Anesthesia & Clinical Research



Yüklə 3,22 Mb.
Pdf görüntüsü
tarix16.02.2017
ölçüsü3,22 Mb.
#8608

Open Access

Review Article



Anesthesia & Clinical

Research

Fukazawa and Lee, J Anesth Clin Res 2013, 4:9

http://dx.doi.org/10.4172/2155-6148.1000352

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 



Keywords: 

Acute kidney injury; Cirrhosis; Endothelial cell; 

Inflammation

Abbreviations: 

DAMP: Damage Associated Molecular Pattern; 

IL-1: Interleukin-1; TNF-α: Tumor Necrosis Factor-α; SIRS: Systemic 

Inflammatory Response Syndrome



Introduction

Acute kidney injury is a well-known and deadly complication of 

liver or biliary tract disease for over a century [1]. Freriches and Flint 

first reported that oliguria in the absence of renal histological changes 

in patients with advanced cirrhosis and ascites in 1861 [2]. Almost a 

century later, Hecker and Sherlock reported rapid and progressive 

azotemia and oliguria in patients with cirrhosis in 1957 [3]. They 

noted near normal kidney histology and full functional recovery of 

kidneys correlated with recovery of hepatic function. Koppel et al. 

also showed that kidneys from patients who succumbed from Hepato-

Renal Syndrome (HRS) were functioned normally when transplanted 

into patients with chronic uremia [4]. These studies suggested that 

HRS is a functional renal disorder without underlying abnormalities in 

kidney structure. Schroeder et al measured the Para-Amino Hippurate 

(PAH) clearance in cirrhosis with renal failure patients, demonstrated 

that intense renal arterial vasoconstriction together with systemic and 

splanchnic vasodilation is the hallmark of HRS [5]. However, despite 

improved understandings of pathophysiology as well as the reversible 

nature of renal failure in HRS, the prognosis of HRS remains extremely 

poor (used to be called as “liver-death syndrome”). Currently, the 

median survival of untreated HRS type 1 is ~2 weeks while that of type 

2 is approximately 4 to 6 months [6]. Liver transplant is the only viable 

treatment but scarcity of donor organs has been a major hindrance and 

a majority of patients with HRS type 1 die while awaiting transplant. 

The latest research discovered the new mechanisms of remote organ 

injury in local sterile inflammation, which may be applicable to the 

pathogenesis of HRS. Now it is becoming increasingly clear that HRS 

is multi-factorial phenomenon. The goals of this brief review are 

to summarize the current understanding and management of HRS 

and provide an evolving area of research in the pathophysiologic 

mechanism of HRS.

Current Definition of Hepato-Renal Syndrome

The International Ascites Club initially defined HRS in 1996 

and subsequently revised in 2007 (Table 1) [7,8]. Those criteria were 

made from the current understanding of liver-kidney interplay as a 

pathophysiologic mechanism for HRS. HRS has two distinct types of 

clinical presentations [9]. Type 1 HRS is an acute form of HRS and 

characterized by rapidly progressive renal failure. Type 1 HRS usually 

develops after several precipitating events such as gastrointestinal 

bleeding, large volume paracentesis, acute alcoholic hepatitis and 

spontaneous bacterial peritonitis [10,11]. Type 1 HRS is commonly 

associated with rapid deterioration of extra-renal organ function 

including the heart, brain, liver, and adrenal glands. Type 2 HRS 

is chronic form of HRS and characterized with moderate and slow 

progressive renal failure associated with diuretics resistant ascites 

[12]. Although there is a clear distinction of two different types of 

HRS, renal impairment is often progressive and can be regarded as 

“continuum” instead of two different entities, such as most patients 

initially represents type 2 HRS and turn into type 1 HRS after several 

episodes of precipitating events. 

Clinical Significance

HRS is a frequent complication in advanced cirrhosis and the 

prevalence of HRS parallels the progression of liver disease in patients 

with cirrhosis [13]. HRS occurs in about 10% of patients admitted to 

hospital with decompensated cirrhosis, with a cumulative probability 

of 18% at 1 year and 39% at 5 years [10]. Also patients with spontaneous 

bacterial peritonitis have a 33% chance of developing HRS [14]. HRS is 

life-threatening complication and type 1 patients has 80% mortality in 



*Corresponding author: Kyota Fukazawa, Department of Anesthesiology, College 

of Physicians and Surgeons of Columbia University, 630 West 168

th

 St, New York, 



NY 10032-3784, USA, E-mail: 

kf2407@columbia.edu 



Received August 16, 2013; Accepted September 25, 2013; Published September 

27, 2013


Citation:  Fukazawa  K,  Lee  HT  (2013) Updates on Hepato-Renal Syndrome. J 

Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Copyright: © 2013 Fukazawa K, et al. This is an open-access article distributed 

under the terms of the Creative Commons Attribution License, which permits 

unrestricted use, distribution, and reproduction in any medium, provided the 

original author and source are credited.

Updates on Hepato-Renal Syndrome

Kyota Fukazawa*and H Thomas Lee

Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, NY, USA



Abstract

Hepato-Renal Syndrome (HRS) is one of the most detrimental conditions in patients with end stage liver failure. 

Historically, HRS was considered a terminal disease associated with cirrhosis and was termed “liver-death syndrome”. 

Furthermore, despite the improved understanding of pathophysiology and the reversibility of renal dysfunction in 

HRS, mortality remains extremely high especially for type 1 HRS. This review summarizes the recent advances 

in the pathophysiology, diagnosis and management of HRS and also provides an evolving area of research in the 

pathophysiologic mechanisms of HRS, which may open the door for new therapeutic approaches.

 Cirrhosis and ascites



 Serum creatinine> 1.5 mg/dL

 No improvement of serum creatinine (decrease to a level of <=1.5 mg/dL) after at 



least 2 days with diuretic withdrawal and volume expansion with albumin

 No signs of shock



 No recent use of nephrotoxic drugs

 Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/



day, microhematuria (>50 red blood cells per high power field) and/or abnormal 

renal ultrasonography

*Criteria  have  been  developed  by  the  International  Ascites  Club.  Modified  from 

[Gut, Salerno, F. et al. 56, 1310-1318, C 2007] 



Table 1: New diagnostic criteria for hepatorenal syndrome*.

Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Page 2 of 8

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 

two weeks and only 10% of patients survive more than 3 months [6]. 

Because of this detrimental prognosis, most patients with type 1 HRS 

die while being evaluated for transplant or waiting for transplant. Those 

prognoses are even worse for patients with apparent precipitating 

factors. Patients with type 2 HRS also has a median survival of 

approximately 6 months [6]. 

Health care costs related to HRS has not been reported but it is 

not difficult to imagine that it is very high considering the detrimental 

nature of this condition. Quiros et al. estimates with using their 

Mexican social security institute database that annual health care costs 

per person for Child-Pugh Score C is $30,249 (seven times higher 

than patients with Child-Pugh Score of A, $4,269) [15]. Also Henry 

Ford study, which compared the economic burden for U.S. patients 

with chronic hepatitis C disease using a large private health insurance 

claims database from 2003 to 2010, the annual health care costs per 

person for decompensated cirrhosis was estimated around $59,995, 

which is triples compared to patients with no cirrhosis ($17,277) [16]. 

Considering the fact that 400,000 cirrhotic patients in the United States, 

and grossly up to 2% of those patients develop HRS (the incidence of 

acute kidney failure in cirrhotic patients was reported to be 10% and 

HRS causes up to 20% of acute kidney failure) , annual US health care 

costs approximates up to $240 million. HRS creates a major economic 

burden under the circumstances that currently no effective therapy 

is available [17,18]. Therefore there is an urgent need for the clearer 

understanding of pathophysiologic mechanisms and the development 

of viable treatment options. 



Pathogenesis of Hepato-renal Syndrome: Basic 

Mechanisms 

The pathophysiological mechanism for HRS remains largely 

unknown but current understanding dictates that decreased 

glomerular filtration rate due to reduction of effective blood volume 

due to splanchnic vasodilation (so-called “splanchnic steal syndrome”) 

and subsequently compensated with activation of renin-angiotensin-

aldosterone and sympathetic nervous system, and release of Anti-

diuretic Hormone (ADH), which leads to profound renal afferent 

artery vasoconstriction (primarily affecting the renal cortex) [19-21]. 

Patients with HRS have extremely low urinary sodium excretion due 

to decreased filtered sodium at glomerulus and increased sodium 

reabsorption in the proximal tubule (“excessive sodium re-absorption”). 

Diuretics such as furosemide and spironolactone have a little effect due 

to decreased delivery and low amount of sodium at the effector site 

(the loop of Henle and distal tubule) (Figure 1). In addition, a small 

amount of filtered water is absorbed at the distal tubules in response to 

high ADH activity leading to oliguria or anuria (“non-osmotic hyper 

secretion of ADH”) [22,23]. 

Currently splanchnic vasodilation is widely accepted as a key 

pathophysiologic change for HRS since it can reasonably explain the 

most of pathophysiologic study data. In early cirrhosis, hepatocyte 

inflammation activates hepatic stellate cells located in the peri-sinusoid 

tissue (space of Disse) to secrete collagen into hepatic sinusoids (scar 

formation) leading to increased portal venous resistance with the 

progression of liver damage. Increase in portal vascular resistance 

increases sheer stress on the venous wall of the portal and splanchnic 

system, and leads to massive production of vasodilators including 

Nitric Oxide (NO) from the vascular endothelial cells [24]. Increased 

sheer stress also causes the formation of the massive collateral network 

by opening preexisting vessels or by increased angiogenesis due to 

up-regulation of growth factors such as vascular endothelial growth 

factor and platelet derived growth factor, which further aggregates the 

reduction of splanchnic vascular resistance [25-28]. 

In addition to sheer stress, current evidences have been shown 

that bacterial translocation from intestinal flora to the portal 

circulation, which is commonly seen in cirrhotic patients with portal 

hypertension, may activate the innate immune system, leading to 

massive production of cytokines including tumor necrosis factor-α 

(TNF-α) and Interleukin-6 (IL-6) [29-31]. TNF-α and endotoxins from 

bacteria further increase the NO production from vascular endothelial 

cells by up-regulating the endothelial nitric oxide synthase and 

inducible nitric oxide synthase, and leads to splanchnic vasodilation 

[32]. In fact, cirrhotic patients with bacterial translocation have lower 

systemic vascular resistance compared with patients who do not [33]. 

Also intestinal decontamination with norfloxacin, decreases TNF-α 

production, alleviate hemodynamic parameters, and renal function 

[34,35]. Those studies have indirectly provided the plausibility of 

bacterial translocation as a mechanism of splanchnic vasodilation in 

cirrhosis. 

It is important to point out that splanchnic vasodilation itself 

is not sufficient for the development of HRS. Other simultaneous 

organ dysfunction precipitates in concert to develop HRS. The auto-

regulation of renal blood flow in cirrhotic patients is right-shifted 

due to activation of the renal sympathetic nervous system and other 

vasoconstrictors [36]. Renal blood flow becomes more dependent on 

the arterial blood pressure with the progression of liver disease. In 

patients with advanced cirrhosis, small changes in perfusion pressure 

will result in a major decrease in renal blood flow. Myocardial pump 

function, which is required to maintain vital organ perfusion by 

counteracting the reduction in volume shift to splanchnic circulation, 

is also impaired, so-called “cirrhotic cardiomyopathy” [37-40]. The 

impairment to generate adequate cardiac output in response to decrease 

effective blood volume directly reduces the renal perfusion pressure, 

contributing to the development of HRS [37,38]. Hypo-perfusion to 

adrenal gland may also cause glucocorticoid insufficiency, which leads 

to circulatory dysfunction and impaired response to vasopressors 

[41]. Previous study with 101 cirrhotic patients in the intensive care 

unit showed that adrenal insufficiency was associated with higher 

mortality with lower mean arterial pressure and higher requirement of 

vasopressors [42]. Furthermore, hydrocortisone administration rapidly 

improved systemic hemodynamics, reduced vasopressor requirements 

and lowered hospital mortality [43]. In summary the pathophysiologic 

mechanisms of HRS are currently understood that cirrhosis-induced 

splanchnic vasodilation is primary causative physiologic change and 

subsequent renal vasoconstriction causes hypo-perfusion of the kidney, 

which leads to HRS when accompanied by impairment of multiple 

organ function.

Although splanchnic vasodilation is currently a most plausible 

causative mechanism of HRS in cirrhosis, there are ample evidences 

have shown that progressive functional renal failure occurs with a wide 

variety of liver injury such as trauma, toxic drugs without cirrhosis 

or splanchnic vasodilation [44,45]. Therefore it remains possible that 

liver injury itself directly or indirectly causes HRS. Most up-to date 

scientific evidences provide that systemic inflammatory response from 

liver injury (release of inflammatory mediators) causes remote organ 

injury as well as hemodynamic disturbances which mimics cirrhosis or 

sepsis. Those evolving new research areas will be discussed later in the 

new basic science research section. 



Current Management of Hepato-renal Syndrome

Unfortunately treatment options for HRS are limited and 



Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Page 3 of 8

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 

mostly supportive which are intended to prolong survival of patients 

awaiting transplant. Those supportive treatments include prevention 

and immediate treatment for precipitating factors for HRS such 

as (i) paracentasis with albumin supplement for tense ascites, (ii) 

antibiotics for spontaneous bacterial peritonitis, (iii) avoidance of 

nephrotoxic medications (e.g. nonsteroidal anti-inflammatory drugs, 

aminoglycosides, radiocontrast media, and diuretics), (iv) low-salt 

diet and free water restriction for patients with hyponatremia, (v) 

considering cortisone replacement therapy for hypotensive patients 

[9,46-49]. 

Few pharmacologic agents are currently available to slow the 

progressive worsening the splanchnic vasodilation and often indicated 

only for the patients waiting for transplant. Terlipressin is a vasopressin 

analog with preferential effects on the vasopressin type 1 receptor in 

splanchnic vasculature, causing greater mesenteric vasoconstriction 

than in kidney or other organ vascular systems [50]. Currently 

terlipressin in combination with albumin infusion is the first line 

vasoconstrictor for HRS type 1 (not currently commercially available 

in the USA). However, terlipressin is only effective for patients who 

have mild kidney and liver dysfunction (serum bilirubin <10 mg/dL) 

[51-53]. Other vasoconstrictors such as oral midodrine, α-adrenergic 

receptor agonist, and subcutaneous octreotide, and a long-acting 

somatostatin analogue, are less effective compared to Terlipressin, 

and considered to be a second line of treatment. (Only indicated if 

Terlipressin is contraindicated or not available) 

 

Figure 1: Current Understandings of the Pathophysiology of Hepato-Renal Syndrome

Development of hepato-renal syndrome are thought to occur through the following pathophysiological events:

(1) Sinusoidal obstruction due to fibrin formation from stellate cells located in space of Disse following hepatocyte injury, (2) Development of portal hypertension and 

increased sheer stress to the portal vessel wall leading to increased production of nitric oxide, (3) Bacterial translocation from intestinal flora to the portal circulation 

activates innate immune system (eg. mononuclear cell), leading to massive production of cytokines  (e.g., TNF-α and IL-6) and nitric oxide leading to (4) Splanchnic 

vasodilation, (5) These inflammatory mediators causes systemic inflammatory response which further aggregates splanchnic vasodilation and extra-organ damage, 

(6) Reduction in effective blood volume due to splanchnic dilatation, (7) Activation of systemic vasoconstricting system including sympathetic nervous system and 

renin-angiotensin-aldosterone system, (8) renal afferent artery vasoconstriction, reduction of glomerular filtration and (8) dramatic reduction in renal function.


Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Page 4 of 8

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 

Non-pharmacologic treatments include renal replacement therapy, 

Transjugular Intrahepatic Portosystemic Shunt (TIPS) and liver 

transplantation. The effectiveness of renal replacement therapy such 

as hemodialysis or continuous veno-venous hemofiltration remained 

undetermined for HRS. Therefore renal replacement therapy is only 

indicated for rescue treatment of transplant candidates with severe 

hyperkalemia, metabolic acidosis, and volume overload rather as a 

treatment for HRS [54]. Transjugular Intrahepatic Portosystemic Shunt 

(TIPS) can temporarily decompress the portal pressure, and decrease 

sympathetic nervous system and renin-angiotensin-aldosterone 

activity [55,56]. However, TIPS acutely increases cardiac output and 

exaggerates peripheral vasodilatation, and is often indicated only for 

the patients with stable liver function as either bridge treatment for 

liver transplant or long-term treatment. Liver transplantation remains 

the best available treatment for suitable candidates with HRS because 

it may cure both liver and the renal dysfunction when it performed at 

an early stage. But this treatment option is limited by the availability of 

organs. Also patients with cirrhosis and renal failure, especially HRS 

type 1, are at high risk for death while awaiting transplantation [57]. 

In 2002, the Model For End-Stage Liver Disease (MELD) score, which 

incorporates kidney function to calculate the level of sickness of patients 

waiting for transplant, was introduced to facilitate the systematic organ 

allocation based on the “sickest first” paradigm for liver transplantation. 

Use of this scoring system has markedly increased the opportunity of 

transplantation for patients with renal failure and has aided in reducing 

mortality among patients awaiting liver transplantation. 



New Basic Research in Hepato-renal Syndrome 

Mechanisms

Near 30 years since Schrier and colleagues proposed the 

“Peripheral Arterial Vasodilatation Hypothesis” as an explanation 

for the abnormal renal sodium and water retention in patients with 

cirrhosis in 1988, splanchnic vasodilation has been believed to be a 

sole causative mechanism for hepato-renal syndrome in cirrhosis 

[24]. Vaso-constrictive pharmacologic treatments for HRS have 

been introduced to treat splanchnic vasodilation on this hypothetic 

ground with partial success. Recently new evidences have provided 

impetus for other novel mechanisms for HRS including “systemic 

inflammatory response” hypothesis. After liver ischemia and 

reperfusion injury, Kuppfer cells release pro-inflammatory mediators 

(Figure 1). Significantly higher level of circulating pro-inflammatory 

cytokines and transcription factors including TNF-α, IL-1α, and IL-6 

has been reported after reperfusion of liver [58-60]. Those mediators 

may promote inflammatory changes in remote organ including lung 

and kidney [59-61]. In addition, damaged hepatocytes release the 

intracellular components such as Damage Associated Molecular Pattern 

Molecules (DAMPs). DAMPs are molecules released by stressed cells 

undergoing necrosis that act as endogenous danger signals to promote 

and exacerbate the inflammatory response. High mobility group box-1 

(HMGB1) is a non-histone nuclear protein but functions as DAMPs 

under stress condition and promotes inflammation [62,63]. High level 

of HMGB1 expression was observed in the hepatocytes after ischemia 

and reperfusion [64]. HMGB1 interacts with the individual members 

of the Toll-Like Receptor (TLR) family, TLR2 and TLR4 in the remote 

organ and innate immune cells, which may also contribute to the HRS 

[65]. Other inflammatory mediators include, circulating bile acids, uric 

acids, histones and nuclear DNA and circulating immune complexes 

may also contribute to the development of acute kidney injury [66]. 

Those hypotheses were recently supported by the finding that the 

observation that vascular endothelial cell damage which is shown by the 

large number of apoptotic cells in the kidney, which is more prominent 

than the proximal tubule cell apoptosis after liver reperfusion [67]. 

Pro-inflammatory mediators released into systemic circulation damage 

renal endothelial cells, and cause a loss of their ability to regulate 

leukocyte recruitment, leading to disruption of endothelial barrier 

[68, 69]. Activated neutrophils in response to those inflammatory 

factors migrate to the injured area guided by endothelial adhesion 

molecules such as E-selectin, P-selectin, and ICAM-1 in the kidney, 

which promotes leukocyte recruitment and extravasations to the renal 

interstitial space[69-72]. Therefore prevention of endothelial damage 

may improve the survival of renal-endothelial cells after liver ischemia-

reperfusion may limit leukocyte infiltration into the kidney parenchyma 

and improve renal function. Future studies with endothelial stabilizing 

agents (such as activation of A

1

 adenosine receptors, protein kinase 



C, HSP-27, activated protein C or sphingosine-1-phosphate) will 

determine whether protecting endothelial integrity will reduce renal 

injury after liver IR injury [73-77].

Another novel discovery of the mechanism of remote organ injury 

is the involvement of intestine as exacerbating sterile inflammation 

by releasing internally-stored IL-17A (Figure 2). Recent spiral of 

discoveries was started from the initial finding that acute kidney injury 

in mice causes hepatic injury, which is mediated by inflammatory 

cytokines (TNF-α, IL-17A, and IL-6). Also portal vein and intestine 

had higher levels of interleukin 17A than peripheral blood. This finding 

suggested that IL-17A is derived from small intestine [78]. Contrary to 

the liver injury following kidney injury, authors found that ischemia-

reperfusion injury of the liver cause acute kidney injury, which is also 

mediated by intestinal-derived IL-17A. High level of IL-17A mRNA 

was expressed particularly in the Paneth cell. Paneth cells are intestinal 

epithelial cell, located in the base of intestinal crypts and adjacent to 

stem cells, secretes bacteriocidal cationic proteins called defensins 

to protect intestinal epithelial barrier against bacteria. After a liver 

or kidney ischemia and reperfusion, Paneth cells also secrete large 

quantities of stored IL-17A, which may be attributed to the aggregation 

of inflammation at the primary site and also leading to remote 

organ injury. In fact, the depletion of Paneth cells ameliorates the 

inflammatory response to primary organ (e.g. liver), but also remote 

organ damage (e.g. kidney injury after liver ischemia-reperfusion 

injury). Based on those observations, it is plausible that hepatic and 

renal injury after hepatic ischemia-reperfusion injury is exacerbated 

by Paneth-cell derived IL-17A [79]. Exacerbated inflammatory 

response causes widespread endothelial damage and hemodynamic 

derangement, which further exacerbate liver dysfunction and also 

cause extra hepatic organ damage, and eventually draw patients into 

“downward spiral of inflammation” and multi-organ failure (Figure 3). 

This “systemic inflammatory response” hypothesis may provide some 

clues to answer the question why kidney injury (HRS) occurs in various 

causes of liver injury without evidence of splanchnic vasodilation. 



New Biomarkers of Hepato-renal Syndrome

Clinical diagnosis of HRS remains difficult and diagnostic criteria 

warrant further refinement. Current international ascites club criteria 

requires urine sample to make a diagnosis and therefore cannot 

establish HRS diagnosis in oligouric or anuric patients. Also they 

cannot identify HRS superimposed on organic renal disease and in 

patients with rapidly evolving liver and renal failure [80]. An Italian 

multicenter study examined the applicability of these diagnostic criteria 

in a prospective trial [81]. Of the 116 patients diagnosed with HRS 

only 64% met all diagnostic criteria, whereas the remaining 36% with 

acute deterioration of serum creatinine to above 1.5 mg/dL could not 


Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Page 5 of 8

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 



 

Figure 3: Systemic Inflammatory Response Hypothesis 

Inflammatory mediators released from cirrhotic liver into systemic circulation reach remote organs including lung, liver and kidney causing endothelial damage and 

further organ injury. In addition, disruption of intercellular integrity of intestinal epithelial cells associated with cirrhosis causes bacterial invasion into circulation leading 

to  substantial  increase  in  circulating  bacterial  Lipopolysaccharide  (LPS).  These  additional  inflammatory  mediators  elicit  endothelial  damages  in  multiple  organs 

(worsening of cirrhosis, development of kidney and lung injury).  Damaged Organs Release Additional (DAMPs) leading to hemodynamic derangements which further 

exacerbate the systemic inflammatory response, leading to malicious aggregating cycle of inflammation, which ultimately leads to multi-organ failure.

 

Figure 2: Mechanisms of Sensing of the Hepatocyte Damage and Amplification of Inflammation by Intestinal Epithelial Cells

In cirrhosis, chronic ischemia and reperfusion of hepatocytes activates sinusoidal Kuppfer cells, leading to production of pro-inflammatory mediators such as TNF-α, 

IL-1α, and IL-6. Damaged hepatocytes alert immune system by releasing Damage-Associated Molecular Pattern Molecules (DAMPs) such As High Mobility Group 

Box-1 (HMGB1), histones, and uric acids into the systemic circulation. Those pro-inflammatory signals are sensed by intestinal immune system, in which reserve the 

largest population of immune cells. DAMPs may activate the Toll-Like Receptor (TLR) family in the intestinal epithelial cells (eg., Paneth cells) and innate immune 

cells (Dendrite cells). Binding of DMAPs to TLR receptor on the Dendrite cells triggers the production of pro-inflammatory mediators such as TNF-α and IL-6 and IL-

1α. Also the binding of DAMPs to TLR receptors in Paneth cells triggers the release of stored IL-17A from Paneth cells. Abbreviations DAMP, Damage Associated 

Molecular Pattern, IL-1, interleukin-1, , IL-17, interleukin-17, MYD-88, Myeloid differentiation primary response gene 88, TNF-α, Tumor Necrosis Factor-α, TLR, Toll 

Like Receptor, TRAM, TRIF-related adaptor molecule, TRIF, TIR-domain-containing adapter-inducing interferon-β.


Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Page 6 of 8

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 

meet one or more of the diagnostic criteria due to anuria, hematuria, 

or proteinuria. This is due to a lack of sensitive clinical biomarker to 

accurately and quickly estimate Glomerular Filtration Rate (GFR) and 

to exclude other etiology of kidney failure. 

Cystatin C (Cys-C) level is one of the serum markers for GFR and is 

under investigation for clinical use. Cys-C freely crosses the glomerular 

membrane and metabolized in the renal proximal tubular cells without 

extra-renal elimination. Also unlike creatinine, Cys-C levels are 

independent of muscle mass, age and sex, and are not influenced by 

inflammatory conditions or malignancy [82]. Serum Cys-C provides a 

good alternative to serum creatinine for the assessment of glomerular 

function in cirrhosis. 

Another good alternative to creatinine, and has been evaluated for 

clinical use, is urinary NGAL. NGAL (Neutrophil Gelatinase-Associated 

Lipocalin, lipocalin-2, siderocalin) is expressed by the damaged tubule 

to induce re-epithelialization and secreted in high levels into the blood 

and urine within two hours of injury [83]. A recent study examined 

the urinary NGAL in 118 patients with cirrhosis [84]. 56% of those 

patients had a kidney failure from a variety of causes consisting chronic 

kidney disease (12%), prerenal azotemia (14%), HRS (17%) and AKI 

(13%). Urinary NGAL levels were significantly different amongst AKI 

(highest), HRS (intermediate), prerenal azotemia, chronic kidney 

disease, and normal kidney function. Therefore it may be used to 

differentiate HRS from other causes of renal failure. This research also 

showed its ability to predict mortality in patients who have cirrhosis 

and kidney failure [84]. However, interpretation of NGAL is affected 

by concomitant systemic infection. Also uninary NGAL is difficult to 

measure in oligouric or anuric patients. 

Other urinary biomarkers being investigated for detection of renal 

function include γ glutamyl transpeptidase, transaminases, liver-type 

fatty acid binding protein, IL 18 and hepatitis A virus cellular receptor-1 

but these markers warrants further investigation in cirrhotic patients. 

Markers of the severity of renal afferent artery vasoconstriction have 

been suggested for the diagnosis of HRS. These markers include 

Sympathetic Nervous System (SNS) activity (plasma noradrenaline 

level) or Renin-Angiotensin-Aldosterone (RAA) activity (plasma renin 

activity) or renal arterial resistance (“renal artery resistive index” in 

ultrasonography) [10,85]. 



Conclusions and Future Implications

In this brief review, we summarized the current understanding of 

pathophysiological mechanisms, therapeutic approach and evolving 

pathophysiologic mechanism of HRS. Collecting the currently available 

evidences together, the pathophysiology of HRS has been recognized 

as more complex rather than solely due to splanchnic vasodilation. 

Splanchnic vasodilation, intestinal barrier disruption and bacterial 

translocation, and exacerbation of systemic inflammatory response 

may work in concert to develop this detrimental condition, HRS. 

Understanding of pathophysiological mechanisms will enable more 

physiology-oriented therapeutic approach (such as pharmacological 

therapy and gene modulation targeted at these signaling molecules 

to improve liver/kidney function and delay the development of HRS) 

other than supportive therapy, which is expected to reduce morbidity 

and mortality of patients with HRS, and significantly reduce the medical 

care cost related to HRS. Future research will elucidate the mechanism 

of development of the Systemic Inflammatory Response Syndrome 

(SIRS) after liver ischemia-reperfusion injury, which includes the 

type of inflammatory mediators other than mediators discussed in 

the previous section, and the origin of those mediators (necrotic 

hepatocytes, Kuppfer cells, endothelial cells, etc.). Although hepatic 

sinusoidal Kuppfer cells are the largest sessile macrophage in the body, 

and large number of hepatic endothelial cells exists in the hepatic 

microcirculation, it is completely unknown whether the mediators 

from Kuppfer cells or hepatic endothelial cells are enough to produce 

sustained and powerful systemic inflammatory response to develop 

HRS. Role of intestine in sterile inflammation is evolving research area 

and may play an important role in transmitting the local inflammation 

to systemic inflammation, which leads to the development of remote 

organ injury including HRS. The mechanisms of renal injury from the 

systemic inflammatory syndrome, especially the role of endothelial cell 

needs to be elucidated.



References

1.  Nothnagel H (1899) Specielle Pathologie und Therapie.(2 edn) BiblioBazaar 

Vienna, pp-63. 

2.  Flint A (1863) Clinical report on hydro-peritoneum, based on analysis of forty-

six cases. Am J Med Sci 45: 306-339. 

3.  Hecker R, Sherlock S (1956) Electrolyte and circulatory changes in terminal 

liver failure. Lancet 271: 1121-1125.

4.  Koppel MH, Coburn JW, Mims MM, Goldstein H, Boyle JD, et al. (1969) 

Transplantation of cadaveric kidneys from patients with hepatorenal syndrome. 

Evidence for the functional nature of renal failure in advanced liver disease. N 

Engl J Med 280: 1367-1371.

5.  Schroeder ET, Shear L, Sancetta SM, Gabuzda GJ (1967) Renal failure in 

patients with cirrhosis of the liver. 3. Evaluation of intrarenal blood flow by para-

aminohippurate extraction and response to angiotensin. Am J Med 43: 887-

896.

6.  Ginès P, Guevara M, Arroyo V, Rodés J (2003) Hepatorenal syndrome. Lancet 



362: 1819-1827.

7.  Arroyo V, Ginès P, Gerbes AL, Dudley FJ, Gentilini P, et al. (1996) Definition and 

diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. 

International Ascites Club. Hepatology 23: 164-176.

8.  Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V (2007) Diagnosis, prevention 

and treatment of hepatorenal syndrome in cirrhosis. Gut 56: 1310-1318.

9.  European Association for the Study of the Liver (2010) EASL clinical practice 

guidelines on the management of ascites, spontaneous bacterial peritonitis, 

and hepatorenal syndrome in cirrhosis. J Hepatol 53: 397-417.

10. Ginès A, Escorsell A, Ginès P, Saló J, Jiménez W, et al. (1993) Incidence, 

predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with 

ascites. Gastroenterology 105: 229-236.

11. Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, et al.(1994) 

Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, 

clinical course, predictive factors and prognosis. Hepatology, 1994. 20(6): 

1495-501. 

12. Ginès P, Schrier RW (2009) Renal failure in cirrhosis. N Engl J Med 361: 1279-

1290.


13. Wadei HM, Gonwa TA (2013) Hepatorenal syndrome in the intensive care unit. 

J Intensive Care Med 28: 79-92.

14. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, et al. (1999) Effect of 

intravenous albumin on renal impairment and mortality in patients with cirrhosis 

and spontaneous bacterial peritonitis. N Engl J Med 341: 403-409.

15. Quiroz ME, Flores YN, Aracena B, Granados-García V, Salmerón J, et al. 

(2010) Estimating the cost of treating patients with liver cirrhosis at the Mexican 

Social Security Institute. Salud Publica Mex 52: 493-501.

16.  Levin J (2011) Disease burden in patients with chronic hepatitis C virus (HCV) 

infection in a United States (US) private health insurance claims database 

analysis from 2003 to 2010.62th Annual Meeting of the American Association 

for the Study of Liver Diseases, San Francisco. 

17. Everhart JE (1994) Digestive Diseases in the United States: Epidemiology and 

Impact. US Department of Health and Human Services, Public Health Service, 

National Institutes of Health, National Institute of Diabetes and Digestive and 

Kidney Diseases. Washington DC, US pp-1447.



Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Page 7 of 8

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 

18. Moreau R, Durand F, Poynard T, Duhamel C, Cervoni JP, et al. (2002) 

Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a 

retrospective multicenter study. Gastroenterology 122: 923-930.

19. Møller S, Hobolth L, Winkler C, Bendtsen F, Christensen E (2011) Determinants 

of the hyperdynamic circulation and central hypovolaemia in cirrhosis. Gut 60: 

1254-1259.

20. Sacerdoti D, Bolognesi M, Merkel C, Angeli P, Gatta A (1993) Renal 

vasoconstriction in cirrhosis evaluated by duplex Doppler ultrasonography. 

Hepatology 17: 219-224.

21. Maroto A, Ginès A, Saló J, Clària J, Ginès P, et al. (1994) Diagnosis of 

functional kidney failure of cirrhosis with Doppler sonography: prognostic value 

of resistive index. Hepatology 20: 839-844.

22. Linas SL, Anderson RJ, Guggenheim SJ, Robertson GL, Berl T (1981) Role 

of vasopressin in impaired water excretion in conscious rats with experimental 

cirrhosis. Kidney Int 20: 173-180.

23. Bichet DG, Van Putten VJ, Schrier RW (1982) Potential role of increased 

sympathetic activity in impaired sodium and water excretion in cirrhosis. N Engl 

J Med 307: 1552-1557.

24. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, et al. (1988) 

Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal 

sodium and water retention in cirrhosis. Hepatology 8: 1151-1157.

25. Van Steenkiste C, Geerts A, Vanheule E, Van Vlierberghe H, De Vos F, et al. 

(2009) Role of placental growth factor in mesenteric neoangiogenesis in a 

mouse model of portal hypertension. Gastroenterology 137: 2112-2124.

26. Paternostro C, David E, Novo E, Parola M (2010) Hypoxia, angiogenesis 

and  liver  fibrogenesis  in  the  progression  of  chronic  liver  diseases.  World  J 

Gastroenterol 16: 281-288.

27. Langer DA, Shah VH (2006) Nitric oxide and portal hypertension: interface of 

vasoreactivity and angiogenesis. J Hepatol 44: 209-216.

28. Sumanovski  LT,  Battegay  E,  Stumm  M,  van  der  Kooij  M,  Sieber  CC  (1999) 

Increased angiogenesis in portal hypertensive rats: role of nitric oxide. 

Hepatology 29: 1044-1049.

29. Bellot P, Francés R, Such J (2013) Pathological bacterial translocation in 

cirrhosis: pathophysiology, diagnosis and clinical implications. Liver Int 33: 31-

39.

30. Sugano S (1992) Endotoxin levels in cirrhotic rats with sterile and infected 



ascites. Gastroenterol Jpn 27: 348-353.

31. Heller J, Sogni P, Barrière E, Tazi KA, Chauvelot-Moachon L, et al. (2000) 

Effects of lipopolysaccharide on TNF-alpha production, hepatic NOS2 activity, 

and hepatic toxicity in rats with cirrhosis. J Hepatol 33: 376-381.

32. Wiest R, Das S, Cadelina G, Garcia-Tsao G, Milstien S, et al. (1999) Bacterial 

translocation  in  cirrhotic  rats  stimulates  eNOS-derived  NO  production  and 

impairs mesenteric vascular contractility. J Clin Invest 104: 1223-1233.

33.  Frances R, Zapater P, Gonzalez-Navajas JM, Munoz C, Cano R, et al. (2008) 

Bacterial DNA in patients with cirrhosis and non-infected ascites mimics the 

soluble immune response established in patients with spontaneous bacterial 

peritonitis. Hepatology  47: 978-985. 

34. Tazi KA, Moreau R, Hervé P, Dauvergne A, Cazals-Hatem D, et al. (2005) 

Norfloxacin  reduces  aortic  NO  synthases  and  proinflammatory  cytokine  up-

regulation in cirrhotic rats: role of Akt signaling. Gastroenterology 129: 303-314.

35. Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, et al. (2007) Primary 

prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome 

and improves survival in cirrhosis. Gastroenterology 133: 818-824.

36. Stadlbauer  V,  Wright  GA,  Banaji  M,  Mukhopadhya  A,  Mookerjee  RP,  et  al. 

(2008) Relationship between activation of the sympathetic nervous system and 

renal blood flow autoregulation in cirrhosis. Gastroenterology 134: 111-119.

37. Ruiz-del-Arbol L, Urman J, Fernández J, González M, Navasa M, et al. (2003) 

Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients 

with spontaneous bacterial peritonitis. Hepatology 38: 1210-1218.

38. Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, et al. (2005) 

Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 42: 

439-447.


39. Arroyo V, Fernandez J, Ginès P (2008) Pathogenesis and treatment of 

hepatorenal syndrome. Semin Liver Dis 28: 81-95.

40. Alqahtani SA, Fouad TR, Lee SS (2008) Cirrhotic cardiomyopathy. Semin Liver 

Dis 28: 59-69.

41. Cooper  MS,  Stewart  PM  (2003)  Corticosteroid  insufficiency  in  acutely  ill 

patients. N Engl J Med 348: 727-734.

42. Tsai MH, Peng YS, Chen YC, Liu NJ, Ho YP, et al. (2006) Adrenal insufficiency 

in patients with cirrhosis, severe sepsis and septic shock. Hepatology 43: 673-

681.

43. Fernández J, Escorsell A, Zabalza M, Felipe V, Navasa M, et al. (2006) Adrenal 



insufficiency in patients with cirrhosis and septic shock: Effect of treatment with 

hydrocortisone on survival. Hepatology 44: 1288-1295.

44. Helwig F, Schutz CA (1935) further contribution to the liver-kidney syndrome. J. 

Lab. and Clin. Med 21: 264. 

45. Wilensky  A  (1939)  Occurrence,  Distribution  and  Pathogenesis  of  So-Called 

Liver Death and/or the Hepatorenal Syndrome. Arch Surg 38: 625-691. 

46. Boyer TD, Zia P, Reynolds TB (1979) Effect of indomethacin and prostaglandin 

A1 on renal function and plasma renin activity in alcoholic liver disease. 

Gastroenterology 77: 215-222.

47. Hampel H, Bynum GD, Zamora E, El-Serag HB (2001) Risk factors for the 

development of renal dysfunction in hospitalized patients with cirrhosis. Am J 

Gastroenterol 96: 2206-2210.

48. Guevara M, Fernández-Esparrach G, Alessandria C, Torre A, Terra C, et al. 

(2004) Effects of contrast media on renal function in patients with cirrhosis: a 

prospective study. Hepatology 40: 646-651.

49. Cárdenas A, Ginès P (2001) Pathogenesis and treatment of fluid and electrolyte 

imbalance in cirrhosis. Semin Nephrol 21: 308-316.

50. Møller S, Hansen EF, Becker U, Brinch K, Henriksen JH, et al. (2000) Central 

and systemic haemodynamic effects of terlipressin in portal hypertensive 

patients. Liver 20: 51-59.

51. Davenport A, Ahmad J, Al-Khafaji A, Kellum JA, Genyk YS, et al. (2012) Medical 

management of hepatorenal syndrome. Nephrol Dial Transplant 27: 34-41.

52. Uriz J, Ginès P, Cárdenas A, Sort P, Jiménez W, et al. (2000) Terlipressin plus 

albumin infusion: an effective and safe therapy of hepatorenal syndrome. J 

Hepatol 33: 43-48.

53. Nazar A, Pereira GH, Guevara M, Martín-Llahi M, Pepin MN, et al. (2010) 

Predictors of response to therapy with terlipressin and albumin in patients with 

cirrhosis and type 1 hepatorenal syndrome. Hepatology 51: 219-226.

54. Wadei HM (2012) Hepatorenal syndrome: a critical update. Semin Respir Crit 

Care Med 33: 55-69.

55. Somberg KA, Lake JR, Tomlanovich SJ, LaBerge JM, Feldstein V, et al. 

(1995)  Transjugular  intrahepatic  portosystemic  shunts  for  refractory  ascites: 

assessment of clinical and hormonal response and renal function. Hepatology 

21: 709-716.

56. Quiroga J, Sangro B, Núñez M, Bilbao I, Longo J, et al. (1995) Transjugular 

intrahepatic portal-systemic shunt in the treatment of refractory ascites: effect 

on clinical, renal, humoral, and hemodynamic parameters. Hepatology 21: 986-

994.


57. Ng CK, Chan MH, Tai MH, Lam CW (2007) Hepatorenal syndrome. Clin 

Biochem Rev 28: 11-17.

58. Wanner GA, Ertel W, Müller P, Höfer Y, Leiderer R, et al. (1996) Liver ischemia 

and reperfusion induces a systemic inflammatory response through Kupffer cell 

activation. Shock 5: 34-40.

59. Tsung A, Hoffman RA, Izuishi K, Critchlow ND, Nakao A, et al. (2005) 

Hepatic  ischemia/reperfusion  injury  involves  functional  TLR4  signaling  in 

nonparenchymal cells. J Immunol 175: 7661-7668.

60. Levy RM, Mollen KP, Prince JM, Kaczorowski DJ, Vallabhaneni R, et al. (2007) 

Systemic  inflammation  and  remote  organ  injury  following  trauma  require 

HMGB1. Am J Physiol Regul Integr Comp Physiol 293: R1538-1544.

61. Tanaka Y, Maher JM, Chen C, Klaassen CD (2007) Hepatic ischemia-

reperfusion induces renal heme oxygenase-1 via NF-E2-related factor 2 in rats 

and mice. Mol Pharmacol 71: 817-825.

62. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, et al. (1999) 

HMG-1 as a late mediator of endotoxin lethality in mice. Science 285: 248-251.

63. Andersson  U,  Wang  H,  Palmblad  K, Aveberger AC,  Bloom  O,  et  al.  (2000) 


Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin Res 4: 352. doi:

10.4172/2155-6148.1000352

Page 8 of 8

Volume 4 • Issue 9 • 1000352

J Anesth Clin Res

ISSN:2155-6148 JACR an open access journal 

High  mobility  group  1  protein  (HMG-1)  stimulates  proinflammatory  cytokine 

synthesis in human monocytes. J Exp Med 192: 565-570.

64. Tsung A, Sahai R, Tanaka H, Nakao A, Fink MP, et al. (2005) The nuclear factor 

HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp 

Med 201: 1135-1143.

65. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, et al. (2004) 

Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility 

group box 1 protein. J Biol Chem 279: 7370-7377.

66. Davis CL, Gonwa TA, Wilkinson AH (2002) Pathophysiology of renal disease 

associated with liver disorders: implications for liver transplantation. Part I. 

Liver Transpl 8: 91-109.

67. Lee HT, Park SW, Kim M, D’Agati VD (2009) Acute kidney injury after hepatic 

ischemia and reperfusion injury in mice. Lab Invest 89: 196-208.

68. Teoh NC, Farrell GC (2003) Hepatic ischemia reperfusion injury: pathogenic 

mechanisms and basis for hepatoprotection. J Gastroenterol Hepatol 18: 891-

902.


69. Sutton TA, Mang HE, Campos SB, Sandoval RM, Yoder MC, et al. (2003) Injury 

of the renal microvascular endothelium alters barrier function after ischemia. 

Am J Physiol Renal Physiol, 285: F191-F198. 

70. Molitoris BA, Sandoval R, Sutton TA (2002) Endothelial injury and dysfunction 

in ischemic acute renal failure. Crit Care Med 30: S235-240.

71. Okusa MD (2002) The inflammatory cascade in acute ischemic renal failure. 

Nephron 90: 133-138.

72. Klausner JM, Paterson IS, Goldman G, Kobzik L, Rodzen C, et al. (1989) 

Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J 

Physiol 256: F794-802.

73. Park SW, Chen SW, Kim M, D’Agati VD, Lee HT (2010) Selective intrarenal 

human A1 adenosine receptor overexpression reduces acute liver and kidney 

injury after hepatic ischemia reperfusion in mice. Lab Invest 90: 476-495.

74. Park SW, Chen SW, Kim M, Brown KM, D’Agati VD, et al. (2010) Protection 

against acute kidney injury via A(1) adenosine receptor-mediated Akt activation 

reduces liver injury after liver ischemia and reperfusion in mice. J Pharmacol 

Exp Ther 333: 736-747.

75. Park SW, Chen SW, Kim M, D’Agati VD, Lee HT (2009) Human activated 

protein C attenuates both hepatic and renal injury caused by hepatic ischemia 

and reperfusion injury in mice. Kidney Int 76: 739-750.

76. Park SW, Chen SW, Kim M, D’Agati VD, Lee HT (2009) Human heat shock 

protein 27-overexpressing mice are protected against acute kidney injury after 

hepatic ischemia and reperfusion. Am J Physiol Renal Physiol 297: F885-894.

77. Park SW, Kim M, Chen SW, Brown KM, D’Agati VD, et al. (2010) Sphinganine-

1-phosphate protects kidney and liver after hepatic ischemia and reperfusion in 

mice through S1P1 receptor activation. Lab Invest 90: 1209-1224.

78. Park SW, Chen SW, Kim M, Brown KM, Kolls JK, et al. (2011) Cytokines induce 

small intestine and liver injury after renal ischemia or nephrectomy. Lab Invest 

91: 63-84.

79. Park SW, Kim M, Brown KM, D’Agati VD, Lee HT (2011) Paneth cell-derived 

interleukin-17A causes multiorgan dysfunction after hepatic ischemia and 

reperfusion injury. Hepatology 53: 1662-1675.

80. Wong F, Nadim MK, Kellum JA, Salerno F, Bellomo R, et al. (2011) Working 

Party  proposal  for  a  revised  classification  system  of  renal  dysfunction  in 

patients with cirrhosis. Gut 60: 702-709.

81. Salerno F, Cazzaniga M, Merli M, Spinzi G, Saibeni S, et al. (2011) Diagnosis, 

treatment and survival of patients with hepatorenal syndrome: a survey on daily 

medical practice. J Hepatol 55: 1241-1248.

82. Randers E, Erlandsen EJ (1999) Serum cystatin C as an endogenous marker 

of the renal function--a review. Clin Chem Lab Med 37: 389-395.

83. Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, et al. (2008) Urine NGAL 

predicts  severity  of  acute  kidney  injury  after  cardiac  surgery:  a  prospective 

study. Clin J Am Soc Nephrol 3: 665-673.

84. Verna EC, Brown RS, Farrand E, Pichardo EM, Forster CS, et al. (2012) Urinary 

neutrophil gelatinase-associated lipocalin predicts mortality and identifies acute 

kidney injury in cirrhosis. Dig Dis Sci 57: 2362-2370.

85. Platt JF, Ellis JH, Rubin JM, Merion RM, Lucey MR (1994) Renal duplex 

Doppler ultrasonography: a noninvasive predictor of kidney dysfunction and 

hepatorenal failure in liver disease. Hepatology 20: 362-369.

Citation: Fukazawa K, Lee HT (2013) Updates on Hepato-Renal Syndrome. J Anesth Clin 

Res 4: 352. doi:

10.4172/2155-6148.1000352

Submit your next manuscript and get advantages of OMICS 

Group submissions

Unique features:

• 

User friendly/feasible website-translation of your paper to 50 world’s leading languages



• 

Audio Version of published paper

• 

Digital articles to share and explore



Special features:

• 

250 Open Access Journals



• 

20,000 editorial team

• 

21 days rapid review process



• 

Quality and quick editorial, review and publication processing

• 

Indexing at PubMed (partial), Scopus, EBSCO, Index Copernicus and Google Scholar etc



• 

Sharing Option: Social Networking Enabled

• 

Authors, Reviewers and Editors rewarded with online Scientific Credits



• 

Better discount for your subsequent articles

Submit your manuscript at: 

http://www.omicsonline.org/submission



Document Outline

  • Title
  • Abstract
  • Corresponding author
  • Keywords
  • Abbreviations
  • Introduction
  • Current Definition of Hepato-Renal Syndrome
  • Clinical Significance
  • Pathogenesis of Hepato-renal Syndrome: BasicMechanisms
  • Current Management of Hepato-renal Syndrome
  • New Basic Research in Hepato-renal SyndromeMechanisms
  • New Biomarkers of Hepato-renal Syndrome
  • Conclusions and Future Implications
  • Table 1
  • Figure 1
  • Figure 2
  • Figure 3
  • References

Yüklə 3,22 Mb.

Dostları ilə paylaş:




Verilənlər bazası müəlliflik hüququ ilə müdafiə olunur ©azkurs.org 2024
rəhbərliyinə müraciət

gir | qeydiyyatdan keç
    Ana səhifə


yükləyin