Rathan M. Subramaniam, MD, PhD, MPH; Catalina Suarez-Cuervo, MD; Renee F. Wilson, MS; Sharon Turban, MD, MHS; Allen Zhang, BS; Cheryl Sherrod, MD, MPH; Jonathan Aboagye, MD, MPH; John Eng, MD; Michael J. Choi, MD; Susan Hutfless, PhD; Eric B. Bass, MD, MPH
Disclaimer: The authors of this article are responsible for its content. Statements in the article should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank Emmanuel Iyoha, Elisabeth Nannes, Oluwaseun Shogbesan, and Yohalakshmi Chelladurai for their contributions to this project.
Grant Support: By the Agency for Healthcare Research and Quality (contract 290-2012-00007-I), U.S. Department of Health and Human Services.
Disclosures: Dr. Subramaniam reports grants from the Agency for Healthcare Research and Quality during the conduct of the study and personal fees from Philips Healthcare outside the submitted work. Ms. Wilson reports other from the Johns Hopkins University Evidence-based Practice Center during the conduct of the study and personal fees from Prism Capital outside the submitted work. Dr. Turban Reports grants from the Agency for Healthcare Research and Quality during the conduct of the study. Dr. Eng reports support from a contract with the Agency for Healthcare Research and Quality. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/Conflict OfInterestForms.do?msNum=M15-1456.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Reproducible Research Statement:Study protocol, statistical code, and data set: Available from Ms. Wilson (e-mail, firstname.lastname@example.org).
Requests for Single Reprints: Rathan M. Subramaniam, MD, PhD, MPH, Associate Professor of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, 601 North Caroline Street, Baltimore, MD 21287; e-mail, email@example.com.
Current Author Addresses: Dr. Subramaniam: Associate Professor of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, 601 North Caroline Street, Baltimore, MD 21287.
Drs. Suarez-Cuervo, Sherrod, Aboagye, and Bass; Ms. Wilson; and Mr. Zhang: Evidence-based Practice Center, Johns Hopkins University, 624 North Broadway, Suite 648, Baltimore, MD 21205.
Drs. Turban and Choi: Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 416, Baltimore, MD 21287.
Dr. Eng: Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287.
Dr. Hutfless: Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Blalock Building, Room 449, 600 North Wolfe Street, Baltimore, MD 21287.
Author Contributions: Conception and design: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, J. Eng, E.B. Bass.
Analysis and interpretation of the data: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, M.J. Choi, S. Hutfless, E.B. Bass.
Drafting of the article: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, J. Eng.
Critical revision of the article for important intellectual content: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, J. Aboagye, J. Eng, M.J. Choi, S. Hutfless, E.B. Bass.
Final approval of the article: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, J. Eng, M.J. Choi, S. Hutfless, E.B. Bass.
Provision of study materials or patients: E.B. Bass.
Statistical expertise: A. Zhang, J. Eng, S. Hutfless.
Obtaining of funding: R.M. Subramaniam, E.B. Bass.
Administrative, technical, or logistic support: R.F. Wilson, A. Zhang, C. Sherrod, E.B. Bass.
Collection and assembly of data: R.M. Subramaniam, C. Suarez-Cuervo, R.F. Wilson, S. Turban, A. Zhang, C. Sherrod, J. Aboagye, J. Eng, M.J. Choi.
Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016;164:406-416. doi: 10.7326/M15-1456
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Published: Ann Intern Med. 2016;164(6):406-416.
Published at www.annals.org on 2 February 2016
N-acetylcysteine, sodium bicarbonate, statins, and ascorbic acid have been studied for reducing contrast-induced nephropathy (CIN).
To evaluate the comparative effectiveness of interventions to reduce CIN in adults receiving contrast media.
MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, and Scopus databases through June 2015. Risk of bias and overall strength of evidence (SOE) of studies were assessed.
Randomized, controlled trials of N-acetylcysteine, sodium bicarbonate, statins, or ascorbic acid that used intravenous (IV) or intra-arterial contrast media and defined CIN with enough data for meta-analysis.
Two reviewers independently extracted data and assessed study quality.
Low-dose N-acetylcysteine plus IV saline compared with IV saline (risk ratio [RR], 0.75 [95% CI, 0.63 to 0.89]; low SOE), N-acetylcysteine plus IV saline compared with IV saline in patients receiving low-osmolar contrast media (RR, 0.69 [CI, 0.58 to 0.84]; moderate SOE), and statins plus N-acetylcysteine plus IV saline versus N-acetylcysteine plus IV saline (RR, 0.52 [CI, 0.29 to 0.93]; low SOE) had clinically important and statistically significant benefits. The following 3 comparisons suggested a clinically important difference that was not statistically significant: sodium bicarbonate versus IV saline in patients receiving low-osmolar contrast media (RR, 0.65 [CI, 0.33 to 1.25]; low SOE), statins plus IV saline versus IV saline (RR, 0.68 [CI, 0.39 to 1.20]; low SOE), and ascorbic acid versus IV saline (RR, 0.72 [CI, 0.48 to 1.01]; low SOE). Strength of evidence was generally insufficient for comparisons of the need for renal replacement, cardiac events, and mortality.
Too few studies were done in patients receiving IV contrast media.
The greatest reduction in CIN was seen with N-acetylcysteine plus IV saline in patients receiving LOCM and with statins plus N-acetylcysteine plus IV saline.
Agency for Healthcare Research and Quality.
Appendix Table. Detailed Search Strategy
Summary of evidence search and selection.
CIN = contrast-induced nephropathy; RCT = randomized, controlled trial.
* 24 647 gray literature results were also found.
† Total does not sum to 371 because the 2 reviewers were not required to agree on reasons for exclusion.
Table 1. Pooled RRs for CIN With NAC Compared With IV Saline
Pooled RRs for development of CIN in comparisons ofN-acetylcysteine plus IV saline versus IV saline in patients receiving contrast media.
CIN = contrast-induced nephropathy; IOCM = iso-osmolar contrast media; IV = intravenous; LOCM = low-osmolar contrast media; NAC = N-acetylcysteine; RR = risk ratio.
Table 2. Summary of the Main Findings and SOE*
Pooled RRs for development of CIN in studies of sodium bicarbonate, statins, and ascorbic acid in patients receiving contrast media.
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Steven D. Weisbord, MD, MSc Paul M. Palevsky, MD
VA Pittsburgh Healthcare System
February 8, 2016
Conflict of Interest:
Drs. Weisbord and Palevsky are the Principal Investigators of the ongoing Department of Veterans Affairs sponsored PRESERVE trial (ClinicalTrials.gov ID#: NCT01467466) , a multi-center randomized clinical trial investigating intravenous sodium bicarbonate and oral N-acetylcysteine for the prevention of serious adverse outcomes following angiography.
N-acetylcysteine versus saline?
To the Editor:
Subramaniam et al. report the results of a systematic review and meta-analysis funded by the Agency for Healthcare Research and Quality that evaluated specific interventions for the prevention of contrast-associated acute kidney injury (CA-AKI) (1). Of particular interest is their finding that ‘low dose N-acetylcysteine compared with IV saline had clinically important and statistically significant benefits.’ Careful inspection of the primary studies included in this meta-analysis clearly demonstrates that this is incorrect. Specifically, the authors report that they used ‘a random-effects model to pool studies comparing N-acetylcysteine with IV saline versus IV saline with or without a placebo.’ Thus, among clinical trials in which all patients received IV saline, they assessed the benefit of N-acetylcysteine compared to either no N-acetylcysteine or to placebo. A review of the studies incorporated into this analysis confirms this was in fact the comparison used in these trials. However, the authors inappropriately conclude that N-acetylcysteine is superior to IV saline for the prevention of CA-AKI. Rather, what their analysis suggests is that among patients who receive IV saline, the administration of N-acetylcysteine is associated with a lower incidence of CA-AKI than the administration of placebo or no N-acetytlcysteine.
The authors’ erroneous and misleading conclusion is potentially dangerous. Providers may interpret this finding as justifying the administration of N-acetylcysteine in lieu of IV crystalloid. It is, of course, much more feasible to administer oral N-acetycysteine than IV fluids to the large number of at-risk patients who undergo contrast-enhanced procedures in the outpatient setting and/or under more urgent circumstances. However, current evidence supports the administration of IV isotonic fluid prior to and following contrast-enhanced imaging procedures as the principal intervention to reduce the risk for CA-AKI in patients at elevated risk. In fact, this intervention is recommended in multiple published guidelines on the prevention of CA-AKI (2-4). Conversely, there has been remarkable inconsistency in the literature with regard to the benefit of N-acetylcysteine, leading some practice guidelines to recommend its use only in conjunction with IV isotonic fluid, while others recommend against its use at all (5). Until large scale randomized clinical trials that are adequately powered to determine the effectiveness of N-acetylcysteine for the prevention of not only CA-AKI, but serious patient-centered outcomes are conducted, suggestions that this agent is effective and can be administered in lieu of IV isotonic fluid are inappropriate.
1. Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016.
2. Palevsky PM, Liu KD, Brophy PD, Chawla LS, Parikh CR, Thakar CV, et al. KDOQI US commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis. 2013;61(5):649-72.
3. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Jr., et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(23):e663-828.
4. Rudnick M. Prevention of Contrast-Induced Nephropathy. In: UptoDate 2015.
5. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation;124(23):e574-651.
Somjot Brar, Ayub Akbari, Swapnil Hiremath
Kaiser Permanente, Los Angeles (SB), Ottawa Hospital Research Institute (AA and SH)
March 3, 2016
Unresolved heterogeneity underlies the apparent benefit of n-acetycysteine and statins in contrast nephropathy
We read the meta-analysis by Subramaniam (1) et. al. with interest. The investigators undertook a herculean effort by including multiple treatments for the prevention of contrast induced-acute kidney injury (CI-AKI), and should be congratulated for their efforts. However, it can be difficult to capture or identify important points of heterogeneity between studies for various treatments in the context of such an undertaking, which have not been adequately recognized in the present report and may have implications on the authors conclusions.For many initial CI-AKI prevention trials, the sample sizes are small with large treatment effects (2). When these small studies have been followed by larger ones, these early promising results are not readily reproducible. Unfortunately, the larger trials are often smaller in number, and the meta-analytic framework does not give them adequate weight. Observing consistency between treatment effects in large and small studies would be reassuring which is lacking for many CI-AKI prevention strategies. Specifically, the result for the greater efficacy of low-dose N-acetylcysteine (NAC), which includes older, smaller trials of lower methodological quality (36 trials, 4874 participants), as compared to high-dose NAC (usually larger, higher quality trials, 18 trials, 4336 participants), makes little biological sense. The largest and possibly the best quality trial, which was done with high-dose NAC, included 2308 patients with a hazard ratio of 1.00 for the primary outcome (3). Even in subgroups at higher risk for CI-AKI, diabetics and estimated GFR <60, no significant benefit was observed. Similarly, the largest trial for statins, with almost 3000 patients, was about six times larger than the next largest trial (4). While this study did show a statistically significant benefit for statin treatment versus no statin treatment, the majority of patients were at very low risk for CI-AKI (CKD stage I or II). When the subset of approximately 500 patients with estimated GFR <60 were analyzed, no significant benefit for statin therapy was observed. These aspects of the literature can be readily lost when seen through the meta-analytical lens. The aim of a meta-analysis is not solely to generate a summary estimate, but provide a structured framework to explore and understand sources of heterogeneity, both statistical and clinical. Identifying important heterogeneity between studies can at times provide more insight than the summary estimates (5). Unfortunately, this can be very time-consuming, in particular when multiple treatments are under review, and requires expertise in the treatments being evaluated.1.Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, et al. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016.2. Hiremath S, Brar SS. The evidence for sodium bicarbonate therapy forcontrast-associated acute kidney injury: far from settled science. Nephrol DialTransplant. 2010 Aug;25(8):2802-43. ACT Investigators. Acetylcysteine for prevention of renal outcomes in patientsundergoing coronary and peripheral vascular angiography: main results from therandomized Acetylcysteine for Contrast-induced nephropathy Trial (ACT).Circulation. 2011 Sep 13;124(11):1250-9.4. Han Y, Zhu G, Han L, Hou F, Huang W, Liu H, Gan J, Jiang T, Li X, Wang W, Ding S, Jia S, Shen W, Wang D, Sun L, Qiu J, Wang X, Li Y, Deng J, Li J, Xu K, Xu B, Mehran R, Huo Y. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. J Am Coll Cardiol. 2014;63:62-70.5. Gonzales DA, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, Natanson C,Danner RL. A meta-analysis of N-acetylcysteine in contrast-inducednephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med. 2007Nov 14;5:32
Eric Bass MD, MPH
Johns Hopkins University
March 4, 2016
Thank you for bringing to our attention the questions about our manuscript on the “Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy.” We summarize below our responses. We agree the text should be clearer about how studies of N-acetylcysteine generally compared N-acetylcysteine plus IV saline to IV saline with or without placebo. This is also true for studies of statins and ascorbic acid, with use of IV saline in the intervention and comparator arms. To make this clearer, we prepared a more detailed version of the Appendix with information about use of IV saline in the intervention and comparisons groups. The new Appendix replaces the original version that was available in the on-line early article. For maximum clarity, we also made the following changes in the final print version of the article: 1) In multiple places, we changed the text from “N-acetylcysteine” to “N-acetylcysteine plus IV saline;” and 2) In the first paragraph of the discussion, we changed “ascorbic acid” to “ascorbic acid plus IV saline.” The fourth paragraph of the results section explains that analyses were based on “studies comparing N-acetylcysteine with IV saline versus IV saline with or without a placebo.” The second paragraph of the statins results indicates that studies “compared a statin plus IV saline with IV saline alone,” and the third paragraph of the statins results states that studies “compared statins added to N-acetylcysteine and IV saline with N-acetylcysteine plus IV saline.” Also, in the third paragraph of the discussion, we refer to the guideline which “suggests using oral N-acetylcysteine with IV fluids…” We checked the meta-analysis and confirmed that the 95% confidence interval for high-dose N-acetylcysteine is correct, and changed the corresponding text to say that “high-dose N-acetylcysteine had a small effect on reducing CIN risk that was clinically unimportant and not statistically significant.”To address concerns about the accuracy of information in Appendix Table 2, we had reviewers re-check all information presented in the appendix, and prepared a more detailed version of the appendix to replace the original on-line early version. The new appendix includes the following changes, none of which change the main findings and conclusions.1. We added a footnote to clarify why the appendix only referred to use of IOCM and LOCM in the study by the ACT Investigators – “The study included patients who received HOCM, but reported results separately by type of contrast media received, so we were able to focus on the results from patients receiving IOCM or LOCM.” 2. We added information about the type of saline (or other fluid) that was used in the intervention and comparison groups of all studies, with footnotes to note when a study did not report the concentration of saline, and a footnote addressing one of the reader’s comments – “the study protocol recommended hydration with 0.9% saline with 93% or more of patients in both groups receiving 0.9% saline.”3. We added wording and footnotes to clarify and provide more detail about characteristics of the studies, including: more information about patient characteristics in ACT 2011 (patients had at least one risk factor for contrast-induced acute kidney injury, and “about half of patients had a creatinine clearance less than 60 mg/min”); clarification of the type of cardiac condition included in Aslanger 2012; clarification of how the contrast media was left to the discretion of the cardiologists in Azmus 2005; clarification of how the study by Erturk 2014 had 3 arms; addition of a footnote to clarify that the study by Hsu 2012 included patients with renal dysfunction; addition of a footnote to clarify that the study by Kefer 2003 included patients with renal dysfunction; clarification that the study by Ochoa 2004 left the choice of contrast media to the discretion of the clinicians and did not report results separately by type of contrast media; clarification that the study by Seyon 2007 included patients with cardiac conditions; clarification that the studies by Beyazal 2014, Boucek 2013, Brar 2008, Kooiman 2014, and Lee 2011 included patients with chronic kidney disease; clarification that Masuda 2007 and Ueda 2011 did not report the concentration of saline used in the comparison group; clarification that the study by Yeganehkhah 2014 included patients at high risk for CIN; clarification that in Patti 2011 hydration was not reported, and only those with pre-existing renal failure were given normal saline; and clarification that in Yun 2014 IV saline was given at physician's discretion for both arms.4. We corrected typographical errors, including: correction of the route of administration used for N-acetylcysteine in ACT with confirmation that it was correctly included in the analysis; correction of the type of contrast media listed for Jaffery 2012 with confirmation that it was correctly included in the analysis; correction of the type and route of administration for the contrast media listed for Boucek 2013 with confirmation that it was correctly included in the analysis; and clarification that the intervention infusion was for 7 hours in Boucek 2013. 5. We added two studies to the appendix (Gomes 2012 and Jo 2009) with confirmation that the studies were correctly included in the analyses and text. After preparing the revised Appendix, we identified places in the body of the article where wording changes could help to clarify the information presented. 1. Results on IV Sodium Bicarbonate versus IV Saline, paragraph 2: changed from "Contrast media was administered via IV in 3 studies and IA in 14 studies, and 1 study did not report the route of administration," to "Contrast media was administered via IV in 2 studies, IA in 14 studies, IV or IA in 1 study, and 1 study did not report the route of administration."2. Results on IV Sodium Bicarbonate versus IV Saline, paragraph 2: changed from "Seven studies used IOCM, 11 used LOCM, 1 used either IOCM or LOCM, and 1 did not report the type of contrast type," to "Six studies used IOCM, 12 used LOCM, and 1 study did not report the type of contrast media."3. Results on N-acetylcysteine plus IV Saline Versus Sodium Bicarbonate, paragraph 1: changed from "1 used IV administration" to "1 did not report route of administration."4. Results on Statins, paragraph 2: changed from "and 1 included only patients with diabetes mellitus" to "and 2 studies included patients with diabetes mellitus and chronic kidney disease."5. Results on Statins, paragraph 3: changed from "high CIN risk" to "diabetes mellitus and chronic kidney disease."6. Results on Ascorbic Acid, paragraph 2: changed from "All of these studies included patients receiving cardiovascular interventions via IA LOCM (Appendix Table 2)" to "These studies included patients receiving cardiovascular interventions with IA administration of LOCM (3 studies), IOCM (1 study), or either LOCM or IOCM (2 studies)." We greatly appreciate the reader’s careful attention to the details presented in the article, and we hope the changes clarify the issues and concerns that were raised.
James Cain MD FACP, FASN, Jamie Goldstone MPH
Valley Nephrology Associates, Jefferson College of Health Sciences
April 25, 2016
The recent meta-analysis of contrast induced nephropathy by Subramanian(1) et. al. and any analysis of N-acetycysteine and creatinine may be in error due to inaccurate creatinine measurementsAn “Urgent Medical Device Correction” dated March 17, 2016 issued by Siemens corporation regarding an interfering substance affecting creatinine measurements using the ”Trinder and Trinder like reaction assays” is brought to our attention. This reaction results in falsely low creatinine determinations in the presence of N-acetylcystein (NAC.) A similar warning was issued in May 2015 by Roche diagnostics.This interference was described by Genzen et. al. in Clinical Biochemistry(2) in October of 2015. The patients studied in this meta –analysis were given NAC in an effort to prevent nephrotoxicity. Falsely decreased results would create the impression of success. The conclusions reached here are valid only if the method used to measure the creatinine is not the Trinder method. No mention was made of the methods used to perform the creatinine assays in the publication.
Eric Bass, MD, MPH
Johns Hopkins Medical Institute
May 11, 2016
Reply to Cain
We appreciate the concern about the possibility of falsely low serum creatinine measurements in the presence of N-acetylcysteine (NAC) when the Trinder and Trinder-like reaction assays are used.(1) When we reviewed the study by Genzen et al (2015),(2) we found that NAC did not have any significant effect on the serum creatinine level at low doses of NAC. Thus, we see no reason to change our conclusion that low strength of evidence indicates that low-dose NAC plus intravenous saline compared with intravenous saline had a clinically important benefit.(3) The concern then mainly applies to studies using high doses of NAC. Many of the studies included in our review used high doses of NAC, which we defined as more than 1200 mg per day. It is possible that a few of the studies used doses of NAC that were high enough to cause a small effect on the creatinine level by the Trinder assay. Unfortunately, very few studies reported what assay was used to measure the serum creatinine. None of the studies reported using the Trinder assay. We cannot rule out the possibility that use of the Trinder assay contributed to a small overestimate of the effect of high-dose NAC, but that would not explain why we did not find a clinically important benefit for high-dose NAC with intravenous saline compared with intravenous saline alone. Although we stand by our conclusions regarding the effects of NAC on contrast induced nephropathy, we agree that studies of NAC to prevent nephrotoxicity should be more consistent in reporting the assay used to measure serum creatinine. Sincerely, Eric B. Bass, MD, MPH Rathan Subramaniam, MD 1 Cain J and Goldstone J. Letters. Ann Intern Med. 2016 in press. 2 Genzen JR, Hunsaker JJ, Nelson LS, Faine BA, Krasowski MD. N-acetylcysteine interference of Trinder-based assays. Clin Biochem. 2016 Jan;49(1):100-4. doi: 10.1016/j.clinbiochem.2015.10.005. Epub 2015 Oct 21. PubMed PMID: 26500003. 3 Subramaniam RM, Suarez-Cuervo C, Wilson RF, Turban S, Zhang A, Sherrod C, Aboagye J, Eng J, Choi MJ, Hutfless S, Bass EB. Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis. Ann Intern Med. 2016 Mar 15;164(6):406-16. doi: 10.7326/M15-1456. Epub 2016 Feb 2. PubMed PMID: 26830221.
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