Effect of N-Acetylcysteine on Serum Creatinine and Kidney Function: Results of a Randomized Controlled Trial

Louise Moist, MD, MSc,1,2 Jessica M. Sontrop, PhD,2 Kerri Gallo, RN,1 Rahul Mainra, MD, MMed,3 Murray Cutler, BMSc,3 Dave Freeman, PhD,1,3 and Andrew A. House, MD, MSc1,2
Background: Evidence for a protective effect of N-acetylcysteine (NAC) on acute and chronic kidney disease is equivocal, and controversy persists about whether NAC affects creatinine level independently of actual kidney function. Study objectives are to investigate whether NAC affects serum creatinine level independently of alterations in other measures of kidney function. Study Design: Double-blind randomized controlled trial. Setting & Participants: Patients with stage 3 chronic kidney disease (n 60), Canada, 2007-2008. Intervention: Participants were randomly allocated to receive 4 doses of oral NAC (each 1,200 mg) or placebo, administered at 12-hour intervals. Outcome: The primary outcome was change in serum creatinine level between baseline and 4 hours after the last treatment dose. In addition, changes in other parameters of kidney function were measured between baseline and 4, 24, or 48 hours after the last treatment dose. Measurements: Serum creatinine, cystatin C, 24-hour urine protein and creatinine excretion, and creatinine clearance. Results: 60 patients, mean age of 70 years, 75% men, 50% had diabetes, with mean creatinine clearance of 43.7 18.8 (SD) mL/min were enrolled. Between baseline and 4 hours posttreatment, serum creatinine level decreased by 0.044 0.15 mg/dL in the NAC group and 0.040 0.18 mg/dL in the placebo group (95% CI for difference, 0.09 to 0.08; P 0.9). No signicant differences between groups were observed for change in serum creatinine, cystatin C, urine protein, urine creatinine, or creatinine clearance values at any time. Limitations: Blinding patients to orally administered liquid NAC is difcult and it is possible that patients receiving NAC were not sufciently blinded. Effects of NAC beyond 48 hours of treatment were not evaluated. Conclusions: In this randomized controlled trial, NAC had no short-term effect on creatinine level and did not decrease urine protein excretion within 48 hours of treatment. Am J Kidney Dis 56:643-650. 2010 by the National Kidney Foundation, Inc. INDEX WORDS: Chronic kidney disease; creatinine clearance; cystatin C, N-acetylcysteine; serum creatinine; urine protein.

-Acetylcysteine (NAC) is a sulfhydrylcontaining compound with potent antioxidant properties.1 It is approved for the prevention or reduction of hepatic injury after toxic acetaminophen ingestion and as a mucolytic to decrease the viscosity of mucus. In terms of potential effects on the kidney, the proposed benecial effects of NAC include attenuation of kidney injury caused by contrast agents,2,3 ischemia,4-6 obstruction,7 and nephrotoxins. However, questions have arisen after reports of an unexpected
From the 1Division of Nephrology, Department of Medicine, 2Department of Epidemiology and Biostatistics, and 3 Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada. Received December 9, 2009. Accepted in revised form March 24, 2010. Originally published online as doi:10.1053/ j.ajkd.2010.03.028 on June 14, 2010. Trial registration: ClinicalTrials.gov; study number: NCT00506506.

decrease in serum creatinine levels in patients administered NAC versus placebo.8-10 Most notably, Hoffmann et al10 showed a signicant decrease in serum creatinine level without change in cystatin C level 4 hours after NAC administration in healthy volunteers. These observations led some to hypothesize that NAC may interact with creatinine either during the in vitro measurement of creatinine, in the production of creatinine, or by the handling of creatinine by the proximal tubule.
Address correspondence to Louise Moist, MD, MSc, Division of Nephrology, Department of Medicine, Victoria HospitalLondon Health Sciences Centre, Rm A2-338, 800 Commissioners Rd E, London, Ontario, Canada N6A 5W9. E-mail: louise.moist@lhsc.on.ca 2010 by the National Kidney Foundation, Inc. 0272-6386/10/5604-0008$36.00/0 doi:10.1053/j.ajkd.2010.03.028

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measurements, were eligible for enrollment. Patients scheduled for radiocontrast procedures or using medications that interfere with the tubular secretion or production of creatinine were excluded. This study was approved by the Institutional Review Board at the University of Western Ontario, and all patients gave written informed consent.

Creatinine is used as a surrogate marker of glomerular ltration rate (GFR) in most studies evaluating the effects of NAC because it is ltered freely at the glomerular basement membrane.11 However, serum creatinine also is dependent on proximal tubular secretion,11,12 muscle mass, dietary intake, sex, and age.13 Therefore, when using serum creatinine level to evaluate interventions such as NAC, it is important to know whether NAC affects kidney function independently of serum creatinine. The interpretation of NAC as increasing GFR and hence improving kidney function may be confounded if NAC enhances tubular secretion of creatinine or augments activity of the enzyme creatinine kinase, leading to a decrease in serum creatinine level.10,14 It is important to evaluate NAC in at-risk patients with impaired kidney function. In contrast to the study of healthy volunteers by Hoffmann et al,10 our previous study of 30 patients with stages 3-4 chronic kidney disease (CKD) showed no change in serum creatinine or cystatin C level after a single oral dose of NAC (600 mg).15 Similarly, 4 doses of NAC (1,200 mg) administered to 29 patients with stages 3-5 CKD produced no change in either serum creatinine or cystatin C level.16 NAC also has been proposed to preserve kidney function in patients with CKD, with one proposed mechanism being a decrease in proteinuria.17 However, most studies reporting this were small, were nonrandomized or not blinded, with nonstandardized diet, and little exploration into potential mechanisms. The objective of this randomized controlled trial is to evaluate change in serum creatinine levels between baseline and 4 hours after the last of 4 doses of NAC (1,200 mg) or placebo in patients with stage 3 CKD. To understand potential mechanisms, we also examined the effects of NAC on serum cystatin C level, creatinine clearance, and proteinuria.

Intervention
Patients were randomly assigned to receive oral liquid NAC (1,200 mg) every 12 hours for 4 doses or placebo (normal saline). Patients were instructed to take NAC or placebo with ginger ale to mask the smell and taste. Randomization was controlled by the pharmacy through generation of a random-numbers chart, and medications were dispensed in a double-blind manner. Neither patients nor those administering the intervention were informed of group assignment at any time during the study. An individualized calendar was given to each patient with the date and time of each test and medication administration. To ensure standardized protein intake during the study, a registered renal dietician instructed patients to follow a standardized protein diet that was based on their diet history. Patients had no medication addition, deletion, or dose change from the time of study enrollment to study completion. Serum for creatinine and cystatin C measurement was obtained just before the initial dose of NAC/placebo at baseline and at 4, 24, and 48 hours from the last dose of NAC/placebo. A 24-hour urine collection for protein and creatinine was obtained at baseline before the initial dose of NAC/placebo and again at 48 hours after the last dose of NAC/placebo. Additional information collected from the clinic chart at study enrollment included age, sex, cause of CKD, comorbid conditions, medications, and the most recent creatinine level and weight in kilograms.

Laboratory Analysis
Serum creatinine was measured using the SYNCHRON LX (Beckman Coulter, www.beckmancoulter.com) system using the Jaff rate method.19 Cystatin C measurements were performed using a latex-enhanced reagent (N Latex Cystatin C; Dade Behring, www.dadebehring.com) with a Behring BN ProSpec analyzer (Dade Behring). Protein was measured using the Beckman-Coulter LX20 with the MTp Pyrogallol Red dye-binding method (lower limit of detection, 60 mg/L). Estimated creatinine clearance was calculated using the Cockcroft-Gault formula.18

Statistical Analysis
Sample size was estimated using data from a recent meta-analysis in which 8 of 15 studies showed an average decrease in serum creatinine level of 0.14 0.32 mg/dL.3 Using this value, 0.05, and power of 80%, we calculated the need for 45 patients. We increased this to 60 patients to account for a 20% breach in protocol or failure to complete all tests. The withdrawal rate after consent, but before randomization, was higher than anticipated (23%); therefore, enrollment was continued until 60 patients were randomly assigned, anticipating an additional 20% would fail to complete the protocol or have missing data. Although no patients withdrew after randomization (Fig 1), breach of protocol was documented for 3 patients. One participant

METHODS
Participants
Patients were screened for enrollment from the CKD clinics at University and Victoria Hospitals, both tertiarycare centers in London, Ontario, Canada, from November 2007 to October 2008. Patients older than 18 years with an estimated creatinine clearance18 of 30-60 mL/min, calculated using the last available creatinine, age, and weight

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Figure 1. Sample ow. Abbreviations: meds, medications; NAC, N-acetylcysteine.

missed 2 doses of NAC and another participant missed 1 dose of NAC. One participant in the placebo group missed the fourth treatment dose. Data from these patients were retained, and results presented in tables and gures reect intention-to-treat analysis. Changes between baseline and each subsequent time were compared between the NAC and placebo groups using independent t tests. For the primary outcome (change in serum creatinine level between baseline and 4 hours after the last dose of NAC or placebo), P 0.05 is considered statistically signicant. For all other comparisons, was decreased to 0.01 using the Bonferroni method (0.05/8) to account for multiple comparisons. Mean standard deviation values are reported.

RESULTS Patient ow is shown in Fig 1. Patients were screened for enrollment between November 2007 and October 2008 and followed up until December 2008. Of 235 patients considered eligible for

the study, 9 subsequently were found to be ineligible because of improved kidney function or using NAC medication. Of 226 eligible patients, 78 gave consent and 148 refused because of scheduling conicts, transportation issues, or lack of interest (Fig 1). Eighteen patients withdrew after giving consent, leaving 30 patients randomly assigned equally to the 2 groups. One participant missed 2 doses of NAC and another participant missed 1 dose of NAC. One participant in the placebo group missed the fourth treatment dose. One participant in the placebo group was missing data for serum creatinine (24 hours after treatment), and 2 participants in the placebo group were missing data for cystatin C (24 hours after treatment). Six patients in the NAC group and 11 in the placebo group had urine protein levels less than the lower limit of

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Table 1. Characteristics of the NAC and Placebo Groups at Study Entry
Characteristic NAC Group (n 30) Placebo Group (n 30) Pa

Moist et al

95% CIb

Mean age (y) Men (%) Cause of CKD (%) Diabetes Hypertension Glomerulonephritis Other Comorbid conditions (%) Coronary artery disease Diabetes mellitus Hypertension Congestive heart failure Peripheral vascular disease Concomitant medication use (%) ACE inhibitors/ARBs Diuretics Calcium channel blockers -Blockers Mean CCr (mL/min) Mean SCr (mg/dL) Median urine protein (mg/d)

68.6 12.5 70.0 36.7 26.7 3.3 30.0

71.6 9.1 83.3 40.0 43.3 0 16.7

0.3 0.4 0.8 0.3 1.0 0.4

8.7 to 2.6 33.5 to 8.2 22.3 to 28.4 9.4 to 40.1 11.2 to 19.1 10.5 to 35.5

20.0 53.3 66.7 10.0 0

26.7 46.7 86.7 6.7 10.0

0.8 0.8 0.1 0.9 0.2

16.9 to 29.4 19.8 to 31.9 3.9 to 41.5 15.1 to 21.9 5.9 to 27.7

73.3 63.3 46.7 43.3 42.9 19.0 2.12 0.70 260.0 (365.0)

66.7 56.7 63.3 56.7 44.5 19.0 2.16 0.79 400.0 (770.0)

0.8 0.8 0.3 0.4 0.8 0.8 0.8

18.2 to 30.5 19.4 to 31.6 10.3 to 40.7 13.5 to 37.9 12.2 to 8.9 0.43 to 0.34 260.0 to 150.0

Note: Values expressed as mean standard deviation, percentage, or median (interquartile range). Conversion factors for units: SCr in mg/dL to mmol/L, 88.4; CCr in mL/min to mL/s, 0.01667. Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CCr, creatinine clearance; CKD, chronic kidney disease; CI, condence interval; NAC, N-acetylcysteine; SCr, serum creatinine. a P for difference calculated using independent-samples t test, Mann-Whitney U, or Fisher exact 2-sided test, as appropriate. b The 95% CI for difference in proportions was calculated using the Wilson procedure with a continuity correction.

detection ( 0.07 mmol/d) and were not included in analyses of 24-hour urine protein excretion. Characteristics of randomly assigned patients are listed in Table 1. Average age was 70.1 11.0 years, 50% had diabetes, 70% were using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mean serum creatinine level was 2.14 0.74 mg/dL, and mean creatinine clearance was 43.7 18.8 mL/min, which is representative of our CKD clinic. Differences between the NAC and placebo groups were not statistically different for any variable. As shown in Table 2 and Fig 2, serum creatinine levels decreased by 0.04 0.2 mg/dL between baseline and 4 hours after the last treatment dose in both the NAC and placebo groups (95% condence interval [CI] for difference, 0.09 to 0.08; P 0.9). Similarly, changes in cystatin C levels between baseline and 4 hours posttreatment did not differ signicantly be-

tween treatment groups (mean difference, 0.03 mg/L; 95% CI, 0.03 to 0.09; P 0.4). Changes between baseline and 24 and 48 hours posttreatment did not differ signicantly between groups for either serum creatinine or cystatin C levels (Table 2; Fig 2). Changes in urine creatinine, protein, and timed creatinine clearance between baseline and 48 hours posttreatment did not differ signicantly between the NAC and placebo groups (Table 3). Although 24-hour urine protein excretion decreased by 73 mg in the NAC group, this was not statistically different from the placebo group, which decreased by 85 mg (95% CI for difference, 180.1 to 205.6; P 0.9). Results were the same when we conducted a per-protocol sensitivity analysis. One adverse reaction to NAC was observed after the rst 2 doses, with new onset of chest tightness and dyspnea. Additional doses of NAC were not administered to this patient.

Table 2. Change in Serum Markers of Kidney Function in Patients With CKD After Treatment With NAC or Placebo
Time Since Last Treatment Dose (h) 4 Changea SD SD SD Mean Diffb (95% CI) Pb Changea Mean Diffb(95% CI) Pb Changea Mean Diffb (95% CI) 24 48 Pb

Baseline SD

SCr (mg/dL) NAC Placebo 0.044 0.040 0.15 0.18 0.004 ( 0.09 to 0.08) 0.9 0.008 0.027c 0.17 0.25 0.02 ( 0.13 to 0.09) 0.7 0.006 0.018

2.12 2.16

0.70 0.79

0.17 0.02 ( 0.08 to 0.12) 0.7 0.213

N-Acetylcysteine in Chronic Kidney Disease

CysC (mg/L) NAC Placebo 0.014 0.013 0.13 0.11 0.03 ( 0.03 to 0.09) 0.4 0.024 0.034d 0.15 0.12 0.06 ( 0.13 to 0.13) 0.11 0.034 0.049 0.13 0.16

1.78 1.77

0.60 0.64

0.08 (0.01 to 0.16)

0.03

Note: The NAC and placebo groups each included 30 patients. Conversion factor for SCr in mg/dL to mmol/L, 88.4. Abbreviations: CKD, chronic kidney disease; CI, condence interval; CysC, cystatin C; diff, difference; NAC, N-acetylcysteine; SCr, serum creatinine; SD, standard deviation. a Mean change from baseline. b Independent t test comparing change in the NAC group with change in the placebo group. c One participant had no data at 24 hours, but had complete data for the primary analysis of change between baseline and 4 hours posttreatment. d Two participants had missing data at 24 hours, but had complete data for the primary analysis of change between baseline and 4 hours posttreatment.

647

Figure 2. Change in (A) serum creatinine and (B) cystatin C levels after treatment with N-acetylcysteine (NAC) or placebo in 60 patients with chronic kidney disease.

DISCUSSION NAC has a controversial history in the prevention and treatment of kidney injury.3,20 Although use of creatinine level as a surrogate marker of kidney function has contributed to some of this controversy, our ndings suggest there is no short-term interaction between NAC and creatinine and no independent effect of NAC on kidney function in patients with CKD. No shortterm changes were observed in urine creatinine, urine protein, creatinine clearance, or cystatin C values. The latter was used as an additional surrogate of kidney function because it may be a more accurate measurement of GFR compared with creatinine and appears to be unaffected by NAC. Serum creatinine level and creatinine clearance are both used as surrogates of kidney function because each can be inuenced by factors other than change in true GFR. Serum creatinine

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Moist et al
Table 3. Change in Urinary Markers of Kidney Function in Patients With CKD 48 Hours After Treatment With NAC or Placebo
48 h After Last Treatment Dose Change From Baseline

Baseline

Mean Diff (95% CI)a

Pa

24-h urine Cr (mg/d) NAC (n 30) Placebo (n 30) 24-h urine protein (mg/d) NAC (n 24)b Placebo (n 19)b CCr (mL/min) NAC (n 25) Placebo (n 27)

1.20 1.28

0.38 0.41

1.20 1.18

0.50 0.43

0.003 0.10

0.34 0.31

0.11 ( 0.06 to 0.27)

0.2

600.0 521.1

835.2 481.2

527.5 435.8

636.7 443.5

72.5 85.3

387.6 168.2

12.8 ( 180.1 to 205.6)

0.9

42.9 44.5

19.0 19.0

41.5 41.0

19.7 19.6

1.4 3.6

14.4 8.9

2.1 ( 4.5 to 8.8)

0.5

Note: Unless otherwise indicated, values are given as mean standard deviation. Conversion factors for units: urine creatinine in mg/d to mmol/d, 8.84; CCr in mL/min to mL/s, 0.01667. Abbreviations: CI, condence interval; CKD, chronic kidney disease; Cr, creatinine; CCr, creatinine clearance; diff, difference; NAC, N-acetylcysteine. a Independent t test comparing change in the NAC group with change in the placebo group. b Missing data resulted from protein values less than the lower limit of detection.

and creatinine clearance were measured to determine a mechanism for any change in creatinine level, such as an increase in secretion as opposed to an independent effect. Our negative ndings contrast with those of previous studies in which a decrease in serum creatinine level after treatment with NAC is documented.2,8-10 Hoffmann et al10 reported a small (0.029 mg/dL), but statistically signicant, decrease in serum creatinine level without a concomitant change in cystatin C level 4 hours after the last of four 600-mg doses of NAC given to healthy volunteers. In the present study of patients with CKD, a 0.044-mg/dL decrease in serum creatinine level between baseline and 4 hours posttreatment was observed in the NAC group; however, a similar decrease occurred in the placebo group, and the change between groups was not statistically different. These ndings highlight the necessity of a control group and the importance of randomization. Moreover, because our study included only patients with CKD, as opposed to the study by Hoffman et al10 of healthy volunteers, our results have greater clinical relevance and are generalizable to the CKD population. Baseline serum creatinine concentrations were higher in our patients with CKD compared with those with normal kidney function in the study by Hoffman et al,10 making these small changes clinically unimportant to patients with CKD. Patients with CKD are be-

lieved to have a higher degree of tubular secretion of creatinine than those with normal kidney function.13 Thus, if NAC affected this mechanism, we would expect to see a much greater decrease in serum creatinine level with concurrent increases in urinary creatinine excretion, when no change was observed. Our results are supported by several other reports in the literature,21,22 including our previous study showing no change in serum creatinine or cystatin C level after a single dose of oral NAC (600 mg) in patients with stage 3 CKD,15 and the recent study of Rehman et al,16 showing no change in serum creatinine or cystatin C level in 29 patients with CKD after 4 doses of oral NAC (1,200 mg). However, these earlier studies can be criticized for small numbers and lack of randomization and a control group. Other in vitro reports document a lack of interaction between NAC and serum creatinine level. For example, Izzedine et al22 added NAC in increasing concentrations to serum samples from volunteers; however, creatinine measurement was not affected by the in vitro addition of NAC. Finally, in a recent meta-analysis of 22 randomized controlled trials, Gonzales et al23 observed that a benecial effect of NAC in preventing contrast-induced nephropathy was driven by 4 small low-quality studies that also documented a NAC-induced decrease in creatinine level from baseline. Because the 18 higher quality studies observed no benet from NAC, the investi-

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649

gators concluded that their meta-analysis showed a lack of efcacy of NAC to prevent contrastinduced nephropathy. Some suggest that NAC may alter activity of the enzyme creatine kinase, leading to a possible decrease in serum creatinine level.10,14 In 1 study, oxidative stress and the production of oxygenfree radicals decreased the activity of rat creatine kinase, although serum creatinine was not measured. This effect was reversed by the antioxidant NAC and dithiothreitol.24 However, it is not proved that NAC increases creatine kinase activity in humans or rats in states of nonoxidative stress, making it difcult to support the assumption that a decrease in serum creatinine level after NAC administration is secondary to enhanced creatine kinase activity. Albuminuria is a direct consequence of renal glomerular/tubular injury and increases with glomerular dysfunction.25 It is a marker for progressive CKD and also a risk factor for cardiovascular disease.26 Levin et al17 proposed that because NAC has properties that hypothetically could attenuate tissue injury, it also could decrease proteinuria. Using a population with paired urine samples before and after cardiac catheterization that was randomly assigned to NAC or placebo, they showed an improvement in albumin-creatinine ratios in the NAC group, but not the placebo group. However, a similar study conducted in patients with proteinuria and nondiabetic CKD found no difference in proteinuria as a surrogate marker of tubular injury in the NAC group compared with the placebo group.27 In our study of patients with CKD, half of whom had diabetes, a decrease in urine protein excretion was observed in both the NAC and placebo groups between baseline and 48 hours posttreatment, although the change was not statistically different between groups and the 95% CI suggested a wide range of effects. It is important to note that we were not powered to evaluate this comparison and did not evaluate the effects of NAC beyond 48 hours of treatment. Our study has several strengths compared with the available literature. A higher dose of NAC was used in repeated doses in a randomized controlled design that included standardized protein intake. We also explored additional proposed mechanisms and outcomes of NAC in kidney injury.

Our study also has signicant limitations, including lack of a true GFR measure using scintigraphic methods, which would better ascertain an effect of NAC on GFR. Additionally, we did not introduce kidney injury to our model, and it is possible that NAC is handled differently in states of tissue hypoxia, altered redox state, or inammation. As such, we were able to evaluate only the effect of NAC on kidney function (creatinine clearance, cystatin C level, and proteinuria) in the absence of exposure to agents that are toxic to the kidney. Furthermore, uid hydration regimens have been shown to be an effective strategy to prevent contrast-induced nephropathy,23,28-30 and if uid loading augments the effect of NAC on kidney function,29 this may explain the lack of effect observed in our study. Alternatively, Gonzales et al23 observed that many NAC trials typically have been conducted using no more than maintenance infusions (1 mL/kg/h) of half-normal or normal saline solution and questioned whether the small nonsignicant benet of NAC in some trials would persist if hydration were individually optimized. It also is important to consider that changes in parameters of kidney function were evaluated only within 48 hours of the last treatment dose of NAC. Although no effects of NAC were observed within this interval, this does not preclude a longer term effect, particularly if serum creatinine is poorly responsive to acute changes in kidney function. Although we used a robust design, the study was underpowered to detect small changes in creatinine levels ( 0.14 0.32 mg/dL). However, if NAC decreased creatinine levels by such a small amount, one would have to question the clinical signicance in patients with stages 3-4 CKD. Variance in creatinine measurement is 3%-5% in our study. This variance should not inuence our results because each group should be affected equally. Finally, although we attempted to mask the smell and taste of NAC by the use of ginger ale, it is difcult to blind patients to the taste of orally administered liquid NAC and it is possible that patients receiving NAC were not sufciently blinded. Our randomized controlled trial of patients with CKD does not show a short-term effect of NAC on serum creatinine level that is independent of true kidney function. NAC did not affect short-term levels of proteinuria or serum cystatin C. If NAC preserves kidney function, the mechanism by which this occurs is not clear. Future

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14. Toprak O. Interactions between serum creatinine, volume status, N-acetylcysteine, and contrast-induced nephropathy. Ren Fail. 2006;28(3):265-266. 15. Mainra R, Gallo K, Moist L. Effect of N-acetylcysteine on renal function in patients with chronic kidney disease. Nephrology (Carlton). 2007;12(5):510-513. 16. Rehman T, Fought J, Solomon R. N-Acetylcysteine effect on serum creatinine and cystatin C levels in CKD patients. Clin J Am Soc Nephrol. 2008;3(6):1610-1614. 17. Levin A, Pate GE, Shalansky S, et al. N-Acetylcysteine reduces urinary albumin excretion following contrast administration: evidence of biological effect. Nephrol Dial Transplant. 2007;22(9):2520-2524. 18. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1): 31-41. 19. Hervey GR. Determination of creatinine by the Jaffe reaction. Nature. 1953;171(4364):1125. 20. Bagshaw SM, Ghali WA. Acetylcysteine for prevention of contrast-induced nephropathy after intravascular angiography: a systematic review and meta-analysis. BMC Med. 2004;2:38-49. 21. Haase M, Haase-Fielitz A, Ratnaike S, et al. NAcetylcysteine does not artifactually lower plasma creatinine concentration. Nephrol Dial Transplant. 2008;23(5): 1581-1587. 22. Izzedine H, Guerin V, Launay-Vacher V, Bernard M, Deray G. Effect of N-acetylcysteine on serum creatinine level. Nephrol Dial Transplant. 2001;16(7):1514-151. 23. Gonzales DA, Norsworthy KJ, Kern SJ, et al. A meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve heterogeneity. BMC Med. 2007;5:32-44. 24. Genet S, Kale RK, Baquer NZ. Effects of free radicals on cytosolic creatine kinase activities and protection by antioxidant enzymes and sulfhydryl compounds. Mol Cell Biochem. 2000;210(1-2):23-28. 25. Toto RD. Microalbuminuria: denition, detection, and clinical signicance. J Clin Hypertens (Greenwich). 2004;6(11 suppl 3):2-7. 26. Tuttle KR. Cardiovascular implications of albuminuria. J Clin Hypertens (Greenwich). 2004;6(11 suppl 3): 13-17. 27. Renke M, Tylicki L, Rutkowski P, et al. The effect of N-acetylcysteine on proteinuria and markers of tubular injury in non-diabetic patients with chronic kidney disease. A placebo-controlled, randomized, open, cross-over study. Kidney Blood Press Res. 2008;31(6):404-410. 28. Eisenberg RL, Bank WO, Hedgock MW. Renal failure after major angiography can be avoided with hydration. AJR Am J Roentgenol. 1981;136(5):859-861. 29. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomized controlled trial. JAMA. 2004;291(19):23282334. 30. Navaneethan SD, Singh S, Appasamy S, Wing RE, Sehgal AR. Sodium bicarbonate therapy for prevention of contrast-induced nephropathy: a systematic review and meta-analysis. Am J Kidney Dis. 2009;53(4): 617-627.

studies are needed to conrm whether NAC preserves kidney function in patients with CKD, and by what mechanism.

ACKNOWLEDGEMENTS
Support: This study was funded by a grant by The Lawson Health Research Institute, London, Canada, and Physicians Services Inc, Ontario, Canada. Financial Disclosure: The authors declare that they have no relevant nancial interests.

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1. Briguori C, Marenzi G. Contrast-induced nephropathy: pharmacological prophylaxis. Kidney Int Suppl. 2006; 100:S30-38. 2. Tepel M, van der GM, Schwarzfeld C, et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med. 2000;343(3):180-184. 3. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int. 2004;65(4):1366-1374. 4. Efrati S, Dishy V, Averbukh M, et al. The effect of N-acetylcysteine on renal function, nitric oxide, and oxidative stress after angiography. Kidney Int. 2003;64(6):2182-2187. 5. Nitescu N, Ricksten SE, Marcussen N, et al. NAcetylcysteine attenuates kidney injury in rats subjected to renal ischaemia-reperfusion. Nephrol Dial Transplant. 2006; 21(5):1240-1247. 6. de Araujo M, Andrade L, Coimbra TM, Rodrigues AC Jr, Seguro AC. Magnesium supplementation combined with N-acetylcysteine protects against postischemic acute renal failure. J Am Soc Nephrol. 2005;16(11):3339-3349. 7. Shimizu MH, Danilovic A, Andrade L, et al. NAcetylcysteine protects against renal injury following bilateral ureteral obstruction. Nephrol Dial Transplant. 2008; 23(10):3067-3073. 8. Kay J, Chow WH, Chan TM, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention: a randomized controlled trial. JAMA. 2003;289(5):553-558. 9. Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol. 2002;40(8):1383-1388. 10. Hoffmann U, Fischereder M, Kruger B, Drobnik W, Kramer BK. The value of N-acetylcysteine in the prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol. 2004;15(2):407-410. 11. Bauer JH, Brooks CS, Burch RN. Clinical appraisal of creatinine clearance as a measurement of glomerular ltration rate. Am J Kidney Dis. 1982;2(3):337-346. 12. Walser M, Drew HH, Guldan JL. Prediction of glomerular ltration rate from serum creatinine concentration in advanced chronic renal failure. Kidney Int. 1993;44(5):11451148. 13. Walser M. Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis. 1998;32(1):23-31.