Liver International ISSN 1478-3223
CIRRHOSIS AND LIVER FAILURE
Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury Rita Garcia-Martinez1, Lorette Noiret1,2, Sambit Sen3, Rajeshwar Mookerjee1 and Rajiv Jalan1 1 Liver Failure Group, UCL Institute for Liver and Digestive Health, The Royal Free Hospital, Pond Street, London NW3 2PF, UK 2 Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, Gower Street, London WC1E 6BT, Uk 3 Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Keywords acute kidney injury – albumin – endothelial dysfunction – human – cirrhosis – refractory ascites – renal blood flow Abbreviations AD, acute decompensation of cirrhosis; AKI, acute kidney injury; EA, endothelial activation; ED, endothelial dysfunction; ELISA, enzyme-linked immunesorbent assay; HR, heart rate; HVPG, hepatic vein portal gradient; MAP, mean arterial pressure; MDA, malondialdehyde; IMA, ischaemia-modified albumin; RPF, renal plasma flow; RBF, renal blood flow; RPP, renal perfusion pressure; SVR, systemic vascular resistance; vWF, von willebrand factor. Correspondence Professor Rajiv Jalan, Liver Failure Group, UCL Institute for Liver and Digestive Health, the Royal Free Hospital Pond Street, London NW3 2PF, UK Tel: +44 2074332795 Fax: +44 2074332871 e-mail: [email protected] Received 7 December 2013 Accepted 9 March 2014
Abstract Background & Aims: In cirrhotic patients with renal failure, renal blood flow autoregulation curve is shifted to the right, which is consequent upon sympathetic nervous system activation and endothelial dysfunction. Albumin infusion improves renal function in cirrhosis by mechanisms that are incompletely understood. We aimed to determine the effect of albumin infusion on systemic haemodynamics, renal blood flow, renal function and endothelial function in patients with acute decompensation of cirrhosis and acute kidney injury. Methods: Twelve patients with refractory ascites and 10 patients with acute decompensation of cirrhosis and acute kidney injury were studied. Both groups were treated with intravenous albumin infusion, 40– 60 g/days over 3–4 days. Cardiac and renal haemodynamics were measured. Endothelial activation/dysfunction was assessed using von Willebrand factor and serum nitrite levels. F2a Isoprostanes, resting neutrophil burst and noradrenaline levels were quantified as markers of oxidative stress, endotoxemia and sympathetic activation respectively. Results: Albumin infusion leads to a shift in the renal blood flow autoregulation curve towards normalization, which resulted in a significant increase in renal blood flow. Accordingly, improvement of renal function was observed. In parallel, a significant decrease in sympathetic activation, inflammation/oxidative stress and endothelial activation/dysfunction was documented. Improvement of renal blood flow correlated with improvement in endothelial activation (r = 0.741, P < 0.001). Conclusions: The data suggest that albumin infusion improves renal function in acutely decompensated cirrhotic patients with acute kidney injury by impacting on renal blood flow autoregulation. This is possibly achieved through endothelial stabilization and a reduction in the sympathetic tone, endotoxemia and oxidative stress.
DOI:10.1111/liv.12528
Advanced liver failure is characterized by haemodynamic alterations initiated by portal hypertension and splanchnic vasodilation. In advanced cirrhosis, systemic vascular resistance (SVR) is markedly reduced and mean arterial pressure (MAP) is maintained through the activation of compensatory mechanisms (renin-angiotensin system, sympathetic nervous system and arginine-vasopressin hormone) (1). Bacterial translocation (2) and bacterial infections (3) are factors that may further deteriorate this impaired circulatory state. Endothelial cells regulate vascular tone and modulate blood flow towards different organs by synthesizing Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
agonist and antagonist in response to different stimuli. Bacterial products (4), inflammatory mediators (5) and reactive oxygen species (6) may activate endothelial cells and induce endothelial activation (EA) and dysfunction (ED). These factors are frequently present in cirrhosis and correlate with progression of the disease (7). Renal blood flow (RBF) is tightly regulated to ensure a relatively stable renal perfusion regardless of daily fluctuations in MAP. Sympathetic activation is involved in this regulation (8). Other factors such as renin-angiotensin system (9), inflammatory mediators and other as yet unidentified factors have been implicated in this RBF/
1
Garcia-Martinez et al.
Albumin improves renal blood flow autoregulation
RPP (renal perfusion pressure) relationship (10). It has been shown that the RBF autoregulation curve (curve linking between RPP and RBF) shifts progressively to the right in cirrhosis, according to the severity of the liver failure and the degree of sympathetic activation (11). Thus, RBF becomes progressively dependent on RPP. Progressive hypoalbuminaemia is a common feature of cirrhosis. Recent studies have shown that albumin is also functionally impaired in cirrhotic patients and associated with the higher risk mortality (12). Infusion of human serum albumin prevents and improves renal dysfunction in cirrhotic patients (13–17). The exact mechanism through which these effects are seen remains unclear. Understanding those mechanisms may help identify possible new pharmacological approaches in patients with renal failure and those at risk. Most studies suggest that this is consequent upon amelioration in the activated renin-angiotensin system. In patients with spontaneous bacterial peritonitis, albumin infusion resulted in a reduction in von Willebrand factor (vWF) and nitric oxide levels suggesting that it may improve ED (18). Renal failure in cirrhosis, particularly hepatorenal syndrome is associated with extremely poor prognosis (19). A significant number of patients with acute decompensation of cirrhosis (AD) does not fulfil criteria for the diagnosis of hepatorenal syndrome (20), and they are classified as having acute kidney injury (AKI) (21). Although a lot is known about the pathophysiological basis of effect of albumin infusion in patients with hepatorenal syndrome, its effects in patients with AD and associated AKI are not clear. The aim of this study was to further understand the pathophysiological and clinical effects of albumin infusion in AD patients with AKI. Specifically, we sought to evaluate the effect of albumin infusion on systemic and renal haemodynamics, RBF autoregulation and endothelial function and further investigate related mechanisms that might be implicated in the regulation of RBF using a group of patients with refractory ascites (RA) as controls. Patients and methods Ethical considerations
The local ethics committee approved this study and the patients who took part gave their informed consent. The present study is a part of studies in patients with acute decompensation of cirrhosis recruited into observational and interventional studies following a prospective assessment (22–24). A retrospective analysis of this data was performed in this study. Patients
Twenty-two patients with clinical, biochemical, radiological and/or histological evidence of cirrhosis and
2
controls in different studies over 5 years (2001–2006) were grouped into two different categories. The first group included patients (n = 12) with chronic decompensation of cirrhosis because of refractory ascites (RA group). The second group of patients (n = 10) recruited subjects with AKI in the setting of an acute decompensation of previously stable liver disease because of a precipitating event (AKI group). AD for this study was defined as a worsening in liver function over a period of 2 to 4 weeks manifested by increasing jaundice (>100 lmol/ L) and AKI. AKI was defined as a rise in serum creatinine of ≥50% from baseline or a rise of serum creatinine by ≥26.4 mmol/L in
CIRRHOSIS AND LIVER FAILURE
Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury Rita Garcia-Martinez1, Lorette Noiret1,2, Sambit Sen3, Rajeshwar Mookerjee1 and Rajiv Jalan1 1 Liver Failure Group, UCL Institute for Liver and Digestive Health, The Royal Free Hospital, Pond Street, London NW3 2PF, UK 2 Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, Gower Street, London WC1E 6BT, Uk 3 Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Keywords acute kidney injury – albumin – endothelial dysfunction – human – cirrhosis – refractory ascites – renal blood flow Abbreviations AD, acute decompensation of cirrhosis; AKI, acute kidney injury; EA, endothelial activation; ED, endothelial dysfunction; ELISA, enzyme-linked immunesorbent assay; HR, heart rate; HVPG, hepatic vein portal gradient; MAP, mean arterial pressure; MDA, malondialdehyde; IMA, ischaemia-modified albumin; RPF, renal plasma flow; RBF, renal blood flow; RPP, renal perfusion pressure; SVR, systemic vascular resistance; vWF, von willebrand factor. Correspondence Professor Rajiv Jalan, Liver Failure Group, UCL Institute for Liver and Digestive Health, the Royal Free Hospital Pond Street, London NW3 2PF, UK Tel: +44 2074332795 Fax: +44 2074332871 e-mail: [email protected] Received 7 December 2013 Accepted 9 March 2014
Abstract Background & Aims: In cirrhotic patients with renal failure, renal blood flow autoregulation curve is shifted to the right, which is consequent upon sympathetic nervous system activation and endothelial dysfunction. Albumin infusion improves renal function in cirrhosis by mechanisms that are incompletely understood. We aimed to determine the effect of albumin infusion on systemic haemodynamics, renal blood flow, renal function and endothelial function in patients with acute decompensation of cirrhosis and acute kidney injury. Methods: Twelve patients with refractory ascites and 10 patients with acute decompensation of cirrhosis and acute kidney injury were studied. Both groups were treated with intravenous albumin infusion, 40– 60 g/days over 3–4 days. Cardiac and renal haemodynamics were measured. Endothelial activation/dysfunction was assessed using von Willebrand factor and serum nitrite levels. F2a Isoprostanes, resting neutrophil burst and noradrenaline levels were quantified as markers of oxidative stress, endotoxemia and sympathetic activation respectively. Results: Albumin infusion leads to a shift in the renal blood flow autoregulation curve towards normalization, which resulted in a significant increase in renal blood flow. Accordingly, improvement of renal function was observed. In parallel, a significant decrease in sympathetic activation, inflammation/oxidative stress and endothelial activation/dysfunction was documented. Improvement of renal blood flow correlated with improvement in endothelial activation (r = 0.741, P < 0.001). Conclusions: The data suggest that albumin infusion improves renal function in acutely decompensated cirrhotic patients with acute kidney injury by impacting on renal blood flow autoregulation. This is possibly achieved through endothelial stabilization and a reduction in the sympathetic tone, endotoxemia and oxidative stress.
DOI:10.1111/liv.12528
Advanced liver failure is characterized by haemodynamic alterations initiated by portal hypertension and splanchnic vasodilation. In advanced cirrhosis, systemic vascular resistance (SVR) is markedly reduced and mean arterial pressure (MAP) is maintained through the activation of compensatory mechanisms (renin-angiotensin system, sympathetic nervous system and arginine-vasopressin hormone) (1). Bacterial translocation (2) and bacterial infections (3) are factors that may further deteriorate this impaired circulatory state. Endothelial cells regulate vascular tone and modulate blood flow towards different organs by synthesizing Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
agonist and antagonist in response to different stimuli. Bacterial products (4), inflammatory mediators (5) and reactive oxygen species (6) may activate endothelial cells and induce endothelial activation (EA) and dysfunction (ED). These factors are frequently present in cirrhosis and correlate with progression of the disease (7). Renal blood flow (RBF) is tightly regulated to ensure a relatively stable renal perfusion regardless of daily fluctuations in MAP. Sympathetic activation is involved in this regulation (8). Other factors such as renin-angiotensin system (9), inflammatory mediators and other as yet unidentified factors have been implicated in this RBF/
1
Garcia-Martinez et al.
Albumin improves renal blood flow autoregulation
RPP (renal perfusion pressure) relationship (10). It has been shown that the RBF autoregulation curve (curve linking between RPP and RBF) shifts progressively to the right in cirrhosis, according to the severity of the liver failure and the degree of sympathetic activation (11). Thus, RBF becomes progressively dependent on RPP. Progressive hypoalbuminaemia is a common feature of cirrhosis. Recent studies have shown that albumin is also functionally impaired in cirrhotic patients and associated with the higher risk mortality (12). Infusion of human serum albumin prevents and improves renal dysfunction in cirrhotic patients (13–17). The exact mechanism through which these effects are seen remains unclear. Understanding those mechanisms may help identify possible new pharmacological approaches in patients with renal failure and those at risk. Most studies suggest that this is consequent upon amelioration in the activated renin-angiotensin system. In patients with spontaneous bacterial peritonitis, albumin infusion resulted in a reduction in von Willebrand factor (vWF) and nitric oxide levels suggesting that it may improve ED (18). Renal failure in cirrhosis, particularly hepatorenal syndrome is associated with extremely poor prognosis (19). A significant number of patients with acute decompensation of cirrhosis (AD) does not fulfil criteria for the diagnosis of hepatorenal syndrome (20), and they are classified as having acute kidney injury (AKI) (21). Although a lot is known about the pathophysiological basis of effect of albumin infusion in patients with hepatorenal syndrome, its effects in patients with AD and associated AKI are not clear. The aim of this study was to further understand the pathophysiological and clinical effects of albumin infusion in AD patients with AKI. Specifically, we sought to evaluate the effect of albumin infusion on systemic and renal haemodynamics, RBF autoregulation and endothelial function and further investigate related mechanisms that might be implicated in the regulation of RBF using a group of patients with refractory ascites (RA) as controls. Patients and methods Ethical considerations
The local ethics committee approved this study and the patients who took part gave their informed consent. The present study is a part of studies in patients with acute decompensation of cirrhosis recruited into observational and interventional studies following a prospective assessment (22–24). A retrospective analysis of this data was performed in this study. Patients
Twenty-two patients with clinical, biochemical, radiological and/or histological evidence of cirrhosis and
2
controls in different studies over 5 years (2001–2006) were grouped into two different categories. The first group included patients (n = 12) with chronic decompensation of cirrhosis because of refractory ascites (RA group). The second group of patients (n = 10) recruited subjects with AKI in the setting of an acute decompensation of previously stable liver disease because of a precipitating event (AKI group). AD for this study was defined as a worsening in liver function over a period of 2 to 4 weeks manifested by increasing jaundice (>100 lmol/ L) and AKI. AKI was defined as a rise in serum creatinine of ≥50% from baseline or a rise of serum creatinine by ≥26.4 mmol/L in
