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URINARY LIVER-TYPE FATTY ACID-BINDING PROTEIN IN SEPTIC SHOCK: EFFECT OF POLYMYXIN B-IMMOBILIZED FIBER HEMOPERFUSION

Nakamura, Tsukasa*; Sugaya, Takeshi; Koide, Hikaru

doi: 10.1097/SHK.0b013e3181891131
Clinical Aspects
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We aimed to determine retrospectively whether urinary liver-type fatty acid-binding protein (L-FABP) levels are altered in patients with septic shock or severe sepsis without shock and whether polymyxin B-immobilized fiber (PMX-F) hemoperfusion affects these levels. Forty patients with septic shock, 20 patients with severe sepsis without shock, 20 acute renal failure (ARF) patients without septic shock (mean serum creatinine, 2.8 mg/dL), and 30 healthy volunteers were included in this study. Polymyxin B-immobilized fiber hemoperfusion was performed twice in 40 patients. In addition, 10 patients with septic shock without PMX-F treatment (conventional treatment) were also enrolled in this study. Their families did not choose PMX-F treatment. Thus, their informed consents to perform PMX-F treatment were not obtained. Septic shock or severe sepsis was defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee. Patients with septic shock were eligible for inclusion in the study if they had a definable source of infection and/or positive blood cultures. Patients with cardiogenic or hemorrhagic shock were excluded from the study. The patients were not randomly allocated to receive PMX-F treatment. Urinary and serum L-FABP levels were measured by enzyme-linked immunosorbent assay method. Plasma endotoxin levels in patients with septic shock were significantly higher than those in patients with severe sepsis (P < 0.05), patients with ARF (P < 0.001), and healthy subjects (P < 0.001). Urinary L-FABP levels in patients with septic shock were significantly higher than those in patients with severe sepsis without shock (P < 0.001), patients with ARF (P < 0.001), and healthy subjects (P < 0.001), whereas serum L-FABP levels showed no significant differences between patients with septic shock, patients with severe sepsis, patients with ARF, and healthy subjects. Urinary L-FABP was not correlated with serum L-FABP. Twenty-eight patients with septic shock survived, and 12 patients died. Polymyxin B-immobilized fiber treatment reduced plasma endotoxin levels (P < 0.01) and urinary L-FABP levels (P < 0.01). In 10 patients with septic shock without PMX-F treatment, L-FABP levels remained high 7 days after initiation of conventional treatment (P = 0.12). These results suggest that urinary L-FABP levels are significantly increased in patients with septic shock and that PMX-F treatment is effective in reducing these levels.

*Department of Medicine, Shinmatsudo Central General Hospital, Chiba; Research Unit for Organ Regeneration, Riken Kobe Institute, Hyogo; and Department of Medicine, Koto Hospital, Tokyo, Japan

Received 6 Nov 2007; first review completed 26 Nov 2007; accepted in final form 31 Jul 2008

Address reprint requests to Hikaru Koide, MD, Department of Medicine, Koto Hospital, 6-8-5 Ojima, Koto-ku, Tokyo 136-0072, Japan. E-mail: hkoide@koto-hospital.or.jp.

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INTRODUCTION

Liver-type fatty acid-binding protein (L-FABP) is a member of the FABPs that are involved in the intracellular transport of bioactive fatty acids and participates in intracellular signaling pathways, cell growth, and differentiation (1). Free fatty acids are bound to albumin, filtered through the glomeruli, and reabsorbed in the proximal tubules (2). Free fatty acids bound to albumin therefore could play a role in the development of tubulointerstitial damage. In humans, L-FABP of 14.4 kd is expressed in the proximal tubules (3). Kamijo et al. (4) have reported that the level of urinary L-FABP reflects the extent of tubulointerstitial damage and that, of the factors tested, only urinary L-FABP correlates with the progression of chronic kidney disease. Contrast medium-induced nephropathy has been reported to be due to involvement of renal ischemic injury, tubular epithelial cell toxicity, or immunologic reactions (5). We reported previously that urinary L-FABP levels can serve clinically as a predictive marker for contrast medium-induced nephropathy (6). However, little is known about urinary L-FABP regulation in cases of acute renal damage induced by septic shock.

Septic shock and multiple organ failure (MOF), including acute renal failure (ARF), are leading causes of mortality and morbidity in the critical care setting. Endotoxin is considered one of the principal biological substances that cause gram-negative septic shock (7). Systemic hypotension resulting in renal ischemia is a contributing but not the sole factor in septic ARF (8). Intrarenal vasoconstriction, owing to an imbalance between vasodilatory and vasoconstrictory substances, results in a decline in renal blood flow and abnormalities in intrarenal blood flow distribution (9). Inflammatory cells infiltrate the kidney, causing local damage by release of oxygen radicals and further production of inflammatory cytokines (8). Recently, peritubular capillary dysfunction is an early event that contributes to tubular stress and renal injury and LPS-provoked peritubular capillary dysfunction (10). Renal proximal tubular epithelial cells (L-FABP-producing cells) are targets for LPS during sepsis/septic shock (11). However, treatment of septic shock ARF is as yet exclusively supportive.

Polymyxin B-immobilized fiber (PMX-F) treatment has been applied to treat severe sepsis in more than 30,000 patients in Japan since 1994 and is covered by the National Health Insurance System (12). We and other investigators have reported that PMX-F treatment is safe and effective for patients with septic shock (7, 12, 13). We hypothesized that urinary L-FABP may be associated with septic shock and that PMX-F treatment may be effective in reducing urinary L-FABP levels, in part, because of reduction of endotoxin. In this study, we examined the clinical relevance of urinary excretion of L-FABP in patients with septic shock and the effect of PMX-F treatment on its levels.

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PATIENTS AND METHODS

Patients

The present study included 40 patients with septic shock (28 men and 12 women; mean age, 58.5 years) and 20 patients with severe sepsis without shock (15 men and 5 women; mean age, 56.0 years) as defined by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (14). Twenty patients with ARF without septic shock (14 men and 6 women; mean age, 56.5 years; mean serum creatinine (Cr), 2.8 mg/dL; hypovolemia, n = 8; drug induced, n = 4; cholesterol embolism, n = 2; rhabdomyolysis, n = 2; and unknown, n = 4) and 30 age-matched healthy volunteers (21 men and 9 women; mean age, 55.5 years). This study was approved by the local ethics committee, and informed consent was obtained from each participant or his/her family. Efficacy of therapy is based on 28-day survival from study enrollment (14). The severity of illness was assessed according to the Acute Physiology and Chronic Health Evaluation (APACHE)-II score within 24 h after admission to the medical intensive care unit. The MOF score was calculated as described by Knaus et al. (15). This score is defined as the total number of failing organ systems. Patients were eligible for inclusion in the study if they had a definable source of infection and/or positive blood cultures. Patients with cardiogenic or hemorrhagic shock were excluded from the study. All patients had already been treated with antibiotics at the time of PMX-F treatment. Patients taking either steroids, immunosuppressive agents, or nonsteroidal anti-inflammatory agents were excluded. Patients with liver disease, malignancy, or heart or renal disease, pregnant women, and patients younger than 18 years were excluded from the study. All patients were transferred from other hospitals or clinics as critically ill patients. Before enrollment, no patient had proteinuria or hematuria; 24-h creatinine clearance (Ccr) was more than 90 mL/min, and the serum Cr level was less than 1.2 mg/dL from the data of other hospitals or clinics.

The PMX-F treatment was performed twice with a 24-h interval in the 40 eligible patients who met the criteria of septic shock. The mean time from admission to PMX-F treatment was 3.5 ± 2.0 days because this is the response time of conventional treatment. Blood and urine samples were collected before the first PMX-F treatment and immediately after the second PMX-F treatment. The hemoperfusion by PMX-F was performed as described previously (7, 12, 16). Polymyxin B-immobilized fiber column was commercially available in Japan (Toray Medical Co Ltd, Tokyo, Japan). Polymyxin B-immobilized fiber comprises PMX bound by means of its amino group to α-chloracetamide methyl polystyrene fibers, at a mean ratio of 7 mg of PMX per 1 g of fiber. The adsorbent column designed for clinical use is a 170-mL polypropylene tube containing 53 g of PMX-F bound covalently to 370 mg of PMX. In the present study, access to blood for direct hemoperfusion with PMX-F was obtained via a double-lumen catheter (Arrow International Inc; Reading, Pa) inserted into the femoral vein by Seldinger method. Direct hemoperfusion was carried out for 2 h at a flow rate of 80 to 100 mL/min. Blood endotoxin levels were determined by the Endospecy (Seikagaku Corporation, Tokyo, Japan) test (16); the normal upper limit is 9.8 pg/mL. Urinary samples were obtained from all patients. Urinary N-acetyl-β-d-glucosaminidase (NAG) was measured by colorimetric assay, with 3-cresolsulfonaphthalein-N-acetyl-β-d-glucosaminide used as a substrate. This substrate is hydrolyzed by NAG with the release of 3-cresolsulfonaphthalein sodium salt quantitated photometrically at 580 nm. After 7 days, five patients were dialyzed because of progressive renal failure. Blood access for dialysis was obtained in the same manner as for PMX-F treatment. Hemodialysis was carried out for 3 h at a flow rate of 100 to 120 mL/min. The patients were not randomly allocated to receive PMX-F treatment. We measured the changes in urinary L-FABP levels in 10 patients with ARF with septic shock without PMX-F treatment whose families did not choose PMX-F treatment.

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L-FABP assay

BALB/C mice were subcutaneously injected once with 50 μg of purified recombinant human L-FABP in Freund complete adjuvant, and the same dose was injected again after 2 weeks. We prepared recombinant human L-FABP using the fusion plasmid system (pMAL-cRI) (17). Spleen cells from immunized mice were fused with murine myeloma P3/X63-AG86.5.3 cells (18). We selected hybridomas in a hypoxanthine aminopterin thymidine medium and screened for antibody production using an enzyme-linked immunosor bent assay and a purified recombinant L-FABP-coated plate. We obtained 18 positive clones by limiting dilution. Expanded cultures from two hybridomas, FABP-2 and FABP-L, were injected into the peritoneal cavities of pristine-primed mice, after which we collected ascitic fluid and fractionated it into IgG by means of protein A column chromatography. The monoclonal antibody (mAb) FABP-2 was conjugated to horseradish peroxidase with the use of succinimidyl-(N-maleimidomethyl) cyclohexane-1-carboxylate, according to the instructions of the manufacturer (Pierce Chemical Co, Rockford, Ill). We coated 96-well microtiter plates with 10 mg/L mAb FABP-L and incubated them overnight. Unreacted sites were blocked with phosphate-buffered saline (PBS) containing 10 g/L bovine serum albumin (BSA) overnight. The plates were washed three times with PBS containing 0.5 g/L Tween-20 with 1 g/L BSA and then dried. We incubated 100 μL of properly diluted standards or samples in the wells of each plate at room temperature for 1 h. They were then washed four times with PBS containing 0.5 g/L Tween-20 and allowed to react with 100 μL of horseradish peroxidase-conjugated FABP-2 for 1 h. After four more washes, 100 μL of enzyme substrate (o-phenylenediamine/H2O2) solution was reacted at room temperature for 30 min, after which the reaction was terminated with the addition of 100 μL of 2 mol/L sulfuric acid. Absorbance was measured at 492 nm on a microplate reader. We prepared standards for the assay by measuring the protein concentration of purified recombinant L-FABP according to Lowry method and adjusting it to make up a series ranging from 0 to 400 ng/mL with PBS containing 10 g/L BSA. The detection antibody has been evaluated in Western blots to test for its specificity as reported previously (4). The enzyme-linked immunosorbent assay kit of L-FABP is now commercially available (CIMIC Co, Ltd, Tokyo, Japan). Interassay coefficient of variation was less than 15%, and intra-assay coefficient of variation was less than 10%.

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Statistical analysis

Data are expressed as mean ± SD. Linear regression analysis was used to evaluate correlations between the two variables. Stepwise multiple regression was performed to evaluate dependency between variables. To analyze differences in clinical variables between the patient and subject group, we used the Mann-Whitney U test for unpaired data and the Wilcoxon rank sum test for paired data. In addition within-group statistical comparisons were by one-way ANOVA followed by the Newman-Keuls post hoc test. P < 0.05 was considered statistically significant. Differences between two groups were evaluated by two-way ANOVA combined with the Newman-Keuls post hoc test.

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RESULTS

Clinical characteristics of the 50 patients with septic shock treated with (n = 40) or without (n = 10) PMX-F treatment are shown in Table 1. The 28-day survival rate was 70%. Patients with septic shock had high blood endotoxin levels and marked hypotension. The effects of PMX-F treatment on systemic hemodynamics in patients with septic shock are shown in Table 2. Polymyxin B-immobilized fiber treatment resulted in a significant increase in both systolic and diastolic blood pressure and a significant decrease in hyperdynamic circulation (cardiac output and cardiac index) in patients with septic shock. Polymyxin B-immobilized fiber treatment ameliorated serum Cr levels, 24-h Ccr and urinary NAG in patients with septic shock. Table 3 shows urinary and serum L-FABP levels. Urinary L-FABP levels were significantly higher in patients with septic shock (PMX-F treatment group) (1,860 ± 1,260 μg/g Cr) than in healthy subjects (4.2 ± 2.4 μg/g Cr; P < 0.001), in patients with ARF (120 ± 84 μg/g Cr; P < 0.001), and in patients with severe sepsis (248 ± 100 μg/g Cr; P < 0.001). In contrast, serum L-FABP levels in patients with septic shock (16.0 ± 6.2 ng/mL) (PMX-F treatment group) were slightly higher than those in patients with severe sepsis (13.0 ± 5.2 ng/mL), in patients with ARF (12.2 ± 4.2 ng/mL), and healthy subjects (6.8 ± 2.2 ng/mL), but statistically not significant. Urinary L-FABP level was not correlated with serum L-FABP levels (r = 0.224, P = 0.124). In addition, urinary L-FABP levels showed no correlation with serum Cr (r = 0.280, P = 0.135), urinary protein (r = 0.196, P = 0.441), urinary NAG (r = 0.550, P = 0.058), APACHE II score (r = 0.260, P = 0.166), and MOF score (r = 0.209, P = 0.267). Urinary L-FABP levels showed no correlation with the need for dialysis. Urinary L-FABP level was correlated only with plasma endotoxin levels (r = 0.827, P = 0.018). These data (n = 40) are summarized in Table 4. Changes in plasma endotoxin and urinary and serum L-FABP levels by PMX-F treatment are shown in Table 5. Polymyxin B-immobilized fiber treatment significantly reduced plasma endotoxin levels (P < 0.01) and urinary L-FABP levels (P < 0.01), but not serum L-FABP levels.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 3

TABLE 3

TABLE 4

TABLE 4

TABLE 5

TABLE 5

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DISCUSSION

In the present study, we offer the first report that urinary L-FABP levels were significantly higher in patients with septic shock than in healthy subjects, in patients with ARF without septic shock, and in patients with severe sepsis without shock. Polymyxin B-immobilized fiber treatment reduced urinary L-FABP levels in the patients with septic shock. Conventional treatment without PMX-F treatment did not reduce urinary L-FABP levels in patients with septic shock, suggesting that lower urinary L-FABP levels may be due to PMX-F treatment, not come from natural history of patients with septic shock. However, this is not a randomized controlled trial as described in Patients and Methods.

In humans, two types of FABP are localized in the kidney (3). One, the liver type, is expressed in the proximal tubules; the other, the heart type, is expressed in the distal tubules. Hayashida et al. (19) reported an inverse correlation between urinary H-FABP levels and the Left Ventricular Stroke Work Index in patients undergoing cardiac surgery. Liver-type fatty acid-binding protein, a small protein of 14.4 kd, is a carrier protein that transports fatty acids to mitochondria or peroxisomes, where fatty acids are metabolized by way of β-oxidation. Transcription of the L-FABP gene is promoted by free fatty acids (20). Liver-type fatty acid-binding protein transports free fatty acids from the cytosol to the nucleus (21) and interacts with the nuclear protein, peroxisome proliferator-activated receptor, which is a nuclear target for free fatty acids and initiates gene expression of enzymes involved in lipid metabolism (22, 23). Liver-type fatty acid-binding protein may play an important role in fatty acid metabolism in the proximal tubules.

Kamijo et al. (4) have reported that urinary L-FABP has potential as a clinical marker for predicting and monitoring the progression of chronic glomerular disease. Tubulointerstitial damage induced by lipid toxicity may be provoked not only by proteinuria but also by other stressors including ischemia and toxins (24, 25). We hypothesized that renal ischemia extending to the proximal tubule tends to overload fatty acids in the cytoplasm and thereby damage tubules by the release of various mediators. Kamijo et al. (4) have reported a significant correlation between urinary L-FABP and urinary protein, suggesting that urinary protein accelerates excretion of L-FABP from the proximal tubules. In the present study, we did not detect a correlation between urinary L-FABP levels and urinary protein levels in patients with septic shock. Therefore, L-FABP regulation in septic shock may differ from that in chronic glomerular disease. In addition, we did not find correlation between urinary L-FABP levels and urinary NAG levels in patients with septic shock. Urinary NAG is used widely as a marker of tubular renal function (24). Urinary L-FABP seems to be regulated by a different mechanism than urinary NAG in patients with septic shock. We did not find any correlation between L-FABP levels and APACHE II score or MOF score. Systemic activation of various mediators and compensatory mechanisms affect the systemic circulation and renal perfusion in sepsis. Within the kidney, both vasoconstrictive and vasodilative mediators are generated, and the balance between them ultimately dictates renal hemodynamics. An imbalance can often result in renal hypoperfusion, a major cause of the development of renal failure (25). In the present study, we did not find a relation between serum Cr levels and urinary L-FABP levels. The mechanisms are unknown.

Sugaya et al. (26) previously assessed peritubular capillary images obtained by intravital CCD videomicroscopy in the posttransplant kidney. The slower the peritubular blood flow, the higher the urinary L-FABP level, and the highest level of urinary L-FABP in the early postischemic period was closely related to the renal ischemic time. It was speculated that urinary L-FABP can serve as a sensitive marker of renal ischemic events. However, it is very difficult to examine the peritubular blood flow in patients with septic shock. In animal models, changes in vascular permeability are thought to be important in the pathogenesis of sepsis-induced organ injury (27). Increased vascular permeability can cause compression of peritubular capillaries and reduced microvascular flow (28). Increased microvascular permeability and global worsening of renal microperfusion and tubular hypoxia might be responsible for developing ARF in cecal ligation and puncture-induced ARF model (28). The same events may occur in human septic shock ARF. In the present study, we showed that L-FABP levels in patients with septic shock are significantly higher than those in patients with ARF without septic shock. It is important to discuss whether other causes of renal ischemia such as hypovolemia or cardiogenic shock will also increase the urinary release of L-FABP. In the present study, we showed that patients with ARF with hypovolemia had lower L-FABP levels when compared with patients with septic shock. In addition, we have recognized that urinary L-FABP levels in cardiogenic shock by acute myocardial infarction were less than 100 μg/g Cr (data not shown). Therefore, very high urinary L-FABP levels may be specific to septic shock.

The liver contains L-FABP alone, but coexpression of H-FABP (distal tubule) and L-FABP (proximal tubule) occurs in the kidney (29). I-FABP and L-FABP are found in the intestine. Kamijo et al. (30) have reported that mAb against L-FABP had no cross-reaction with other FABP families such as H-FABP and I-FABP. Recently, Kamijo et al. (31) have reported that urinary L-FABP level in patients with kidney disease was significantly higher than in patients with liver disease and healthy subjects and that urinary L-FABP levels in patients with liver disease were not significantly higher than in healthy subjects. In addition, the excretion rate of filtered serum L-FABP was only 0.2% ± 0.2% in kidney disease and 0.1% ± 0.2% in liver disease. Therefore, they suggested that serum L-FABP levels do not have an influence on urinary L-FABP levels. In the present study, we showed that urinary L-FABP levels were not correlated with serum L-FABP levels, suggesting that the main source of urinary L-FABP is the kidney.

Recently, Schefold et al. (32) have reported that simultaneously reducing circulating endotoxin and IL-6 levels by selective extracorporeal immunoadsorption improved organ system functions in septic shock. In Japan, PMX-F treatment has been applied to patients with severe sepsis under the health insurance system since 1994. Serious side effects have not been detected. Patient outcome is an important end point for the approval of new therapeutic treatments. Tani et al. (33) summarized the difference in survival rates between patients who received PMX-F treatment and those who received conventional therapy without PMX-F treatment. Despite the greater severity of illness in the PMX-F treatment group, the survival rate was higher than that of the control group (34).

Uriu et al. (7) have reported that PMX-F treatment is effective in ameliorating hemodynamic changes in patients with septic shock. In the present study, it is suggested that PMX-F treatment ameliorated hemodynamic factors and reduced plasma endotoxin levels and consequently urinary L-FABP levels in patients with septic shock. The precise mechanisms of these effects are still unclear. Recently, it has been shown that LPS provoked peritubular capillary dysfunction (10). LPS can exacerbate ischemic tubular injury and ARF (35). Renal proximal tubular epithelial cells are targets for LPS during sepsis/septic shock (11). We speculate that PMX-F treatment may be effective in reducing urinary L-FABP levels, in part, because of amelioration of tubular ischemia (hypoxia), amelioration of abnormal hemodynamic factors, and reduction of plasma endotoxin in patients with septic shock. Recently, Yamamoto et al. (36) have reported that, among the urinary markers, urinary L-FABP was the most closely correlated with the decrease of peritubular blood flow. In addition, using living-related transplantation, they have reported the efficacy of urinary L-FABP as a biomarker of peritubular ischemia occurring after renal transplantation and further reported that the initial urine L-FABP level of transplanted kidney was the biomarker directly reflecting clinical outcome in terms of hospital stay. In the present study, PMX-F treatment ameliorated serum Cr, 24-h Ccr and urine volumes. Therefore, it is possible that the reducing effects of PMX-F treatment on L-FABP could attenuate renal damage in patients with septic shock. Recently, we have reported that urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG; oxidative stress marker) seems to be associated with septic shock and that PMX-F treatment is effective in reducing urinary 8-OHdG levels in these patients (37). Oxidative stress is a consequence of critical illness including septic shock, and increased oxidative stress is associated with poor outcome (38). Li et al. (39) have reported that oxidative damages were positively related with LPS. Various stresses including oxidative stress to proximal tubules can lead to an overload of fatty acids and thereby damage tubules by the release of inflammatory factors. We found the co-relationship between urinary 8-OHdG and urinary L-FABP levels (data not shown). Thus, the reduced L-FABP in urine by PMX-F treatment is, in part, due to decline of oxidative stress.

Recently, Lerolle et al. (40) have reported that Doppler-based determination of resistive index on day 1 in patients with septic shock may help identify those who will develop ARF. We are now studying the correlation between urinary L-FABP and resistive index and whether PMX-F treatment affects resistive index in patients with septic shock. The timing of PMX-F treatment and the duration of the effect, particularly in relation to the level of renal function, are important issues. Some investigators have reported that PMX-F treatment should be started as soon as possible before the patient's condition deteriorates (41). They concluded that PMX-F treatment should be applied before any other type of blood purification therapy. Recently, Hirasawa et al. (42) have reported that cytokine removal with continuous hemodiafiltration (CHDF) would be effective for the treatment of severe sepsis and septic shock. However, we did not perform CHDF treatment in the present study. It would be needed to examine the effect of CHDF on urinary L-FABP excretion in the future.

These results suggest that urinary excretion of L-FABP likely serves as a useful indicator of tubular injury in patients with septic shock and that PMX-F treatment is effective in reducing tubular injury, in part, because of reducing plasma endotoxin in these patients. Histopathologic data would be needed to confirm tubulointerstitial injuries in patients with ARF with septic shock in the future. Our data may bring new insight into our understanding of the clinical implications of L-FABP expressed in the proximal tubules in septic shock.

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Keywords:

Fatty acid-binding protein; septic shock; polymyxin B-immobilized fiber; renal proximal tubule

©2009The Shock Society