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:
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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
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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
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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
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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
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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.
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Res 4: 352. doi:
10.4172/2155-6148.1000352
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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
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