N-Acetylcysteine Effect On Serum Creatinine and Cystatin C Levels in CKD Patients

N-Acetylcysteine Effect on Serum Creatinine and Cystatin C Levels in...
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572274/?report=printable
Clin J Am Soc Nephrol. Nov 2008; 3(6): 16101614.
PMCID: PMC2572274
doi: 10.2215/CJN.01560408
N-Acetylcysteine Effect on Serum Creatinine and Cystatin C Levels in CKD

Patients
Tariq Rehman,* Jason Fought, and Richard Solomon*
*Division of Nephrology, Fletcher Allen Health Care and University of Vermont, Burlington, Vermont; and St. David's Hospital, Georgetown,
Texas
Correspondence: Dr. Richard Solomon, UHC 2309, 1 South Prospect Street, Burlington, VT 05401. Phone: 802-847-5030; Fax:
802-847-3607; E-mail: rsolomon@uvm.edu
Received April 1, 2008; Accepted June 27, 2008.
Copyright 2008 by the American Society of Nephrology
Abstract
Background and objectives: N-acetylcysteine (NAC) has been widely used as a prophylactic therapy for
contrast-induced nephropathy (CIN). Its efficacy is controversial because of heterogeneity in study results
and because of evidence that NAC can alter serum creatinine levels without affecting glomerular filtration
rate. This confounding effect of N-acetylcysteine on serum creatinine has not been rigorously tested,
however, in a population at risk for CIN and following doses of NAC currently recommended for
prophylaxis of CIN.
Design, setting, participants, & measurements: Double-dose NAC was administered in the absence of
iodinated contrast media to 29 stage 3 to 5 stable chronic kidney disease patients. Serum creatinine and
cystatin C were measured before and 4 h and 48 h after the last dose of NAC.
Results: There was no effect of NAC on either serum creatinine or cystatin C levels.
Conclusion: NAC, in doses currently recommended for prophylaxis of CIN, has no effect on serum
creatinine or cystatin C levels. It is therefore unlikely that the heterogeneity seen in clinical trials of NAC
prophylaxis for CIN is related to a confounding effect on serum creatinine.
N-Acetylcysteine (NAC) has been reported to protect the kidney from injury induced by contrast media,
ischemia, and toxins. In all these studies, glomerular filtration rate (GFR) is the surrogate marker of kidney
injury and serum creatinine changes are the measured metric of GFR. Critical to understanding the
mechanism of such a beneficial effect of NAC is knowledge of whether NAC can alter the serum level of
creatinine independent of a change in GFR. NAC has been reported to decrease serum creatinine levels in
subjects with normal kidney function. This reduction in serum creatinine was not accompanied by a change
in serum cystatin C levels. This suggests an effect independent of a change in GFR, such as an increase in
tubular secretion of creatinine or a decrease in creatinine production (1). In clinical practice, NAC is most
often recommended for patients with impaired kidney function scheduled to receive iodinated contrast
media. It therefore is important to test whether NAC can have a similar effect, independent of change in
GFR, in individuals with impaired kidney function. If so, it is possible that NAC provides no renoprotection
and its use for prophylaxis of contrast-induced nephropathy (CIN) should be reexamined.
Few studies have addressed the effect of NAC on serum creatinine independent of a change in GFR.
Izzedine et al. studied the effect of NAC on serum creatinine in vitro to exclude a potential analytical
interaction between them (2). In the range of NAC concentration between 102 and 600 mg/L, no analytical
interference with the measurement of serum creatinine by any of the commonly used analytic reactions was
observed. The peak serum concentration of NAC after a 600-mg oral dose was estimated to be 465 mg/L.
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However, with very high level of NAC (50 g/L), the serum creatinine decreases by 50%.
Hoffmann et al. studied the effect of NAC in vivo (1). In this study, 50 healthy volunteers with normal renal
function received 600 mg of oral NAC twice a day for a total of four doses. This study suggested a small
but significant effect of NAC on serum creatinine independent of GFR, as reflected by the unchanged
cystatin C. A number of clinical observations has shown that cystatin C is a more sensitive marker than
creatinine for the estimation of GFR (3). The Hoffmann et al. data are difficult to apply to clinical practice,
as patients who are likely to receive NAC are not those with normal kidney function. Haase et al. (4) also
studied 30 patients with normal kidney function who received intravenous NAC for 24 h in association with
cardiac surgery. No change in the ratio of serum creatinine to cystatin C was observed at the end of the 24 h
infusion or 48 h after the cessation of the infusion compared with baseline values. In addition, there was no
effect on urinary creatinine excretion during the infusion (4). However, in clinical practice, NAC is
generally recommended for patients with chronic kidney disease as reflected in a GFR of less than 60
ml/min per 1.73 m2. Mainra et al. (5) studied 30 patients with stage 3 chronic kidney disease and
administered a single 600 mg dose of NAC. They observed no change in serum creatinine or cystatin C at 4,
24, or 48 h after the dose (5). While this study does not support the Hoffmann et al. observation, it may be
relevant that only a single dose was administered.
Materials and Methods
Patients
A total of 30 patients, age 18 to 89 yr, with chronic kidney disease (estimated GFR (eGFR) <60 ml/min per
1.73 m2) and a less than 10% difference between the baseline creatinine and the average creatinine values
from the previous 6 mo were prospectively enrolled from the kidney clinic of a tertiary care hospital
between May 2007 and December 2007. The study was approved by Institutional Review Board at the
University of Vermont, and all patients gave written informed consent. Demographic information recorded
at baseline included age, gender, serum creatinine, eGFR calculated by the 4-variable Modification of Diet
in Renal Disease study equation, and cystatin C. Subjects were excluded if they were unable to give
informed written consent or unwilling to return for follow-up blood samples, or developed any condition,
which in the judgment of one of the investigators might lead to unstable renal function during the trial.
Additionally, they were excluded if they were taking any medications that could interfere with tubular
secretion or production of creatinine including gemfibrozil, fenofibrate, trimethoprim, sulfasoxasole,
cimetadine, and ranitidine.
Protocol
The design of the protocol was to compare changes in serum creatinine after 4 doses of NAC to baseline
values. Serum creatinine and cystatin C were measured in the same blood sample before the first dose of
NAC (baseline) and at 4 h and 48 h after taking the last dose of NAC. We used cystatin C and serum
creatinine as markers of GFR, rather than 24-h collections for calculation of creatinine clearance. NAC, as
a liquid solution, was taken orally as 1200 mg every 12 h for four doses. Compliance with the medication
was confirmed verbally.
Serum creatinine was measured using an enzymatic dry slide method (Ortho-Clinical Diagnostics,
Rochester, NY). Serum cystatin C was measured using the BNII nephelometer (Dade Behring, Deerfield,
IL) using a particle-enhanced immunonepholometric assay (N Latex cystatin C). The same method was
used for all patients.
Outcome Measures
The primary outcome was the change in serum creatinine at 4 h after the last dose of NAC compared with
the baseline serum creatinine. This time point was identical to the time at which Hoffmann et al. (1) found a
significant decrease in serum creatinine. Secondary outcomes included the change in serum creatinine at 48
h following the last dose and changes in cystatin C and the ratio of creatinine to cystatin C at 4 and 48 h
after the last dose of NAC.
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Statistical Analysis
Paired t tests were used to analyze 4 h and 48 h changes in serum creatinine, cystatin C, and the ratio of
serum creatinine to cystatin C compared with baseline values.
Results
Thirty patients started the trial. One patient was dropped because of incomplete data. For the remaining 29
patients, the baseline demographic characteristics are reported in Table 1. Our patients were typical of
patients with stage 3 to 5 chronic kidney disease with a mean age of 65 yr. The primary cause of chronic
kidney disease was diabetes and hypertension in 38% and 41% of patients, respectively. Subject in stage 3
and 4 CKD were equally represented and the average eGFR was 32 ml/min per 1.73 m2.
Serum creatinine and cystatin C levels did not change significantly at either 4 h or 48 h following the last
dose of NAC compared with the baseline values (Table 2; Figures 1 and 2). However, a small but
statistically significant reduction in the ratio of serum creatinine to cystatin C was observed at 4 h but not
48 h.
Discussion
NAC is a modified form of L-cysteine, an amino acid that is a precursor to reduced glutathione. It is known
to be a potent antioxidant that scavenges oxygen-free radicals in the body. It also has vasodilatory
properties derived from enhanced nitric oxide availability (6). NAC was introduced to clinical use in 1960s
as a mucolytic agent in pulmonary diseases including cystic fibrosis (7). More recently, NAC has been used
to prevent acute kidney injury following the administration of iodinated contrast media (CIN). CIN is
typically defined as either an absolute (44 umol/L) or relative (25%) increase in serum creatinine within
48 to 72 h of contrast media exposure. CIN occurs following intravenous and intra-arterial administration of
contrast and is associated with both in-hospital and long-term adverse events. Because exposure to contrast
media is predictable, CIN prevention is a logical target of many innovative therapeutic interventions.
Tepel et al. was the first to report that NAC reduced the incidence of CIN in patients undergoing contrastenhanced computed tomography scanning (8). The promising results of this study led to widespread use of
NAC to prevent CIN, particularly following intra-arterial administration of CM. Since that seminal study,
additional single-center studies have been conducted with mixed results. Additionally, a number of
meta-analyses did not uniformly support the efficacy of NAC (9). The dose of NAC used in most of these
studies was 600 mg orally twice a day for 2 days (total dose 2400 mg) similar to that reported by Tepel et
al. (8).
More recent studies have compared higher doses (1200 mg for four doses) to this standard dose. This
double-dose NAC was shown to be more efficacious in preventing CIN than the standard dose (10,11).
These observations call our attention to the unique aspects of NAC pharmacology, including its low
bioavailability (1214), extensive first pass metabolism (15), and possible dose-dependent antioxidant
characteristics (16).
Some CIN prevention trials have reported a decrease in serum creatinine in the group randomized to NAC
compared with the control arm. These observations have fueled the speculation regarding an artifactual
effect of NAC on serum creatinine. However, these clinical trial observations may be confounded by the
administration of large amounts of intravenous fluids as part of the prophylaxis strategy. This explanation,
however, is inadequate to explain all of the trial results. For example, Tepel et al. (8) observed a 36-mol/L
decrease in serum creatinine in the NAC arm compared with an 18-mol/L increase in serum creatinine in
the control arm given the same amount of fluid (8). Briguori et al. reported a 5-mol/L decrease in serum
creatinine in patients given 600 mg by 4 doses and a 13-mol/L decrease in patients given 1200 by 4 doses
(10). Both groups received the same intravenous fluid challenge. These results suggest that the combination
of NAC and intravenous saline might result in a greater increase in GFR than intravenous saline alone. By
contrast, the administration of 1200 mg of NAC in two divided doses together with 1 ml/kg per hour of
0.9% saline over a 24-h period did not alter serum creatinine in patients with chronic kidney disease before
coronary angiography (17).
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The efficacy of NAC for prevention of CIN remains controversial despite the large number of prospective
randomized clinical trials. Critical to the analyses of the clinical trial data are whether NAC can alter serum
creatinine, the most widely used marker of acute kidney injury, independent of a change in GFR. Creatinine
is endogenously produced from the nonenzymatic metabolism of creatine primarily in skeletal muscle. It is
freely filtered at the glomerulus and also secreted in the proximal tubules by the organic cation transport
system. An effect of NAC either on creatinine production or tubular secretion could alter serum levels
without a corresponding change in GFR.
An effect of NAC on creatine kinase, the enzyme that reversibly phosphorylates creatine, has been reported
in animals subjected to oxidative stress (18). Oxidative stress resulted in inhibition of creatine kinase
favoring the nonenzymatic conversion of creatine to creatinine (19). The inhibition of creatine kinase by
reactive oxygen species is reversed by NAC, theoretically reducing the generation of creatinine under these
conditions. Whether such an effect occurs in humans or in the absence of oxidative stress is unknown.
Contrast media administration is associated with an increase in urinary markers of oxidative stress (20) and
can induce oxidative stress, inhibited by NAC, in proximal tubule cells (Briguori C, personal
communication). Whether contrast media causes oxidative stress in skeletal muscle is speculative.
An effect of NAC on tubular secretion could also affect serum creatinine levels. Many pharmacologic
agents are known to interfere with tubular secretion of creatinine leading to an increase in serum creatinine
levels independent of a change in GFR. One way to look for such an effect is to compare change in serum
creatinine with another GFR marker that does not undergo tubular secretion. One such marker is cystatin C,
a small peptide produced constitutively by nucleated cells (21). It is eliminated through glomerular filtration
and does not undergo tubular secretion (22). Many studies suggest that cystatin C is a more accurate marker
of GFR for this reason. A change in serum creatinine in the absence of a change in cystatin C would
support the hypothesis that NAC stimulates tubular secretion of creatinine.
In our study, we enrolled patients with chronic kidney disease (stage 3 to 5) and assessed the effects of
NAC on renal function in the absence of CM, using two surrogate markers of GFR, serum creatinine and
cystatin C. These markers were measured simultaneously before and 4 h and 48 h after four 1200 mg doses
(4800 mg total dose) of NAC given at 12-h intervals over 48 h.
Our study found that neither serum creatinine nor cystatin C was altered by administration of
double-dose NAC to patients with chronic kidney disease and moderate to severe decreases in GFR. A
small, statistically significant decrease in the ratio of serum creatinine to cystatin C was observed at 4 h but
not 48 h. It is unclear whether this small change has any clinical or physiologic significance. Although our
results support the observations reported by Mainra, they do not completely refute the observations of
Hoffmann et al. (1). Despite using significantly higher doses of NAC compared with Mainra et al. (5) (4800
mg versus 600 mg total dose), we found no change in serum creatinine levels suggesting that tubular
secretion of creatinine was not affected. However, the lack of a stimulatory effect on tubular secretion of
creatinine might reflect the fact that maximum levels of tubular secretion existed before NAC dosing in
these patients with well-established chronic renal insufficiency. Tubular secretion of creatinine is known to
increase as the level of serum creatinine increases until a transport maximum is reached (23,24). The serum
creatinine at which the transport maximum occurs is unknown and may differ between normal kidneys and
diseased kidneys. The Hoffmann et al. (1) patients had a serum creatinine of 88 mol/L and presumably
normal kidneys. Under these conditions, tubular secretion of creatinine was probably not at its maximum.
An alternative explanation for the lack of effect of NAC on serum creatinine in our study might be that the
dose of NAC used was insufficient to stimulate tubular secretion in these diseased kidneys. Nevertheless,
we think that any effect of NAC on serum creatinine seen in clinical trials of CIN prophylaxis is likely to
represent a true change in GFR.
Limitations
Our study has several limitations. The sample size is small, raising the possibility of a type II error. Our
patients were not undergoing oxidative stress as might occur during contrast media administration. If NAC
reduces creatinine generation by protecting the activity of creatine kinase during oxidative stress as
suggested by others, our study protocol would not have been adequate to explore this effect. Our patient
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population is 99% white limiting the generalizability of these observations to other ethnic groups.
Conclusion
Our study did not find any change in serum creatinine after administration of double-dose NAC in
patients with moderate to severe renal impairment either 4 h or 48 h after the last dose. We did not find any
changes in cystatin C levels during these same time periods. We conclude that changes in serum creatinine
seen in CIN prophylaxis clinical trials are likely related to changes in GFR and not confounded by effects of
NAC independent of GFR.
Disclosures.
None.
Acknowledgments
The authors thank Elaine Gay who provided the clinical research support that enabled this study to be
completed. This study was supported by a grant from FlowMedica (Fremont, California).
Notes
Published online ahead of print. Publication date available at www.cjasn.org.
References
1. Hoffmann U, Fischereder M, Kruger B, Drobnick W, Kramer BK: The value of N-acetylcysteine in the
prevention of radiocontrast agent-induced nephropathy seems questionable. J Am Soc Nephrol 15:
407410, 2004. [PubMed: 14747387]
2. Izzedine H, Guerin V, Launay-Vacher V, Bernad M, Deray G: Effect of N-acetylcysteine on serum
creatinine level. Nephrol Dial Transplant 16: 15141515, 2001. [PubMed: 11427659]
3. Dharnidharka VR, Kwon C, Stevens G: Serum cystatin C is superior to serum creatinine as a marker of
kidney function: a meta-analysis. Am J Kidney Dis 40: 221225, 2002. [PubMed: 12148093]
4. Hasse M, Hasse-Fielitz A, Ratnaike S, Reade MC, Bagshaw SM, Morgera S, Dragun D, Bellomo R:
N-acetylcysteine does not artifactually lower plasma creatinine concentration. Nephrol Dial Transplant 23:
15811587, 2008. [PubMed: 18202091]
5. Mainra R, Gallo K, Moist L: Effect of N-acetylcysteine on renal function in patients with chronic kidney
disease. Nephrology 12: 510513, 2007. [PubMed: 17803476]
6. Efrati S, Dishy V, Averbukh M, Blatt A, Krakover R, Weisgartern J, Morrow JD, Stein MC, Golik A: The
effect of N-acetylcysteine on renal function, nitric oxide, and oxidative stress after angiography. Kidney Int
64: 21822187, 2003. [PubMed: 14633141]
7. Sheffner A: The mucolytic action of acetylcysteine. Tuberculol Thorac Dis 23: 3133, 1966.
[PubMed: 5934348]
8. Tepel M, Van Der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W: Prevention of radiographiccontrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 343: 180184, 2000.
[PubMed: 10900277]
9. Gonzales D, Norsworthy KJ, Kern SJ, Banks S, Sieving PC, Star RA, Natanson C, Danner RL: A
meta-analysis of N-acetylcysteine in contrast-induced nephrotoxicity: unsupervised clustering to resolve
heterogeneity. BMC Med 5: 3245, 2007. [PMCID: PMC2200657] [PubMed: 18001477]
10. Briguori C, Columbo A, Violante A, Balestrieri P, Golia B, Scarpato P, Elia P, Lepore S, Ricciardelli B:
Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart
J 25: 206211, 2004. [PubMed: 14972420]
11. Marenzi G, Assanelli E, Marana I, Lauri G, Campodonico J, Grazi M, De Metrio M, Galli S, Fabbiocchi
27-09-2014 22:24
6 of 10
F, Montorsi P, Veglia F, Bartorelli A: N-Acetylcysteine and contrast-induced nephropathy in primary

angioplasty. N Engl J Med 354: 27732782, 2006. [PubMed: 16807414]
12. Olsson B, Johansson M, Gabrielsson J, Bolme P: Pharmacokinetics and bioavailability of reduced and
oxidized N-acetylcysteine. Eur J Clin Pharmacol 34: 7782, 1988. [PubMed: 3360052]
13. Moldeus P, Cotgreave IA: N-acetylcysteine. Methods Enzymol 234: 482492, 1994.
[PubMed: 7808322]
14. Borgstrom L, Kagedal B, Paulsen O: Pharmacokinetics of N-acetylcysteine in man. Eur J Clin
Pharmacol 31: 217222, 1986. [PubMed: 3803419]
15. Sjodin K, Nilsson E, Hallberg A, Tunek A: Metabolism of N-acety-L-cysteine: some structural
requirements for the deacetylation and consequences for the oral bioavailability. Biochem Pharmacol 38:
39813985, 1989. [PubMed: 2597179]
16. Cotgrease I, Moldeus P, Schuppe I: The metabolism of N-acetylcysteine by human endothelial cell.
Biochem Pharmacol 42: 1316, 1991. [PubMed: 2069586]
17. Hussain A, Day A, Pilkey R, Yeates KE: N-acetylcysteine (NAC) does not acutely alter serum
creatinine levels in patients with chronic kidney disease prior to coronary angiography [Abstract]. J Am Soc
Nephrol 15: 348A, 2004.
18. Genet S, Kale RK, Baquer NA: Effects of free radicals on cytosolic creatine kinase activities and
protection by antioxidant enzymes and sulfhydryl compounds. Mol Cell Biochem 210: 2328, 2000.
[PubMed: 10976754]
19. Wyss M, Kaddurah-Daouk R: Creatine and creatinine metabolism. Physiol Rev 3: 11081213, 2000
20. Bakris G, Lass N, Gaber AO, Jones JD, Burnett JC Jr: Radiocontrast medium-induced declines in renal
function: a role for oxygen free radicals. Am J Physiol 258: F115F120, 1990. [PubMed: 2301588]
21. Abrahamson M, Olafason I, Palsdottir A, Ulvsback M, Lundwall A, Jensson O, Grubb A: Structure and
expression of the human cystatin C gene. Biochem J 268: 287294, 1990. [PMCID: PMC1131430]
[PubMed: 2363674]
22. Tenstad O, Roald AB, Grubb A, Aukland K: Renal handling of radiolabelled human cystatin C in the
rat. Scand J Clin Lab Invest 56: 409414, 1996. [PubMed: 8869663]
23. Hatano M: Clinical study of tubular creatinine secretion in renal dysfunction. Nippon Jinzo Gakkai Shi
11: 10971104, 1991
24. Herrera J, Rodriquez-Iturbe B: Stimulation of tubular secretion of creatinine in health and in conditions
associated with reduced nephron mass: evidence for tubular functional reserve. Nephrol Dial Transplant 3:
623629, 1998
Figures and Tables
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Figure 1.
Serum creatinine values at time 0 (baseline) and 4 h and 48 h after the last dose of N-acetylcysteine in each of the 29
subjects.
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Figure 2.
Serum cystatin C values at time 0 (baseline) and 4 h and 48 h after the last dose of N-acetylcysteine in each of the 29
subjects.
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Table 1.
Baseline characteristics of study patients

Characteristic
Age (yr) (mean SD)
Value
65.3 11.7
Male (%)
59
Female (%)
41
Baseline serum creatinine (mg/dl) (mean SD)
2.05 0.70
Baseline estimate glomerular filtration rate (MDRD) (mean SD)
32.3 9.8
Stage 3 CKD (%)
48
Stage 4 CKD (%)
48
Stage 5 CKD (%)
Cause of CKD
diabetic nephropathy (%)
38
hypertension (%)
41
miscellaneous (%)
21
CKD, chronic kidney disease.
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Table 2.
Study results at each time point

Time 0
Time 4 h after Last Dose of
Time 48 h after Last Dose of
(baseline)
NAC
NAC
Serum creatinine (mg/dl)
2.06 0.69
2.02 0.70
2.07 0.75
Cystatin C (mg/L)
1.73 0.66
1.76 0.62
1.77 0.65
Metric
Ratio serum creatinine/cystatin
1.22 0.24
1.17 0.21
1.20 0.28
C
aP
= 0.0295 by paired t test versus time 0.
Articles from Clinical Journal of the American Society of Nephrology : CJASN are provided here courtesy of American
Society of Nephrology
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Clin J Am Soc Nephrol. Nov 2008; 3(6): 16101614.