Clin Exp Nephrol DOI 10.1007/s10157-015-1092-4
ORIGINAL ARTICLE
The urinary levels of prostanoid metabolites predict acute kidney injury in heterogeneous adult Japanese ICU patients: a prospective observational study Haruyo Ujike-Omori • Yohei Maeshima • Masaru Kinomura • Katsuyuki Tanabe Kiyoshi Mori • Hiroyuki Watatani • Norikazu Hinamoto • Hitoshi Sugiyama • Yoshiki Sakai • Hiroshi Morimatsu • Hirofumi Makino
•
Received: 2 October 2014 / Accepted: 2 February 2015 Ó Japanese Society of Nephrology 2015
Abstract Background Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients. Methods The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the Electronic supplementary material The online version of this article (doi:10.1007/s10157-015-1092-4) contains supplementary material, which is available to authorized users. H. Ujike-Omori Y. Maeshima (&) M. Kinomura K. Tanabe H. Watatani N. Hinamoto H. Makino Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan e-mail: [email protected] K. Mori Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan H. Sugiyama Center for chronic kidney disease and peritoneal dialysis, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Y. Sakai Ono Pharmaceutical Co., Ltd, Osaka, Japan H. Morimatsu Department of Anesthesiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1a), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined. Results Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6OXO-PGF1a/Cr (r = 0.57, p \ 0.0001) and 11-dehydroTXB2/Cr (r = 0.47, p \ 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1a/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1a/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC–area under the curve (AUC): 0.75]. Conclusions Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1a/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients. Keywords Acute kidney injury Prostaglandin Thromboxane ICU
Introduction Acute kidney injury (AKI) is frequently observed in critically ill patients in the ICU and is associated with increased mortality [1]. AKI occurs in 5–7 % of hospitalized patients and 20–25 % of ICU admissions [2]. Unfortunately,
123
Clin Exp Nephrol
the serum creatinine (sCr) level increases at later time points and cannot be used to detect or diagnose early renal tubular injury prior to a decline in the glomerular filtration rate (GFR). Therefore, the identification of more reliable and early biomarkers for AKI is required. To date, urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), L-type fatty acidbinding protein (L-FABP) and a number of other markers have been examined with respect to their role in the early and accurate detection of AKI [3–5]. Prostaglandins (PGs) are derived from the metabolism of arachidonic acid, with the first step being catalyzed by the cyclooxygenase (COX) system. PGs are produced at various sites in the kidneys and have been implicated to regulate glomerular hemodynamics, renin secretion and tubular transport [6]. Prostacyclin (prostaglandin I2: PGI2), a major PG, exerts vasoprotective effects, including vasodilation, inhibition of platelet aggregation and the proliferation of vascular smooth muscle cells [7]. Prostacyclindeficient mice with a genetic disruption in prostaglandin I2 synthetase (PGIS) develop renal fibrosis and arterial sclerosis [8], suggesting its involvement in the maintenance of a normal kidney structure. In addition, the renoprotective effects of prostacyclin and its analogs have been reported in various experimental models, including gentamycin-induced tubular injury [9], diabetic nephropathy [10–12] and unilateral ureteral obstruction [13, 14]. In contrast, thromboxane A2 (TXA2) exerts effects opposite to those of PGI2, in association with the development of vascular lesions [7]. PGE2 is one of the major prostanoids generated by the kidneys [15] and affects both vascular tone and the epithelial function. PGE2 also modulates renal sodium and water excretion [16]. PGI2 is rapidly metabolized into a nearly inactive product, 6-keto-PGF1a. Thromboxane is similar to prostaglandins in that its rate of production is relatively low in normal subjects and inhibiting its synthesis has little effect on the renal function [17]. Meanwhile, urinary prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1a) and TXA2 metabolite (11-dehydro-TXB2) are relatively stable and reflect the production of each prostanoid. In a previous report of 10 patients undergoing coronary artery bypass grafting, the urinary and plasma levels of TXB2 and 6-keto PGF1a increased, and a significant correlation (r = 0.87, p less than 0.01) was observed between the urinary NAG and TXB2 levels [18]. Low-dose prostaglandin E1 (PGE1), which has a similar function to that of PGE2, was also found to prevent deterioration of the renal function under surgical anesthesia in 109 adult patients [19]. Furthermore, patients with acute oliguric renal failure immediately after transplantation show high urinary PGE2 concentrations, and rejection crises are characterized by a twofold increase in urinary PGE2 excretion [20].
123
To date, the performance of urinary prostanoid metabolites for predicting AKI in critically ill patients has not been examined. Therefore, in the present study, we aimed to evaluate the potential of urinary prostanoid metabolites in diagnosing and predicting AKI in heterogeneous ICU patients.
Materials and methods Study design and population The current study was conducted as a prospective observational study. We prospectively collected data for adult patients [20 years of age admitted to the ICU at Okayama University Hospital, Okayama, Japan, between November 2010 and July 2011. Ninety-three Japanese patients were randomly enrolled in total, and written informed consent was obtained from each subject. However, if prior consent could not be obtained due to critical illness or the use of sedatives or anesthetics, delayed consent was obtained [21]. The study protocol was approved by the Institutional Ethics Review Board of Okayama University Hospital (No. 673). This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network (registration number: UMIN 000004503). Endstage renal disease (ESRD) was defined as chronic kidney failure treated with either dialysis or transplantation and non-dialyzed patients, whose baseline eGFR was less than 15 mL/min/1.73 m2. Patients with ESRD and those who were discharged within 24 h after admission to the ICU were excluded. The following clinical variables were evaluated: age, sex, body mass index (BMI), reason for admission (medical issue or type of surgery), complications of diabetes mellitus, a diagnosis of sepsis, as defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee [22], the use of contrast exposure within 48 h preceding ICU admission, prior medication with non-steroidal anti-inflammatory drugs (NSAIDs), the use of diuretics or human atrial natriuretic peptide (hANP) medications during the ICU stay, the initiation of RRT, in-hospital mortality and the length of in-hospital and ICU stay. Disease severity was evaluated according to the Acute Physiology and Chronic Health Evaluation (APACHE) II score within 24 h of ICU admission [23]. The primary outcome was the development of AKI within 7 days after ICU admission, according to the Acute Kidney Injury Network (AKIN) classification [24]. The presence of AKI was assessed daily by calculating the change in sCr from baseline to the maximum sCr level and based on the cumulative daily urine output. The severity of
Clin Exp Nephrol Table 1 Patient characteristics and clinical outcomes Non-AKI (n = 69, 74.2 %)
AKI (n = 24, 25.8 %)
Age, years
66.0 [59.0–71.5]
60 [52.5–68.7]
Male, n (%)
52 (75.4 %)
17 (24.6 %)
0.0077
BMI, kg/m2
21.6 [19.0–24.3]
24.0 [20.1–27.6]
0.0814
Medical
5 (7.3 %)
6 (25.0 %)
Elective surgery
59 (85.5 %)
14 (58.3 %)
Emergency surgery
5 (7.3 %)
4 (16.7 %)
Patient type, n (%)
p value (vs. Non-AKI) 0.075
0.018
APACHE II
12 [8.5–15]
14.5 [10–19.8]
0.0438
Diabetes, n (%)
13 (19.1 %)
7 (29.1)
0.304
Sepsis, n (%)
5 (7.2 %)
4 (16.7 %)
0.179
Contrast exposure in preceding 48 h, n (%) NSAIDs, n (%)
13 (18.8 %) 7 (10.1 %)
4 (16.7 %) 1 (4.17 %)
0.812 0.368
18 (26.1 %)
20 (83.3 %)
\0.0001 \0.0001
Medication used during ICU stay (initial 7 days), n (%) Furosemide
4 (5.8 %)
12 (50.0 %)
Baseline Cr, mg/dL
hANP
0.79 [0.68–0.93]
0.78 [0.62–0.97]
0.990
Baseline eGFR, mL/min per 1.73 m2
71.5 [61.7–86.2]
72.5 [49.2–92.3]
0.819
Baseline eGFR \60, n (%)
9 (13.0 %)
7 (29.1 %)
0.0714
WBC, 104/lL
8495 [6185–11340]
8195 [5301–11928]
0.8589
CRP, mg/dL
6.32 [3.21–8.90]
5.99 [1.96–11.52]
0.9044
BUN, mg/dL
12.9 [9.7–16.7]
23.6 [14.1–29.9]
0.0003
sCr, mg/dL
0.77 [0.63–0.93]
0.94 [0.64–1.29]
0.0735
sAlbumin, mg/dL
2.5 [2.2–2.9]
3 [2.6–3.3]
0.0057
0.66 [0.56–0.79]
0.62 [0.47–0.98]
0.853
6.0 [5.0–8.5] 114.2 [86.4–171.3]
11.5 [8.5–21] 244.7 [188.5–471.0]
Day 1 following ICU admission
sCr (ICU discharge), mg/dL Outcome ICU stay, day ICU stay, h
\0.0001 \0.0001
RRT during ICU stay, n (%)
0
2 (8.3 %)
0.0153
Hospital mortality, n (%)
2 (2.9 %)
1 (4.2 %)
0.762
The baseline Cr level was measured approximately 1–2 months before ICU admission. The values are expressed as the median [interquartile range] BMI body mass index, NSAIDs non-steroidal anti-inflammatory drugs, ICU intensive care unit, eGFR estimated glomerular filtration rate, WBC white blood cell, CRP C-reactive protein, BUN blood urea nitrogen
AKI was categorized according to the AKIN classification [24], as follows: stage 1, an increase in sCr of 0.3 mg/dL or 1.5–2 times the baseline level or a reduction in urine output (\0.5 mL/kg/h) for 6 h; stage 2, an increase in sCr 2–3 times the baseline level or a reduction in urine output (\0.5 mL/kg/h) for 12 h; stage 3, an increase in sCr more than 3 times the baseline level or a sCr level greater than 4.0 mg/dL after a rise of at least 0.5 mg/dL and/or the need for acute RRT or a reduction in urine output (\0.5 mL/kg/ h) for 24 h or anuria for 12 h. The baseline renal function of all 93 patients was assessed based on a retrospective analysis of the sCr levels recorded 1–2 months prior to ICU admission. Additionally, the sCr level at the time of ICU discharge
was evaluated. The GFR was estimated according to the Modification of Diet in Renal disease equation for Japanese [25]. In the AKI group, established AKI was defined as a diagnosis of AKI by Day 1 (the day after ICU admission), and newly diagnosed AKI was defined as a diagnosis of AKI after Day 1, and with subsequent fulfillment of the AKIN criteria within 1 week.
Measurement of urinary biomarkers After ICU admission (Day 0), urinary collection was initiated until the following morning (Day 1). Serum
123
Clin Exp Nephrol Table 2 Estimated causes of the ICU admission
MOF multiple organ failure
Estimated causes for the ICU admission
Non-AKI (n = 69)
AKI (n = 24)
Surgery for solid tumor
47
6
Liver transplantation
3
8
Surgery for benign disease
4
0
Cardiac surgery
5
0
Pneumonia, respiratory failure
4
3
Peritonitis
0
2
Abscess
2
0
Infective endocarditis, Myocarditis
2
1
Severe pancreatitis (MOF)
0
1
Ileus
0
1
Rupture of an abdominal aortic aneurysm
0
1
Hemorrhagic shock
0
1
Subarachnoid hemorrhage
2
0
samples were obtained on Days 1 and 3. The samples were stored at -80 °C until use soon after centrifugation. All samples were aliquoted and stored to avoid repeated cycles of freezing and thawing. Therefore, the duration of storage in the freezer did not differ between the groups. EIA for PGE2, 2,3-dinor-6-OXO-PGF1a and 11-dehydro-TXB2 Enzyme immunoassays (EIAs) of the urinary levels of human PGE2, 2,3-dinor-6-OXO-PGF1a and 11-dehydroTXB2 were performed using the EIA kit for each prostanoid according to the manufacturer’s instructions (Cayman Chemical, USA). All samples were examined in duplicate, and the mean value for an individual’s serum was utilized for the statistical analysis. The mean minimum detectable dose of PGE2 2,3-dinor-6-OXOPGF1a and 11-dehydro-TXB2 was 15.6, 78 and 15.6 pg/ mL, respectively. In each assay, we observed a proper standard curve using serial dilutions of recombinant human prostanoids as described in the manufacturer’s instructions. The stability of the urinary samples with respect to each prostanoid was confirmed after freezing and thawing (data not shown). Other clinical parameters The concentrations of sCr, blood urea nitrogen (BUN), white blood cells (WBCs) and C-reactive protein (CRP) were measured using routine laboratory methods (SRL, Inc., Okayama, Japan). The urinary levels of albumin, NAG and creatinine were also determined (SRL, Inc.), and the serum and urinary creatinine levels were measured according to the enzymatic colorimetric method.
123
Statistical analysis All values are expressed as proportions or the median [interquartile range]. Continuous variables were compared using the Wilcoxon rank-sum test, while categorical variables were expressed as proportions and compared using the Chi squared test. The correlation analyses were performed using Spearman’s test. The predictive performance of the urinary biomarkers was determined using an ROC curve analysis, and a p value of\0.05 was considered to be statistically significant. All statistical analyses were performed using the JMP version 9.0 software program (SAS Institute, Inc., Cary, NC, USA).
Results Characteristics of study groups Of the 93 patients, 24 (25.8 %) developed AKI within 7 days after ICU admission (Table 1). Among all AKI patients, fourteen (58.3 %) developed AKIN stage 1 disease, eight (33.3 %) developed AKIN stage 2 disease and two (8.3 %) developed AKIN stage 3 disease. The median age was 66 years in the non-AKI group and 61 years in the AKI group, although the difference was not statistically significant. The leading cause of ICU admission was surgical intervention in 92.5 % of the patients in the non-AKI group and 77.8 % of the patients in the AKI group. In the AKI group, two patients (7.4 %) required RRT and one patient died. The length of both ICU and hospital stay was significantly longer in the AKI group than in the non-AKI group. In this study, CKD was defined by the baseline eGFR under 60 mL/min/1.73 m2. There were 16 patients with CKD (n = 7 for AKI group, n = 9 for Non-AKI) as shown in Table 1. CKD stage of
Clin Exp Nephrol
(a) 6000
uPGE2/Cr (ng/gCr)
those patients is shown in Supplementary Table 1. As compared with patients in the CKD stage 3a, patients in the CKD stage 3b developed AKI more frequently. There were no differences with respect to age, BMI or the use of NSAIDs prior to admission to the ICU. In addition, the AKI group exhibited higher APACHE II scores than the non-AKI group, whereas the mean baseline eGFR values were similar between the groups.
r =-0.005 p =0.96
3000
0 0
Estimated causes of AKI
Associations between the urinary biomarkers and the fold increase in sCr
2.5
Fold increase of sCr (Day 1/Baseline)
(b) u2,3-dinor-6-OXO-PGF1α/Cr (x103,ng/gCr)
The two major causes of developing AKI in the hospital are prerenal disease and acute tubular necrosis (ATN), although AKI occurs due to multifactorial etiologies. In the present study population, AKI most commonly occurred in postoperative patients, particularly recipients of liver transplantation (Table 2).
1.25
120
r =0.57 p
ORIGINAL ARTICLE
The urinary levels of prostanoid metabolites predict acute kidney injury in heterogeneous adult Japanese ICU patients: a prospective observational study Haruyo Ujike-Omori • Yohei Maeshima • Masaru Kinomura • Katsuyuki Tanabe Kiyoshi Mori • Hiroyuki Watatani • Norikazu Hinamoto • Hitoshi Sugiyama • Yoshiki Sakai • Hiroshi Morimatsu • Hirofumi Makino
•
Received: 2 October 2014 / Accepted: 2 February 2015 Ó Japanese Society of Nephrology 2015
Abstract Background Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients. Methods The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the Electronic supplementary material The online version of this article (doi:10.1007/s10157-015-1092-4) contains supplementary material, which is available to authorized users. H. Ujike-Omori Y. Maeshima (&) M. Kinomura K. Tanabe H. Watatani N. Hinamoto H. Makino Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan e-mail: [email protected] K. Mori Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan H. Sugiyama Center for chronic kidney disease and peritoneal dialysis, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Y. Sakai Ono Pharmaceutical Co., Ltd, Osaka, Japan H. Morimatsu Department of Anesthesiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1a), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined. Results Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6OXO-PGF1a/Cr (r = 0.57, p \ 0.0001) and 11-dehydroTXB2/Cr (r = 0.47, p \ 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1a/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1a/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC–area under the curve (AUC): 0.75]. Conclusions Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1a/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients. Keywords Acute kidney injury Prostaglandin Thromboxane ICU
Introduction Acute kidney injury (AKI) is frequently observed in critically ill patients in the ICU and is associated with increased mortality [1]. AKI occurs in 5–7 % of hospitalized patients and 20–25 % of ICU admissions [2]. Unfortunately,
123
Clin Exp Nephrol
the serum creatinine (sCr) level increases at later time points and cannot be used to detect or diagnose early renal tubular injury prior to a decline in the glomerular filtration rate (GFR). Therefore, the identification of more reliable and early biomarkers for AKI is required. To date, urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), L-type fatty acidbinding protein (L-FABP) and a number of other markers have been examined with respect to their role in the early and accurate detection of AKI [3–5]. Prostaglandins (PGs) are derived from the metabolism of arachidonic acid, with the first step being catalyzed by the cyclooxygenase (COX) system. PGs are produced at various sites in the kidneys and have been implicated to regulate glomerular hemodynamics, renin secretion and tubular transport [6]. Prostacyclin (prostaglandin I2: PGI2), a major PG, exerts vasoprotective effects, including vasodilation, inhibition of platelet aggregation and the proliferation of vascular smooth muscle cells [7]. Prostacyclindeficient mice with a genetic disruption in prostaglandin I2 synthetase (PGIS) develop renal fibrosis and arterial sclerosis [8], suggesting its involvement in the maintenance of a normal kidney structure. In addition, the renoprotective effects of prostacyclin and its analogs have been reported in various experimental models, including gentamycin-induced tubular injury [9], diabetic nephropathy [10–12] and unilateral ureteral obstruction [13, 14]. In contrast, thromboxane A2 (TXA2) exerts effects opposite to those of PGI2, in association with the development of vascular lesions [7]. PGE2 is one of the major prostanoids generated by the kidneys [15] and affects both vascular tone and the epithelial function. PGE2 also modulates renal sodium and water excretion [16]. PGI2 is rapidly metabolized into a nearly inactive product, 6-keto-PGF1a. Thromboxane is similar to prostaglandins in that its rate of production is relatively low in normal subjects and inhibiting its synthesis has little effect on the renal function [17]. Meanwhile, urinary prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1a) and TXA2 metabolite (11-dehydro-TXB2) are relatively stable and reflect the production of each prostanoid. In a previous report of 10 patients undergoing coronary artery bypass grafting, the urinary and plasma levels of TXB2 and 6-keto PGF1a increased, and a significant correlation (r = 0.87, p less than 0.01) was observed between the urinary NAG and TXB2 levels [18]. Low-dose prostaglandin E1 (PGE1), which has a similar function to that of PGE2, was also found to prevent deterioration of the renal function under surgical anesthesia in 109 adult patients [19]. Furthermore, patients with acute oliguric renal failure immediately after transplantation show high urinary PGE2 concentrations, and rejection crises are characterized by a twofold increase in urinary PGE2 excretion [20].
123
To date, the performance of urinary prostanoid metabolites for predicting AKI in critically ill patients has not been examined. Therefore, in the present study, we aimed to evaluate the potential of urinary prostanoid metabolites in diagnosing and predicting AKI in heterogeneous ICU patients.
Materials and methods Study design and population The current study was conducted as a prospective observational study. We prospectively collected data for adult patients [20 years of age admitted to the ICU at Okayama University Hospital, Okayama, Japan, between November 2010 and July 2011. Ninety-three Japanese patients were randomly enrolled in total, and written informed consent was obtained from each subject. However, if prior consent could not be obtained due to critical illness or the use of sedatives or anesthetics, delayed consent was obtained [21]. The study protocol was approved by the Institutional Ethics Review Board of Okayama University Hospital (No. 673). This study was registered with the Clinical Trial Registry of the University Hospital Medical Information Network (registration number: UMIN 000004503). Endstage renal disease (ESRD) was defined as chronic kidney failure treated with either dialysis or transplantation and non-dialyzed patients, whose baseline eGFR was less than 15 mL/min/1.73 m2. Patients with ESRD and those who were discharged within 24 h after admission to the ICU were excluded. The following clinical variables were evaluated: age, sex, body mass index (BMI), reason for admission (medical issue or type of surgery), complications of diabetes mellitus, a diagnosis of sepsis, as defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee [22], the use of contrast exposure within 48 h preceding ICU admission, prior medication with non-steroidal anti-inflammatory drugs (NSAIDs), the use of diuretics or human atrial natriuretic peptide (hANP) medications during the ICU stay, the initiation of RRT, in-hospital mortality and the length of in-hospital and ICU stay. Disease severity was evaluated according to the Acute Physiology and Chronic Health Evaluation (APACHE) II score within 24 h of ICU admission [23]. The primary outcome was the development of AKI within 7 days after ICU admission, according to the Acute Kidney Injury Network (AKIN) classification [24]. The presence of AKI was assessed daily by calculating the change in sCr from baseline to the maximum sCr level and based on the cumulative daily urine output. The severity of
Clin Exp Nephrol Table 1 Patient characteristics and clinical outcomes Non-AKI (n = 69, 74.2 %)
AKI (n = 24, 25.8 %)
Age, years
66.0 [59.0–71.5]
60 [52.5–68.7]
Male, n (%)
52 (75.4 %)
17 (24.6 %)
0.0077
BMI, kg/m2
21.6 [19.0–24.3]
24.0 [20.1–27.6]
0.0814
Medical
5 (7.3 %)
6 (25.0 %)
Elective surgery
59 (85.5 %)
14 (58.3 %)
Emergency surgery
5 (7.3 %)
4 (16.7 %)
Patient type, n (%)
p value (vs. Non-AKI) 0.075
0.018
APACHE II
12 [8.5–15]
14.5 [10–19.8]
0.0438
Diabetes, n (%)
13 (19.1 %)
7 (29.1)
0.304
Sepsis, n (%)
5 (7.2 %)
4 (16.7 %)
0.179
Contrast exposure in preceding 48 h, n (%) NSAIDs, n (%)
13 (18.8 %) 7 (10.1 %)
4 (16.7 %) 1 (4.17 %)
0.812 0.368
18 (26.1 %)
20 (83.3 %)
\0.0001 \0.0001
Medication used during ICU stay (initial 7 days), n (%) Furosemide
4 (5.8 %)
12 (50.0 %)
Baseline Cr, mg/dL
hANP
0.79 [0.68–0.93]
0.78 [0.62–0.97]
0.990
Baseline eGFR, mL/min per 1.73 m2
71.5 [61.7–86.2]
72.5 [49.2–92.3]
0.819
Baseline eGFR \60, n (%)
9 (13.0 %)
7 (29.1 %)
0.0714
WBC, 104/lL
8495 [6185–11340]
8195 [5301–11928]
0.8589
CRP, mg/dL
6.32 [3.21–8.90]
5.99 [1.96–11.52]
0.9044
BUN, mg/dL
12.9 [9.7–16.7]
23.6 [14.1–29.9]
0.0003
sCr, mg/dL
0.77 [0.63–0.93]
0.94 [0.64–1.29]
0.0735
sAlbumin, mg/dL
2.5 [2.2–2.9]
3 [2.6–3.3]
0.0057
0.66 [0.56–0.79]
0.62 [0.47–0.98]
0.853
6.0 [5.0–8.5] 114.2 [86.4–171.3]
11.5 [8.5–21] 244.7 [188.5–471.0]
Day 1 following ICU admission
sCr (ICU discharge), mg/dL Outcome ICU stay, day ICU stay, h
\0.0001 \0.0001
RRT during ICU stay, n (%)
0
2 (8.3 %)
0.0153
Hospital mortality, n (%)
2 (2.9 %)
1 (4.2 %)
0.762
The baseline Cr level was measured approximately 1–2 months before ICU admission. The values are expressed as the median [interquartile range] BMI body mass index, NSAIDs non-steroidal anti-inflammatory drugs, ICU intensive care unit, eGFR estimated glomerular filtration rate, WBC white blood cell, CRP C-reactive protein, BUN blood urea nitrogen
AKI was categorized according to the AKIN classification [24], as follows: stage 1, an increase in sCr of 0.3 mg/dL or 1.5–2 times the baseline level or a reduction in urine output (\0.5 mL/kg/h) for 6 h; stage 2, an increase in sCr 2–3 times the baseline level or a reduction in urine output (\0.5 mL/kg/h) for 12 h; stage 3, an increase in sCr more than 3 times the baseline level or a sCr level greater than 4.0 mg/dL after a rise of at least 0.5 mg/dL and/or the need for acute RRT or a reduction in urine output (\0.5 mL/kg/ h) for 24 h or anuria for 12 h. The baseline renal function of all 93 patients was assessed based on a retrospective analysis of the sCr levels recorded 1–2 months prior to ICU admission. Additionally, the sCr level at the time of ICU discharge
was evaluated. The GFR was estimated according to the Modification of Diet in Renal disease equation for Japanese [25]. In the AKI group, established AKI was defined as a diagnosis of AKI by Day 1 (the day after ICU admission), and newly diagnosed AKI was defined as a diagnosis of AKI after Day 1, and with subsequent fulfillment of the AKIN criteria within 1 week.
Measurement of urinary biomarkers After ICU admission (Day 0), urinary collection was initiated until the following morning (Day 1). Serum
123
Clin Exp Nephrol Table 2 Estimated causes of the ICU admission
MOF multiple organ failure
Estimated causes for the ICU admission
Non-AKI (n = 69)
AKI (n = 24)
Surgery for solid tumor
47
6
Liver transplantation
3
8
Surgery for benign disease
4
0
Cardiac surgery
5
0
Pneumonia, respiratory failure
4
3
Peritonitis
0
2
Abscess
2
0
Infective endocarditis, Myocarditis
2
1
Severe pancreatitis (MOF)
0
1
Ileus
0
1
Rupture of an abdominal aortic aneurysm
0
1
Hemorrhagic shock
0
1
Subarachnoid hemorrhage
2
0
samples were obtained on Days 1 and 3. The samples were stored at -80 °C until use soon after centrifugation. All samples were aliquoted and stored to avoid repeated cycles of freezing and thawing. Therefore, the duration of storage in the freezer did not differ between the groups. EIA for PGE2, 2,3-dinor-6-OXO-PGF1a and 11-dehydro-TXB2 Enzyme immunoassays (EIAs) of the urinary levels of human PGE2, 2,3-dinor-6-OXO-PGF1a and 11-dehydroTXB2 were performed using the EIA kit for each prostanoid according to the manufacturer’s instructions (Cayman Chemical, USA). All samples were examined in duplicate, and the mean value for an individual’s serum was utilized for the statistical analysis. The mean minimum detectable dose of PGE2 2,3-dinor-6-OXOPGF1a and 11-dehydro-TXB2 was 15.6, 78 and 15.6 pg/ mL, respectively. In each assay, we observed a proper standard curve using serial dilutions of recombinant human prostanoids as described in the manufacturer’s instructions. The stability of the urinary samples with respect to each prostanoid was confirmed after freezing and thawing (data not shown). Other clinical parameters The concentrations of sCr, blood urea nitrogen (BUN), white blood cells (WBCs) and C-reactive protein (CRP) were measured using routine laboratory methods (SRL, Inc., Okayama, Japan). The urinary levels of albumin, NAG and creatinine were also determined (SRL, Inc.), and the serum and urinary creatinine levels were measured according to the enzymatic colorimetric method.
123
Statistical analysis All values are expressed as proportions or the median [interquartile range]. Continuous variables were compared using the Wilcoxon rank-sum test, while categorical variables were expressed as proportions and compared using the Chi squared test. The correlation analyses were performed using Spearman’s test. The predictive performance of the urinary biomarkers was determined using an ROC curve analysis, and a p value of\0.05 was considered to be statistically significant. All statistical analyses were performed using the JMP version 9.0 software program (SAS Institute, Inc., Cary, NC, USA).
Results Characteristics of study groups Of the 93 patients, 24 (25.8 %) developed AKI within 7 days after ICU admission (Table 1). Among all AKI patients, fourteen (58.3 %) developed AKIN stage 1 disease, eight (33.3 %) developed AKIN stage 2 disease and two (8.3 %) developed AKIN stage 3 disease. The median age was 66 years in the non-AKI group and 61 years in the AKI group, although the difference was not statistically significant. The leading cause of ICU admission was surgical intervention in 92.5 % of the patients in the non-AKI group and 77.8 % of the patients in the AKI group. In the AKI group, two patients (7.4 %) required RRT and one patient died. The length of both ICU and hospital stay was significantly longer in the AKI group than in the non-AKI group. In this study, CKD was defined by the baseline eGFR under 60 mL/min/1.73 m2. There were 16 patients with CKD (n = 7 for AKI group, n = 9 for Non-AKI) as shown in Table 1. CKD stage of
Clin Exp Nephrol
(a) 6000
uPGE2/Cr (ng/gCr)
those patients is shown in Supplementary Table 1. As compared with patients in the CKD stage 3a, patients in the CKD stage 3b developed AKI more frequently. There were no differences with respect to age, BMI or the use of NSAIDs prior to admission to the ICU. In addition, the AKI group exhibited higher APACHE II scores than the non-AKI group, whereas the mean baseline eGFR values were similar between the groups.
r =-0.005 p =0.96
3000
0 0
Estimated causes of AKI
Associations between the urinary biomarkers and the fold increase in sCr
2.5
Fold increase of sCr (Day 1/Baseline)
(b) u2,3-dinor-6-OXO-PGF1α/Cr (x103,ng/gCr)
The two major causes of developing AKI in the hospital are prerenal disease and acute tubular necrosis (ATN), although AKI occurs due to multifactorial etiologies. In the present study population, AKI most commonly occurred in postoperative patients, particularly recipients of liver transplantation (Table 2).
1.25
120
r =0.57 p
