Author + information
- Received June 4, 2008
- Revision received September 19, 2008
- Accepted October 13, 2008
- Published online March 24, 2009.
- Shuji Morikawa, MD*,
- Takahito Sone, MD*,
- Hideyuki Tsuboi, MD*,
- Hiroaki Mukawa, MD*,
- Itsuro Morishima, MD*,
- Michitaka Uesugi, MD*,
- Yasuhiro Morita, MD*,†,
- Yasushi Numaguchi, MD‡,
- Kenji Okumura, MD§,* ( and )
- Toyoaki Murohara, MD†
- ↵*Reprint requests and correspondence:
Dr. Kenji Okumura, Cardiovascular Research Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
Objectives This study was designed to examine the protective effects of atrial natriuretic peptide (ANP) on contrast-induced nephropathy (CIN) after coronary angiography.
Background Contrast-induced nephropathy is a common complication after angiography. Some studies have shown that ANP has renal protective effects, but the beneficial effects for CIN prevention remain to be clearly shown.
Methods In a prospective, controlled, randomized trial in 254 consecutive patients with serum creatinine concentrations of ≥1.3 mg/dl, patients received either ANP (0.042 μg/kg/min; ANP group, n = 126) or Ringer solution alone (control group, n = 128). Treatment of either type was initiated 4 to 6 h before angiography and continued for 48 h.
Results There were no significant differences in age, sex, diabetes mellitus, or baseline serum creatinine level between the 2 groups. The prevalence of CIN, defined as a 25% increase in creatinine or an increase in creatinine of ≥0.5 mg/dl from baseline within 48 h, was significantly lower in the ANP group than in the control group (3.2% vs. 11.7%, respectively; p = 0.015). Multivariate analysis revealed that the use of >155 ml of contrast medium (odds ratio: 6.89; p < 0.001) and ANP treatment (odds ratio: 0.24; p = 0.016) were significant predictors of developing CIN. The incidence of an increase in creatinine of ≥25% or of ≥0.5 mg/dl from baseline at 1 month was also significantly lower in the ANP group than in the control group (p = 0.006).
Conclusions In addition to hydration, ANP administration is effective in the prevention of CIN in patients with chronic renal failure, and the effect was maintained for 1 month.
Contrast-induced nephropathy (CIN) is one of the most important clinical complications associated with coronary angiography, accounting for 10% of all causes of hospital-acquired renal failure (1,2); it has been reported to occur in 11% to 44% of patients with moderate renal insufficiency (1,3). Contrast-induced nephropathy is associated with considerably increased morbidity and mortality, including the need for transient dialysis and/or extended hospitalization, and can lead to chronic end-stage renal disease (1,3,4). Although several prevention strategies have been investigated extensively in recent years, no optimal strategy for preventing CIN has yet been established. The most recent guidelines (5) recommend intravenous volume expansion, the use of low- or iso-osmolality contrast media, and limits on the volume of contrast media.
Atrial natriuretic peptide (ANP) is a potent endogenous diuretic and natriuretic substance (6) that has been shown to improve renal function and perfusion in animal models (7,8) and in clinical ischemic renal failure (9–11). Animal studies have shown ANP to be beneficial in preventing CIN, but clinical studies (12–14) have not yet provided clear results; 1 clinical study failed to show any beneficial effect of the short-term administration of ANP with respect to CIN (14). The present study was a prospective, randomized, single-center control trial to evaluate the effect of the middle-term administration of ANP on the occurrence of CIN in patients with chronic renal insufficiency undergoing coronary angiography or intervention.
This single-center (Ogaki Municipal Hospital), randomized controlled trial compared infusion of ANP in addition to intravenous hydration with hydration alone in treatment to prevent renal failure in patients with chronic renal insufficiency undergoing coronary angiography or intervention. Consecutive eligible patients between the ages of 20 and 85 years who had a serum creatinine concentration of ≥1.3 mg/dl and <6 mg/dl were considered for enrollment. The indications for the procedure were determined by each patient's cardiologist. Exclusion criteria were pregnancy, lactation, acute renal failure, end-stage renal failure on dialysis, acute myocardial infarction, multiple myeloma, pulmonary edema, cardiogenic shock, a systolic blood pressure of <110 mm Hg, dehydration, a history of allergies to contrast media or ANP, having received contrast media within 7 days of the study entry, having received an infusion of ANP within 1 month of the study entry, parenteral use of diuretics, and the administration of dopamine, N-acetylcysteine, metformin, sodium bicarbonate, fenoldopam, mannitol, or nonsteroidal anti-inflammatory drugs (NSAIDs) during the study. The study protocol was approved by the local ethics committee, and all patients provided their written, informed consent before study entry.
Patients were randomly assigned to receive either 0.042 μg/kg/min of ANP (Carperitide, Asubio Pharma Co., Ltd., Tokyo, Japan, and Daiichi-Sankyo Co., Ltd., Tokyo, Japan) plus 1.3 ml/kg/h of Ringer solution, both intravenously (ANP group), or Ringer solution alone (control group) before and after contrast administration. The ANP and Ringer solution infusions were initiated 4 to 6 h before the angiographic procedure and continued for 48 h after it. All patients were encouraged to drink if they were thirsty. Iomeprol (Iomeron 400, Eisai Co., Ltd., Tokyo, Japan), a nonionic, low-osmolality contrast medium, was used in all patients. All decisions regarding procedural hemodynamics, including contrast volume, were left to the discretion of the cardiologist. We calculated the sample size of our study assuming a CIN rate of 15% in the control group based on the rate previously reported in patients undergoing coronary angiography (15). Moreover, we assumed that the incidence of CIN decreases to almost one-fourth by the administration of ANP. Using a 2-sided chi-square test with a significance level of 0.05 and 80% power, 122 patients would be necessary in each group.
Serum creatinine and cystatin C were measured at 12 to 24 h before the procedure and at 24 h, 48 h, 1 week, and 1 month after the procedure. The glomerular filtration rate (GFR) was calculated using the level-modified Modification of Diet in Renal Disease modified for Japanese: estimated glomerular filtration rate (eGFR) = 0.741 × 175 × age in years−0.203× serum creatinine−1.154; with female sex adjustment: eGFR female = eGFR × 0.742 (16). Urinary β2-microglobulin and N-acetyl-β-D-glucosaminidase (NAG) were measured at 12 to 24 h before the procedure, and at 48 h, 1 week, and 1 month after the procedure.
The primary end point was the incidence of CIN, defined as a 25% increase in creatinine or an increase in creatinine of 0.5 mg/dl from baseline at the maximum value obtained within 48 h after the procedure (17,18). The following secondary end points were also assessed: 1) a 25% increase in creatinine within 48 h; 2) an increase in creatinine of ≥0.5 mg/dl from baseline within 48 h; 3) changes in serum creatinine, eGFR and serum cystatin C concentrations, and urinary β2-microglobulin and NAG until 1 month after the procedure; and 4) a 25% increase in creatinine or an increase in creatinine of ≥0.5 mg/dl from baseline at 1 month after the procedure.
Statistical analysis was based on an intention-to-treat analysis for all subjects after initial therapy. Categorical variables were expressed as percentages and analyzed by the chi square or Fisher exact test, as appropriate. Continuous variables were expressed as mean ± SD and compared with the Student ttest unless otherwise indicated. When data were not normally distributed, they were expressed as median and interquartile ranges and compared with the nonparametric Mann-Whitney Utest. Two-way repeated-measures analysis of variance was used to test for linear trend in eGFR. Univariate and multivariate analysis determined which factors correlated with developing CIN. The volume of contrast media to predict CIN was used to determine the optimal cutoff value (155 ml; sensitivity, 68.4%; specificity, 75.7%) by receiver-operator characteristic curve analyses. Values of p < 0.05 were considered to be statistically significant. All statistical analyses were performed using the Statistical Package for the Social Sciences version 13.0 (SPSS Inc., Chicago, Illinois).
A total of 272 patients were initially enrolled in the study. However, 4 patients refused to participate in the study and 7 patients were excluded (5 patients, systolic blood pressure of <110 mm Hg; 2 patients, chronic dialysis). Of the 261 patients who were randomized, 254 completed the study. Seven patients did not complete the study; 4 patients did not obtain follow-up serum creatinine concentration levels. One patient of these 4 did not have a creatinine concentration taken 24 h after the procedure, and the remaining 3 did not have a creatinine concentration taken 48 h after the procedure. In all 4 patients, serum creatinine concentration was assessed 1 week after the procedure; none have developed clinical renal failure, and the serum creatinine concentration available at follow-up did not reach an increase of ≥25% or an increase of ≥0.5 mg/dl from baseline. Three patients committed protocol violations; all received NSAIDs. Thus, 126 ANP patients and 128 control patients were included in the protocol analysis (Fig. 1).
The baseline characteristics of the patients are shown in Table 1.The number of patients with hypertension, diabetes mellitus, and a history of congestive heart failure or myocardial infarction was similar between the ANP and control groups, as was the number receiving angiotensin-converting enzyme inhibitors, angiotensin II receptor blocker, calcium-channel blockers, diuretics, and statins before the angiographic procedure. There were no significant differences in left ventricular ejection fraction (LVEF) measured before the procedure. The LVEF was measured primarily by radionuclide or contrast ventriculography; if these were not available, echocardiography was used. The mean contrast volume administered did not differ significantly between groups.
In terms of renal function, there were no significant differences between the 2 groups in baseline serum creatinine, eGFR, cystatin C, urinary β2-microglobulin, or NAG before the procedure (Table 2).
Changes in renal function and prevalence of CIN
When compared with the control group, ANP infusion of 0.042 μg/kg/min produced a significant decrease in systolic blood pressure (−9.3 ± 14.7 mm Hg vs. −3.2 ± 14.6 mm Hg at 24 h and −8.0 ± 20.0 mm Hg vs. −2.7 ± 14.0 mm Hg at 48 h; both p < 0.001), with an increase in the 2-day urine volume (4,067 ± 1,068 ml vs. 3,686 ± 1,254 ml; p = 0.042). The changes in serum creatinine, eGFR and serum cystatin C, and urinary parameters of β2-microglobulin and NAG at 24 h, 48 h, 1 week, and 1 month after the procedure are shown in Table 2. In the control group, there was a more significant deterioration than in the ANP group of serum creatinine, eGFR, and cystatin C from 48 h to 1 month after the procedure. However, there were no statistically significant differences between the 2 groups in changes in urinary β2-microglobulin or NAG at 48 h, 1 week, and 1 month from baseline values.
The eGFR gradually and slightly deteriorated until 1 week, and was mildly improved at 1 month in the control group, whereas a similar deterioration was observed at 24 h in the ANP group, but was completely restored at 1 week and remained at baseline levels until 1 month (p = 0.016 for the interaction of group with linear trend) (Fig. 2).
Figure 3shows the incidence of CIN using different criteria. The incidence of an increase in serum creatinine of ≥25% or of ≥0.5 mg/dl from baseline was significantly lower in the ANP group (n = 4 of 126, 3.2%) than in the control group (n = 15 of 128, 11.7%) (p = 0.015; odds ratio [OR]: 0.25; 95% confidence interval [CI]: 0.08 to 0.77). The incidence of an increase in serum creatinine of ≥0.5 mg/dl was 8.6% (n = 11) in the control group and 2.4% (3 patients) in the ANP group (p = 0.042; OR: 0.26; 95% CI: 0.07 to 0.95). The incidence of an increase in serum creatinine of ≥25% from baseline was 10.9% (n = 14) in the control group and 3.2% (n = 4) in the ANP group (p = 0.023; OR: 0.27; 95% CI: 0.09 to 0.84).
By univariate analysis, there were 2 significant predictive factors for the incidence of CIN, which was defined as an increase of ≥0.5 mg/dl or ≥25% from baseline serum creatinine level, contrast volume of ≥155 ml, and ANP administration (Table 3).The LVEF, anemia, and the use of other medications such as angiotensin-converting enzyme inhibitors or statins were not associated with the incidence of CIN. Only variables with a value of p < 0.2 on univariate analysis were included in the multivariate model. The use of contrast volume of ≥155 ml (p < 0.001; OR: 6.89; 95% CI: 2.4 to 19.3) and ANP administration (p = 0.016; OR: 0.24; 95% CI: 0.07 to 0.77) were independent predictors for developing CIN. The eGFR levels in patients diagnosed with CIN were much improved at 1 month when compared with those at 48 h (25.7 ± 6.7 ml/min/1.73 m2vs. 21.2 ± 7.9 ml/min/1.73 m2in the control group [n = 15; p = 0.001] and 33.7 ± 6.7 ml/min/1.73 m2vs. 27.2 ± 8.4 ml/min/1.73 m2in the ANP group [n = 4; p = 0.057]). However, the incidence of an increase in serum creatinine of ≥0.5 mg/dl at 1 month was 9.4% (n = 12) in the control group and 1.6% (n = 2) in the ANP group (p = 0.016; OR: 0.16; 95% CI: 0.03 to 0.71). The incidence of an increase of ≥25% was 11.7% (n = 15) in the control group and 1.6% (n = 2) in the ANP group (p = 0.006; OR: 0.12; 95% CI: 0.03 to 0.54). The incidence of an increase of ≥25% or of ≥0.5 mg/dl from baseline at 1 month was 12.5% (n = 16) in the control group and 2.4% (n = 3) in the ANP group (p = 0.006; OR: 0.17; 95% CI: 0.05 to 0.60). On multivariate analysis, the use of contrast volume of ≥155 ml (p < 0.001) and no use of ANP (p = 0.006) were significantly associated with worse renal function at 1 month. There were 19 patients in the control group and 5 patients in the ANP group with an increase in serum creatinine of ≥0.5 mg/dl or ≥25% from baseline during 1-month follow-up (p = 0.006; OR: 0.24; 95% CI: 0.09 to 0.66).
One patient in the control group required temporary dialysis, but there was no significant difference in the need for dialysis between therapies (p = 0.32). The event of congestive heart failure requiring hospital admission occurred in 1 patient in each group during 1-month follow-up, but no other major adverse events were observed.
We showed in the present study that intravenous ANP administration in addition to hydration during 48 h reduces the incidence of CIN and renal dysfunction in patients with chronic renal insufficiency undergoing coronary angiography or intervention.
The pathophysiology of CIN is poorly understood, and little is known about the underlying cellular mechanisms (17); however, they certainly involve the interplay of multiple factors. After contrast exposure, there is a brief period of vasodilatation followed by renal vasoconstriction, which is presumably triggered by angiotensin, vasopressin, and endothelin, resulting in a decrease in renal blood flow (18). Moreover, the stasis of iodinated contrast in the renal tubules and collecting ducts allows for direct cellular injury to and death of renal tubular cells (18,19). The ANP has been reported to have beneficial effects on the events induced by contrast media. These include natriuretic effects; for example, increasing the GFR by dilating the afferent arterioles while constricting the efferent arterioles (20). The ANP also blocks the tubular reabsorption of sodium and chloride, redistributes renal medullary blood flow, and disrupts tubuloglomerular feedback (21,22). With respect to circulating humoral factors, ANP antagonizes the secretion of renin and aldosterone (23) and suppresses endothelin release (24). These renal effects of ANP may prevent CIN by decreasing the period of renal hypoperfusion, ischemia, and the stasis of contrast media. Renal dysfunctions are classified as glomerular, indicated by creatinine, eGFR, and cystatin C levels, and tubular, potentially measured by urinary NAG activity and β2-microglobulin. The renal protective effects of ANP were found to be expressed in creatinine, eGFR, and cystatin C levels, but not in β2-microglobulin or NAG levels. The present findings indicate that ANP is likely to protect glomerular and hemodynamic functions rather than renal tubular function.
The biggest problem in the present study was determining how long ANP should be administered and what dose of ANP should be used. Previous studies have examined the effects of ANP on renal outcome in acute renal failure of various etiologies. One study showed that ANP infusion (0.01, 0.05, or 0.1 μg/kg/min) initiated 30 min before and continued for 30 min after the angiographic procedure did not reduce the incidence of CIN in patients with chronic renal insufficiency (14). In another study, ANP had no beneficial effect on the need for dialysis in a heterogeneous group of patients with acute renal failure (25). The failure to show a clear-cut beneficial effect of ANP in acute renal failure in these studies could be explained by an excessive dose of ANP (0.2 μg/kg/min) and a short infusion period. Because these studies showed that patients treated with ANP had significantly lower blood pressure than control groups, ANP infusion might induce a marked and sudden decrease in blood pressure, followed by reduced renal perfusion, particularly in cases of acute renal failure, which is characterized by a loss of autoregulatory capacity (26). Additionally, hypotension may account for the lack of beneficial effect by ANP administration. In contrast, another study showed that ANP infused at a rate of 0.05 μg/kg/min for 5 days decreased the probability of dialysis in ischemic acute renal failure after cardiac surgery (27). Furthermore, it has previously been shown in patients with ischemic acute renal failure that ANP at an infusion rate of 0.05 μg/kg/min induces selective dilatation of the renal afferent arterioles with an increase of approximately 40% in renal blood flow and GFR without any major hemodynamic disturbances, such as a decrease in systemic vascular resistance or mean arterial pressure; these effects are not achieved with a low dose of ANP (0.025 μg/kg/min) (11). In these studies, however, most patients received dopamine for arterial pressure support during the study period. Without dopamine, ANP might have induced a marked and sudden decrease in blood pressure. The results of these previous studies led us to choose an infusion rate of 0.042 μg/kg/min and infusion for 48 h after the procedure in addition to a 4- to 6-h infusion before it; our selected dose and infusion time could explain the beneficial effects of ANP on renal outcome in the present study.
CIN is diagnosed when serum creatinine concentrations reach a peak value within 1 to 2 days after contrast media administration with an increase over the baseline concentration lasting 1 to 5 days (18,28). However, the serum creatinine peak is postponed in patients with pre-existing impaired renal function, and the increase may last for 7 to 21 days (29). In the present study, we measured cystatin C as well as serum creatinine and eGFR until 1 month after the procedure. Cystatin C has been identified as a novel biomarker that is more sensitive in detecting early kidney dysfunction than creatinine and eGFR (30). Because it is conceivable that cystatin C, a marker of GFR, is not affected by tubular transport, it has been recommended to include serum level monitoring of cystatin C when assessing kidney function in patients undergoing coronary angiography (31). In the present study, serum creatinine, eGFR, and cystatin C levels were deteriorated, reaching a trough at 1 week after the procedure, and the deterioration persisted even up to 1 month in the control group. In contrast, although there was a similar deterioration of these markers for kidney dysfunction at 24 h in the ANP group, they then improved considerably and renal functions were restored to baseline by 1 month after the procedure. These findings indicate that ANP administration has beneficial effects on renal functions for at least 1 month. It has been shown that even small changes in the deterioration of renal function can have a significant impact on mortality (3,32). This was recently confirmed in a large database of 27,608 patients who were treated with contrast media during coronary angiography (33). Thus, the prevention of small changes in renal function may be important, as seen in the present study with respect to serum creatinine, eGFR, and cystatin C levels.
Larger contrast volumes have been associated with an increased risk of CIN (18). The nephritic effect of contrast media is dose dependent: ordinarily, the higher the dose, the higher the risk for CIN (17). Although no definitive threshold limit of contrast volume has yet been established, contrast volumes >100 to 200 ml are associated with a higher incidence of CIN in high-risk patients (17,28). In the present study, multivariate analysis showed that the incidence of the deterioration of renal function even at 1 month after the procedure were independently prevented by ANP administration regardless of using a contrast volume >155 ml.
The present study was a single-center study and was not blinded. A larger, multicenter, double-blinded, adequately powered randomized trial is required to confirm the beneficial effects of ANP administration on CIN.
The present study shows that a systemic protocol of continuous intravenous hydration with ANP is a safe and effective method of preventing CIN in patients with chronic renal insufficiency undergoing angiographic procedures. Moreover, renal function is maintained by ANP up to 1 month after the procedure. These results suggest the possibility that ANP administration may reduce long-term mortality as well as the initiation of dialysis after coronary angiography and intervention.
- Abbreviations and Acronyms
- atrial natriuretic peptide
- confidence interval
- contrast-induced nephropathy
- estimated glomerular filtration rate
- left ventricular ejection fraction
- nonsteroidal anti-inflammatory drugs
- Received June 4, 2008.
- Revision received September 19, 2008.
- Accepted October 13, 2008.
- American College of Cardiology Foundation
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