Ascorbic Acid for the Prevention of Contrast-Induced Nephropathy After Coronary Angiography in Patients With Chronic Renal Impairment: A Randomized Controlled Trial

Authors


  • Presented in part at the 5th Slovenian Congress of Nephrology With International Participation held 17–20 October 2012 in Bled, Slovenia.

Address correspondence and reprint requests to Assist. Mag. Benjamin Dvoršak, MD, Univerzitetni klinični center Maribor, Klinika za interno medicino, Oddelek za nefrologijo, Ljubljanska 5, Maribor-2000, Slovenia. Email: benjamin.dvorsak@yahoo.com

Abstract

To determine the incidence of contrast-induced nephropathy (CIN) and to assess the effectiveness of ascorbic acid in the prevention of CIN after coronary angiography in patients with chronic renal impairment. CIN is the third most common cause of hospital-acquired renal failure. It is well documented that periprocedural hydration is effective in the prevention of CIN. Little data exist on the effectiveness of ascorbic acid, a vitamin with antioxidative action. Patients with stable serum creatinine level >107 μmol/L (n = 81) undergoing coronary angiography were randomized to receive either ascorbic acid (N = 40) or placebo (N = 41) before the procedure. All patients received intravenous volume expansion with normal saline before the procedure. CIN was defined as an increase of serum creatinine level >25% from baseline measured 3 to 4 days after the procedure. CIN occurred totally in 5/81 patients (6.2%); in two patients (3%) in the ascorbic acid group and in three patients (7.3%) in the placebo group (P = 0.512). Postprocedural worsening of renal function (postprocedural increase of serum creatinine level) was present in 10/81 patients (12.3%) in the ascorbic acid group and in 19/81 patients (23.4%) in the placebo group (P = 0.038). No patient required dialysis treatment. We found no statistically significant impact of ascorbic acid on the incidence of CIN in patients with chronic renal impairment undergoing coronary arteriography or angioplasty. Ascorbic acid may still have some protective role in CIN reflected in lower incidence of worsening of renal function in the treated group.

Contrast-induced nephropathy (CIN) is the third most common cause of hospital-acquired acute renal failure, accounting for 11% of cases [1]. CIN is characterized by reduction of renal function following the intravascular administration of radiographic contrast media (CM). Renal failure usually develops 24 to 48 h after CM exposure, serum creatinine concentration typically peaks on the third to fifth day after CM exposure and usually returns to baseline value within 1 to 3 weeks [2]. Although generally mild and reversible, acute renal failure due to CIN is associated with prolonged hospital stay, increased morbidity and mortality [3-5]. In a retrospective analysis of 7586 patients after percutaneous coronary intervention the incidence of CIN was 3.3%, the hospital mortality rate was 22% in patients who developed CIN, compared with only 1.4% in patients who did not develop CIN. The increased risk of death persisted after 1 year (mortality rate 12.1% compared with 3.4%) and after 5 years (mortality rate 44.6% compared with 14.5%) [6]. The occurrence of CIN after percutaneous coronary intervention was also associated with an increased incidence of myocardial infarction (24% in patients with CIN vs. 11.6% in patients without CIN) and target vessel revascularization at 1 year (28.8% in patients with CIN vs. 20.3% in patients without CIN) [7].

The most commonly used definition of CIN is an increase in serum creatinine of 44.2 μmol/L (0.5 mg/dL), or a 25% increase from the baseline value, assessed at 48 h after the procedure [8].

The incidence of CIN varies widely depending on the risk factors present and generally ranges from 1.9% to 33.9% [1, 9, 10]. In patients with multiple risk factors, the incidence of CIN can rise to more than 50% [11]. Although CIN requiring dialysis is relatively rare, it is associated with high hospital and 1-year mortality rates [3, 6, 12, 13].

The pathogenesis of CIN is complex and poorly understood. It involves interplay of multiple factors. Contributing mechanisms are renal vasoconstriction, oxidative stress and direct tubular toxicity leading to hypoxia of the outer medulla [14]. Alterations in the metabolism of prostaglandin, nitric oxide, endothelin and adenosine may play a role.

Outer medulla usually operates on the verge of hypoxia because the tubular epithelial cells vigorously consume oxygen for the reabsorption of sodium [14]. About 80% of the renal oxygen consumption is used by Na-K-ATPase, hence dehydration, salt depletion, and renal hypoperfusion drive the medulla to reabsorb more sodium, and thus consume more oxygen and increase the risk of hypoxia [15, 16]. Renal blood flow is regulated by vasoactive mediators; endothelin and adenosine are strong vasoconstrictors, whereas nitric oxide (NO) and prostaglandin PGE2 are potent vasodilators [17, 18]. After infusion of CM there is a brief initial increase in renal blood flow, followed by a prolonged reduction in renal blood flow [19]. Total renal blood flow is reduced by up to 50% up to 4 h after injection of CM, vasoconstriction is dose-dependent and more pronounced in diabetes mellitus [20].

Contrast media also reduce the production of nitric oxide (NO), which is a potent vasodilator. The reduction in NO production is proportional to the osmolality of the CM [21].

Vasoconstriction and loss of autoregulatory capacity can contribute to additional renal injury through the release of reactive oxygen species (superoxide anion, hydrogen peroxide and hydroxyl radical) [20]. There are limited data on the role of reactive oxygen species in the pathogenesis of CIN and are mainly based on animal model studies. Heyman et al. demonstrated in a rat model that the antioxidant N-acetylcysteine could block the shunting of blood from the outer medulla to the cortex after exposure to CM [22]. There is an increased oxidative stress and reduced antioxidant capacity in diabetes, chronic renal failure and in the elderly [20]. Direct tubular toxicity is another possible mechanism [23].

Several risk situations for CIN were described. Impaired renal function is the most important independent risk predictor for CIN. Risk of CIN is increased in patients with an estimated glomerular filtration rate (eGFR) <60 mL/min or creatinine levels >106.1 μmol/L (>1.2 mg/dL) [11]. Other risk situations are: diabetes mellitus, cardiovascular disease, periprocedural hemodynamic instability, older age, use of nephrotoxic drugs, use of high-osmolar CM, higher volume of CM (>100 mL), intra-arterial administration of CM, anemia, liver disease and immunoglobulinopathies [11, 24].

Intravenous volume expansion is the only strategy that has been shown consistently to reduce the risk of CIN [25]. There are limited data on the most appropriate type of fluid, but the evidence indicates that isotonic saline or bicarbonate solution is probably more effective than half-normal saline [12]. Suggested rate of infusion is 1.0–1.5 mL/kg per h, 3 to 12 h before and 6 to 12 h after the procedure [26].

There are currently no approved pharmacologic agents for the prevention of CIN. Pharmacologic agents that showed some benefit in trials are ascorbic acid, N-acetylcysteine (NAC), statins, theophylline, and prostaglandin E1 [25]. Furosemide, mannitol, and endothelin receptor antagonist are potentially detrimental [25]. Tested in many studies, NAC has not been consistently shown to be effective [25]. There are only two blinded, placebo-controlled studies on the effectiveness of ascorbic acid in the prevention of CIN. One showed ascorbic acid to be effective [27] and the other did not [28]. The aim of our randomized, double-blind, placebo-controlled prospective study was to determine the incidence of contrast-induced nephropathy and to assess the impact of ascorbic acid on incidence of contrast-induced nephropathy in patients with renal dysfunction after coronary arteriography or angioplasty.

Patients and Methods

A total of 83 patients with stable serum creatinine levels >107 μmol/L (>1.2 mg/dL), undergoing elective coronary angiography or angioplasty were randomized to receive either ascorbic acid or placebo. Exclusion criteria were: regular medication containing vitamin C, acute renal failure, end-stage renal disease, radiocontrast procedure in the last 3 months, cardiogenic shock and acute myocardial infarction. Eighty-one patients completed the study. The randomization scheme is shown in Figure 1. Patients received ascorbic acid or placebo in 500 mg capsules, 3 g orally before the procedure and 2 g after the procedure in the evening and the next morning. There were 40 patients in the ascorbic acid group and 41 patients in the placebo group. All the patients received intravenous volume expansion with normal saline 50–100 mL/h for 2 h before the procedure and for at least 6 h afterward. The infusion rate was tailored according to the patient's comorbidities (heart failure). Patients did not receive nephrotoxic drugs before the procedure, use of diuretics was discouraged. In all patients nonionic low-osmolal contrast agent iopamidol (Iopamiro 370) was used.

Figure 1.

Randomization scheme is shown.

Baseline serum creatinine and cystatin C levels were measured one day before the procedure, and follow-up serum creatinine and cystatin C levels were measured 3 to 4 days after the procedure. All laboratory analyses were done in our hospital laboratory. eGFR was calculated by MDRD (Modification of Diet in Renal Disease) formula and by simple cystatin formula (100/cystatin C).

Contrast-induced nephropathy was defined as an increase of serum creatinine level >25% from baseline or increase of serum cystatin C level >25% from baseline, measured 3 to 4 days after the procedure.

Estimated sample size (computer program Power and Sample Size Calculation ver. 2.1.31, Vanderbilt University, Nashville, TN, USA) was 38 patients per treatment group (power 0.9).

Data are reported as mean (range, SD) for continuous variables, and as absolute values and percentages for discrete variables. Continuous variables were analyzed by two-sample independent or paired t-test as appropriate. Categorical variables were analyzed by χ2 and Fisher's exact test for small samples. Nonparametric Mann–Whitney test was used.

Significance level was 5% (P < 0.05).

Statistical analyses were performed using the SPSS for Windows computer program (version 15.0).

Written informed consent was obtained from all patients. The National Medical Ethics Committee of the Republic of Slovenia approved the study protocol (No.: 38/07/08).

Results

Of the 83 patients randomized, 81 patients completed the study. Two patients were lost to follow-up. The baseline clinical and procedural characteristics are presented in Table 1. No statistically significant differences were detected between the groups except in preprocedural creatinine concentration; patients in the ascorbic acid group had higher preprocedural creatinine level (P = 0.028). Preprocedural and postprocedural serum creatinine levels in the ascorbic acid group and in the placebo group are presented in Figure 2 and Figure 3, respectively.

Figure 2.

Preprocedural and postprocedural serum creatinine levels in the ascorbic acid group are shown.

Figure 3.

Preprocedural and postprocedural serum creatinine levels in the placebo group are shown.

Table 1. Patients' clinical and procedural characteristics
 Ascorbic acidPlaceboP-valueAll
  1. eGFR, estimated glomerular filtration rate (mL/min per 1.73 m2); MDRD, Modification of Diet in Renal Disease; SD, standard deviation.
Male31 (77.5%)28 (68.3%) 59 (72.8%)
Female9 (22.5%)13 (31.7%) 22 (27.2%)
All40 (49.4%)41 (50.6%) 81 (100%)
Contrast-induced nephropathy2 (5%)3 (7.3%)0.5125 (6.2%)
Age (years)70.7 (49–85; SD ± 9.3)70.7 (50–88; SD ± 8.9)0.49370.7 (49–88; SD ± 9.0)
Body weight (kg)83.2 (57–120; SD ± 16.2)80.5 (52–117; SD ± 14.7)0.21781.8 (52–120; SD ± 15.4)
Contrast agent volume (mL)144.6 (35–415; SD ± 86.0)130.6 (40–287; SD ± 63.4)0.287137.4 (35–415; SD ± 75.0)
Preprocedural creatinine (μmol/L)139.4 (108–218; SD ± 24.0)133.3 (103–268; SD ± 30.9)0.028136.3 (103–268; SD ± 27.7)
Postprocedural creatinine (μmol/L)130.1 (69–337; SD ± 43.3)130.7 (88–228; SD ± 31.8)0.300130.4 (69–337; SD ± 37.7)
Preprocedural cystatin C (mg/L)1.21 (0.63–2.15; SD ± 0.3)1.24 (0.78–1.92; SD ± 0.3)0.3081.23 (0.63–2.15; SD ± 0.3)
Postprocedural cystatin C (mg/L)1.17 (0.69–2.8; SD ± 0.4)1.20 (0.64–2.59; SD ± 0.4)0.3651.18 (0.64–2.80; SD ± 0.4)
Preprocedural eGFR (MDRD)45.4 (28–62; SD ± 10.0)46.9 (16–64; SD ± 11.0)0.21946.2 (16–64; SD ± 10.5)
Postprocedural eGFR (MDRD)51.4 (17–89; SD ± 14.8)48.9 (19–79; SD ± 13.7)0.25150.1 (17–89; SD ± 14.2)
Preprocedural eGFR (cystatin C)88.6 (46–158; SD ± 24.8)84.3 (52–128; SD ± 19.1)0.30886.4 (46–158; SD ± 22.1)
Postprocedural eGFR (cystatin C)92.3 (35.7–144.9; SD ± 24.4)91.2 (38.6–156.2; SD ± 25.9)0.36591.7 (35–156; SD ± 25.0)
Diabetes mellitus18 (45%)17 (41.5%)0.46135 (43.2%)
Heart failure15 (37.5%)13 (31.7%)0.37728 (34.5%)

Contrast-induced nephropathy occurred totally in 5/81 patients (6.2%) when CIN was defined as an increase of serum creatinine level >25% from baseline; in two patients (3%) in the ascorbic acid group and in three patients (7.3%) in the placebo group. There was no statistically significant difference between the groups (P = 0.512). Clinical and procedural characteristics of patients with and without CIN are presented in Table 2. CIN occurred in 5/81 patients as well, when CIN was defined as an increase of serum cystatin C level >25% from baseline. Only two patients had CIN when CIN was defined as an absolute increase of serum creatinine level >44.2 μmol/L.

Table 2. Clinical and procedural characteristics of patients with and without contrast-induced nephropathy (CIN)
 With CINWithout CINP-valueAll
  1. eGFR, estimated glomerular filtration rate (mL/min per 1.73 m2); MDRD, Modification of Diet in Renal Disease; SD, standard deviation.
Male3 (60%)56 (73.7%) 59 (72.8%)
Female2 (40%)20 (26.3%)0.41422 (27.2%)
All5 (6.2%)76 (93.8%) 81 (100%)
Ascorbic acid2 (40%)38 (50%) 40 (49.4%)
Placebo3 (60%)38 (50%)0.51241 (50.6%)
Age (years)71.8 (61–79; SD ± 8.3)70.6 (49–88; SD ± 9.1)0.38670.7 (49–88; SD ± 9.0)
Body weight (kg)89.2 (73–120; SD ± 19.7)81.3 (52–118; SD ± 15.1)0.20381.8 (52–120; SD ± 15.4)
Contrast agent volume (mL)144.2 (110–261; SD ± 65.5)136.9 (35–415; SD ± 76.0)0.386137.4 (35–415; SD ± 75.0)
Preprocedural creatinine (μmol/L)143.6 (103–218; SD ± 47.5)135.8 (108–268; SD ± 26.4)0.389136.3 (103–268; SD ± 27.7)
Postprocedural creatinine (μmol/L)204.4 (139–337; SD ± 78.0)125.5 (69–228; SD ± 28.3)0.001130.4 (69–337; SD ± 37.7)
Preprocedural cystatin C (mg/L)1.37 (0.99–1.66; SD ± 0.3)1.22 (0.63–2.15; SD ± 0.3)0.1911.23 (0.63–2.15; SD ± 0.3)
Postprocedural cystatin C (mg/L)2.07 (1.12–2.8; SD ± 0.66)1.11 (0.64–2.0; SD ± 0.3)0.0011.18 (0.64–2.80; SD ± 0.4)
Preprocedural eGFR (MDRD)42.8 (28–61; SD ± 12.4)46.4 (16–64; SD ± 10.5)0.23846.2 (16–64; SD ± 10.5)
Postprocedural eGFR (MDRD)29.4 (17–47; SD ± 11.0)51.5 (19–89; SD ± 13.3)0.00150.1 (17–89; SD ± 14.2)
Preprocedural eGFR (cystatin C)76.3 (60–101; SD ± 21.7)86.9 (46–158; SD ± 22.2)0.19186.4 (46–158; SD ± 22.1)
Postprocedural eGFR (cystatin C)53.5 (35–89; SD ± 21.5)94.8 (50–156; SD ± 22.7)0.00191.7 (35–156; SD ± 25.0)
Diabetes mellitus1 (20%)34 (44.7%)0.27635 (43.2%)
Heart failure1 (20%)27 (35.5%)0.43228 (34.5%)

When we analyzed patients with postprocedural increase of serum creatinine level, worsening of renal function was present in 10/81 patients (12.3%) in the ascorbic acid group and in 19/81 patients (23.4%) in the placebo group. The difference was statistically significant (P = 0.038). Frequency of preprocedural/postprocedural change of serum creatinine levels in treatment groups is presented in Table 3. Patients with CIN were more often men, they were older, heavier, they had higher preprocedural serum creatinine level, cystatin C level and lower eGFR and they received a higher volume of CM compared with patients without CIN. The difference between the groups regarding those parameters was not statistically significant. No patient required dialysis treatment.

Table 3. Frequency of preprocedural/postprocedural change of serum creatinine levels in treatment groups
 Ascorbic acidPlaceboP-valueAll
Creatinine decrease3022 52
Creatinine increase10190.03829

Of the patients in which CIN occurred, in two patients serum creatinine level had normalized in the following weeks after the procedure, serum creatinine remained elevated in one patient, and for two patients we had no data on later serum creatinine level.

Discussion

We conducted a randomized, double-blind, placebo-controlled prospective trial to determine the incidence of CIN and to assess the impact of ascorbic acid on the incidence of CIN in patients with renal dysfunction after coronary angiography or angioplasty.

The overall incidence of CIN was 6.2%; 3% in the ascorbic acid group and 7.3% in the placebo group. The difference was not statistically significant. The incidence of CIN was 6.2% as well, when CIN was defined as an increase of serum cystatin C level >25% from baseline. We found less worsening of renal function, defined as an increase of serum creatinine level after the procedure, in the ascorbic acid group compared to the placebo group.

There are several reasons why potentially beneficial effect of ascorbic acid could not be expressed. First, the sample size was quite small. Second, the incidence of CIN in our patients with renal impairment was comparable to the incidence in patients with normal renal function in many studies and about 50% lower compared to similar studies involving patients with renal impairment [27, 29-31]. This relatively low incidence of CIN may be explained by low volumes of CM used and extensive preprocedural parenteral hydration. We used relatively low volumes of CM. Average volume of CM used in our study was 137.4 mL, which is less than in most other studies. Reported mean volumes of CM used by other researchers in coronary angiography or angioplasty are: Aspelin, 163 mL [32], Spargias, 274 mL [27], Aguiar-Souto, 260 mL [29], Zaytseva, 216 mL [33], Boscheri, 106 mL [28], Briguori, 172 mL [34], and Huber, 206 mL [35]. Iopamidol was shown to have low incidence of CIN [31]. Using iodixanol, interventional cardiologists at our center reported impaired visualization of arteries compared to iopamidol.

Spargias et al. reported a significantly lower incidence of CIN after coronary angiography or intervention in patients with chronic renal impairment that received ascorbic acid before the procedure compared to placebo [27]. They randomized 231 patients to receive 3 g of ascorbic acid or placebo orally at least 2 h before the procedure, followed by 2 g of ascorbic acid or placebo at night and in the morning after the procedure. The overall incidence of CIN was 14.7%, 9% in the ascorbic group and 20% in the placebo group. CIN was defined as an absolute increase of serum creatinine level >0.5 mg/dL (44.2 μmol/L) or a relative increase of >25% measured 2 to 5 days after the procedure. All patients were hydrated intravenously with normal saline 50 to 125 mL/h 2 h before and 6 h after the procedure. Mean preprocedural serum creatinine was 124.5 μmol/L and mean volume of CM used was 274 mL.

Boscheri et al. reported low incidence of CIN after coronary angiography or intervention in 143 patients with chronic renal impairment [28]. The incidence of CIN was 5.6% overall, 6.8% in the ascorbic acid group, and 4.3% in the placebo group. There was no statistically significant difference in the incidence of CIN between the groups. CIN was defined as an increase of serum creatinine level >25% measured 2 days after the procedure. Patients received 1 g of ascorbic acid or placebo orally 20 min before the procedure. All patients received intravenous infusion of 500 mL normal saline 2 h before and up to 6 h after the procedure. Mean preprocedural serum creatinine was 154 μmol/L and mean volume of CM used was 106 mL.

The incidence of CIN in Spargias's study was twice that of Boscheri's and our study. This may be due to higher volumes of CM used in Spargias's study. The mean volume of CM administered in Spargias's study was almost twice that of our study, Boscheri et al. reported even lower values. Relatively low incidence of CIN in our study may be one possible explanation for the non-effectiveness of ascorbic acid in reducing the incidence of CIN after coronary angiography.

Another factor important in this aspect is low bioavailability of ascorbic acid at supraphysiologic doses. Ascorbic acid is the main water-soluble vitamin with antioxidant activity, it is a cofactor for several enzymes involved in the biosynthesis of collagen, carnitine, and neurotransmitters. It protects plasma lipids from peroxidation, scavenges reactive oxygen species and plays a role in recycling of alpha tocopherol [36, 37]. Ascorbic acid protects normal nitric oxide (NO) synthesis, improves endothelial function and NO-mediated vasodilation [38, 39]. In diabetic patients administration of ascorbic acid increases renal blood flow [40]. When given orally, ascorbic acid is well absorbed at lower doses, but less than 50% of a 1250-mg dose is absorbed [41].

In spite of the lack of significant proof of reducing the incidence of CIN, ascorbic acid may have some protective role in CIN, expressed by the reduction of worsening of renal function after coronary angiography in the ascorbic acid group. In reducing the risk of CIN after coronary angiography, intravenous hydration remains the most important preventive measure.

Fear of CIN should not be an excuse not to use the best diagnostic or therapeutic procedure for the patient or not to use CM in CT examinations resulting in insufficient radiologic investigations.

Limitations

We should mention some limitations of our study. The study was performed in one center and the sample size was small. Patients with acute myocardial infarction and cardiogenic shock were not included; therefore, the incidence of CIN and impact of ascorbic acid on the incidence of CIN in those patients remains untested.

The incidence of CIN was relatively low in our patients. This might be due to the extensive parenteral hydration, use of minimal required volume of low-osmolal nonionic CM and only moderately elevated baseline serum creatinine levels. Therefore, the potentially beneficial effect of ascorbic acid could not be expressed.

Conclusions

According to our study, ascorbic acid does not reduce the incidence of contrast-induced nephropathy after coronary angiography in patients with chronic renal impairment. Ascorbic acid may still have some protective role in the prevention of contrast-induced nephropathy reflected in the lower incidence of worsening of renal function in the treated group, especially in high-risk patients.

Intravenous hydration is, to date, the most important preventive measure in prevention of contrast-induced nephropathy. Further study is needed to test if intravenous application of ascorbic acid is more effective compared to oral application in the prevention of contrast-induced nephropathy in patients with chronic renal impairment.

Intravenous application of ascorbic acid could also be used for rapid achievement of high blood concentration of ascorbic acid, which might be useful in the prevention of CIN in high risk patients when urgent procedure with application of CM is needed.

Acknowledgments

We deny any financial support, conflict of interests or experimental investigation on human subjects without informed consent.

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