|Year : 2016 | Volume
| Issue : 1 | Page : 60-66
Cystatin C as an early diagnostic marker for contrast nephropathy in diabetic patients undergoing coronary angiography
Abdallah Mostafa1, Amira Al-Hendy2, Ahmed Emara1, Ezzat Adly3
1 Department of Cardiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Cardiology, Banha Insurance Hospital, Banha, Egypt
|Date of Submission||05-Oct-2014|
|Date of Acceptance||20-Jan-2015|
|Date of Web Publication||18-Mar-2016|
MBBCh, 13511 Banha, Qalubia
Source of Support: None, Conflict of Interest: None
The aim of this study was to assess the utility of cystatin C as an early biomarker for acute kidney injury (AKI) compared with serum creatinine.
Contrast-induced nephropathy (CIN) is a form of AKI that is caused by exposure to contrast media in diagnostic imaging and interventional procedures such as angiography. At present, serum creatinine and creatinine clearance are standard tests for CIN. A few studies have been published that have analyzed the potential use of cystatin C in AKI.
Patients and methods
We studied 30 diabetic and 20 nondiabetic consecutive patients with normal serum creatinine undergoing coronary angiography (CA). The nondiabetic group was used to assess diabetes as a risk factor for CIN. After providing informed consent, the patients underwent the following before CA: estimation of blood glucose, glycosylated hemoglobin, serum creatinine, blood urea, estimated creatinine clearance, and cystatin C. Serum cystatin C was measured by means of the enzyme-linked immunosorbent assay technique and was evaluated again at 24 h after CA, whereas serum creatinine was evaluated at 24 and 72 h after CA.
In patients with CIN there was a significant increase in serum cystatin C 24 h after angiography, whereas serum creatinine increased significantly only at 72 h after the procedure. The incidence of CIN was 20% in the diabetic group, 5% in the nondiabetic group, and 14% in the whole population sample.
The present study highlights the importance of serum cystatin C in detecting AKI associated with contrast administration earlier than serum creatinine.
Keywords: Contrast-induced nephropathy, coronary angiography, cystatin C
|How to cite this article:|
Mostafa A, Al-Hendy A, Emara A, Adly E. Cystatin C as an early diagnostic marker for contrast nephropathy in diabetic patients undergoing coronary angiography. Menoufia Med J 2016;29:60-6
|How to cite this URL:|
Mostafa A, Al-Hendy A, Emara A, Adly E. Cystatin C as an early diagnostic marker for contrast nephropathy in diabetic patients undergoing coronary angiography. Menoufia Med J [serial online] 2016 [cited 2020 Feb 28];29:60-6. Available from: http://www.mmj.eg.net/text.asp?2016/29/1/60/178981
| Introduction|| |
Recent improvements in radiodiagnostic procedures and in cardiovascular percutaneous interventions, together with increased life expectancy, have resulted in the subjection of an increasing number of patients to contrast medium-enhanced examinations or cardiac and angiographic procedures requiring iodinated contrast medium injection .
Contrast medium-induced nephropathy is currently defined either as an acute decrease in renal function after intravascular administration of an iodinated contrast medium without evidence of other causes or as an absolute increase in serum creatinine values of 0.5 mg/dl or a 25% relative increase from baseline values within 48-72 h after injection of a contrast media. Contrast medium-induced damage is the third highest cause of hospital-acquired acute renal failure, and in half of these cases it occurs after invasive cardiac procedures .
Acute renal injury is typically diagnosed by measuring serum creatinine. Unfortunately, creatinine is an unreliable indicator during acute changes in kidney functions . The lack of early biomarkers of acute kidney injury (AKI) in humans has led to a number of clinical trials investigating highly promising therapies for AKI in adults, such as cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1).
Cystatin C is a cysteine protease inhibitor that is synthesized and released into the blood at a relatively constant rate by all nucleated cells. It is freely filtered by the glomerulus and completely reabsorbed by the proximal tubule. As blood levels of cystatin C are not significantly affected by age, sex, race, or muscle mass, it is a better predictor for glomerular function compared with serum creatinine in patients with chronic kidney disease .
Our aim was to test the hypothesis that cystatin C could represent an early biomarker of renal injury and to assess the relationship between serum cystatin C and serum creatinine in patients with normal serum creatinine undergoing percutaneous coronary angiography (CA).
| Patients and methods|| |
The study was conducted on 30 diabetic and 20 nondiabetic consecutive patients with normal serum creatinine undergoing CA due to coronary artery disease. Patients with pre-existing chronic kidney disease (serum creatinine>2 mg/dl) or end-stage renal disease requiring dialysis, patients with severe decompensated heart failure, patients with severe hypertension, and patients in cardiogenic shock were excluded from the study.
The study population was divided into two groups at the beginning of the study:
Group I: This included 30 diabetic patients.
Group II: This included 20 nondiabetic patients (control group).
At the end of the study, the population was further subdivided into four groups according to the occurrence of contrast-induced nephropathy (CIN):
Group IA: This group included six diabetic patients who developed CIN.
Group IB: This group included 24 diabetic patients who did not develop CIN.
Group IIA: This included one nondiabetic patient who developed CIN.
Group IIB: This included 19 nondiabetic patients who did not develop CIN.
Patients were determined to have diabetes mellitus if their fasting plasma glucose level was repeatedly at greater than or equal to 126 mg/dl or if they were receiving oral hypoglycemic drugs or insulin . The normal range of glycosylated hemoglobin was 4-7%; for diabetic patients under good control the concentration was 7%; for patients in fair control it was 7-10%; and for poorly controlled patients it was 10% . The normal range of serum creatinine among adults was less than 1.5 mg/dl . Estimated creatinine clearance was measured using the Cockcroft-Gault formula . CA was defined as a nonsurgical procedure used to treat stenotic (narrowed) coronary arteries of the heart found in coronary heart disease .
After providing informed consent, all patients underwent the following before CA: estimation of blood glucose, glycosylated hemoglobin, serum creatinine, blood urea, estimated creatinine clearance, and cystatin C. Serum cystatin C was measured by the enzyme-linked immunosorbent assay technique  and was evaluated again at 24 h after CA, whereas serum creatinine was evaluated at 24 and 72 h after CA.
The collected data were tabulated and analyzed using SPSS version 16 software (SPSS Inc., Chicago, Illinois, USA). Categorical data were presented as number and percentages, whereas quantitative data were expressed as mean and SD and range. Fisher's exact test, the Student t-test, the paired t-test, Spearman's correlation coefficient (r), the Mann-Whitney U-test, and the Wilcoxon test were used as tests of significance. The receiver operating characteristic curve was used to determine the cutoff values of serum creatinine (CR), creatinine clearance (CCL), and cyst and the amount of contrast with optimum sensitivity and specificity in early diagnosis (prediction) of CIN among diabetic patients. The accepted level of significance in this work was stated at 0.05. P values greater than 0.05 were considered insignificant; P values less than 0.05 were considered significant; and P values less than 0.001 were considered highly significant .
| Results|| |
In group I (the diabetic group), the mean age was 51.2 ± 5.6 years; there were 25 male (83.3%) and five female (16.7%) patients; 20 were hypertensive (66.7%) and 10 were normotensive patients (33.3%); there were 14 smokers (46.7%), 10 nonsmokers (33.3%), and six ex-smokers (20%); the mean weight in this group was 79 ± 7.5 kg, whereas the mean BMI was 27.8 ± 3.0 [Table 1].
In group II (the control group), the mean age was 50.6 ± 4.4 years; there were 16 male (80.0%) and four female (20.0%) patients; 17 were hypertensive (85.0%) and three were normotensive (15.0%); there were 13 smokers (65.0%), five nonsmokers (25.0%), and two ex-smokers (10%); the mean weight in this group was 82.8 ± 7.3 kg, whereas the mean BMI was 28.7 ± 1.96 [Table 1].
There was no statistically significant difference between the two groups regarding age, sex, hypertension, smoking, weight, and BMI [Table 1].
CIN developed in six diabetic patients (20% of the diabetic group) and in one nondiabetic patient (5% of the control group) [Table 2].
|Table 2: Incidence of contrast-induced nephropathy among the studied groups|
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With respect to the most important risk factors for CIN there was no statistically significant difference between the two groups with regard to basal serum creatinine, total amount of dye, amount of dye/kg, and exposure to drugs [Table 3].
In our study, the diabetic group (group I) comprised 25 male patients (83.3%) and five female patients (16.7%). Group IA (CIN) included five male patients (83.3%) and one female patient (16.7), whereas group IB (normal) included 20 male patients (83.3%) and four female patients (16.7%). There was no statistically significant difference between the two groups regarding the sex distribution of the patients [Table 4].
The mean age in group IA (CIN) was 59. 8 ± 1.2 and that in group IB (normal) was 49.04 ± 3.8. There was statistically significant difference between the two groups regarding age. Older patients were more prone to CIN [Table 4].
In group IA (CIN) the mean serum level of HbA1c was 9.5 ± 1.3, whereas in group IB (normal) it was 6.5 ± 1.01.
There was statistically significant difference between the two groups regarding serum level of glycosylated hemoglobin. Patients with increased levels of HbA1c were more prone to CIN [Table 4].
In group IA (CIN) all patients were exposed to drugs: three patients (50%) were on angiotensin converting enzyme inhibitors (ACEI) and three patients were on angiotensin receptor blockers (ARBS). In group IB (normal) three patients were on ACEI (12.5%) and five were on ARBS and 16 (66.7%) patients were not on drugs. There was statistically significant difference between the two groups with regard to exposure to drugs. Patients with greater exposure to drugs were more prone to CIN [Table 4].
In group IA (CIN) the mean length of the procedure was 47.5 ± 4.6 min, whereas in group IB (normal) it was 19.5 ± 5.02. There was statistically significant difference between the two groups regarding length of the procedure. Patients with greater procedural length were more prone to CIN [Table 4].
In group IA (CIN) the mean total amount of dye was 323 ± 18.6 ml, whereas in group IB (normal) it was 119.3 ± 33.1 ml. There was statistically significant difference between the two groups with respect to total amount of dye. Patients exposed to increased total amount of dye were more prone to CIN [Table 4].
In group IA (CIN) the mean amount of dye/kg was 4.3 ± 0.8 ml, whereas in group IB (normal) the mean amount of dye/kg was 1.5 ± 0.4 ml. There was a statistically significant difference between the two groups with regard to the amount of dye/kg. The greater the amount of dye/kg, the greater the incidence of CIN [Table 4].
In group IA (CIN) three patients (50%) had peripheral vascular diseases (PVDs), whereas in group IB one patient had PVD.
There was a statistically significant difference between the two groups with regard to the presence of PVD [Table 4]. Patients with PVD were more prone to CIN.
Specific changes in the diabetic contrast-induced nephropathy group (group IA)
The mean CR1 (basal) was 1.28 ± 0.1 mg/dl, the mean CR2 (after 24 h) was 1.3 ± 0.2 mg/dl, and the mean CR3 (after 72 h) was 2.03 ± 0.2 mg/dl. There was no statistically significant difference between serum creatinine before and 24 h after CA but there was a statistically significant difference between basal serum creatinine and serum creatinine after 72 h. CIN cannot be diagnosed by changes in serum creatinine level except after more than 24 h [Table 5].
|Table 5: Comparison between levels of serum creatinine before and 24 and 72 h after the procedure in group IA|
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The mean CYS 1 (basal) was 829.2 ± 40.1 and the mean CYS 2 (after 24 h) was 2133.3 ± 123.2 ng/ml.
There was a statistically significant difference between basal serum cystatin C and serum cystatin C 24 h after CA. CIN can be diagnosed by changes in serum cystatin C during the first 24 h after CA [Table 6].
|Table 6: Comparison between values of creatinine clearance before and 24 and 72 h after the procedure in group IA|
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By using the receiver operating characteristic curve for basal serum creatinine, the best cutoff point was determined to be greater than or equal to 1.15 with a sensitivity of 83.3%, specificity of 91.7%, and area under the curve (AUC) of 0.85. Diabetic patients with basal serum creatinine greater than or equal to 1.15 mg/dl are at high risk for CIN and should undergo preventive measures [Figure 1].
|Figure 1: Receiver operating characteristic (ROC) curve for basal serum creatinine and c ystatin C.|
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For basal creatinine clearance the best cutoff point was determined to be 85.45 or less with a sensitivity of 83.3%, specificity of 83.3%, and AUC of 0.87. Diabetic patients with basal creatinine clearance of less than or equal to 85.45 ml/min/1.73m 2 are at high risk for CIN and should undergo preventive measures [Figure 2].
|Figure 2: Receiver operating characteristic (ROC) curve for basal creatinine clearance.|
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For basal serum cystatin C the best cutoff point was determined to be at least 787.5, with sensitivity of 100%, specificity of 83.3%, and AUC of 0.87. Diabetic patients with basal serum cystatin C greater than or equal to 787.5 ng/ml are at high risk for CIN and should undergo preventive measures [Figure 1].
Factors found to be significantly associated with CIN occurrence were entered in the logistic regression model to detect significant predictors of CIN. It was seen that significant elevation in cystatin C, increased amount of contrast media/kg, elevated basal serum creatinine, exposure to drugs, PVD, decreased basal creatinine clearance, and uncontrolled diabetes mellitus were the significant predictors of CIN among the studied diabetic patients [Table 7].
|Table 7: Stepwise forward binary logistic regression analysis for predictors of contrast-induced nephropathy among diabetic patients|
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| Discussion|| |
Recent improvements in radiodiagnostic procedures and in cardiovascular percutaneous interventions, together with increased life expectancy, have resulted in the subjection of an increasing number of patients to contrast medium-enhanced examinations or cardiac and angiographic procedures requiring contrast medium injection .
CIN is an important cause of iatrogenic acute renal failure and carries significant risk for the affected patient. CIN is the third leading cause of acute renal failure in hospitalized patients .
The reported incidence of CIN varies widely, ranging from 2 to 50% according to the presence or absence of risk factors .
Diabetic patients represent a significant proportion of those undergoing contrast exposure because of the high prevalence of diabetes in the general population and the ability of the disease to cause a broad spectrum of cardiovascular diseases that require radiological procedures using contrast media. The incidence of CIN in diabetic patients varies from 5.7 to 29.4% .Various studies have reported cystatin C as an easily and rapidly assessable marker that can be used for accurate information on renal function impairment . Further, its measurement offers a simpler and more sensitive screening test than serum creatinine for early changes in glomerular filtration rate (GFR) .
As for other biomarkers, NGAL was originally identified as a 25-kDa protein covalently bound to gelatinase in neutrophils . Bachorzewska-Gajewska and colleagues found that NGAL was a sensitive biomarker of AKI after contrast administrations for CA. They found a significant increase in serum NGAL at 2 and 4 h after percutaneous coronary intervention (PCI) and a rise in urinary NGAL at 4 and 12 h after PCI .
IL-18 is a proinflammatory cytokine that is released in response to injury to the renal tubules . IL-18 is both a mediator and a biomarker of ischemic AKI as proven by the rise of IL-18 expression in the kidney in AKI, the protective effect of IL-18 inhibition against AKI in animal models, and the rise of IL-18 in the urine in both humans and animals after AKI. However, compared with other biomarkers, such as KIM-1 and cystatin C, IL-18 appears to be relatively less sensitive .
KIM-1 is a biomarker of AKI in humans. Urinary KIM-1 levels were significantly higher in patients with ischemic acute tubular necrosis (ATN) compared with patients with other forms of acute renal failure or chronic kidney disease . It is likely that NGAL and KIM-1 will emerge as temporally sequential biomarkers of AKI, with NGAL being the most sensitive at the earliest time points and KIM-1 adding significant specificity at slightly later time points .
The current study was performed to investigate cystatin C as an early biomarker for CIN in diabetic patients undergoing CA.
It included 30 diabetic patients (group I) and 20 nondiabetic patients (control group; group II). All 50 patients had normal baseline serum creatinine and presented for either diagnostic CA or PCI in the cath. lab of El Menoufiya University Hospital.
For all patients serum creatinine level was measured at baseline and at 24 and 72 h after CA; serum cystatin C was measured at baseline and 24 h after CA.
There was no statistically significant difference between the two groups as regards age, basal serum creatinine, total amount of dye, amount of dye/kg, and exposure to drugs, which are the most important predictors of CIN other than diabetes.
In our study the incidence of CIN in the diabetic group was 20%. This result agreed with the study by Rahman , which stated that diabetic patients undergoing PCI have a higher incidence of CIN compared with nondiabetic patients.
In our study the incidence of CIN in the nondiabetic (control) group was 5%. This result agreed with the study by Chong and Tan , which stated that the incidence of CIN in nondiabetic patients was 4.3%.
According to the results of our study, diabetes was about five times more likely to develop in patients with CIN than in controls (odds ratio for CIN 4.8).
In our study older patients were more prone to CIN. This result agreed with the study of Kini et al. , which reported that several studies have provided evidence that older age is an independent predictor of CIN.
In our study patients with uncontrolled diabetes and increased levels of HbA1c were more prone to CIN. This result agreed with the study of Mogensen , which stated that diabetic nephropathy (DN) is more likely to develop in patients with lower degrees of glycemic control.
In our study patients exposed to drugs such as ACEI and ARBS were more prone to CIN. This result agreed with the study of Toprak et al. .
In our study, patients with prolonged mean length of procedure were more prone to CIN. This can be explained by the prolonged contact time of contrast media with tubular epithelial cells.
In our study, patients with increased mean total amount of dye and mean amount of dye/kg were more prone to CIN. This result agreed with the study of Marenzi et al. , which stated that most of the studies indicate that a higher volume of contrast medium is deleterious in the presence of other risk factors.
In our study, three patients (50%) in group IA (CIN) had PVD, whereas one patient in group IB had PVD. There was a statistically significant difference between the two groups. This result agreed with the study of Nikolsky et al. , which reported that CIN was independently associated with peripheral arterial disease.
In our study, patients with increased mean basal serum creatinine and mean basal serum cystatin C were more prone to CIN with best cutoff point of at least 1.15 mg/dl for basal creatinine and at least 787.5 ng/ml for basal cystatin C.
In our study patients with decreased mean basal estimated creatinine clearance were more prone to CIN with cutoff point of 85.45 ml/min/1.73 m 2 or less.
In our study there was a correlation between basal cystatin C and different studied variables in the diabetic group, as serum cystatin C was directly proportional to basal creatinine and inversely proportional to basal creatinine clearance.
There was a significant change in serum cystatin C levels in the diabetic CIN group after 24 h, whereas significant change in serum creatinine did not occur except after 72 h in the same group.
| Conclusion|| |
Cystatin C is a predicative biomarker for acute renal injury after percutaneous CA as it increases earlier than the rise in serum creatinine at 24 h after angiography .
| Acknowledgements|| |
I thank my professors for guiding Ezzat Adly and supporting my work.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]