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 . 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 . 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 , or kidney injury molecule-1 , 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 . 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  or whether it is after cardiac surgery . 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 . 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.