluid use is beneficial for the prevention of contrast-induced AKI, while N-acetylcysteine use is not as well established. Diuretics are clearly beneficial in the treatment of acute decompensated heart failure. Ultrafiltration is less promising and can lead to adverse side effects. Although terlipressin use in hepatorenal syndrome is associated with reduced mortality, it is not available in the United States; combination therapy with midodrine, octreotide, and albumin provides an alternative. Fluid resuscitation is frequently used in critically ill patients with AKI; however, overly aggressive fluid resuscitation is frequently associated with an increased risk of mortality. A 3-step approach that combines guided fluid resuscitation, establishment of an even fluid balance, and an appropriate rate of fluid removal may be beneficial. If fluid resuscitation is needed, crystalloid solutions are preferred over hetastarch solutions. Renal replacement therapy is the last resort in AKI treatment, and timing, modality, and dosing are discussed. Research suggests that AKI leads to an increased incidence of subsequent chronic kidney disease. However, this relationship has not been fully established and additional studies are needed for clarification.
Conclusion
Despite major advances in AKI research, serum creatinine remains the major biomarker for the detection of AKI. The following interventions have shown to be beneficial: IV fluids for contrast-induced AKI; diuretics for acute decompensated heart failure/cardiorenal syndrome; and combination therapy with midodrine, octreotide, and albumin for hepatorenal syndrome. Fluid resuscitation in a patient with AKI should be used with caution because too liberal use of fluids can be associated with increased mortality. AKI appears to be related to increased rates of subsequent chronic kidney disease, and patients with AKI should therefore be monitored closely. Recent studies on renal replacement therapy have neither revealed an optimal timing for initiation of dialysis nor a clear advantage for a specific dialysis modality.
PMCID: PMC4171794  PMID: 25249802
Acute kidney injury; biological markers; cardio-renal syndrome; hepatorenal syndrome; kidney tubular necrosis–acute; renal insufficiency–chronic; renal replacement therapy
20.  N-Acetylcysteine as adjunctive treatment in severe malaria: A randomized double blinded placebo controlled clinical trial 
Critical care medicine  2009;37(2):516-522.
Objective
Markers of oxidative stress are reported to be increased in severe malaria. It has been suggested that the antioxidant N-acetylcysteine (NAC) may be beneficial in treatment. We studied the efficacy and safety of parenteral N-acetylcysteine as an adjunct to artesunate treatment of severe falciparum malaria.
Design
A randomized double-blind placebo controlled trial on the use of high dose intravenous NAC as adjunctive treatment to artesunate.
Setting
A provincial hospital in Western Thailand and a tertiary referral hospital in Chittagong, Bangladesh.
Patients
One hundred and eight adult patients with severe falciparum malaria.
Interventions
Patients were randomized to receive N-acetylcysteine or placebo as adjunctive treatment to intravenous artesunate.
Measurements and main results
A total of 56 patients were treated with NAC and 52 received placebo. NAC had no significant effect on mortality, lactate clearance times (p=0.74) or coma recovery times (p=0.46). Parasite clearance time was increased from 30h (range 6h to 144h) to 36h (range 6h to 120h) (p=0.03), but this could be explained by differences in admission parasitemia. Urinary F2-isoprostane metabolites, measured as a marker of oxidative stress, were increased in severe malaria compared to patients with uncomplicated malaria and healthy volunteers. Admission red cell rigidity correlated with mortality, but did not improve with NAC.
Conclusion
Systemic oxidative stress is increased in severe malaria. Treatment with N-acetylcysteine had no effect on outcome in patients with severe falciparum malaria in this setting.
doi:10.1097/CCM.0b013e3181958dfd
PMCID: PMC2731834  PMID: 19114891
N-Acetylcysteine; Severe malaria; Adjunctive treatment
21.  Renal Cell Protection of Erythropoietin beyond Correcting The Anemia in Chronic Kidney Disease Patients 
Cell Journal (Yakhteh)  2013;15(4):378-380.
Currently many patients with chronic renal failure have profited from the use of erythropoietin to correct anemia (1,2). In chronic kidney disease, anemia is believed to be a surrogate index for tissue hypoxia that continues preexisting renal tissue injury (1-3). Erythropoietin is an essential glycoprotein that accelerates red blood cell maturation from erythroid progenitors and facilitates erythropoiesis. It is a 30.4 kD glycoprotein and class I cytokine containing 165 amino acids (3,4). Approximately 90% of systemic erythropoietin in adults is produced by peritubular interstitial fibroblasts in the renal cortex and outer medulla of the kidney (3-5). A feedback mechanism involving oxygen delivery to the tissues seems to regulate erythropoietin production. Hypoxia-inducible factor regulates transcription of the erythropoietin gene in the kidney, which determines erythropoietin synthesis (3-5). Erythropoietin is an essential glycoprotein that accelerates red blood cell maturation from erythroid progenitors and mediates erythropoiesis in the bone marrow (4-6). Kidney fibrosis is the last common pathway in chronic renal failure irrespective of the initial etiology (5,6). Constant inflammatory cell infiltration and pericyte-myofibroblast transition lead to renal fibrosis and insufficiency which result in decreased production of erythropoietin (4-7). Thus far, therapeutic efforts to treat patients with chronic renal failure by administering erythropoietin have been made only to correct anemia and putative hypoxic tissue damage. The introduction of recombinant human erythropoietin has marked a significant advance in the management of anemia associated with chronic renal failure (6-9). With an increasing number of patients with chronic renal failure receiving erythropoietin treatment, emerging evidence suggests that erythropoietin not only has an erythropoietic function, but also has renoprotective potential. In fact, in recent years, the additional non-erythropoietic tissue/ organ protective efficacy of erythropoietin has become evident, especially in the kidneys (5-12). Various investigations have shown the kidney protective property of erythropoietin in acute kidney injury. In a study to evaluate the ameliorative effects of erythropoietin on renal tubular cells, we studied 40 male rats. We found that erythropoietin was able to prevent the increase in serum creatinine and blood urea nitrogen. Furthermore, co-administration of gentamicin and erythropoietin effectively reduced kidney tissue damage compared to the control group. However, the protective properties of erythropoietin were also evident in our study. When the drug was applied after gentamicin- induced tubular damage we were able to show that the drug was still effective after tissue injury onset. This indicates that erythropoietin may have curative effects in addition to its preventive properties (13). Thus, erythropoietin is a promising kidney protective agent to prevent, ameliorate or attenuate tubular damage induced by gentamicin or other nephrotoxic agents that act in a similar manner to this drug (14-17). Recent studies have elucidated the cellular mechanism involved in kidney erythropoietin production and the consequent events that lead to kidney fibrosis, showing that they are closely related to each other (18-20). In contrast to previous findings, fibroblasts originating from damaged renal tubular epithelial cells do not have an important role in kidney fibrosis, but renal erythropoietin- producing cells, stemming from neural crests, have been shown to trans-differentiate into myofibroblasts after long-term exposure to inflammatory situations related to kidney fibrosis. In fact, almost all myofibroblasts expressing α-smooth muscle actin originate from renal erythropoietin-producing cells, which are naturally peritubular interstitial fibroblastic cells expressing neural cell marker genes but not α-smooth muscle actin. Macrophages and myofibroblasts are responsible for fibrosis in the renal tissue. Macrophages could be differentiated to phenotype M1 (classically activated) or M2 (wound healing) according to the distinctive cytokine production and behavior that follows different routes of activation (6,8,21,22). While erythropoietin can disengage macrophages by stopping the activity of NF-κB, it is possible that one of the mechanisms explaining the antifibrotic effects of erythropoietin in chronic kidney disease is in vivo macrophage regulation (20-25). These important findings stipulate the missing link in chronic renal failure between anemia and kidney fibrosis (6,8,21,22). In patients with chronic kidney disease, anemia due to reduced erythropoietin production eventually appears (1,4,5). Recombinant human erythropoietin has been used for more than 20 years in chronic kidney disease to recompense for reduced endogenous erythropoietin production (1,4,5,25). Recent investigations have pointed out that erythropoietin administration improves kidney functions in chronic kidney disease either directly or indirectly (17-24). The therapeutic benefits of erythropoietin beyond the correction of anemia are still questioned. However, it is notable that various pieces of evidence simply reflect the pleiotropic effects of erythropoietinon on the central nervous, cardiovascular system and on the kidney (18,20,25). In brief, clinical evidence shows the kidney protective potential of erythropoietin in patients with chronic renal failure, however, additional clinical investigations are crucial to outline when to start erythropoietin treatment and what is the optimal erythropoietin dosage for slowing disease progression in patients with chronic renal failure. The application of erythropoietin treatment for renoprotection may need to be earlier than that for erythropoiesis, while it is possible that the erythropoietin attenuation of renal fibrosis through macrophage regulation and endothelial cell protection operates through other unidentified mechanisms. While agents restoring the initial function of renal erythropoietin-producing cells could delay kidney fibrosis, further laboratory studies are necessary to clarify the cellular target of erythropoietin in the kidney and for developing a novel erythropoietin derivative or mimetic for kidney protection.
PMCID: PMC3866543  PMID: 24381864
Erythropoietin; Erythropoiesis
22.  The Efficacy of Hydration with Normal Saline Versus Hydration with Sodium Bicarbonate in the Prevention of Contrast-induced Nephropathy 
Background:
Contrast-induced acute kidney injury [contrast-induced nephropathy (CIN)] is one of the major causes of hospital-acquired acute renal failure. Volume supplementation is the most effective strategy to prevent acute renal failure caused by contrast; but the effects of sodium bicarbonate regimens are unknown in CIN prevention. The aim of this survey is to compare the efficacy of hydration with normal saline versus hydration with sodium bicarbonate in the prevention of the CIN in patients undergoing coronary angiography.
Materials and Methods:
In a clinical trial, 350 patients undergoing coronary interventions were randomized into two groups: One group received normal saline and another group received sodium bicarbonate before and after infusion of the contrast. Patients in both the groups had received N-acetylcysteine. CIN was defined as relative increase in serum creatinine equal to or more than 25% of baseline or increase to 0.5 mg/dl in 48 h after the injection of the contrast.
Results:
CIN was seen in 46 patients (13.1%) after coronary interventions. Incidence of CIN in patients receiving normal saline (19.4%) was more than in patients receiving sodium bicarbonate (6.9%) (P = 0.001). Hemodialysis was needed only in one patient who received saline normal. Relative risk to induce CIN in both groups was as 2.8 and was in the range of 1.50-5.25 with confidence interval of 95% and P = 0.001. Thus, the probability of CIN was significantly more in the usage of normal saline.
Conclusion:
This survey showed that hydration with sodium bicarbonate is superior to hydration with normal saline and has better protection effects.
doi:10.4103/1995-705X.137489
PMCID: PMC4124663  PMID: 25104980
Contrast; nephropathy; sodium bicarbonate
23.  Early detection and intervention using neutrophil gelatinase-associated lipocalin (NGAL) may improve renal outcome of acute contrast media induced nephropathy: A randomized controlled trial in patients undergoing intra-arterial angiography (ANTI-CIN Study) 
BMC Nephrology  2011;12:39.
Background
Patients with pre-existing impaired renal function are prone to develop acute contrast media induced nephropathy (CIN). Neutrophil gelatinase-associated lipocalin (NGAL), a new biomarker predictive for acute kidney injury (AKI), has been shown to be useful for earlier diagnosis of CIN; however, urinary NGAL values may be markedly increased in chronic renal failure at baseline. Results from those studies suggested that urinary NGAL values may not be helpful for the clinician. An intravenous volume load is a widely accepted prophylactic measure and possibly a reasonable intervention to prevent deterioration of renal function. The aim of our study is to evaluate NGAL as an early predictor of CIN and to investigate the clinical benefit of early post-procedural i.v. hydration.
Methods/Design
The study will follow a prospective, open-label, randomized controlled design. Patients requiring intra-arterial contrast media (CM) application will be included and receive standardized, weight-based, intravenous hydration before investigation. Subjects with markedly increased urinary NGAL values after CM application will be randomized into one of two study groups. Group A will receive 3-4 ml/kg BW/h 0.9% saline intravenously for 6 hours. Group B will undergo only standard treatment consisting of unrestricted oral fluid intake. The primary outcome measure will be CIN defined by an increase greater than 25% of baseline serum creatinine. Secondary outcomes will include urinary NGAL values, cystatin C values, contrast media associated changes in cardiac parameters such as NT-pro-BNP/troponin T, changes in urinary cytology, need for renal replacement treatment, length of stay in hospital and death.
We assume that 20% of the included patients will show a definite rise in urinary NGAL. Prospective statistical power calculations indicate that the study will have 80% statistical power to detect a clinically significant decrease of CIN of 40% in the treatment arm if 1200 patients are recruited into the study.
Discussion
A volume expansion strategy showing a benefit from earlier intervention for patients with markedly elevated urinary NGAL values, indicating a CIN, might arise from data from this study.
Trial registration
ClinicalTrials.gov NCT01292317
doi:10.1186/1471-2369-12-39
PMCID: PMC3170259  PMID: 21849080
24.  Contrast-induced nephropathy in interventional cardiology 
Development of contrast-induced nephropathy (CIN), ie, a rise in serum creatinine by either ≥0.5 mg/dL or by ≥25% from baseline within the first 2–3 days after contrast administration, is strongly associated with both increased inhospital and late morbidity and mortality after invasive cardiac procedures. The prevention of CIN is critical if long-term outcomes are to be optimized after percutaneous coronary intervention. The prevalence of CIN in patients receiving contrast varies markedly (from <1% to 50%), depending on the presence of well characterized risk factors, the most important of which are baseline chronic renal insufficiency and diabetes mellitus. Other risk factors include advanced age, anemia, left ventricular dysfunction, dehydration, hypotension, renal transplant, low serum albumin, concomitant use of nephrotoxins, and the volume of contrast agent. The pathophysiology of CIN is likely to be multifactorial, including direct cytotoxicity, apoptosis, disturbances in intrarenal hemodynamics, and immune mechanisms. Few strategies have been shown to be effective to prevent CIN beyond hydration, the goal of which is to establish brisk diuresis prior to contrast administration, and to avoid hypotension. New strategies of controlled hydration and diuresis are promising. Studies are mixed on whether prophylactic oral N-acetylcysteine reduces the incidence of CIN, although its use is generally recommended, given its low cost and favorable side effect profile. Agents which have been shown to be ineffective or harmful, or for which data supporting routine use do not exist, include fenoldopam, theophylline, dopamine, calcium channel blockers, prostaglandin E1, atrial natriuretic peptide, statins, and angiotensin-converting enzyme inhibitors.
doi:10.2147/IJNRD.S21393
PMCID: PMC3165908  PMID: 21912486
contrast-induced nephropathy; contrast media; acute kidney injury; percutaneous coronary intervention
25.  N-Acetylcysteine Enhanced Contrast Provides Cardiorenal Protection 
STRUCTURED ABSTRACT
Objective
We sought to evaluate the cardiac and renal effects of an N-Acetylcysteine (NAC) enhanced intracoronary radiographic contrast agent.
Background
Recent studies suggest that high dose NAC dosing provides better protection from contrast induced nephropathy and the anti-oxidant properties of NAC may also provide cardiac protection. The use of angiographic contrast agents as a drug delivery vehicle for cardiorenal protection effects has not been investigated.
Methods
In a pig model of prolonged cardiac ischemia-reperfusion NAC-enhanced contrast (C-NAC) was tested and compared to Iopamidol contrast-only (C). Myocardium and renal function were assessed after 24 hours.
Results
There was no significant difference in the area-at-risk for myocardial infarction (MI) between C and C-NAC. In contrast, MI size was about 40% smaller in C-NAC treated animals. These findings were associated with a significant difference in MI morphology. MI’s in the C-NAC group had a mottled appearance, whereas in C they were homogeneous and had a discrete border zone. These differences could explain a higher incidence of periprocedural ventricular arrhythmias in the C-NAC group. Histopathological analysis of the myocardium revealed a reduction in programmed cell death by C-NAC that may explain the increase in ischemia tolerance. Last, C-NAC administration blunted the rise in serum creatinine levels by about 60 percent and protected from renotubular apotosis.
Conclusions
N-Acetylcysteine enhanced contrast medium reduces MI size and protects renal function in a pig model of ischemia and reperfusion.
doi:10.1016/j.jcin.2008.11.011
PMCID: PMC2819370  PMID: 19463428
Contrast medium; ischemia; reperfusion; antioxidants

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