Abstract
Contrast-induced nephropathy (CIN) is the third leading cause of acute kidney injury (AKI) in hospitalized patients. Diabetes mellitus remains a consistent independent predictor of contrast nephropathy. Aim: To determine frequency and predictors of contrast-induced nephropathy after cardiac catheterization in type II diabetic patients. Patients and methods: The study included 200 type II diabetic patients who underwent cardiac catheterization; serial measurement of serum creatinine and creatinine clearance (Before contrast exposure and 48 h), creatinine clearance was calculated using Cockcroft–Gault formula. Contrast-induced nephropathy was defined as rise in serum creatinine 48 h after contrast exposure of ≥0.5 mg/dL or increased >25% compared to base line creatinine. Results: incidence of CIN in type II diabetic patients was 21.5%; incidence of CIN in diabetic patients with microalbuminuria was 17%, while incidence of CIN in patients with macroalbuminuria levels was 26%. There was a statistically significant difference between the patients who suffered from CIN post-procedure and patients who did not suffer from CIN regarding the ejection fraction and age with low ejection fraction and older patients in CIN group. Multiple logistic regression analysis for CIN predictors showed that pre-contrast serum creatinine to be the strongest predictor for being at risk of contrast-related, followed by age, and lastly albumin/creatinine ratio. Conclusion: Our findings suggest that diabetic patients, despite having a normal baseline creatinine are at an increased risk of developing CIN post-coronary angiography, patients at risk of CIN are older patients with high pre-contrast serum creatinine and high urine albumin/creatinine ratio.
Introduction
Cardiac catheterization (coronary angiography and percutaneous coronary intervention {PCI}) utilizes a significant amount of contrast media that causes an increased incidence of contrast-induced nephropathy (CIN).Citation1,Citation2 CIN is commonly defined as a 25% or 0.5 mg/dL rise from the baseline creatinine (Cr) within 48-h post-PCI or contrast procedures.Citation3,Citation4 CIN is an adverse event that results in increased morbidity including the need for renal dialysis and mortality.Citation5 In fact, although usually transient, its resolution needs 1–3 weeks on average, the impairment of renal function may be permanent in some cases with the risk of progression towards chronic renal failure and the necessity of a temporary or permanent dialysis.Citation6 Prevention is the key to reduce the incidence of CIN and it begins with identification of the high risk patient coupled with appropriate peri-procedural management. Many studies have been conducted to identify the main risk factors for CIN, in fact many score systems have been proposedCitation7–12 and increasing number of guidelines have been suggested in literatureCitation13,Citation14 to help lessen the complication of CIN. The most widely recognized risk predictor of CIN is the elevated serum creatinine or reduced GFR pre-contrast administration. In clinical practice AKI is defined as serum creatinine ≥1.5 mg/dL or glomerular filtration rate, GFR ≤60 mL/min/1.73 m2).Citation15 Several reports of CIN prophylactic therapies have been published.Citation16 These include pre-saline hydration,Citation17 high-dose oral N-acetylcysteine (NAC),Citation18 the use of an iso-osmolar contrast agentCitation19 and prophylactic hemofiltration.Citation20 In our center, patients with baseline Cr ≥ 1.5 mg/dL receive routine oral NAC and saline pre-hydration prior to PCI. Patients with normal baseline Cr do not receive prophylaxis. Many diabetic patients have subclinical nephropathy despite a normal baseline creatinine and hence may be predisposed to a higher risk of developing CIN.Citation21 Few studies have, however investigated the role of albuminuria as possible independent predictors of CIN. The aim of our study was to make a profile of patients at highest risk of developing CIN after coronary angiography and/or percutaneous coronary intervention, in order to take appropriate prevention measures, analyzing the risk factors, evaluated extensively in the literature, and assessing if albuminuria considered as risk factor for CIN among albuminuric diabetic patients with a normal baseline creatinine who received prophylaxis saline before undergoing cardiac catheterization.
Patients and methods
We conducted a cohort study involving 200 patients with type II diabetes mellitus presenting to the cardiology department at our hospital to undergo cardiac catheterization (coronary angiography or PCI) during the period from January 2012 to January 2013. Patients underwent PCI according to the current guidelines.Citation22 Patients with documented serum Cr taken within 2 weeks prior to and 48 h after coronary angiography were identified from our cardiac database. We excluded patients who had serum creatinine >1.5 mg/dL, patients who had recent contrast exposure before coronary angiography, patients who suffered from previous myocardial infarction, suffering from cardiogenic shock or sever decompensated heart failure. A total of 500 patients were screened and 200 patients were enrolled into the final analysis. Every patient was subjected to history taking; with emphasis on history of diabetes mellitus, hypertension, pre-existing renal impairment defined as elevated serum creatinine >1.5 mg/dL “The average upper cut-off value used in most Egyptian laboratories”, history of drug intake as angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARBs) and other nephrotoxic drug as non-steroidal anti-inflammatory drugs (NSAIDs), aminoglycosides, acyclovir, methotrexate, sulfa antibiotic, triamterene. Clinical examination wad done with emphasis on weight and height, BMI, blood pressure, pulse assessment with examination of peripheral pulsations. Serum creatinine was measured using the Jaffe reaction with adsorbent (picrate) method. Creatinine clearance (mL/min) was calculated using Cockcroft–Gault formula:
Two-dimensional transthoracic echocardiography with continuous and pulse wave Doppler studies were performed using echocardiographic machine. General Electric vivid 3 (General Electric Healthcare Company, Waukesha, WI) equipped with 2.5 and 3.5 MHz probes. Standard M-mode measurements of left ventricular end-diastolic dimension, end-systolic dimension, fractional shortening and ejection fraction. LVMI was calculated by Devereux's formula considering the diastolic measurements of left ventricular internal diameter (LVID), interventricular septal thickness (IVST) and posterior wall thickness (PWT):
Coronary angiography was done in the standard fashion after gaining femoral artery access puncture using Seldinger’s technique. The standard coronary views were obtained, which included an average six left coronary and two right coronary artery injections giving sufficient data to enable quantitative angiography.
Prophylaxis therapy
All patients received CIN prophylaxis. Intravenous hydration was administered at a rate of 1 mL/kg/h of normal saline for 6–12 h prior to, and 12–24 h after, cardiac catheterization unless contraindicated due to fluid overload or pulmonary congestion. Patients received oral NAC 1.2 g bid from the day before PCI till the day after. Patients received 300 mg aspirin loading before PCI and were continued at 100 mg/day. All patients received low osmolality non-ionic contrast iopromide (Ultravist®, Berkeley, CA) during PCI (volume ∼100 mL). The administration of oral metformin was stopped before PCI and for at least 2 days after PCI. Serum creatinine was measured within 2 weeks before PCI, 2-day post-PCI and daily thereafter if deemed necessary to monitor renal function by the nephrologist.
Primary end point
CIN in our study was defined as an increase of ≥25% or ≥0.5 mg/dL from the baseline serum Cr within 48 h after PCI. Procedural data were entered by the interventional cardiologists performing the PCI. The patient’s medical records were entered into the computer database by research coordinators.
Statistical analysis
Data were fed to the computer using IBM SPSS (Statistical Package for the Social Sciences) software package version 20.0. Qualitative data were described using number and percent. Comparison between different groups regarding categorical variables was tested using chi-squared test. The distributions of quantitative variables were tested for normality using Shapiro–Wilk test and D’Agstino test, also Histogram and QQ plot were used for vision test. If it reveals normal data distribution, parametric tests was applied. If the data were abnormally distributed, non-parametric tests were used. Quantitative data were described using mean, standard deviation, minimum and maximum. Comparison between two independent populations was done using independent t-test. Agreement of the different predictive with the outcome was used and was expressed in sensitivity, specificity, positive predictive value, negative predictive value and accuracy. Receiver operating characteristic curve (ROC) was plotted to analyze a recommended cutoff, the area under the ROC curve denotes the diagnostic performance of the test. Odd ratio (OR) and 95% confidence interval were used to calculate the ratio of the odds of an event occurring in one patient group to the odds of it occurring in the control group. Univariate and multivariate logistic regression were assessed.
Results
The study population was subdivided at the end of the study according to occurrence of contrast-induced nephropathy into two groups:
Group A: Included 157 patients who did not develop contrast-induced nephropathy after coronary catheterization.
Group B: Included 43 patients who developed contrast-induced nephropathy after coronary catheterization.
Baseline patient characteristics
Gender was well matched between both groups, patients who developed CIN were more older (62.4 ± 5.8 vs. 54.8 ± 5.4, p < 0.001), used ACEI/ARBs more frequently (93.3% vs. 37.6%, p < 0.001) , had higher base line serum creatinine (1.18 ± 0.19 vs. 1.05 ± 0.15, p < 0.001), had lower creatinine clearance (78.26 ± 22.07 vs. 92.75 ± 9.27, p < 0.001) (), higher Alb/Cr ratio (583.4 ± 471.91 vs. 343.2 ± 358.8, p = 0.003) () and lower ejection fraction (38.0 ± 5.8 vs. 57.1 ± 9.7, p < 0.001) (). There was highly significant difference as regard pre- and post-procedure blood urea, serum creatinine and GFR among CIN versus no CIN group ().
Table 1. Comparison between “CIN group” and “No CIN group” according to demographic data.
Table 2. Comparison between “CIN group” and “No CIN group” according to blood urea, serum creatinine and GFR.
Table 3. Comparison between “CIN group” and “No CIN group” according to urinary albumin and albumin/creatinine ratio.
Table 4. Comparison between “CIN group” and “No CIN group” according to ejection fraction and left ventricular mass index.
Table 5. Comparison between pre- and post-procedure blood urea, serum creatinine and GFR in “CIN group” and “No CIN group”.
Incidence of CIN
Overall incidence of CIN in type II diabetic patients was 21.5% (43 out of 200 patients), incidence of CIN in diabetic patients with microalbuminuria was 17% (17 out of 100 patients), while incidence of CIN in diabetic patients with macroalbuminuria was 26% (26 out of 100 patients).
Predictors of CIN
CIN risk is higher if the patient aged >61 years (sensitivity 53.4, specificity 91.0%, p < 0.001), baseline serum creatinine >1.29 mg/dL (sensitivity 98.2, specificity 87.5%, p < 0.001) ( and ) ( and ), baseline Alb/Cr >109 mg/g (sensitivity 86.0, specificity 50.9%, p = 0.02) () (). Stepwise regression analysis for the most important predictors for contrast-induced nephropathy, revealed that the predictors for CIN in diabetic patients in this study arranged by its importance: pre-contrast Creatinine to be the strongest predictor for being at risk of contrast-related AKI (OR, 1.622; 95% CI, 0.893–1.814; p ≤ 0.001), followed by age (OR, 1.001; 95% CI, 1.248–1.205; p ≤ 0.001), and an Alb/Cr (OR, 1.003; 95% CI, 1.000–1.005; p = 0.022) ().
Figure 1. ROC curve for the best cut off point of age for prediction of contrast-induced nephropathy.
Figure 2. ROC curve for the best cut off point of pre-contrast serum creatinine for prediction of contrast-induced nephropathy.
Figure 3. ROC curve for the best cut off point of albumin/creatinine ratio in prediction of contrast-induced nephropathy.
Table 6. Agreement (sensitivity, specificity and accuracy) for age and CIN.
Table 7. Agreement (sensitivity, specificity and accuracy) for pre-procedure serum creatinine and CIN.
Table 8. Agreement (sensitivity, specificity and accuracy) for albumin/creatinine ratio and CIN.
Table 9. Multiple logistic regression for predicting CIN cases.
Discussion
CIN is one of the most common causes of acute kidney injury in hospitalized patients. Previous studies have shown an increased rate of CIN in 12–26% of patients with myocardial infarction who underwent percutaneous coronary intervention.Citation23–31 Studies have also shown a correlation between CIN and multiple risk factors including diabetes mellitus, a previous history of chronic kidney disease and the amount of contrast used during the procedure.Citation25–31 The majority of the studies that showed a higher incidence of CIN in patients who received contrast agent during the intervention included patients with advanced renal disease, cardiogenic shock, volume depletion, poor ejection fraction and decreased cardiac output secondary to myocardial infarction. Although the frequency of CIN has decreased over the past decade from a general incidence of 15–7%.Citation32 Patients with diabetic nephropathy undergoing PCI have a very high risk of developing CIN and therefore prophylaxis is routinely indicated prior to PCI.Citation33 There is no conclusive evidence as to whether the presence of diabetes mellitus with normal renal function should be offered routine CIN prophylaxis.Citation34 In the current study the overall incidence of CIN among diabetic patients was 21.5%, the incidence of CIN among patients with microalbuminuria was 17%, while the incidence of CIN among patients with macroalbuminuria was 26%, this finding suggests that patients with diabetes with normal pre-procedure serum creatinine and having albuminuria remain at a significant risk for CIN. Five (8.6%) of these patients with normal serum creatinine who developed CIN had creatinine clearance <60 mL/min per 1.73 m2, this highlights the importance of calculation of creatinine clearance for all diabetic patients during the preparation to contrast exposure and not to use creatinine levels only to determine patients who will receive reno-protective strategies and post-procedural close follow up of creatinine levels, especially with the ease of calculating creatinine clearance by the use of Cockcroft–Gault formula. The current study revealed that patients who develop CIN are usually older, use ACEI/ARBs more frequently, have higher base line serum creatinine and higher Alb/Cr ratio. To be more accurate we tried to use ROC curves to set up cut off points beyond which the incidence of CIN increases, age older than 61 years old, baseline serum creatinine >1.29 mg/dL, baseline Alb/Cr ratio >109 mg/g were predictors of CIN. The elderly remain at a higher risk of CIN after PCI, a few studies have found age older than 70 years to be an independent predictor of CIN in multivariate analysis.Citation35 As expected, the presence of a previous renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, turned out to be a very sensitive index of CIN.Citation36,Citation37 Based on the available evidence in the literature the risk of CIN is inversely related to the calculated estimated GFR (eGFR).Citation38
Study limitations
The main limitation of this study is the small number of patients, which was reflected on the number of patients who developed CIN, and so studying the predictors of CIN in such a small number could lead to inaccurate results. The results are from a single medical center, and also not all “post-PCI nephropathy” is “contrast-induced nephropathy”, pre-renal causes and cholesterol emboli can also induce nephropathy, The type of ARF (ischemic, nephrotoxic, or atheroembolic) could not be determined precisely as renal biopsies were not performed. In addition the impossibility to conclude causality or exclude unmeasured confounding as a contributor to the observed association, we cannot exclude the presence of a selection bias and the possibility that other factors, might have contributed, at least in part, to renal impairment, and influenced the clinical outcome of our patients.
Conclusion
The current study revealed that diabetic patients who developed CIN were older (>61 years), used ACEI/ARBs more frequently, had higher base line pre-contrast serum creatinine (>1.29 mg/dL), higher pre-contrast Alb/Cr ratio (>109 mg/g). Pending further studies to confirm these results, in light of these data, it would be important to be able to better define the role of both pre-procedural albuminuria level with respect contrast nephropathy and to assess if pre-procedural risk stratification with this factor as an adjunct to established clinical risk factors, may be useful as form of early identification of high risk patients for contrast-induced nephropathy.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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