Contrast induced nephropathy or Contrast induced acute kidney injury is an unwanted side effects after contrast medium exposure for a decades of time without effective treatment or appropriate measures. Moreover, the incidence of CIN varies depending on the definition sets and hypercholesterolemia remains as a vague risk factor for contrast induced nephropathy till now. We studied the changes in serum cystatin C (CyC) and serum creatinine (sCr) levels in normal renal function people correlated with the other baseline characteristics.
Methods: 290 patients with sCr level of lower than 120µmol/l, and estimated glomerular filtration rate (eGFR) of more than 60 ml/min/1.73 m2 on baseline were enrolled in this prospective study. CyC and sCr levels are measured before, 24 hours and 3days after the contrast angiogram in the participants. Contrast induced nephropathy (CIN) was evaluated by 10% increase in serum CyC level and 25% raise in the sCr level from the baseline after 24 hours of contrast medium exposure.
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Results: 38(13.1%) of the patients found to have 10% increase in CyC level and 5 out of 290 patients (1.7%) resulted in a rise of sCr level of more than 25% from the pre contrast exposure level. In our study, we defined CIN as combination of 10% increase in CyC and 25% increase in 25% of sCr level and revealed that 14.48% of patients occurred. There was statistical significant in age (P=0.046), total cholesterol level (P=0.027), high density lipoprotein cholesterol (P=0.044) and low density lipoprotein cholesterol (P=0.035), between CIN and non CIN groups. There was no significant different in contrast volume, sex, fasting blood glucose, glycosylated hemoglobin and left ventricular ejection fraction, etc. Logistic regression revealed that hypercholesterolemia as independent risk factors for CIN (B= 1.010, 95% Confidence interval (1.001-1.020), P=0.028).
Conclusion: According to the sensitivity, safety and technically uncomplicated procedure, CTCA are performing more and more in this era. The incidence of CIN is also relatively lower due to improvement in the contrast medium quality. Our study result showed that hypercholesterolemia should be regarded as an important risk factor for CIN.
Keywords: CIN contrast induced nephropathy; AKI acute kidney injury; CyC serum Cystatin C; sCr serum creatinine; contrast medium.
Contrast Induced Acute Kidney Injury (CI-AKI), previously Contrast Induced Nephropathy (CIN), is an important cause of hospital-acquired acute renal failure, a well known complication after contrast media (CM) exposure, accounting for 12% of all cases, and is associated with prolong hospital stay, considerable morbidity and mortality. (1, 2)
The development of radiographic contrast medium originated since 1918, by using the sodium iodide to image the ventricular systems in neurology and improvement in the side effects over the era especially. Nowadays, the use of iodinated contrast medium is more and more in all purposes of diagnostic investigations due to improvement in the contrast medium quality and imaging tools, especially in contrast enhanced CT angiogram, interventions and therapeutic procedures, the research data showed that approximately 80 million doses of iodinated intra-vascular CM were used around the world in 2003, probably making CM as one of the most commonly used medications in the world (3). But CIN remains as one of the major complications without a certain effective treatment exists (4). Additionally, CIN is the third most common cause of acute kidney injury. CIN is usually defined as increasing of 0.5 mg/dl (44umol/mL) serum creatinine (sCr) concentration or 25% above baseline within 48 hours after contrast exposure, when alternative explanations for renal impairment have been excluded (5,6, 7, 8). One study suggested that CIN can be defined as 10% increase in serum Cystatin-C level after 24 hours of contrast medium exposure (9). CIN is the renal function acute deterioration after parenteral administration of radio-contrast media with the lack of other causes. Prevention is crucial because of association with the unnecessary prolonged hospitalization, the risk of permanent renal damage and also reported that may associate with a five folds increase in mortality as well (10). Most episodes of CIN are self-limiting and resolve within 1-2 weeks (11), whereas it can progress to long term chronic kidney disease (CKD) in certain cases with preexisting risk factors. The risk factors for CIN include CKD, diabetes mellitus(DM), congestive heart failure, age of the patients, major cardiovascular co-morbidities, hypovolemia, administration of high doses of contrast medium, and concomitant use of drugs that interfere with the regulation of renal perfusion (12).
CystatinC (CyC) is a cationic non-glycosylated low molecular weight basic plasma protein, family of cysteine protease inhibitors, comprises of 122 amino acids with a molecular weight of 13kDa. It is not only produced at a constant rate by all nucleated cells, but also not metabolized in the serum, and is freely filtered by the glomeruli (13). CyC has been proposed as an alternative to serum creatinine to evaluate GFR, owing to the absence of variations related to age, sex, and muscle mass. Manetti L et al suggested that there may be variability in the CyC generation rate, in particular in states associated with higher or lower cell turnover, such as hyperthyroid or hypothyroid states (15). However, in some studies changes of CyC have enabled investigators to detect earlier changes of GFR than creatinine after administration of contrast media. So that VandeVoorde RG et al stated that it is a better predictor for glomerular function than is serum creatinine in patients with chronic kidney disease (14).
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We sought to prospectively assess the possible association between contrast volume and CIN incidence by measuring the changes in sCr and CyC level after iodinated contrast medium exposure in study patients.
290 patients, who admitted to the First Affiliated Hospital of Dalian Medical University, Cardiac ward from 2011 December to 2012 September, had undergone either computed tomography coronary angiogram or peripheral angiography or interventions, were enrolled in this prospective study. Patients who were ≥20 years old with stable sCr levels of < 2mg/dl were eligible for this study. If the patients have one of the following criteria were ruled out from this study: multiple myeloma, eGFR of less than equal to 60ml/min before angiogram, pulmonary edema, recent exposure to iodine contrast medium before 2days of the study entry, thyroid abnormalities; inability to follow breath-hold commands, previous history of allergy to iodine contrast media, pregnancy, acute heart failure or patients presenting with acute emergency condition and current treatment of peritoneal dialysis or hemodialysis. The Institutional Ethics Review Board approved this study, and informed consent was obtained from all patients.
Measurement of the other factors
Hypertension was defined as a systolic blood pressure (BP) of ≥140 mmHg, a diastolic BP of ≥90 mmHg, or by previous history or the use of antihypertensive medication. Diabetes mellitus (DM) was diagnosed as fasting plasma glucose level more than 7mmol/L, two-hour postprandial plasma glucose level greater than 11.1mmol/L, HbA1c ≥ 6.5%, or treatment with either oral hypoglycemic agents or insulin. Dyslipidemia was defined as a serum total cholesterol concentration of ≥180 mg/dl, serum high-density lipoprotein-cholesterol concentration of ≤40 mg/dl, serum triglyceride concentration of ≥150 mg/dl, serum low-density lipoprotein-cholesterol of ≥140 mg/dl, or receiving treatment with any of lipid lowering agents.
Obesity was defined as a body mass index (BMI) ≥28 kg/m2. Weight was measured to the nearest 0.5 kg and also the height was measured to the nearest 0.5cm. Smoking was assessed by the questionnaire. We did the relevant clinical investigations on all of the patients who participated in this study.
Computed Tomography Angiogram
The coronary angiogram or peripheral angiogram was performed by DUAL SOURCE SOMATOM DEFINITION FLASH (SIEMENS). Iopromide (Ultravist 370 mgI/ml, Bayer Pharma AG, Berlin, Ger.), is non-ionic low osmolar low viscous water soluble contrast, due to its lower nephrotoxicity, at a rate of 3-6ml/s followed by 50 mL of normal saline solution. The dose of contrast medium was depending upon the patient's body weight and renal function test investigation results before the procedure, ranging from 50ml-160ml. All of the patients were not treated with loading dose of cholesterol lowering agents, statin; prior to the procedure and none of the patients received the preventive strategy like N-acetyl cysteine, fenoldopam, sodium bicarbonate or intravenous saline infusion etc, after the procedure. All of the patients were encourage drinking fluid orally as much as possible after the procedure.
Measuring of the renal function
After the angiography examination, all of the patients took oral fluid as much as possible for 24 hours. CyC, sCr and BUN levels were investigated before procedure, 24h and 72 hours after the procedure. sCr and CyC levels were measured by Hitachi 7600 automatic biochemical analyzer by means of particles enhanced transmission immunoassay in our hospital laboratory. Plasma Urea level (BUN) was investigated by the urease method. %CyC changes and %sCr changes were calculated as follows:
%CyC = (Day1 Post procedural CyC - Pre procedural CyC)/ Pre procedural CyC x 100
%sCr = (Day1 Post procedural sCr - Pre procedural sCr)/ Pre procedural sCr x 100
Glomerular Filtration Rate
The level-modified Modification of Diet in Renal Disease (MDRD) equations were developed on the basis of white and black patients, not suitable for the Asian ethnics (16, 17). The estimated glomerular filtration rate (eGFR) was calculated using the MDRD equation, modified for the Chinese, in which eGFR (ml per min per 1.73 m2) = 175*sCr-1.234*age in years-0.179, whereas for female sex adjustment, female eGFR = eGFR * 0.79 (18).
Analysis was performed with IBM SPSS 20.0 software for Windows (IBM SPSS, Inc, Chicago, IL, USA) and Excel, version 2010 for Windows (Microsoft Corporation). Continuous variables were expressed as mean ± standard deviation (SD) and the categorical variables were expressed as percentage. The changes occurring at different point of time were analyzed by using the repeated measures. We classified the patients into two groups based on the %CyC change and %sCr change according to the current CIN definition. The independent sample T test was used to compare the means of continuous and categorical variables between two groups. Moreover, we divided the patients into 3 groups depending on the contrast volume and analyzed by using one way ANOVA. The logistic regression analysis was performed to evaluate the relationship between continuous data. All P-values are two sided and P-values of less than 0.05 are considered as statistically significant.
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The baseline clinical characteristics of all patients are listed in Table-1. 42 patients, 14.48% (42/290) were diagnosed as CIN depending on the combination of increase in 10% of CyC and rise in 25% of sCr from base line. 10% increasing in CyC levels was found in 38 (13.1%) patients out of 290 and the other was 5 (1.7%) in all patients. The statistical significant was found between CIN and non CIN groups in the following data; age (P=0.046), total cholesterol level (P=0.027), high density lipoprotein cholesterol (P=0.044) and low density lipoprotein cholesterol (P=0.035), etc. The changes in CyC, sCr, BUN (blood urea nitrogen) and eGFR levels were showed in table 2. Both CyC and sCr levels were increased after 24hours of contrast medium exposure, but BUN level was decreased after 24hours exposure.
Although hypertension, diabetes, and anemia etc. are the risk factors for the contrast medium induced acute kidney injury and worsening the renal function after the stressful condition, but we didn't find the significant correlation between these factors when comparing within this two groups as the data of blood glucose levels, blood pressure at single point time and hemoglobin levels are approximately the same between this two groups. (Systolic BP 138.86±16.86 vs. 137.43±15.60, P=0.586; diastolic BP 85.05±14.07 vs. 83.90±11.75, P= 0.570; hemoglobin 139.07±15.248 vs. 139.56±16.68, P=0.858; glycosylated hemoglobin 6.88±1.15 vs. 6.56±1.36, P= 0.805; FBG 5.75±1.18 vs. 5.90±1.64, P= 0.570).
In the subgroup of CIN patients, the average baseline values of CyC, sCr and BUN although lower, and the eGFR was higher than those without CIN (0.802±0.21 vs. 0.867±0.21, 62.10±15.98 vs. 63.04±15.02, 5.19±1.33 vs. 5.71±1.52, 130.21±31.49 vs. 121.18±29.05). However, the fluctuation in CyC, sCr and eGFR values were more prominent in CIN subgroup at 1D after the procedure. Not only CyC and sCr values increased in CIN group more obviously compared to non CIN group. (0.92±0.24 vs. 0.86±0.21, 67.55±16.71 vs. 62.54±16.33), also eGFR was reduced obviously in CIN group (116.94±27.32 vs. 123.70±32.05).
Logistic regression of forward stepwise analysis showed that hypercholesterolemia was independently associated with the risk of CIN (B= 1.010, 95% Confidence interval (1.001-1.020), P=0.028).
Nearly all of the participants had mild fluctuation in sCr and CyC level and progress to further renal function deterioration had not occurred in any patients in subsequent days, and most of them returned to base line level after 3 days from the contrast medium exposure, but the mean levels of CyC and sCr were still higher than baseline in CIN group. All of the patients from the study groups did not undertake for hemodialysis, peritoneal dialysis etc.
Table1. Baseline characteristics of all of the patients, CIN and non CIN groups (mean ± SD)
Male, n (%)
Female, n (%)
BMI; Body Mass Index, BP; blood pressure (mmHg), FBG; fasting blood glucose (mmol/L), HbA1c; glycosylated hemoglobin, HDL; High density lipoprotein (mg/dl), LDL; Low density lipoprotein (mg/dl), UACR; urinary albumin creatinine ratio(mg/g), Hs-CRP; Highly sensitive C reactive protein, eGFR; estimated glomerular filtration rate (ml/min/1.73m2),
* represents P value of less than 0.05.
Continuous variables are described as mean ±SD and categorical variables are expressed as total number and percentage of the whole population. (Parentheses)
Table2. CyC, sCr, BUN and eGFR changes after contrast angiography.
Changes from baseline for CyC, sCr, BUN and eGFR
Marker Mean±SD %changes from baseline P value
Pre angiography 0.858±0.21 - -
24h 0.864±0.22 1.06±9.17 0.208
Day3 0.851±0.21 -0.46±9.16 0.138
Pre angiography 62.90±15.41 - -
24h 63.27±16.45 0.65±10.04 0.324
Day3 62.73±15.89 -0.04±9.63 0.632
Pre angiography 5.64±1.51 - -
24h 5.04±1.46 -7.69±27.74 0.000Ç‚
Day3 5.13±1.36 -5.99±24.68 0.000Ç‚
eGFR(ml. min-1 . 1.73m-2)
Pre angiography 122.49±29.52 - -
24h 122.72±31.45 0.23±15.72 0.799
Day3 123.38±29.78 0.90±14.68 0.298
*To convert the values for serum creatinine to milligram per deciliter, divided by 88.4.
Ç‚ represents P value of less than 0.05.
Figure1. Serial changes in serum levels of CyC, sCr and BUN, and eGFR of all participants.
Table3. Comparisons of Parameters in 3 groups according to contrast volume.
No of patients (n, %)
Pre CyC (mg/l)
Pre sCr (µmol/l)
Pre BUN (mmol/l)
Contrast volume Group I <70ml, Group II 70-110ml, Group III > 110ml.
Cholesterol, Triglyceride, HDL (high density lipoprotein cholesterol) and LDL (low density lipoprotein cholesterol) are described in mg/dl.
Ç‚ compared with first group, P < 0.05.
# compared with second group, P < 0.05.
Figure 2. Incidence of CIN according to contrast volume.
Table4. CyC, sCr, BUN and eGFR change in 3 groups according to the contrast volume.
Contrast volume Group I <70ml, Group II 70-110ml, Group III ≥110ml.
# compared with second group, P < 0.05.
Table5. Logistic regression between CIN and baseline variable.
CIN is one of the most important co-morbidities after exposure to contrast media. As the contrast enhanced computed tomographic angiography of coronary artery or peripheral angiogram are becoming more popular nowadays and routinely do in our daily clinical practice. CTCA not only is safe to perform, regarding as a reliable sensitive tool for investigating or evaluating the peripheral vascular stenosis, coronary artery stenosis, etc. Hence, CTCA is becoming more popular clinical investigation method for estimating the vascular morphology. But unwanted co-morbidity of CIN should also be a concern for the safety of patients. So, physicians should pay a particular attention to the patients' renal function status and risk of developing CIN before the contrast enhanced procedure to prevent CIN and long term evolution to chronic kidney disease as early as possible.
CIAKI is a kind of disease without effective treatment although we did a lot of research works for decades, and it is one of the major unwanted adverse effects that can get after the contrast medium exposure. In fact, AKI was defined by change in the sCr level, Richard Solomon et al argued that sCr is not linearly related to GFR level and also some confounding bias existed when calculating the GFR based upon the sCr levels. (19) One report showed that vast majority of CIN studies had been based on only pre-contrast and post-contrast levels of sCr without appropriate control measures; therefore, the probability of the CIN incidence was overestimated (20). Several papers published before argued about the discordant results between eGFR and sCr level in diagnosing CIN. (21,22) Taner Erselcan, et al also conveyed that significant discordance was present in differential sCr and measured eGFR in hospitalized patients, proposing that calculations of CIN incidence only based on sCr level may make an error. But they didn't suggest measuring GFR by nuclear medicine and suggested to find a specific biomarker as an alternative. (23) Tajiri K et al stated that CIN could be a transient disorder but an early decrease in eGFR and increase in oxidative stress are associated with long term chronic kidney insufficiency, therefore long-term follow up and prevention of chronic renal insufficiency with an adequate medical intervention should be done for the safety of patients (24).So, we need to find out the early renal injury bio-markers to give an appropriate measures for those who need to have an intervention as soon as possible.
Previous studies testified that the sCr concentration usually peaks on the second or third day after exposure to contrast medium and usually returns to the baseline value within 2 weeks (25). In our study, both sCr and CyC level increased after 24 hours of contrast medium exposure and decreased under the baseline level after 3 days of the procedure. But for the case of BUN, the BUN level decreased after the first day and again increased after 3 days, this may due to the reasons of hydration after the procedure as all of the patients were encouraged to drink as much as possible after CTA. Moreover, the contrast medium of different osmolar classes were used very routinely in daily clinical practice, the safety of the contrast medium should be monitored aggressively. Hence, we need to do more about the changes in renal function biomarkers to find out the exact relationship and changes of biomarkers after exposure. So, we can give early intervention to prevent the progression of transient renal injury to CKD.
Toyonari T., Toyoaki M. et al showed that oral rehydration after the CTCA is a crucial factor in prevention of CIN, CyC can detect more sensitively than sCr in evaluating renal function related to oral fluid volume especially in diabetes patients (27). Recent study stated that oral rehydration before and after the contrast media exposure is as effective as intravenous rehydration in the prevention of CIN (28). Additionally, all of the patients participated in our study were encouraged to drink as much as possible after the contrast media exposure. Bell GW, Edwardes M et al reported that the incidence of CIN after the coronary computed tomographic angiography in normal patient as 0% when defined as sCr level increase in 0.5mg/dl and 4.3% if increase in 25% from baseline(29). However, the reported range of CIN after iodinated contrast media exposure due to computed tomography as 0-11%.(30) Therefore, our data also showed the same result as mentioned above, 0% if sCr rise more than 0.5mg/dl and 1.7% if ≥ 25% sCr rise from the baseline. So, the data also suggested that fluctuation in CyC level of more than 10% was 13.1%, this population should take additional caution and proper follow up for early prevention of CIN (9).
As mentioned above, the risk factors for CIN include pre-existing CKD, DM, congestive heart failure, hypovolemia and amount of contrast volume administered during the procedure (12). In our study, we didn't find the statistical correlation between the above factors as both non CIN and CIN groups. Both of the diabetes and non-diabetes patients had the similar fasting blood glucose levels and glycosylated hemoglobin levels. Moreover, we enrolled the patients who had normal cardiac function (LVEF 58.72±3.37) and normal renal function of pre contrast exposure eGFR according to aMDRD equation adjusted for Chinese as 122.49±29.52ml/min/1.73m2. One more fact is that single point measuring of blood pressure also similarly the same between both groups.
In addition, contrast volume is also an independent risk factor for developing CIN (12). The European society of radiology guideline also suggested to use the lowest amount of contrast medium consistent with the diagnostic result in 2011 (31). In this study, the contrast medium used was non-ionic iodinated low osmolar contrast medium and mean volume was also lower (ranging from 50-160ml) than the amount mentioned in the other studies. So these factors may contribute to the relatively low risk of CIN in our study.
Yang D et al described that long term hypercholesterolemia as a risk factor for contrast related AKI by means of disorders prostaglandin intra-renally and abnormal nitric oxide system induced lipid peroxidation (32). Another experiment reported that hypercholesterolemia could reduce nitric oxide production and consequently leading to reduced GFR after injection of contrast medium (33). Giuseppe Patti et al indicated that short term pre-treatment with loading dose of atorvastatin will decrease incidence of CIN and shorter hospital stay in patients who suffered from acute coronary syndromes with percutaneous coronary intervention and this high dose atorvastatin may have an effect on renal protection by anti-inflammation (26). Pakfetrat et al testified that hypercholesterolemia is a strong predictor of the risk of contrast related acute kidney injury (34). In our study, hypercholesterolemia was also intensely associated with the risk of CIN.
Although the risk of CIN in our study of non-renal insufficiency patients was relatively low, we need to pay more attention to those who resulted in increasing in CyC level of more than 10% and sCr level of more than 25% from baseline. A proper follow up should be recommended for every person with high risk of renal insufficiency. Furthermore, obese patients and patients with high blood cholesterol level should give a particular care after every contrast medium exposure for early prevention.
Our study had a number of possible limitations. Firstly, our study sample size was just 290 patients, so this will not have been sufficient enough to represent the whole population accurately. Secondly, this study was not a multicenter study and just conducted in a single center.