Introduction: The role of curcuminoids, a striking antioxidant, in prevention of contrast-induced acute kidney injury (CI-AKI) remains unknown. We aimed to evaluate the efficacy and safety of curcuminoids in preventing CI-AKI in patients undergoing elective coronary angiography (CAG) and/or percutaneous coronary intervention (PCI). Methods: We randomized 114 patients who were undergoing elective CAG and/or PCI to receive curcuminoids, 4 g/day (1 day before and 1 day after the procedure, n = 56), or placebo (n = 58). Serum creatinine was assessed at baseline, 12, 24, and 48 h after contrast exposure. The primary endpoint was development of CI-AKI defined as serum creatinine increase ≥0.3 mg/dL within 48 h after contrast exposure. The secondary endpoint was the occurrence of kidney injury defined by >30% increase in urine neutrophil gelatinase-associated lipocalin (NGAL). Results: Baseline characteristics were comparable between the two groups. Seven (12.7%) in curcuminoids group and eight (14.0%) in placebo group developed CI-AKI (p = 0.84). The incidence of increased urine NGAL was comparable in the placebo and curcuminoids group (39.6% vs. 50%, respectively; p = 0.34). None in both groups had drug-related adverse events. Conclusion: This is a pilot study to demonstrate the safety and tolerability of curcuminoids in patients undergoing elective CAG and/or PCI. Curcuminoids have no protective effects against kidney injury after elective CAG and/or PCI.

Contrast-induced acute kidney injury (CI-AKI) is a major complication with adverse outcomes after contrast medium exposure. The incidence of CI-AKI is 1–2% in patients with normal renal function [1], but increases up to 25% in patients with certified risk factors, such as chronic kidney disease (CKD), diabetes, congestive heart failure, advanced age, and concurrent use of nephrotoxic agents [2, 3]. It is well established that the occurrence of CI-AKI increases the morbidity and mortality [2]. Recent evidence demonstrates that CI-AKI is associated with higher risk of major cardiovascular event at 5 years [4]. Therefore, strategies to prevent CI-AKI are essential. Currently, CI-AKI is defined as an acute deterioration in renal function after intravenous administration of contrast medium measured by an absolute increase in serum creatinine ≥0.3 mg/dL from baseline within 48 h after contrast medium injection without evidence of other causes [5]. However, the changing of serum creatinine within 48 h after contrast medium injection might result in a delay for diagnosing CI-AKI. The urine neutrophil gelatinase-associated lipocalin (NGAL) has been proved to be an early, sensitive, noninvasive biomarker for CI-AKI following invasive cardiology procedures [6, 7]. Therefore, the earlier detection of CI-AKI with urine NGAL could be diagnostically and therapeutically beneficial.

The mechanisms of CI-AKI are complex but may be related to direct renal tubular toxicity, vasoconstriction, and high oxidative stress [8]. Curcuminoids, a commonly used coloring agent and spice in food, have been shown to possess the striking antioxidant effect [9, 10]. Data from our group and others have demonstrated cardiovascular protective effects of curcuminoids in cardiac patients [9, 11, 12]. Therefore, we aimed to investigate whether curcuminoids could prevent the occurrence of CI-AKI in patients undergoing elective coronary angiography (CAG) and/or percutaneous coronary intervention (PCI) compared to placebo. We also examined the incidence of increased urine NGAL after elective CAG and/or PCI to detect the possibly minor kidney injury between curcuminoids and placebo groups.

Study Population

This study was a randomized, double-blind, placebo-controlled, single-center study performed between January 2013 and January 2015 at Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Patients aged ≥18 years who underwent elective CAG and/or PCI were eligible in this study. Exclusion criteria included hypersensitivity to contrast medium or curcuminoids, AKI from any causes as evidenced by a change in serum creatinine ≥0.3 mg/dL [5] within 14 days prior to the study, acute heart failure, hemodynamic instability, having received nonsteroidal anti-inflammatory drugs or aminoglycoside within 14 days prior to the study, serum alanine-aminotransferase concentration 3 times greater than the upper limit of normal, or bilirubin concentration 2 times greater than upper limit of normal.

Study Protocol

Approval was obtained from the Ethics Committee of the Faculty of Medicine, Chiang Mai University (Thai Clinical Trial Registry number, TCTR20160721001). The study was performed according to Declaration of Helsinki and Good Clinical Practice guidelines. The study was reported in accordance with the CONSORT statement extension for randomized pilot and feasibility trials [13]. All patients provided written informed consent to participate in the study. Curcuminoids and placebo used in the present study were provided in caplet form by the Research and Development Institute, Government Pharmaceutical Organization, Bangkok, Thailand. One curcuminoid capsule contained 250 mg of curcuminoids, which consisted of curcumin, desmethoxycurcumin, and bisdemethoxycurcumin, in a ratio of 1.0:0.6:0.3, respectively, confirmed by high-performance liquid chromatography/mass spectrometry. The capsules containing curcuminoids and placebo were opaque and could not be distinguished on the basis of appearance or flavor.

Enrolled patients were randomly allocated to receive placebo or curcuminoids 4 capsules 4 times/day (4 g/day) in addition to standard therapy according to standard guideline [5]. Curcuminoids were administered over a 24-h period, beginning 12 h before CAG and/or PCI and continuing until 12 h after the procedure. Patient with CKD stage 3–5 (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) and left ventricular ejection fraction >40% was given intravenous isotonic saline (1 mL/kg/h) starting 12 h before procedure and continuing until 12 h after contrast medium administration. To assign patients to curcuminoids or placebo, a block randomization sequence was obtained by a statistical consultant who was not involved in the study. Assigned therapy was fully blinded; operators and investigators performing post-procedural assessment were not aware of the randomization assignment. Randomization assignments were concealed from the participants and study team.

Blood samples were taken to measure serum creatinine concentrations before randomization and at 12, 24, and 48 h after contrast medium administration. Renal function was assessed using eGFR calculated by CKD Epidemiology Collaboration formula [14]. Urine samples were collected at baseline and 4 h postcoronary procedures. Samples were stored at −70°C until assayed. The urine NGAL concentrations were measured using a commercially ELISA kit (Bioporto, Denmark) following the manufacturer’s instructions. All urine specimens were diluted to achieve concentration for optimal density according to the ELISA kit instruction before performing an ELISA assay to fit the concentrations of respective NGAL protein in the linear range of the standard curve. The measurements were made in duplicate and in a blinded fashion.

The primary endpoint was to compare the incidence of CI-AKI in patients undergoing elective CAG and/or PCI between curcuminoid and placebo groups. The secondary endpoint was to compare the incidence of the increase in urine NGAL after elective CAG and/or PCI between curcuminoid and placebo groups.

Definitions

The CI-AKI was defined as an increase in serum creatinine concentration ≥0.3 mg/dL or ≥1.5 times from baseline serum creatinine within 48 h after contrast medium injection accompanied with the absence of other causes of AKI [5, 15]. The increase in urine NGAL was defined as an increase in urine NGAL >30% after procedure compared to baseline urine NGAL [7].

Sample Size Calculation

Since this study was a pilot study, the number of participants to be recruited was estimated using the stepped rules of thumb proposed by Whitehead et al. [16]. A sample size of 50 participants per group was required as giving standardized effect sizes <0.1 and 80% powered main trial.

Statistical Analysis

All analyses were done on an intention-to-treat basis. Demographic and perioperative variables were compared between groups with t test for normally distributed values; otherwise, the Mann-Whitney U test was used. Proportions were compared by Fisher’s exact test. Continuous variables are presented as mean ± SD or median (interquartile range) when appropriate. Categorical variables are displayed as percentages. Risk ratio (RR) and 95% confidence interval (CI) to assess the risk of the primary endpoint according to potential confounding variables were determined by generalized linear model. Multivariable analyses were performed for variables with a p value <0.1 in univariable analysis. The linear mixed model was used to evaluate the effect of treatment assignments on serum creatinine and urine NGAL changes. A two-tailed p value <0.05 was considered statistically significant. The statistical software STATA version 16 was used for analyses.

We screened 138 patients between January 2013 and January 2015. Of those, 114 patients who met the inclusion criteria were randomly assigned to a curcuminoid group (n = 56) or a control group (n = 58) (Fig. 1). The most common reason patients did not participate in the study was their reluctance to stay in the hospital for 48 h following the procedure. All randomized patients were given their assigned treatment, and all completed follow-up and were included in the analysis. The baseline clinical characteristics of the two groups are shown in Table 1, which are well balanced with the exception of those receiving curcuminoids who tend to have a lower prevalence of diabetes. There were no significant differences of baseline serum creatinine level and urine NGAL between the two groups. Of the 114 patients, 29.8% underwent diagnostic CAG only and 70.2% had additional PCI performed. The median eGFR was 75.0 (59.9–95.0) mL/min/1.73 m2, and 29 patients (25.4%) had baseline eGFR <60 mL/min/1.73 m2. The volume of contrast medium administration was not different between the curcuminoids and control groups (Table 2).

Fig. 1.

CONSORT flow diagram.

Fig. 1.

CONSORT flow diagram.

Close modal
Table 1.

Baseline patient characteristics

VariablesCurcuminoid group (n = 56)Control group (n = 58)
Age, years 64.5±10.9 63.8±11.3 
Weight, kg 59.0±10.5 58.4±12.8 
Male sex, n (%) 37 (66.1) 33 (56.9) 
Systolic blood pressure, mm Hg 137.8±24.8 132.3±20.2 
Diastolic blood pressure, mm Hg 73.4±13.4 72.6±12.1 
Current smoking, n (%) 2 (3.6) 3 (5.2) 
Anemia (hemoglobin <10 g/dL), n (%) 4 (7.1) 5 (8.6) 
Comorbidities, n (%) 
 Diabetes 11 (19.6) 21 (36.2) 
 Hypertension 42 (75.0) 35 (60.3) 
 Dyslipidemia 29 (51.8) 26 (44.8) 
 Coronary artery disease 20 (35.7) 23 (39.7) 
 Heart failure 11 (19.6) 13 (22.4) 
 Stroke 2 (3.6) 4 (6.9) 
Medications, n (%) 
 Aspirin 53 (94.6) 58 (100) 
 Clopidogrel 44 (78.6) 47 (81.0) 
 ACEI or ARB 45 (80.4) 42 (72.4) 
 Beta-blocker 40 (71.4) 48 (82.8) 
 Diuretic 16 (28.6) 18 (31.0) 
 Calcium channel blocker 12 (21.4) 12 (20.7) 
 Statin 48 (85.7) 51 (87.9) 
LVEF, % 55.6±15.9 53.3±16.9 
Serum creatinine, mg/dL 1.0 (0.8–1.2) 1.0 (0.8–1.3) 
eGFR, mL/min/1.73 m2 80.9 (61.9–97.8) 71.6 (50.8–91.2) 
eGFR <60 mL/min/1.73 m2, n (%) 12 (21.4) 17 (29.3) 
Urine NGAL, ng/mL 25.4 (12.1–64.7) 23.4 (12.8–69.6) 
VariablesCurcuminoid group (n = 56)Control group (n = 58)
Age, years 64.5±10.9 63.8±11.3 
Weight, kg 59.0±10.5 58.4±12.8 
Male sex, n (%) 37 (66.1) 33 (56.9) 
Systolic blood pressure, mm Hg 137.8±24.8 132.3±20.2 
Diastolic blood pressure, mm Hg 73.4±13.4 72.6±12.1 
Current smoking, n (%) 2 (3.6) 3 (5.2) 
Anemia (hemoglobin <10 g/dL), n (%) 4 (7.1) 5 (8.6) 
Comorbidities, n (%) 
 Diabetes 11 (19.6) 21 (36.2) 
 Hypertension 42 (75.0) 35 (60.3) 
 Dyslipidemia 29 (51.8) 26 (44.8) 
 Coronary artery disease 20 (35.7) 23 (39.7) 
 Heart failure 11 (19.6) 13 (22.4) 
 Stroke 2 (3.6) 4 (6.9) 
Medications, n (%) 
 Aspirin 53 (94.6) 58 (100) 
 Clopidogrel 44 (78.6) 47 (81.0) 
 ACEI or ARB 45 (80.4) 42 (72.4) 
 Beta-blocker 40 (71.4) 48 (82.8) 
 Diuretic 16 (28.6) 18 (31.0) 
 Calcium channel blocker 12 (21.4) 12 (20.7) 
 Statin 48 (85.7) 51 (87.9) 
LVEF, % 55.6±15.9 53.3±16.9 
Serum creatinine, mg/dL 1.0 (0.8–1.2) 1.0 (0.8–1.3) 
eGFR, mL/min/1.73 m2 80.9 (61.9–97.8) 71.6 (50.8–91.2) 
eGFR <60 mL/min/1.73 m2, n (%) 12 (21.4) 17 (29.3) 
Urine NGAL, ng/mL 25.4 (12.1–64.7) 23.4 (12.8–69.6) 

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NGAL, neutrophil gelatinase-associated lipocalin.

Table 2.

Periprocedural features

VariablesCurcuminoid group (n = 56)Control group (n = 58)
Indications for CAG and/or PCI, n (%) 
 Post-MI angina 4 (7.1) 2 (3.4) 
 NSTEMI or unstable angina 19 (33.9) 19 (32.8) 
 STEMI 7 (12.4) 13 (22.4) 
 Heart failure 4 (7.1) 7 (12.1) 
 Chronic stable angina 20 (35.7) 17 (29.3) 
 Preoperative cardiac surgery 2 (3.6) 
Intervention, n (%) 
 CAG only 19 (33.9) 15 (25.9) 
 Balloon angioplasty only 1 (1.8) 1 (1.7) 
 Stent placement 36 (64.3) 42 (72.4) 
Contrast volume, mL 60 (25–120) 70 (30–120) 
VariablesCurcuminoid group (n = 56)Control group (n = 58)
Indications for CAG and/or PCI, n (%) 
 Post-MI angina 4 (7.1) 2 (3.4) 
 NSTEMI or unstable angina 19 (33.9) 19 (32.8) 
 STEMI 7 (12.4) 13 (22.4) 
 Heart failure 4 (7.1) 7 (12.1) 
 Chronic stable angina 20 (35.7) 17 (29.3) 
 Preoperative cardiac surgery 2 (3.6) 
Intervention, n (%) 
 CAG only 19 (33.9) 15 (25.9) 
 Balloon angioplasty only 1 (1.8) 1 (1.7) 
 Stent placement 36 (64.3) 42 (72.4) 
Contrast volume, mL 60 (25–120) 70 (30–120) 

CAG, coronary angiography; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

The primary endpoint of an occurrence of CI-AKI was found in 7 patients (12.7%) in curcuminoid group and 8 patients (14.0%) in control group (RR 0.91; 95% CI, 0.35–2.33, p = 0.84). After adjustment for diabetes status, the risk of CI-AKI development was not different between the two groups (RR 1.04; 95% CI, 0.41–2.62). Furthermore, the incidence of increased urine NGAL ≥30% after procedure was not different between the two groups (39.6% in curcuminoid group vs. 50.0% in control group, p = 0.34, respectively). The levels of serum creatinine and urine NGAL after contrast medium administration at each time point were not different between the two groups (Fig. 2). Neither patients in curcuminoid group nor those in control group experienced drug-related adverse events, and none discontinued the studied drugs prematurely.

Fig. 2.

AKI makers before and after contrast medium administration. a Serum creatinine before and 12, 24, and 48 h after contrast medium administration. b Urine NGAL before and 4 h after contrast medium administration. The linear mixed model was used to evaluate the effect of treatment assignments on serum creatinine and urine NGAL changes.

Fig. 2.

AKI makers before and after contrast medium administration. a Serum creatinine before and 12, 24, and 48 h after contrast medium administration. b Urine NGAL before and 4 h after contrast medium administration. The linear mixed model was used to evaluate the effect of treatment assignments on serum creatinine and urine NGAL changes.

Close modal

This is a pilot study to evaluate the efficacy and safety of curcuminoid therapy for the prevention of CI-AKI in patients undergoing elective CAG and/or PCI. To the best of our knowledge, the effect of curcuminoids has never been examined in this group of patients previously. We found that the incidence of CI-AKI was not different between curcuminoid and placebo groups. The reason why we could not demonstrate renal protective effect of curcuminoids in patients undergoing coronary procedures might be explained by the low incidence of CI-AKI in the study. In this study, the incidence of CI-AKI defined by rising of serum creatinine in placebo group was 14.0%, while other studies that could demonstrate renal protective effect of the agent of interest had a background incidence of CI-AKI around 23–24% [17, 18]. Also, the patients in this study had high baseline eGFR of 75.0 (59.9–95.0) mL/min/1.73 m2 and only 25.4% of them had baseline eGFR <60 mL/min/1.73 m2.

We have demonstrated that there was no difference between the curcuminoid group and the control group in terms of the incidence of increased urine NGAL following elective coronary procedure. Urine NGAL is well described as an early, sensitive, and noninvasive biomarker for AKI [19]. The NGAL is a protein that is covalently bound to gelatinase in neutrophils and is normally expressed at very low levels in a variety of human tissues, including the kidney, stomach, colon, and lung [20]. NGAL expression is significantly increased systemically and in injured distal renal tubular epithelial cells during AKI. Urine NGAL concentrations rise due to impaired NGAL reabsorption by the damaged proximal tubular cells and direct excretion by the damaged distal tubular cells [21]. Previous experimental and clinical studies have demonstrated that urine NGAL can be easily detected in the blood and urine shortly after AKI [22]. Urine NGAL has long been recognized as an early marker and predictor of CI-AKI severity in CKD patients undergoing coronary procedures [23]. As a result, earlier detection of CI-AKI with urine NGAL could be diagnostically and therapeutically advantageous. Furthermore, because urine NGAL is more sensitive than serum creatinine to detect kidney, it may be a useful tool for detecting minor kidney injury in the absence of rising serum creatinine.

The strength of this study is that it was a randomized, placebo-controlled study with reasonable sample size for pilot study. Moreover, urine NGAL, a sensitive biomarker for AKI, was used for early detection of CI-AKI. However, there were several limitations of this study. First, the follow-up period after coronary procedure was merely 48 h. Although CI-AKI commonly occurs in the first 48 h after contrast medium exposure, it could occur as long as 7 days after the exposure. Longer follow-up time may be needed to detect CI-AKI. Second, CI-AKI is a condition of exclusion as there is no single laboratory measure for diagnosing this condition. There are several causes of AKI after coronary procedure accompanied with contrast medium administration such as atheroembolic disease, cardiorenal syndrome, and sepsis. Thus, measurement bias is inevitable.

In the present study, we demonstrated that curcuminoids did not reduce the incidence of CI-AKI, as measured by an increase in serum creatinine and urine NGAL, after elective coronary procedure. These findings could be due to the fact that the studied population was a relatively low-risk group to develop CI-AKI. Therefore, the degree of kidney injury after contrast medium administration may be small and the power of the study might not be sufficient due to a small number of sample size. Based on results of this study, the sample size required with a power of 80% to detect the difference between curcuminoid and control groups in the incidence of increased urine NGAL post-CAG and/or PCI is 377 participants per group. We believe it is feasible to conduct these types of studies, as 114 out of 138 screened patients participated, and all patients adhered to the treatment since curcuminoids only required a 24-h period.

While curcuminoids have not demonstrated kidney-protective effects in our study or in other studies of patients undergoing elective abdominal aortic aneurysm repair [24] or CKD [25], it is necessary to confirm their preventive effect on kidney injury, as indicated by increased urine NGAL, in a larger population at high risk for CI-AKI. In conclusion, this is a pilot study to demonstrate the safety and tolerability of curcuminoids in patients undergoing elective CAG and/or PCI. Curcuminoids could not prevent the occurrence of kidney injury detected by an increase in serum creatinine and urine NGAL following contrast medium administration in patients with a low-risk profile.

Effect of curcuminoids on contrast-induced nephropathy after coronary intervention was approved by the Ethics Committee of the Faculty of Medicine, Chiang Mai University, approval number MED-13-1404-FB. The investigations were carried out in accordance with the Declaration of Helsinki, including written informed consent of all participants.

The authors declare no conflict of interest.

This study was funded by Thai Traditional Medical Knowledge Fund (31/2556), Thailand and the Faculty of Medicine Endowment Fund for medical research (44/2556), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Research idea and study design: Kajohnsak Noppakun, Janjira Jitraknatee, Yuttitham Suteeka, Arintaya Phrommintikul, and Wanwarang Wongcharoen; data acquisition: Janjira Jitraknatee, Yuttitham Suteeka, and Siriluck Gunaparn; data analysis/interpretation: Kajohnsak Noppakun, Janjira Jitraknatee, Chidchanok Ruengorn, Surapon Nochaiwong, and Wanwarang Wongcharoen; statistical analysis: Kajohnsak Noppakun, Chidchanok Ruengorn, Surapon Nochaiwong, and Wanwarang Wongcharoen; manuscript preparation, review, and editing: Arintaya Phrommintikul and Wanwarang Wongcharoen; supervision or mentorship: Wanwarang Wongcharoen. Each author contributed important intellectual content to the content of this manuscript, and its drafting or revision, and accepted accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

This study does not cover the posting of data in public databases. However, data are available upon request directly to the corresponding author and are subject to approval by the Ethics Committee of the Faculty of Medicine at Chiang Mai University, Chiang Mai, Thailand.

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