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Association of Urinary Neutrophil Gelatinase-Associated Lipocalin With Long-Term Renal Outcomes in ICU Survivors

A Retrospective Observational Cohort Study

Isshiki, Rei; Asada, Toshifumi; Sato, Dai; Sumida, Maki; Hamasaki, Yoshifumi; Inokuchi, Ryota; Matsubara, Takehiro; Ishii, Takeshi; Yahagi, Naoki; Nangaku, Masaomi; Noiri, Eisei; Doi, Kent

doi: 10.1097/SHK.0000000000000580
Clinical Science Aspects
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Background: Epidemiological studies recently suggested that acute kidney injury (AKI) in intensive care units (ICUs) increases the risk of chronic kidney disease development and progression. However, whether any AKI biomarker can predict long-term renal outcomes in ICU survivors remains unclear. This study was undertaken to elucidate the role of urinary biomarkers for long-term renal outcome prediction after ICU discharge.

Methods: This retrospective observational study examined 495 adult patients who had been admitted to the ICU of the University of Tokyo Hospital. Major adverse kidney events (MAKE): death, incident end-stage renal disease (ESRD), and halving of estimated glomerular filtration rate (eGFR), at hospital discharge and long-term renal outcomes of 30% reduction of eGFR or incident ESRD were evaluated.

Results: Among all the enrolled 495 patients, 393 patients were discharged from the hospital without MAKE. Data of eGFR up to two years after ICU discharge were available for 173 patients; 63 patients (36.4%) were positive for long-term renal outcomes. Step-wise logistic regression analysis demonstrated that male sex and urinary neutrophil gelatinase-associated lipocalin (NGAL) measured at ICU admission showed significant associations with long-term renal outcomes. Receiver operating characteristic curve analysis showed the area under the curve of 0.66 (95% confidence interval 0.57–0.74) for prediction of long-term renal outcome by urinary NGAL.

Conclusion: Urinary NGAL measured at ICU admission was significantly associated with long-term renal outcomes after hospital discharge in MAKE-free ICU survivors. Urinary NGAL measurements at ICU might be useful to identify a high risk population of kidney disease progression after intensive care.

*Department of Nephrology and Endocrinology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

Department of Emergency and Critical Care Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

22nd Century Medical and Research Center, The University of Tokyo, Bunkyo-ku, Tokyo, Japan

§Japan Science and Technology Agency/Japan International Cooperation Agency (JST/JICA), Science and Technology Research Partnership for Sustainable Development (SATREPS), Tokyo, Japan

Address reprint requests to Dr Kent Doi, PhD, Department of Emergency and Critical Care Medicine, University Hospital, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8655, Japan. E-mail: kdoi-tky@umin.ac.jp

Received 19 November, 2015

Revised 14 December, 2015

Accepted 26 January, 2016

KD has received grants from the Tokyo Society of Medical Sciences. For the remaining authors none was declared.

The authors report no conflicts of interest

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (www.shockjournal.com).

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INTRODUCTION

Reportedly, the prevalence of acute kidney injury (AKI) reaches as high as two-thirds of all intensive care unit (ICU) patients. AKI is strongly associated with high mortality and lengthened hospital stay (1). In addition to the short-term outcomes of mortality and ICU stay, ICU patients complicated with AKI are at high risk of long-term comorbidity of chronic kidney disease (CKD) (2). Although most AKI was previously regarded as reversible, results of recent studies suggest that AKI increases the risk of CKD development and progression (3–6). A great deal of interest has arisen in the idea that AKI and CKD are not mutually distinct: they should be regarded as an integrated clinical syndrome (7). Recently, the potential long-term physical, cognitive, and mental health problems after intensive care have been suggested (8). Long-term CKD progression after ICU discharge should also be regarded as an important outcome of postintensive care.

Probably because of insufficient evidence of CKD progression in ICU survivors and a lack of good predictive markers, not all ICU survivors are followed up by nephrologists after hospital discharge. However, to prevent CKD progression in survivors of AKI episodes in ICUs, it is necessary to stratify patients who are at higher risk for CKD progression. Several risk factors for long-term renal outcomes following AKI have been established: older age (4,9), AKI severity (4,9), frequency of AKI episodes (10), low levels of serum albumin (4,9), and diabetes complication (11). Recent reports have described that newly emerging AKI biomarkers can predict long-term outcomes. Urinary interleukin-18 and kidney injury molecule-1 (KIM-1) measured postoperative period could predict 3-year mortality in an adult cardiac surgery cohort (12). Urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinases-2 (TIMP-2) were able to predict 9-month incidence of a composite end point of all-cause mortality or the need for dialysis (13). However, it remains unclear whether newly emerging AKI biomarkers can predict progressive CKD in ICU survivors. This study evaluated the possible role of three urinary biomarkers (L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocain (NGAL), and N-acetyl-β-D-glucosaminidase (NAG)) for long-term renal outcome prediction in an adult ICU population.

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PATIENTS AND METHODS

Study design

This is a retrospective observational study. Four hundred ninety-five adult critically ill patients who had been admitted to the ICU of The University of Tokyo Hospital during December 2008 through March 2011 were evaluated. End-stage renal disease (ESRD; chronic dialysis and kidney transplant) patients were excluded. The study protocol, which was approved by The University of Tokyo institutional review board, adhered to the Declaration of Helsinki. Informed consent was obtained at enrollment. The following clinical variables during ICU and hospital stay were evaluated: age, sex, complication of diabetes mellitus, acute physiology and chronic health evaluation (APACHE) II score (14), diagnosis sepsis defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (15), length of ICU stay, and length of hospital stay.

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Assessment of kidney function

Baseline kidney function was defined by the estimated GFR calculated with the last outpatient value of serum creatinine measurement within 6 months before ICU admission. The GFR was estimated using the Modification of Diet in Renal Disease Eq. (16). For a patient with no known creatinine value before admission, the baseline was defined as the minimum among the inpatient value before ICU admission, the last value before hospital discharge, and the estimated value using the Modification of Diet in Renal Disease equation for the lower end of the normal range (i.e., 75 mL/min per 1.73 m2). Pre-existing CKD was determined as estimated GFR <60 mL/min per 1.73 m2. Acute kidney injury (AKI) was defined as a >50% relative increase or absolute increase >0.3 mg/dL compared with baseline serum creatinine according to the KDIGO Clinical Practice Guideline for Acute Kidney Injury (17). In addition, increasing rate of serum creatinine (peak serum creatinine measured within 1 week after ICU admission divided by baseline value described above) was used to evaluate the severity of AKI as a continuous variable.

A composite outcome of major adverse kidney events (MAKE) was defined at hospital discharge as positive for patients who underwent long-term dialysis, had a 50% decrease in eGFR, or died (18). The outcome of CKD progression after hospital discharge was defined as positive for ICU survivors who showed 30% reduction of eGFR compared with baseline or incident ESRD within 2 years after hospital discharge (19). We retrospectively reviewed medical records and determined the outcome for each patient. This study was conducted as a retrospective observational study. Therefore, the frequency of clinic visits was determined by each physician who followed up the patients.

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Urinary biomarker measurement

Urine samples were collected at ICU admission and were then frozen at −80°C within 1 h of collection. Urinary L-FABP and NGAL were measured using commercially available enzyme-linked immunosorbent assay kits (Human L-FABP Assay Kit; CMIC Co Ltd, Tokyo, Japan; NGAL ELISA Kit [KIT 036]; BioPorto, Gentofte, Denmark). Urinary NAG was measured at The University of Tokyo Hospital Clinical Laboratory using the 4-HP-NAG substrate method (L-Type NAG; Wako Pure Chemical Industries Ltd, Osaka, Japan).

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Statistical analyses

Data are presented as median [interquartile]. Continuous variables were compared using Wilcoxon rank-sum tests when the normality assumption did not hold. Categorical variables were compared using a Pearson chi-square or Fisher exact test. To identify the best predictors of CKD progression, we conducted univariate and step-wise logistic regression analysis. The urinary biomarker performance was ascertained using receiver operating characteristic (ROC) curve analysis. Optimal cut-off values were ascertained using the Youden index (sensitivity + specificity – 1), which is a common summary measure of the ROC curve representing the maximum potential effectiveness of a marker (20). Comparisons of ROC curves were performed as reported previously (21). To evaluate the clinical usefulness of the biomarkers, we calculated the positive predictive value (PPV), which denotes the probability that the patient will progress to CKD, and calculated the negative predictive value (NPV), which denotes the probability that the patient is less likely to progress to CKD, with different cut-off values. To evaluate the impact of the biomarkers evaluated in this study of CKD progression, we determined the continuous net reclassification improvement (NRI) index and the integrated discrimination improvement (IDI) index (22). Calculations were conducted using statistical analysis software (JMP ver. 10.0; SAS Institute Inc, Cary, NC) and R 3.1.1 (R Foundation for Statistical Computing, Vienna, Austria). A conventional criterion of α level 0.05 was used to assess statistical significance.

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RESULTS

Occurrence of AKI in ICU

This study retrospectively examined 495 adult critically ill patients who had been admitted to the ICU of the University of Tokyo Hospital. In-hospital mortality in this cohort was 14.1%. AKI had been diagnosed in 264 (53.3%) patients within 1 week after ICU admission. Renal replacement therapy was necessary for 80 patients (16.2%). Significantly older age, higher frequency of pre-existing CKD and sepsis, higher peak serum creatinine and APACHE II score, longer length of ICU stay, and significantly elevated urinary biomarker levels of L-FABP, NGAL, and NAG at ICU admission were observed for patients with AKI than for non-AKI patients (Table 1).

Table 1

Table 1

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MAKE at hospital discharge

We assessed the development of major adverse kidney events (MAKE) including death, incident dialysis dependency, and halving of eGFR (18) at hospital discharge. Of 495 patients, 70 patients died during hospital stay; 32 patients showed renal dysfunction progression (i.e., halving of eGFR or incident dialysis dependency) at hospital discharge. The two major causes of death in hospital were infection (n = 19, 27.1%) and heart disease (n = 19, 27.1%) (see Table, Supplemental Digital Content 1, at http://links.lww.com/SHK/A372, which presents the causes of death in hospital and after discharge). Significantly older age, higher frequency of pre-existing CKD and sepsis, higher increase rate of serum creatinine, higher APACHE II score, longer ICU stay, and higher urinary biomarker levels of L-FABP, NGAL, and NAG at ICU admission were observed for patients with MAKE (Table 2).

Table 2

Table 2

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Long-term outcome of CKD progression after hospital discharge

Of the 393 patients who were discharged from the hospital without MAKE, 32 patients died within 2 years after hospital discharge. The major cause of death was malignancy (n = 11, 34.4%). The Table, Supplemental Digital Content 1, at http://links.lww.com/SHK/A372, presents the causes of death during the hospital stay and after discharge. Data of eGFR up 2 years after ICU discharge was available in 173 patients (Fig. 1). The other 220 patients had no information related to eGFR after hospital discharge. These patients showed significantly higher baseline eGFR evaluated before ICU admission. However, no significant difference was found for AKI severity and urinary biomarker levels during the hospital stay (see Table, Supplemental Digital Content 2, at http://links.lww.com/SHK/A373, which demonstrates baseline clinical data of MAKE-free patients at hospital discharge). These MAKE-free patients at hospital discharge were not expected to show CKD progression. Among them, 63 patients (36.4%) showed CKD progression.

Fig. 1

Fig. 1

A significantly higher frequency of male sex, pre-existing CKD, and sepsis, higher increase rate of serum creatinine during ICU stay were observed in the CKD progressors (Table 3). A significantly longer ICU stay and hospital stay were observed in the CKD progressors, although the APACHE II score was not significantly different from that of the non-CKD progressors. The relative frequencies of mild AKI (stage 1) for all AKI in each group were similar (50.0% in the CKD progressors vs. 47.6% in the non-CKD progressors). Urinary L-FABP, NGAL, and NAG levels measured at ICU admission were significantly higher for CKD progressors than for non-CKD progressors (Table 3, Fig. 2). Receiver operating characteristic curves (ROCs) for prediction of long-term renal outcome of urinary biomarkers are shown in Figure 3. The area under the curve of ROC curves (AUC-ROC) values of urinary L-FABP, NGAL, and NAG for the prediction of CKD progression were, respectively, 0.59, 0.66, and 0.65. The sensitivity, specificity, positive predictive value (PPV), and NPV are presented in Table 4.

Table 3

Table 3

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Table 4

Table 4

Univariate logistic regression analyses showed that urinary NGAL and NAG were significantly associated with CKD progression (Table 5). To identify the possible predictors of CKD progression, we conducted a step-wise logistic regression analysis incorporating the parameters that showed P values of less than 0.1 in univariate analysis and found significant association of two variables urinary NGAL and male sex with CKD progression.

Table 5

Table 5

We evaluated whether addition of biomarkers to the clinical model improves the prediction of CKD progression. In the clinical model, we incorporated sex, complications of CKD and sepsis, and increased rate of serum creatinine because these parameters showed P values of less than 0.1 in univariate analysis. Addition of three urinary biomarkers to the clinical model was evaluated by the continuous NRI and the IDI indices. Among the three biomarkers, only urinary NGAL significantly improved risk prediction of CKD progression when evaluated using continuous NRI (Table 6).

Table 6

Table 6

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DISCUSSION

This study demonstrated a urinary AKI biomarker NGAL was significantly associated with long-term renal outcomes in ICU survivors who were MAKE-free at hospital discharge. Most patients who survived an episode of AKI were previously regarded as having a good long-term prognosis. However, results of recent studies suggest that AKI increases the risk of CKD development and progression. Lo et al. (3) reported that an episode of dialysis-requiring AKI is a strong independent risk factor for long-term risk of progressive CKD and mortality in patients with pre-existing normal or near normal kidney function. Another study revealed a significant association between dialysis-requiring AKI and increased risk of chronic dialysis (5). In addition, mild AKI appears to have significant impacts on long-term outcomes such as mortality and ESRD (6,23). In accordance with previous studies, this study found that increased serum creatinine of patients during the ICU stay, which determines AKI severity, was significantly associated with MAKE (death, incident dialysis dependency, and halving of eGFR) at hospital discharge. It remained unclear whether ICU survivors who were discharged from the hospital without MAKE would show CKD progression. This study revealed a certain portion of this population (63 of 173 patients) who showed CKD progression for the next 2 years. In addition, AKI severity was insufficient to predict CKD progression in ICU survivors without MAKE at the time of hospital discharge.

Many studies have highlighted the usefulness of damage biomarkers in management of AKI, but then, few reports in the literature describe tests of biomarkers for their ability to predict long-term outcomes of renal dysfunction. Liu et al. (24) evaluated the prediction of CKD progression by urinary NGAL and reported an independent association of urinary NGAL with progression of CKD. Urinary NGAL was measured when the enrolled patients were clinically stable. Coca et al. (25) reported that the highest values of urinary biomarkers including NGAL and L-FABP were associated independently with long-term mortality in Translational Research in Biomarker Endpoints in an AKI cohort. However, they did not assess long-term renal function. The present report is the first describing that urinary biomarkers measured in critically ill conditions can predict long-term outcomes of CKD progression.

Urinary NGAL was selected as a significant variable associated with CKD progression, although increasing rate of serum creatinine during the ICU stay (i.e., AKI severity) was not selected for multiple logistic analyses. The best predictive factor for progression of CKD is not the etiology of glomerular injury, but the degree of tubulointerstitial damage such as fibrosis and inflammatory cell infiltration (26). A possible explanation is that urinary biomarkers might reflect tubular epithelial cell injury better than serum creatinine (27). During the last decade, many researchers have examined the role of novel AKI biomarkers in ICU populations (28). These biomarkers are regarded as reflecting tubular damage, whereas changes of serum creatinine reflect kidney function. Recently, the Acute Dialysis Quality Initiative (ADQI) has discussed the need to redefine the diagnostic criteria for AKI to incorporate tubular damage biomarkers such as NGAL, KIM-1, IL-18, and L-FABP (29). Incorporation of damage markers into the diagnostic criteria for AKI will be to create a new category of AKI, subclinical AKI, diagnosed by elevations of damage markers alone, not functional markers (30). Haase et al. (31) reported that patients with subclinical AKI have an increased risk of adverse outcomes (need for renal replacement therapy, hospital mortality, or their combination) compared with patients without functional or damage markers elevations. It is noteworthy that urinary NGAL showed a low AUC-ROC value of 0.66 in this study, although a significant association with long-term renal outcomes. Considering its clinical use, prediction of CKD progression by urinary NGAL alone might be insufficient. Other urinary biomarkers of L-FABP and NAG showed no significant association in this study. We did not study other biomarkers such as KIM-1, IL-18, and TIMP-2/IGFBP-7, which were evaluated recently for prediction of long-term mortality in a large post-cardiac surgery cohort (13,32). Some combination of these biomarkers with NGAL might produce a better AUC-ROC value.

Results obtained in this study suggest that ICU survivors who were negative for MAKE at hospital discharge should be followed up after hospital discharge, as documented by Goldstein et al. (33). Recent KDIGO practice guidelines for AKI recommend that patients surviving AKI be evaluated 3 months after AKI for resolution, new onset, or worsening of pre-existing CKD (17). Considering the healthcare resources necessary to follow ICU survivors, AKI patients should be stratified according to CKD risk. For this purpose, urinary biomarker measurement including NGAL might be helpful. Further investigation must be conducted to ascertain the optimal biomarker measurement in terms of choice of marker, timing, and threshold.

This analysis is subject to several limitations. First, we studied adult patients at a single ICU, which might have limited external validity. Our findings should be confirmed through multicenter ICU studies. Second, because of the retrospective observational nature of study, clinical information including eGFR of nearly half of the MAKE-free patients was not available. No significant difference was found for AKI severity between the patients whose data were available and those whose data were not available. However, a significantly higher rate of complication of diabetes was observed in the followed-up patients compared with the lost-follow patients. This might have confounded our results of low AUC-ROC of biomarkers because diabetes might have some effect on deteriorating kidney function, independently of acute kidney damage. Further investigation in a prospective manner is necessary. Third, AKI was diagnosed only with serum creatinine. Although the KDIGO criteria suggest the use of another criterion based on urine output, recent studies have frequently employed the serum creatinine-based criterion alone. There is little evidence validating the urine output criteria for determining the severity of AKI compared with serum creatinine (34). Fourth, we defined CKD progression as a 30% reduction of eGFR over 2 years. Coresh et al. (19) have reported that declines in eGFR smaller than a doubling of serum creatinine concentration can be alternative end points for CKD progression because that are still strongly associated with the risk of ESRD and mortality. It is noteworthy that eGFR calculated using serum creatinine levels might be influenced by progressive muscle atrophy in this study because all the patients were survivors of intensive care (35). Finally, we measured urinary biomarkers at a single time point. Sequential measurements must be taken in future studies to improve biomarker performance remarkably (25).

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CONCLUSIONS

Urinary NGAL measured at ICU admission were found to be associated significantly with long-term renal outcomes after hospital discharge in MAKE-free ICU survivors. Our results suggest that AKI biomarkers measured during critical illness can be useful in stratification of ICU survivors for postintensive care follow-up.

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Acknowledgments

The authors thank Dr Yutaka Yatomi, Dr Tatsuo Shimosawa, and Ms Mami Haba (The University of Tokyo) for their support.

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Keywords:

Acute kidney injury; biomarkers; chronic kidney disease; disease progression; neutrophil gelatinase-associated lipocalin; postintensive care syndrome; ADQI; Acute Dialysis Quality Initiative; AKI; acute kidney injury; APACHE; acute physiology and chronic health evaluation; CKD; chronic kidney disease; ESRD; end-stage renal disease; GFR; glomerular filtration rate; ICU; intensive care unit; IDI; integrated discrimination improvement; IGFBP-7; insulin-like growth factor-binding protein-7; KDIGO; Kidney Disease Improving Global Outcomes; KIM-1; kidney injury molecule-1; L-FABP; L-type fatty acid-binding protein; MAKE; major adverse kidney events; NAG; N-acetyl-β-D-glucosaminidase; NGAL; neutrophil gelatinase-associated lipocalin; NPV; negative predictive value; NRI; net reclassification improvement; PICS; postintensive care syndrome; PPV; positive predictive value; ROC; receiver operating characteristic; TIMP-2; tissue inhibitor of metalloproteinase-2; TRIBE; Translational Research in Biomarker Endpoints

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