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Effect of Calcium Dobesilate in Preventing Contrast-Induced Nephropathy in Patients with Diabetes and Chronic Kidney Disease

Abstract

OBJECTIVES:

This study assessed the protective effect of calcium dobesilate against contrast-induced nephropathy (CIN) after coronary angiography (CAG) or percutaneous coronary intervention (PCI) in patients with diabetes and chronic kidney disease (CKD).

METHODS:

A total of 130 patients with diabetes and CKD estimated glomerular filtration rate: 30-90 mL/min/1.73m2 were enrolled and included in the analysis. They were divided into experimental (n=65) and control groups (n=65). Patients in the experimental group were administered oral calcium dobesilate (500 mg) three times daily for 2 days before and 3 days after the procedure. The serum creatinine (SCr), cystatin C (Cys C), and neutrophil gelatinase-associated lipocalin (NGAL) levels were measured before and after the procedure.

RESULTS:

The mean SCr level at 24h after the procedure was found to be significantly lower in the experimental group than in the control group (79.1±19.6 μmol/L vs. 87.0±19.3 μmol/L, p=0.023). However, the Cys C and NGAL levels were not significantly different between the two groups at all measurement time points (all p>0.05). The incidence of CIN defined by the SCr level was significantly lower in the experimental group than in the control group (3 [4.6%] vs. 13 [20.0%], p=0.017). However, the incidence of CIN defined by the Cys C level was not statistically different between the two groups (7 [10.8%] vs. 7 [10.8%], p=1.000).

CONCLUSIONS:

This study revealed that calcium dobesilate has no preventive effect against CIN in patients with diabetes and CKD.

Calcium dobesilate; Contrast-Induced Acute Kidney Injury; Diabetes Mellitus; Chronic Renal Insufficiency; Coronary Angiography


INTRODUCTION

Iodinated contrast medium (CM) is widely used with the development of coronary artery intervention therapies such as coronary angiography (CAG) and percutaneous coronary intervention (PCI). Contrast-induced nephropathy (CIN) is a critical complication of CM. CIN is the third most common cause of hospital-acquired acute kidney failure. The incidence of CIN in the general population is approximately 3% (11. Mautone A, Brown JR. Contrast-induced nephropathy in patients undergoing elective and urgent procedures. J Interv Cardiol. 2010;23(1):78-85. https://doi.org/10.1111/j.1540-8183.2009.00523.x
https://doi.org/10.1111/j.1540-8183.2009...
). However, the risk factors for CIN are diabetes mellitus, chronic renal dysfunction, advanced age, and congestive heart failure (22. Yeganehkhah MR, Iranirad L, Dorri F, Pazoki S, Akbari H, Miryounesi M, et al. Comparison between three supportive treatments for prevention of contrast-induced nephropathy in high-risk patients undergoing coronary angiography. Saudi J Kidney Dis Transpl. 2014;25(6):1217-23. https://doi.org/10.4103/1319-2442.144255
https://doi.org/10.4103/1319-2442.144255...
,33. Aurelio A, Durante A. Contrast-induced nephropathy in percutaneous coronary interventions: pathogenesis, risk factors, outcome, prevention and treatment. Cardiology. 2014;128(1):62-72. https://doi.org/10.1159/000358042
https://doi.org/10.1159/000358042...
). The incidence of CIN in patients with diabetes can reach up to 29.4% (44. Kim CS, Choi JS, Park JW, Bae EH, Ma SK, Jeong MH, et al. Concomitant renal insufficiency and diabetes mellitus as prognostic factors for acute myocardial infarction. Cardiovasc Diabetol. 2011;10:95. https://doi.org/10.1186/1475-2840-10-95
https://doi.org/10.1186/1475-2840-10-95...
). CIN can increase the in-hospital costs and duration as well as lead to hemodialysis and death (55. Liss P, Persson PB, Hansell P, Lagerqvist B. Renal failure in 57 925 patients undergoing coronary procedures using iso-osmolar or low-osmolar contrast media. Kidney Int. 2006;70(10):1811-7. https://doi.org/10.1038/sj.ki.5001887
https://doi.org/10.1038/sj.ki.5001887...
,66. Gupta R, Gurm HS, Bhatt DL, Chew DP, Ellis SG. Renal failure after percutaneous coronary intervention is associated with high mortality. Catheter Cardiovasc Interv. 2005;64(4):442-8. https://doi.org/10.1002/ccd.20316
https://doi.org/10.1002/ccd.20316...
). In addition, the incidence of long-term cardiovascular adverse events in patients with CIN is far higher than that in patients without CIN (77. Narula A, Mehran R, Weisz G, Dangas GD, Yu J, Genereux P, et al. Contrast-induced acute kidney injury after primary percutaneous coronary intervention: results from the HORIZONS-AMI substudy. Eur Heart J. 2014;35(23):1533-40. https://doi.org/10.1093/eurheartj/ehu063
https://doi.org/10.1093/eurheartj/ehu063...
). Thus, CIN has become a hot topic in both the kidney and heart research fields.

Intravenous hydration therapy can reduce the incidence of CIN; hence, hydration has become the most widely used method for preventing CIN (88. Thomsen HS, Morcos SK, Almen T, Bellin MF, Bertolotto M, Bongartz G, et al. Nephrogenic systemic fibrosis and gadolinium-based contrast media: updated ESUR Contrast Medium Safety Committee guidelines. Eur Radiol. 2013;23(2):307-18. https://doi.org/10.1007/s00330-012-2597-9
https://doi.org/10.1007/s00330-012-2597-...
). In addition to hydration, N-acetylcysteine, statins, and other drugs are used to prevent CIN (99. Wang N, Qian P, Kumar S, Yan TD, Phan K. The effect of N-acetylcysteine on the incidence of contrast-induced kidney injury: A systematic review and trial sequential analysis. Int J Cardiol. 2016;209:319-27. https://doi.org/10.1016/j.ijcard.2016.02.083
https://doi.org/10.1016/j.ijcard.2016.02...
-10. Liu LY, Liu Y, Wu MY, Sun YY, Ma FZ. Efficacy of atorvastatin on the prevention of contrast-induced acute kidney injury: a meta-analysis. Drug Des Devel Ther. 2018;12:437-44. https://doi.org/10.2147/DDDT.S149106
https://doi.org/10.2147/DDDT.S149106...
1111. Ali-Hasan-Al-Saegh S, Mirhosseini SJ, Ghodratipour Z, Sarrafan-Chaharsoughi Z, Rahimizadeh E, Karimi-Bondarabadi AA, et al. Strategies Preventing Contrast-Induced Nephropathy After Coronary Angiography: A Comprehensive Meta-Analysis and Systematic Review of 125 Randomized Controlled Trials. Angiology. 2017;68(5):389-413. https://doi.org/10.1177/0003319716661445
https://doi.org/10.1177/0003319716661445...
), although the effects of these drugs are controversial and require confirmation. However, the effects of these agents on CIN remain unclear in patients with diabetes and chronic kidney disease (CKD). Calcium dobesilate, a vascular protective drug, is used for the treatment of microvascular diseases (1212. Tejerina T, Ruiz E. Calcium dobesilate: pharmacology and future approaches. Gen Pharmacol. 1998;31(3):357-60. https://doi.org/10.1016/S0306-3623(98)00040-8
https://doi.org/10.1016/S0306-3623(98)00...
) such as diabetic retinopathy and diabetic nephropathy. Some studies have suggested that calcium dobesilate can reduce blood viscosity, platelet activity, and capillary permeability (1313. Yun KJ, Kim HJ, Kim MK, Kwon HS, Baek KH, Roh YJ, et al. Risk Factors for the Development and Progression of Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus and Advanced Diabetic Retinopathy. Diabetes Metab J. 2016;40(6):473-81. https://doi.org/10.4093/dmj.2016.40.6.473
https://doi.org/10.4093/dmj.2016.40.6.47...
), as well as alleviate microcirculatory and hemorheological abnormalities (1414. Szlavy L, Repa I, Lengye I, Lamboy L. Effects of intravenous streptokinase and CLS 2210 (calcium dobesilate) on the biochemical markers of early acute myocardial infarction: a historic comparison with both studies. Angiology. 1992;43(9):741-7. https://doi.org/10.1177/000331979204300904
https://doi.org/10.1177/0003319792043009...
). The pathogenesis of CIN might be related to vasoconstriction, inflammation, and cytotoxicity caused by contrast agents (1515. Wichmann JL, Katzberg RW, Litwin SE, Zwerner PL, De Cecco CN, Vogl TJ, et al. Contrast-Induced Nephropathy. Circulation. 2015;132(20):1931-6. https://doi.org/10.1161/CIRCULATIONAHA.115.014672
https://doi.org/10.1161/CIRCULATIONAHA.1...
-16. Mamoulakis C, Tsarouhas K, Fragkiadoulaki I, Heretis I, Wilks MF, Spandidos DA, et al. Contrast-induced nephropathy: Basic concepts, pathophysiological implications and prevention strategies. Pharmacol Ther. 2017;180:99-112. https://doi.org/10.1016/j.pharmthera.2017.06.009
https://doi.org/10.1016/j.pharmthera.201...
17. Kwasa EA, Vinayak S, Armstrong R. The role of inflammation in contrast-induced nephropathy. Br J Radiol. 2014;87(1041):20130738. https://doi.org/10.1259/bjr.20130738
https://doi.org/10.1259/bjr.20130738...
1818. Kurtul A, Ornek E. Platelet to Lymphocyte Ratio in Cardiovascular Diseases: A Systematic Review. Angiology. 2019;70(9):802-18. https://doi.org/10.1177/0003319719845186
https://doi.org/10.1177/0003319719845186...
). Hence, we speculated that calcium dobesilate might play a preventive role in CIN through the aforementioned mechanism. Thus, this study assessed whether calcium dobesilate has a potential protective effect against CIN in patients receiving CAG or PCI.

MATERIALS AND METHODS

This study was a prospective, randomized, single-blind, controlled trial. This study was funded by the Chinese Cardiovascular Association V.G Foundation (No. 2017-CCA-VG-021) and the clinical medical research project of the Second Hospital of Tianjin Medical University (2020LC12). All patients signed an informed consent form before participating in the study. This study was conducted in accordance with the Declaration of Helsinki, a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects (1919. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-4. https://doi.org/10.1001/jama.2013.281053
https://doi.org/10.1001/jama.2013.281053...
).

Study population

We included 160 patients with diabetes who had been diagnosed with stage 2-3 CKD (estimated glomerular filtration rate [eGFR] was between 30 and 90 mL/min/1.73m2) and scheduled for coronary angiography between April 2017 and December 2019. The exclusion criteria were as follows: (1) acute myocardial infarction requiring primary PCI; (2) severe heart failure, above New York Heart Association (NYHA) class III; (3) infectious diseases, severe hepatic insufficiency, and acute cerebrovascular diseases; (4) severe coagulation disorder and active bleeding; (5) diabetic ketoacidosis, lactic acidosis, or other acute complications of diabetes; (6) other clinical conditions causing renal function damage; (7) pregnancy or malignant tumor; and (8) allergy to calcium dobesilate.

Sample size calculation

Based on the study by Gruberg et al. (2020. Gruberg L, Mintz GS, Mehran R, Gangas G, Lansky AJ, Kent KM, et al. The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency. J Am Coll Cardiol. 2000;36(5):1542-8. https://doi.org/10.1016/S0735-1097(00)00917-7
https://doi.org/10.1016/S0735-1097(00)00...
), the incidence of CIN in patients with diabetes and CKD following CAG was reported to be 37%. This study was the first to evaluate the preventive value of calcium dobesilate; hence, we assumed that the preventive effect of calcium dobesilate was not less than that of N-acetylcysteine. We used the incidence of N-acetylcysteine, which was 11% according to the study by Albarazy et al. (2121. Alharazy SM, Kong N, Saidin R, Gafor AH, Maskon O, Mohd M, et al. Serum neutrophil gelatinase-associated lipocalin and cystatin C are early biomarkers of contrast-induced nephropathy after coronary angiography in patients with chronic kidney disease. Angiology. 2014;65(5):436-42. https://doi.org/10.1177/0003319713483918
https://doi.org/10.1177/0003319713483918...
), to calculate the sample size with a power of 80% and α=0.05, with a 95% confidence interval (CI). Consequently, 40 patients in each group will be required to show a significant result (2222. D'Agostino RB, Chase W, Belanger A. The Appropriateness of Some Common Procedures for Testing the Equality of Two Independent Binomial Populations. The American Statistician. 1988;42(3):198-202.). Considering the loss and refusal to follow-up, 80 patients were required in each group.

Study protocol

The patients were allocated 1:1 into experimental and control groups according to a systematic randomization computer-generated list by an independent medical staff who was not involved in the study. All patients received the standard treatment of aspirin and clopidogrel for coronary heart disease. In addition, other treatments such as statins, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, nitrates, calcium channel blockers, and diuretics were used according to the underlying diseases of the patients. The experimental group received an oral dose of 500 mg calcium dobesilate (Hainan Linheng Pharmaceutical Co., Ltd., Haikou, China) three times daily for 2 days before and 3 days after the procedure. All patients were administered the standard hydration therapy: intravenous infusion of 0.5-1 mL/kg/h normal saline 6-12h before the procedure and up to 12-24h after the procedure. Interventional cardiologists performed all CAG or PCI procedures using the standard method according to the latest guidelines. All patients received a low osmolar CM (Iohexol, GE Healthcare, Shanghai, China).

Data and sample collection

Demographic data such as age, sex, height, weight, medication history were collected. The left ventricular ejection fraction was measured by echocardiography using the modified biplane Simpson’s method. Baseline blood and urine tests were routinely performed in all patients during admission. Blood samples were collected from all patients at 24 and 72h after the procedure to measure the levels of blood urea nitrogen (BUN), serum creatinine (SCr), serum uric acid (UA), and serum cystatin C (Cys C). The SCr level was measured using the sarcosine oxidase method (BS2000M, Mindray Medical International Co., Ltd., Shenzhen, China). Urine samples were collected at 6 and 48h after CAG or PCI for the measurement of neutrophil gelatinase-associated lipocalin (NGAL) using the enzyme-linked immunosorbent assay method (XLPCC, Shanghai Xinle Bio-technology Co., Ltd, Shanghai, China). Urine samples were stored at −80°C until analysis. The eGFR in each patient was calculated using the Modification of Diet in Renal Disease Formula (2323. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12. https://doi.org/10.7326/0003-4819-150-9-200905050-00006
https://doi.org/10.7326/0003-4819-150-9-...
). Hypertension was defined as a blood pressure of ≥140/90 mmHg or current use of antihypertensive medication. Mehran CIN-risk scores were initially developed for the simple evaluation of an individual patient’s risk of developing CIN. It included eight clinical and procedural variables: hypotension, intra-aortic balloon pump, congestive heart failure, CKD, diabetes, age >75 years, anemia, and volume of CM (2424. Mehran R, Aymong ED, Nikolsky E, Lasic Z, Iakovou I, Fahy M, et al. A simple risk score for prediction of contrast-induced nephropathy after percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol. 2004;44(7):1393-9.).

Endpoint

The primary endpoint of the study was the incidence of CIN, which was defined as an increase of >44 μmol/L or >25% in the level of SCr (2525. Ad-hoc working group of ERBP, Fliser D, Laville M, Covic A, Fouque D, Vanholder R, et al. A European Renal Best Practice (ERBP) position statement on the Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines on acute kidney injury: part 1: definitions, conservative management and contrast-induced nephropathy. Nephrol Dial Transplant. 2012;27(12):4263-72. https://doi.org/10.1093/ndt/gfs375
https://doi.org/10.1093/ndt/gfs375...
) or of 25% in the level of basal Cys C after 48-72 h of CAG or PCI (2626. Xu Q, Wang NN, Duan SB, Liu N, Lei R, Cheng W, et al. Serum cystatin c is not superior to serum creatinine for early diagnosis of contrast-induced nephropathy in patients who underwent angiography. J Clin Lab Anal. 2017;31(5):e22096. https://doi.org/10.1002/jcla.22096
https://doi.org/10.1002/jcla.22096...
).

Statistical analyses

Statistical analyses were performed using Statistical Package for Social Sciences 22.0 version (SPSS, SPSS. Inc., Chicago, IL, USA). Continuous variables are presented as means±standard deviations or medians (interquartile ranges), as appropriate. Normally distributed continuous variables were compared between the groups using an independent samples t-test. Differences in the mean values of continuous variables measured at baseline and after 24 and 72h of the procedure were compared using repeated measures analysis of variance. Non-normally distributed continuous data were compared between the groups using the Mann-Whitney U test. Differences in the mean values of non-normally distributed continuous variables measured at baseline and after 24 and 72 hours of the procedure were compared using the Friedman test. Categorical variables are presented as frequencies (percentages). Comparisons between the groups were performed using the χ2 test. The Wilcoxon rank-sum test was used for the comparison of rank variable data. Univariate logistic regression analysis was performed in all patients to identify the risk factors for CIN. Sex, age, medical history, heart rate, NYHA cardiac functional classification, levels of biomarkers (such as glutamic oxaloacetate transaminase, glutamic pyruvate transaminase, N-terminal pro-B-type natriuretic peptide, serum albumin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, hemoglobin, glycosylated hemoglobin, UA, SCr, and Cys C), eGFR, volume of CM, and Mehran CIN-risk scores were used for univariate logistic regression analysis. Thereafter, the statistically significant variables in the univariate analysis were used in multivariate analysis to determine the independent risk factors and to calculate the odds ratio (OR). For all tests, a p value of <0.05 was considered statistically significant.

RESULTS

Baseline characteristics

Overall, 160 patients were allocated 1:1 to the experimental (n=80) or control group (n=80). Fifteen patients from both the groups were not included in statistical analysis because of intolerance to intervention, withdrawal from the study, or incomplete data (Figure 1). The baseline characteristics of all patients are shown in Table 1. No significant differences were found in the baseline characteristics, except the triglyceride level and previous history of cerebral infarction, between the two groups (p>0.05). The coronary angiography results are summarized in Table 2. No significant difference was found between the two groups in terms of coronary artery lesions, proportion of coronary intervention, and volume of CM (p>0.05).

Figure 1
Flow chart of patient selection.
Table 1
Baseline clinical characteristics of the patients.
Table 2
Comparison of coronary artery angiography results between the two groups.

Patients in the experimental group had significantly lower SCr level and higher eGFR after the procedure than patients in the control group

The levels of BUN, SCr, UA, and eGFR before and 24 and 72h after CAG or PCI are presented in Table 3, and the changes of them are shown in Figure 2A-D. The initial BUN, SCr, and UA level and eGFR were not significantly different between the two groups. At 24 and 72h after CAG or PCI, no significant differences were found in the BUN and UA levels between the two groups (all p>0.05). However, the mean SCr level at 24h after the procedure was significantly lower in the experimental group than in the control group (p=0.023). Likewise, the eGFR at 24 and 72h after CAG or PCI was significantly higher in the experimental group than in the control group (p=0.016). Compared with the levels of the aforementioned biomarkers before and after the procedure, the BUN level decreased in the first 24h after the procedure and thereafter, significantly increased at 72h in both the groups (both p<0.001). The SCr level at 24h was significantly lower than those at baseline and 72h after the procedure in the experimental group (p=0.004). Meanwhile, the mean SCr levels at 24 and 72h after the procedure were significantly higher than that at baseline in the control group (p=0.018). The eGFR at all three measurement time points did not statistically differ in the control group (p=0.329). However, the eGFR at 24h after the procedure was significantly higher than that at baseline and 72h after the procedure in the experimental group (p<0.001).

Table 3
Comparison of renal function biomarkers between two groups.
Figure 2
The Comparison of the blood urea nitrogen (A), serum creatinine (B), uric acid (C), eGFR (D), Cystatin C (E), and NGAL (F) levels between the experimental (calcium dobesilate receiving) and control groups. Abbreviations: BUN, blood urea nitrogen; eGFR, estimated glomerular filtration rate; NGAL, neutrophil gelatinase-associated lipocalin *p<0.05, compared with the control group, # p<0.05, compared with the other two measurement time points in the same group.

Cys C and NGAL levels were not significantly different between two groups

Table 3 shows the levels of Cys C and NGAL before and after the procedure in the two groups, and Figure 2E-F show the changes of Cys C and NGAL. The Cys C and NGAL levels were not significantly different between the two groups at any of the three measurement time points (all p>0.05). In both the groups, a slight increase in the Cys C level was observed at 24 and 72h compared with baseline, without significance. The NGAL level significantly increased at 6h after the procedure (both p<0.001) and thereafter, decreased in 48 h in both the groups.

Difference in changes in all renal function biomarkers, except SCr and eGFR between the two groups were not significant

The changes in the BUN, SCr, UA, Cys C, and NGAL levels and eGFR were calculated by subtracting the baseline values from the peak values measured after the procedure (Table 3). The changes in the SCr level were significantly higher in the control group than in the experimental group (p=0.006). However, the changes in the eGFR were significantly lower in the control group than in the experimental group (p=0.004). No significant differences were found in the changes in the BUN, UA, Cys C, and NGAL levels between the two groups (all p>0.05).

Incidence of CIN defined by the SCr level, but not by the Cys C level significantly differed between the two groups

A total of 3 (4.6%) patients in the experimental group and 13 (20.0%) in the control group were diagnosed with CIN, when CIN was defined by the SCr level (an increase in the SCr level by 25% or an SCr level of >44 μmol/L). A statistically significant difference was found between the two groups for the incidence of CIN (p=0.017) (Table 3). However, when CIN was defined by the Cys C level (an increase in the Cys C level by >25% after the procedure), seven (10.8%) patients were diagnosed with CIN in the two groups. No statistical difference was found between the two groups for the incidence of CIN (p=1.000) (Table 3). None of the patients in either group required dialysis therapy.

Logistic regression analysis showed that calcium dobesilate affected the incidence of CIN defined by the SCr level, but not by the Cys C

Univariate logistic regression analysis was performed in all patients to identify the risk factors for CIN. The results of univariate logistic regression analysis are shown in Table 4. Diuretics, calcium dobesilate, serum albumin level, heart rate, NYHA class III (compared with NYHA class I), and Mehran CIN risk score were significantly associated with the incidence of CIN defined by the SCr level. However, only age, diuretics, NYHA class III (compared with NYHA class I), and Mehran CIN risk score were associated with the incidence of CIN defined by the Cys C level.

Table 4
Univariate logistic regression analysis for the incidence of CIN.

Significant variables in univariate analysis were used in multivariate analysis, and the OR was adjusted according to age, sex, volume of CM, baseline SCr level, and baseline eGFR. The risk factor for CIN defined by the SCr level was diuretics. Calcium dobesilate (OR=0.071, 95% CI: 0.012-0.404, p=0.003), serum albumin level, and heart rate were protective factors for CIN. The Mehran CIN risk score was the only risk factor for CIN defined by the Cys C level (Table 5).

Table 5
Multivariate logistic regression analysis for occurrence of CIN.

DISCUSSION

In this study, calcium dobesilate reduced the incidence of SCr and CIN, as defined by the SCr level after CAG/PCI. However, no significant differences were observed in the levels of Cys C and NGAL, which are the more sensitive biomarkers, between the two groups. In addition, no statistical difference was found between the two groups in CIN defined by the Cys C level. Therefore, the results of this study did not support the effect of calcium dobesilate in preventing CIN in patients with diabetes and CKD.

Previous studies have reported that N-acetylcysteine, statins, and other drugs may prevent CIN (99. Wang N, Qian P, Kumar S, Yan TD, Phan K. The effect of N-acetylcysteine on the incidence of contrast-induced kidney injury: A systematic review and trial sequential analysis. Int J Cardiol. 2016;209:319-27. https://doi.org/10.1016/j.ijcard.2016.02.083
https://doi.org/10.1016/j.ijcard.2016.02...
-10. Liu LY, Liu Y, Wu MY, Sun YY, Ma FZ. Efficacy of atorvastatin on the prevention of contrast-induced acute kidney injury: a meta-analysis. Drug Des Devel Ther. 2018;12:437-44. https://doi.org/10.2147/DDDT.S149106
https://doi.org/10.2147/DDDT.S149106...
1111. Ali-Hasan-Al-Saegh S, Mirhosseini SJ, Ghodratipour Z, Sarrafan-Chaharsoughi Z, Rahimizadeh E, Karimi-Bondarabadi AA, et al. Strategies Preventing Contrast-Induced Nephropathy After Coronary Angiography: A Comprehensive Meta-Analysis and Systematic Review of 125 Randomized Controlled Trials. Angiology. 2017;68(5):389-413. https://doi.org/10.1177/0003319716661445
https://doi.org/10.1177/0003319716661445...
). However, to the best of our knowledge, no study has reported the preventive effect of calcium dobesilate on CIN. This study was the first randomized controlled trial to assess the effect of calcium dobesilate in preventing CIN in patients with diabetes and CKD.

The results showed a significant difference in the SCr level and eGFR after the application of calcium dobesilate compared with the control group. In addition, the incidence of CIN defined by the SCr level was significantly lower in patients pretreated with calcium dobesilate. The use of calcium dobesilate was also an independent protective factor for CIN. Thus, the above results indicate the preventive effect of calcium dobesilate on CIN.

To confirm the preventive effect of CIN, we measured the Cys C and NGAL levels to evaluate kidney function impairment. Cys C, a 13kDa non-glycosylated protein, is a sensitive biomarker of kidney function (2727. Shlipak MG, Ix JH, Bibbins-Domingo K, Lin F, Whooley MA. Biomarkers to predict recurrent cardiovascular disease: the Heart and Soul Study. Am J Med. 2008;121(1):50-7. https://doi.org/10.1016/j.amjmed.2007.06.030
https://doi.org/10.1016/j.amjmed.2007.06...
). The serum Cys C level has been shown to be a better endogenous marker of GFR and more sensitive for rapid detection of acute changes in renal function, especially after PCI, than the SCr level (2828. Nozue T, Michishita I, Mizuguchi I. Predictive value of serum cystatin C, β2-microglobulin, and urinary liver-type fatty acid-binding protein on the development of contrast-induced nephropathy. Cardiovasc Interv Ther. 2010;25(2):85-90. https://doi.org/10.1007/s12928-010-0014-3
https://doi.org/10.1007/s12928-010-0014-...
). In patients with CIN, the level of Cys C increases within 24h after CAG, which is earlier than the time required for the SCr level to increase (2929. Wang M, Zhang L, Yue R, You G, Zeng R. Significance of Cystatin C for Early Diagnosis of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography. Med Sci Monit. 2016;22:2956-61. https://doi.org/10.12659/MSM.897241
https://doi.org/10.12659/MSM.897241...
). NGAL is a 25 kDa glycoprotein of the lipocalin superfamily. Recently, NGAL has been considered a predictor of acute kidney injury because the serum and urine levels of NGAL increase before the SCr level increases (3030. Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, et al. Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care. 2007;11(4):R84. https://doi.org/10.1186/cc6089
https://doi.org/10.1186/cc6089...
). Studies have revealed that the NGAL level increases at 2h after the application of CM, whereas the SCr level increases at least after 12-24h of the application of CM (2929. Wang M, Zhang L, Yue R, You G, Zeng R. Significance of Cystatin C for Early Diagnosis of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography. Med Sci Monit. 2016;22:2956-61. https://doi.org/10.12659/MSM.897241
https://doi.org/10.12659/MSM.897241...
). According to a meta-analysis by Briasoulis et al., the NGAL level in the serum and urine have high specificity and sensitivity in the early diagnosis of CIN (3131. Briasoulis A, Pala M, Telila T, Merid O, Akintoye E, Vogiatzi G, et al. Statins and contrast-induced nephropathy: a systematic review and meta-analysis. Curr Pharm Des. 2017. https://doi.org/10.2174/1381612823666170913170527
https://doi.org/10.2174/1381612823666170...
). However, no significant difference was found between the experimental and control groups for the Cys C and NGAL levels after the procedure. Meanwhile, the incidence of CIN defined by the Cys C level was similar in both the groups. Risk factor analysis for CIN revealed that the Mehran score alone was an independent risk factor for CIN. Therefore, these results suggest that calcium dobesilate barely prevents CIN.

Considering the aforementioned factors, it may be reductive to the reducibility of calcium dobesilate, which consumes hydrogen peroxide (H2O2) in the Trinder reaction of the sarcosine oxidase assay, inhibiting the oxidative coloration of chromogenic phenol and thus, interfering with the detection of SCr, causing a negative interference (3232. Guo X, Hou L, Cheng X, Zhang T, Yu S, Fang H, et al. Strong Negative Interference by Calcium Dobesilate in Sarcosine Oxidase Assays for Serum Creatinine Involving the Trinder Reaction. Medicine (Baltimore). 2015;94(23):e905. https://doi.org/10.1097/MD.0000000000000905
https://doi.org/10.1097/MD.0000000000000...
). Compared with the control group, SCr significantly decreased after the application of calcium dobesilate. The eGFR calculated based on the SCr level and CIN (as defined by the SCr level) were interfered, which led to the illusion of CIN prevention by calcium dobesilate. However, the results of other renal function biomarkers suggested that calcium dobesilate may not have the capability of protecting renal function and preventing CIN.

However, although many studies have confirmed the renal protective effect of calcium dobesilate, it cannot reduce the occurrence of CIN through short-term application. Calcium dobesilate is used for the treatment of diabetic retinopathy and diabetic nephropathy (3333. Zhang X. Therapeutic effects of calcium dobesilate on diabetic nephropathy mediated through reduction of expression of PAI-1. Exp Ther Med. 2013;5(1):295-9. https://doi.org/10.3892/etm.2012.755
https://doi.org/10.3892/etm.2012.755...
,3434. Zhou Y, Qi C, Li S, Shao X, Mou S, Ni Z. Diabetic Nephropathy Can Be Treated with Calcium Dobesilate by Alleviating the Chronic Inflammatory State and Improving Endothelial Cell Function. Cell Physiol Biochem. 2018;51(3):1119-33. https://doi.org/10.1159/000495491
https://doi.org/10.1159/000495491...
). Studies have suggested that the therapeutic effect of calcium dobesilate depends on the reduction of endothelin levels (3333. Zhang X. Therapeutic effects of calcium dobesilate on diabetic nephropathy mediated through reduction of expression of PAI-1. Exp Ther Med. 2013;5(1):295-9. https://doi.org/10.3892/etm.2012.755
https://doi.org/10.3892/etm.2012.755...
) and thereby, dilation of blood vessels; antioxidant effects (3535. Jafarey M, Changizi Ashtiyani S, Najafi H. Calcium dobesilate for prevention of gentamicin-induced nephrotoxicity in rats. Iran J Kidney Dis. 2014;8(1):46-52.); and amelioration of microinflammation (3636. Schalkwijk CG, Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond). 2005;109(2):143-59.,3737. Zhou Y, Yuan J, Qi C, Shao X, Mou S, Ni Z. Calcium dobesilate may alleviate diabetes-induced endothelial dysfunction and inflammation. Mol Med Rep. 2017;16(6):8635-42. https://doi.org/10.3892/mmr.2017.7740
https://doi.org/10.3892/mmr.2017.7740...
). In addition, studies have demonstrated that calcium dobesilate prevents acute renal injury induced by streptomycin and gentamicin in animals (3535. Jafarey M, Changizi Ashtiyani S, Najafi H. Calcium dobesilate for prevention of gentamicin-induced nephrotoxicity in rats. Iran J Kidney Dis. 2014;8(1):46-52.). Therefore, the pharmacological effect of calcium dobesilate in the pathogenesis of CIN might be targeted prevention of CIN. Although the pathogenesis of CIN has not yet been clarified, it is believed that the pathological mechanism of CIN might be related to the hemodynamic changes caused by contrast agent-induced vasoconstriction, which further leads to renal ischemia and a decrease in the eGFR (1515. Wichmann JL, Katzberg RW, Litwin SE, Zwerner PL, De Cecco CN, Vogl TJ, et al. Contrast-Induced Nephropathy. Circulation. 2015;132(20):1931-6. https://doi.org/10.1161/CIRCULATIONAHA.115.014672
https://doi.org/10.1161/CIRCULATIONAHA.1...
). In addition, many studies have shown that CM is cytotoxic and augments reactive oxygen species and renal oxidative stress, which can cause autophagy or apoptosis of renal tubular epithelial cells (1616. Mamoulakis C, Tsarouhas K, Fragkiadoulaki I, Heretis I, Wilks MF, Spandidos DA, et al. Contrast-induced nephropathy: Basic concepts, pathophysiological implications and prevention strategies. Pharmacol Ther. 2017;180:99-112. https://doi.org/10.1016/j.pharmthera.2017.06.009
https://doi.org/10.1016/j.pharmthera.201...
,3838. Rosenberger C, Rosen S, Heyman SN. Renal parenchymal oxygenation and hypoxia adaptation in acute kidney injury. Clin Exp Pharmacol Physiol. 2006;33(10):980-8. https://doi.org/10.1111/j.1440-1681.2006.04472.x
https://doi.org/10.1111/j.1440-1681.2006...
), resulting in renal damage. Furthermore, studies have shown that CIN is associated with a systemic inflammatory response and CRP and other inflammatory biomarkers are significantly associated with the incidence of CIN (1717. Kwasa EA, Vinayak S, Armstrong R. The role of inflammation in contrast-induced nephropathy. Br J Radiol. 2014;87(1041):20130738. https://doi.org/10.1259/bjr.20130738
https://doi.org/10.1259/bjr.20130738...
,1818. Kurtul A, Ornek E. Platelet to Lymphocyte Ratio in Cardiovascular Diseases: A Systematic Review. Angiology. 2019;70(9):802-18. https://doi.org/10.1177/0003319719845186
https://doi.org/10.1177/0003319719845186...
). According to a study by Zhou et al., calcium dobesilate might have angio-protective properties and protect endothelial cells partly by ameliorating high glucose-induced endothelial dysfunction and inflammation (3737. Zhou Y, Yuan J, Qi C, Shao X, Mou S, Ni Z. Calcium dobesilate may alleviate diabetes-induced endothelial dysfunction and inflammation. Mol Med Rep. 2017;16(6):8635-42. https://doi.org/10.3892/mmr.2017.7740
https://doi.org/10.3892/mmr.2017.7740...
); therefore, calcium dobesilate might be used to prevent CIN through this mechanism.

Hence, we speculated that calcium dobesilate should have a preventive effect against CIN. However, this study failed to show the preventive effect, which may be because of the following reasons: 1. the renal protective effect of calcium dobesilate is weaker than that of hydration therapy, and the effect of calcium dobesilate is covered up. Therefore, the effect of calcium dobesilate can be further verified in individuals who cannot tolerate hydration therapy for cardiac insufficiency. 2. Because of the limited sample size, this study did not explore the preventive effect in different pretreatment periods and dosages of calcium dobesilate. Hence, further research with a longer medication duration or increased dosage might lead to better results. 3. The results without significance may be related to the limited sample size of this study, and the conclusions of this study can be further confirmed by increasing the sample size.

This study has some limitations. First, sample size of the study was relatively small. Second, our study was not a multicenter, double-blind placebo-control study. In the future, a multicenter, double-blind placebo-control study with a large sample size should be conducted to confirm this conclusion.

CONCLUSION

This study found that calcium dobesilate does not prevent CIN in patients with diabetes and chronic renal failure.

ACKNOWLEDGMENTS

This study was supported by a grant from the Chinese Cardiovascular Association V.G foundation (2017-CCA-VG-021) and the clinical medical research project of the Second Hospital of Tianjin Medical University (2020LC12).

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Publication Dates

  • Publication in this collection
    18 Oct 2021
  • Date of issue
    2021

History

  • Received
    4 Mar 2021
  • Accepted
    15 July 2021
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