ORIGINAL ARTICLE

JNEPHROL 2010; 23 ( 04 ) : 478-482

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The efficacy of n-acetylcysteine in preventing contrast-induced nephropathy in type 2 diabetic patients without nephropathy
Fuat Sar 1, Tayyibe Saler 1, Alphan Ecebay 1, Zuhal A. Saglam 1, Savas Ozturk 2, Rumeyza Kazancioglu 2 Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul - Turkey 2 Department of Nephrology, Haseki Training and Research Hospital, Istanbul - Turkey
1
Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul - Turkey Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul - Turkey Department of Internal Medicine, Haseki Training and Research Hospital, Istanbul - Turkey Department of Nephrology, Haseki Training and Research Hospital, Istanbul - Turkey

AbstrAct
Background: N-acetylcysteine (NAC) is reported to have potential for prevention of contrast-induced nephropathy(CIN), however, there is not enough data related to its effects on diabetic patients without nephropathy. Methods: A total of 45 diabetic patients without nephropathy undergoing a computerized tomography (CT) investigation and who would be receiving radio-opaque medication (300 mg iohexaol/100 mL) were enrolled. They were randomized to have either high-dose NAC (1200 mg) plus saline hydration (Group 1, n=25) or only saline hydration (Group 2; n=20). Serum creatinine levels were determined 72 hours post-contrast. CIN was defined as 0.3 mg/dL elevation of creatinine from baseline and/or an increment of 20% over baseline creatinine and/or 20% decrement of estimated GFR. Results: In Group 1, serum creatinine decreased from 0.83 to 0.79 mg/dL, whereas serum creatinine increased from 0.81 to 0.94mg/dL in Group 2 (not significant for both groups). However there was a significant difference between the creatinine variation of two groups (p=0.031). Furthermore, the groups were analyzed according to overall incidence of CIN. The increase of serum creatinine and decrement of estimated GFR in Group 2 were significantly higher than in Group 1. Conclusion: Adding NAC to saline hydration seems more beneficial than saline hydration alone in preventing contrast-induced renal function deterioration in type 2 diabetic patients without nephropathy. Key words: Contrast media, Nephropathy, N-acetyl-

IntroductIon
High glucose concentrations can lead to various changes through glucose auto-oxidation, generation of superoxide radicals and production of advanced glycation end products (AGEs). The resulting oxidative stress and decrement in the antioxidant capacity are held responsible for the development of diabetic vascular complications (1-3). As can be anticipated, diabetes mellitus on its own is a risk factor for nephropathy. As the third leading cause of hospital-acquired acute renal failure, contrast induced nephropathy (CIN) is an important health problem. While the incidence depends on the severity of the risk factors of the patient, it may be prevented by several precautions. Contrast induced nephropathy is defined as an acute deterioration in renal function (>%20-50 or 0.3 mg/dL increase from baseline in serum creatinine levels) following (24-72 h) exposure to contrast media (4, 5). While the incidence of CIN is below 1% in patients with normal renal function, it is demonstrated that it accounts for more than 50 percent of all episodes of acute renal failure in high-risk patients (6, 7). As previously mentioned, CIN is one of the major causes of acute renal injury among inpatients; therefore preventive measures for CIN are crucial (8). Some preventive strategies like saline hydration, administration of N-acetylcysteine (NAC), calcium channel blockers, teophylline, mannitol or hemodialysis are also recommended. Considering the role of oxidative stress in the progression of CIN, NAC may be expected to be effective in preventing CIN in most patient populations. However, previous studies mostly report the importance of NAC in

cystein, Diabetes mellitus

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2010 Societ Italiana di Nefrologia - ISSN 1121-8428

JNEPHROL 2010; 23 ( 04 ) : 478-482

preventing CIN only at high- risk patients and there is a lack of studies including low-risk patients for CIN. This study aimed to analyze the incidence of CIN in type 2 diabetic patients without obvious nephropathy and the efficacy of NAC in preventing CIN compared to saline hydration in this patient population.

Methods
This study was a prospective open-label, parallel group study. The local ethics committee approved the study protocol. Informed consent was obtained from each patient. Forty-five type 2 diabetic patients with normal renal functions (mean serum creatinine <1.2 mg/dL, 24-h urinary protein level <150 mg/d and creatinine clearance >60 mL/ min) who were scheduled for elective radiological investigation requiring intravenous contrast media administration for abdominal computerized tomography (CT) were eligible for the study. Exclusion criteria: 1. Body mass index lower than 21 or greater than 30 kg/m2; 2. Patients with concomitant systemic diseases, i.e., heart failure, substantial edema, uncontrolled hypertension, hypoalbuminemia (serum albumin level <3.5 g/dL), or ascites due to chronic liver disease; 3. Patients who have had any nephrotoxic agents (i.e., nonsteroidal anti-inflammatory drugs, aminoglycoside or intravenous contrast agent) or drugs affecting the renin angiotensin aldosterone system within the last 30 days; 4. Patients who had allergic hypersensitivity or other vasoactive reactions to the contrast agents. The patients were randomly assigned to receive either NAC at the standard dose (1200 mg) along with intravenous saline hydration (Group 1; n=25; M/F=13/12) or only saline hydration (Group 2; n=20; M/F=11/9). The Modification of Diet in Renal Disease (MDRD) formula was also used to estimate glomerular filtration rate (eGFR): (MDRD-GFR (mL/min/1.73 m2) = 186*(serum creatinine)-1.154*(age)-0.203*(0.742 if female)). The pre-procedure mean serum creatinine levels and eGFR were also matched (p=0.068 and 0.376, respectively). As indicated, each patient underwent a CT examination and intravenously received 100 mg of iohexaol (300 mg/ mL). Group 1 was given 1200 mg oral NAC, 1 hour before the contrast application and continued to NAC oral (1200 mg/day) during the following 2 days after the administration of contrast agent along with intravenous saline hydration. Physiological saline (0.9% NaCl) was given intravenously at a rate of 1 mL/kg of body weight per hour for 12 hours before and 24 hours after the procedure.

Group 2 was given only intravenous physiological saline with the same dose and duration. Serum creatinine, urea, albumin, sodium and potassium were measured at the time of admission and 72 hours after the administration of the contrast agent. Volume status of both groups was monitored closely and hydration was found to be satisfactory. CIN was defined as 0.3 mg/dL elevation of creatinine from baseline and/or an increment of 20% over baseline creatinine and/or 20% decrement of eGFR.

Statistical analysis
Baseline characteristics of the study groups were compared using the 2-tailed t-test. Serum creatinine concentrations and eGFRs were compared within and between groups using variance analysis. Difference in incidence of CIN between groups was tested using an x2 test. The overall level of significance was set at 0.05. Data were analyzed with SPSS v10.0 (SPSS Inc, Chicago, IL, USA).

results
Patient demographics, drugs, and pre-contrast and post-contrast laboratory parameters of both groups are given in Table I. Both groups were age matched. Duration of diabetes was also similar in both groups. After the procedure, the mean serum creatinine levels of Group 1 decreased from 0.83 0.15 mg/dL to 0.79 0.21 mg/ dL whereas in Group 2 the mean serum creatinine levels increased from 0.81 0.17 mg/dL to 0.94 0.16 mg/dL, which were insignificant within the both groups (p=0.15 and 0.24, respectively). On the other hand, the change ratio in serum creatinine (post-procedural/ pre-procedural) compared between the both groups was statistically significant (Group 1: 0.95 0.16, Group 2: 1.080.21, p=0.03). Although the eGFR of Group 1 increased and the eGFR of Group 2 decreased after the procedure, these changes were statistically insignificant within the groups. Similarly, the changes were statistically significant between the groups (p=0.021) (Fig. 1). According to the other definition of CIN, which is expressed as an increase of 0.3 mg/dL from baseline in serum creatinine levels, there was no increase of serum creatinine in Group 1. There was an increase in serum creatinine in 3 patients in Group 2. When the blood urea levels of both groups were assessed before and after procedure, there was no significant difference. The dif479

Sar et al: NAC for prevention of nephropathy in diabetics

TABLE I DEMOGRAPHIC AND BIOCHEMICAL DATA OF THE GROUPS Group 1 (n:25) Age Gender (male/female) Duration of diabetes (years) Urea (mg/dL) Pre-contrast Post-contrast Pre-contrast Serum albumin level (g/dL) Post-contrast Pre-contrast Creatinine (mg/dL) Post-contrast Pre-contrast Estimated GFR (mL/min) Post-contrast Insulin Metformin or other oral antidiabetics Medications ASA Beta-blockers Diuretics Statins
NS = not significant.

Group 2 (no:20) 53.59.9 11/9 5.92.6 35.47.7 39.38.0 3.90.1 3.90.1 0.81 0.17 0.94 0.16 97.828.6 90.825.0 None 18 12 1 None 15

P value 0.07 0.33 0.34 0.23 0.44 0.36 0.54 0.15 0.24 0.39 0.21

60.011.3 13/12 6.73.1 38.25.2 37.36.4 4.00.1 3.90.1 0.83 0.15 0.790.21 90.925.1 99.435.7 None 22 10 3 None 18

NS

ference in changes of blood urea, sodium and potassium levels were not significant either.

dIscussIon
We observed that, by lowering serum creatinine levels, NAC provides a significant benefit in preventing CIN in diabetic patients without nephropathy following contrast media administration. Similarly, in an animal model Pinto et al (9) showed that the combination of hyperhydration and NAC had no superior protective effect compared with NAC administered alone. However, in the literature, this preventive effect was observed in patients with serum creatinine above normal levels. In one study, Tadros et al (10) administered prophylactic NAC in addition to saline hydration to patients with serum creatinine >1.2 mg/dL and reported that the best preventive effect was observed in patients with serum creatinine >2 mg/dL. In another study by Tepel et al (11), among the 83 patients included, the incidence of CIN was 2% in the patients re-

Fig. 1 - Variation of eGFR of the groups according to the study procedure. eGFR of Group 1 increased and eGFR of Group 2 decreased after the procedure. These changes were statistically insignificant within the groups but significant between the groups (p=0.021).

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JNEPHROL 2010; 23 ( 04 ) : 478-482

ceiving NAC, and 21% in patients who did not. The suggested explanation was that NAC reduced the incidence of CIN markedly in patients at high risk. In a meta-analysis in which 8 studies were analyzed, adding 400 mg to 600 mg of NAC to saline hydration before and on the day of contrast media administration reduced CIN progression by 56% compared to saline hydration prophylaxis alone in patients with chronic renal insufficiency (12). On the other hand, Boccalandro et al (13) demonstrated 12% CIN in patients with chronic renal disease receiving NAC plus saline hydration and 13% CIN in patients receiving only saline hydration. This result suggested that administration of NAC did not provide better protection against CIN than the saline hydration does alone in patients with chronic renal disease. Briguori et al (14) dwelled on the dosage of the contrast media administered and suggested that NAC would be renoprotective only if the amount of contrast media was below 140 mL. In another study, 110 patients with basal creatinine >1.2 mg/dL were given NAC along with prophylactic hydration. As a result, the renoprotective effect of NAC was observed mostly in patients with basal serum creatinine > 2 mg/dL (10). In a study by Baker et al (15) patients were prospectively randomized to either a rapid protocol of i.v. NAC or only i.v. hydration. The overall incidence of CIN was lower in the first group. In another study, standard versus double dose of NAC (600 mg vs. 1200 mg) in patients with chronic renal failure and reported that 1200 mg twice daily NAC was shown to be more effective in preventing CIN than 600 mg twice daily (16). Since oxidative stress is one of the key features both in diabetes mellitus and CIN, NAC would be expected to show a renoprotective effect through its antioxidant properties. Consequently, when added to hydration it should provide more protection against CIN than only hydration alone in diabetic patients with normal renal function. The present study demonstrated a renoprotective effect when NAC was used along with hydration in the patient group presented above. There was a reduction in mean serum creatinine levels in patients receiving NAC + hydration while in the other group receiving only hydration the serum creatinine levels increased. The differences were not significant but evident. Furthermore, when the mean serum creatinine and eGFR levels of both groups after the procedure were compared, the result was statistically significant. This study has some limitations. The patient number of the groups was low. The results of the statistical analysis and the beneficial effect of NAC would be more strik-

ing in large groups of patients fulfilling the study criteria. Moreover, we cannot provide the real delivered amount of saline in each group, which could strengthen our observation regarding the protective effect of NAC by ruling out any confounding factor related to the volume infusion. In any case, in a metaanalysis where the most recent data available from prospective, randomized, controlled trials about CIN was evaluated, Reddan et al (17) reported that a more a standardized definition of CIN, appropriate timing of SCr measurements, volume expansion protocols and pharmacologic prophylactic strategies should be defined for future studies regarding the prevention of CIN. Still, the mean serum creatinine and eGFR values of both groups indicate a beneficial effect of NAC following contrast media administration. This outcome also emphasizes the fact that diabetes mellitus is a disorder causing oxidative stress and it is highly probable that NAC displays a preventive effect against CIN through its antioxidant properties. Moreover, this outcome also demonstrates that NAC may provide a beneficial effect and be better used against CIN in patients without any risk factor other than diabetes. It is evident that possible beneficial effects of prophylactic NAC administration against other systemic disorders causing oxidative stress may be demonstrated with additional large studies as well as chronic disorders like diabetic nephropathy.

Financial support: None.

Conflict of interest statement: None declared.

Address for correspondence: Savas Ozturk, MD Haseki Egitim ve Arastirma Hastanesi Nefroloji Servisi Haseki/Fatih Istanbul, Turkey savasozturkdr@yahoo.com 481

Sar et al: NAC for prevention of nephropathy in diabetics

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Received: July 08, 2009 Revised: October 02, 2009 Accepted: October 13, 2009

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