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Ann Thorac Surg 2009;88:124-130. doi:10.1016/j.athoracsur.2009.04.023
© 2009 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Novel Biomarkers Early Predict the Severity of Acute Kidney Injury After Cardiac Surgery in Adults

Michael Haase, MDa,b, Rinaldo Bellomo, MDa,*, Prasad Devarajan, MDc, Qing Ma, MDc, Michael R. Bennett, PhDc, Martin Möckel, MDd, George Matalanis, MDe, Duska Dragun, MDd, Anja Haase-Fielitz, BPharma,b

a Department of Intensive Care, Austin Health, Melbourne, Australia
e Department of Cardiac Surgery, Austin Health, Melbourne, Australia
b Department of Nephrology and Intensive Care Medicine, Charité University Medicine, Berlin, Germany
d Department of Cardiology, Charité University Medicine, Berlin, Germany
c Department of Pediatrics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio

Accepted for publication April 9, 2009.

* Address correspondence to Dr Bellomo, Department of Intensive Care, Austin Hospital, Heidelberg, Victoria, 3084, Australia (Email: rinaldo.bellomo{at}austin.org.au).


Drs Bellomo, Devarajan, and Haase disclose that they have financial relationships with Abbott Diagnostics and Biosite.

 

   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: The purpose of this study was to investigate the ability of neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, and their combination in predicting the duration and severity of acute kidney injury (AKI) after cardiac surgery in adults.

Methods: Using data from a prospective observational study of 100 adult cardiac surgical patients, we correlated early postoperative concentrations of plasma NGAL and serum cystatin C with the duration (time during which AKI persisted according to the Acute Kidney Injury Network criteria) and severity of AKI (change in serum creatinine) and with length of stay in intensive care.

Results: We found a mean AKI duration of 67.2 ± 41.0 hours which was associated with prolonged hospitalization (p < 0.001). NGAL, cystatin C, and their combination on arrival in intensive care correlated with subsequent AKI duration (all p < 0.01) and severity (all p < 0.001). The area under the receiver operating characteristic curve for AKI prediction was 0.77 (95% confidence interval: 0.63 to 0.91) for NGAL and 0.76 (95% confidence interval: 0.61 to 0.91) for cystatin C on arrival in intensive care. Both markers also correlated with length of stay in intensive care (p = 0.037; p = 0.001). Neutrophil gelatinase-associated lipocalin and cystatin C were independent predictors of AKI duration and severity and of length of stay in intensive care (all p < 0.05). The value of cystatin C on arrival in intensive care appeared to be due to a carry-over effect from preoperative values.

Conclusions: Immediately postoperatively, NGAL and cystatin C correlated with and were independent predictors of duration and severity of AKI and duration of intensive care stay after adult cardiac surgery. The combination of both renal biomarkers did not add predictive value.

In cardiac surgical patients, acute kidney injury (AKI) is a major postoperative complication [1, 2]. Duration and severity of AKI are associated with adverse patient outcomes [3, 4]. Early diagnosis of AKI may contribute to timely intervention aimed at improving outcome [5]. The early diagnosis of AKI has been problematic owing to the absence of tests with sufficient accuracy that can be performed early in the course of injury and predict subsequent loss of kidney function. In response to this problem, several biomarkers have been recently investigated as possible tools for the early detection of AKI. Among these biomarkers, particularly promising results have been reported for neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C [6–10]. For example, urine NGAL appeared to be of value in the prediction of occurrence, duration and severity of AKI after pediatric cardiac surgery [5–7], and serum cystatin C predicted AKI 1 to 2 days earlier than serum creatinine in critically ill patients [8]. Also, serum cystatin C appears to be superior to serum creatinine to detect chronic kidney disease [11].

However, no studies in adult patients, in whom multiple comorbidities are common and can be expected to act as confounding variables, have tested the ability of NGAL or cystatin C to predict the duration and severity of AKI after cardiac surgery. This is unfortunate, as validation of novel renal biomarkers in studies including adult patients aiming to extend our knowledge already gained in pediatric populations [5, 6, 10] appears important.

Accordingly, in the present study, we took advantage of a previous study [12] and assessed the association of NGAL and cystatin C and their combination with duration and severity of AKI in patients after adult cardiac surgery.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Population
In a previous prospective cohort study, we enrolled 100 adult patients who underwent cardiac surgery necessitating the use of cardiopulmonary bypass (CPB) at a tertiary hospital [12]. We excluded patients undergoing emergency operation (operation performed within 24 hours after cardiac symptoms commenced) or off-pump surgery, patients presenting with advanced chronic kidney disease (serum creatinine greater than 300 µmol/L or on chronic hemodialysis), kidney transplant patients, and patients less than 18 years old. The Institutional Review Board approved the study (December 12, 2005), and written informed consent was received from each patient.

At our center, postoperative renal replacement therapy was initiated if the patient fulfilled at least one of the following clinical criteria: oliguria (urine output less than 100 mL in 6 hours) that has been unresponsive to fluid resuscitation measures, hyperkalemia ([K+] greater than 6.5 mmol/L), severe acidemia (pH less than 7.2), or clinically significant organ edema (for example, lung) in the setting of renal failure.

Outcomes
Primary outcome measures were the duration and severity of AKI. Duration of AKI was defined as time during which AKI according to the Network definition [13] occurred and persisted. Severity of AKI was defined by the change in serum creatinine from baseline to peak value within the first 5 postoperative days—a linear and therefore more powerful variable compared to cut-off values. In addition, we used novel renal biomarkers to predict the occurrence of AKI. Length of stay in the intensive care unit (ICU) and in the hospital was used as a secondary outcome. Potential risk factors for AKI after cardiac surgery are defined in Table 1.


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  		Table 1 Definitions of Acute Kidney Injury and Potential Risk Factors for It
 
Sampling and Measurement of Renal Biomarkers
We obtained blood samples preoperatively and at 6 hours for measurement of plasma NGAL and serum cystatin C. As in virtually all patients sampling at 6 hours after commencement of CPB was closely related to the immediate period after arrival of the patient in ICU (arrival in ICU was 5.5 ± 1.9 hours after commencement of CPB), we refer to this time point of sampling as "on arrival in ICU." Within 5 minutes after sampling for NGAL and cystatin C measurement, we centrifuged samples at 2,000g for 5 minutes and stored the supernatant in equal volumes at –80°C until measurement [6]. Plasma NGAL was measured by the Triage Meter (Biosite, San Diego, CA), and serum cystatin C using nephelometric technology [15]. The inter- and intra-assay coefficient of variation for NGAL was less than 8%, and for cystatin, less than 4.5%. Serum creatinine was measured preoperatively and daily after the operation utilizing the modified Jaffe method standardized by isotope dilution mass spectroscopy (Beckman Coulter Synchron LX System; Beckman Coulter, Brea, CA), with an inter- and intra-assay coefficient of variation of less than 4%.

Statistical Analysis
We tested all linear data for normal distribution using histograms. When data were normally distributed, the t test was used to test numerical data comparing patients who had AKI with those who did not. When data were not normally distributed, the Mann-Whitney U test was used. Fisher's exact or the {chi}2 test was used for categorical values as appropriate. Correlations between the severity or duration of AKI and concentrations of NGAL, cystatin C, and their combination, measured on arrival in ICU were evaluated by Pearson's rank correlation test. We considered the strength of a correlation as weak for correlation coefficients ranging from 0.1 to 0.3, moderate as 0.3 to 0.6, and strong as greater than 0.6. Renal biomarkers were combined by means of multiplication of the serum/plasma concentrations for each biomarker. We assessed renal biomarkers and their combination on their ability to detect AKI by calculation of the area under the curve of the receiver operating characteristic (AUC-ROC). An AUC-ROC value of 0.90 to 1.0 indicated excellent, 0.80 to 0.89 good, 0.70 to 0.79 fair, 0.60 to 0.69 poor, and 0.50 to 0.59 indicated no useful value. The AUC-ROCs were compared according to the method of Hanley and McNeil [16]. Linear multivariate regression analyses were performed to assess predictors of AKI duration and severity and lengths of stay in ICU and in hospital, including clinically relevant preoperative and intraoperative variables if their univariate p value was less than 0.1, and renal biomarkers on arrival in ICU. Logarithmic transformations were applied when necessary before regression analyses were performed. We used SPSS version 15.0 (SPSS, Chicago, IL) and MedCalc version 9.3.9.0 (MedCalc Software, Mariakerke, Belgium).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Patients
Forty-six patients had AKI, with a mean AKI duration of 67.2 ± 41.0 hours. Of these 46 patients, within 48 hours, 20 patients had both a serum creatinine increase greater than 50% and greater than 26.4 µmol/L [greater than 0.3 mg/dL] from baseline to peak value. An additional 12 patients were identified through an absolute increase in serum creatinine greater than 26.4 µmol/L [greater than 0.3 mg/dL] within 48 hours (but relative increase less than 50%). In another 14 patients without significant creatinine increase, AKI was diagnosed by a prolonged urine output reduction. Patients who had AKI were older, had an increased European System for Cardiac Operative Risk Evaluation (EuroSCORE), were more likely to present with chronic kidney disease and preoperative atrial fibrillation and to have simultaneous coronary artery revascularization and valve surgery (Table 2). Duration of AKI correlated with length of stay in ICU (correlation coefficient 0.459, p < 0.001) and in hospital (correlation coefficient 0.400, p < 0.001). Change in serum creatinine from preoperative to postoperative peak value within the first 5 postoperative days correlated with length of stay in ICU (correlation coefficient 0.407, p < 0.001) and in hospital (correlation coefficient 0.435, p < 0.001).


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  		Table 2 Characteristics of Patients According to the Acute Kidney Injury Network Definition
 
NGAL and Cystatin C Predicting Duration and Severity of AKI
At baseline, plasma NGAL concentration was similar in patients with and without AKI, whereas serum cystatin C concentration was significantly different (Fig 1). On arrival in ICU, the concentrations of NGAL and cystatin C were significantly higher in patients having AKI compared with patients with stable kidney function. At 24 hours postoperatively, concentrations of NGAL and cystatin C were higher in patients with subsequent AKI.


Figure 1
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  		Fig 1. Plasma neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C in patients in whom acute kidney injury (AKI) developed (n = 46), according to the Network definition [13] considering urine output, compared with patients in whom AKI did not develop (n = 54) at baseline, on arrival in the intensive care unit (ICU), and at 24 hours after commencement of cardiopulmonary bypass (mean values with SEM). Acute kidney injury was defined as an increase in serum creatinine 0.3 mg/dL (more than 26.4 µmol/L) or more than 50% from baseline to peak value, or urine output less than 0.5 mL/kg body weight per hour for more than 6 hours within the first 48 hours postoperatively. The black bars indicate patients with AKI, and the white bars indicate patients who did not have AKI. All p values are by Mann-Whitney U test. Panel A: serum NGAL at baseline, p = 0.46; on arrival in ICU, p = 0.003; at 24 hours, p < 0.001. Panel B: serum cystatin C at baseline, p < 0.001; on arrival in ICU, p = 0.005; at 24 hours, p < 0.001.

 
For both NGAL and cystatin C concentrations on arrival in ICU, we found a moderate to strong correlation with the duration and severity of AKI (Table 3). The correlation increased slightly when both markers were combined. Both NGAL and cystatin C on arrival in ICU were found to be independent predictors of duration and severity of AKI (Table 4). Also, peripheral vascular disease and atrial fibrillation (all p < 0.05) were independent risk factors for AKI duration.


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  		Table 3 Correlation of Renal Biomarkers on Arrival in Intensive Care Unit With Clinical Outcomes
 

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  		Table 4 Multivariate Regression Analyses for Renal Biomarkers on Arrival in the Intensive Care Unit
 
Serum NGAL and Serum Cystatin C as Predictors of AKI
For serum NGAL and cystatin C, performance characteristics for the prediction of AKI are shown in Table 5. We found fair to good prediction of AKI occurrence by plasma NGAL and cystatin C. On arrival in ICU, we found both high sensitivity and specificity for a serum NGAL concentration greater than 150 ng/mL and a serum cystatin C concentration greater than 1.1 mg/L. The predictive value increased when both novel renal biomarkers on arrival in ICU were combined, but this improvement did not reach statistical significance in a direct AUC-ROC comparison (NGAL versus combination, p = 0.28; cystatin C versus combination, p = 0.24).


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  		Table 5 Performance Characteristics of Renal Biomarkers on Arrival in the Intensive Care Unit to Predict Occurrence of AKI a
 
To further explore the role of preoperative chronic kidney disease on the predictive value of serum cystatin C on arrival in ICU, we calculated the value of absolute and relative change in serum cystatin C concentrations from baseline to arrival in ICU (AUC-ROC 0.48 [95% confidence interval [CI]: 0.30 to 0.66] and 0.43 [95% CI: 0.25 to 0.61], respectively). Serum cystatin C measured at baseline had an AUC-ROC to predict the occurrence of AKI of 0.72 (95% CI: 0.62 to 0.82).

NGAL and Cystatin C and Length of Stay in ICU and in Hospital
Both NGAL and cystatin C concentrations on arrival in ICU correlated with the length of stay in ICU (Table 3). Renal biomarker concentration on arrival in ICU did not correlate with length of stay in hospital (Table 3). Both NGAL and cystatin C were found to be independent predictors of length of stay in ICU (Table 4). In addition to NGAL and cystatin C, the only other independent predictor of length of stay in ICU was simultaneous coronary artery revascularization and valve surgery (standardized β-coefficient 0.310, p = 0.028). Renal biomarkers on arrival in ICU were not independent predictors of length of stay in hospital, in contrast to simultaneous coronary artery revascularization and valve surgery (standardized β-coefficient 0.339, p = 0.032)—the only independent predictor of this outcome.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
In this study, we analyzed data from a previously published prospective cohort study of 100 adult cardiac surgical patients. We found that NGAL and cystatin C correlated with and were independent predictors of AKI duration and severity and length of stay in ICU. When combined, their association with subsequent AKI increased further but without reaching significance. The value of cystatin C on arrival in intensive care appeared to be mostly due to a carry-over effect from preoperative values. We further found that duration and severity of AKI were associated with prolonged hospitalization.

Acute kidney injury after cardiac surgery affects a considerable proportion of adult patients [3, 17] and children [18] and carries significant costs [19]. Even minimal increments in serum creatinine are independently associated with an increase in morbidity and mortality [3]. Also, increasing duration of AKI decreases the likelihood of renal recovery, with a simultaneous increase of the risk for end-stage renal disease [4]. Regrettably, serum creatinine is not a robust marker for AKI, being dependent on several nonrenal factors [8, 20]. An increase in creatinine may be measured only after a considerable loss of glomerular filtration rate, and reflects an acute reduction of glomerular filtration rate only several days after the injurious event. In a previous study, even measurement of serum creatinine on arrival in ICU after cardiac surgery was not found to be a useful predictor of AKI [12]. Accordingly, NGAL has been previously investigated and found to be associated with the duration and severity of AKI in children undergoing cardiac surgery for congenital heart disease [5]. Despite our previous publication on NGAL and cystatin C in adult patients [12], there are still some limitations to our knowledge of their ability to predict AKI and its duration and severity in adult cardiac surgical patients. Therefore, a study was needed to explore the value of novel biomarkers in predicting the duration and the severity of AKI in adults. Such information is crucial to establishing the biological plausibility and overall clinical robustness of such biomarkers.

An ideal renal biomarker should not only be able to predict occurrence of AKI—as previously shown for urine and serum NGAL by Mishra and colleagues [6] in pediatric patients, for urine NGAL by Wagener and colleagues [7], and for plasma NGAL by Haase-Fielitz and colleagues [12] in adults—but should also predict the duration and severity of AKI, as both are associated with important adverse postoperative outcomes [3, 4]. In our patient cohort, we confirmed that the duration and the severity of AKI were associated with worse patient outcome. The prediction of the duration and severity of AKI using NGAL and cystatin C captures the association of the biomarker with the whole range of creatinine increases and does not depend on an arbitrary cut-off of creatinine increase. As use of novel renal biomarkers measured at 24 hours postoperatively might well be too late for therapeutic intervention, we focused on assessment as early as on arrival in the ICU. A previous study found good value of novel renal biomarkers on arrival in ICU to predict a combined endpoint of need for postoperative renal replacement therapy and in-hospital mortality (AUC-ROC >0.9) [12]—however, it has to be acknowledged that the incidence for this endpoint was low (n = 5).

The rapid rise and subsequent fall in NGAL (occurring while glomerular filtration is being lost) suggests that NGAL is likely to be a marker of cardiac surgery–associated tubular injury. These observations imply that, in children, tubular injury may be of even greater importance or greater proportional extent as indicated by the excellent predictive value of NGAL in this setting [5]. Being able to separate those with subsequent AKI from those without AKI, the preoperative serum cystatin C concentration appears to reflect baseline glomerular filtration rate more accurately than serum creatinine [11]. Such preoperatively increased concentration may also have contributed to its postoperative value in the prediction of AKI duration and severity—with serum cystatin C rather reflecting preoperative renal impairment than predicting acute changes in renal function. In contrast, the specific value of NGAL appears to be its dynamic ability to react on acute injurious events to the kidney tubules [21]. This ability of NGAL may be based on a potential cross talk between the injured kidney and lungs or liver, thus delivering greater amounts of NGAL to the kidney and its direct release from injured tubular cells [21].These findings also suggest that these two markers may be complementary in nature and clinical implications.

There are clinical implications from these findings. An early predictive marker for duration and severity of AKI may increase awareness of developing AKI. That may lead to greater justification for and efforts to intensify monitoring of cardiac and renal function, more scrupulous avoidance of nephrotoxic medications, hypotension, and hypovolemia, or their earlier treatment. Patients identified by these biomarkers may receive more prolonged invasive hemodynamic monitoring and greater measures to optimize renal perfusion and hydration by shifting the range of hemodynamic targets to a higher mean arterial pressure or cardiac output. In addition, earlier intervention with renal replacement therapy [22] may be considered for patients with markedly elevated biomarker levels in whom fluid overload is developing but they have not yet displayed increased serum creatinine owing to hemodilution and the time required for reestablishment of a steady state in creatinine concentration according to glomerular filtration rate [5]. Novel, regenerative, antioxidant, anti-inflammatory, and antiapoptotic therapies for AKI are under investigation [23, 24]. The availability of early and specific biomarkers opens the way to controlled studies of the potential efficacy of these interventions in humans. Several studies now describe a cut-off of NGAL greater than 150 ng/mL to predict AKI after cardiac surgery [5, 10, 12], which, once confirmed in multicenter trials, may turn out useful in clinical practice by guiding timely interventions of nephroprotection.

Our study has several strengths. This study focused on the value of NGAL and cystatin C for AKI during the immediate period after arrival in ICU when specific and timely interventions may have greater therapeutic opportunity. Serum or plasma renal markers may be of value as they are independent of the availability and the amount of urine. This study has addressed the ability of these two biomarkers to predict duration and severity of AKI in adult patients after cardiac surgery. We acknowledge that another study [25] has not found similar reliable associations between plasma NGAL and AKI and cystatin C and AKI. However, those investigators used a different technique for NGAL measurement, had mean NGAL and cystatin C levels that were considerably higher than those seen in our patients, and used a definition of AKI that was more sensitive and less specific than ours. These factors may explain, at least in part, the different observations.

Our study has some limitations. This study was a post-hoc analysis, yet one of the largest in adults in this field. The postoperative peak concentration of NGAL may have been missed, and that may have contributed to the less pronounced findings for length of stay in hospital. However, more frequent measurement is unlikely to have substantially changed the main study findings regarding AKI duration and severity. We investigated two specific renal biomarkers, hence not including some of the most recently published renal biomarkers, for example, serum liver fatty acid-binding protein [26]. Portilla and colleagues [26] investigated this marker in pediatric cardiac surgical patients and found it valuable in the prediction of AKI occurring in 8 children compared with 8 children in whom AKI did not develop. The study of further novel biomarkers remains an important area of research.

In conclusion, in a cohort of 100 adult cardiac surgery patients, we found that NGAL and cystatin C correlated with and were independent predictors of duration and severity of AKI after adult cardiac surgery. Cystatin C appears rather to be a marker of chronic renal impairment than of acute worsening renal function in this setting. The combination of both renal biomarkers increased their predictive value to some degree, but probably not enough to justify the extra costs. We consider that these observations justify pilot studies of kidney protection in cardiac surgery based on biomarker-directed early AKI.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
Doctor Haase holds a postdoctoral Feodor-Lynen Research Fellowship from the Alexander von Humboldt-Foundation, Germany. This study was partly funded by a grant from the Australian and New Zealand College of Anaesthetists and by the Austin Hospital Anaesthesia and intensive care Trust Fund. Doctor Devarajan has received limited researched grant support from Biosite Incorporated and Abbott Diagnostics.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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 Nephrol Dial TransplantHome page
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