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Ann Thorac Surg 2012;93:577-583. doi:10.1016/j.athoracsur.2011.10.048
© 2012 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Combination of Two Urinary Biomarkers Predicts Acute Kidney Injury After Adult Cardiac Surgery

Daisuke Katagiri, MDa, Kent Doi, MD, PhDa,*, Kenjiro Honda, MDa,d, Kousuke Negishi, MD, PhDa, Toshiro Fujita, MD, PhDa, Motoyuki Hisagi, MD, PhDb, Minoru Ono, MD, PhDb, Takehiro Matsubara, MD, PhDc, Naoki Yahagi, MD, PhDc, Masao Iwagami, MDd, Takayasu Ohtake, MD, PhDd, Shuzo Kobayashi, MD, PhDd, Takeshi Sugaya, PhDe, Eisei Noiri, MD, PhDa

a Department of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
b Department of Cardiothoracic Surgery, The University of Tokyo, Tokyo, Japan
c Department of Critical Care Medicine, The University of Tokyo, Tokyo, Japan
d Department of Nephrology, Immunology, and Vascular Medicine, Shonan Kamakura General Hospital, Kamakura, Japan
e CMIC Co. Ltd, Tokyo, Japan

Accepted for publication October 20, 2011.

Abbreviations and Acronyms AKI = acute kidney injury; AUC = area under the curve; CKD = chronic kidney disease; CPB = cardiopulmonary bypass; GFR = glomerular filtration rate; IDI = incremental discrimination improvement; L-FABP = L-type fatty acid-binding protein; NAG = N-acetyl-β-D-glucosaminidase; NGAL = neutrophil gelatinase-associated lipocalin; NRI = net reclassification index; POD = postoperative day; ROC = receiver operating characteristics

* Address correspondence to Dr Doi, Department of Nephrology and Endocrinology, University Hospital, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan (Email: kdoi-tky{at}umin.ac.jp).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Urinary L-type fatty acid-binding protein (L-FABP) has not been evaluated for adult post-cardiac surgery acute kidney injury (AKI) to date. This study was undertaken to evaluate a biomarker panel consisting of urinary L-FABP and N-acetyl-β-D-glucosaminidase (NAG), a more established urinary marker of kidney injury, for AKI diagnosis in adult post-cardiac surgery patients.

Methods: This study prospectively evaluated 77 adult patients who underwent cardiac surgery at 2 general hospitals. Urinary L-FABP and NAG were measured before surgery, at intensive care unit arrival after surgery (0 hours), 4, and 12 hours after arrival. The AKI was diagnosed by the Acute Kidney Injury Network criteria.

Results: Of 77 patients, 28 patients (36.4%) developed AKI after surgery. Urinary L-FABP and NAG were significantly increased. However, receiver operating characteristic (ROC) analysis revealed that the biomarkers' performance was statistically significant but limited for clinical translation (area under the curve of ROC [AUC-ROC] for L-FABP at 4 hours 0.72 and NAG 0.75). Urinary L-FABP showed high sensitivity and NAG detected AKI with high specificity. Therefore, we combined these 2 biomarkers, which revealed that this combination panel can detect AKI with higher accuracy than either biomarker measurement alone (AUC-ROC 0.81). Moreover, this biomarker panel improved AKI risk prediction significantly compared with predictions made using the clinical model alone.

Conclusions: When urinary L-FABP and NAG are combined, they can detect AKI adequately, even in a heterogeneous population of adult post-cardiac surgery AKI. Combining 2 markers with different sensitivity and specificity presents a reasonable strategy to improve the diagnostic performance of biomarkers.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Acute kidney injury (AKI) is an extremely severe complication for patients who undergo cardiac surgery. Recently, Lassnigg and colleagues [1] reported a significant association of small serum creatinine changes with increased mortality in a large cardiac surgery cohort. Accordingly, the Acute Kidney Injury Network (AKIN) has proposed new AKI diagnostic criteria, in which AKI is defined as an absolute increase in serum creatinine of greater than or equal to 0.3 mg/dL or a relative increase of greater than or equal to 1.5-fold from baseline [2]. To date, small increases of serum creatinine after cardiac surgery have not received much attention, possibly because a large amount of fluid is frequently given to patients during cardiac surgery. Although a small creatinine increase will predict adverse outcomes, the limitations of serum creatinine for early detection and accurate estimation of renal injury in AKI are well known [3]. Therefore, development of new AKI biomarkers has been emphasized to introduce more sensitive and accurate renal biomarkers to clinical use.

As the first clinical evaluations, new AKI biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 were examined mostly in pediatric post-cardiac surgery patients. In this homogeneous cohort, which has fewer comorbid diseases and more readily apparent onset of renal insult, these biomarkers exhibited excellent performance for AKI prediction and detection [4, 5]. We also reported that urinary L-type fatty acid-binding protein (L-FABP) is useful for early detection of AKI after pediatric cardiac surgery [6]. However, previous reports described that the biomarkers' accuracy is not good in more heterogeneous cohorts of adult post-cardiopulmonary bypass (CPB) surgery patients [7]. For instance, urinary NGAL failed to show high sensitivity and specificity in adult post-cardiac surgery AKI [8, 9]. No report in the relevant literature has described the performance of urinary L-FABP in adult post-cardiac surgery AKI.

This study was undertaken to evaluate whether urinary L-FABP is predictive of AKI occurrence after cardiac surgery in adult patients who were treated at 2 general hospitals. Additionally, we examined a possible combination of urinary L-FABP and N-acetyl-β-D-glucosaminidase (NAG), a more established urinary marker of kidney injury [10], to establish a more useful diagnostic tool than single-marker measurements. Among several biomarkers that detect proximal tubular injury [11], we decided to measure urinary NAG for the following reasons. First, L-FABP is expressed in the cytoplasm of proximal tubular epithelial cells in normal conditions [12], whereas NAG is a lysosomal brush border enzyme. Different localization of biomarkers expression was expected to be complementary to detect tubular cell damage. Second, both urinary L-FABP and NAG have been approved in Japan as in vitro diagnostics.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Patient Population
A total of 77 adult patients undergoing scheduled cardiac surgery at The University of Tokyo Hospital (Tokyo, Japan) and Shonan Kamakura General Hospital (Kamakura, Japan) were studied prospectively. Patients with end-stage renal disease or renal transplant were excluded. The study protocol was approved by the Institutional Review Board and informed consent was obtained from each participant. The presence of AKI was assessed by calculating the change in serum creatinine from the baseline (before surgery) to the maximum serum creatinine; AKI was defined as an absolute increase in serum creatinine of more than 0.3 mg/dL or a 50% increase from the baseline [2]. In the protocol of a large multicenter prospective observational study of adult post-cardiac surgery AKI by the Translational Research Investigating Biomarkers Endpoints (TRIBE)-AKI consortium (n = 1,219), specimen collection was stopped on postoperative day 3 (POD 3) in subjects who had not yet shown an increase in serum creatinine because more than 90% of AKI patients showed their highest serum creatinine within 3 days [13]. In the present study, we determined the observational period as extending until POD 3 to identify AKI directly related to cardiac surgery. Preexisting severe chronic kidney disease was determined by estimated glomerular filtration rate lower than 30 mL/minute per 1.73 m2, as calculated using the modification of diet in renal disease equation with a known baseline creatinine value [chronic kidney disease (CKD) stages 4 and 5] [14].

Urinary Biomarker Measurement
For each patient 4 urine samples were obtained, corresponding to presurgery, 0 hours (intensive care unit [ICU] arrival), and 4 and 12 hours after ICU arrival. They were then frozen at –80°C within 1 hour of collection. Urinary L-FABP was measured using commercially available enzyme-linked immunosorbent assay kits (Human L-FABP Assay Kit; CMIC Co. Ltd, Tokyo, Japan) [15–17]. Briefly, a sandwich is formed of the L-FABP antigen between the anti-L-FABP antibody coated at the bottom of a microplate and the free anti-L-FABP antibody conjugated with peroxidase. Its optimal density is measured after incubation with substrate to determine the L-FABP concentration. Urinary NAG and creatinine were measured at the University of Tokyo Hospital Clinical Laboratory using an autoanalyzer (Hitachi 917; Boehringer Mannheim Biochemica, Indianapolis, IN).

Statistical Analyses
Data were expressed as mean ± standard deviation. Continuous variables were compared using t tests or Wilcoxon rank sum tests when the normality assumption did not hold. Categoric variables were compared using the Pearson {chi}2 or Fisher exact test. The performance of urinary biomarkers was determined using receiver operating characteristic (ROC) curve analysis. The differences in ROC curves were tested using a nonparametric method [18]. These calculations were performed using software (JMP ver. 8.0; SAS Institute Inc, Cary, NC). Improvement of AKI risk prediction by the biomarker panel of urinary L-FABP and NAG was evaluated using the net reclassification index (NRI) and incremental discrimination improvement (IDI), as described previously [13, 19]. A conventional criterion of alpha level 0.05 was used to determine statistical significance.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
Patient Characteristics and Changes in Serum Creatinine
Table 1 presents baseline clinical data, surgical procedures, and outcomes of the enrolled patients. Of 77 adult post-cardiac surgery patients, AKI was diagnosed in 28 (36.4%) within 3 days after surgery (POD 3). Serum creatinine measured before surgery in the AKI group was significantly higher than that in the non-AKI group (Table 2). Preexisting severe CKD (estimated glomerular filtration rate < 30) was found dominantly in the AKI group. Only one AKI patient showed the highest serum creatinine value before 12 hours after ICU arrival, although approximately 30% of non-AKI patients showed the highest creatinine values before surgery or at 0 hours. Two patients showed their highest values of serum creatinine at POD 6. These peak values were observed after complication with low-output syndrome caused by sudden-onset arrhythmia in both cases, indicating that direct insult of cardiac surgery on renal dysfunction is not strongly considered. Although no difference was found in the frequency of CPB between the AKI group and the non-AKI group, the operation time and CPB time in the AKI group were significantly longer than those of the non-AKI group. The ICU stay in the AKI group was significantly longer. Death in the ICU occurred only in the AKI group (Table 1).


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  		Table 1 Patient Characteristics and Clinical Outcomes
 

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  		Table 2 Serum Creatinine Values
 
Urinary L-FABP and NAG Levels in AKI
Frequency of complication with diabetes, hyperthyroidism, and autoimmune disease, which can influence the urinary NAG level [20–23], was not significantly different between the groups (Table 1).The AKI group had significantly higher urinary L-FABP than the non-AKI group at 0, 4, and 12 hours (Fig 1 A). Significant differences in urinary NAG were observed only at 4 and 12 hours (Fig 1B). Notably, the increases of urinary L-FABP and NAG in the AKI group at 0 hours were not observed when these urinary markers were evaluated by correction with urine creatinine concentration (Fig 1C;D). Urinary creatinine concentration in the non-AKI group was significantly lower at 0 hours (Fig 2), which might increase urinary L-FABP and NAG corrected by urinary creatinine concentration in the non-AKI group.


Figure 1
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  		Fig 1. Urinary L-type fatty acid-binding protein (L-FABP) and N-acetyl-β-D-glucosaminidase (NAG) in the perioperative period of cardiac surgery. Urinary L-FABP (A) and (C) and NAG (B) and (D) were measured before surgery (pre), at intensive care unit arrival (0 hours), and 4 and 12 hours thereafter. Of 77 enrolled patients, 28 patients were diagnosed as having acute kidney injury (AKI). Box plots show the median (center line), the 25th and 75th percentiles, and the range (whiskers). Results are presented as absolute concentration (A) and (B) and corrected by urinary creatinine (Cre) concentration (C) and (D). (#, p < 0.05.)

 

Figure 2
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  		Fig 2. Change in urinary creatinine concentration. Urinary creatinine was measured using the same sample used for L-type fatty acid-binding protein and N-acetyl-β-D-glucosaminidase measurements. (#, p < 0.05; AKI = acute kidney injury.)

 
Combination of Urinary L-FABP and NAG
The ROC curve analysis revealed that urinary L-FABP and NAG could detect AKI with statistical significance (Table 3) and they had better performance without correction by urine creatinine concentration at 0 and 4 hours. Notably, urinary L-FABP and NAG at 4 hours, respectively, detected AKI with high sensitivity (92.9%) and high specificity (100.0%). However, their areas under the curve of ROC (AUC-ROCs) were insufficiently high for clinical translation. To improve the performance of urinary L-FABP and NAG in AKI diagnosis, we developed a panel consisting of these 2 biomarkers. A fitted multiple logistic regression model of the combination of urinary L-FABP and NAG was used to achieve the best performance [formula: 3.74 –1.06 x log10 L-FABP at 4 hours (ng/mL)–0.09 x NAG at 4 hours (IU/L)]. Calculation of the AUC-ROC demonstrated better performance (AUC-ROC 0.81 [95% CI, 0.68 to 0.89]) by the combination of the 2 biomarkers than by a single measurement. A multiple logistic regression analysis incorporating variables that were significantly different between the AKI and the non-AKI groups (serum creatinine before surgery, operation time, and the combination of urinary L-FABP and NAG at 4 hours) revealed that only the biomarker panel of urinary L-FABP and NAG among those parameters was associated with AKI occurring after surgery (p = 0.001).


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  		Table 3 Receiver Operating Curve Analysis for Urinary L-FABP at Various Time Points
 
Improvement of AKI prediction by addition of this biomarker panel to the clinical model was evaluated. The clinical model incorporated age, gender, complications of diabetes and hypertension, operation time, and serum creatinine measured before surgery. Addition of the panel of urinary L-FABP and NAG to this clinical model significantly increased AUC-ROC [biomarker + clinical model 0.86 (95% CI, 0.74 to 0.93) versus clinical model 0.79 (95% CI, 0.66 to 0.88), p < 0.05] (Fig 3). We also determined the net reclassification improvement (NRI) and the IDI indices. All patients were categorized as being at low (<10%), intermediate (10% to 30%), or high (>30%) risk, based on a predictive model incorporating the clinical variables. Addition of the biomarker panel significantly improved risk prediction when evaluated using NRI (0.27 ± 0.12, p = 0.034; Table 4) and IDI (0.16 ± 0.05, p < 0.001).


Figure 3
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  		Fig 3. Improvement of acute kidney injury (AKI) prediction by adding the panel of urinary L-type fatty acid-binding protein (L-FABP) and N-acetyl-β-D-glucosaminidase measurements. Receiver operating characteristic (ROC) curves for AKI risk prediction by a clinical model (area under the curve-ROC 0.79) and a combined model with the biomarker panel and clinical predictors (black line; AUC-ROC 0.86). Clinical predictors (gray line) included age, gender, complication of diabetes and hypertension, operation time, and serum creatinine measured before surgery.

 

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  		Table 4 Risk Classification for Biomarker Panel After Addition to Clinical Model
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
This study evaluated the performance of urinary L-FABP and NAG as AKI biomarkers in an adult post-cardiac surgery cohort. New AKI biomarkers including urinary L-FABP were examined mostly in pediatric post-cardiopulmonary bypass surgery patients as the first clinical evaluations [6]. Urinary L-FABP measured at 4 hours in pediatric post-cardiac surgery patients detected AKI with an AUC-ROC value of 0.81. This report describes data of urinary L-FABP in adult post-cardiac surgery patients and the AUC-ROC value of urinary L-FABP at 4 hours, which was 0.72. Recently, we calculated the AUC-ROC values for mortality prediction of urinary L-FABP with an established AKI with a septic shock cohort (0.99) and a mixed ICU cohort (0.89) [16, 17]. The former cohort is more homogeneous because all enrolled patients were severely ill. Considering these results, it can be concluded that urinary L-FABP also shows reduced performance in more heterogeneous populations, as is true also of the other AKI biomarkers.

Combining urinary L-FABP with NAG increased the AUC-ROC value to 0.81 in the present study. Han and colleagues [24, 25] described the advantages of combining biomarkers (urinary kidney injury molecule-1, NGAL, and NAG) to improve their performance. Optimal combinations of candidate urinary biomarkers remain unclear. When 2 different biomarkers showed similar sensitivity and specificity, combining these 2 markers will not improve their performance. In this study, urinary L-FABP showed high sensitivity (92.9% at 4 hours), although urinary NAG showed high specificity (100.0% at 4 hours). Combining 2 markers with different sensitivity and specificity is a reasonable strategy to improve the diagnostic performance of biomarkers. It is noteworthy that temporal patterns of increases in urinary biomarkers will also be regarded as establishing a better biomarker panel for AKI diagnosis [26].

Normalization of urinary biomarkers to urine creatinine concentration has been conducted frequently. Although this manipulation is expected to decrease the effects of variation in water excretion, the non-steady state of creatinine balance in AKI patients might reduce the markers' accuracy. In this study, urinary creatinine concentration in the non-AKI group was significantly lower than in the AKI group at 0 hours (Fig 2); urinary L-FABP and NAG in the non-AKI group were increased by urine creatinine correction, although they were decreased in the AKI group. Actually, significant differences of these 2 markers between the AKI group and the non-AKI group were resolved by urine creatinine correction (Fig 1). Recently, timed urine collection has been suggested to estimate the actual excretion rate of AKI biomarkers [27]. Further investigation is necessary to determine the optimal normalization for urinary L-FABP and NAG.

Several limitations might affect the results obtained in this study. First, the number of patients (n = 77) might be insufficient to determine the reliability and generalizability of urinary L-FABP and NAG, although the patients were enrolled at 2 general hospitals. Recently, a large multicenter cohort study (TRIBE-AKI) of 1,219 adult patients undergoing cardiac surgery evaluating urinary interleukin-18, urinary NGAL, or plasma NGAL was reported [13]. Second, reportedly, urinary NAG can be influenced by urea in urine [28]. No data related to urinary urea concentration are available in this study. Third, AKI was diagnosed using only serum creatinine, although the Acute Kidney Injury Network criteria suggest another criterion based on urine output. Recent studies have frequently employed the serum creatinine-based criterion alone [29], possibly because administrative databases usually do not include urine output data. Urine output presents advantages over serum creatinine because of its rapid response to renal insult. Nevertheless, it can be influenced by fluid status and the use of diuretics. In addition, correction by urine creatinine concentration might change the performance of AKI biomarkers, as discussed above. Finally, AKI diagnosis based on serum creatinine might underestimate renal injury. A recent multicenter pooled analysis of NGAL in AKI revealed that the subgroup of increased NGAL with no serum creatinine elevation (NGAL-positive creatinine-negative) had adverse clinical outcomes, including mortality, dialysis requirement, ICU stay, and overall hospital stay [30]. Hard outcomes such as dialysis, hospital stay, and death should be evaluated to confirm the utility of new AKI biomarkers.

Will the biomarker panel of urinary L-FABP and NAG have a significant impact on clinical practice? Several potentially effective AKI treatments that have been proven by animal studies have not translated successfully to clinical use, generally because of the limited capability of serum creatinine and urine output for detecting the optimal therapeutic window for AKI [31]. Improvement of AKI prediction through the use of new biomarkers will enable enrollment of patients who might benefit from specific interventions in new clinical trials. Translation of new AKI biomarkers to clinical use is now confronting a need for improved evaluation of the incremental performance above established clinical predictors and a potential over-reliance on the sole use of ROC analysis for assessing biomarker utility [32, 33]. This study demonstrated the additional contribution of the panel of urinary L-FABP and NAG to conventional clinical risk predictors not only by ROC analysis but also by the NRI and IDI indices, evaluation methods developed recently by Pencina and colleagues for risk prediction [19].

In conclusion, urinary L-FABP and NAG was able to detect AKI adequately, even in a heterogeneous population of adult post-cardiac surgery AKI, when these biomarkers were combined. Moreover, this biomarker panel improved AKI prediction over the clinical model. Combining 2 markers with different sensitivity and specificity is expected to be a good strategy to improve the diagnostic performance of biomarkers.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was partly supported by KAKEN-HI No. 21790795, MEXT, Japan (K.D.), KAKEN-HI No. 22790780, MEXT, Japan (K.N.), and Asahi Kasei Kuraray Medical Co., Ltd (E.N., K.D.).


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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