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Abstract
Background: Quantification of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein (IFGBP-7), which is commercially known as NephroCheck™(NC) test have been suggested as promising tools for the early detection of acute kidney injury (AKI) after cardiac surgery involving cardio-pulmonary bypass (CPB).
Objectives: The aim of the present study was to test the hypothesis that single value of postoperative NC test performed at 4 hours after surgery can predict AKI in off-pump coronary artery bypass grafting (OPCABG) surgery.
Setting and Design: This prospective single-center study was conducted at the tertiary cardiac center in India from December 2017 to November 2018.
Methods: Ninety adult patients of both sex undergoing elective OPCABG were included. Anesthesia was standardized to all patients. Urine samples were collected preoperatively and at 4 hours after surgery for NC test. Urine output, serum creatinine, estimated glomerular filtration rate (eGFR) were also measured. AKI staging was based on kidney disease improving global outcomes (KDIGO) guidelines.
Statistical Analysis: To assess the predictability of NC test for the primary endpoint, area under the receiver operating characteristic curve (ROC), was calculated.
Results: Thirteen patients developed AKI in the study cohort (14.4%) out of which 7 patients (7.8%) developed stage 2/3 AKI and the remaining stage 1 AKI. Baseline renal parameters were similar between AKI and non-AKI group. The area under curve (AUC) of NC test at 4 hours after surgery was 0.60 [95% confidence interval (CI): 0.42-0.77]. Postoperative NC test performed at 4 hours after surgery did not predict AKI in this study population (P = 0.24). There were no significant differences in duration of mechanical ventilation, length of intensive care stay and hospital stay between the two groups (P > 0.05).
Conclusion: NephroCheck™ test performed at 4 hours after surgery did not identify patients at risk for developing AKI following OPCABG surgery.
Keywords: Acute kidney injury, biomarker, IGFBP7, off-pump cardiac surgery, TIMP-2
How to cite this article: Introduction 
Acute kidney injury (AKI) is a worldwide health problem associated with high morbidity and mortality.[1],[2] Incidence of AKI following cardiac surgery using cardiopulmonary bypass (CPB) ranges between 20-30%.[3] AKI in cardiac surgical patients is associated with the increase in the length of intensive care stay (ICU) stay, hospital stay, mortality, a potential risk of chronic renal dysfunction and increased hospital resource utilization.[4] The mortality of patients who develop severe AKI following cardiac surgery requiring renal replacement therapy (RRT) can be as high as 60%.[5],[6] As the creatinine elevation in AKI may be delayed and lack of precise/prompt biomarkers of renal injury, AKI is often diagnosed late in the course of the disease.[7],[8] Current diagnostic criteria for AKI rely on changes in serum creatinine or urine output, which can be influenced by perioperative administration of intravenous fluids and diuretics.
Identifying patients at higher risk of AKI is critical for the introduction of aggressive nephroprotective measures to prevent morbidity and mortality. Serum creatinine is the most widely used for the assessment of renal function and detection of kidney disease. However, creatinine levels have limited value in critically ill and cardiac surgery patients, as they might not adequately reflect acute changes.[9] Therefore, identifying biomarkers to predict the development and severity of AKI early after cardiac surgery is important. Quantification of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein (IFGBP-7) have been suggested as promising tools for the early detection of AKI in critically ill patients.[10] These biomarkers are commonly quantified using commercially available point-of-care NephroCheck™ test (NC). These markers are released by injured renal tubules and have shown to be of great predictive value for AKI in a various studies conducted on cardiac surgical patients.[11],[12],[13] Most of the studies conducted on urinary (TIMP-2) * (IFGBP-7) involves on-pump cardiac surgeries, as the benefit is larger in on-pump patients due to the higher prevalence of AKI in this population.[14] However, knowledge about the NC test exclusively in off-pump coronary artery bypass grafting (OPCABG) patients remains limited. We hypothesized that elevation of NC value within 4 hours after OPCABG surgery predicts a high risk of AKI in the early post-operative period. The principal outcome of the study was to test the hypothesis that single value of postoperative NC performed at 4 hours can predict AKI in OPCABG surgery patients. The 4-hour time point was chosen to predict AKI as early as possible after surgical insult and also based on fact that previous study by Wang et al.[15] showed NC predicts AKI at 4 and 12 hours after cardiac surgery.
Methods Ethics approval for this prospective observational study was provided by the institute ethical committee (NHH/AEC-CL-2017-216). After obtaining written informed consent, 90 adult patients of both sex undergoing elective OPCABG were included in this study during the period of December 2017 to November 2018. Patients undergoing OPCABG were enrolled, as OPCABG is the most commonly performed surgery in this subcontinent and also to intend to know predictive capability of AKI exclusively in OPCABG. Cardiac surgery under CPB, emergency cardiac surgery, patients with chronic kidney disease (CKD) on regular dialysis (acute or chronic), post renal transplant patients, were excluded from the study. After a thorough pre-operative evaluation, all anti-anginal and antihypertensive medications were continued till the morning of surgery with exception of angiotensin converting enzyme inhibitors (ACE) inhibitors and angiotensin receptor blockers (ARBs). Invasive arterial line monitoring was established before anesthesia induction. Anesthesia was induced with intravenous fentanyl, midazolam and titrated doses of propofol. Muscle paralysis was achieved with vecuronium. Anesthesia was maintained with oxygen+ air+ 1 minimum alveolar concentration (MAC) of isoflurane along with intermittent fentanyl and vecuronium boluses. The perioperative management tailored to achieve fast-tracking. Heparin was administered prior to the grafting according to the discretion of surgical team with dose range 2-4 mg/kg to maintain the activated coagulation time greater than 300 seconds. Urine output was recorded hourly. Nephrotoxic agents such as hydroxyethyl starch, aminoglycoside antibiotics and nonsteroidal anti-inflammatory drugs were not administered in the perioperative period. OPCABG was done after midline sternotomy using myocardial stabilizer (Octopus) for the distal coronary anastomosis. Proximal anastomosis on aorta was performed with a systolic arterial pressure (SAP) of 80-90 mmHg and the distal anastomosis performed with SAP of 110 – 120 mmHg unless indicated otherwise. A mean arterial pressure of 70 mmHg was maintained throughout the procedure at other times other than indicated above. Reversal of heparinization at the end of grafting was achieved with protamine. To maintain hemodynamics within the target range, noradrenaline, adrenaline and nitroglycerin infusions were used as necessary at the discretion of the attending anesthesiologist. Triggers for transfusion of allogeneic blood and coagulation products were used as recently described.[16] Patients were shifted to the cardiac intensive care unit (ICU) and trachea was extubated when appropriate after a short period of elective postoperative ventilation. Urine samples (minimum of 0.5 ml) was collected after induction of anesthesia before surgical incision and at 4 hours post cardiac surgery in specimen collection cups without additives and the samples were centrifuged and flash frozen within 2 hours of sample collection and were stored at ≤-70°C, each sample had 1 freeze/thaw cycle. A total of 180 urine samples were collected and analyzed. Nephrocheck was measured and quantified by the Nephrocheck point-of-care analyzer (Astute Medical, San Diego, CA, USA).
Clinical and laboratory information were recorded which included age, sex, body weight, height, history of previous cardiac surgery, European System for Cardiac Operative Risk Evaluation (EuroSCORE), number of grafts, chronic obstructive pulmonary disease (COPD), cerebrovascular accidents (CVA), diabetes mellitus (DM), hypertension, recent myocardial infarction (MI), pulmonary artery pressure, left ventricular ejection fraction (LVEF), hemoglobin, preoperative eGFR, serum creatinine, hourly urine output, duration of mechanical ventilation, length of ICU/hospital discharge and death. The renal function was assessed using parameters such as serum creatinine and blood urea nitrogen at pre-operative, 24-hour and 48-hour post-operative time intervals. In agreement with the kidney disease improving global outcomes (KDIGO) recommendations for AKI definition, AKI stage 1 was defined as an increase in serum creatinine by 1.5-1.9 times baseline or absolute increase in serum creatinine by 0.3 mg/dL within the first 48 hours after surgery.[17] AKI stage 2 was defined as an increase in serum creatinine by 2 times baseline values. AKI stage 3 was defined as increase in serum creatinine by >3 times baseline values or maximum serum creatinine greater than 4 mg/dL or initiation of RRT. We did not utilize urine output criteria for defining AKI because of its limitations after cardiac surgery due to fluid administration and diuretics usage. The cut-off for the detection of AKI in post-cardiac surgery patient using NC test at 4-hour after cardiac surgery is >0.3 with sensitivity of 80% and specificity of 83%.[11]
Statistical analysis
This study included a subgroup population (those undergoing OPCABG) from a larger study which includes both on-pump CABG and OPCABG. A total of 90 patients who underwent OPCABG were included in this study. Continuous variables with a normal distribution were expressed as mean ± standard deviation (SD). Dichotomous data were expressed as numbers and percentages. Patients with AKI and non-AKI were compared by Student's t test, Mann-Whitney U test, or Chi-square test, as appropriate. The association between potential risk factors and the outcome AKI was quantified by logistic regression analysis and represented as odds ratio (OR) with 95% confidence interval (CI). To assess the predictability of NC test for the primary endpoint, area under the receiver operating characteristic curve (ROC), was calculated. For all statistical tests, a P value of <0.05 was considered statistically significant. Data were analyzed by using statistical package for social sciences (SPSS Inc., Chicago, IL version 22.0).
Results A total 90 OPCABG patients were included in this study. A total 13 (14.44%) patients developed AKI in postoperative period in which 6 patients (6.67%) developed stage 1 AKI and 7 patients (7.78%) developed stage 2/3 AKI. Baseline characteristics of 90 patients are given in [Table 1]. Clinical characteristics and operative variables of AKI group compared with non-AKI group are provided in [Table 2]. Preoperative renal function assessed by serum creatinine (0.98 ± 0.17 vs. 0.99 ± 0.14, P = 0.92) and eGFR (76.92 ± 15.89 vs. 78.99 ± 13.42, P = 0.61) showed no significant difference between the two groups. Similarly, there was no statistically significant difference in preoperative NC value between AKI and non-AKI group (0.45 ± 0.91 vs. 0.43 ± 0.59, P = 0.23). Patients who developed AKI had significantly lower height and weight than in patients with no AKI. In addition, the incidence of diabetes mellitus, recent myocardial infarction, prolonged surgical duration, re-exploration was higher in patients with AKI as compared to those with no AKI. Further, logistic regression analysis showed patients who had recent MI (OR-8.5, P = 0.03) and re-explored (OR-25.45, P = 0.01) had more likelihood of AKI, as shown in [Table 3]. Comparing with preoperative NC value, postoperative NC value at 4 hours after surgery were lower in both AKI and non-AKI group [Table 4]. However, in this study cohort, there was no significant difference in duration of postoperative mechanical ventilation, ICU stay, and hospital stay between those developed AKI from those who did not develop AKI [Table 5]. Our study showed that one-time NC test immediately performed at 4 hours after OPCABG did not predict AKI (P = 0.24). AUC value of the ROC curve for the postoperative NC was 0.60 (0.42-0.77) [Figure 1].
Table 2: Demographic and clinical data of patients who developed AKI as compared to no AKI following OP-CABG
Figure 1: ROC curve for AKI prediction by using postoperative Nephrocheck test performed at 4 hours after OPCABG [AUC 0.60 (0.42-0.77)] (P = 0.24) Discussion AKI is characterized by a rapid deterioration of kidney function and is not uncommon in patients after cardiac surgery. Although AKI is often related to the involvement CPB, OPCABG patients also carries significant risk of AKI. Seabra et al.[18] concluded that OPCABG may be associated with a lower incidence of postoperative AKI but may not affect dialysis requirement, a serious complication after cardiac surgery. Garg et al.[14] mentioned that the incidence of AKI following OPCABG was 17.5%, which is relatively higher than our study results. Importantly, there is increasing evidence that AKI is associated with serious short- and long-term complications leading to increased morbidity, mortality, and high economic burden.[19] In patients developing AKI after cardiac surgery, RRT was required in 2-5% and mortality was as high as 50%.[20]
The diagnosis of AKI in post cardiac surgery is based on KDIGO classification, which requires clinical tools like serum creatinine and urine output measurement. Identifying AKI based on these tools delays the AKI detection and moreover influenced by muscle mass and volume status. Any error or delay in diagnosis of AKI leads to significant impact on perioperative outcome. Given the limitations of serum creatinine and urine output, efforts have been made to identify biomarkers that could serve as “renal troponin”. One such biomarker is urinary (TIMP-2) * (IFGBP-7).[21] These G1 cell cycle arrest proteins synthesized in and secreted by the renal tubular epithelial cells, are found to accumulate in the urine after ischemic renal injury. Elevated NC test indicate renal tubule cell stress that precedes AKI, and this is believed to be reason that NC levels corresponds to risk for AKI. Previous clinical studies assessed the utility of NC test as independent predictors of AKI.[22] Intending to translate an encouraging finding into a diagnostic tool for the risk assessment of AKI, the food and drug administration approved NC test in the United States of America in 2014.
Although several biomarkers are available for predicting AKI, NC test was analyzed in detail in cardiac surgical patients involving CPB. Being a point-of-care test, NC gained more attention because it is easy to perform with small urine sample and availability of results within few minutes. Previous studies in cardiac surgical patients mentioned that NC can reliably predict AKI in the early postoperative period.[11],[12],[13] However, our results are contrary to these results. The possible reason for inability of NC in predicting AKI in our study patients could be due to early measurement after surgery. In contrast to our study results, Meersch et al.[11] showed early predictive capability of NC as early as 4 hours after surgery in detecting AKI. This discrepancy could be explained based on the fact that our study was performed in off-pump cardiac surgery, in which the risk of AKI development on the day of surgery may be limited.[14] Moreover, Meersch et al.[11] included patients undergoing valvular and combined surgeries with assumed higher risks of kidney injury due to longer CBP and aortic cross clamps (ACC) times. Cummings et al.[23] studied urinary [TIMP-2] •[IGFBP7] at eight perioperative timepoints in 400 cardiac surgery patients, in which they found intraoperative elevations of [TIMP-2] •[IGFBP-7] can predict moderate-severe AKI and could provide opportunity to alter postoperative management to prevent kidney injury. Similar to Meersch et al., Cummings et al.[11],[23] included complex cardiac surgery patients with prolonged CPB and ACC times which could increase the risk of AKI. In addition to it, difference in baseline CKD stage and Thakar score between those who developed stage 2 or 3 AKI and who did not, could be reason for early prediction of stage 2/3 AKI by using NC test in their study. However, in our study, baseline serum creatinine, eGFR, and NC were similar between AKI and non-AKI patients indicates baseline kidney functions were similar could be reason for inability of NC test to predict AKI on the day of surgery. Bell et al.[24] utilized NC test to predict AKI in general ICU patients, in which they mentioned that NC test did not predict AKI, which is in agreement with our results. Mayer et al.[25] evaluated the NC in 110 cardiac surgical cases involving CPB. They observed that elevated NC values one hour after initiation of CPB and 24 hours after weaning from CPB in patients with AKI. However, at 4-hour after weaning from CPB, NC value did not differ between patients with AKI and without AKI similar to our study results. Further, they suggested that hemodilution due to CPB priming and perioperative fluid therapy were the reasons for decrease in NC value at 4-hour after CPB. Wetz et al.[12] and Gunnerson et al.[13] studied NC test in cardiac surgical patients and found that NC test has greater predictive capacity to detect AKI, which is again in contrast to our results. Wang et al.[15] observed combination of urinary TIMP-2 and IGFBP7 at 4 hour after postoperative ICU admission identifies patients at risk for developing AKI, not just stage 2–3 AKI following cardiac surgery. However, it should be noted that Wang et al. addressed AKI in patients who have undergone cardiac surgery under CPB along with OPCABG in contrast to our study where only OPCABG were studied. Engelman et al.[26] concluded that early detection of AKI following cardiac surgery using NC and subsequent implementation of a predefined staged protocol decreases postoperative stage 2/3 AKI without increase in cost or length of stay.
Another important observation we noted in our study was there is decrease in mean NC value after surgery comparing with preoperative value. This could be explained by (i) period of fasting prior to elective surgery leading to hemoconcentration (ii) liberal use of crystalloids during intraoperative period (iii) limited kidney injury due to avoidance of CPB and (iv) less requirement of blood transfusion during surgery with OPCABG. Further, our study results showed that there is no significant difference in mechanical ventilation duration, ICU stay and hospital stay between AKI and non-AKI patients, which is similar to Bell et al. study results.[24]
Limitations
First, our study is the single center study, which itself has limitations because of limited sample size. Second, in our study cohort, number of patients developed AKI was less than expected, which could affect the power of the study. Third, another problem is the lack of a “gold-standard” definition for AKI after cardiac surgery. Fourth, we did not perform NC test at different time points in postoperative period which could alter the predictive capability of NC test in OPCABG.
Conclusion On the basis of findings in 90 patients who underwent elective OPCABG surgery, we conclude that single value of NC test performed at 4 hours after surgery was not predictive of AKI.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
Correspondence Address:
Muralidhar Kanchi
Department of Anaesthesia and Intensive Care, Narayana Institute of Cardiac Sciences, Narayana Health City, Bangalore - 560 099, Karnataka
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aca.aca_56_21
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