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(Circulation. 2004;110:2837-2842.)
© 2004 American Heart Association, Inc.

Coronary Heart Disease

Ascorbic Acid Prevents Contrast-Mediated Nephropathy in Patients With Renal Dysfunction Undergoing Coronary Angiography or Intervention

Konstantinos Spargias, MD; Elias Alexopoulos, MD; Stamatis Kyrzopoulos, MD; Panayiotis Iacovis, MD; Darren C. Greenwood, MSc; Athanassios Manginas, MD; Vassilis Voudris, MD; Gregory Pavlides, MD; Christopher E. Buller, MD; Dimitrios Kremastinos, MD; Dennis V. Cokkinos, MD

From the Department of Cardiology (K.S., E.A., S.K., P.I., A.M., V.V., G.P., D.K., D.V.C.), Onassis Cardiac Surgery Centre, Athens, Greece; the Biostatistics Unit and Nutrition Epidemiology Group (D.C.G.), University of Leeds, Leeds, UK; and the Division of Cardiology (C.E.B.), University of British Columbia, Vancouver, Canada.

Reprint requests to Dr K.S. Spargias, Onassis Cardiac Surgery Centre, 356 Syngrou Ave, 176 74, Athens, Greece. E-mail spargias{at}ocsc.gr

Received February 19, 2004; de novo received May 5, 2004; revision received June 30, 2004; accepted July 1, 2004.

	Abstract

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Background— Contrast agents can cause a reduction in renal function that may be due to the generation of reactive oxygen species. Conflicting evidence suggests that administration of the antioxidant acetylcysteine prevents this renal impairment. The action of other antioxidant agents has not been investigated.

Methods and Results— We conducted a randomized, double-blind, placebo-controlled trial of ascorbic acid in 231 patients with a serum creatinine concentration 1.2 mg/dL who underwent coronary angiography and/or intervention. Ascorbic acid, 3 g at least 2 hours before the procedure and 2 g in the night and the morning after the procedure, or placebo was administered orally. Contrast-mediated nephropathy was defined by an absolute increase of serum creatinine 0.5 mg/dL or a relative increase of 25% measured 2 to 5 days after the procedure. Contrast-mediated nephropathy occurred in 11 of the 118 patients (9%) in the ascorbic acid group and in 23 of the 113 patients (20%) in the placebo group (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.17 to 0.85; P=0.02). The mean serum creatinine concentration increased significantly in the placebo group (from 1.36±0.50 to 1.50±0.54 mg/dL, P<0.001) and nonsignificantly in the ascorbic acid group (from 1.46±0.52 to 1.52±0.64 mg/dL, P=0.07). The mean increase in serum creatinine concentration was greater in the placebo group than in the ascorbic acid group (difference of 0.09 mg/dL; 95% CI, 0.00 to 0.17; P=0.049).

Conclusions— Prophylactic oral administration of ascorbic acid may protect against contrast-mediated nephropathy in high-risk patients undergoing a coronary procedure.

Key Words: contrast media • kidney • angiography • angioplasty • antioxidants

	Introduction

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Acute deterioration in renal function caused by radiographic contrast agents is generally mild and transient but can result in lasting renal dysfunction and the need for renal replacement therapy and is the third leading cause of new-onset renal failure in hospitalized patients.¹ Moreover, contrast-mediated nephropathy (CMN) has been associated with increased in-hospital and long-term morbidity, mortality, and extended hospitalization.^2–7 Commonly used definitions of CMN include (1) an absolute increase in the serum creatinine concentration of at least 0.5 mg/dL and (2) a relative increase of at least 25% from the baseline value.⁸ The incidence of CMN in the general patient population undergoing coronary angiography is low and has been estimated to be <2%.⁹ However, patients with preexisting renal impairment and diabetes mellitus are at substantially greater risk of developing CMN, in the range of 20% to 80%.^2,5,7,8 Other factors may also contribute to risk, including volume depletion, the volume and osmolality of the contrast agent used, and congestive heart failure.¹⁰

Although the precise insult underlying CMN is uncertain, it has been speculated that it occurs because of the vulnerability of the renal medullary circulation to stimuli that disrupt the balance between the high metabolic needs of its tubular segments and their hypoxic environment.¹¹ Adequate medullary blood flow is normally maintained by the interplay of vasodilator and vasoconstrictor influences, mediated by local nitric oxide, prostaglandin, adenosine, and endothelin systems within the medulla.¹¹ Infusion of radiographic contrast agents, with the attendant increases in osmotic load and viscosity, increases the hypoxia of the renal medulla and increases renal free-radical production through postischemic oxidative stress.^11–13

Several interventions for the prevention of CMN have been tested in clinical trials. At present, only hydration and use of iso-osmolar contrast agents have shown consistent benefit.^4,14–16 Recent studies have produced conflicting results regarding the efficacy of the antioxidant acetylcysteine.^17–25 The antioxidant ascorbic acid has been shown to attenuate renal damage caused by a variety of insults, such as postischemic stress, cisplatin, aminoglycosides, and potassium bromate in animals and has an extensive safety record as a dietary supplement in humans.^26–29 We undertook a randomized, placebo-controlled trial of ascorbic acid for prevention of CMN in patients with impaired renal function undergoing an invasive coronary procedure.

	Methods

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Patients
Patients undergoing clinically driven, nonemergent coronary angiography or intervention in our institution were eligible for inclusion if their serum creatinine concentration was 1.2 mg/dL (106 µmol/L) on their most recent sample drawn within 3 months of the planned procedure. Patients were excluded for any of the following reasons: known acute renal failure, end-stage renal disease requiring dialysis, intravascular administration of contrast medium within the previous 6 days, anticipated readministration of contrast medium within the following 6 days, use of vitamin C supplements on a daily basis during the week before the procedure, or inability to administer the study medication at least 2 hours before the procedure. The institutional research ethics committee approved the study protocol, and all patients gave written, informed consent before inclusion.

Study Protocol
The patients were randomly assigned to receive either 3 g of ascorbic acid supplied in chewable tablets or placebo at least 2 hours before the start of the index procedure, followed by 2 g of ascorbic acid or placebo the night and the morning after the procedure. Randomization was performed locally in blocks of 10 by means of sealed boxes. A Research Fellow not involved in the procedure was designated for preparation of the study drugs and random assignment of treatment. Hydration with 50 to 125 mL/h IV normal saline was started in all patients from randomization until at least 6 hours after the procedure. The variation of the hydration rate allowed for adjustments according to the left ventricular ejection fraction and the presence of clinical heart failure in individual patients. Hospital procedures require accurate hourly recording of all in-hospital volume inputs in patients undergoing percutaneous coronary interventions. All patients were encouraged to drink if they were thirsty. The choice of the type of contrast agent was left to the interventional cardiologist performing the procedure, but use of a nonionic, low- or iso-osmolar contrast agent was encouraged.

Baseline serum creatinine concentration was measured from a blood sample drawn at the time of randomization, and the follow-up serum creatinine concentration was measured 2 to 5 days after the procedure. All measurements were performed in a single, hospital-based laboratory with consistent methodology. Baseline and follow-up creatinine clearances were calculated by applying the Cockcroft-Gault formula, with adjustment for female patients.³⁰ CMN was defined as an absolute rise of serum creatinine concentration measured 2 to 5 days after the procedure of at least 0.5 mg/dL or a relative rise of at least 25% from baseline.

Antioxidant Status
The effect of the study drug on the plasma total antioxidant status (Randox Laboratories Ltd) was investigated in the last 20 patients recruited into the study (10 patients in each study arm). Total antioxidant status was determined in blood samples drawn at the time of randomization, at the beginning of the procedure, and during the following morning.

Statistical Methods
Assuming a 21% incidence of the study end point in the control group, we found that a sample size of 220 patients would be required (110 per treatment group) to detect a 70% relative reduction in the incidence of the end point by ascorbic acid with 90% power at the conventional, 2-sided significance level of 5%.

Data are reported as mean±SD for continuous variables and as percentages for discrete variables. Continuous variables were analyzed by the 2-sample independent or paired t test as appropriate, and categorical variables, by the ² or Fisher exact test. Logistic regression was performed with the primary end point of CMN as the dependent variable (binary outcome) and the study treatment assignment as the independent variable. The influence of any baseline imbalances between the study groups was explored by logistic regression adjusting for imbalanced covariate(s). Secondary analyses included comparison of the absolute change in serum creatinine concentration and creatinine clearance among the study groups and of the mean baseline and follow-up creatinine concentration and creatinine clearance within each group. The prespecified analysis was performed on an intention-to-treat basis in those patients in whom both baseline and follow-up serum creatinine measurements were obtained. A sensitivity analysis was performed in which patients lost to follow-up were deemed to have changes in postprocedural renal function that reflected the change seen in the overall study population. All tests were 2-sided, and a significance level of 5% was used. Statistical analyses were performed with SPSS software (version 9.05, SPSS, Inc).

	Results

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Of the 238 patients randomized, 231 completed the study (Figure 1). None developed acute renal failure requiring dialysis. Of the 7 patients who did not return for the follow-up serum creatinine concentration measurement, none was rehospitalized during the immediate postprocedural period for any reason.

View larger version (18K): [in this window] [in a new window]   Figure 1. Flow chart of trial progress.

The baseline clinical, biochemical, and procedural characteristics of the 231 patients are shown in Table 1. The mean volumes and types of contrast agent used and the mean volumes of hydration were similar between the study groups. Patients in the ascorbic acid group were somewhat older.

View this table: [in this window] [in a new window]   TABLE 1. Clinical, Biochemical, and Procedural Characteristics of Study Patients

In the control group, the mean serum creatinine concentration increased from 1.36±0.50 to 1.50±0.54 mg/dL (P<0.001). In the ascorbic acid group, the mean serum creatinine concentration increased from 1.46±0.52 to 1.52±0.64 mg/dL (P=0.07). The mean absolute increase in serum creatinine concentration was significantly greater in the control compared with the ascorbic acid group (difference of 0.09 mg/dL; 95% confidence interval [CI], 0.00 to 0.17; P=0.049; Table 2). In a similar manner, the mean creatinine clearance decreased significantly in the control group but not in the ascorbic acid group (Table 2). The mean absolute decline in creatinine clearance was significantly greater in the control group compared with the ascorbic acid group (difference of 5.4 mL/min; 95% CI, 3.0 to 7.8; P<0.001). Despite the increases in serum creatinine concentrations observed, serum urea concentrations decreased significantly in both study arms the day after the procedure (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Baseline and Follow-Up Creatinine Clearance, Serum Urea, and Creatinine Concentrations; Absolute Changes From Baseline After Administration of Contrast Agent; and Incidence of CMN in the Study Groups

By our definition of CMN, this condition occurred in 34 patients (15%): 11 of the 118 patients (9%) in the ascorbic acid group and 23 of the 113 patients (20%) in the control group (odds ratio [OR], 0.38; 95% CI, 0.17 to 0.85; P=0.02). The results of the logistic regression analysis remained unchanged after adjusting for imbalances in age (OR, 0.36; 95% CI, 0.16 to 0.79; P=0.01), baseline creatinine concentration (OR, 0.40; 95% CI, 0.18 to 0.86; P=0.02), or both (OR, 0.36; 95% CI, 0.16 to 0.79; P=0.01).

In the sensitivity analysis including patients lost to follow-up, CMN occurred in 35 patients (15%): 11 of the 121 patients (9%) in the ascorbic acid group and 24 of the 117 patients (21%) in the placebo group (OR, 0.39; 95% CI, 0.18 to 0.83; P=0.015).

The mean times of follow-up serum creatinine concentration measurement were similar in the study groups: for the ascorbic acid group, 2.36±0.74 days and for the control group, 2.27±0.70 days (P=0.34). A history of diabetes mellitus requiring pharmaceutical treatment was present in 24% of patients either with or without CMN occurrence.

The CMN incidence tended to be higher among patients having their serum creatinine concentration measured on days 3 to 5 compared with day 2 (Figure 2). Table 3 shows the incidence of other commonly used definitions of acute contrast agent–induced reduction in renal function in the study groups.

View larger version (33K): [in this window] [in a new window]   Figure 2. Occurrence of CMN in relation to day of follow-up creatinine concentration measurement. Lighter-color stacks represent patients with CMN. Numbers in stacks represent proportions within overall study population. P=0.07 for comparison of CMN incidence between day 2 and days 3 to 5. Abbreviation is as defined in text.

View this table: [in this window] [in a new window]   TABLE 3. Incidence of Other Commonly Used Definitions of Acute Renal Function Reduction After Administration of Contrast Agent in the Study Groups

The mean absolute change in the total antioxidant status after study drug administration was 0.03±0.09 mmol/L in the ascorbic acid group versus –0.9±0.14 mmol/L in the control group (difference of 0.12 mmol/L; 95% CI, 0.02 to 0.22; P=0.02). Total antioxidant status decreased significantly in the control group on the morning after the procedure (from 1.46±0.11 to 1.36±0.12 mmol/L, P=0.03) but not in the ascorbic acid group (from 1.32±0.09 to 1.30±0.15 mmol/L, P=0.61).

	Discussion

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The key finding of this study is that prophylactic oral administration of the antioxidant ascorbic acid appears to diminish the incidence of CMN in patients with impaired renal function undergoing percutaneous coronary procedures. Concordantly, the absolute increase in serum creatinine concentration and the absolute decrease in creatinine clearance after contrast agent administration were reduced by administration of oral ascorbic acid.

Minor imbalances of baseline characteristics observed between treatment groups are typical of small studies. In the present study, both the mean baseline serum creatinine concentration and age tended to be higher and the baseline creatinine clearance lower in the ascorbic acid group. It has been shown that in patients undergoing cardiac catheterization, there is an exponential increase in the risk for CMN above a threshold baseline serum creatinine concentration of 1.2 mg/dL.³¹ Advancing age has also been associated with an increased incidence of CMN in some studies.^5,31 The imbalances that we observed would be expected to increase the incidence of the primary end point in the ascorbic acid group and therefore, tend to strengthen our overall findings.

We defined CMN as at least a 0.5 mg/dL absolute or a 25% relative increase in the baseline serum creatinine concentration measured 2 to 5 days after the procedure. Though arbitrary, these definitions have been widely used in previous studies of CMN and have been linked to prolonged hospitalization and increased in-hospital and long-term mortality in patients undergoing percutaneous coronary interventions.^3–7

The incidence rates of CMN are, however, sensitive to the definition used. When the definition of at least a 0.5 mg/dL or at least a 25% relative increase in the baseline serum creatinine concentration was applied in previous studies, the incidence of CMN after coronary intervention was found to be 14.5% in unselected patients (mean serum creatinine value of 1.3±0.4 mg/dL) and 37% in patients with a baseline serum creatinine value 1.8 mg/dL.^2,3 When the definition of at least a 0.5 mg/dL absolute serum creatinine increase was applied in previous studies, the incidence of CMN was found to be 2.5% in patients with a baseline serum creatinine value of 1.2 to 1.9 mg/dL and 22.4% in patients with a serum creatinine of 2.0 to 2.9 mg/dL.⁵ In another study including elderly patients with a mean serum creatinine level of 1.3±0.7 mg/dL, the incidence of this end point was 11.5%.³² Therefore, the incidence of CMN is considerably lower when the definition of at least a 0.5 mg/dL absolute increase is used. This fact is confirmed by the findings of our study (Table 3). The definitions of a 0.3 mg/dL absolute increase and a 25% relative increase in the baseline serum creatinine concentration yielded similar incidences of CMN when applied in our study population.

The serum creatinine concentration peaks 3 to 5 days after exposure to contrast media.^4,6 In contradiction to other studies that measured serum creatinine concentration within 48 hours after exposure, we opted to measure it at least 48 hours and as long as 5 days after exposure to increase the sensitivity and capture size of the effect. The tendency for a higher CMN occurrence among our patients having their serum creatinine concentration measured in days 3 to 5 compared with day 2 supports this approach.

Recent studies have demonstrated that isotonic (rather than half-isotonic) hydration and the use of the iso-osmolar, nonionic agent iodixanol rather than the low-osmolar, nonionic iohexol reduced CMN (defined as a 0.5 mg/dL absolute serum creatinine concentration increase) by an estimated 65% and 88%, respectively.^15,16 All patients in our study received isotonic hydration commencing at least 2 hours before the procedure and for at least 6 hours afterward. The randomization effect and available data from 41% of study patients ensure that hydration was well balanced between the study groups, and for the given baseline risk of our patients, the mean volume inputs were comparable to those observed in landmark studies, such as the NEPHRIC and CONTRAST trials.^16,33 The significant decline in mean serum urea concentrations observed in both study groups the day after the procedure alludes to the efficiency of the hydration protocol used. In addition, an iso-osmolar contrast agent was used in the majority of patients overall and in a slightly greater proportion of control patients (66.4% versus 58.5%). These practices would be expected to have resulted in a reduced incidence of CMN in our study group compared with older studies. Importantly, our results indicate that ascorbic acid is effective when added to these previously proven interventions.

Contrast agents reduce the medullary partial pressure of oxygen even though they increase medullary blood flow, probably because of osmotic diuresis and increased workload in medullary tubules.^11,34,35 Results of work in both animals and humans have implicated reactive oxygen species in the pathogenesis of contrast-induced nephrotoxicity.^12,13 Based on these observations, the effect of the thiol-containing antioxidant acetylcysteine in preventing CMN was first tested by Tepel et al¹⁷ in patients undergoing computed tomography scanning. An impressive 90% reduction in the incidence of contrast-induced nephropathy (defined as a 0.5 mg/dL absolute serum creatinine increase) was noted. Although several subsequent studies examining the effect of oral or intravenous acetylcysteine in the incidence of CMN in patients undergoing percutaneous coronary procedures showed disparate results, a meta-analysis of 7 randomized, placebo-controlled studies including 805 patients showed that compared with hydration alone, acetylcysteine significantly reduced the risk of CMN in patients with impaired renal function.^8,17–25 The lack of consistency in the results of the acetylcysteine trials is reminiscent of the trials of antioxidants for the primary and secondary prevention of vascular disease and cardioprotection.³⁶ Among the possible explanations suggested of how this can be so are ineffective antioxidants and inappropriate selection of patients and end points.

Ascorbic acid is a potent, water-soluble antioxidant capable of scavenging a wide array of reactive oxygen species that can cause damage to macromolecules such as lipids, DNA, and proteins.³⁷ In addition, ascorbic acid can regenerate other antioxidants, acting as a coantioxidant.³⁷ The bioavailability of orally administered ascorbic acid doses of 2 to 3 g is 36% to 44%, and the time of its maximum excretion rate is 2.7 hours.^38,39 These doses of oral ascorbic acid have been shown to reverse endothelial vasomotor dysfunction within 2 hours after administration in patients with coronary artery disease and are therefore, biologically relevant.⁴⁰ The significant differences observed in the changes of the plasma total antioxidant status as early as 2 hours after administration of the study drug in our patients denote the biological effect of ascorbic acid.

Some limitations of our study should be noted. Although appropriately powered, it included only 231 patients from a single institution. In view of the low incidence of contrast-mediated renal failure requiring supportive measures, a more liberal definition of CMN was used. Surrogate end points may not always correlate with clinical events, but a study designating renal failure as the primary end point would require a prohibitively large sample size. Although the occurrence of CMN as defined in our study has been linked to prolonged hospitalization and increased in-hospital and long-term mortality in patients undergoing percutaneous coronary interventions,^3–7 the exact clinical impact of the study findings remains largely unknown.

All patients were discharged from the hospital at least 1 day after the procedure, and those who underwent complex percutaneous coronary interventions were discharged 2 days after the procedure. No further clinical follow-up was required after hospital discharge, but patients demonstrating a significant rise in serum creatinine level were contacted and their clinical status was ascertained. Unlike the majority of previous studies, our study did not exclude patients undergoing elective and ad hoc percutaneous coronary interventions. This resulted in a larger contrast load, which might have placed our patients at higher risk for developing CMN from what their baseline renal function would justify. However, the other way of seeing this is that the increased contrast load may have led to a higher incidence of CMN in the placebo group and therefore, may have increased the power of the study to detect the ascorbic acid effect.

The results of this study show that ascorbic acid, a safe, well-tolerated, inexpensive, and readily available oral antioxidant, appears to prevent the complication of CMN after invasive coronary imaging procedures in patients with preexisting renal dysfunction. This benefit was observed despite routine hydration and use of modern iso-osmolar or low-osmolar radiographic contrast agents. These findings are consistent with the hypothesis that CMN is caused in whole or in part by oxidative stress.

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