- Email: [email protected]
586 RENAL NKCC2 TRANSPORTER TRIGGERS ENHANCED URINARY AMMONIA EXCRETION DURING INDUCED HYPERAMMONEMIA: A NOVEL TARGET OF THERAPY FOR HEPATIC ENCEPHALOPATHY?
POSTERS suggesting that mild edema is noticeable in spite of ongoing osmotic regulation. Conclusion: Osmotic regulation is ongoing in the CNS of rats with biliary cirrhosis as shown using longitudinal, in vivo high resolution spectroscopy. Mild brain edema is noticeable in spite of osmoregulation and before the presence of clinical symptoms. 584 ASSOCIATIONS BETWEEN BAROREFLEX SENSITIVITY, CARDIOVASCULAR REGULATION AND CENTRAL HYPOVOLAEMIA IN CIRRHOSIS AND PORTAL HYPERTENSION C. Mortensen1 , J.L. Madsen2 , F. Bendtsen1 , S. Møller2 . 1 Department of Medical Gastroenterology, 2 Centre of Functional and Diagnostic Imaging and Research, Section of Clinical Physiology and Nuclear Medicine, Hvidovre Hospital, Hvidovre, Denmark E-mail: [email protected] Background and Aims: Patients with cirrhosis often develop extrahepatic complications that affect the regulation of the circulation. Arterial vasodilatation leads to arterial hypotension and abnormal distribution of the blood volume with central hypovolaemia and a cardiac dysfunction described as cirrhotic cardiomyopathy. The control of the arterial blood pressure (MAP) and heart rate (HR) is abnormal and the responses to changes in posture are impaired with reduced baroreflex sensitivity (BRS). This study was undertaken to compare autonomic and cardiac responsiveness in cirrhosis and healthy individuals in relation to degree of portal hypertension, liver dysfunction, and central volaemia. Methods: Ten patients with cirrhosis (Child class A/B/C: 4/4/2) and 10 matched controls were included in the study. We assessed autonomic and cardiac function, including MAP, HR, BRS, stroke volume (SV) and end-diastolic index (EDI) by a Task ForceR Monitor V2.2-system in all patients and controls at baseline after 1 h rest in the supine position and after passive tilt for 1 /2 h. BRS was determined by the sequence method. The patients underwent a full haemodynamic examination with determination of portal pressure (mean hepatic venous gradient (HVPG: 14.4±4.7 mmHg), indocyanine green clearance (ICG), and central blood volume (CBV). Results: Supine HR was significantly higher in cirrhotic patients than in the controls (p < 0.01). SV (56 vs 85 ml, p < 0.01) and EDI (51 vs 71 ml/sqm, p < 0.03) were significantly reduced in the patients. BRS was significantly lower in patients (9.8 vs 19.9 ms/mmHg, p < 0.02). During tilting, HR increased in both patients and controls (p < 0.001) without differences between the two groups. In contrast, MAP, SV, and BRS changed only in the controls. In the patient group EDI correlated significantly with HVPG (r = −0.63, p < 0.05), MAP (r = −0.73, p < 0.02) and ICG (r = 0.70, p < 0.03). BRS correlated with MAP (r = −0.61, p < 0.04) and CBV (0.86, p < 0.0001). Conclusions: Patients with cirrhosis exhibit impaired cardiovascular regulation and cardiac function relating to the degree of portal hypertension and liver dysfunction, and a differential autonomic response to passive tilting. The relation between the reduced BRS and central hypovolaemia suggests that impaired cardiovascular control is involved in the central haemodynamic changes in cirrhosis.
585 CARDIAC ADRENERGIC FUNCTION ASSESSED BY 123 I-METAIODOBENZYL/GUANIDINE MYOCARDIAL SCINTIGRAPHY IN PATIENTS WITH CIRRHOSIS C. Mortensen1,2,3 , J.L. Madsen2,3 , F. Bendtsen1,3 , S. Møller2,3 . 1 Department of Gastroenterology, 2 Department of Clinical Physiology and Nuclear Medicine, Centre of Functional Imaging and Research, Hvidovre Hospital, 3 Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark E-mail: [email protected] Background and Aims: Autonomic and cardiac dysfunction is frequent in cirrhosis, and includes impaired baroreflex sensitivity in the setting of increased sympathetic nervous (SN) activity. The recently described cirrhotic cardiomyopathy encompasses latent diastolic and systolic dysfunction as well as prolonged QT-interval. 123 I-metaiodobenzylguanidine (MIBG) is a physiologic analogue of noradrenaline. It reflects noradrenaline concentrations, storage, release and uptake and thereby cardiac sympathetic neuronal function. This can be quantified by the heart/mediastinum (H/M) ratio and washout-rates determined by a myocardial scintigraphy. In patients with heart failure, these variables have been shown to predict survival and cardiac events. In this study we aimed to investigate cardiac sympathetic neuronal function in cirrhosis by MIBG scintigraphy. Methods: Ten patients with cirrhosis and 10 age- and sex-matched controls participated in the study. 15 and 240 minutes after intravenous injection of 200 MBq of MIBG, planar recordings of thorax were produced by scintigraphy. Washout rate (WOR) was calculated as the difference in myocardial counts in early and late scintigrams, corrected for mediastinal background counts and radioactive decay. Patients underwent liver vein catherization with splanchnic and systemic haemodynamic investigations and measurement of portal pressure. Results: Patients had significant portal hypertension (mean HVPG =16 mmHg) as well as reduced systemic vascular resistance (mean 1244 dyn x S/cm5 ). MIBG-scintigraphy revealed significantly increased washout rate in patients with cirrhosis (19.5% (2–22)), compared to controls (10.5% (11–29), P = 0.005). Early and late heart/mediastinal rates did not differ in patients or controls. In the cirrhotic patients, WOR correlated significantly with central circulation time, an estimate of central hypovolaemia (r = −0.64, P < 0.05) and QTF interval (r = 0.71, p = 0.01). Conclusions: Increased WOR by MIBG scintigraphy in cirrhosis reflects abnormal cardiac sympathetic function that seems associated with changes in central haemodynamic regulation and cardiac conductance abnormalities. MIBG scintigraphy in cirrhotic patients can be a useful tool for the assessment of autonomic dysfunction and merits further research as a potential marker of cirrhotic haemodynamic derangement and cardiomyopathy. 586 RENAL NKCC2 TRANSPORTER TRIGGERS ENHANCED URINARY AMMONIA EXCRETION DURING INDUCED HYPERAMMONEMIA: A NOVEL TARGET OF THERAPY FOR HEPATIC ENCEPHALOPATHY? L. Mpabanzi1,2,3 , D. Dhar2 , C. Dejong1 , R. Jalan3 , S. Olde Damink1,2 . 1 Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands; 2 Hepato-Pancreato-Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, 3 Liver Failure Group, UCL Hepatology, Royal Free Hospital, University College London, University College London and Royal Free Hospital, London, UK E-mail: [email protected] Background and Aims: The kidney plays a major role in the hyperammonemia seen after an upper gastrointestinal bleed in patients with cirrhosis. In the kidney, ammonia is synthesized by
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POSTERS proximal tubular cells, after which 40–80% is reabsorbed in the medullary thick ascending limb (MTAL) of Henle’s loop. Urinary renal ammonia excretion is mainly regulated by ammonia reabsorption via the co-transporter NKCC2 in the MTAL. NKCC2 accounts for more than half of the response of increased urinary ammonia excretion that occurs during chronic metabolic acidosis. This study aims at describing renal ammonia handling and expression of NKCC2 in a model of induced hyperammonemia. Methods: Male rats were fed a hyperammonemic diet (mixture of amino acids mimicking hemoglobin) for 7 consecutive days (HD group). The control group was fed ad libitum (AL group). Arterial and renal vein blood was collected and para-amino hippuric acid was used to determine renal blood flow. The ureter was cannulated to collect urine samples. Expression of renal NKCC2 was measured using immunohistochemistry. Results: The hyperammonemic diet successfully increased arterial ammonia levels in the HD group (HD-group: 85.4 (40.1–121.4) mmol/L and AL-group: 50.6 (20.0–114.4) mmol/L (p = 0.04)). Total renal ammoniagenesis was significantly increased in the HD group [239.41 (144.3–484.9) nmol/100bw/min vs 140.6 (40.1– 333.5) nmol/100bw/min]. Urinary ammonia excretion was 167.1 (25.8–411.9) nmol/100bw/min in the HD group and 58.5 (32.2– 63.0) nmol/100bw/min in the AL group (p = 0.03). The kidney increased the amount of ammonia excreted via the urine in the hyperammonemic HD-group (urinary ammonia excretion ALgroup: 13.2 (3.7–49.9)% of total renal ammoniagenesis and HDgroup 57.1 (23.8–66.5)%. Immunohistochemistry showed a marked overexpression of the renal NKCC2 in the HD group. The pH in the HD group was 7.35 (7.02–7.47) and 7.39 (7.33–7.45) in the AL group (p > 0.05). Conclusion: The kidneys are important in regulating ammonia homeostasis and respond by increased urinary ammonia excretion during hyperammonemia which is associated with increased expression of the NKCC2 co-transporter. NKCC2 may be a novel target for the treatment of hyperammonemia and subsequently hepatic encephalopathy. 587 CHARACTERIZATION OF MACROPHAGES FROM ASCITIC FLUID OF CIRRHOTIC PATIENTS WITH SPONTANEOUS BACTERIAL PERITONITIS J.C. Nieto1 , E. Sanchez2 , C. Romero2 , E. Roman2 , C. Guarner2 , C. Juarez1 , G. Soriano2 , S. Vidal1 . 1 Dep. Immunology of Hospital S. Pau & Institut Rec. Hospital S. Pau, 2 Dep. Gastroenterology of Hospital S. Pau., Barcelona, Spain E-mail: [email protected] Background and Aim: Spontaneous bacterial peritonitis (SBP) is a frequent and life-threatening complication in cirrhotic patients with ascites. Diagnosis of SBP is established when the number of neutrophils in ascitic fluid exceeds 250/mm3 . However, the inflammatory status of macrophages from ascitic fluid during SBP is not well known. The aim was to analyze the phenotype of macrophages in ascitic fluid from cirrhotic patients with and without SBP. Patients and Methods: Cells were isolated from the ascitic fluid of: 12 cirrhotic patients with SBP either with positive (n = 7, CPSBP) or negative bacterial culture (n = 5, CN-SBP) at diagnosis and 5 days after starting antibiotic treatment; and cirrhotic patients with sterile ascites (n = 4, SA, <250 neutrophils/mm3 and negative culture). The functional phenotype of macrophages was analyzed by flow cytometry with antibodies against: HLA-DR, CD86, CD64 and CD11b; and scavenger receptors: CD36, CD163, CD206. The levels of TNF, IL-6 and IL-10 in ascitic fluid were determined by ELISA. Results: Macrophages from CP-SBP patients expressed the lowest expression of CD11b and HLA-DR, and the highest expression of
CD64 (Table 1). CP-SBP patients showed the highest percentage of CD36+ and the lowest percentage of CD163+ and CD206+ macrophages. Expression of all these markers on the CN-SBP macrophages was intermediate between CP-SBP and SA patients. The differences in CD11b, HLA-DR, CD163 and CD206 expression between CP-SBP, CN-SBP and SA macrophages were significantly reduced after treating SBP patients with antibiotics. IL-6 levels in ascitic fluid of CP-SBP and CN-SBP were comparable and significantly higher than in SA. However, IL-10 levels in CNSBP were slightly higher than in CP-SBP. Antibiotic treatment significantly reduced IL-6 levels in both groups of SBP patients. Table 1. Phenotype of macrophages from ascitic fluid
SA CP-SBP CN-SBP
CD11b MFI
HLA-DR MFI
CD64 MFI
CD36+ % cells
CD163 MFI
CD206+ % cells
8.41±1.67 4.54±0.74 * 6.19±0.86
20.30±4.37 7.50±1.08** 14.38±2.99†
0.50±0.05 2.837±0.65* 2.04±0.47*
26.10±6.11 46.37±6.07* 36.90±11.93
21±2.27 4.39±0.86*** 6.38±0.66***
70.32±5.80 36.79±8.90* 52.64±13.65
MFI: Mean Fluorescence intensity *p < 0.05, **p < 0.01, ***p < 0.001: t test SA vs CP-SBP or CN-SBP. † p < 0.05: t test CP-SBP vs CN-SBP.
Conclusions: We were able to establish the characteristic profile of macrophages from ascitic fluid of cirrhotic patients with or without SBP. The presence of viable bacteria reduced the antigen presentation activity and increased the phagocytic capability of macrophages from ascitic fluid of SBP patients. Macrophages of CPSBP or CN-SBP patients shifted towards a SA macrophage phenotype after antibiotic treatment. 588 ALBUMIN RESTORES RENAL BLOOD FLOW (RBF) AUTOREGULATION IN PATIENTS WITH REFRACTORY ASCITES AND ACUTE-ON-CHRONIC LIVER FAILURE (ACLF) THROUGH STABILIZATION OF ENDOTHELIAL FUNCTION J. O’Brien, R. Garcia-Martinez, L. Noiret, N. Davies, R. Mookerjee, R. Jalan. Hepatology, Liver Failure Group, University College, Institute of Hepatology, Royal Free Hospital, London, UK E-mail: [email protected] Background and Aims: Hemodynamic alterations in liver failure are associated with endothelial dysfunction, a pro-inflammatory state and sympathetic activation which lead to disturbed RBF autoregulation and renal failure. Albumin is a multifunctional protein that has been shown in several studies to prevent and treat renal dysfunction in patients with advanced cirrhosis and liver failure. We hypothesized that the beneficial effects of albumin in cirrhosis is likely to be through mechanisms in addition to volume expansion. The aims of the study were to investigate the effects of albumin on systemic and renal hemodynamics, inflammation and endothelial dysfunction in refractory ascites and patients with acute kidney injury (AKI) in the setting of ACLF. Patients and Methods: Twenty-two patients were recruited [Group 1, n = 12, refractory ascites; Group 2, n = 10 patients with AKI admitted with an acute deterioration of their liver function due to either alcoholic hepatitis or infection]. Both groups were treated with Albumin 60 g/d over 3–4 days. Cardiac output (CO) and renal blood flow (RBF) hemodynamics were measured. Endothelial dysfunction was assessed through measurement of von Willebrand factor (vWF) and serum nitrite (NO) levels. F2a Isoprostanes (F2a), resting neutrophil burst and Interleukin (IL)-6 were quantified as markers of oxidative stress, endotoxemia and inflammation respectively. Results: Albumin therapy was associated with significant improvements in hemodynamic parameters (increased RBF, MAP, decreased CO, HR; p < 0.05) which resulted in a shift in the RBF autoregulation curve towards normalization (Fig 1). In parallel, improvement of renal dysfunction (creatinine, creatinine clearance and Na+ excretion; p < 0.05 each), sympathetic activation (noradrenaline levels; P < 0.01), inflammation/oxidative stress (F2a
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585 CARDIAC ADRENERGIC FUNCTION ASSESSED BY 123 I-METAIODOBENZYL/GUANIDINE MYOCARDIAL SCINTIGRAPHY IN PATIENTS WITH CIRRHOSIS C. Mortensen1,2,3 , J.L. Madsen2,3 , F. Bendtsen1,3 , S. Møller2,3 . 1 Department of Gastroenterology, 2 Department of Clinical Physiology and Nuclear Medicine, Centre of Functional Imaging and Research, Hvidovre Hospital, 3 Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark E-mail: [email protected] Background and Aims: Autonomic and cardiac dysfunction is frequent in cirrhosis, and includes impaired baroreflex sensitivity in the setting of increased sympathetic nervous (SN) activity. The recently described cirrhotic cardiomyopathy encompasses latent diastolic and systolic dysfunction as well as prolonged QT-interval. 123 I-metaiodobenzylguanidine (MIBG) is a physiologic analogue of noradrenaline. It reflects noradrenaline concentrations, storage, release and uptake and thereby cardiac sympathetic neuronal function. This can be quantified by the heart/mediastinum (H/M) ratio and washout-rates determined by a myocardial scintigraphy. In patients with heart failure, these variables have been shown to predict survival and cardiac events. In this study we aimed to investigate cardiac sympathetic neuronal function in cirrhosis by MIBG scintigraphy. Methods: Ten patients with cirrhosis and 10 age- and sex-matched controls participated in the study. 15 and 240 minutes after intravenous injection of 200 MBq of MIBG, planar recordings of thorax were produced by scintigraphy. Washout rate (WOR) was calculated as the difference in myocardial counts in early and late scintigrams, corrected for mediastinal background counts and radioactive decay. Patients underwent liver vein catherization with splanchnic and systemic haemodynamic investigations and measurement of portal pressure. Results: Patients had significant portal hypertension (mean HVPG =16 mmHg) as well as reduced systemic vascular resistance (mean 1244 dyn x S/cm5 ). MIBG-scintigraphy revealed significantly increased washout rate in patients with cirrhosis (19.5% (2–22)), compared to controls (10.5% (11–29), P = 0.005). Early and late heart/mediastinal rates did not differ in patients or controls. In the cirrhotic patients, WOR correlated significantly with central circulation time, an estimate of central hypovolaemia (r = −0.64, P < 0.05) and QTF interval (r = 0.71, p = 0.01). Conclusions: Increased WOR by MIBG scintigraphy in cirrhosis reflects abnormal cardiac sympathetic function that seems associated with changes in central haemodynamic regulation and cardiac conductance abnormalities. MIBG scintigraphy in cirrhotic patients can be a useful tool for the assessment of autonomic dysfunction and merits further research as a potential marker of cirrhotic haemodynamic derangement and cardiomyopathy. 586 RENAL NKCC2 TRANSPORTER TRIGGERS ENHANCED URINARY AMMONIA EXCRETION DURING INDUCED HYPERAMMONEMIA: A NOVEL TARGET OF THERAPY FOR HEPATIC ENCEPHALOPATHY? L. Mpabanzi1,2,3 , D. Dhar2 , C. Dejong1 , R. Jalan3 , S. Olde Damink1,2 . 1 Department of Surgery, Maastricht University Medical Centre, and NUTRIM School of Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht, The Netherlands; 2 Hepato-Pancreato-Biliary and Liver Transplant Surgery, Royal Free Hospital, University College London, 3 Liver Failure Group, UCL Hepatology, Royal Free Hospital, University College London, University College London and Royal Free Hospital, London, UK E-mail: [email protected] Background and Aims: The kidney plays a major role in the hyperammonemia seen after an upper gastrointestinal bleed in patients with cirrhosis. In the kidney, ammonia is synthesized by
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POSTERS proximal tubular cells, after which 40–80% is reabsorbed in the medullary thick ascending limb (MTAL) of Henle’s loop. Urinary renal ammonia excretion is mainly regulated by ammonia reabsorption via the co-transporter NKCC2 in the MTAL. NKCC2 accounts for more than half of the response of increased urinary ammonia excretion that occurs during chronic metabolic acidosis. This study aims at describing renal ammonia handling and expression of NKCC2 in a model of induced hyperammonemia. Methods: Male rats were fed a hyperammonemic diet (mixture of amino acids mimicking hemoglobin) for 7 consecutive days (HD group). The control group was fed ad libitum (AL group). Arterial and renal vein blood was collected and para-amino hippuric acid was used to determine renal blood flow. The ureter was cannulated to collect urine samples. Expression of renal NKCC2 was measured using immunohistochemistry. Results: The hyperammonemic diet successfully increased arterial ammonia levels in the HD group (HD-group: 85.4 (40.1–121.4) mmol/L and AL-group: 50.6 (20.0–114.4) mmol/L (p = 0.04)). Total renal ammoniagenesis was significantly increased in the HD group [239.41 (144.3–484.9) nmol/100bw/min vs 140.6 (40.1– 333.5) nmol/100bw/min]. Urinary ammonia excretion was 167.1 (25.8–411.9) nmol/100bw/min in the HD group and 58.5 (32.2– 63.0) nmol/100bw/min in the AL group (p = 0.03). The kidney increased the amount of ammonia excreted via the urine in the hyperammonemic HD-group (urinary ammonia excretion ALgroup: 13.2 (3.7–49.9)% of total renal ammoniagenesis and HDgroup 57.1 (23.8–66.5)%. Immunohistochemistry showed a marked overexpression of the renal NKCC2 in the HD group. The pH in the HD group was 7.35 (7.02–7.47) and 7.39 (7.33–7.45) in the AL group (p > 0.05). Conclusion: The kidneys are important in regulating ammonia homeostasis and respond by increased urinary ammonia excretion during hyperammonemia which is associated with increased expression of the NKCC2 co-transporter. NKCC2 may be a novel target for the treatment of hyperammonemia and subsequently hepatic encephalopathy. 587 CHARACTERIZATION OF MACROPHAGES FROM ASCITIC FLUID OF CIRRHOTIC PATIENTS WITH SPONTANEOUS BACTERIAL PERITONITIS J.C. Nieto1 , E. Sanchez2 , C. Romero2 , E. Roman2 , C. Guarner2 , C. Juarez1 , G. Soriano2 , S. Vidal1 . 1 Dep. Immunology of Hospital S. Pau & Institut Rec. Hospital S. Pau, 2 Dep. Gastroenterology of Hospital S. Pau., Barcelona, Spain E-mail: [email protected] Background and Aim: Spontaneous bacterial peritonitis (SBP) is a frequent and life-threatening complication in cirrhotic patients with ascites. Diagnosis of SBP is established when the number of neutrophils in ascitic fluid exceeds 250/mm3 . However, the inflammatory status of macrophages from ascitic fluid during SBP is not well known. The aim was to analyze the phenotype of macrophages in ascitic fluid from cirrhotic patients with and without SBP. Patients and Methods: Cells were isolated from the ascitic fluid of: 12 cirrhotic patients with SBP either with positive (n = 7, CPSBP) or negative bacterial culture (n = 5, CN-SBP) at diagnosis and 5 days after starting antibiotic treatment; and cirrhotic patients with sterile ascites (n = 4, SA, <250 neutrophils/mm3 and negative culture). The functional phenotype of macrophages was analyzed by flow cytometry with antibodies against: HLA-DR, CD86, CD64 and CD11b; and scavenger receptors: CD36, CD163, CD206. The levels of TNF, IL-6 and IL-10 in ascitic fluid were determined by ELISA. Results: Macrophages from CP-SBP patients expressed the lowest expression of CD11b and HLA-DR, and the highest expression of
CD64 (Table 1). CP-SBP patients showed the highest percentage of CD36+ and the lowest percentage of CD163+ and CD206+ macrophages. Expression of all these markers on the CN-SBP macrophages was intermediate between CP-SBP and SA patients. The differences in CD11b, HLA-DR, CD163 and CD206 expression between CP-SBP, CN-SBP and SA macrophages were significantly reduced after treating SBP patients with antibiotics. IL-6 levels in ascitic fluid of CP-SBP and CN-SBP were comparable and significantly higher than in SA. However, IL-10 levels in CNSBP were slightly higher than in CP-SBP. Antibiotic treatment significantly reduced IL-6 levels in both groups of SBP patients. Table 1. Phenotype of macrophages from ascitic fluid
SA CP-SBP CN-SBP
CD11b MFI
HLA-DR MFI
CD64 MFI
CD36+ % cells
CD163 MFI
CD206+ % cells
8.41±1.67 4.54±0.74 * 6.19±0.86
20.30±4.37 7.50±1.08** 14.38±2.99†
0.50±0.05 2.837±0.65* 2.04±0.47*
26.10±6.11 46.37±6.07* 36.90±11.93
21±2.27 4.39±0.86*** 6.38±0.66***
70.32±5.80 36.79±8.90* 52.64±13.65
MFI: Mean Fluorescence intensity *p < 0.05, **p < 0.01, ***p < 0.001: t test SA vs CP-SBP or CN-SBP. † p < 0.05: t test CP-SBP vs CN-SBP.
Conclusions: We were able to establish the characteristic profile of macrophages from ascitic fluid of cirrhotic patients with or without SBP. The presence of viable bacteria reduced the antigen presentation activity and increased the phagocytic capability of macrophages from ascitic fluid of SBP patients. Macrophages of CPSBP or CN-SBP patients shifted towards a SA macrophage phenotype after antibiotic treatment. 588 ALBUMIN RESTORES RENAL BLOOD FLOW (RBF) AUTOREGULATION IN PATIENTS WITH REFRACTORY ASCITES AND ACUTE-ON-CHRONIC LIVER FAILURE (ACLF) THROUGH STABILIZATION OF ENDOTHELIAL FUNCTION J. O’Brien, R. Garcia-Martinez, L. Noiret, N. Davies, R. Mookerjee, R. Jalan. Hepatology, Liver Failure Group, University College, Institute of Hepatology, Royal Free Hospital, London, UK E-mail: [email protected] Background and Aims: Hemodynamic alterations in liver failure are associated with endothelial dysfunction, a pro-inflammatory state and sympathetic activation which lead to disturbed RBF autoregulation and renal failure. Albumin is a multifunctional protein that has been shown in several studies to prevent and treat renal dysfunction in patients with advanced cirrhosis and liver failure. We hypothesized that the beneficial effects of albumin in cirrhosis is likely to be through mechanisms in addition to volume expansion. The aims of the study were to investigate the effects of albumin on systemic and renal hemodynamics, inflammation and endothelial dysfunction in refractory ascites and patients with acute kidney injury (AKI) in the setting of ACLF. Patients and Methods: Twenty-two patients were recruited [Group 1, n = 12, refractory ascites; Group 2, n = 10 patients with AKI admitted with an acute deterioration of their liver function due to either alcoholic hepatitis or infection]. Both groups were treated with Albumin 60 g/d over 3–4 days. Cardiac output (CO) and renal blood flow (RBF) hemodynamics were measured. Endothelial dysfunction was assessed through measurement of von Willebrand factor (vWF) and serum nitrite (NO) levels. F2a Isoprostanes (F2a), resting neutrophil burst and Interleukin (IL)-6 were quantified as markers of oxidative stress, endotoxemia and inflammation respectively. Results: Albumin therapy was associated with significant improvements in hemodynamic parameters (increased RBF, MAP, decreased CO, HR; p < 0.05) which resulted in a shift in the RBF autoregulation curve towards normalization (Fig 1). In parallel, improvement of renal dysfunction (creatinine, creatinine clearance and Na+ excretion; p < 0.05 each), sympathetic activation (noradrenaline levels; P < 0.01), inflammation/oxidative stress (F2a
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