Predicting acute kidney injury using urinary liver-type fatty-acid binding protein and serum N-terminal pro-B-type natriuretic peptide levels in patients treated at medical cardiac intensive care units

Acute kidney injury (AKI) is a common clinical syndrome that affects critically ill patients and is strongly associated with increases in morbidity, mortality, and long-term loss of kidney function [1–3].

Serum creatinine is unable to identify early renal tubular injury before the decrease in glomerular filtration rate [4, 5], so an early and reliable biomarker of AKI is still needed to facilitate timely intervention and to prevent complications. However, it is also possible that a single biomarker may inadequately assess the risk of AKI because the syndrome is complex and multifactorial [4]. Combining different biomarkers in a single assessment could improve early prediction of AKI in the critically ill.

Liver-type fatty acid-binding protein (L-FABP), a marker of renal tubular injury, is an endogenous antioxidant protein spanning 14 kDa that is expressed in proximal tubular epithelial cells [6, 7]. Found in the cytoplasm of tubular cells, L-FABP is rapidly released into the tubular lumen in response to ischemia [8] or oxidative stress [8, 9]. To date, urinary L-FABP has been shown to be useful for the early prediction of AKI after surgery (particularly cardiac) [10, 11], sepsis [12], and emergency coronary angiography or percutaneous coronary intervention for acute coronary syndrome [13, 14]. However, there is limited information about the clinical utility of urinary L-FABP for predicting AKI in a heterogeneous cohort of patients treated in medical cardiac intensive care units (CICUs).

Another important and potentially relevant marker is N-terminal pro-B-type natriuretic peptide (NT-proBNP), a marker of hemodynamic stress [15]. High serum levels of NT-proBNP reflect hemodynamic deterioration, myocardial wall stress, myocardial ischemia, derangements in volume loading conditions, activation of the renin-angiotensin-aldosterone system and sympathetic nervous system, and renal dysfunction, all of which may lead to the development of AKI [16–20]. Several studies have also explored the association of NT-proBNP with the development of AKI after cardiac surgery [21] and coronary angiography or percutaneous coronary intervention [16, 22]. However, few studies have examined the clinical utility of NT-proBNP in medical CICUs.

In the present study, we prospectively investigated the predictive value of urinary L-FABP on admission, both independently and in combination with serum NT-proBNP, for predicting AKI in patients hospitalized to medical CICUs.

Urinary L-FABP levels correlated with age (r = 0.06, p = 0.02), hemoglobin (r = − 0.06, p = 0.03), eGFR (r = − 0.28, p < 0.0001), hs-CRP (r = 0.21, p < 0.0001), NT-proBNP (r = 0.17, p < 0.0001), and hs-TnT levels (r = 0.26, p < 0.0001), and LVEF (r = − 0.07, p = 0.01). Serum NT-proBNPlevels correlated with age (r = 0.27, p < 0.0001), hemoglobin (r = − 0.31, p < 0.0001), eGFR (r = − 0.48, p < 0.0001), and hs-CRP levels (r = 0.44, p < 0.0001), and LVEF (r = − 0.46, p < 0.0001).

Of the 1273 patients, 224 (17.6%) developed AKI (48 had stage 2 or 3 disease). Compared with the non-AKI group, the patients in the AKI group were older; had higher heart rate; higher white blood cell count; higher levels of glucose, hs-CRP, NT-proBNP, hs-TnT, and L-FABP; and lower levels of hemoglobin, eGFR, and LVEF; more patients in the AKI group had the following: a history of intraaortic balloon pump or diuretic therapy; hypertension or diabetes mellitus; and acute decompensated heart failure (Table 1).

The median length of CICU stay in the AKI group (4.0 (3.0–6.0) days) was longer than that in the non-AKI group (3.0 (2.0–4.0) days) (p < 0.001). During the 6-month follow-up period, there were 94 all-cause deaths (7.4%), of which 66 were cardiovascular related. During the first week after admission, 24 patients died, of which all deaths were related to cardiovascular issues. Patients with AKI had higher risk of 1-week mortality compared to those who did not (4.9% vs 1.2%, p = 0.0002). Patients with AKI had higher risks of all-cause death and cardiovascular death than patients without AKI (both, p = 0.0003) (Fig. 1).

Patients were divided into tertiles according to their urinary L-FABP and serum NT-proBNP levels. In the multivariate logistic analyses, both L-FABP and NT-proBNP were independent predictors of AKI when assessed as either continuous variables (p < 0.0001 and p = 0.006, respectively) or variables categorized by tertile (p < 0.0001 and p = 0.009, respectively, when comparing the third tertile with the first tertile) (Table 3). Intraaortic balloon pump use and the eGFR also remained significantly associated with AKI. Moreover, Fig. 2 shows that the incidence of AKI gradually increased as the L-FABP and NT-proBNP tertile increased. As shown in Fig. 3, patients in whom both markers were in the highest tertile had the highest risk of AKI, whereas those who had both biomarkers in the lowest tertile had the lowest risk of AKI (p < 0.0001).

Variables	Multivariate model 1		Multivariate model 2
	OR (95% CI)	P value	OR (95% CI)	P value
Age (per 10 years increment)	1.15 (0.98–1.37)	0.09	1.16 (0.98–1.37)	0.08
Hypertension	1.42 (0.97–2.10)	0.07	1.33 (0.91–1.94)	0.14
Diabetes mellitus	1.31 (0.90–1.91)	0.16	1.26 (0.87–1.83)	0.22
Acute decompensated heart failure	1.26 (0.81–1.96)	0.30	1.47 (0.96–2.25)	0.08
Mechanical ventilation before admission	1.24 (0.47–3.27)	0.67	1.30 (0.51–3.30)	0.58
IABP before admission	2.49 (1.41–4.42)	0.002	2.48 (1.40–4.37)	0.002
Heart rate (per 10 beats per minute increment)	1.01 (0.94–1.08)	0.82	1.02 (0.95–1.09)	0.54
White blood cell count (per ×103/μL increment)	1.04 (0.99–1.09)	0.17	1.04 (0.99–1.09)	0.11
Hemoglobin (g/dL) (per 1 g/dL increment)	0.94 (0.87–1.02)	0.14	0.94 (0.87–1.02)	0.13
eGFR (per 10 mL/min/1.73m2 increment)	0.91 (0.83–0.99)	0.03	0.85 (0.78–0.92)	< 0.001
Glucose (per 10 mg/dL increment)	1.02 (0.99–1.04)	0.20	1.02 (1.00–1.05)	0.10
hs-CRP (per 10-fold increment)	1.06 (0.85–1.34)	0.60	1.15 (0.92–1.44)	0.21
NT-proBNP (per 10-fold increment)	1.58 (1.14–2.19)	0.006
Tertile of NT-proBNP (pg/mL)
First (< 425)			1.0
Second (425–2730)			1.79 (0.98–3.25)	0.06
Third (> 2730)			1.97 (1.19–3.26)	0.009
hs-TnT (per 10-fold increment)	0.96 (0.78–1.18)	0.67	1.02 (0.83–1.24)	0.88
Urinary L-FABP (per 10-fold increment)	2.66 (2.03–3.48)	< 0.001
Tertile of Urinary L-FABP (ng/mL)
First (< 3.3)			1.0
Second (3.3–11.5)			1.42 (0.87–2.30)	0.16
Third (> 11.5)			3.40 (2.13–5.44)	< 0.001
LVEF (per 10% increment)	1.12 (0.98–1.29)	0.11	1.11 (0.96–1.27)	0.15
Diuretics	0.98 (0.68–1.49)	0.98	0.93 (0.64–1.37)	0.71

Multivariate model adjusted for all baseline variables with p < 0.05 on univariate analysis. NT-proBNP and L-FABP levels were assessed as either continuous variables (model 1) or variables categorized into tertiles (model 2)

AKI acute kidney injury, OR odds ratio, CI confidence interval, IABP intraaortic balloon pump, eGFR creatinine-based estimated glomerular filtration rate, hs-CRP high-sensitivity C-reactive protein, NT-proBNP N-terminal pro-B-type natriuretic peptide, hs-TnT high-sensitivity cardiac troponin T, L-FABP liver-type fatty acid-binding protein, LVEF left ventricular ejection fraction

The main findings of this study were as follows. First, admission levels of both urinary L-FABP and serum NT-proBNP were independent predictors of developing AKI in patients treated in medical CICUs. Second, patients with L-FABP and NT-proBNP in the upper tertiles were most strongly associated with an increased risk of AKI. Third, combining L-FABP and NT-proBNP improved the predictive value for AKI beyond that achieved with any single biomarker or baseline model alone, as demonstrated by the NRI and IDI. Fourth and finally, patients who developed AKI had a higher risk of death at 1 week and at 6 months than patients who did not develop AKI. These findings indicate that assessing both urinary L-FABP and serum NT-proBNP levels on admission may help with the early risk stratification of AKI in patients admitted to medical CICUs.

Medical CICUs have evolved from their origins of focusing exclusively on patients with acute coronary syndromes and now provide comprehensive critical care to patients with a range of acute cardiovascular illnesses and complex comorbidities [27, 28]. These include patients with diabetes mellitus, hypertension, dyslipidemia, and CKD, and those who use therapeutic devices. Recent prospective studies have shown that, as with patients treated in surgical intensive care units, AKI is commonly and is strongly associated with increased mortality [27]. However, the utility of urinary L-FABP for predicting AKI has not been fully evaluated in medical CICU settings, and there was a need to confirm the reliability and generalizability of L-FABP in heterogeneous populations before its clinical use could be advocated. Thus, we, for the first time, demonstrated that the combined use of urinary L-FABP and serum NT-proBNP, which are individually independent predictors of AKI, could improve the early prediction of AKI in a large (n = 1273), heterogeneous cohort of patients treated at medical CICUs not including cardiac surgery cases.

Type 1 cardiorenal syndrome reflects an abrupt worsening of cardiac function leading to AKI [29]. The combination of urinary L-FABP, a marker of renal tubular injury, and NT-proBNP, a marker of hemodynamic stress, to assess for the development of the cardiorenal syndrome is conceptually attractive. The data presented herein not only support both of these as independent predictors of AKI but also show that combining L-FABP and NT-proBNP can improve the risk reclassification and discrimination for AKI among medical patients in the CICU. Indeed, patients whose results for both markers were in the highest tertile were approximately eightfold more likely to develop AKI than those whose results for both markers were in the lowest tertile. It is crucial that these biomarkers benefit from being readily measurable, easily accessible, relatively inexpensive, and reproducible with high sensitivity and specificity. Following confirmation of our data in other independent cohorts, this combination approach to screening could be included in an algorithm for predicting AKI on admission to a CICU.

In the present study, urinary L-FABP was weakly (r = 0.17), although statistically significantly, correlated with NT-proBNP. This weak correlation suggests that they may target two different pathophysiological dysregulations of AKI: renal tubular injury and hemodynamic stress. Also, the coefficient for correlation between urinary L-FABP and age and between urinary L-FABP hemoglobin was less than 0.2, which was consistent with the results of previous studies [30, 31].

Recently, the predictive value of combining urinary L-FABP with other urinary AKI biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL) [32, 33], interleukin-18 [34], or kidney injury molecule-1 [11], for the development of AKI after cardiac surgery have been studied. Especially, a combination of urinary L-FABP and NGAL may be the most promising strategy for predicting AKI. With respect to the plasma NGAL evaluation along with B-type natriuretic peptide (BNP) in acutely decompensated heart failure, the GALLANT trial showed prognostic values for plasma NGAL, alone and in combination with BNP in acutely decompensated heart failure [35]. These findings lead us to speculate that a biomarker panel consisting of L-FABP, BNP or NT-proBNP, and urinary or plasma NGAL may improve the early prediction of AKI in patients admitted to medical CICUs. Further investigation is desired to confirm the usefulness of this approach.

It should be noted that we measured urinary L-FABP only at the point of admission to the CICU. The decision for this was based on reports of whether this is the best time for predicting AKI in patients with acute decompensated heart failure [36] or whether it is after cardiac surgery [37]. Thus, although we showed that admission measurements of urinary L-FABP may help physicians predict AKI, we do not know whether L-FABP, NT-proBNP, or a combination of both could also be used for monitoring markers. Indeed, we do not know whether improvements in these biomarkers would have affected the study outcomes.

The treatments in this study were also not randomized or controlled, making it difficult to evaluate the effects of treatments on the progression of AKI. For example, AKI was significantly associated with the frequent use of diuretics, whereas some patients underwent emergency coronary angiography or percutaneous coronary intervention and intraaortic balloon pump insertion before samples were obtained. These differences in treatment strategy may have had potentially significant confounding effects on the study results. However, even when we entered these factors into our multivariate logistic analyses, both L-FABP and NT-proBNP remained valid, significant, independent predictors of AKI. Thus, we believe that these did not contribute to significant confounding.

Observational studies suggest an association between AKI and the subsequent development of CKD and ESRD, even following apparent renal recovery [3, 38]. Thus, it is interesting to see if urinary L-FABP could predict CKD and ESRD. However, we could not evaluate this issue because of the study design focused on the early prediction of AKI. Nevertheless, when we retrospectively collected serum creatinine data between 3 and 6 months after discharge in 926 patients (73%) from the study group, the progression to ESRD occurred in 29 patients, including 7 patients who received hemodialysis. The incidence rate for the progression to ESRD in patients with AKI was significantly higher than in patients without AKI (15.6% vs 0.5%, p < 0.0001). Patients in the third tertile of L-FABP had the highest risk of the progression to ESRD (p < 0.0001, when compared with patients in both the first or second tertile; 8.8% vs 0.6% or 0.7%), speculating that higher levels of urinary L-FABP may be associated with the development of ESRD. A larger prospective study is needed to clarify this issue.

There are a few other limitations in the present study. First, it was conducted at a single institution. Second, we evaluated urinary L-FABP as the absolute concentration, but did not use urinary creatinine correction, because the urinary creatinine excretion rate may change over time under non-steady-state conditions [39]. Nevertheless, when we analyzed L-FABP using urinary creatinine correction, the results were comparable with those obtained without creatinine correction (data not shown). Further investigation is necessary to determine the optimal normalization for urinary L-FABP. Third, AKI was only defined using the elevation of serum creatinine because of the inconsistent data recorded and the potential alterations in urine volume induced by medical therapy. This may lead to the neglect of a part of the renal insult, which may be determined by urine output. Finally, the incidence of AKI in this study was 17.6%, which was lower than that reported in two recent studies (28.7% and 31.6%) [40, 41]. This difference may be attributable to differences in the severity of patients’ disease, with higher frequencies of mechanical ventilation and higher values for NT-proBNP in the previous research.

Combining measurements for two independent predictors of AKI, namely, urinary L-FABP and serum NT-proBNP, when patients are admitted to a CICU, improves the early prediction of AKI beyond that achieved when using either predictor in isolation.