Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Renal Disease
Sodium Bicarbonate-Ascorbic Acid Combination for Prevention of Contrast-Induced Nephropathy in Chronic Kidney Disease Patients Undergoing Catheterization
Kota KomiyamaTakashi AshikagaDai InagakiTomonori MiyabeMarina AraiKiyotaka YoshidaSatoshi MiyazawaAkihiro NakadaIwanari KawamuraShinichiro MasudaSho NagamineRintaro HojoYuya AoyamaTakaaki TsuchiyamaSeiji FukamizuTakashi ShibuiHarumizu Sakurada
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2017 Volume 81 Issue 2 Pages 235-240

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Abstract

Background: Sodium bicarbonate and ascorbic acid have been proposed to prevent contrast-induced nephropathy (CIN). The present study evaluated the effect of their combined use on CIN incidence.

Methods and Results: We prospectively enrolled 429 patients with chronic kidney disease (CKD: baseline estimated glomerular filtration rate <60 mL/min/1.73 m2) prior to elective coronary catheterization. CIN was defined as absolute (≥0.5 mg/dL) or relative (≥25%) increase in serum creatinine within 72 h. In the saline hydration (n=218) and combined sodium bicarbonate+ascorbic acid (n=211) groups, a total of 1,500–2,500 mL 0.9% saline was given before and after the procedure. In addition, the combination group received 20 mEq sodium bicarbonate and 3 g ascorbic acid i.v. before the procedure, followed by 2 g ascorbic acid after the procedure and a further 2 g after 12 h. There were no significant differences between the basic characteristics and contrast volume in the 2 groups. CIN occurred in 19 patients (8.7%) in the saline group, and in 6 patients (2.8%) in the combined treatment group (P=0.008).

Conclusions: Combined sodium bicarbonate and ascorbic acid could prevent CIN following catheterization in CKD patients.

Acute renal dysfunction is a serious complication of contrast agent use.1 This contrast-induced nephropathy (CIN) occurs more commonly in patients with pre-existing renal dysfunction.24 Once CIN occurs, patients are more likely to experience in-hospital death and have a markedly less favorable long-term prognosis.2,46 The incidence of CIN is <2% in patients with normal renal function,7 but 11–45% in patients with diabetes or chronic kidney disease (CKD).8,9 Given that non-nephrotoxic contrast agents are currently unavailable, prevention of the onset of CIN is extremely important, especially for CKD. In a study of CKD patients who underwent an elective coronary procedure, Tamura et al noted that a single i.v. bolus of sodium bicarbonate (20 mEq), in addition to standard hydration, prevented CIN more effectively than standard hydration alone.10 The PREVENT trial, however, suggested that hydration with sodium bicarbonate was not superior to hydration with sodium chloride in preventing CIN in patients undergoing coronary or endovascular angiography and intervention.11 Similarly, although Spargias et al reported that ascorbic acid protected against CIN in high-risk patients undergoing a coronary procedure,12 the REMEDIAL trial could not prove the superiority of ascorbic acid.13 No published studies have examined the efficacy of combined i.v. sodium bicarbonate and ascorbic acid for the prevention of CIN. The aim of the current prospective randomized trial was therefore to determine whether i.v. sodium bicarbonate and ascorbic acid, in addition to a saline hydration protocol, provided more effective prevention of CIN than saline hydration alone in CKD patients undergoing elective catheter procedures.

Methods

Patients

This study included 429 patients (344 men, 85 women; mean age, 73.7±10.1 years) with renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) who were scheduled to undergo elective angiography (including coronary angiography, aortography, and venography) or intervention (including percutaneous coronary intervention and endovascular treatment) with a catheter at Tokyo Metropolitan Hiroo Hospital. The present study was performed with the approval of the hospital ethics committee. All of the patients provided informed consent and were randomly allotted to one of the following 2 groups: saline hydration alone (saline group: n=218); or sodium bicarbonate+ascorbic acid combined (combination group: n=211). We excluded patients aged <20 years and those who were pregnant or undergoing maintenance dialysis. Patients with acute conditions such as acute myocardial infarction and unstable angina, those with severe cardiac failure (New York Heart Association class III or higher), those with severe respiratory diseases, and patients who had undergone catheter procedures involving the use of a contrast agent within the previous 48 h were also excluded from this study. The contrast agent used was iopamidol, a hypotonic, non-ionic contrast medium (Iopamiron-370; Bayer Pharma, Berlin, Germany). Non-steroidal anti-inflammatory drugs14 and diuretics such as furosemide15 can increase the risk of developing CIN. The use of these drugs was therefore discontinued 12 h prior to each procedure. Metformin was stopped ≥48 h before the procedure and resumed at least 72 h after the procedure, in order to prevent metformin-associated lactic acidosis.16

The eGFR was calculated in accordance with the following formula, proposed by the Japanese Society of Nephrology:17

eGFR=194×(serum creatinine)−1.094×(age)−0.287 [for women: ×0.739].

CIN Definition

Various definitions of CIN have been proposed. The most common definition was used in the present study, that is, CIN was defined as absolute increase in serum creatinine ≥0.5 mg/dL or relative increase ≥25% within 72 h of a procedure involving the use of a contrast agent.18

Procedure

The treatment protocol is shown in Figure 1. The saline group received 0.9% physiological saline 6–15 h before, and during, the procedure at a rate of 1.5 mL/kg/h. This rate was then increased to 2.5 mL/kg/h for 6 h after the procedure. The total amount of saline administered was 1,500–2,500 mL; this was defined as the “saline hydration protocol”. In the combination group, sodium bicarbonate (20 mL=20 mEq; Meyron 84, Otsuka Pharmaceutical, Tokyo, Japan) and ascorbic acid (3 g) were given i.v. before the procedure. Ascorbic acid (2 g) was then administered after the procedure, followed by another 2 g of ascorbic acid 12 h later after the procedure; this group also received the same saline hydration protocol as the saline group.

Figure 1.

Treatment protocols. The saline group received 0.9% physiological saline 6–15 h before, and during, the procedure at a rate of 1.5 mL/kg/h. This rate was then increased to 2.5 mL/kg/h for 6 h after the procedure. The total amount of saline administered was 1,500–2,500 mL (saline hydration protocol, blue arrows). In the combination group, sodium bicarbonate (20 mL=20 mEq; Meyron 84, Otsuka Pharmaceutical, Tokyo, Japan) and ascorbic acid (3 g) were given i.v. before the procedure. Ascorbic acid (2 g) was then administered after the procedure, followed by another 2 g of ascorbic acid 12 h later after the procedure; this group also received the same saline hydration protocol as the saline group.

Statistical Analysis

Categorical data are expressed as % (n). The continuous data are expressed as mean±SD. Categorical data were analyzed using Fisher’s exact test or the chi-squared test. Between-group comparisons of the continuous data were conducted using unpaired t-test, and skewed data were assessed using Mann-Whitney U-test. All tests were 2-sided, and a significance level of 0.05 was set. Univariate analysis was used to evaluate which factors were associated with the incidence of CIN. Those associated with the incidence of CIN were analyzed using a multivariable ordinal logistic regression model to identify a set of predictors for CIN. Statistical analysis was performed using SPSS version 23 (IBM SPSS Statistics, IBM, Armonk, NY, USA).

Results

Clinical Characteristics

The clinical characteristics of the 429 patients enrolled in this study are listed in Table 1. No significant differences in age, sex, body mass index, baseline serum creatinine level, or eGFR were observed between the 2 groups. Hemoglobin and left ventricular ejection fraction were close to normal. Although there was a significant difference between the procedures used in the 2 study groups, the contrast and hydration volumes did not differ significantly. The distribution of risk factors for arteriosclerosis was similar in the 2 study groups, and there were no significant differences in the medicines used.

Table 1. Clinical Subject Characteristics
  Saline group
(n=218)
Combination group
(n=211)
P-value
Baseline demographics, comorbidities and medications
 Age (years) 74.1±10.0 73.1±10.2 0.45
 Female 18.3 (40) 21.3 (45) 0.47
 BMI (kg/m2) 23.8±4.4 24.5±4.4 0.13
 Baseline serum creatinine (mg/dL) 1.52±0.64 1.62±0.79 0.14
 Baseline eGFR (mL/min/1.73 m2) 39.5±9.5 35.8±10.79 0.25
 Hemoglobin (g/dL) 12.3±2.1 12.4±5.9 0.97
 LVEF (%) 55.8±15.0 55.0±15.1 0.59
 Diabetes mellitus 51.8 (113) 45.5 (96) 0.21
 Hypertension 89.4 (195) 90.1 (190) 0.88
 Hyperlipidemia§ 64.2 (140) 68.2 (144) 0.42
 ACEI or ARB 56.9 (124) 65.9 (139) 0.06
 Diuretic 38.1 (83) 41.2 (87) 0.55
 Statin 61.0 (133) 64.9 (137) 0.43
Procedure 0.04
 Angiography alone 58.3 (127) 48.3 (102)
 Intervention†† 41.7 (91) 51.7 (109)
Volume of contrast and saline hydration
 Contrast volume (mL) 103.1±60.0 103.8±55.7 0.91
 Hydration volume (mL) 2,149.3±442.1 2,144.2±495.1 0.92
 Pre-procedure saline hydration time (h) 11.3±3.6 10.8±3.6 0.19

Data given as mean±SD or % (n). HbA1c(NGSP) ≥6.5% and/or anti-blood sugar therapy; blood pressure >140/90 mmHg and/or antihypertensive therapy; §low-density lipoprotein ≥140 mg/dL and/or anti-lipidemia therapy; including coronary angiography, aortography and venography; ††including percutaneous coronary intervention and endovascular treatment. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction.

Serum Creatinine Concentration

Serum creatinine concentrations are listed in Table 2. Baseline serum creatinine was slightly higher in the combination group than in the saline group, but this difference was not statistically significant. Although no significant differences in creatinine levels were observed between the 2 groups 72 h after the procedure, a significantly greater reduction in the absolute level of creatinine was observed in the combination group at this time-point.

Table 2. Change in Serum Creatinine Concentration After Contrast Use
  Saline group
(n=218)
Combination group
(n=211)
P-value
Serum creatinine (mg/dL)
 Baseline 1.52±0.64 1.62±0.79 0.14
 ≤72 h after 1.54±0.74 1.55±0.77 0.86
 Absolute change 0.01±0.39 −0.07±0.31 0.02

Incidence of CIN

The incidence of CIN (i.e., increase in the serum creatinine level by ≥0.5 mg/dL or by ≥25% within 72 h of contrast media administration) was significantly higher in the saline group than in the combination group (8.7% vs. 2.8%, respectively, P=0.008; Figure 2). None of the patients who received sodium bicarbonate and ascorbic acid during this study had any adverse effects. This suggests the safety of sodium bicarbonate and ascorbic acid, and the possibility that combined sodium bicarbonate+ascorbic acid treatment could provide an effective means of preventing the onset of CIN.

Figure 2.

Incidence of, vs. definition of, contrast-induced nephropathy (CIN). CIN was defined as (1) absolute increase of serum creatinine (Cre) ≥0.5 mg/dL or (2) ≥25% relative increase within 72 h. I.v. ascorbic acid and sodium bicarbonate in the combination group prevented CIN more effectively than in the saline group, in chronic kidney disease patients undergoing elective catheter procedures.

Risk Factors for CIN

Risk factors for the incidence of CIN are listed in Table 3. On univariate analysis the incidence of CIN was associated with saline hydration alone; total contrast volume/pre-procedure eGFR ≥3; pre-procedure saline hydration time; diabetes mellitus; and smoking. The incidence of CIN was not associated with sex, age, baseline eGFR, hypertension, hyperlipidemia, or coadministration of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or statins. Among these variables, CIN was strongly predicted by total contrast volume/pre-procedure eGFR ratio ≥3 (OR, 9.09; 95% CI: 3.25–24.52; P<0.001) and by use of saline hydration alone (OR, 4.41; 95% CI: 1.67–11.69; P=0.003), after adjusting for significant univariate predictors.

Table 3. Predictive Value of Risk Factors for CIN
  Univariate analysis Multivariate analysis
OR 95% CI P-value OR 95% CI P-value
Without sodium bicarbonate/ascorbic acid 3.26 1.28–8.34 0.009 4.41 1.67–11.69 0.003
Age (per 10-year increase) 0.66 0.46–0.95 0.024      
Male 2.00 0.83–4.80 0.124      
BMI ≥24.0 0.60 0.25–1.43 0.247      
30≤baseline eGFR<60 1.40 0.61–3.19 0.422      
15≤baseline eGFR<30 0.80 0.35–1.82 0.589      
Baseline eGFR <15 0.94 0.92–0.96 1.000      
Total contrast volume/pre procedure eGFR ≥3 6.91 2.54–18.82 <0.001 9.09 3.25–25.42 <0.001
Pre-procedure saline hydration time
(per 1-h increase)
0.06 0.34–0.46 <0.001      
Intervention 1.24 1.01–1.52 0.040      
Diabetes mellitus 2.35 0.99–5.56 0.047 2.54 1.03–6.26 0.420
Hypertension§ 0.83 0.24–2.89 0.733      
Hyperlipidemia 0.63 0.28–1.43 0.267      
Smoking (current/former) 2.94 0.99–8.73 0.043      
ACEI/ARB 0.67 0.30–1.50 0.325      
Statin 0.62 0.28–1.39 0.243      

Including percutaneous coronary intervention and endovascular treatment; HbA1c(NGSP) ≥6.5% and/or anti-blood sugar therapy; §blood pressure >140/90 mmHg and/or anti-hypertensive therapy; low-density lipoprotein ≥140 mg/dL and/or anti-lipidemia therapy. CIN, contrast-induced nephropathy. Other abbreviations as in Table 1.

Discussion

This study has shown, for the first time, that use of i.v. sodium bicarbonate and ascorbic acid and a saline hydration protocol in patients with CKD undergoing elective procedures can prevent CIN more effectively than saline hydration alone. Concordantly, the absolute level of serum creatinine observed following contrast media administration was significantly reduced in patients who received i.v. sodium bicarbonate and ascorbic acid.

In this study, CIN occurred in 19 patients (8.7%) in the group who received saline hydration alone. This incidence rate was lower than that reported in previous studies.8,9 The achievement of sufficient hydration using 0.9% saline could explain this lower CIN incidence. Several interventions for the prevention of CIN have been tested in clinical trials. At present, only saline hydration has shown consistent benefits1922 whereby isotonic, rather than hypotonic, hydration reduced the incidence of CIN.23 A clear and consistent protocol for saline hydration, however, has not been established. In the present study, the saline hydration group received 0.9% physiological saline at 1.5 mL/kg/h for 6–15 h prior to the procedure and at 2.5 mL/kg/h for 6 h after the procedure.

Previous studies have compared the individual effects of sodium bicarbonate, ascorbic acid, and normal replacement fluids on CIN.1013 The present study, however, has shown that the combination of sodium bicarbonate and ascorbic acid had a statistically significant preventive effect on CIN. Although no acceptable pathological explanation has been proposed for CIN, it is likely to reflect nephrocyte damage caused by ischemic changes in the renal medulla and contrast agent-induced oxidative stress.2426 Ischemia also leads to an increased production of free radicals, which increases oxidative stress and contributes to renal dysfunction.2729 Sodium bicarbonate induces blood alkalinization, which has a protective effect against oxidative stress on kidneys.10,30 Ascorbic acid is a free radicals scavenger and powerful antioxidant that is considered to attenuate the renal damage caused by a variety of insults including oxidative stress in animals; this compound also has an excellent safety record as a dietary supplement in humans.12,3134 These activities may contribute to the synergistic effects of sodium bicarbonate and ascorbic acid on CIN prevention observed in the present study, as compared with either one individually.

The low cost of sodium bicarbonate (¥97/20 mEq) and ascorbic acid (¥86/0.5 g) indicates the excellent cost-effectiveness of this treatment.

Several previous studies have shown that minimization of the volume of contrast in catheterizations contributed to the prevention of CIN.3537 Abe et al reported that a total contrast volume/pre-procedure eGFR ratio ≥3 was a significant predictor of CIN in patients with stable angina pectoris (OR, 2.07; 95% CI: 1.01–4.26; P=0.048).38 In the present study, this factor was an even stronger predictor of CIN; the second strongest predictor was non-use of sodium bicarbonate and ascorbic acid. This indicates that reducing the amount of contrast media had the most important effect on CIN risk, followed by use of i.v. sodium bicarbonate and ascorbic acid along with the saline hydration protocol.

In any clinical setting, contrast agents are used sparingly in patients with renal dysfunction because the associated risk of renal damage has a markedly negative effect on prognosis and quality of life. One study has illustrated this, finding that 25.2% of patients with renal dysfunction and 46.8% of those without renal dysfunction undergo testing and treatment with intracardiac catheters.39 Revascularization using intracardiac catheters, however, can be highly beneficial in patients with renal dysfunction because they are prone to arteriosclerosis and coronary disease-related complications. The present study has shown that combined treatment with sodium bicarbonate and ascorbic acid could facilitate the extension of these interventions to patients with CKD by reducing the incidence of CIN.

Study Limitations

The present results should be interpreted in the context of several potential limitations. First, the results cannot be extended to patients with very low eGFR, because the average eGFR in this study was 36.3±10.2 mL/min/1.73 m2. Second, this was a single-center study and further work will be required to determine its relevance to other treatment settings. Third, the present study included only patients undergoing elective coronary catheterization and cannot therefore be extended to emergency situations. Finally, given that the present hospital has 1 catheterization laboratory, the admittance of emergency cases could sometimes postpone or delay elective catheter procedures; this resulted in case-by-case differences in the procedure starting times, which affected preoperative saline load.

Conclusions

The incidence of CIN was reduced by minimizing the volume of contrast media and by using a combination of sodium bicarbonate and ascorbic acid. This safe and inexpensive therapy could improve clinical outcomes in CKD patients undergoing elective catheter procedures.

Disclosures

The authors declare no conflict of interest.

Name of Grant

None.

References
 
© 2017 THE JAPANESE CIRCULATION SOCIETY
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