|Year : 2016 | Volume
| Issue : 1 | Page : 94-100
|A comparison of definitions of contrast-induced nephropathy in patients with normal serum creatinine
Mohammad Reza Khatami1, Nasrin Nikravan1, Mojtaba Salari-Far2, Safieh Davoudi2, Mohammad Reza Pahlavan-Sabbagh3
1 Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran
2 Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
3 Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
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|Date of Web Publication||15-Jan-2016|
| Abstract|| |
Contrast-induced nephropathy (CIN) is the third leading cause of acute kidney injury in hospitalized patients. The prevalence of CIN is reported to range from 0% to 50%, depending not only on patient condition and the procedure used but also the definition of CIN applied. We aimed to determine the best diagnostic indicator of CIN in patients with normal serum creatinine. This study included 206 patients with normal serum creatinine who underwent coronary angiography/angioplasty. Serum creatinine level and glomerular filtration rate (GFR) were measured before and on the second and fifth days after contrast administration. The incidence of CIN based on a 25% increase in serum creatinine was calculated and compared with the incidence based on a 25% decrease in GFR or an increase of at least 0.5 mg/dL in serum creatinine. Of 206 patients, 127 were male (61.7%) and 79 were female (38.3%); the mean age was 59.56 ± 10.3 years. The prevalence of CIN was 30% based on a 25% increase in serum creatinine, 23% based on a 25% decrease in GFR (P <0.012) and 3.8% based on a serum creatinine increase of at least 0.5 mg/dL (P <0.0001). The serum creatinine levels remained within the normal range in the majority of patients with CIN based on the different definitions. In patients with normal serum creatinine, the absolute increase in serum creatinine may describe the prevalence of CIN more accurately than the relative increase in serum creatinine or relative decrease in GFR.
|How to cite this article:|
Khatami MR, Nikravan N, Salari-Far M, Davoudi S, Pahlavan-Sabbagh MR. A comparison of definitions of contrast-induced nephropathy in patients with normal serum creatinine. Saudi J Kidney Dis Transpl 2016;27:94-100
|How to cite this URL:|
Khatami MR, Nikravan N, Salari-Far M, Davoudi S, Pahlavan-Sabbagh MR. A comparison of definitions of contrast-induced nephropathy in patients with normal serum creatinine. Saudi J Kidney Dis Transpl [serial online] 2016 [cited 2018 Mar 17];27:94-100. Available from: http://www.sjkdt.org/text.asp?2016/27/1/94/174086
| Introduction|| |
Contrast-induced nephropathy (CIN) is characterized by a rapid decline in renal function after contrast media exposure in the absence of other obvious causes of acute kidney injury (AKI). The widespread use of contrast media  has focused attention on CIN as the thirdleading cause of AKI among hospitalized patients,  which is associated with significant morbidity and mortality. , Previous history of renal failure is the most important risk factor for CIN  and a glomerular filtration rate (GFR) of 60 mL/min is considered the cut-off point for at-risk patients. , Other important risk factors for CIN include the presence of diabetes,  the type and amount of contrast media  and patient hemodynamic status during the procedure.  Since the first report of CIN in 1954,  there has been no consensus on the optimal definition of CIN. CIN is commonly defined by a 25% relative increase in serum creatinine, a 25% relative decrease in GFR or a 0.5 mg/ dL absolute increase in serum creatinine. ,
Clinically, serum creatinine is the standard marker of kidney function; however, creatinine is not a real-time marker of changes in renal function and several factors other than renal function may affect serum creatinine levels.
Direct measurement of GFR is the most sensitive method of evaluating kidney function,  but is rarely used in clinical practice. Several GFR measurement methods are used in clinical practice, including the Cockcroft- Gault (C-G),  Modification of Diet in Renal Disease (MDRD)  and Chronic Kidney Disease Epidemiology Collaboration (CKD- EPI)  equations.
We compared the prevalence of CIN using the various available definitions to determine the most accurate predictor of CIN in patients with normal serum creatinine.
| Methods|| |
In this study, we enrolled 206 adult patients who were subjected to coronary angiography after all patients provided written informed consent. All patients had normal serum creatinine (≤1.5 mg/dL for males and ≤1.3 mg/ dL for females) and none had received nephrotoxins in the week preceding the procedure.
Angiography was performed with lowor medium-osmolality contrast medium, with infusion fluid administered 4 h before the procedure and continuing 8 h afterward. Serum creatinine levels were measured immediately before the procedure and on the second and fifth days after angiography. Patients who developed hemodynamic instability or required nephrotoxic agents were excluded thereafter. The GFR was measured using three formulas; the C-G equation was adjusted for body surface area calculated using the Du Bois and Du Bois equation.  The patients were categorized as having CIN by different definitions on the second and fifth days after the procedure. Statistical analysis was performed using the SPSS (v.18) software. The quantitative parameters were compared using Friedman's ANOVA test. The qualitative parameters were compared by Chi-squared and Z-test performed using the Z-test calculator. A P-value <0.05 was considered to indicate statistical significance.
| Results|| |
Of 206 patients, 127 were male (61.7%) and 79 were female (38.3%); the mean age was 59.56 ± 10.3 years. Although the mean hemoglobin (Hb) was 13.69 ± 1.68 g/L, 34 patients (16.5%) were anemic (Hb <12.5) and 69 patients (33.5%) had diabetes. The average volume of contrast media used was 236 ± 70 mL; 113 patients received Visipaque, 90 patients received Omnipaque and only two patients received Ultravist. The mean baseline serum creatinine was 0.96 ± 0.21 mg/dL. The GFR values measured by C-G, CKD-EPI and MDRD were 82.4 ± 22 mL/min/1.73 m 2 body surface area, 79 ± 18 mL/min and 80.5 ± 21, respectively; these differences were significant (P = 0.014). Despite the fact that all patients had normal serum creatinine, 32 (15.5%), 37 (18%) and 34 (16.5%) patients had a GFR <60 mL/min as calculated by C-G, CKD-EPI and MDRD, respectively (P = 0.69). [Table 1] shows the clinical and laboratory characteristics of patients according to the various diagnostic definitions.
|Table 1: Characteristic data of patients with CIN according to the different definitions and the different GFR equations.|
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The prevalence of CIN also varied according to the diagnostic definition. [Figure 1] shows the overall incidence of CIN according to the definition used and [Figure 2] shows the prevalence of CIN on the second and fifth days after contrast media exposure according to definition.
|Figure 1: The prevalence of CIN according to different definitions and different GFR equations.|
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|Figure 2: The prevalence of CIN according to the different definitions on Days 2 and 5 after contrast exposure.|
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As shown in [Table 1], the prevalence of CIN is significantly different between the definitions of 25% relative increase in serum creatinine or 25% relative decline in GFR with that of a 0.5 mg/dL absolute increase in serum creatinine (P < 0.0001). However, when the cut-off point of CIN is defined as a 20% reduction in the GFR, the prevalence of disease is identical to that defined by a 25% increase in serum creatinine (30% in both).
All but three patients had serum creatinine >1.5 mg/dL after angiography. Thus, the serum creatinine levels remained within the normal range in the majority of patients with CIN based on the different definitions. Interestingly, no patients with GFR <60 mL/min (28-38 patients based on the different equations) developed CIN.
| Discussion|| |
We compared the prevalence of CIN in patients with normal serum creatinine according to the different diagnostic definitions. The upper limit of normal serum creatinine was assumed to be 1.5 mg/dL.  In our study, the incidence of CIN was 30.5% based on a 25% relative increase in serum creatinine. According to the relative reduction in GFR, the prevalence of CIN was 19.9%, 23.7% and 20.8% when GFR was measured using the C-G, MDRD or CKD-EPI equations, respectively. The lowest prevalence of CIN (3.8%) resulted from a definition of a 0.5 mg/dL absolute increase in serum creatinine.
Serum creatinine is not an optimal indicator of renal function as the level is affected by many factors, including hydration status, diet and medications. , Therefore, the relative increase in serum creatinine may not reflect the true prevalence of CIN in patients with normal serum creatinine; instead, the GFR change may be a better index of this condition (P <0.012). Some studies showed that 13.9- 34.1% of patients with normal serum creatinine had reduced GFR. ,
Using the same set of patients in all calculations, our study clearly showed a discrepancy in the prevalence of CIN when defined as an increase in serum creatinine compared with a decrease in GFR (P <0.012). Although the majority of patients with CIN maintained a normal serum creatinine range, a serum creatinine increase of as little as 5% can detect CIN with 75% sensitivity and 72% specificity.  Moreover, it was evident that even small changes in serum creatinine can affect the long-term survival of these patients. 
In the literature, a 25% relative increase in serum creatinine is considered equivalent to a 25% decrease in the GFR; however, this assumption is not a mathematical reality. At every serum creatinine level in every patient, a 25% increase in serum creatinine is equivalent to only a 20% decrease in GFR; likewise, a 25% decrease in the GFR is seen when serum creatinine is increased by at least 33%. Importantly, the difference in prevalence of CIN becomes highly significant when the CIN is defined as a 0.5 mg/dL increase in serum creatinine (P <0.0001; [Table 1]. Interestingly, patients with a 40% increase in serum creatinine in this study did not reach the threshold of at least 0.5 mg/dL absolute creatinine.
No reports have compared the various methods of GFR calculation in CIN. We compared the C-G, CKD-EPI and MDRD equations and found significant differences among them; the highest value resulted from C-G and the lowest from CKD-EPI. Unfortunately, we were unable to compare these values by standard methods of GFR measurement to determine which is more accurate. One study suggested that CKD-EPI is a better predictor of GFR, with no significant difference compared with MDRD. Overall, a lower bias is reported with MDRD, whereas the best accuracy is seen with both CKD-EPI and MDRD. 
In our study, the prevalence of disease was significantly higher on the fifth day after the procedure than on the second day (20.4% vs. 10.2%). Although many factors may play roles in this finding, perhaps the most important is proper hydration to dilute the serum creatinine the day after the procedure.
Another interesting result was that 32 patients (15.5%) had GFR <60 mL/min (mean = 51.2, range = 34.4-59.8 mL/min); however, none of these patients developed CIN. Interpretation of this observation is difficult due to the small sample size. Millward et al  reported that six of 48 patients had decreased GFR, but only one of them had abnormal serum creatinine.
A 10% prevalence of CIN is reported in patients with normal renal function. One study reported that none of the patients with Cystatin-C levels <0.85 mg/L had CIN. 
Newhouse et al  demonstrated that patients with a serum creatinine of 0.6-1.2 mg/dL had a 25% increase in serum creatinine even in the absence of contrast media exposure.
Erselcan et al  and Rao et al  showed that the changes in serum creatinine before and after contrast media exposure were not sufficient for a CIN diagnosis. Two other studies that compared the serum creatinine and GFR found a 50-77% concordance between them. , Other studies showed either concordance  or discordance  between serum creatinine and GFR.
Kiyokuni et al  assessed the three definitions of CIN and showed that a 0.5 mg/dL increase in serum creatinine is the best predictor of the long-term outcome in these patients. Solcum et al  also showed that the definition of a 0.5mg/dL increase in serum creatinine is a better indicator of future cardiovascular events and renal diseases. Based on this study, a 25% relative increase in serum creatinine is a moresensitive but less-specific marker of long-term outcome. According to Harjai et al, both delta Cr >25% and absolute increase of 0.5 mg/dL serum creatinine in patients with contrast nephropathy are the most valuable predictors of major cardiovascular events in six months.  Other studies have demonstrated that a 0.5 mg/dL increase in serum creatinine is the better predictor of both short-term and longterm outcomes compared with a 25% relative increase in serum creatinine. 
We concluded that in patients with normal serum creatinine, the definition of CIN according to a 0.5 mg/dL absolute increase in serum creatinine significantly reduced the prevalence of the disease compared with the definition based on a 25% relative increase in serum creatinine or a 20-25% relative decrease in GFR. Corroborating results from other studies, our findings suggest that the absolute increase in serum creatinine may be a more reliable indicator of CIN in patients with normal serum creatinine.
| Acknowledgment|| |
This work has been sponsored by a grant from the Deputy Research of the Tehran University of Medical Sciences, Tehran, Iran.
Conflict of Interest: None declared.
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Mohammad Reza Khatami
Nephrology Research Center, Tehran University of Medical Sciences, Tehran
[Figure 1], [Figure 2]
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