Contrast-induced nephropathy (CIN) after primary percutaneous coronary intervention (PPCI) is associated with adverse short- and long-term outcomes. The aim of this study was to evaluate the predictive value of gamma-glutamyl transferase (GGT) for risk of CIN in patients with ST-segment elevation myocardial infarction who underwent PPCI. A total of 473 patients were enrolled in the study. A relative increase in serum creatinine ≥25%, or an absolute increase ≥0.5 mg/dl, from the baseline within 72 hours of contrast exposure was defined as CIN. Patients were divided into 3 groups according to GGT tertiles (tertile 1, GGT <19 U/L; tertile 2, GGT 19 to 33 U/L; and tertile 3, GGT >33 U/L) on admission. Demographics, clinical risk factors, laboratory parameters, CIN incidence, and other inhospital clinical outcomes were compared among GGT tertiles. CIN incidence was significantly higher in tertile 3 (29%) compared with tertiles 1 (11%) and 2 (11%, p <0.001). Inhospital death incidence was significantly increased across tertiles (from tertile 1 to tertiles 2 and 3, 1%, 4%, and 5%, respectively, p <0.05). In receiver operating characteristic analysis, a threshold value of GGT >26.5 U/L had 70% sensitivity and 60% specificity for CIN. After including variables found significant in univariate analysis, the presence of diabetes mellitus (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.22 to 2.31, p <0.001), C-reactive protein (for each 1 mg/L increase; OR 1.01, 95% CI 1.00 to 1.02, p = 0.007), contrast volume (for each 1-ml increase; OR 1.01, 95% CI 1.00 to 1.02, p = 0.012), and GGT >26.5 U/L (OR 2.59, 95% CI 1.48 to 4.53, p <0.001) were found as independent associates of CIN in multivariate regression analysis. Each 1 U/L increase in GGT was also associated with CIN risk (OR 1.04, 95% CI 1.03 to 1.06, p <0.001). In conclusion, GGT on admission was a significant and independent predictor of CIN after PPCI in patients with ST-segment elevation myocardial infarction.
Gamma-glutamyl transferase (GGT) is a commonly used diagnostic test responsible for the extracellular catabolism of glutathione, a major component of intracellular antioxidant protective mechanisms. This reaction produces cysteinyl-glycine components, which are a potent reducer of Fe +3 in the extracellular surroundings that is able to simultaneously compose Fe +2 and a free thiyl radical; subsequent reactions lead to the formation of superoxide anion radical ( <SPAN role=presentation tabIndex=0 id=MathJax-Element-1-Frame class=MathJax style="POSITION: relative" data-mathml='O2−’>O−2O2−
O 2 −
), hydrogen peroxide (H 2 O 2 ). These events are known to play main role in the evolution of atherosclerosis. Several epidemiology and pathology studies have found association of GGT with incident cardiovascular events. Gul et al reported that GGT was a readily available clinical laboratory value associated with inhospital adverse outcomes in patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PPCI). Therefore, it is a useful biomarker for cardiovascular risk stratification in clinical practice. The aim of this study is to investigate whether higher GGT levels are associated with an increased risk of contrast-induced nephropathy (CIN) after PPCI in STEMI.
Methods
A total of 473 patients (age 61 ± 12 years, 78% men) were enrolled into the study presenting with STEMI to the Department of Cardiology of Yuksek Ihtisas Education and Research Hospital from January 2010 to December 2012. This study was designed in a retrospective manner. Data collection regarding clinical, demographic, and laboratory characteristics of patients and inhospital events were conducted on the basis of a review of medical records. Primary end point was considered as development of CIN, and secondary end points were considered as inhospital death, acute kidney injury requiring renal replacement therapy, and stroke. The ethics committee of the Yuksek Ihtisas Education and Research Hospital approved this study. Written informed consent was taken from the patients themselves in life and first-degree relatives of patients who died.
We excluded patients with end-stage renal disease (estimated glomerular filtration rate <15 ml/min/1.73 m 2 ), renal transplantation, systemic inflammatory disease, active infections, known liver disease including all kind of chronic hepatitis, hepatobiliary disease, a history of alcohol consumption, hematologic and malignant disease, congestive heart failure, and missing or unavailable GGT values.
STEMI was defined as typical chest pain >30-minute duration with ST-segment elevation measured at the J point, should be found in 2 contiguous leads and be ≥0.25 mV in men <40 years, ≥0.2 mV in men >40 years, or ≥0.15 mV in women in leads V 2 and V 3 and/or ≥0.1 mV in other leads or left bundle branch block.
All PPCI procedures were performed with femoral approach according to standard techniques. All patients received nonionic low osmolar contrast media (CM). Anticoagulation and antiplatelet therapies were given according to current guideline recommendations for patients with STEMI. Predilection and direct stenting with bare metal stent or drug-eluting stent was left to the discretion of the interventional cardiologist according to patient need. Immediately after intervention, all patients received intravenous isotonic saline solution (0.9%) at a rate of 1 ml/kg/hour for 12 hours (or 0.5 ml/kg/hour for 12 hours in cases of overt heart failure). After PPCI, all patients were admitted to the coronary care unit; aspirin 100 mg, clopidogrel 75 mg, and statins were continued in all patients. The use of adrenergic blocking agents and angiotensin-converting enzyme inhibitors was left to the discretion of the interventional cardiologists.
Cardiovascular risk factors were confirmed on the basis of a review of medical records. Diabetes mellitus was defined as previous using antidiabetic drugs or fasting blood glucose >126 mg/dl. Patients using antihypertensive drugs or blood pressure measurements >140/90 mm Hg after 2 consecutive measurements were defined as hypertension.
The serum creatinine concentration was measured in all patients on hospital admission, daily for the 3 days after contrast exposure. Serum GGT activity and complete blood counts of patients were measured on the admission to the emergency department before PPCI. Serum GGT levels and other biochemical parameters were measured by the enzymatic colorimetric test at 37°C, and L-gamma-glutamyl-3-carboxy-4-nitroanilide was used as substrate. This analysis was done with the Roche/Hitachi analyzer (Mannheim, Germany). C-reactive protein (CRP) and fasting serum levels of glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were measured using standard enzymatic methods within 24 hours. Estimated glomerular filtration rate was calculated by applying the Modification of Diet in Renal Disease formula to the serum creatinine concentration. CIN was defined a relative increase of ≥25% or absolute increase of ≥0.5 mg/dl in creatinine concentrations within 72 hours after PPCI. Transthoracic echocardiography was performed for each patient immediately after PPCI in intensive cardiac care unit. All measurements were performed using a commercially available machine (Vivid 7 GE Medical System, Horten, Norway) with a 3.5-MHz transducer.
All statistical studies were carried out using the SPSS program (version 15.0; SPSS, Chicago, Illinois). Distribution properties of the data were performed using the Kolmogorov-Smirnov test. As mean ± SD for normally distributed data, median (interquartile range) was given for non-normally distributed data. The study population was divided into tertiles on the basis of the admission GGT values: first tertile (n = 151, GGT <19 U/L), second tertile (n = 161, GGT 19 to 33 U/L), and third tertile (n = 161, GGT >33 U/L). Analysis of variance test were used when normally distributed between the groups of numerical data analysis, analysis of the data is not normally distributed, and Kruskal-Wallis test were used. Categorical variables were compared using the chi-square test or Fisher’s exact test. Results were shown as a percent. Receiver operating characteristic (ROC) analysis was conducted to determine the cutoff value of GGT for predicting CIN. We performed logistic regression analysis with CIN or inhospital mortality as the dependent variable. The variables that were statistically significant according to the univariate analysis were included in the final multivariate model to identify the CIN or inhospital mortality predictors. Multivariate logistic regression analysis, which included variables with a p value <0.1, was carried out to identify independent predictors of CIN or inhospital mortality predictors. A p value <0.05 was considered statistically significant. Model discrimination was defined using area under the ROC curve, and calibration was assessed using the Hosmer-Lemeshow statistic.
Results
Demographic, clinical, and laboratory characteristics of patients are summarized in Table 1 . CIN developed in 80 patients (16.9%). The overall inhospital mortality rate was 3.3% (16 patients). CIN incidence was significantly higher in tertile 3 (29%) compared with tertiles 1 (11%) and 2 (11%, p <0.001). In addition, inhospital death incidence was significantly increased across tertiles (from tertile 1 to tertiles 2 and 3, 1%, 4%, and 5%, respectively, p <0.05; Figure 1 , Table 2 ). ROC curve analysis showed that at a cutoff of 26.5 U/L, the value of GGT exhibited 70% sensitivity and 60% specificity for predicting CIN (area under the ROC curve = 0.679, 95% CI 1.84 to 5.13, p <0.019; Figure 2 ). In separate analysis for inhospital mortality, both GGT levels >26.5 U/L (OR 1.036, 95% CI 1.001 to 1.074, p = 0.03) and CIN development (OR 1.10, 95% CI 1.026 to 1.204, p <0.0001) were significant factors that increased the risk of mortality. Other inhospital adverse outcomes among the 3 groups were not statistically different ( Table 2 ). Univariate logistic regression analysis indicated that GGT >26.5 U/L was a highly significant predictor of CIN (p <0.001). After including variables found significant in univariate analysis, the presence of diabetes mellitus (p <0.001), CRP (for each 1 mg/L increase, p = 0.007), contrast volume (for each 1-ml increase, p = 0.012), and GGT >26.5 U/L (p <0.001) were found as independent associates of CIN in multivariate regression analysis ( Table 3 ). Each 1 U/L increase in GGT levels was also associated with 1.04-fold risk of CIN (p <0.001). Hosmer-Lemeshow test showed that the model fit the data well (p = 0.34). Area under the ROC curve showed that the model has good discrimination capability (area under the curve 0.724, 95% CI 0.673 to 0.764, p <0.001).
| Variable | Tertile | p value | ||
|---|---|---|---|---|
| 1 | 2 | 3 | ||
| Age (years) | 63.3±11,.5 | 60.3±12.6 | 58.8±12 | 0.03 |
| Men | 110 (70%) | 127 (80%) | 130(82%) | 0.007 |
| Systolic blood pressure (mm Hg) | 127(110-145) | 130(110-145) | 130(110-145) | 0,899 |
| Diastolic blood pressure (mm Hg) | 80(70-90) | 80(70-90) | 77(60-90) | 0,827 |
| Heart rate (beat per minute) | 75(70-85) | 77(70-85) | 75(69-83) | 0.404 |
| Left ventricular ejection fraction (%) | 50(40-55) | 48(40-53) | 45(39-53) | 0.019 |
| Left ventricular ejection fraction <%40 | 29(6.1% ) | 33(6.9%) | 44(9.3%) | 0,01 |
| Current smoker | 67(42%) | 65(41%) | 70(44%) | 0,733 |
| Diabetes mellitus | 51(32%) | 55(35%) | 56(35%) | 0.554 |
| Hypertension | 76(48%) | 69(44%) | 77(49%) | 0,910 |
| Previous coronary artery disease | 42(27%) | 36(23%) | 42(27%) | 0,669 |
| Serum creatinine (mg/dL) | 0.87(0.71-1) | 0.85(0.75-1) | 0.87(0.73-1.03) | 0,515 |
| Estimated glomerular filtration rate (ml/min) | 92.1±25.4 | 93.8±24.5 | 94.4±28.8 | 0.736 |
| Serum albumin (mg/dL) | 4(3.7-4.1) | 4(4.2-4.5) | 4.2(4-4.5) | 0.951 |
| Hemoglobin (g/L) | 13.9±1.4 | 13.9±1.6 | 14.1±1.6 | 0.362 |
| Platelet count (x1000/mm 3 ) | 250.1±39.4 | 257±32.2 | 255±39.6 | 0.666 |
| White blood cell, (x1000/mm 3 ) | 10.5(8.5-12.5) | 11.5(9-13.5) | 11.5(9-14) | 0.02 |
| Serum potassium (mmol/L) | 4.2(4-4.4) | 4(4.2-4.5) | 4.2(4-4.5) | 0.951 |
| Serum sodium (mmol/L) | 140(138-141) | 140(138-141) | 140(138-141) | 0.560 |
| Low-density lipoprotein (mg/dL) | 105(85-126) | 105(80-124) | 107(81-134) | 0.608 |
| Total cholesterol (mg/dL) | 168(147-197) | 172(145-200) | 175(140-204) | 0.933 |
| High-density lipoprotein (mg/dL) | 39.9±9.7 | 38.9±8.8 | 37.5±8.8 | 0.068 |
| Triglycerides (mg/dL) | 110(81-150) | 123(89-185) | 130(88-197) | 0.022 |
| C-reactive protein (mg/L) | 6.6(3.4-14) | 8.4(3.4-16.4) | 10.5(4.1-33.1) | 0.001 |
| Fasting blood glucose (mg/dL) | 103(90-133) | 107(90-140) | 105(90-130) | 0.759 |
| Angiotensin converting enzyme inhibitors / Angiotensin receptor blocker use | 31(20%) | 37(23%) | 44(28%) | 0.085 |
| Number of narrowed coronary arteries | ||||
| 1 | 64(41%) | 65(41%) | 58(37%) | 0.684 |
| ≥2 | 94(60%) | 93(59%) | 100(67%) | 0.684 |
| Total length of stents (mm) | 18(15-20) | 18(15-20) | 18(15-20) | 0.689 |
| Number of stents | 1.2±0.5 | 1.3±0.8 | 1.2±0.6 | 0.389 |
| Total diameter of stents (mm) | 3(2.75-3) | 3(3-3.5) | 3(3-3.5) | 0.469 |
| Contrast medium volume (mL) | 130(100-150) | 130(110-150) | 130(100-160) | 0.760 |
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